CATALYTIC SYSTEMS ADAPTED TO GLYCEROL MEDIUM ...

CATALYTIC SYSTEMS ADAPTED TO GLYCEROL MEDIUM. APPLICATIONS IN

SELECTIVE PROCESSES.

Marta Rodríguez Rodríguez

ADVERTIMENT. L'accés als continguts d'aquesta tesi doctoral i la seva utilització ha de respectar els drets

de la persona autora. Pot ser utilitzada per a consulta o estudi personal, així com en activitats o materials d'investigació i docència en els termes establerts a l'art. 32 del Text Refós de la Llei de Propietat Intel·lectual (RDL 1/1996). Per altres utilitzacions es requereix l'autorització prèvia i expressa de la persona autora. En qualsevol cas, en la utilització dels seus continguts caldrà indicar de forma clara el nom i cognoms de la persona autora i el títol de la tesi doctoral. No s'autoritza la seva reproducció o altres formes d'explotació efectuades amb finalitats de lucre ni la seva comunicació pública des d'un lloc aliè al servei TDX. Tampoc s'autoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant als continguts de la tesi com als seus resums i índexs. ADVERTENCIA. El acceso a los contenidos de esta tesis doctoral y su utilización debe respetar los

derechos de la persona autora. Puede ser utilizada para consulta o estudio personal, así como en actividades o materiales de investigación y docencia en los términos establecidos en el art. 32 del Texto Refundido de la Ley de Propiedad Intelectual (RDL 1/1996). Para otros usos se requiere la autorización previa y expresa de la persona autora. En cualquier caso, en la utilización de sus contenidos se deberá indicar de forma clara el nombre y apellidos de la persona autora y el título de la tesis doctoral. No se autoriza su reproducción u otras formas de explotación efectuadas con fines lucrativos ni su comunicación pública desde un sitio ajeno al servicio TDR. Tampoco se autoriza la presentación de su contenido en una ventana o marco ajeno a TDR (framing). Esta reserva de derechos afecta tanto al contenido de la tesis como a sus resúmenes e índices. WARNING. Access to the contents of this doctoral thesis and its use must respect the rights of the author. It

can be used for reference or private study, as well as research and learning activities or materials in the terms established by the 32nd article of the Spanish Consolidated Copyright Act (RDL 1/1996). Express and previous authorization of the author is required for any other uses. In any case, when using its content, full name of the author and title of the thesis must be clearly indicated. Reproduction or other forms of for profit use or public communication from outside TDX service is not allowed. Presentation of its content in a window or frame external to TDX (framing) is not authorized either. These rights affect both the content of the thesis and its abstracts and indexes.

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Chapter 1 !

General Introduction

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51.+,),%;!$#"%)&1)1"%:$+') .+)H(D!&'&%;1$()T$!3)&+()I5E53.)!#"11D!"56%.+,1)#$&!'."+1<)I.+!$)'*$+2)

'*$)+5/9$#)"4)659%.!&'."+1)#$6"#'.+,)'*$)9$+$4.'1)"4) '*$)51$)"4),%;!$#"%)&1)1"%:$+') .+)!*$/.!&%)

'#&+14"#/&'."+1).+!%5(.+,)!&'&%;'.!)6#"!$11$12)*&1).+!#$&1$()!"+1.($#&9%;<))

Metallicmolecularspecies

reduction nucleation growth

stabilisingagent

!"#$%&'()(

!

!"#!

! "#$%&'$($)!*+&!'&,#'*-!#$!$#$.%/*/01-&2!'&/%*(#$-!($!)01%&'#0!3&2(435!(*!(-!'&3/'6/70&!*+&!

,(#$&&'($)!%#$*'(74*(#$!#8!9:';3&!&%(#*<=>?@5! ($!A+(%+!*+&1!%0&/'01!2&3#$-*'/*&2!*+&!/2B/$*/)&-!

#8! )01%&'#0! #B&'! #*+&'! %#$B&$*(#$/0! -#0B&$*-5! ($%042($)!A/*&'<!C01%&'#0!A/-! 8#4$2! *#!7&!+()+01!

&88(%(&$*! ($! -#3&! #')/$(%! *'/$-8#'3/*(#$-! -4%+! /-! *+&! /D/.E(%+/&0! '&/%*(#$! #8! /3($&-! /$2!

/$(0($&-5! *+&!E(%+/&0! '&/%*(#$!#8! ($2#0&-!#'! *+&! '($).#,&$($)!#8! -*1'&$&!#F(2&!A(*+!$./$(-(2($&<!

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%#$2&$-/*(#$-! #8! /02&+12&-!A(*+! ($2#0&-! /$2! ?5>.%1%0#+&F/2(#$&-5! ($! *+&! /7-&$%&! #8! /$1! /%(2!

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3&2(43! 4$2&'! %/*/01-*.8'&&! %#$2(*(#$-! 4-($)! /'10! $(*'(0&-5! 7&$D10! $(*'(0&-! /$2! /0-#! -*&'(%/001!

+($2&'&2! $(*'(0&-! ($! %#37($/*(#$!A(*+! -#2(43! /D(2&<! L*! -+#402! 7&! /0-#! +()+0()+*&2! *+&!A#'6! #8!

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*+&!-1$*+&-(-!#8!N+.,1'/$-!OM%+&3&!?<NP<!

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! L*!+/-!7&&$!-,&%40/*&2!*+/*!)01%&'#0!8/%(0(*/*&-!*+&-&!$#$.%/*/01-&2!#')/$(%!*'/$-8#'3/*(#$-!

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*'/$-(*(#$!-*/*&-!/$2!($*&'3&2(/*&-<=>N@!"#$%&'$($)!*+(-!0/-*!&F/3,0&5!*+&!/4*+#'-!,'#,#-&2!*+/*!

($!*+&!8('-*!-*&,!#8!*+(-!'&/%*(#$!*+&!RS!)'#4,-!#8!)01%&'#0!,'#3#*&!*+&!8#'3/*(#$!#8!/$!,.#0&8($!

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! T+&!2&B&0#,3&$*!#8!3&*/00(%!%/*/01*(%!-1-*&3-!($!)01%&'#0!(-!#$&!#8!*+&!*#,(%-!#8!'&-&/'%+!($!

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-1-*&3-! /-! A&00! /-! *+&! (33#7(0(-/*(#$! #8! 3&*/0! $/$#,/'*(%0&-! 8#'! %/*/01-(-! ($! $&/*! )01%&'#0<!

"#$%&'$($)!*+&!+#3#)&$&#4-!-1-*&3-5!A&!+/B&!2&3#$-*'/*&2!*+&!(3,#'*/$*!'#0&!#8!)01%&'#0!($!

*+&! V+.%/*/01-&2! W/4-#$XY+/$2! %/'7#%1%0(-/*(#$! OM%+&3&! ?<KP<=>K@! G0*+#4)+5! /-! 3&$*(#$&2!

7&8#'&5!*+&!,#*&$*(/0!'&/%*(B(*1!/$2!%##'2($/*(#$!/7(0(*1!#8!*+&!+12'#F10!)'#4,-!($!)01%&'#0!%#402!

7&! /! 0(3(*/*(#$! ($! %/*/01-(-5! 7&%/4-&! #8! *+&! 8#'3/*(#$! #8! -(2&! ,'#24%*-! #'! *+&! %#3,&*(*(#$! *#!

CHO

O

O

CN

CN

catalyst-free

solvent, 80 ºC O

OCN

NH2

toluene, 360 min, <15% yieldethanol, 360 min, <15% yieldethylene glycol, 90 min, 80% yieldwater, 130 min, 71 % yieldglycerol, 60 min, 93% yield

!"#"$%&'(#)$*+,-)(*#''

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(#%-"$%4+* -',(* 8RFFRU=.6?V.* @V>* [email protected]:(#%'P':Q:E/"-E/''$'+'&('&)* 8FRX=* $)#%B'(%B)-6@Y>* '&$*

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/2$#"-",40,)*E/"-E/%&)*FRX.* (/%-* ("E%!*D%,,*0)* %&(#"$4!)$*'&$*$))E,2*)IE,'%&)$* %&* (/)* -)!(%"&*

O5@*"3*(/%-*!/'E()#*'&$*%&*(/)*!/'E()#*Z*"3*(/%-*R/)-%-5*

*

*

*

X

R1 R1

R2

CO[Rh(µ-OMe)(cod)]2

glycerol, !X

R1R1

O

R2

X = O, NTs, C(COOEt)2R1 = H, Me; R2 = H, OMe, NO2

up to 95% yield

!"#$%&'()(

!

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! "#!$%&'(!)*+,-./!#%(#*012$3!4.5647.8!7,.!9*4:7!.;-<5/.!69!-!$('=8*56/-4!+>+/6-88*7*6#!4.-+7*6#!

?.7@..#! 5,.#>/! -A*8.! -#8! 8*.7,>/! -+.7>/.#.8*+-4?6;>/-7.0! [email protected](! 7,*:! 5D?/*+-7*6#! 8*8! #67!

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69!64G-#*+!-A*8.:!-#8!-/J>#.:!*:!-!:/6@!546+.::(!@,*+,!4.KD*4.:!,*G,!7.<5.4-7D4.:!LM+,.<.!$0N?O0!

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-!4.G*6:./.+7*C.!<-##.40!!

!51&'6'$!"7!$('=]*56/-4!+>+/6-88*7*6#!4.-+7*6#!69!64G-#*+!-A*8.:!-#8!-/J>#.:^!-O!I,.4<-/!RRV^!?O!VDRRV^!+O!

\DRRV0!

! I,.!\DRRV!D:*#G!1V5[\D3!+6<5/.;.:!-:!+-7-/>:7:!+-#!-/:6!?.!-55/*.8!76!*#7.4#-/!-/J>#.:(!*#!

+6#74-:7! 76!VDRRV!@,*+,! *:!G.#.4-//>!-55/*.8!@*7,! 7.4<*#-/!-/J>#.:(!-#8! 7,*:! 9-+7! :D55647:! 7,.!

8*99.4.#7!<.+,-#*:7*+!5-7,@->!*#!+6<5-4*:6#!@*7,!VDRRV!L8.7-*/.8!*#!V,-57.4!'O0!_-:.8!6#!]PI!

+-/+D/-7*6#:(12%+(!2&3! 7,.!54656:.8!<.+,-#*:<! 964!\DRRV!D:*#G! 1V5[\D3! +6<5/.;.:! LM+,.<.!$0EO!

R1 N N N H(R3)

NN N

R1 R2 NN N

R1R2

1 4 1

5

!

NN N

R1 R21 4 N

N N

R1R2

1

5

R2

H(R3)

H(R3)

H(R3)

"Cu"

1:1 regioisomeric mixture

1,4-disubstituted1,2,3-triazole

1,5-disubstituted1,2,3-triazole

[Cp*Ru](a)

(b)(c)

!"#"$%&'(#)$*+,-)(*#''

!

! "#!

!"#$"!%&'%"()%*+!,-#.)/)0"%12%"()%!,)."#"1$%-+3#0*!%10%"()%+0+"+#-%456778%.1/,-)9%6!"),%:8;%-)#*+03%

"1% "()% +0")$/)*+#")% !<% :"% "(+!% ,1+0";% #% $)3+1!)-)."+=)% 19+*#"+=)% .15,-+03% &)">))0% "()% ")$/+0#-%

0+"$13)0% 10% "()% #?+*)% #0*% "()% #-@'0)% 6!"),% A8% "1% 21$/% #% $5"()0#.'.-)% +0")$/)*+#")% !!<% B"),% C%

.10!+!"!%10%#%$)*5."+=)%)-+/+0#"+10%"1%#221$*%"()%"$+#?1-)%$+03%6+0")$/)*+#")%!!!8;%21--1>)*%&'%"()%

$)#-+!+03% 12% "()% D;EF$)3+1+!1/)$% +0% !"),% G<% H()% IF.11$*+0#"+10% 12% "()% #-@'0)% "1% "()% 45% .)0"$)%

6+0")$/)*+#")% !8% #0*% "()% 21$/#"+10%12% "()% $5"()0#.'.-)% 6+0")$/)*+#")% !!8% #$)% "()% @)'% ,1+0"!% "1%

)9,-#+0%>('%"()%45::C%5!+03%JC,K45L%.1/,-)9)!%-)#*!%"1%"()%D;EF*+!5&!"+"5")*%D;M;NF"$+#?1-)%#0*%

#-!1%"1%25--'%!5&!"+"5")*%"$+#?1-)!;%+0%.10"$#!"%"1%C5::C<%70%"()%.#!)%12%"()%C5F.#"#-'!)*%$)#."+10;%

01"% 10-'% /101/)"#--+.% ,#"(>#'!% (#=)% &))0% ,$1,1!)*% #0*% +"% +!% 3)0)$#--'% -+/+")*% "1% ")$/+0#-%

#-@'0)!% 6!))% C(#,")$% N8<% 70% !,+")% 12% "()% ,1")0"+#-% 12% D;EF+!1/)$!% +0% !)=)$#-% 2+)-*!% 12%/)*+.+0#-%

.()/+!"$'%#0*%&+1.()/+!"$';%"(+!%45::C%(#!%01"%&))0%#!%*)=)-1,)*%#!%"()%C5::C%*5)%/#+0-'%"1%

"()% (+3()$% .1!"% 12% "()% .#"#-'!"!% #0*% "()% (#$!()$% $)#."+10% .10*+"+10!% .1/,#$)*% "1% C5<JEOL% 7"% +!%

+/,1$"#0"%"1%01")%"(#"%5!+03%1"()$%45%.1/,-)9)!%#!%.#"#-'!"!;JEDL%"()%D;PF$)3+1+!1/)$%.#0%#-!1%&)%

1&"#+0)*;%#!%+0%"()%.#!)%12%C5::C<%

!"#$%&%'()*'Q$1,1!)*%.#"#-'"+.%/).(#0+!/%21$%45::C%5!+03%JC,K45L%.1/,-)9)!%,$1=+*+03%"()%D;EF*+!5&!"+"5")*%

D;M;NF"$+#?1-)!<JPR.L%

% :,#$"%2$1/%15$%.10"$+&5"+10%10%"(+!%!5&S)."%5!+03%C5MTUQ!%!"#&+-+!)*%+0%3-'.)$1-;%/)0"+10)*%

+0%"()%,$)=+15!%!)."+10;%"()$)%+!%10-'%10)%$),1$"%,5&-+!()*%&'%V#$.W#FX-=#$)?%")'%&<JEML%.10.)$0+03%

"()% C5::C% +0% "(+!% /)*+5/;% +0% >(+.(% "()'% *)!.$+&)*% #0% )22+.+)0"% !+/,-)% C57Y3-'.)$1-% .#"#-'"+.%

RuII

LCl L

RuIICl N

NN

R2

R1

RuIVCl N

NN

R2

R1

RuIICl N N

N R2

R1

A

BC

D

R1

N N N R2

I

II

III

2L

NN N

R2R1

15

!"#$%&'()(

!

!"#!

!"!#$%&'()&#*$&+)$+,),#-(.&('&/0123-!45!#-#4#$3&/06072#)-,8(9$!&,#&)((%&#$%+$),#4)$&:!$$&;<*$%$&

7=>&-.&?*,+#$)&7@=&&

!"#$%&'()*+&,-+&./&)$0)*123412)-$5+*$46)$0)2)&+78)94$+5$9):$(343&'41($-'-4)8-"$

$ A*(!+*-.$!& *,B$& 5$$.& C-3$9"& 4!$3& -.& *(%(D$.$(4!& <,#,9"!-!& ,!& 5(#*& 9-D,.3!& -.&

()D,.(%$#,99-<&<,#,9"!-!E>7F&,.3&()D,.(<,#,9"!#!=E>1F&G.&#*$&<(.#$H#&('&#*$&)$+9,<$%$.#&('&<(%%(.&

()D,.-<& !(9B$.#!&5"&(#*$)!&%()$&$.B-)(.%$.#,9& ')-$.39"& !(9B$.#!0& #*$&3$B$9(+%$.#&('& <,#,9"#-<&

+)(<$34)$!&-.&C,#$)&%$3-4%&*,!&5$$.&(.$&('&#*$&%(!#&!#43-$3&,)$,!=&G.&#*-!&!$.!$0&B,)-$#-$!&('&

C,#$)2!(9459$& +*(!+*-.$!& *,B$& ,++$,)$3& #*)(4D*& #*$& "$,)!0E>>F& :!$$& I-D4)$& /=/& '()& !(%$&

$H,%+9$!@& ,.3& ,%(.D& #*$%& /070>2#)-,8,2J2+*(!+*,3,%,.#,.$& :AKL@& ,.3& -#!& 3$)-B,#-B$!& :!$$&

I-D4)$&/=6@=E>MF&&

!;1<.*)$!"!&N,#$)2!(9459$&+*(!+*-.$!=&

& AKL& *,!& 5$$.& '4.<#-(.,9-!$3& -.& 3-''$)$.#& C,"!& #(& (5#,-.& !$B$),9& *"3)(!(9459$& AKL&

3$)-B,#-B$!O& !(%$&('& #*$%&,)$&<(99$<#$3& -.&I-D4)$&/=6=&K*$&AKL&<,D$&*,!&5$$.&*+'4.<#-(.,9-!$3&

9$,3-.D&#(&*2%(.(,9P"9,#$3&Q4,#$).,)"&,%%(.-4%&!,9#!&:=>?@@0E7R0&>JF&)-.D2(+$.$3&3-%$#*"9,#$3&

AKL& :08+=>?@E>SF& ()& )-.D2(+$.$3& 3-,<$#"9,#$3& AKL& :A?=>?@=E>RF& K*$& '4.<#-(.,9-!,#-(.& (.& #*$&

%$#*"9$.$&+(!-#-(.&<9(!$&#(&+*(!+*()4!&,#(%&*,!&,9!(&9$3&#(&(#*$)&*"3)(!(9459$&AKL&3$)-B,#-B$!&

9-P$& +*(!+*-.(& ,9<(*(9!& !4<*& ,!& =>?,B@@CDEEMTF& ()& =>?,BEF!,G)H8IDEJEM/F& 3-+*(!+*-.$&

3$)-B,#-B$!&!4<*&,!&=>?=!=*EM6F&,.3&,%-.(+*(!+*-.$!&!4<*&,!&=>?,B@@CKE=6=EM7F&&

P P P

SO3Na

SO3Na

NaO3S

SO3Na

SO3Na

SO3Na

TPPMS TPPDS TPPTS

Ph2PNMe3

AMPHOS

P OHHO OH

THMP

PPh2

H3N

H3NPPh2

Br

Br

Cl

diam-BINAP

!"#"$%&'(#)$*+,-)(*#''

!

! "#!

!!"#$%&'()*!"#$!%&'!()*+!(+,+-.+'!/0'1)(),23,+!"#$!'+145%.45+(6!

! #/+(+! "#$! '+145%.45+(! /%5+! 3++&! (+15+'! *%4&,0! %(! ,47%&'(! 8)1! )17%&)*+.%,,4-! -)*9,+:+(!

%99,4+'! 4&! /)*)7+&+)2(! %;2+)2(! -%.%,0(4(6<=>?! @)*+! )8! ./+(+! )17%&)*+.%,,4-! -)*9,+:+(! %&'!

./+41!%99,4-%.4)&(!A4,,!3+!(/)A!4&!-/%9.+1!B6!C+A!1+9)1.(!%1+!'+'4-%.+'!.)!./+41!2(+!%(!(.%34,4(+1!

8)1!DE"(!FG2H!".H!"'!)1!$7I!4&!A%.+1!F@-/+*+!J6KI6<>B?!

!+,-&.&'()/!G2E"(!(.%34,4(+'!30!"#$!1+9)1.+'!30!"/4,499).!")'%&6<>B%H!>B3?L!(0&./+(4(!)8!G2E"(!F.)9I!%&'!./+41!

%99,4-%.4)&(!4&!/0'1)7+&%.4)&!)8!%1+&+(!F3)..)*I!

! C),,)A4&7!)21! %4*!)8! '+5+,)94&7! -%.%,0.4-! (0(.+*(! 4&! 7,0-+1),! %&'!'2+! .)! ./+! (4*4,%14.0H! 4&!

.+1*(! )8! 9),%14.0H! 3+.A++&! 7,0-+1),! %&'! A%.+1H! %,,! ./+(+! /0'1)(),23,+! "#$! '+145%.45+(! -)2,'!

9).+&.4%,,0!(+15+!%(!,47%&'(!8)1!.1%&(4.4)&!*+.%,!-)*9,+:+(H!%(!(.%34,4(+1(!8)1!DE"(!)1!%(!-%.%,0(.(!

30! 4.(+,8! %,()! 4&! 7,0-+1),6! $-.2%,,0H! %,./)27/! ./+0! /%5+! &).! 3++&! A4'+,0! %99,4+'! .)! '+5+,)9!

NN

N

P

PTA

NN

N

P

RX

PTARN

NN

P

MeMe

dmoPTA

NN

N

POO

MeMe

DAPTA

NN

N

P R'

HO R

R = R' = PhR = H, R' = PhR = H, R' = p-MeOC6H4

PTA-CRR'OHN

NN

P R'

PhHN R

NN

N

P P iPr

iPr

NN

N

P OH

NN Me

PTA-CH(1-MeIm)OH

R = R' = PhR = H, R' = PhR = H, R' = p-MeOC6H4

PTA-CRR'NHPh

PTA-PiPr2

R = alkyl, benzyl, etcX = I, Br, Cl, OTf, etc

NN

N

P [Ru(COD)(COT)]

THF; H2 (3 bar): 70 ºCwith [PTA]/[M] = 0.8

Ru@PTA NPs

colloidal solution in THF

R R

R = H, OMe

Ru@PTA NPs

H2 (10 bar), 293 K

60–100% conversion

1) purification

2) dissolution in water

Ru@PTA NPsaqueous

colloidal solution

!"#$%&'()(

!

!"#!

!"#"$%#&!'(%(#)*('&+'#,&('*)-&.*/'0)1'1234(',"5)'-)*2+(#3"#)-'#,"#'#,)()'678'-)3&5"#&5)('()35)'

#2' #,&(' 9.392():' ;"-&)3+2' &%( #*:' .()-' <$%!)32$' "(' (2$5)+#' &+' #,)' 6-=!"#"$%()-' &+#3"*2$)!.$"3'

!%!$2&(2*)3&("#&2+' 20' >+?=)+%+2$(' .(&+<' 6-' !2*9$)@)(' A6-;$BCBD' !2+#"&+&+<' 678' "(' $&<"+-' "('

!"#"$%#&!'93)!.3(23('>E!,)*)'F:G?:AHID''

!!"#$%$&'()'6-=!"#"$%()-'&+#3"*2$)!.$"3'!%!$2&(2*)3&("#&2+'20'>+?=)+%+2$('.(&+<'"'6-'!2*9$)@'3)923#)-'J%'

;"-&)3+2'&%(#*:AHID''

' 7,)' ("*)' <32.9' "$(2' 3)923#)-' #,)' .()' 20' <$%!)32$' "(' (2$5)+#' "+-' ,%-32<)+' -2+23' &+' #,)'

3)-.!#&2+'20'"$$%$&!'"$!2,2$('1&#,'K.=J"()-'!2*9$)@)('!2+#"&+&+<'678'$&<"+-('>E!,)*)'F:FL?:AHHD''

!!"#$%$&'('*'K.=!"#"$%()-'3)-.!#&2+'20'"$$%$&!'"$!2,2$('&+'<$%!)32$'3)923#)-'J%';32!,)#'"+-';"-&)3+2'&%(#*:AHHD'

' M.3' <32.9' ,"(' "$(2' !2+#3&J.#)-' #2' #,&(' "&*' .(&+<' #,)',=*2+2"$4%$"#)-' "**2+&.*' ("$#('

>+,-.?' >())' "J25)' N&<.3)' F:B?' "(' (#"J&$&()3(' 023' #,)' 93)9"3"#&2+' 20' 6-O6(' &+' <$%!)32$' >E!,)*)'

F:FF?:APGD' 7,)' !"#"$%#&!' (%(#)*' 1"(' "!#&5)' &+' !32((=!2.9$&+<(/' ,%-32<)+"#&2+(' "+-' 2+)=92#'

()Q.)+#&"$' 932!)(()(/' "+-' #,)' !233)(92+-&+<' !"#"$%#&!' 9,"()' !2.$-' J)' 3)!%!$)-' #,"+4(' #2' #,)'

)00&!&)+#'!"#"$%(#'&**2J&$&("#&2+:'

R1

R2HO

R1 = H; R2 = H, nBu, Ph, CH2C(Me)=CH2R1 = Ph; R2 = H

cis-[PdCl2(DAPTA)2] 0.2 mol%

glycerol, 75 ºC, 0.3–24 h O

R1

R2

77–90% yield

PdCl

Cl

NNN

PO

OMe

Me

N N

NP

O

Me

O

Me

cis-[PdCl2(DAPTA)2]

R H

OH[RuCl2(!6-C6H6)(DAPTA)] 5 mol%

KOH (40 mol%)

glycerol, 100 ºC, 6–15 h R H

OH

isomerisation transfer hydrogenation

R H

O [RuCl2(!6-C6H6)(DAPTA)]

RuCl

ClN N

NP

O

Me

O

Me

up to 90% yield

!"#"$%&'(#)$*+,-)(*#''

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!

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! K&! 5=$! D%9$9! 0/! 5=79! 875$1%541$! 0C$1C7$L!L$!L788! &$M5! "$C$806! 5=$! "7//$1$&5! 0DN$357C$9! 0/! 5=79!

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\2ZX\I()!HWJ! P)!d%&@G!F)!B)!e%&&%G!c)!;4&G!.(*)"-<#*&8'5*$'.(*5,"&0'/0'/G!=G!O()!H2J! f)!?)!c)!f%&!U9%=%RG!Y)!B)!`=$!c%#87G!F)!U9#%78G!])!F0="!]%=7#G!F)!B)!d%1#0G!A"78':,$(58'>"C8'/0'4G!IIG!

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HOOJ! .%:! >)! A)! B&%95%9G! ])! `)!f%1&$1G!!$""#'D<"/(0)$2Q' ;<"*$2' %#+':$%-)(-"G!KM/01"!^&7C$1975<! >1$99G!?$L!d01RG!'665[!.D:!>)!B&%95%9G!?)!E@=D%87G!D<"/8'A*-8'>"C8'/0'0G!OGG!(,OX(O*)!

HO*J! d)!a4G!P)!]n1o#$G!D<"/8'A*-8'>"C8'/0'3G!IFG!IZZ,XIZ2,)!HO(J! .%:! d)! a4G! P)! ]n1o#$G!!$""#' D<"/8'/0'0G!4FG! OO*2XOO(-[! .D:! B)! Tp%SVq8C%1$SG! Q)! `%"7$1&0G!L77&8' A-(8'

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HO\J! .%:!B)!E)!Tp%SVq8C%1$SG!])!P1%&309G!j)!l%951%Vj%11$71%G!>)!`103=$5G!Q)!`%"7$1&0G!D<"/8'D*//,#8'/0''G!IHG!W*,-XW**2[!.D:!B)!f08/90&G!B)!;&$S=R0G!A)!F$<04=%9G!T)!A%C01G!!$""#'D<"/8'R"))8'>"C8'/0'/G!=G!2XO*[!.3:!])!U)!a%13p%G!e)!a%13p%VF%1p&G!E)!>71$9G!!$""#'D<"/8'/0')G!43G!O,,2XO,(()!

HOZJ! ;)!B6%17370G!c)!B83%8"$G!!$""#'D<"/8'/006G!44G!WZX2-)!HOWJ! Q)!>%3$G!>)!e0<09G!l)!`%9508"7G!>)!T0#p&@4$S "$ F%1p%G!B)!c)!B83s&5%1%G!D<"/A,0D<"/'/0'/G!=G!O(WIX

O(2I)!HO2J! .%:!b)! Y=%&@G!_)!T$!K87C$71%!Q7@7$1G! ;)!c0<$1G! P)! ]n1o#$G!D<"/8' A*-8'>"C8'/0'/G!I4G! 2O,-X2O\W[! .D:! ])!

a%13p%Vq8C%1$SG!B,$8'E8'M#*$18'D<"/8'/0'4G!ZO\2XZOZ2[!.3:!;)!_=%&"$8L%8G!d)!_)!A%7801G!F)!_4#%1G!E8'S*&8'R(T8'/0'2G!F4=G!(\ZX(-W[!.":!T)!B)!B80&90G!B)!j%$S%G!c)!`=7&3=788%G!a)!a4788$&%G!U)!F)!>%9501G!T)!])!c%#r&G!B,$8'E8'U$18'D<"/8'/0'2G!WO*XW(*)!

NN

N

P BrPh[PdCl2(cod)]

H2 (3 bar)

glycerol, 18 h60 ºC

PdNPs

!"#$%&'()(

!

!""!

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!"F$% 7*%1'39'MZ3-K[/%)*%Z:3.[-9/%;*%\*%)3S5.3->=/%0+#5-(678#+#5-!"&,-(!""%/%/9:/%"F"E"FF*%!DG$% )*%1*%I:>.:3/%\U%DG"D"]Y"^"%)"/%!"#!*%!D"$% _*%6`5à'b'/%A*%c4b'/%_*%7'5'a4/%0*%U-5'b'/%\*%24S:>-/%C*%6'.-/%6;55-(!"&,-(<8=-(>$+-(!"#%/%?@/%d^"E

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Chapter 2 !

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N3

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THF, 25 ºC, 2 hNN N

Ph

I

a) N

NNN

NN

N

NN N

tBu tBu

tBuTTTA

b) N3Me PhMe

HO

Me [RuClCp*(COD)] (2 mol%)

toluene, 25 ºC, 30 minNN N

Ph

MeHO

MeMe

93% yield

CF393% yield

c) N3 PhS nBu[{Ir(COD)Cl}2] (2 mol%)

CH2Cl2, N2, rtovernight

NN N

nBu

SPh

> 95% yield

F3C

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NN N

Bn Ph

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Ph Ph BnN3glycerol, MW100 ºC, 30 min

NN N

Bn Ph

Ph

1 a 1a

Cu(I) salt (2.5 mol%)

Ph Ph BnN3 solvent100 ºC, 20 h

NN N

Bn Ph

Ph

1 a 1a

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R R' BnN3glycerol, MW

30 min, 100 ºC

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Bn R'(R)

R(R')

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Bn TBDMS

Ph

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TBAF

THF, r.t.24 h

TBAF

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)*.&"#$&/'3?$*"&"''>&13),$&+*&"#$&1%$1)%)"+'*&'I&"%+)-'3$&.#&+*&$"#23$*$&(32,'3&D$.+0D&78)93$&:;@E&

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(32,$%'3&)/&/'3?$*"&0*.$%&D+,%'4)?$&.+$3$,"%+,&#$)"+*(&4)/&?$%+I+$.;&

NN N

Bn Ph

Ph

!"

NN N

Ph

Ph

!"

Ph NN N

Ph

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PhnOctyl NN N

nOctyl

nPr

!"

nPr NN N

nOctyl

Ph

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TMS

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R R' BnN3 solvent, MW100 ºC, 30 min

NN N

Bn R'(R)

R(R')

! "!"#$#%&#'&#(&#)&#*

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*#01&%'&%(#&1#)-*3*0%#1&%/-0:'*#<&

R R' BnN3solvent, 100 ºC

NN N

Bn R'(R)

R(R')

! "!"#$#%&#'&#(&#)&#*

!"#$%&'())(

!

!"#!

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NN N

Bn TMS

R

!"#

R TMS BnN3glycerol, MW100 ºC, 30 min$!"#"$"%&

%!"#"$"'("

CuCl (2.5 mol%)NN N

Bn R

TMS

!&'

NN N

Bn R

12a, R = Me13a, R = Ph

8a, 80% conv. 8a/12a = 37:63 maj-8a/min-8a = 93:79a, 100% conv. 9a/13a = 40:60 maj-9a/min-9a = 99:1

a) Under microwave dielectric heating

b) Under thermal conditions (oil bath)

NN N

Bn TMS

R

!"#

R TMS BnN3glycerol

100 ºC, 20 h"

CuCl (2.5 mol%)NN N

Bn R

TMS

!&'

NN N

Bn R

8a, 73% conv. 8a/12a = 53:47 maj-8a/min-8a = 93:79a, 100% conv. 9a/13a = 27:73 maj-9a/min-9a = 99:1

$!"#"$"%&%!"#"$"'( 12a, R = Me

13a, R = Ph

NN N

Bn TMS

R

!"#$%"!"#"$"%&!"#$&"!"#"$"'(

R TMSglycerol, MW100 ºC, 30 min%!"#"$"%&

&!"#"$"'(

CuCl (2.5 mol%)a) no reaction

b)

glycerol, MW100 ºC, 30 min

CuCl (2.5 mol%)no reaction

c) NN N

Bn TMS

Me

!"#$%"

Me TMS BnN31,4-dioxane100 ºC, 20 h% "

CuCl (2.5 mol%)NN N

Bn Me

TMS

!'($%"

31% yieldmaj-8a/min-8a = 90:10No formation of 12a

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(

NBn N

[Cu]

N

SiMe3

R

OOH

OH

H

I Me3SiOOH

OH H

NBn N

[Cu]

N

OH

R

OOH

H

IIIII

TMSOOH

OH TMSOOH

OTMSHOOH

OH TMSClImidazole

DMF, 0 ºC5 h

(a)

Me3SiOOH

OSiMe3

Me3SiOOH

OH

Me3SiOOH

OSiMe3

Me3SiOOH

OHNN N

Bn SiMe3

Me

!"#$%"

:*;((CEA.(=>?

:6;(((CE

A.(=>? (

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#

Energy

.

1,3-dipole

N N N Bn

HOMO

LUMO

HOMO

LUMO

dipolarophile

Ph Ph

!"#$%&'())(

!

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A+=A#>()B=$;!#+(!%=>*B)(+()!,.BC&+(!WEX;E!

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I*(+,-!.(J=! K! K:! KFL! K4L! KM! KNL!

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Erel (eV)

BnN3 (A)

HOMO0 eV

LUMO

HOMO

LUMO

Diphenylacetylene

+ 0.57 eV

+ 6.01 eV

0

+ 5.91 eV

BnN3/glycerol (A5')

LUMO+ 5.41 eV

HOMO0 eV

!E = + 5.34 eV!E = + 4.84 eV

!"#$%&'())(

!

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NN N

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NN N

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NN N

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& Synthetic Methods

Metal-Free Intermolecular Azide–Alkyne Cycloaddition Promoted

by Glycerol

Marta Rodr�guez-Rodr�guez,[a, b] Emmanuel Gras,[c] Miquel A. Peric�s,*[b] andMontserrat G�mez*[a]

Abstract: Metal-free intermolecular Huisgen cycloadditionsusing nonactivated internal alkynes have been successfullyperformed in neat glycerol, both under thermal and micro-wave dielectric heating. In sharp contrast, no reaction occursin other protic solvents, such as water, ethanol, or diols. DFTcalculations have shown that the BnN3/glycerol adduct pro-motes a more important stabilization of the corresponding

LUMO than that produced in the analogous BnN3/alcoholadducts, favoring the reactivity with the alkyne in the firstcase. The presence of copper salts in the medium did notchange the reaction pathway (Cu(I) acts as spectator),except for disubstituted silylalkynes, for which desilylationtakes place in contrast to the metal-free system.

Introduction

Azide–alkyne cycloadditions (AAC) represent a powerful toolfor the synthesis of 1,2,3-triazoles, valuable heterocycles in-volved in diverse fields, such as biochemistry, organic synthe-sis, or materials science.[1] Although this reaction was first re-ported in 1893 by Michael[2] and in particular developed byHuisgen in the 1960s,[3] it was not up to the beginning of the21st century that the reaction found widespread practical in-terest after overcoming kinetic and regioselective concerns bytransforming the thermally activated process into a catalytic re-action, mainly by using copper-based systems.[1,4] Since then,many catalytic systems have been described, also includingmetals other than copper (such as Ag,[5] Ru,[6] Ir,[7] or Ni[8]),which allow access to substituted-1,2,3-triazoles from organicazides and alkynes. The use of internal alkynes leading to theformation of 1,4,5-trisubstituted 1,2,3-triazoles generally re-quires harsher conditions, and activated alkynes (either substi-tuted by electron-withdrawing groups or strained).

For biological and pharmacological applications, metal-freeAAC methodologies (back to the origins) still remain attractiveapproaches.[9] Bertozzi and co-workers first used the strained-promoted strategy involving substituted cycloalkynes for bio-conjugation purposes.[10] Another elegant method is throughintramolecular AAC reactions by taking advantage of the favor-able entropy effects.[11] However, to the best of our knowledge,intermolecular cycloadditions between organic azides and non-activated internal alkynes under metal-free conditions remainan important challenge to be solved.

In the last years, with the purpose of using ecofriendly sol-vents, we have developed glycerol catalytic phases. They ex-hibit appealing properties mainly regarding the immobilizationof the metal species, probably owing to the supramolecular ar-rangement shown by glycerol.[12] In particular, Cu2O nanoparti-cles prepared in neat glycerol led to the synthesis of 1,4-disub-stituted-1,2,3-triazoles, permitting an easy recycling of the cat-alytic phase.[13] With the assumption of glycerol having a nonin-nocent role in this process, we decided to investigate themetal-free AAC in glycerol for the synthesis of 1,4,5-trisubsti-tuted 1,2,3-triazoles.

Results and Discussion

As a benchmark reaction, the intermolecular azide–alkyne cy-cloaddition (AAC) between diphenylacetylene (1) and benzylazide (a) in neat glycerol under microwave dielectric heatingfor 30 minutes was chosen, affording 1-benzyl-4,5-diphenyl-1,2,3-triazole (1a ; Table 1).[14] The organic products were isolat-ed by a biphasic liquid–liquid extraction after adding dichloro-methane to the reaction mixture. The triazole 1a was exclu-sively obtained in a high yield of 85% (Table 1, entry 1). Withthe aim of investigating the effect of copper in this reaction,[15]

we carried out the synthesis in the presence of a copper salt(2.5 mol% of CuCl), obtaining 1a in almost the same isolated

[a] M. Rodr�guez-Rodr�guez, Prof. M. G�mez

Laboratoire H�t�rochimie Fondamentale et Appliqu�e (LHFA)

Universit� de Toulouse, UPS and CNRS UMR 5069

118, route de Narbonne, 31062 Toulouse cedex 9 (France)

E-mail : [email protected]

[b] M. Rodr�guez-Rodr�guez, Prof. M. A. Peric�sInstitute of Chemical Research of Catalonia (ICIQ)

The Barcelona Institute of Science and Technology

Avda. Paısos Catalans, 16, 43007 Tarragona (Spain)


[c] Dr. E. Gras

Laboratoire de Chimie de Coordination (LCC)

Centre National de la Recherche Scientifique (CNRS)


Supporting information for this article is available on the WWW under

http://dx.doi.org/10.1002/chem.201503858.

Chem. Eur. J. 2015, 21, 18706 – 18710 � 2015 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim18706

Full PaperDOI: 10.1002/chem.201503858

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yield (Table 1, entry 2). This evidences the spectator role ofcopper (see Table S1 in the Supporting Information).[16] A simi-lar trend was observed under classical thermal-promoted con-ditions (Table 1, entries 3 and 4), albeit in lower yields (<35%)after 20 h. In the absence of glycerol (i.e. , under solvent-freeconditions), the product was obtained in only 18% yield(Table 1, entry 5). No copper was detected by ICP-AES analysisof neat glycerol (<3 ppm).

To better control the temperature (the reaction conditionswere set at a targeted temperature, controlled by an externalinfrared temperature sensor),[17] we employed a MW instru-ment combining both internal optical fiber and external infra-red temperature sensors (Figure S1 in the Supporting Informa-tion). We carried out the cycloaddition at different tempera-tures (100, 140, and 180 8C, according to the internal opticalfiber sensor) and observed that the yield obtained at 180 8Cwas comparable to that obtained working with the instrumentequipped only with an infrared sensor (Table S2 in the Sup-porting Information). Under classical heating conditions (oilbath), only 65% yield was achieved at 180 8C in the same reac-tion time, which is consistent with a less efficient heat transfer.

Then, we decided to study the influence of the solventunder metal-free conditions. Surprisingly, no reaction tookplace when using other alcohol-based solvents, including etha-nol and diols, such as ethylene glycol, propane-1,2-diol, andpropane-1,3-diol (Table 1, entry 6). Water gave a very low con-version of benzyl azide of 13% (Table 1, entry 7). Aprotic polarsolvents, such as 1,4-dioxane and fluorobenzene, also disfa-vored the cycloaddition (Table 1, entries 8 and 9). The varyingreactivity observed by using different protic solvents can beexplained by the solvent interaction with an external electricfield. Alcohols, in particular polyols, form extensive hydrogenbonds, which in turn correlate with long relaxation times (thetime taken to achieve the random state after being submittedto an external electric field).[18] Therefore, water (9.2 ps), etha-nol (170 s), ethylene glycol (170 ps), or propane-1,3-diol(340 ps) exhibit shorter relaxation times than glycerol(1,215 ps), making it more relevant than other protic solventsfor synthetic purposes under microwave conditions, as illustrat-ed here for the AAC reaction.

Under thermal conditions (Table S3 in the Supporting Infor-mation), the reactivity in the different solvents follows thesame trend, except for ethylene glycol and water for which 1awas obtained in 25 and 31% yield, respectively (33% yield inglycerol ; Table 1, entry 3), after 20 h at 100 8C. This clearly con-trasts with the lack of reactivity observed under microwaveheating (Table 1, entries 6 and 7), despite the high internaltemperature achieved under MW activation (see above).

With these results in hand, we decided to study the scopeof the process by using other internal alkynes (Table 2). For thesymmetrical disubstituted alkynes 2–5 (Table 2, entries 1–4),moderate to high yields were obtained (32–90%). No transes-terification reaction between the alkyne 2 or the triazole 2aand glycerol was observed, in contrast to the reaction in etha-nol (see Tables S4 and S5 in the Supporting Information). It isimportant to note that the nonactivated 4-octyne reacted withBnN3 to give 1-benzyl-4,5-dipropyl-1,2,3-triazole 5a in 71% iso-

lated yield (after 1 h under microwave irradiation; Table 2,entry 4).

Unsymmetrically substituted alkynes 6 and 7 led to analmost equimolar mixture of both regioisomers (Table 2, en-tries 5 and 6). In view of synthetic applications and to explorethe role of the silyl group as a directing group during the cy-cloaddition,[19] we carried out the synthesis of triazoles 8–10from the corresponding alkynes containing silyl-based groups,such as SiMe3 (alkynes 8 and 9 ; Table 2, entries 7 and 8) andSi(tBu)Me2 (10 ; Table 2, entry 9). As expected, the 4-silyl-substi-tuted heterocycle was obtained as the major regioisomer[20]

and as the sole product for the bulky tert-butyldimethylsilyl(TBDMS) derivative (Table 2, entry 9).

Phenyl (b) and n-octyl (c) azides also gave the expected tria-zoles; conversions and yields were lower than those obtainedwhen using benzyl azide (Figure 1).[21] In contrast to benzyland n-octyl azides, PhN3 tends to decompose under the reac-tion conditions employed.[22]

We studied the effect of Cu(I) in the synthesis of silyl-basedtriazoles 8a–10a. For the synthesis of 10a, bearing a TBDMSgroup, the reactivity was similar to the one observed in the ab-sence of Cu(I). However, for the TMS-substituted ones (8a, 9a),a mixture of two triazoles was obtained: the expected 8a or9a and the desilylated 1-benzyl-4R-1,2,3-triazole (R=Me (11a),Ph (12a)), which was obtained as a single regioisomer(Scheme 1). Under the classical thermal conditions, the samebehavior was observed (Scheme S1 in the Supporting Informa-tion).

Table 1. Azide–alkyne cycloaddition of diphenylacetylene and benzylazide in neat glycerol.[a]

Entry Solvent Conversion [%][b][c] Isolated yield [%][d]

1 glycerol 85 85 (85)2[e] glycerol 86 82 (80)3[f] glycerol 37 33 (33)4[e][f] glycerol 42 28 (27)5 – 20 18[g]

6[h] protic solvent n.r. –7 H2O 13 n.d.8 1,4-dioxane n.r. –9 fluorobenzene n.r. –

[a] Results from duplicate experiments. Reaction conditions: benzyl azide(0.4 mmol) and diphenylacetylene (0.6 mmol) in solvent (1 mL) under mi-crowaves activation (250 W) at 100 8C for 30 minutes (temperature con-trolled by external infrared sensor). [b] Based on benzyl azide. [c] Deter-mined by 1H NMR spectroscopy using 2-methoxynaphthalene as an inter-nal standard. [d] In brackets: yields determined by 1H NMR spectroscopyusing 2-methoxynaphthalene as an internal standard. [e] In the presenceof 2.5 mol% of CuCl. [f] Reaction in a sealed tube under thermal activa-tion at 100 8C for 20 h. [g] Determined by 1H NMR spectroscopy using 2-methoxynaphthalene as an internal standard. [h] Results obtained withthe following alcohols as solvents: ethanol, ethylene glycol, propane-1,2-diol, and propane-1,3-diol.

Chem. Eur. J. 2015, 21, 18706 – 18710 www.chemeurj.org � 2015 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim18707

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Control experiments proved that the desilylation neithertook place on the alkyne 8 or 9 nor on the triazole 8a or 9a(Scheme S2 in the Supporting Information). In addition, whenthe AAC reaction was carried out in dioxane, no correspondingdesilylation occurred. Monitoring the reaction by GC-MS dem-onstrated that the formation of 9a is faster than that corre-sponding to 12a (after 5 min, the ratio 9a/12a was approxi-mately 3.4:1; after 15 min, the ratio was approximately 1.2:1,with full conversion of BnN3). Once BnN3 was consumed com-pletely, desilylation of the alkyne 9 could be observed (Fig-ure S4 in the Supporting Information). These facts led us topropose that the desilylation giving 12a (and 11a) occursupon coordination of the alkyne to copper (intermediate I inScheme 2), which is promoted by glycerol that is undoubtedly

close to the coordination sphere owing to its interaction withBnN3 through hydrogen bonds (see below). Intermediate IIthen evolves to give the favored regioisomer 1-benzyl-4R-1,2,3-triazole, according to the accepted Cu-catalyzed mecha-nisms.[4b,23] The formation of the corresponding silyl derivativeof glycerol was proven by NMR spectroscopy (see Figures S5and S6 in the Supporting Information).[24] Alkyne 10 did notgive the corresponding desilylated triazole, probably as a con-sequence of the steric hindrance triggered by the TBDMSgroup around the metal center.

To rationalize the effect of glycerol in AAC reactions, westudied the interaction of glycerol with benzyl azide by theo-retical calculations (DFT B3LYP, 6-31G*), taking into account theability of glycerol to form hydrogen bonds.[25,26] For compara-tive purposes, we also analyzed this effect with ethanol andseveral diols (ethylene glycol, 1,2-, and 1,3-propanediol). Theresulting BnN3/alcohol adducts increase the dipolar characterof BnN3 in relation to neat benzyl azide (see calculated charges

Table 2. Azide–alkyne cycloaddition of internal alkynes and benzyl azidein neat glycerol.[a]

Entry Alkyne Product Conv. Yield(R, R’) [%][b][c] [%][c]

1[d] 2(CO2Me)

100 78

23(CH2OMe)

96 90

34(CH2OH)

56 32

4[e] 5(Pr)

73 71

56(Ph, CO2Me)

91 83[f]

67(Ph, Me)

49 49[f]

78(Me, TMS)

65 62 (9:1)[g]

89(Ph, TMS)

92 85 (9:1)[g]

910(Ph, TBDMS)

85 84[h]

[a] Results from duplicate experiments. Reaction conditions: benzyl azide(0.4 mmol) and the corresponding alkyne (0.6 mmol) in solvent (1 mL)under microwaves activation (250 W) at 100 8C for 30 min (temperaturecontrolled by external infrared sensor). [b] Based on benzyl azide. [c] De-termined by 1H NMR spectroscopy using 2-methoxynaphthalene as an in-ternal standard. [d] Reaction time: 15 min. [e] Reaction time: 60 min.[f] Regioisomer ratio: 1:1. [g] In brackets: regioisomer ratio (major isomer:1-benzyl-4-trimethylsilyl-5R-1,2,3-triazole (for R=Me: maj-8a ; for R=Ph:maj-9a) ; minor isomer: 1-benzyl-5-trimethylsilyl-4R-1,2,3-triazole (for R=Me: min-8a ; for R=Ph: min-9a). [h] Only one isomer was obtained (1-benzyl-4-tert-butyldimethylsilyl-5-phenyl-1,2,3-triazole) ; see ref. [20] .

Figure 1. 1,4,5-Trisubstituted 1,2,3-triazoles from phenyl (1b) and n-octylazides (1c, 5c, 9c). Isolated yields are given (conversions are given in brack-ets).

Scheme 1. Reactivity of silyl-based alkynes in the presence of CuCl under mi-crowave activation. Data from NMR analysis.

Scheme 2. Plausible Cu-mediated desilylation of SiMe3-based alkynes pro-moted by glycerol.


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in Figure S7 in the Supporting Information). It is important tonote that in the case of polyols (ethylene glycol, 1,2-propane-diol, and glycerol) the intramolecular hydrogen bonds triggeran additional stabilization of the corresponding BnN3/alcoholadduct (see Figure S8 in the Supporting Information). The anal-ysis of the relative energies of frontier orbitals for the differentBnN3/alcohol adducts (see Figure S9 in the Supporting Infor-mation) showed that the BnN3/glycerol LUMO, which overlapswith the dipolarophile HOMO (diphenylacetylene was chosenfor the calculations), is more stable than the ones obtained forthe other adducts (see Table S6 in the Supporting Information).In consequence, the reactivity should be enhanced, as ob-served in this work for a range of alkynes.

Conclusion

We have shown that glycerol acts as a noninnocent solvent formetal-free azide–alkyne cycloadditions, promoting the reactionbetween internal alkynes and organic azides in contrast toother protic solvents, both under classical and dielectric heat-ing. Moreover, the reactivity in glycerol was particularly en-hanced by microwave heating, probably owing to the long re-laxation time of glycerol in comparison with other protic sol-vents, which is related to its supramolecular arrangementthrough intermolecular hydrogen bonds. At a molecular level,analysis of the frontier orbitals for the BnN3/glycerol adductpointed to a higher stabilization of the corresponding LUMOthan that for comparable adducts involving ethanol and diols.This trend justifies the increase of the reaction rate accordingto a concerted pathway for the metal-free cycloaddition.

These results permit us to envisage the formation of fullysubstituted 1,2,3-triazoles by using a metal-free methodology,which is particularly interesting for the synthesis of drugs andnatural products.

Experimental Section

General

All manipulations were performed by using standard Schlenk tech-niques under argon atmosphere. Unless stated otherwise, commer-cially available compounds were used without further purification.Glycerol was treated under vacuum at 80 8C overnight prior to use.NMR spectra were recorded on Bruker Avance 300, 400, and 500spectrometers at 293 K. GC analyses were carried out on an AgilentGC6890 with a flame ionization detector using a SGE BPX5 columncomposed of 5% of phenylmethylsiloxane. Reactions under micro-wave activation were carried out on single-mode microwave CEMExplorer SP 48, 2.45 GHz, Max Power 300 W Synthesis System, CEMFocused MicrowaveTM Synthesis System Model Discover, andAnton Paar Monowave 300 instruments. Theoretical studies werecarried out by using the following software: SPARTAN’14 for Win-dows and Linux, Wavefunction, InC. 18401 Von Karmaan Avenue,suite 307, Irvine, CA 92612, USA. Calculations were carried out withDensity Functional B3LYP by using the basis set 6-31G*.

General AAC procedure in glycerol under microwave activa-tion

A sealed tube equipped with a stirring bar was successivelycharged with the corresponding alkyne (0.6 mmol) and glycerol(1 mL); the mixture was stirred at room temperature for 5 min.Benzyl azide (0.4 mmol, 53.2 mg) was then added and the sealedtube was placed into the microwave reactor (100 8C, 250 W) for30 min (or the appropriate time). It is important to note that atroom temperature the reaction mixture gave a kind of emulsionbut that at 100 8C a homogeneous solution was obtained (i.e. , re-agents and products were soluble in glycerol).[27] The organic prod-ucts were extracted with dichloromethane (6�2 mL). The com-bined chlorinated organic layers were filtered through a Celite padand the resulting filtrate was concentrated under reduced pres-sure. The products were purified by chromatography (silica shortcolumn, eluent: cyclohexane/ethyl acetate 1:1) to determine theisolated yields of the corresponding triazoles.

Compound maj-8a : Yellow oil ; IR (neat): n=1606, 1497, 1416,1248 cm�1; 1H NMR (500 MHz, CDCl3): d=0.35 (s, 9H), 2.22 (s, 3H),5.51 (s, 2H), 7.15–7.20 (m, 2H), 7.27–7.39 ppm (m, 3H); 13C{1H} NMR(125 MHz, CDCl3): d=�0.9, 9.3, 51.2, 127.2, 128.1, 128.9, 135.1,138.1, 143.8 ppm; HRMS (ESI+): m/z [M++H]+ calcd for C13H20N3Si :246.1412; found: 246.1421; elemental analysis calcd (%) forC13H19N3Si: C 63.63, H 7.80, N 17.11; found: C 63.22, H 7.88, N16.94.

Compound 10a : Yellow oil ; IR (neat): n=1606, 1497, 1456, 1249cm�1; 1H NMR (500 MHz, CDCl3): d=0.05 (s, 6H), 0.90 (s, 9H), 5.35(s, 2H), 6.94–7.00 (m, 2H), 7.05–7.10 (m, 2H), 7.21–7.28 (m, 3H),7.35–7.40 (m, 2H), 7.43–7.48 (m, 1H) ppm; 13C{1H} NMR (125 MHz,CDCl3) d=5.3, 26.6, 51.4, 127.6, 127.9, 128.2, 128.5, 128.8, 129.3,130.4, 135.6, 142.8, 144.1, 173.4 ppm; HRMS (ESI+): m/z [M+H]+

calcd for C21H28N3Si: 350.2050; found: 350.2047; elemental analysiscalcd (%) for C21H27N3Si : C 72.16, H 7.79, N 12.02; found: C 72.24, H8.27, N 11.87.

Compound 5c : Yellow oil ; IR (neat): n=1611, 1570, 1544,1247 cm�1; 1H NMR (500 MHz, CDCl3): d=0.89 (t, J=7.0 Hz, 3H),0.98 (t, J=7.4 Hz, 3H), 0.98 (t, J=7.4 Hz, 3H), 1.20–1.40 (m, 10H),1.53–1.62 (m, 2H), 1.68–1.77 (m, 2H), 1.83–1.96 (m, 2H), 2.55–2.61(m, 4H), 4.16–4.20 (m, 2H) ppm; 13C{1H} NMR (125 MHz, CDCl3): d=13.85, 13.98, 14.05, 22.58, 22.60, 22.94, 24.49, 26.69, 27.23, 29.06,29.70, 30.35, 31.71, 47.89, 132.44, 144.71 ppm; HRMS (ESI+): m/z[M+H]+ calcd for C16H32N3: 266.2591; found: 266.2594; elementalanalysis calcd (%) for C16H31N3: C 72.40, H 11.77, N 15.83; found: C72.13, H 12.28, N 15.53.

Acknowledgements

Financial support from the Centre National de la RechercheScientifique (CNRS), the Universit� de Toulouse 3 – Paul Sabati-er, and MINECO (grant CTQ2012-38594-C02-01) are gratefullyacknowledged. The authors thank Pierre Lavedan and St�-phane Massou for NMR discussions and DOSY experiments.M.R. thanks the CNRS for a PhD grant.

Keywords: azide–alkyne cycloaddition · density functionalcalculations · glycerol · metal-free reactions · microwaveactivation

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Org. Chem. 2013, 9, 2715–2750; b) N. V. Sokolova, V. G. Nenajdenko,


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[13] F. Chahdoura, C. Pradel, M. G�mez, ChemCatChem 2014, 6, 2929–2936.[14] For a selected contribution on the microwave-assisted synthesis in glyc-

erol, see: W.-J. Zhou, X.-Z. Zhang, X.-B. Sun, B. Wang, J.-X. Wang, L. Bai,Russ. Chem. Bull. Int. Ed. 2013, 62, 1244–1247.

[15] For the Cu-catalyzed synthesis of 1-benzyl-4,5-diphenyl-1,2,3-triazole byusing preformed well-defined complexes (15a : 72% yield after 48 h at80 8C; 15b : 68% yield after 12 h at 120 8C in DMF) and heterogeneouscatalyst (15c : 54% yield after 24 h at 80 8C), see: a) S. Hohloch, D.

Scheiffele, B. Sarkar, Eur. J. Inorg. Chem. 2013, 3956–3965; b) B.-H. Lee,C.-C. Wu, X. Fang, C. W. Liu, J.-L. Zhu, Catal. Lett. 2013, 143, 572–577;c) P. Li, L. Wang, Y. Zhang, Tetrahedron 2008, 64, 10825–10830.

[16] We tested different Cu(I) salts that gave similar results under the samecatalytic conditions (see Table S1 in the Supplementary Information).

[17] a) M. A. Herrero, J. M. Kremsner, C. O. Kappe, J. Org. Chem. 2008, 73,36–47; b) D. Obermayer, C. O. Kappe, Org. Biomol. Chem. 2010, 8, 114–121.

[18] C. Gabriel, S. Gabriel, E. H. Grant, B. S. J. Halstead, D. M. P. Mingos, Chem.Soc. Rev. 1998, 27, 213–223.

[19] For selected contributions, see: a) L. Li, T. Shang, X. Ma, H. Guo, A. Zhu,G. Zhang, Synlett 2015, 695–699; b) S. J. Coats, J. S. Link, D. Gauthier,D. J. Hlasta, Org. Lett. 2005, 7, 1469–1472; c) D. J. Hlasta, J. H. Acker-man, J. Org. Chem. 1994, 59, 6184–6189; d) A. Padwa, M. W. Wanna-maker, Tetrahedron 1990, 46, 1145–1162.

[20] For 8a, the assignment of both regioisomers was carried out by NOESYNMR correlations (see Figure S2 in the Supporting Information). For 9aand 10a, desilylation reactions with tetrabutylammonium fluoride(TBAF) were carried out to unambiguously determine the major isomer(see Figure S3 in the Supporting Information).

[21] Reaction conditions: azide (0.4 mmol) and the corresponding alkyne(0.6 mmol) in solvent (1 mL) under microwave activation (250 W) at100 8C for 1 h (1c), 2 h (5c), or 30 min (9c). For 1b, similar conditionswere used but with applying a power of 150 W for 1 h. Reactions in-volving PhN3 were protected from light.

[22] 70 and 56% of PhN3 were recovered from a glycerol solution of PhN3

after 30 min under MW activation at 150 and 250 W, respectively. Underclassical heating, 95% of PhN3 was recovered after 20 h at 100 8C.

[23] B. T. Worrell, J. A. Malik, V. V. Fokin, Science 2013, 340, 457–460.[24] A control experiment between glycerol and TMSCl was carried out to

identify the major concomitant silylglycerol derivative observed (see Ex-perimental part of the Supporting Information, Scheme S3 and FiguresS5 and S6).

[25] T. Kusukawa, G. Niwa, T. Sasaki, R. Oosawa, W. Himeno, M. Kato, Bull.Chem. Soc. Jpn. 2013, 86, 351–353.

[26] DOSY NMR experiments were inconclusive on the effect of different sol-vents on the interaction with reagents involved in azide–alkyne cyclo-additions (see Table S7 in the Supporting Information).

[27] When using other solvents instead of glycerol (water, ethanol, ethyleneglycol, propane-1,2-diol, propane-1,3-diol, dioxane, fluorobenzene), thereagents and products were soluble, even at room temperature for eth-anol, dioxane and fluorobenzene.

Received: September 25, 2015Published online on November 6, 2015


Full Paper

!!!!!!!!!!!!!!!!!!!!!!

Chapter 3 !

Key Non-Metal Ingredients for Cu-Catalysed Azide–Alkyne Cycloaddition in Glycerol

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04!.#:$+&3*#/!73-8!-8%!.&4*-+,!*-&1.-1&%!#5!+!"1'(()!+/+,#91%!'P391&%!Q<@0)<!C83*!.#:$,%K!.#1,2!

%553.3%/-,4! .+-+,4*%!66"! &%+.-3#/*! 3/!7+-%&!#&!1/2%&! *#,>%/-J5&%%! .#/23-3#/*D!1*3/9! ,#7!.+-+,4*-!

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*10*-&+-%*!1*3/9!CCOW"1",!+*!.+-+,4*-!#/!7+-%&!#&!1/2%&!/%+-!.#/23-3#/*<!

TTM

OH

N NN

NN N Ph

PhI) II)OH

N NN

NN

N

NN N

PhPh

PhCu

Cl

NN

NPh

TTM!CuCl

III)

R1 R2N3TTM!CuCl (0.5 mol%)

H2Oa or neatb, rtNN N

R2R1

NN N

Ph R1

R1 = Ph (99% yield, 4h)a

R1 = CH2NMe2 (95% yield, 4h)a

NN N

nOct R1


R1 = CO2Et (99% yield, 15h)a

NN N

Bn R1


R1 = Ph (99% yield, 15h)b

R1 = 2-pyridyl (99% yield, 8h)a

R1 = PhCH2CH2 (99% yield, 4h)b

R1 = nBu (98% yield, 16h)a,c

R1 = nHex (98% yield, 16h)a,c

R1 = 4-chlorobutyl (64% yield, 18h)a,c

R1 = CO2Et (96% yield, 12h)a

R1 = p-HOCH2C6H4 (92% yield, 2h)a

R1 = CH2OH (84% yield, 6h)a

R1 = CH2NMe2 (97% yield, 4h)a

R1 = CH2NH2 (47% yield, 5h)a,d

c 0.25% mol cat. at 40ºCd 1.0% mol cat. in 2:1 tBuOH/H2O

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PhBnN3

CuI (1 mol%)

1.5 h, rtglycerol

NN N

Bn Ph

94% isolated yield

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Ph BnN3CuI (1 mol%)

1.5 h, rtglycerol

NN N

Bn Ph

13 a 13a

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Octylamine Undecylamine Oleylamine

Dioctylamine Trioctylamine

Et3N

Triethylamine

(iPr)2EtN

Diisopropylethylamine(DIPEA)

Trioctylmethylammonium chloride(TOMACl)

Me NH210Me NH27 NH2Me

7 8

Me NH7 Me7

Me N7 Me7

Me 7

Me N7 Me7

Me 7

MeCl

Me Nn Men

Me n

MeCl

Aliquat! 336Mixture of compounds with n = 7 or 9

NNMe

MeMe

Me

Tetramethylethylenediamine(TMEDA)

NH2H2N

Ethylenediamine(EN)

NH2

NH2

o-Phenylenediamine(o-PDA)

NN

Phenantroline(PHEN)

NN

N

N

Urotropine

NH3C CH3

2,6-Lutidine

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Ph BnN3

CuI (1 mol%)

1.5 h, rtglycerol

NN N

Bn Ph

13 a 13a

Additive (5 mol%)

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Ph PhN3

CuI (1 mol%)

1.5 h, rtglycerol

NN N

Ph Ph

13 b 13b

Additive (5 mol%)

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Ph BnN3

CuI (1 mol%)

1.5 h, rtsolvent

NN N

Bn Ph

13 a 13a

Additive (5 mol%)

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R R'N3

CuI (1 mol%)

1.5 h, rtglycerol

NN N

R' R

13–22 a, b 13a–22a13b, 17b, 19b, 22b

Oleylamine (5 mol%)

NN N

Bn Ph

13a

99%

NN N

Bn CO2Et

14a

90%

NN N

Bn

15a

91%

NN N

BnX

X = CO2Me, 16a94%

X = Br, 17a89%

X = OH, 18a96%

NN N

Bn

19a

68%

NN N

Bn Ar Ar = 4-NO2-C6H4, 20a89%

Ar = 4-OMe-C6H4, 21a83%

NN N

Bn

22a

79%

NMe2

NN N

Ph Ph

13b

96%

NN N

PhBr

5b

89%

NN N

Ph

19b

53%

NN N

Ph

22b

75%

NMe2

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R R'N3CuI (1 mol%)

glycerol, rt

NN N

R' R

13, 14, 15, 17 a, b 13a, 14a, 15a, 17a13b

NN N

Bn Ph

13a

NN N

Bn CO2Et

14a

NN N

Bn

15a

17a

NN N

BnBr

NN N

Ph Ph

13b

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R BnN3

CuI (1 mol%)

1.5 h, rtglycerol

NN N

Bn R(R')

1, 6, 23 1a, 6a, 23a

NN N

Bn Ph

1a

NN N

Bn CO2Me(Ph)

6a

CuI (5 mol%), Oleylamine (25 mol%), 24 h: no reaction

NN N

Bn

R'Oleylamine (5 mol%)

R'(R)

Ph Ph(CO2Me)

I

Ph

23a

no reaction

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Ph BnN3

CuI (1 mol%)

1.5 h, rtglycerol

NN N

Bn Ph

13 13a

Oleylamine (5 mol%)

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HNHNNH

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HN

CH3

H3C

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Cu(n)

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Cl

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Cl

Cl

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N

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N

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Ph BnN3

CuI (1 mol%)

1.5 h, rtglycerol

NN N

Bn Ph

13 13a

!"#$%&'()**+ (5 mol%)

a

NaX (5 mol%)

NaOAc, 95% conversion, 87% yieldNaN3, 97% conversion, 93% yield

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a)

Ph BnN3

CuI (1 mol%)

1.5 h, rtglycerol

NN N

Bn Ph

13 13a

,-.!/" (5 mol%)

a

NaN3 (5 mol%)

98% conversion, 93% yield

b)

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Bn Ph

CuI (1 mol%)Aliquat 336! (5 mol%)

96% conversion (NMR)89% yield (NMR)90% isolated yield

NaN3Ph1.5 h, rtglycerol

13 13a

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&Copper Nanoparticles

Key Non-Metal Ingredients for Cu-catalyzed “Click” Reactions in

Glycerol: Nanoparticles as Efficient Forwarders

Marta Rodr�guez-Rodr�guez,[a, b] Patricia Llanes,[b]

Christian Pradel,[a]Miquel A. Peric�s,*[b] and

Montserrat G�mez*[a]

Abstract: The effect of long-alkyl-chain amines in CuI-assist-

ed azide–alkyne cycloadditions of terminal alkynes with or-

ganic azides in glycerol and other environmentally benign

solvents (water, ethanol) has been examined. The presence

of these additives favors the in situ formation of CuI-based

nanoparticles and results in an increase of the catalytic reac-

tivity. In glycerol, liquid-phase transmission electron micros-

copy (TEM) analyses, enabled by the negligible vapor pres-

sure of this solvent, proved that CuInanoparticles are re-

sponsible for the observed catalytic activity. The wide variety

of alkynes and azides of which this effect has been investi-

gated (14 combinations) confirms the role played by these

additives in Cu-catalyzed Huisgen cycloadditions.

Introduction

Copper-catalyzed azide-alkyne cycloaddition (CuAAC) reactions

represent a successful method for the synthesis of 1,2,3-tria-

zoles,[1]

as indicated by the thousands of works published in

this field,[2a]

including enantioselective CuAAC transforma-

tions.[2b,c]

This remarkable success is mainly due to the process

versatility in terms of solvent compatibility, copper sources

(salts, well-defined complexes, preformed nanoparticles, (un)-

supported systems), functional group tolerance, and energy

supplies (conventional heating, microwave activation) among

others. However, this hands-on behavior leads to some con-

cerns with regard to understanding (“who does what”), associ-

ated with the lack of conclusive studies in relation to CuAAC

mechanism(s),[3]

in particular for in situ generated systems

using CuIstarting materials. The most frequently used precur-

sors, copper halides, are quite insoluble in the common organ-

ic solvents, especially CuI.[4]

The presence of any additive (im-

purity) can improve the solubility of copper species in the

medium, inducing then an increase of catalytic activity. In this

context, organic bases play a decisive task, favoring both the

coordination to metal (as Lewis bases) and the formation of

active intermediates such as copper acetylides. Polydentate ni-

trogen-based ligands have been proved as particularly efficient

copper partners, stabilizing CuIspecies

[5]and enhancing the

rate of CuAAC processes.[6]

In this area, CuIcomplexes contain-

ing tris-(triazolyl)methane tripodal ligands, which are highly

proficient in CuAAC reactions,[1f, 7]

represent an elegant ap-

proach to illustrate the role of Lewis bases (Figure 1). These li-

gands can efficiently stabilize catalytic precursors (I) and also

intermediates acting as hemi-labile scaffolds (II), which gener-

ates vacant sites for the coordination of reagents.

In agreement with these important, ancillary tasks, base-free

catalytic CuAAC systems using CuIcomplexes as copper source

are rare. To the best of our knowledge, only one recent publi-

cation by Garc�a-Alvarez and Vidal reports on a CuIsystem able

to catalyze CuAAC reactions in glycerol in the absence of any

added base.[8]

Following our work on the use of glycerol as a solvent in

metal-catalyzed processes[9]

and more recently in metal-free

AAC for the synthesis of fully substituted 1,2,3-triazoles,[10]

in

which the activation of both alkynes and benzylazide by glyc-

erol was proved, we planned to evaluate the activity of CuI

salts towards click reactions in this solvent, with the aim of un-

Figure 1. Tris(triazolyl)methane ligands for CuI-catalyzed AAC.[1f, 7]

Small

square denotes vacant site on copper.

[a] M. Rodr�guez-Rodr�guez, C. Pradel, Prof. M. G�mez

Laboratoire H�t�rochimie Fondamentale et Appliqu�e (LHFA)

UPS and CNRS UMR 5069

Universit� de Toulouse



[b] M. Rodr�guez-Rodr�guez, Dr. P. Llanes, Prof. M. A. Peric�sInstitute of Chemical Research of Catalonia (ICIQ)

The Barcelona Institute of Science and Technology

Avda. Paısos Catalans, 16, 43007 Tarragona (Spain)


Supporting information for this article can be found under http://

dx.doi.org/10.1002/chem.201604048.

Chem. Eur. J. 2016, 22, 18247 – 18253 � 2016 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim18247

Full PaperDOI: 10.1002/chem.201604048

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derstanding the role of added exogenous base in glycerolmedium.

Results and Discussion

We selected the cycloaddition between phenylacetylene andbenzyl azide as the benchmark reaction, using CuI as catalystsource in neat glycerol at room temperature (Scheme ofTable 1). The reaction did not work at all at short reactiontimes (1.5 h), 84% conversion being achieved after 24 h(entry 1, Table 1). In the course of our research, the high effi-ciency of this methodology under exactly the same “base-free”reaction conditions was reported, triazole 1a being isolated bythese authors in 94% yield in short reaction times.[8] This seri-ous discrepancy between independent runs of an easy-to-per-form process, almost fulfilling the requirements in the Corn-forth definition of an “ideal chemical process”[11] led us to thinkthat some uncontrolled factor was operating. Given the practi-cal importance of azide–alkyne cycloadditions, we decided todeeply characterize the different components involved in theprocess in an attempt to rationalize this behavior.[12] This ana-lytical study showed that the success of the reaction dependedon the quality (source) of BnN3 (entries 2–4, Table 1) and that,rather surprisingly, high-purity samples of azide were unreac-tive. In fact only one commercially available lot of BnN3 fa-vored the cycloaddition (entry 2, Table 1).

We analyzed the “active” BnN3 by GC-MS and NMR (Figur-es S1–S3 in the Supporting Information). In contrast to theother BnN3 samples (Figures S4–S9 in the Supporting Informa-tion), this one was contaminated by some compounds that, ac-cording to MS, appeared to correspond to amines containinglong alkyl chains. To test the possible catalytic effect of theseimpurities, we carried out the cycloaddition in the presence ofamines using high purity, home-made BnN3 (Table 2). We ob-

served that when 5 mol% of amine with respect to benzylazide was used, primary (entries 1–3), secondary (entry 4), andtertiary (entry 5) long-alkyl-chain-based mono-amines led tohigh yields of the corresponding 1,2,3-triazole, 1a. For short-alkyl-chain derivatives, such as triethylamine or diisopropyle-

Table 1. Azide–alkyne cycloaddition of phenylacetylene and benzyl azidein the presence of CuI.[a]

Entry Bn-N3 Source/Batch code[b] Conv. (yield) [%][c]

1[d] Home-made <584 (69)[e]

2 Alfa-Aesar/C25Z013[f] 100 (80)3 Alfa-Aesar/AE040501 <54 Aldrich/BCBL4667V <5

[a] Reaction conditions: CuI (1 mol%), benzyl azide (0.5 mmol), and phe-nylacetylene (0.5 mmol) in glycerol (0.5 mL) at 25 8C for 1.5 h. Triazole 1awas not obtained in the absence of copper (18% conversion, <5% yieldfor 1a) ; [b] for certificates of analyses, see the Supporting Information;[c] determined by 1H NMR analysis using 2-methoxynaphthalene as inter-nal standard; conversions based on BnN3; [d] for BnN3 synthesis, seeref. [24] ; [e] in italics, data after 24 h reaction; [f] data coming from twodifferent commercial flasks.

Table 2. Azide-alkyne cycloaddition of phenylacetylene and the corre-sponding azide in the presence of CuI and amine.[a,b]

Entry Azide Amine Product, Conv. (yield) [%][b]

1 a NH2(octyl) 1a, 96 (93)52 (44)[c]

2 a NH2(undecyl) 1a, 96 (93)3 a Oleylamine 1a, 100 (>99)

98 (94)[c]

Run 4: 100 (85)[d]

4 a NH(octyl)2 1a, 100 (96)95 (88)[c]

5 a N(octyl)3 1a, 96 (88)97 (73)[c]

6 a NEt3 1a, 28 (16)7 a NEt(iPr)2 1a, 36 (6)8 a TOMACl 1a, 37 (19)9[e] a Aliquat�336 1a, 20 (<5)10 a TMEDA 1a, 83 (70)11 a EN 1a, 30 (12)12 a o-PDA 1a, 30 (10)13 a PHEN 1a, 15 (6)14 a Urotropine 1a, 20(<5)15 a 2,6-lutidine 1a, 34(26)16 b – 1b, <517 b NH2(octyl) 1b, 100 (94)

39 (9)[c]

18 b Oleylamine 1b, 100 (98)100 (87)[c]

19 b NH(octyl)2 1b, 83 (89)88 (87)[c]

20 b N(octyl)3 1b, 88 (88)100 (12)[c]

21 b NEt3 1b, 10 (6)22 b TMEDA 1b, 70 (76)23 b EN 1b, 21 (19)24 b Urotropine 1b, <5

[a] Reaction conditions: CuI (1 mol%), amine (5 mol%), benzyl or phenylazide (0.5 mmol), and phenylacetylene (0.5 mmol) in glycerol (0.5 mL) at25 8C for 1.5 h; [b] determined by 1H NMR analysis using 2-methoxynaph-thalene or 1,3,5-trimethoxybenzene as internal standard; conversionsbased on BnN3; [c] in italics, conversion (yield) using 1 mol% of amine;[d] see Figure S10 in the Supporting Information for the recycling of thecatalytic phase; [e] Aliquat� 336: Ammonium salts containing a mixture ofC8 and C10 alkyl chains with C8 predominating.


Full Paper

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thylamine, low yields were achieved (<16%, entries 6 and 7,Table 2). When the amount of added amine decreased(1 mol%), the reaction also worked (entries 1 and 3–5), espe-cially for oleylamine, dioctyl, and trioctyl amine (entries 3–5).Ammonium salts, such as trioctylmethylammonium chloride(TOMACl) and Aliquat�336 (ammonium salt containing a mix-ture of C8 and C10 alkyl chains, often used as a metal extrac-tion reagent[13]), did not favor the cycloaddition (entries 8 and9).

Dinitrogenated (EN=ethylenediamine; o-PDA=ortho-phe-nylenediamine and PHEN=phenantroline, entries 11–13,Table 2) and tetranitrogenated (urotropine, entry 14) ligandsdid not trigger a positive outcome (yields <12%). TMEDA (tet-ramethylethylenediamine) was an exception to this behavior(70% yield, entry 10). The use of 2,6-lutidine, known by its per-formance in CuAAC in aqueous medium,[14] gave a very lowyield (entry 15).

The same trend could be found when phenyl azide wasused instead of benzyl azide (entries 16–24, Table 2): Thesystem was inactive in the absence of an added amine(entry 16). However, high yields could be isolated in the pres-ence of amines containing a long alkyl chain (up to 94%, en-tries 17–20). For “light” amines (entries 21–24, ), only the CuI/TMEDA system was active, as previously observed with BnN3

(entries 10 and 22, Table 2).Furthermore, this “super” amine effect was examined in

other polar solvents, such as water, ethanol, or 1,4-dioxane.Under the same conditions as described above, the behaviorwas comparable to that observed in glycerol. Without any ad-ditive or in the presence of NEt3, low yields were obtained (<13%, entries 1–6, Table 3). However, in the presence of dioctyl-amine (entries 7–9) or oleylamine (entries 10–12), the increaseof catalytic activity was clearly apparent.

It is important to mention that the catalytic phase could berecycled up to four times without significant loss of efficiency(entry 3, Table 2; see Figure S10 in the Supporting Information),showing the ability of glycerol to immobilize the catalyst. Thedramatic effect observed after the fourth run is undoubtedlyrelated to the leaching of copper (more than 1000 ppm deter-mined by ICP-MS).

With these results in hand, a representative set of Cu-cata-lyzed azide–alkyne cycloadditions involving the use of differentalkynes (1–10) and organo-azides (a, b) (Scheme 1) was carriedout in the presence of oleylamine. The corresponding triazoleswere obtained in high to quantitative yield. Even those tria-zoles bearing alkyl substituents at C-4 (3a, 7a, 7b) were ob-tained in moderate to high yields (53–91%). No transesterifica-tion reactions with glycerol were detected for alkynes contain-ing ester groups (2a, 4a). For selected triazoles, the reactionswere also carried out in the absence of added amine, as con-trol experiments. In all cases, low yields (<25%, see Table S1 inthe Supporting Information) were recorded even at longertimes (up to 7 h). Unfortunately, this catalytic system, workingunder favorable conditions, was not active using internal al-kynes, such as diphenylacetylene, methyl phenylpropiolate, or1-iodo-2-phenylacetylene (Figure S11 in the Supporting Infor-mation).

With the aim of understanding the observed reactivity, weanalyzed the structural behavior of copper salts. From a coordi-nation point of view, the CuI motif leads to a large variety ofstructures corresponding to both discrete molecular com-

Table 3. Azide-alkyne cycloaddition of phenylacetylene and benzyl azidein the presence of CuI and amine.[a]

Entry Solvent Amine Conv. (yield) [%][b]

1 H2O – 22 (13)2 EtOH – 12 (<5)3 Dioxane – 11 (<5)4 H2O NEt3 15 (<5)5 EtOH NEt3 17 (<5)6 Dioxane NEt3 24 (11)7 H2O NH(octyl)2 100 (93)8 EtOH NH(octyl)2 66 (48)9 Dioxane NH(octyl)2 100 (99)10 H2O Oleylamine 99 (94)11 EtOH Oleylamine 59 (48)12 Dioxane Oleylamine 94 (81)

[a] Reaction conditions: CuI (1 mol%), amine (5 mol%), benzyl azide(0.5 mmol), and phenylacetylene (0.5 mmol) in the appropriate solvent(0.5 mL) at 25 8C for 1.5 h; [b] determined by 1H NMR analysis using 2-me-thoxynaphthalene or 1,3,5-trimethoxybenzene as internal standard; con-versions based on BnN3.

Scheme 1. Scope of azide-alkyne cycloaddition catalyzed by CuI/aminesystem in glycerol. Figures indicate isolated yields.


Full Paper

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plexes[15] and polymeric networks,[16] depending on the natureof the ligands involved and also the reaction conditions. Thisstructural variety is especially remarkable when N-based li-gands are involved,[17] in particular for diamines (EN, TMEDA,PHEN) and short-alkyl-chain tertiary amines (NEt3, NEtiPr2) likethose used in this work.[18] Some of them give complex struc-tures based on closed-cubane “Cu4I4” tetramers;[18a,19] we couldprove this trend by the X-ray diffraction analysis of the Cu4I4-TMEDA system (Figures S12 and S13 in the Supporting Infor-mation).[20]

In contrast, long-alkyl-chain amines favor the stabilization ofmetal (and metal oxide) nanoparticles.[21] Presuming the forma-tion of copper-based nanoclusters under our reaction condi-tions,[22] TEM analyses of CuI in glycerol and in the presence ofdifferent amines were carried out (Table S2 in the SupportingInformation). Actually, the formation of well-dispersed nano-particles was observed in the presence of long-alkyl-chainamines, including ammonium derivatives (Figure 2). HR-TEMand EDX analyses of a CuI/dioctylamine mixture in glycerolconfirmed the CuI nature of the nanoparticles and the pres-ence of the amine on the nanoparticle surface (Figure S14 inthe Supporting Information). It is worth noting that ammoni-um salts such as TOMACl and Aliquat�336 did not lead to cata-lytically active systems, although the formation of well-dis-persed nanoparticles was also observed. The lack of catalyticactivity in these last cases is probably due to the very strongelectrostatic interaction between the ionic ligands and thenanoparticles: As a result, CuI-based nanoparticles are tightlysurrounded by anion/cation shells, and this leads to small andwell-dispersed particles. However, this stabilizing interactionshields the surface of the nanoparticles and prevents the requi-site approach of the reactants to the catalytic copper centers.In contrast, hemi-labile amine ligands, while still preventingparticle agglomeration by steric shielding, can be easily de-tached, leading to free coordination sites on copper that arenecessary for the reaction to proceed.[23]

Interestingly, the presence of additional ionic compounds inthe reaction medium was shown to influence the course of thereaction as well. Thus, when an equimolar mixture of Ali-quat�336 and a sodium salt (NaOAc or NaN3) was added to thenon-productive reaction mixture, the system turned active(Figure 3). TEM analyses of CuI in glycerol in the presence of

both Aliquat�336 and sodium salt evidenced the formation ofmicelle-like arrangements, giving high local density of copperand therefore favoring the reactivity. This effect can especiallybe observed in the case of the mixture Aliquat�336/NaOAc,where cylindrical micelles were identified, containing thecopper species at the surface (accessible to the reagents) andthe more hydrophobic constituents (ammonium alkyl species)probably placed inside of these nano-objects. A similar trendcould be observed using TOMACl/NaN3 (Figure S15 in the Sup-porting Information). It is important to note that CuI/NaN3 andCuI/NaOAc systems (in the absence of any nitrogen-basedligand) were not active. In addition, this reactivity behaviorpoints to the feasibility of CuAAC by a one-pot three-compo-nent approach. Actually, with Bn-Br, NaN3 and phenylacetyleneas starting materials, 1a was isolated in 90% yield (seeScheme S1 in the Supporting Information)

Correlating reactivity and structure, it seems that the forma-tion of nanoparticles favors the catalytic process, which pointsto a beneficial (cooperative) effect between neighboring CuI

centers for the activation of both azide and alkyne reactantsduring the cycloaddition, as already noted in our previouswork involving the use of Cu2O nanoparticles as catalytic pre-cursors in glycerol medium.[9a]

In fact, for short-chain alkyl amines such as DIPEA (DIPEA=N,N-diisopropylethylamine), ethylenediamine, or urotropine,agglomerates similar to those observed for CuI in the absenceof any additive were formed (Table S2 in the Supporting Infor-mation), affording inactive catalytic systems (Table 2). Only CuI/TMEDA led to the simultaneous formation of nanoparticlesand agglomerates. As we have already mentioned, this systemdepicted high catalytic activity in azide–alkyne cycloadditions(entries 10 and 22, Table 2).

We were also interested in establishing the oxidation stateof copper involved in the active species. For that, we reusedthe catalytic phase corresponding to the active CuI/dioctyla-mine system (after reaction between phenylacetylene andbenzyl azide). TEM analysis after catalysis showed smallernanoparticles than before (ca. 1.4 nm (after) vs. 2.1 nm(before); Table S2 in the Supporting Information) ; the catalyticphase was then much less active (33% in the second runversus 100% in the first one). HR-TEM coupled to an electronicdiffraction analysis showed that particles after the first catalytic

Figure 2. TEM images for CuI-based systems containing oleylamine (a), dioctylamine (b), and TOMACl (trioctylmethylammonium chloride) (c) in glycerol. Scalebars=50 nm.


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run consisted of Cu0 (Figure S16 in the Supporting Informa-tion). This indicated to us that the initially formed CuI-richnanoparticles suffer reductive deactivation as a concomitantoff-cycle of the CuAAC reaction. In contrast, the reutilization ofthe CuI/oleylamine system gave the same activity as for thefirst run (for both cases, nearly full conversion). HR-TEM/elec-tronic diffraction analysis proved that in this case, nanoparti-cles were mainly formed by CuI after catalysis (Figure S17 inthe Supporting Information). In addition, XPS analysis evi-denced the absence of CuII species after reaction (absence ofthe corresponding strong satellites, see Figure S18 in the Sup-porting Information). These data point to CuI-based nanoparti-cles as being responsible for the observed reactivity.

Conclusions

In this work, we could prove the key role of “impurities” ran-domly present in commercial samples of benzyl azide. Its accu-rate analyses led us to identify them (long-alkyl chain amines)and to examine their impact on CuI-based catalytic systemsapplied in azide-alkyne cycloadditions in different solvents. Asa practical result of this study, we have been able to establishthat the addition of small amounts (5 mol%) of primary, secon-dary, or tertiary amines containing C8, C11, or C18 carbon chains(CuI/amine ratio=1/1 or 1/5) secures the success in the syn-

thesis of 1,4-disubstituted 1,2,3-triazoles under mild reactionconditions (low metal loading of 1 mol%, short time of 1.5 h,and room temperature), in environmentally benign glycerol. Asa consequence, a warning should be made on experimentalprocedures for the CuAAC reaction in polar solvents not in-volving the use of appropriate amines: Their success or failurestrongly depends on the presence/absence of amine-type im-purities in the employed azide. The use of glycerol as a non-volatile solvent enabled the (HR)TEM analysis of solutions con-stituted by CuI and amine, before and after catalysis. It couldbe learned from these studies that CuI, in the presence oflong-alkyl-chain amines in glycerol at room temperature, givesrise to the formation of small and well-dispersed CuI nanoparti-cles, in contrast with the agglomerates formed from eitherbulk CuI or mixtures of CuI with low-weight amines. It is im-portant to mention that the presence of ammonium saltsmainly containing C8 chains (TOMACl, Aliquat� 336) did notprovide an efficient catalytic system in spite of the formationof well-dispersed nanoparticles. This was almost certainlycaused by the stabilization of CuI nanoparticles by electrostaticeffect, thus blocking the access of reagents to the CuI centers.However, tuning the ionic species present in the reactionmedium, the catalytic system turned active through the forma-tion of organized systems.

Figure 3. Effect of the salts in azide–alkyne cycloaddition. TEM images corresponding to the mixtures of CuI, Aliquat� 336, and NaX (1/5/5 ratio, respectively):NaOAc (left; scale bar=1 mm, inset scale bar=100 nm), including an inserted image of one of the cylindrical micelle-like objects; NaN3 (right; scalebar=50 nm).


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Altogether, this study led us to establish a correlation be-tween the in situ formation of CuI nanoparticles in glyceroland other polar solvents and their catalytic activity. Thesenano-objects, generated due to the presence of long-alkyl-chain amines, favor the activation of both reagents, alkyne andazide partners, by cooperative effect between neighboring CuI

centers.The inconsistencies found working under the “same” condi-

tions induce the desire to understand and discover new issuesfor known reactions. The use of controlled-quality compounds(reagents, catalysts, solvents) permits a dramatic reduction ofthese effects, establishing reproducible and sustainable proto-cols.

Experimental Section

General procedure for the azide-alkyne cycloaddition

CuI (0.9 mg, 0.005 mmol) and the corresponding amine (0.005–0.25 mmol) were added to glycerol (0.5 mL) in a Schlenk tubeequipped with a stirring bar under Ar atmosphere. The alkyne(0.5 mmol) and the azide (0.5 mmol, 67 mg for BnN3

[24] and 60 mgfor PhN3) were added consecutively to the reaction medium. Themixture was stirred at 25 8C for 1.5 h (or the stated time). The or-ganic products were extracted from the catalytic mixture with di-chloromethane (6�2 mL). The combined chlorinated organic layerswere filtered through a Celite� pad and the resulting filtrate wasconcentrated under reduced pressure. The products were purifiedby chromatography (silica gel short column, eluent: cyclohexane/ethyl acetate) in order to determine the isolated yields of the cor-responding triazoles.

Acknowledgements

Financial support from the Centre National de la RechercheScientifique (CNRS), the Universit� de Toulouse 3—Paul Sabati-er, MINECO (grants CTQ2012-38594-C02-01 and CTQ2015-69136-R), DEC (grant 2014SGR827) and ICIQ Foundation aregratefully acknowledged. S. Ladeira and R. Brousses are ac-knowledged for the resolution of the XRD structure. M.R.thanks the CNRS and MINECO (CTQ2012-38594-C02-01) fora PhD grant.

Keywords: azide–alkyne cycloaddition · copper · glycerol ·long-chain amines · nanoparticles

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Cure, Y. Coppel, T. Dammak, P. F. Fazzini, A. Mlayah, B. Chaudret, P. Fau,Langmuir 2015, 31, 1362–1367.

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[24] S. G. Alvarez, M. T. Alvarez, Synthesis 1997, 413–414.

Received: August 25, 2016Published online on October 28, 2016


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Preparation of new enantiopure PTA-based derivatives. Some applications in

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/30!2'60!)/.82/8.0!-H!"#$)! :*!60*0.'&@!/30!Q)-H/R!"!20*/.0!I+*1)!/-!&-?F>'&0*/!/.'*)+/+-*!,0/'&)@!

?3+&0!%.-/-*'/+-*!-.!'&S(&'/+-*!-228.)!%.0H0.0*/+'&&(! +*!/30!Q3'.1R!P!'/-,)4!#30!)(*/30)+)!-H!,F

'&S(&'/01!"#$!10.+>'/+>0)!9J+68.0!K4T';!+)!1-*0!)/'./+*6!H.-,!%3-)%3+*0!)-8.20)!)823!')!"UC7!-.!

"9BUC5U;T4AVG!#30!I')+2+/(!-H!"#$!?')!10/0.,+*01!I(!L'.0*)I-8.6!&%(#+-!9%.'!-H!W4VX

AYG;!'*1!'&)-!

I(!J+)30.!'*1!$&(0'!&%(#+-!9%.'!-H!E4X4AZG;4!:*!'2+1+2!'N80-8)!)-&8/+-*)!9%U!&-?0.!/3'*!E4W;@!"#$!+)!

/F%.-/-*'/01! 9J+68.0! K4TI;@! ')! 0=%02/01! 2-*)+10.+*6! /30! [0?+)! I')0! 23'.'2/0.! -H! /30! /0./+'.(!

',+*-! 6.-8%)! -H! "#$4! J8./30.!/F%.-/-*'/+-*! +)! /30.,-1(*',+2'&&(! &0))! H'>-8.'I&0! 180! /-! /30!

+*)/'I+&+/(! 2'8)01! I(! /30! 3(I.+1+\'/+-*! -H! *+/.-60*! 20*/.0)! ')! ?0&&! ')! I(! /30! 10)/'I+&+)+*6!

0&02/.-)/'/+2!.0%8&)+-*!-H!/?-!%-)+/+>0!23'.60)!2&-)0!?+/3+*!/30!)',0!,-&028&0@!')!%.->01!I(!#0(

121%13!2'&28&'/+-*)4AY'G!"#$!2'*!I0!'&S(&'/01!'/!P!'/-,)!9J+68.0!K4T2;!I(!*82&0-%3+&+2!)8I)/+/8/+-*)@!

8)+*6! H-.! +*)/'*20!]0:AOXG! -.! ^*B&AZG! ')! '&S(&'/+*6! '60*/)4! _+,+&'.! /-! /30! %'.0*/! %3-)%3+*0! "#$@!

/30)0!N8'/0.*'.(!',,-*+8,!10.+>'/+>0)!'.0!)-&8I&0!+*!%-&'.!)-&>0*/)4!P0>0./30&0))@!/30(!0=3+I+/!

'! &-?0.!)-&8I+&+/(! +*!-.6'*+2!)-&>0*/)!+*!.0&'/+-*!/-!"#$@!180!/-!/30!%.0)0*20!-H!/30!',,-*+8,!

H8*2/+-*'&+/(4AOOG!]->+*6!-*!/-!6&(20.-&@!/30!)-&>0*/!-H!23-+20!+*!/3+)!"3L!#30)+)@!/30!/F'&S(&'/01!

"#$! 10.+>'/+>0)! '.0! 6&(20.-&F)-&8I&0@!?30.0')! "#$! +)! +*)-&8I&0! +*! /3+)! )-&>0*/4AOCG! :*! -8.! 6.-8%@!

)0>0.'&!/F'&S(&'/01!"#$!2-,%-8*1)!?0.0!)(*/30)+)01!'*1!8)01!H-.!/30!)/'I+&+)'/+-*!-H!%'&&'1+8,!

N N

NP

RuClCl

R

R A PTA

!"#$%"%&'()*(+*)#,*#)%)&'($-"#*!./01%2#3*3#"'4%&'4#25*6(7#*%$$8'9%&'()2*')*#)%)&'(2#8#9&'4#*9%&%8:2'25*

!

! "#$!

!"!#$"%&'()*+,-./0.+1,'!,2)3(*%#)456789,:;*,("&")3&'(,+3+&*<,="+,"(&'>*,'!,(%#++?(#@$)'!2,%*"(&'#!+A,

;3/%#2*!"&'#!+,"!/,#!*?$#&,&"!/*<,$%#(*++*+,-+**,B(;*<*,6466,'!,(;"$&*%,614,

!!"#$%&'()*!C@!(&'#!")'+"&'#!,#D,.:EF!"1,!?E)G3)"&'#!H,81,;?.%#&#!"&'#!H,(1,;?E)G3)"&'#!H,/1,I#=*%?%'<,

D@!(&'#!")'+"&'#!4,

, :;*,)#=*%?%'<,<*&;3)*!*,$#+'&'#!+,-+**,C'2@%*,J461,;">*,8**!,")+#,D@!(&'#!")'+*/,2'>'!2,

%'+*, &#, .:E, /*%'>"&'>*+, '!, =;'(;, &;*, 6AKAL?&%'"M"(3()#;*N"!*, %'!2, %*+@)&+, 7AJAO?&%'+@8+&'&@&*/,

-C'2@%*, J4K/1456K9, 0*>*%&;*)*++A, &;*, D@!(&'#!")'+"&'#!, "&, &;*, @$$*%?%'<, <*&;3)*!*, $#+'&'#!A,

"/P"(*!&,&#,&;*,.,(*!&%*,#D,.:EA,'+,#D,$"%"<#@!&,'<$#%&"!(*,8*("@+*,&;*+*,&%"!+D#%<"&'#!+,)*"/,

&#, (;'%"), .:E, $;#+$;'!*+4, E, +&*%*#2*!'(, (*!&%*, '+, &;*!, 2*!*%"&*/, '!, ()#+*, $%#N'<'&3, &#, &;*, .,

"&#<A, &;@+, $#&*!&'"))3, *!"8)'!2, *DD'('*!&, )'2"!/?&#?<*&"), &%"!+D*%, #D, &;*, +&*%*#(;*<'("),

'!D#%<"&'#!4, Q!, &;'+, ="3A, ", !*=, ()"++, #D, (;'%"), ="&*%?+#)@8)*, .:E?8"+*/, $;#+$;'!*+, ("!, 8*,

"((*++'8)*4,:;*,D'%+&,=#%G,%*$#%&'!2,"!,@$$*%?%'<,<#/'D'("&'#!,#D,.:E,="+,$@8)'+;*/,83,C%#+&,#&*

%8556J9, :;*3, /*+(%'8*/, D#%, &;*, D'%+&, &'<*, &;*, G*3, +&*$, #D, )'&;'"&'#!, #D, #!*, @$$*%?%'<,<*&;3)*!*,

$#+'&'#!, &#, #8&"'!, &;*, (#%%*+$#!/'!2, .:ERI', /*%'>"&'>*A, =;'(;, ="+, '+#)"&*/, "+, ", =;'&*, ;'2;)3,

$3%#$;#%'(,$#=/*%,'!,;'2;,3'*)/,-S,TUV14,W*("@+*,#D,'&+,$3%#$;#%'(,!"&@%*A,.:ERI',="+,'!/'%*(&)3,

(;"%"(&*%'+*/, 83, %*"(&'#!, ='&;, X7Y4, :;*, /*@&*%"&'#!, +*)*(&'>*)3, #((@%%*/, "&, #!*, #D, &;*, !?.,

<*&;3)*!*,$#+'&'#!+4,:;*,+*)*(&'>*,)'&;'"&'#!,"&,&;'+,+'&*,<'2;&,8*,/@*,&#,",8*&&*%,+&"8')'+"&'#!,#D,

&;*,D#%<*/,("%8"!'#!4,

!+,-&.&'()/'I'&;'"&'#!,#D,&;*,@$$*%?%'<,<*&;3)*!*,$#+'&'#!,#D,.:E4,

! :;*,&;@+,%*+@)&"!&,.:ERI',/*%'>"&'>*,#$*!+,&;*,="3,&#,",2%*"&,/*"),#D,$#++'8')'&'*+,'!,&;*,

/*>*)#$<*!&, #D, !*=, (;'%"), .:E?8"+*/, $;#+$;'!*, )'2"!/+4, :;'+, ;'2;)3, %*"(&'>*, #%2"!#)'&;'@<,

!@()*#$;')*, ("!, 8*, "//*/, #!&#, ", >"%'*&3, #D, *)*(&%#$;')*+, -B(;*<*, J471, +@(;, "+,

NN

N

PR

NN

N

P

H NN

N

P

R

R = alkyl group

a) b) c)

NN

N

Pd)

RRR

NN

N

P nBuLi

THF NN

N

P Lior N

NN

P

LiD2O

NN

N

P D

not observed

!"#$%&'()*(

!

!"#$!

!"#$%$&"$'&"()*'+,-./-012 345+,-612 7#8*"98*'2 $%2 :*;$)*',-6/-<12 7)82 (=()*'>,-?12 @"*'*2 '9);"*;(!2

';%7;*A(*'2A*)*%7;*2$)*2$%2;B$2';*%*$A*)(!2!7%C$)2!*);%*'>22

!!"#$%$&'()!D*7!;(E(;92$F2G@HIJ(2;$B7%8'2'*E*%7#2*#*!;%$&"(#*'>2

! K$=*2$F2;"*'*2!"(%7#2G@H/C7'*828*%(E7;(E*'2"7E*2C**)2L'*827'2#(A7)8'2()2;"*2'9);"*'('2$F2

;%7)'(;($)2=*;7#2!$=&#*M*'2NO(AL%*2.>.P+2&%*'*);()A2"(A"27!;(E(;92 ()28(FF*%*);2!7;7#9;(!2&%$!*''*'2

N)(;%(#*2 "98%7;($)',-0+2 -?12 $%2 ;%7)'F*%2 "98%$A*)7;($)',-<C1P>2 Q$B*E*%+2 7##2 ;"*2 %*&$%;*82 !"(%7#2 G@H2

8*%(E7;(E*'2 B*%*2 )$;2 ';*%*$!"*=(!7##92 &L%*+2 L'*82 7'2 %7!*=(!2 =(M;L%*+2 7)82 ()2 !$)'*RL*)!*2

B(;"$L;2()8L!()A27)92';*%*$'*#*!;(E(;9>22

S)25T--+2G*%LUU()(27)82V$)'7#E(2&%(#+>,-<C12%*&$%;*82$)2;"*2L'*2$F2 S%NSP2!$=&#*M*'2$F2G@H/

C7'*82 W/&"$'&"()$2 7#!$"$#'2 NO(AL%*2 .>.7P+2 7'2 'L(;7C#*2 !7;7#9;(!2 '9';*='2 F$%2 ;"*2 ;%7)'F*%2

"98%$A*)7;($)2$F2:*;$)*'27'2B*##27'2X+W/L)'7;L%7;*82!7%C$)9#2!$=&$L)8'>2@"*2'7=*2A%$L&27#'$2

%*&$%;*82 ;"*2 F(%';2 (=(87U$#9#2 L&&*%/%(=2 G@H2 8*%(E7;(E*'>,-<!12 @"*2 DLNSSP2 !$=&#*M*'2 NO(AL%*2 .>.CP2

!$);7()()A2;"*'*2"*;*%$/8$)$%2 #(A7)8'2'"$B*8272=$8*%7;*2!7;7#9;(!27!;(E(;92 ()2;"*2%*8L!;($)2$F2

7!*;$&"*)$)*>2 O$##$B()A2 B(;"2 ;"*2 '7=*2 =*;7#+2 O%$';2 &%( #+,2 &%*&7%*82 G@H/C7'*82 W/

7=()$&"$'&"()*'27)82!$$%8()7;*82 ;"*=27'2C(8*);7;*2 #(A7)8'2 ;$2DLNSSPI7%*)*2!*);%*'>,-?12@"*'*2

DLNSSP2!$=&#*M*'2NO(AL%*2.>.!P2B*%*2F$L)82;$2C*27!;(E*2!7;7#9';'2F$%2;"*27RL*$L'2&"7'*2"98%7;($)2

$F2)(;%(#*'>2Y$%*2%*!*);#9+2;"*2'7=*2A%$L&2%*&$%;*82;"*2'9);"*'('2$F2G@H/C7'*82-.-/8$)$%2#(A7)8'2

7)82 ;"*(%2 !$%%*'&$)8()A2 DLNSSPI7%*)*2 !$=&#*M*'2 NO(AL%*2 .>.8P+2 C*()A2 7#'$2 7!;(E*2 ()2 ;"*2 )(;%(#*2

"98%7;($)>,-0122

!*+,-.$&'('2@%7)'(;($)2=*;7#2!$=&#*M*'2!$);7()()A2G@H/C7'*82#(A7)8'2L'*82()2!7;7#9'('>2

NN

N

P Li*ClPR2NN

N

P P*

R

R

R

O

R'

NN

N

P *

HO

R'R

*

CO2

NN

N

P *

O

OLi

R

NHPh

R'NN

N

P *

PhHN

R'R

*

NN

N

P *

HO

R*

NN N

P *OH*

IrCl

R = Ph, p-Me2N-C6H4

NNMe

RuCl

MeMe

Me

Cl

NN

N

P *

NHPh

Ph*

RuCl

Me

Ph

NN

N

P P*

RuCl

Me

iPr

iPrCl

a) b) c) d)

R = H or N-methylimidazol-2-yl

R

Cl

!"#$%"%&'()*(+*)#,*#)%)&'($-"#*!./01%2#3*3#"'4%&'4#25*6(7#*%$$8'9%&'()2*')*#)%)&'(2#8#9&'4#*9%&%8:2'25*

!

! "#$!

! "#$#%&'#(#))*! &+! &'#! ,#)&! +-! +.%! /0+1(#23#*! #040&5+6#%574((8! 9.%#! :;<=,4)#2!

9'+)9'50#)! '4$#! 0+&! ,##0! 9%#$5+.)(8! %#9+%&#2! 50! &'#! (5&#%4&.%#>! ;'#)#! 7+69+.02)! +9#0! &'#!

9+))5,5(5&8!+-! 7%#4&503!0#1!3(87#%+(! ?402!14&#%@! )+(.,(#!+9&574((8!9.%#! 74&4(8)&)! -+%! 4)866#&%57!

&%40)-+%64&5+0)! +-! 50&#%#)&>! ;'5)! 5)! 47&.4((8! &'#! 6450! 3+4(! +-! &'5)! 7'49&#%A! &+! 9%#94%#! 0#1!

#040&5+9.%#!:;<=,4)#2!2#%5$4&5$#)! 50! +%2#%! &+!.)#! &'#6!4)! 7'5%4(! (53402)! -+%! &%40)5&5+0!6#&4(=

,4)#2!7+69(#B#)!402!4()+!4)!7'5%4(!+%340+74&4(8)&)>!

!"#$%&'()*'$+,-$-.'/(''.0,$

!"#"1$23&4+3+*.0,$05$*6&$&,+,*.04(3&$278$460'46.,&'$

C+((+1503! &'#! )&%4&#38!+-! C%+)&!#&*%85DEFG! -+%! &'#!.99#%=%56! -.07&5+04(5)4&5+0!+-!:;<! ?#!@!

&'%+.3'! &'#! -+%64&5+0! +-! &'#! :;<HI5! )9#75#)*! +.%! -5%)&! 4&&#69&!14)! &+! 9%#94%#! 4! J=9'+)9'50+!

4(7+'+(! .)503! ,#0K4(2#'82#! ?#9@! 4)! #(#7&%+9'5(#! ?L7'#6#! F>M4@>DEN4G

! ;'#! %#).(&503! 65B&.%#! +-!

)&#%#+5)+6#%)*! 254)&#%#+6#%)! :!;"<";!=>#?! 402! :!;!<";"=>#?*! 14)! )#94%4&#2! ,8! 7+(.60!

7'%+64&+3%49'8!4--+%2503!,+&'!254)&#%#+6#%)>!!

!

!@/6&A&$!"B!:%#94%4&5+0!+-!4!%47#657!65B&.%#!+-!254)&#%#+6#%)!+-!J=9'+)9'50+!4(7+'+(!#?"!

! O5&'!&'#!456!+-!+,&450503!40!#040&5+9.%#!J=9'+)9'50+!4(7+'+(*!&'#!65B&.%#!+-!&'#!-+.%!

)&#%#+5)+6#%)! 14)! )#94%4&#2! ,8! 9%#94%4&5$#! 7'5%4(! ).9#%7%5&574(! -(.52! 7'%+64&+3%49'8! ?LCP@*!

(#42503!&+!4!'53'(8!#--575#0&!)#94%4&5+0!?C53.%#!F>Q4@>!R9+0!)#94%4&5+0*!).5&4,(#!)503(#!7%8)&4()!-+%!

S=%48! 25--%47&5+0! 404(8)5)! 1#%#! +,&450#2! +-! +0#! +-! &'#! &1+! #040&5+6#%)! +-! #47'! 945%! +-!

254)&#%#+6#%)A! :";"=>#?! ?C53.%#! F>Q,@! 402! :!;"=>#?! ?C53.%#! F>Q7@*! ,8! )(+1! #$49+%4&5+0! +-! 4!

257'(+%+6#&'40#! )+(.&5+0>! ;'#)#! )&%.7&.%#)*! &+3#&'#%! 15&'!ME:! "TU! )9#7&%4*! 4((+1#2! .)!

2#&#%650503!&'#!4,)+(.&#!7+0-53.%4&5+0!+-!#47'!)&#%#+7#0&%#>!!

!

NN

N

P

24

Ph

O

H

25

NN

N

(S)(S)P(R)(R)

HO

Ph

NN

N

(S)(S)P(S)(S)

HO

Ph

NN

N

(R)(R)P(S)(S)

HO

Ph

NN

N

(R)(R)P(R)(R)

HO

Ph

(S,R/R,S)-2646% isolated yield

(S,S/R,R)-2641% isolated yield

1) nBuLi, rt, THF

2) aldehyde, –78 ºC, THF

100% conversion50:50 dr

!"#$%&'()*(

!

!"#$!

!!"#

$"# # %"#

&'()*+# ,-.#!"#$%&'(!)'*&!(#'+# )%,#-,.!&!)/'0#12#34$#'+#!#(/5)6&,#'+#7#-),&,'/-'(,&-# +'&#/08#,!9%#.,!:#%!-#1,,0#!--/*0,;#)%!0:-#)'#)%,#<=&!2#;/++&!9)/'0#-)&69)6&,-#!0;#)%,#>?@#ABC#-.,9)&!1#1"#<=&!2#9&2-)!D#-)&69)6&,#'+#9'(.'60;#2!3!"4/0#E,DD/.-'/;-#;&!F0#!)#)%,#GHI#.&'1!1/D/)2#D,J,DK#9"#<=&!2#9&2-)!D#-)&69)6&,#'+#9'(.'60;#2"3!"4/0#E,DD/.-'/;-#;&!F0#!)#)%,#GHI#.&'1!1/D/)2#D,J,D"L#4'&#9D!&/)2#&,!-'0-M#'0D2#%2;&'*,0-#!))!9%,;#)'#'52*,0#!0;#9!&1'0#!)'(-#!&,#-%'F0L#

N0# '&;,&# )'# !++'&;# 9%/&!D# 1/;,0)!),# @OP=1!-,;# 9'(.'60;-M# F,# ;,9/;,;# )'# .&,.!&,#

,0!0)/'.6&,#Q=!(/0'.%'-.%/0,-LR?ST#N0#!;;/)/'0M#)%/-#-9!++'D;#F'6D;#1,#J,&2#6-,+6DM#0')#'0D2#!-#

9%/&!D#D/*!0;#+'&#)&!0-/)/'0#(,)!D#9'(.D,5,-M#16)#!D-'#!-#1/+609)/'0!D#9%/&!D#'&*!0'9!)!D2-)LR?UT#

# O'#.&,.!&,#)%,-,#'.)/9!DD2#.6&,#Q=!(/0'.%'-.%/0,-M#F,#,0J/-/'0,;#)%,#!;;/)/'0#'+#@OPV

W/#)'#,0!0)/'.6&,#/(/0,-M#&,0;,&/0*#/0#)%/-#F!2#@OP#;,&/J!)/J,-#+,!)6&,;#12#!0#!(/0'#*&'6.#/0#Q#

.'-/)/'0# )'#.%'-.%'&6-L#X6&# +/&-)#!)),(.)#F!-# )'#6-,#!0#,0!0)/'.6&,#:,)/(/0,#!-#,D,9)&'.%/D,L#

O%,# .&,.!&!)/'0# '+# :,)/(/0,# /5# /0J'DJ,;# )%,# 9'0;,0-!)/'0# '+# 1,0Y'.%,0'0,# E/6"# F/)%# )%,#

!!!!!4!"# !!!!!4!"#

!!!!!4!"#!!!!!4!"#

!"#$%"%&'()*(+*)#,*#)%)&'($-"#*!./01%2#3*3#"'4%&'4#25*6(7#*%$$8'9%&'()2*')*#)%)&'(2#8#9&'4#*9%&%8:2'25*

!

! "#"!

!"#"$%&'()!* +6,-.-'/!"01!$/01#2%"!* +!",* 3#$#104!5*60* 7%819:* #;;&)5%"<* 9=>* 0%!15* &;* $/!*5!4%)!5*

3&2'&("5*+?3/!2!*9@9,@*

!#$%&'&()*)(A)!'#)#$%&"*&;*$/!*3/%)#1*B!$%2%"!(!+*(

* 7/!* #55%$%&"*&;* A7CDE%* $&* B!$%2%"!*!+* 5%5* "&$*F&)B* +?3/!2!*9@G,:* !H!"* %"3)!#4%"<* $/!*

$!2'!)#$()!*&;*$/!*#55%$%&"*+%"*3&2'#)%4&"*F%$/*$/!*')!'#)#$%&"*&;*$/!*I-'/&4'/%"&*#13&/&14,@*J$*

4!!24*$/#$*$/!*B!$%2%"!*%4*"&$*#3$%H#$!5*!"&(</*;&)*$/!*#55%$%&"*&;*A7CDE%@*J"*&)5!)*$&*!"/#"3!*

$/!*)!#3$%H%$0:*KLMNOP$=*F#4*#55!5*#4*E!F%4*#3%5*$&*$/!*)!#3$%&"*2%Q$()!*$&*#3$%H#$!*$/!*B!$%2%"!@*

R&F!H!):*F/#$*/#''!"!5*F#4*$/!*#55%$%&"*&;*KLMNOP$=*$&*A7C*+')&6#610*;&)2%"<*#*KDS*6&"5,T=UV:*

!H!"*F/!"*$/!*6&)&"*)!#<!"$*F#4*')!H%&(410*2%Q!5*F%$/*$/!* %2%"!*#"5*#55!5*$&<!$/!)*$&*$/!*

4&1($%&"* 3&"$#%"%"<* $/!* A7CDE%@* 7/!* )!#3$%&"* F#4* #14&* 3#))%!5* &($* %"* $/!* ')!4!"3!* &;* 7WPXC*

+$!$)#2!$/01!$/01!"!5%#2%"!,:* %"* &)5!)* $&* ')!H!"$* $/!* #<<1&2!)#$%&"* &;* $/!* &)<#"&1%$/%(2@*

R&F!H!):*$/!)!*F#4*"&*3&"H!)4%&"*("5!)*4(3/*3&"5%$%&"4@*

!#$%&'&()*,*C$$!2'$4* $&*')!'#)!*#*5%#4$!)!&2!)%3*2%Q$()!*&;*I-#2%"&'/&4'/%"!*-.*60*#55%$%&"*&;*A7CDE%* $&*B!$%2%"!*!+@*** J"* &)5!)* $&* !"/#"3!* $/!* )!#3$%H%$0:* F!* 5!3%5!5* $&* (4!* #* 1!44* 4$!)%3#110* 5!2#"5%"<*

!"#"$%&'()!*#15%2%"!* %"4$!#5*&;* #* B!$%2%"!:* !H!"* $/&(</* $/!*"(26!)*&;*5%#4$!)!&2!)4*F&(15*

%"3)!#4!* 5(!* $&* $/!* <!"!)#$%&"* &;* &"!* #55%$%&"#1* 4$!)!&<!"%3* 3#)6&"* 3!"$)!@* C15%2%"!*-/*F#4*

4(33!44;(110*')!'#)!5*;)&2*6!"Y#15!/05!*+!,,*#"5*$/!*!"#"$%&'()!*+6,-.-'/!"01!$/01#2%"!*+!",:*

(4%"<*W<?O9*#4*5!/05)#$%"<*#<!"$*+?3/!2!*9@Z,@*

!#$%&'&()*0(A)!'#)#$%&"*&;*3/%)#1*#15%2%"!(-/*(

Ph(S)(S)

CH3

NH2

Ph Ph

O

27 28

TiCl4

toluene, reflux24 h

Ph Ph

N(S)(S)

Ph

CH3

29

42% isolated yield

NN

N

P

24

Ph

N

Ph

29

NN

N

(S)(S)P

HN

Ph

(S,S)-30 (R,S)-30

1) nBuLi, rt, THF

2) imine, rt to 45 ºC, THF

(S)(S)Ph

CH3Ph

(S)(S)Ph

CH3

NN

N

(R)(R)P

HN

PhPh

(S)(S)Ph

CH3

Ph(S)(S)

CH3

NH2

Ph H

O

25 28

MgSO4

CH2Cl2, rt24 h

Ph H

N(S)(S)

Ph

CH3

31

99% isolated yield

!"#$%&'()*(

!

!"#$!

! !"#$ %&&'(')*$ )+$ ,!-./'$ ()$ 0"'1%2$ %2&'3'*#$ !"$ 2#&$ ()$ 2)4$ 0)*5#16')*$ 7889:;$ )<(%'*'*=$ %$

3'>(?1#$)+$8$&'%6(#1#)3#16$ 71%(')$@ABCDBAB@:$ 7E0"#3#$FGH:G$!"#$1#%0(')*$4%6$%26)$0)*&?0(#&$ '*$

("#$ I1#6#*0#$)+$ JK8LMN(C$4'("$ ("#$ %'3$)+$ #*"%*0'*=$ ("#$ 1#%0('5'(O$ ("1)?="$ /#4'6$ %0'&P%66'6(#&$

%0('5%(')*$ )+$ ("#$ #2#0(1)I"'2#G$ Q)4#5#1;$ ("#$ &#6'1#&$ I1)&?0(6$ 4#1#$ *)($ )<6#15#&;$ %II#%1'*=$

6'=*%26$'*$8R,$STU$("%($I1#6?3%<2O$0)11#6I)*&$()$("#$%&&'(')*$)+$JK8LMN(C$()$,!-G$

!#$%&'&()*+$,1#I%1%(')*$)+$%$&'%6(#1#)3#1'0$3'>(?1#$)+$VP%3'*)I")6I"'*#$!,$<O$%&&'(')*$)+$,!-./'$()$%2&'3'*#$!"G$$

$ -+(#1$ ("#6#$?*6?00#66+?2$ 1#6?2(6$?6'*=$ ("#$#*%*(')I?1#$%2&'3'*#$!"$ %*&$W#('3'*#$,-$ %6$

#2#0(1)I"'2#6$ '*$ ("#$ %&&'(')*$ )+$ ,!-./';$ 4#$ &#0'&#&$ ()$ 3)5#$ ()$ )I('0%22O$ I?1#$ +P%&'%P

<?(O26?2+'*O2W#('3'*#6G$ !"#$ +'16($ 6O*("#6'6$ )+$ +P%&'%P<?(O26?2+'*O2W#('3'*#6$ 4%6$ 1#I)1(#&$ <O$

N223%*$&%(#,-$'*$RDDDGXCRY$!"#$6?2+'*O2$=1)?I$"%6$I1)5#*$'(6$#++'0'#*0O$%6$0"'1%2$%?>'2'%1O;$<#0%?6#$)+$

<)("$ '(6$ %<'2'(O$ ()$ %0('5%(#$ ("#$ '3'*#$ 4'("$ 1#=%1&$ ()$ *?02#)I"'2'0$ %&&'(')*$ %*&$ '(6$ #%6#$ ()$ <#$

1#3)5#&$7&#I1)(#0(')*:$?*&#1$3'2&$0)*&'(')*6$<O$%0'&$(1#%(3#*(GXCCY$-2(")?="$("#$6O*("#6'6$)+$+P

%&'%P<?(O26?2+'*O2%2&'3'*#6$ '6$ 2#66$ 0"%22#*='*=$ ("%*$ ("%($ )+$ W#('3'*#6;$ 4#$ 4%*(#&$ ()$ ?6#$ %*$

#*%*(')I?1#$ W#('3'*#$ &#1'5#&$ +1)3$ ("#$ 0)*&#*6%(')*$ )+$ <#*Z)I"#*)*#$ 7,+:$ %*&$ ("#$

#*%*(')I?1#$ 7.:P%&'%P<?(O26?2+'*%3'&#$ 7!![$ E0"#3#$ FGA:;$ 4'("$ ("#$ %'3$ )+$ =#(('*=$ )*2O$ (4)$

&'%6(#1#)3#16$<O$1#%0(')*$4'("$,!-./'G$$

!#$%&'&()*.(,1#I%1%(')*$)+$0"'1%2$W#('3'*#(!)*((

NN

N

P

24

NN

N

(S)(S)P(S)(S)

HN

(S,S,S)-321) nBuLi, rt, THF

2) imine, rt, THF

33% conversion

(S)(S)Ph

CH3

Ph H

N(S)(S)

Ph

CH3

31

NN

N

(R)(R)P

HN

(R,S,S)-32

(S)(S)Ph

CH3

NN

N

(S)(S)P(R)(R)

HN

(S,R,S)-32

(S)(S)Ph

CH3

PhH

(S)(S)

PhHH

Ph

NN

N

(R)(R)P(R)(R)

HN

(R,R,S)-32

(S)(S)Ph

CH3

PhH

58:29:8:5 dr

tBuS(R)(R)

NH2Ph Ph

O

27 33

Ti(OEt)4

THF, reflux24 h

Ph Ph

NS(R)(R)

O

tBu

3461% isolated yield

O

[!]D26 = –103.9 (c 1.01, CHCl3)

!"#$%"%&'()*(+*)#,*#)%)&'($-"#*!./01%2#3*3#"'4%&'4#25*6(7#*%$$8'9%&'()2*')*#)%)&'(2#8#9&'4#*9%&%8:2'25*

!

! "#$!

! "#$!%&&'(')*!)+!,"-./'!()!(#$!0;12<2&#"&234(56746+'*568$('9'*$!!"!:;)<$$&$&!74<<$77+4665!

0=<#$9$!>?@1?!"#$!&'%7($;$)9$;'<!9'A(4;$!B%7!7$:%;%($&!35!<)649*!<#;)9%()C;%:#5D!)3(%'*'*C!

>EF!5'$6&!)+!(#$!+';7(!$64('*C!&'%7($;$)9$;!%*&!>GF!5'$6&!)+!(#$!7$<)*&!)*$?!H*+);(4*%($65D!B$!

B$;$! *)(! %36$! ()! C$(! 74'(%36$! 7'*C6$! <;57(%67! +);! I2;%5! &'++;%<(')*! %*%657'7J! (#$;$+);$D! (#$!

7($;$)<#$9'7(;5! )+! 3)(#! &'%7($;$)9$;7! '7! *)(! %77'C*$&?! K);! <6%;'(5! ;$%7)*7D! (#$! +';7(! $64('*C!

&'%7($;$)9$;!'7!C)'*C!()!3$!<%66$&D!+;)9!*)B!)*D!!#$%!%*&!(#$!7$<)*&!)*$D!!#$&?!!

!'()*+*,"-.!,;$:%;%(')*!)+!%!&'%7($;$)9$;'<!9'A(4;$!)+!L2:#)7:#'*)!746+'*%9'&$!!#!35!%&&'(')*!)+!,"-./'! ()!746+'*568$('9'*$!!"?!!

! K)66)B'*C! (#$! 7%9$! 7(;%($C5D! B$! %67)! (%<86$&! (#$! :;$:%;%(')*! )+! %*)(#$;! L2:#)7:#'*)!

746+'*%9'&$! &$;'M$&! +;)9! %*! $*%*('):4;$! <2$2()656746+'*568$('9'*$?! K);! (#'7! :4;:)7$D! B$!

:;$:%;$&! (#$! 746+'*568$('9'*$!!/! 35! <)*&$*7%(')*! )+! 3$*N):#$*)*$! 0&/1! %*&! (#$! $*%*('):4;$!

0612$2()656746+'*%9'&$!0!01!9$&'%($&!35!"'0OP(1>!0=<#$9$!>?QE1?!R9'*$!!/!B%7!'7)6%($&!'*!)*65!

STF!5'$6&!%<<)4*('*C!(#$!9)&$;%($!<)*M$;7')*!)+!(#$!7(%;('*C!9%($;'%6!0UVF1?!

!'()*+*,"-%1,,;$:%;%(')*!)+!<#';%6!8$('9'*$,!/-,

! W$M$;(#$6$77D!(#$!%&&'(')*!)+!,"-./'!()!746+'*568$('9'*$!!/!&'&!*)(!6$%&!()!(#$!$A:$<($&!

L2:#)7:#'*)! 746+'*%9'&$?! "#$! *4<6$):#'6'<! %&&'(')*! )+! (#$! );C%*)6'(#'49!&'&! *)(! )<<4;! )*! (#$!

'9'*)! C;)4:!34(! )*()! (#$! 746+'*56!9)'$(5! 07437('(4(')*! ;$%<(')*! '*M)6M'*C! *4<6$):#'6'<! %&&'(')*!

:647! $6'9'*%(')*! )+! 3$*N):#$*)*$! '9'*$1D! 6$%&'*C! ()! %*! 4*$A:$<($&! &'%7($;$)9$;'<! 9'A(4;$!

0VSXUT! &;1! )+! Y2746+'*56:#)7:#'*$! !2! 0=<#$9$! >?QQ1?! R*! (#'7! <%7$D! (#$! &'%7($;$)7$6$<('M'(5! B%7!

76'C#(65!+%M)4;%36$!()!)*$!)+!(#$!(B)!&'%7($;$)9$;7D!B#'<#!9%5!3$!&4$!()!(#$!%7599$(;'<!QDS2

'*&4<(')*!<)*(;)66$&!35!(#$!7(%;('*C!<#';%6!'9'*$?!!

Ph Ph

NS(R)(R)

O

tBu

34

NN

N

P

24

NN

N

(S)(S)P

HN

Ph

(S,R)-35 (R,R)-35

1) nBuLi, rt, THF

2) imine, rt, THF

40% isolated yield (first eluting diastereomer) 35-147% isolated yield (second eluting diastereomer) 35-2

Ph

S(R)(R)O

tBu

NN

N

(R)(R)P

HN

PhPh

S(R)(R)O

tBu


S(S)(S)

Ph Ph

O

27 36

Ti(OEt)4

CH2Cl2, reflux48 h

28% isolated yield

O

NH2

H3CPh Ph

NS(S)(S)O

CH3

3736% conversion

!"#$%&'()*(

!

!"#$!

! "#$!%&''$($)*!+$#,-&./(!.+0$(-$%!/0&)1! *#$!$2*.3430/3'&)43&5&)$! &)! 6.57,(&0.)!8&*#! *#$!

%&'%2+/*430/3'&)43&5&)$! #,0! +$$)! ,3($,%4! ($7.(*$%! &)! *#$! 3&*$(,*/($! '.(! ($3,*$%! &5&)$09:;<=! >)!

1$)$(,3?! *#$! ,%%&*&.)! .'! .(1,).5$*,33&6! ($,1$)*0! *.! 0/3'&)43&5&)$0! 6./3%! 1&-$! *8.! %&''$($)*!

)/63$.7#&3&6! ,**,6@0! %$7$)%&)1! .)! *#$! A(&1),(%! ($,1$)*?! ($0/3*&)1! .)! *#$! '.(5,*&.)! .'! *#$!

0/+0*&*/*&.)! 7(.%/6*! .(! *#$! ,%%&*&.)! 7(.%/6*9!B#&3$! *#$! %&'%2+/*43! 1(./7! %.$0! ).*! 7$(5&*! *#$!

0/+0*&*/*&.)!7(.%/6*!,*!*#$!0*$($.1$)&6!0/37#/(!,*.5!+$6,/0$!.'!&*0!0*$(&6!#&)%(,)6$?!*#$!$2*.343!

1(./7!.''$(0!3$00!0*$(&6!&57$%&5$)*!,)%!)/63$.7#&3$0!,($!,+3$!*.!,**,6@!*#$!0/37#/(!,*.5!3$,%&)1!

*.! *#$! 0/+0*&*/*&.)! 7(.%/6*?! ,0!8$! .+0$(-$%9! ! C.*#! %&,0*$($.5$(0!8$($! 0$7,(,*$%! +4! 6.3/5)!

6#(.5,*.1(,7#4! &0.3,*&)1! *#$5! &)! 3.8!4&$3%! D;<E!.'! *#$! '&(0*!$3/*&)1!%&,0*$($.5$(!,)%!F;E!.'!

*#$! 0$6.)%! .)$G9! "#$! 6.)-$(0&.)! .'! *#&0! ($,6*&.)! 8,0! &)6.573$*$! D,(./)%! HIEG! ,)%! 8$!

($6.-$($%!/)($,6*$%!&5&)$!73/0!+$)J.7#$).)$9!"#$!0*$($.6#$5&0*(4!.'!+.*#!%&,0*$($.5$(0!8,0!

).*! ,00&1)$%9! C,0$%! .)! *#$! 3&*$(,*/($! 7($6$%$)*0?:;K=! 8$! 7(.7.0$! *#,*! *#$! )/63$.7#&3&6!

0/+0*&*/*&.)! ($,6*&.)! .66/(0!8&*#! &)-$(0&.)! .'! 0*$($.6#$5&0*(4! ,*! *#$! 0/37#/(! 0*$($.6$)*($9! >)!

*#&0! 6,0$! *#$! ,+0.3/*$! 6.)'&1/(,*&.)! .'! *#$! 0/37#/(! ,*.5! ($5,&)0! +! %/$! *.! ,! 6#,)1$! &)! *#$!

7(&.(&*4!.'! *#$!0/+0*&*/$)*0!,66.(%&)1! *.!L,#)2>)1.3%2M($3.1! DL>MG! (/3$09!N.(!63,(&*4! ($,0.)0?! *#$!

'&(0*!$3/*&)1!%&,0*$($.5$(!&0!1.&)1!*.!+$!6,33$%?!'(.5!).8!.)?!!"#$!,)%!*#$!0$6.)%!.)$?!!"#%9!!

!&'()*)+ ,-$$! M($7,(,*&.)! .'! ,! %&,0*$($.5$(&6! 5&O*/($! .'! P20/3'&)437#.07#&)$! !"! +4! ,%%&*&.)! .'! M"QRS&! *.!0/3'&)43@$*&5&)$!!.9+

! Q3*#./1#!6.57./)%!!"!8,0!/)$O7$6*$%?!8$!0#./3%!,30.!7,4!,**$)*&.)!*.!&*!+$6,/0$!.'!&*!

&0! ,! -$(4! &)*$($0*&)1! 6#&(,3! M"Q2%$(&-,*&-$?! 8#&6#! 6./3%! +$! /0$%! ,0! 3&1,)%! '.(! *(,)0&*&.)!5$*,3!

6.573$O$09! P2T/3'&)437#.07#&)$0! 6,)! ,6*! ,0! +&%$)*,*$! 3&1,)%0! *#(./1#! *#$! 7#.07#.(/0! ,)%!

.O41$)! ,*.509!U.($.-$(?! *#$! ,%%&*&.),3! 0*$($.1$)&6! 6,(+.)! 6$)*($! 6./3%!#$37! *.! &)6($,0$! *#$!

$),)*&.0$3$6*&-&*4! ($1,(%&)1! ,773&6,*&.)0! &)! ,0455$*(&6! 6,*,340&09! >)! 07&*$! .'! *#$! )/5$(./0!

3&*$(,*/($! ($7.(*0! .)! *#$! /0$! .'! 7#.07#&)$20/3'.O&%$0! ,0! 3&1,)%0! '.(! 5,)4! 5$*,325$%&,*$%!

Ph Ph

NS(S)(S)O

p-Tol

37

NN

N

P

24

NN

N

(S)(S)P S(S)(S)O

(S,S)-38 (R,S)-38

1) nBuLi, rt, THF

2) sulfinylimine, rt, THF


p-TolN

NN

(R)(R)P S(S)(S)O

p-TolPh Ph

NH

benzophenone imine detected in the reaction mixture


p-Tol = 4-Me-C6H4

NN

N

(S)(S)P

HN

PhPh

S (S)(S)O

p-Tol

NN

N

(R)(R)P

HN

PhPh

S(S)(S)O

p-Tol

!"#$%"%&'()*(+*)#,*#)%)&'($-"#*!./01%2#3*3#"'4%&'4#25*6(7#*%$$8'9%&'()2*')*#)%)&'(2#8#9&'4#*9%&%8:2'25*

!

! "#$!

!"#$%&'"(#!)'$%*+,-./%0#"01/12#(341%/51#4/6)!7/89%:4&)$;437'%37)$1/51")<#!)<1%*+,=./%'(1/'&/!71(/

3"'!10!15/#%/37'%37)$19>'"#$1/#55:0!%?/

/ @)!7/ !71/ #)(/'&/ )(3"'<)$A/ !71/ %;$!71%)%/ '&/ 89%:4&)$;437'%37)$1/!"*/61/510)515/ !'/ :%1/

0'((1"0)#44;/ #<#)4#>41/ #$5/ 1$#$!)'3:"1/ BC;*,6<-;D9(1$!7;4/ B6D9$9!'4:1$1%:4&)$#!1/ B!#D/ B#4%'/

E$'6$/#%/F$51"%1$/"1#A1$!D+,G./)$%!1#5/'&/!71/%:4&)$;4E1!)()$1/!$/#%/1410!"'37)41?/H71/#55)!)'$/'&/

IHFJK)/ 6':45/ 3"'0115/ $101%%#")4;/ '$!'/ !71/ %:4&)$#!1/ A"':3*/ !7:%/ A1$1"#!)$A/ (1$!7'4/ #%/

0'$0'()!#$!/ 3"'5:0!?/ L'61<1"*/61/ '>!#)$15/ !71/ %#(1/ "1#0!)<)!;/ !7#$/ !7#!/ :%)$A/!$*/ >:!/6)!7/

7)A71"/ 5)#%!1"1'%1410!)<)!;/ BGMN,C/ 5"D*/ 67)07/ (#;/ >1/ 5:1/ !'/ !71/ #%;((1!")0/ C*,9)$5:0!)'$/

0'$!"'4415/>;/!71/%!#"!)$A/07)"#4/%:4&)$#!1?/O$/!7)%/0#%1/!71/0'$<1"%)'$/B"1#0!)'$/('$)!'"15/>;/PCI/

QRSD*/ 6#%/ #4%'/ )$0'(341!1/ B-TUD/ &)$5)$A/ :$"1#0!15/ (1$!7;4/ $9!'4;4%:4&)$#!1/ )$/ !71/ 0":51/

()2!:"1?/

!%&'()(* +,-.! I"13#"#!)'$/ '&/ #/ 5)#%!1"1'(1")0/ ()2!:"1/ '&/ 89%:4&)$;437'%37)$1/ !"/ >;/ #55)!)'$/ '&/ IHFJK)/ !'/BC;*,6<-;D9(1$!7;4/B6D9$9!'4:1$1%:4&)$#!1/B!#D?/*

O$/'"51"/!'/51!1"()$1/!71/#>%'4:!1/0'$&)A:"#!)'$/'&/1#07/5)#%!1"1'(1"*/61/!")15/!'/A1!/

%)$A41/0";%!#4%/&'"/V9"#;/5)&&"#0!)'$/#$#4;%)%?/F0!:#44;*/61/%:0011515/!'/'>!#)$/%:)!#>41/0";%!#4%/'&/

!71/ &)"%!/ 14:!)$A/ 5)#%!1"1'(1"?/ W:"3")%)$A4;*/ !71/ %'4<15/ 0";%!#4/ %!":0!:"1/ "1<1#415/ :%/ #$'!71"/

0'(3':$5/ BX)A:"1/ Y?=#D?/ H71/ '2;A1$/ 6#%/ !"#$%&1""15/ &"'(/ %:437:"/ !'/ 37'%37'":%*/ ;)145)$A/ #/

!7)'1!71"/ 37'%37)$1/ '2)51/ B+/D?/ O$/ #55)!)'$*/ +// 0";%!#44)%15/ )$/ #/ 01$!"'%;((1!")0/ A"':3/ #%/ #/

"#01()0/0'(3':$5/BX)A:"1/Y?=>D?/O$0'$%)%!1$!4;*/!71/(1#%:"1(1$!/'&/!71/'3!)0#4/"'!#!)'$/'&/!71/

%)$A41/0";%!#4%*/)((15)#!14;/#&!1"/!71/V9"#;/0";%!#44'A"#37;*/A#<1/#/<#4:1/5)%!)$0!/!'/Z1"'/B+8.[,=/\/

J,M?P/B9*C?]]*/^L^4PDD?/

/

p-TolS(S)(S)O

39

NN

N

P

24

NN

N

(S)(S)P S(S)(S)O

(S,S)-38 (R,S)-38

1) nBuLi, rt, THF

2) menthyl sulfinate, rt, THF


p-Tol

NN

N

(R)(R)P S(S)(S)O

p-Tol

menthol detected in the reaction mixture


O

CH3

CH3H3C

HO

CH3

CH3H3C

!"#$%&'()*(

!

!"##!

!"!

#

!

$"#

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NN

N

P SO

CH3

40

2!"# 2""#

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&,'.1&!6'5)-!'-!S+,)*)!T8ITU!1/!)-&%0)!.%##!+/-5)0&'/-!/.!)$+,!&1)28!

NN

N

P S p-Tol

O

40

NN

N

P SO

38

p-Tol

NN

N

PSO p-Tol

NN

N

P S+O

38'

p-Tol

zwitteronic1,2,3-thiaoxaphosphetane

NN

N

P

NH2

PhPh*

O

R'R

O

R' R

!"#$%&'()*(

!

!"#$!

!!"#$%$& '()'&!"#$%&'()(*+$, "-+./.0+, (1, *2+, %&'%%34*5-64-1#75-, .48#-#.'5, 0'(4&, 96*+&, .:, .7$, 6436+;4+7*, 3.6#",*'+.*)+7*,46#70,<=%>?@,.6,3.6+,96*+&,3:A,?+-(B,+."2,"()&(47$C,DE<,FGH,9EIJ,GKLC,#7,M>M-D:,"2+)#".-,62#1*6,.'+,#7$#".*+$A,

F+/+'*2+-+66C, .-*2(402, *2+, "(7/+'6#(7, B.6, "()&-+*+C, B+, "(4-$, 7(*, 0+*, *2+, &'#).'5,

.)#7(&2(6&2#7+,'*,"()&-+*+-5,&4'+A,G#7(',#)&4'#*#+6,B+'+,.-B.56,1(')+$,#7,3(*2,6*+&6A,!1*+',

&4'#1#".*#(7, 35, "(-4)7, "2'().*(0'.&25C, *2+, 25$'("2-('#$+, 6.-*, ')C, .6, B+--, .6, *2+, &'#).'5,

.)#7(&2(6&2#7+,'*C,B+'+,*'.761(')+$,#7*(,*2+6+,#)&4'#*#+6C,.7$,B+,B+'+,.3-+,*(,#6(-.*+,(7+,(1,

*2+)A,N2#6,&'($4"*,B.6,14--5,"2.'."*+'#6+$,.6,"()&(47$,'+&9O#04'+,PAQ:C,#7,B2#"2,*2+,<N!,".0+,#6,

(&+7+$,9&'(3.3-5,$4+,*(,*2+,."#$#",)+$#4):C,.7$,.,146+$,J%#)#$.L(-#7+,'#70,#6,1(')+$A,,

!,-./0$&'(1&FGH,6#07.-6,(1, *2+,.)#7+,'*,.7$,*2+,35%&'($4"*, 1(')+$, #7,."#$,)+$#4),9'+:A,FGH,6&+"*'.,B+'+,'+"('$+$,#7,M>M-DA,M2+)#".-,62#1*6,0#/+7,#7,&&),.7$,"(4&-#70,"(76*.7*6,0#/+7,#7,KLA,,! R+,*'#+$, *(, '.*#(7.-#6+,2(B,6#$+,&'($4"*,'+, "(4-$,3+, 1(')+$C, #7,('$+', *(, #)&'(/+, *2+,

657*2+6#6, (1, *2+, $+6#'+$, .)#7(&2(6&2#7+, 9'*:A, N2+, 146+$, J%#)#$.L(-#$#7+, '#70, 1(')+$, #7,

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.)#7(&2(6&2#7+, )(-+"4-+C, .6, B+, &'(&(6+, #7, *2+, 1(--(B#70, )+"2.7#6), 9="2+)+, PAES:A, !"#$#",

"(7$#*#(76,.'+,'+;4#'+$,*(,&'()(*+,*2+,"-+./.0+,(1,*2+,%&'%%34*5-64-1#75-,0'(4&,#7,"()&(47$,+2C,

.7$,47$+',64"2,"(7$#*#(76C,*2+,&'#).'5,.)#7(&2(6&2#7+,'+).#76,&'(*(7.*+$,9'):A,N2+,.7.-56#6,

35,H<%K<TM%G=,(1,*2+,&'(*(7.*+$,&'#).'5,.)#7(&2(6&2#7+,9'):,6++)6,*(,3+,#7,.0'++)+7*,B#*2,

.,)(7(%&'(*(7.*+$,6&+"#+6A,U1,*2+,&'(*(7.*#(7,(""4'6,#7,(7+,(1,*2+,*2'++,7#*'(0+7,.*()6,(1,*2+,

NN

N

P

HN

Ph

35-1

Ph

S(R)(R)O

tBua) HCl

(4 M in 1,4-dioxane)

MeOH, 0 °C, 3 hN

NN

P

H2N

PhPh

41

b) PS-DBU

CH2Cl2/MeOH 1:1rt, 4 h

NN

N

P

NH2

PhPh

42

–97.5 ppm –87.0 ppm –94.4 ppm

!HCl

* * *

NN CH3

N

P

43

N

PhPh

! = –70.3 (31P)

! = 7.87 (1H)! = 155.5 (13C)

! = 2.06 (1H)! = 44.9, d, 3JC-P = 2.2 (13C)

IR (neat): " = 1597 cm-1 (C=N)MS (ESI+): m/z = 351 [M+H]

NN

N

P

NH2

PhPh

42

! = –94.4 (31P)

! = 4.55 (1H)! = 66.5, d, 1JC-P = 25.8, (13C)

! = 5.12, d, 2JH-P = 20.4 (1H)! = 64.8, d, 1JC-P = 33.8 (13C)

H

* *

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43

NN

N

P

HN

PhPh

35

+ HClN

NN

P

NH2

PhPhCl

HNN

N

P

NH2

PhPh

ClN

NN

P

NH2

PhPh

NN

N

PNH2

PhPh

HNN

N

P

NH2

PhPhCl

NN

N

PNH2

PhPh

HNN

N

P

NH2

PhPh

hydrolysis

NN

N

PPh

NH2

Ph

O

H

NN

N

PN

PhPh

H

Cl1,3-hydrogen

migration

H

protonation

41

ring-opening

IN-alkylation

IIH HH

HH H

III

H

H H

IV

– H2O

HNHN

N

P

NH2

PhPh

IV'

ring closureH

H H

S(R)(R)OtBu

*

Cl tBu

O

MeO tBu

O+MeOH

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NN

N

P

NH2

PhPh

42

CF3

CF3

SCN

44

NN

N

PPh

Ph

SNHHN

F3C

CF3

45

CH2Cl2, rt, 24 h

complex reaction mixture7% isolated yield

* *

!"#$%&'()*(

!

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(&'"7/$"7&:!

R

X

R'

R = alkyl, aryl, heteroaryl, etc.; R' = H, CO2R'', alkyl, aryl etc.

EWG

EWG = CO2R'', CN, COR'', CHO, PO(OEt)2, SO2Ph, SO3Ph, SOPh, etc.

P- or N-based catalyst EWG

XH

R

X = O, NCO2R'', NSO2Ar, NPOR2'' etc.

R'

R3EE = N, P

O

X

a) Morita-Baylis-Hillman reaction

b) Generally accepted mechanism with aldehydes

O

XR3EMichael addition

aldolreaction

R'CHO

O

XR3E

O R'proton shift

O

XR3E

HO R'

elimination

V VI

VIIVIII

OH

R' X

O

*

*

!"#$%"%&'()*(+*)#,*#)%)&'($-"#*!./01%2#3*3#"'4%&'4#25*6(7#*%$$8'9%&'()2*')*#)%)&'(2#8#9&'4#*9%&%8:2'25*

!

! "#$!

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! 5?&!(')'-.)*(!'/.@@&)%*(!;+%@')*+,!+;!':*%*0*,&/!%&2%&/&,)/!'!(?'--&,A*,A!',0!'))%'()*8&!

)'%A&)9!5?&!*,)%*,/*(!%*,A7/)%'*,!+;!)?&/&!/@'--!?&)&%+(.(-&/!@'B&/!)?&@!8&%/')*-&!(?*%'-!13*-0*,A!

1-+(B/! *,! +%A',*(! /.,)?&/*/9! 5?&! ;*%/)! 2%+)+(+-/! ;+%! )?&! &,',)*+/&-&()*8&! /.,)?&/*/! +;! ':*%*0*,&/!

(+,/*/)&0! *,! )?&! 3/&! +;! (?*%'-! /31/)%')&/! +%! (?*%'-! '3C*-*'%*&/9DEEF! 6/.@@&)%*(! 2%+)+(+-/! 3/*,A!

+%A',+@&)'--*(!(')'-./)/!?'8&!1&&,!'-/+!G*0&-.!3/&0!4'%!,*)%+A&,!)%',/;&%!)+!+-&;*,/!',0!'-/+!4'%!

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%&2+%)&0! ;+%! )?&! ;*%/)! )*@&! )?&!3/&!+;! (?*%'-! '@*,&/! )+!2%+8*0&! /*@2-&!'/.@@&)%*(! '((&//! )+!O7

;+%@.-':*%*0*,&/! ;%+@! <=>73,/')3%')&0! '-0&?.0&/! ',0! P7'(.-')&0! ?.0%+C.('%1'@')&/! QR(?&@&!

E9ST'U9! 5?&.! 2%+2+/&0! '! %&'()*+,! 2')?G'.! QR(?&@&! E9ST1U! *,! G?*(?! )?&! ;*%/)! /)&2! */! )?&!

;+%@')*+,!+;!'!(?*%'-! *@*,*3@! *,)&%@&0*')&! Q+,U!1&)G&&,!)?&!'-0&?.0&!',0! )?&!+%A',+(')'-./)9!

#3-B.!A%+32/!*,!)?&!(')'-./)!(+,)%+-!)?&!/)&%&+/&-&()*8*).!+;!)?&!,3(-&+2?*-*(!'))'(B!1.!)?&!'@*,+!

A%+32=! A&,&%')*,A! '! (?*%'-! &,'@*,&! *,)&%@&0*')&! Q,U9! 5?*/! *,)&%@&0*')&! (',! ('%%.! +3)! '!

,3(-&+2?*-*(! '))'(B! +,! )?&! &-&()%+2?*-*(! ,*)%+A&,! ')+@! %&-&'/*,A! )?&! -&'8*,A! A%+329! 5?&!

&,',)*+23%&!':*%*0*,&!*/!+1)'*,&0!1.!?.0%+-./*/!+;!*,)&%@&0*')&!,+9!

O

H

PTA-basedorganocatalyst (15 mol%)

O2N

Me

O

46 47

O

Me

48

OH

O2N

*THF, rt

NN

N

(S)(S)P(S)(S)

HO

Ph

(S,S)-2635-2

NN

N

P

HN

PhPh

S(R)(R)O

tBu

NN

N

P

Lit. 1 h, 82% yield

17 h, 55% conv.5% ee

17 h, 96% conv.9% ee

NN

N

(S)(S)P(R)(R)

HO

Ph

(S,R)-26

17 h, 90% conv.rac

*

!"#$%&'()*(

!

!"#$!

!!"#$%$&'()*!"#!$%&%'"(!)*+%,%!-.!-'/"&-*"0"(1)%2!"34'424&"04-&!'%"*04-&5!6#!7'-8-)%2!'%"*04-&!8"0+9"1:!

! ;40+!0+%)%!8'%*%2%&0)! 4&!,4&2<!9%!9"&0%2!0-!0%)0!-='!%&"&04-8='%!7>?!*-,8-=&2)!")!

-'/"&-*"0"(1)0)!4&!0+%!"34'424&"04-&!'%"*04-&!6%09%%&!0+%!%'#+,@A@+%B%&"(!C'*#!"&2!0+%!%&'%@6=01(!

-@C0-)1(-B1#*"'6","0%! C+,#! CD*+%,%!E:AF#:! G-&H%')4-&)! "&2!%&"&04-)%(%*04H404%)!9%'%! H%'1! (-9!

=)4&/!0+%!%&'%@6=01()=(.4&1(!7>?!2%'4H"04H%!-+.)&-'!0+%!+12'-*+(-'42%!)"(0!')!4&!0+%!8'%)%&*%!-.!"&!

%B*%))!-.!6")%!C.+(,.%/!/%&%'"04-&!-.!!0+%!8'4,"'1!",4&%#:!

!!"#$%$&'(/,!?3424'4&"04-&!'%"*04-&!*"0"(13%2!61!%&"&04-8='%!7>?@6")%2!2%'4H"04H%):!

R H

O

PGHN

LG

PG = Boc, Cbz, TsLG = OAc, OTs

NH

R H

ON

PG

a) Organocatalysed aziridination reaction from !,"-unsaturated aldehydes

b) Proposed reaction pathway

N

R

PGHN

LG

N

RNLGPG

N

RN

NH

R H

O

IX X

XI

R H

ON

PG

intramolecular ring closure

PG

hydrolysis

aza-Michael reaction

Ar

OSiR'3Ar

Ar OSiR'3Ar

Ar OSiR'3Ar

Ar OSiR'3Ar

ArOSiR'3Ar

H

O

BocHN

OTs

PTA-based organocatalyst (10 mol%) N

(S)(S)

(R)(R)

Boc

H

ON

(S)(S)

(S)(S)

Boc

H

O

trans-51 cis-51CH2Cl2, rt, 24 h

NN

N

P

HN

Ph

35-1

Ph

S(R)(R)O

tBu

3 equiv. NaOAc5% conv., 87:13 trans/cis

8% ee

NaOAc

NN

N

P

H2N

PhPh

41

!HCl

5 equiv. NaOAc18% conv., 77:23 trans/cis

3% ee

49 50

**

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!

! "#$!

!"#$%&'(%)&*+,'-(%)&**

* ./,* '01$$,(+%-* !"'$%&'(%)&* )2* '34,/14,056789* :,()&,067;9* '&4* ,0(,+0567<9* %0* '* =)>,+2?3*

$,(/)4* ()* )@('%&* !"'$%&)* '-%405* >/%-/* +,=+,0,&(* 2?&4'$,&('3* @?%34%&A* @3)-:0* 2)+* (/,*

-)&0(+?-(%)&* )2* -)$=3,B* &'(?+'3* =+)4?-(0* '&4* @%)'-(%C,* $)3,-?3,0D* E'0%-'3315* (/,* +,'-(%)&*

-)&0%0(0* )2* '&* ,&)3'(,* F(/,* ,&)3%0'(%)&* =+)-,00* %0* =+)$)(,4* @1* '* -'('310(G* +,'-(%&A* >%(/* '&*

,3,-(+)=/%3%-*&%(+)A,&*0)?+-,5*?0?'331*'&*'H)4%-'+@)B13'(,*+,'A,&(*FI-/,$,*7DJKGD**

!!"#$%$&'()*&L,&,+'3*+,'-(%C%(1*='((,+&*)2*!"'$%&'(%)&*+,'-(%)&0D&

M)-?0%&A*(/,*'((,&(%)&*)&*(/,*!"'$%&'(%)&*)2*N":,()*,0(,+05*(/%0*(+'&02)+$'(%)&*/'0*@,,&*

>%4,31* ,B=3)+,45* ?0%&A* @)(/* )+A'&)-'('310(0* '&4* $,('3"@'0,4* -'('310(0D6OP9* QR+A,&0,&* #&* %856OK9*

+,=)+(,4* 2)+* (/,* 2%+0(* (%$,* (/,* ,&'&(%)0,3,-(%C,* !"'$%&'(%)&* )2* N":,()* ,0(,+0* >%(/*

'H)4%-'+@)B13'(,0* -'('310,4* @1* -/%+'3* -)==,+FSSGT@%0)B'H)3%&,* -)$=3,B,0* FI-/,$,* 7DJJGD* ./,*

+,'-(%)&* $)0(* 3%:,31* =+)-,,40* (/+)?A/* '* -)$=3,B* %&* >/%-/* (/,* 4%0()+(,4* 0U?'+,* =3'&'+* V?FSSG*

-,&(+,* %0* -/,3'(,4* ()* (/,*N":,()*,0(,+*,&)3'(,D*./,*,3,-(+)=/%3%-*'(('-:*)2* (/,*'H)4%-'+@)B13'(,*

)--?+0*)&()*(/,*3,00*/%&4,+,4*2'-,*)2*(/,*-)==,+FSSG*,&)3'(,D*M+)$*(/,*)(/,+*/'&45*(/,*A+)?=*)2*

QR+A,&0,&* 4,C,3)=,4* '30)* (/,* 2%+0(* )+A'&)-'('310,4* !"'$%&'(%)&* )2* N":,()* ,0(,+0* ?0%&A* '*

U?%&%4%&,"4,+%C,4* '3:'3)%4* FN"%0)-?=+,%4%&,5* N"SVWG* FI-/,$,* 7DJJGD6OJ9* #3(/)?A/* (/,* '?(/)+0* 4%4*

&)(*=+)C%4,*$,-/'&%0(%-*0(?4%,05* (/,1*0?==)0,4*(/'(*'&*,&)3'(,*-)&('%&%&A*'*-/%+'3*'$$)&%?$*

FN"SVW"XYG*-)?&(,+*%)&*%0*'*3%:,31*%&(,+$,4%'(,D**

!!"#$%$&'())*!"#$%&'(%)&*)2*N":,()*,0(,+0*-'('310,4*@1*'*V?"@'0,4*-)$=3,B*)+*'&*)+A'&)-'('310(*F!"SVWGD**

#2(,+*(/,0,*(>)*2%+0(*+,=)+(,4*,B'$=3,0*?0%&A*'*$,('3"*)+*'&*)+A'&)"@'0,4*-'('310(5*)(/,+*

,22%-%,&(*-'('31(%-*010(,$0*/'C,*@,,&*4,0-+%@,4*%&*(/,*3%(,+'(?+,D6OZ9*[,*>'&(,4*()*,C'3?'(,*)?+*

R1R2

O catalyst-promoted enolisation

R1R2

O N NR3

R3

R1R2

ONNH

R3R3*

Hcat.

R1R2

O

N NR4

R4R1

R2

ON*

Cu

O

N N

OMe Me

TfO OTf

O

OR3

cat.

CO2R3

NHR4

R4

Cu(II)-bisoxazoline complex

NH O

N

H

!-ICD

Ph Ph

OH

!"#$%&'()*(

!

!"#$!

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1)5,!13,-,49.-.:$ ;1-2$ 3,-,49-*3$ .9.-"8.$ #")"$ -".-"($ *!$ -2"$ <=,8*!,-*1!$ 1>$ "-294$ ?=

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A!$B$#,.$10-,*!"($ *!$ 41#$9*"4($,.$,$ ),3"8*3$8*@-6)"/$6.*!5$ -2"$ %&'%=06-94.64>*!94$%&'$(")*+,-*+"$

#!%&$,.$1)5,!13,-,49.-$AD32"8"$E:?F,B:$G1!+").*1!.$#")"$2*52")$09$,((*!5$3177")AHHB$-)*>4,-"$,.$

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01-2$3,.".$AD32"8"$E:?F0B:$

!()*+,+'$-"#',B$L)5,!13,-,49."($<=,8*!,-*1!$6.*!5$#!%&$,.$1)5,!13,-,49.-I$0B$G6=3,-,49."($<=,8*!,-*1!$6.*!5$

#!%&$,!($#!%"$,.$4*5,!(.:$$

'((*-*1!$1>$-")8*!,4$,4M9!".$-1$*.,-*!.$

$ N634"172*4*3$ ,((*-*1!.$ -1$ -2"$ G=F$ 3,)01!94$ 5)167$ 1>$ *.,-*!.$ -1$ 10-,*!$ F=.60.-*-6-"($ F=

29()1@9=?=1@*!(14"$ .3,>>14(.$ ,)"$ +")9$ 6.">64$ )",3-*1!.$ (6"$ -1$ -2"$ 7)"."!3"$ 1>$ -2"."$81-*>.$ *!$

!,-6),4$ 7)1(63-.$ ,!($ ()65$ 3,!(*(,-".:OPEQ$ L!"$ 1>$ -2"."$ *!-")".-*!5$ -),!.>1)8,-*1!.$ *.$ -2"$

,4M9!94,-*1!$1>$*.,-*!.$-1$,>>1)($F=,4M9!94=F=29()1@9=?=1@*!(14".:$$N1!=,.988"-)*3$+").*1!.$2,+"$

O

CO2Et N NBoc

Boc

PTA-based organocatalyst (5 mol%)

NN

N

P

HN

Ph

35-1

Ph

S(R)(R)O

tBu

45 % conv., rac

toluene, rt

O

CO2EtN

HN Boc

Boc*

O

CO2Et N NBoc

Boc

PTA-based ligand (5.5 mol%)

CH2Cl2, rt

O

CO2EtN

HN Boc

Boc*

Cu(OTf)2 (5 mol%)

NN

N

P

HN

Ph

35-1

Ph

S(R)(R)O

tBu

82% conv., 13% ee (R)

35-2

NN

N

P

HN

PhPh

S(R)(R)O

tBu

74% conv., 11% ee (R)

a)

b)

52 53 54

52 53 54

*

* *

!"#$%"%&'()*(+*)#,*#)%)&'($-"#*!./01%2#3*3#"'4%&'4#25*6(7#*%$$8'9%&'()2*')*#)%)&'(2#8#9&'4#*9%&%8:2'25*

!

! "##!

!""#$%"&"'()"%$*+,#-$%,"./0'$1,#234556$*+,#-$!,+7;7/"."8(202',2$298!"#"7%"8,&"%$+,'&"8$2(:)'";"+$

9+$29.9'0+.+45<6$(8$,#&('&,#-$9$=*>?@AB$CD3E7%,919!,202'(45FGFH6*#%"27I7"#"J$+0+.":$9+$29.9'0+.F45I6$

K"80$8"2"#.'03$./"$"#9#.,(+"'"2.,&"$&"8+,(#$(L$./,+$.89#+L(8:9.,(#$M9+$)*!',+/"%$ ,#%")"#%"#.'0$

!0$N,*$#&*%8F45E6$9#%$O*($#&*%8545P6$Q/"$-8(*)$(L$N,*$8")(8."%$./9.$./"$+0+.":$=*>?2/,89'$-*9#,%,#"$

)8(&,%"+$9#$"LL,2,"#.$8(*."$.($./"+"$"#9#.,(:"8,29''0$"#8,2/"%$)8()98-0',2$9'2(/('+F$R#$./"$(./"8$

/9#%3$ ./"$-8(*)$(L$O*($*+"%$9$2(:!,#9.,(#$(L$=*>$9#%$9$2/,89'$)/(+)/,#"$ ',-9#%$.($9LL(8%$./"$

+9:"$2'9++$(L$2(:)(*#%+$CS2/":"$GFTGJF$

!!"#$%$&'()'&U'V0#0'9.,(#$(L$,+9.,#+$*+,#-$=*>$9#%$9$2/,89'$)/(+)/,#"$8")(8."%$!0$O*($#&*%8545P6&

$ W(''(M,#-$ ./"$ M(8V$ (L$ O*($ #&* %853$ M"$ %"2,%"%$ .($ ."+.$ ./"$ )"8L(8:9#2"$ (L$ (*8$ 2/,89'$

)/(+)/,#"+$9+$ ',-9#%+$ ,#$ ./,+$9+0::".8,2$ .89#+L(8:9.,(#$ CS2/":"$GFT5JF$ >#$9$ L,8+.$9..":).3$ ./"$

8"92.,(#$!".M""#*;7!"#10',+9.,#$ C**J$ 9#%$)/"#0'92".0'"#"$ C+,J$ *+,#-$ ./"$ &#"&7!*.0'+*'L,#0'$ XQU$

,*-)$9+$',-9#%$%,%$#(.$M(8VF$>#$(8%"8$.($,#28"9+"$./"$8"92.,&,.03$;7!"#10',+9.,#$M9+$L*#2.,(#9',+"%$

M,./$9$=WY$-8(*)$C2(:)(*#%$*.JF$>#$./,+$29+"3$*+,#-$./"$+9:"$XQU$%"8,&9.,&"$,*-)$9+$2/,89'$',-9#%$

./"$ 8"92.,(#$ %,%$ #(.$ M(8V$ #",./"8F$ Z(M"&"83$ ./"$ ,*-+$ %,9+."8"(:"8$ '"%$ .($ 9$ /,-/$ 2(#&"8+,(#$

C<<[J3$!*.$*#L(8.*#9."'0$./"$)8(%*2.$M9+$892":,2F$

!!"#$%$&'()*$U'V0#0'9.,(#$(L$,+9.,#+$*+,#-$./"$%,9+."8"(:"8+$(L$,*$9+$2/,89'$',-9#%+F$

!

N

O

O

R1

R2 R3

CuI (5 mol%)ligand (6 mol%)

Et3N (2 equiv.)tBuOMe, 40 ºC

NO

R1

*

PPh2

NH

ONH

BnTs

ligandup to 99% yieldup to 94% ee

HO

R3

R2

NO

Bn

*HO

Ph

N

O

O

Bn

Ph

CuI (5 mol%)PTA-based ligand (6 mol%)

Et3N (2 equiv.)tBuOMe, 40 ºC, 24 hR

55, R = H56, R = CF3

13 57, R = H58, R = CF3

NN

N

(S)(S)P

HN

Ph

35-1

Ph

S(R)(R)O

tBu

35-2

NN

N

(R)(R)P

HN

PhPh

S(R)(R)O

tBu

57

35-2, no reaction

58

35-2, no reaction35-1, 66% conv., rac

R

NO

Bn

*HO

Ph

H

NO

Bn

*HO

Ph

CF3

!"#$%&'()*(

!

!"#$!

!"#$%&%$'()%*+%,++-.%/012-3$%(4/(4#+)5)*42+

+ 6*+ (74+ 8'2(+ "4'$29+ &%$%*-/%*(')*)*:+ 5%84/;842+ 7'<4+ &4/%54+ <4$"+ )*(4$42()*:+ )*+ (74+

37'$5'/4;()/'8+ 24/(%$=+ >'$()/;8'$8"9+ 4*'*()%3;$4+ ?-'5)*%+ &%$%*)/+ '/)#2+ '*#+ 42(4$2+ 7'<4+ &44*+

;24#+'2+3%(4*()'8+4*@"54+)*7)&)(%$2+'*#+(74$'34;()/+':4*(2ABCDE(7424+3$%34$()42+7'<4+2()5;8'(4#+

'+ :$4'(+ #4'8+ %,+ )**%<'()%*+ %*+ 2"*(74()/+ 54(7%#2+ ,%$+ (74)$+ 3$43'$'()%*=BCFE+ 174+ '##)()%*+ %,+

&)2G3)*'/%8'(%H+#)&%$%*+ B.IG3)*HIE+ $4':4*(+ (%+ )5)*42+ /'('8"24#+&"+ ($'*2)()%*+54('8+ /%5384J42+ )2+

(74+5%2(+4,,)/)4*(+'33$%'/7+(%+',,%$#+(7424+3$%#;/(2=+K885'*+&%(#,-BCIE($43%$(4#+,%$+(74+,)$2(+()54+

(74+&%$"8'()%*+%,+ 4*'*()%3;$4++-G%&'%-&;("82;8,)*"8H'8#)5)*42+ )*+ '+ 7):78"+ #)'2(4$4%2484/()<4+L'"+

;2)*:+ /'('8"()/+ '5%;*(2+ %,+ GF9M-#)/"/8%74J"8)5)#'@%8-I-"8)#4*4H/%334$G6H+ %&'%-&;(%J)#4+

BN;O%.;G6N"HE+GP/7454+Q=IC'H=+R%$S4*+&%(#,-BCME+'82%+/%*($)&;(4#+)*+(7)2+,)48#+$43%$()*:+'+2($'(4:"+

,%$+(74+/%*<4$2)%*+%,+'8#47"#42+(%+4*'*()%54$)/'88"+4*$)/74#+?-'5)*%+&%$%*'(42+(7$%;:7+(74+./(

0.%1-:4*4$'(4#+ +-2)8"8)5)*4+ )*(4$54#)'(4=+ 174+ '##)()%*+ %,+ .IG3)*HI9+ /'('8"24#+ &"+ '+ >(GDH+

37%237%*)(4+/%5384J9+%//;$2+'/$%22+(74+)5)*4+NTU+#%;&84+&%*#9+84'#)*:+(%+'*+)*(4$54#)'(4+(7'(+

/'*+#)$4/(8"+&4+'/"8'(4#+(%+:)<4+'+8'$:4+<'$)4("+%,++-'/"8-?-'5)*%+&%$%*)/+42(4$2+GP/7454+Q=IC&H=+

!%L4<4$9+(%+2)538),"+(74+3$%/4229+V)'%+&%(#,=BIWSE+$4/4*(8"+3$%<)#4#+'+#)$4/(8"+&%$"8'()%*+%,++-.%/-

3$%(4/(4#+ )5)*429+ &4)*:+ )*+ (7)2+ /'24+ (74++-.%/+ :$%;3+ 4'2"+ (%+ $45%<4+ ,%$+ 2"*(74()/+ 3;$3%242=+

174"+ ;24#+ '2+ /'('8"()/+ 3$4/;$2%$+ '+5)J(;$4+ %,+ N;N8+ '*#+ (74+ /7)$'8+ 37%237)*4X2;8,%J)#4+ 8):'*#+

3$%3%2)*:+ '+ &)#4*('(4+ /%%$#)*'()%*+ (%+ /%334$+ (7$%;:7+ (74+ 2;837;$+ '*#+ 37%237%$;2+ '(%52+

GP/7454+Q=IC/H=++

!"#$%"%&'()*(+*)#,*#)%)&'($-"#*!./01%2#3*3#"'4%&'4#25*6(7#*%$$8'9%&'()2*')*#)%)&'(2#8#9&'4#*9%&%8:2'25*

!

! "#$!

!!"#$%$&'()*&!"#$"%"&'(')*"+,"'(-./('(-0%"1+(##$2(/3"%+'2+24'()&+;.(/0-+5.(,)&2+42$2&)/+"%'"$%6+(7+8--,(&+#&*

%89:;<=(>+47+?2$@"&+#&*%89:;<A>+/7+B)(2+#&*%85;=C@>+

! D(%"1+ 2&+ '3"+ E2$@+ 2F+ B)(2G%+ H$2I#:+ E"+ "&*)%)2&"1+ '3('+ 2I$+ &#"&.4I'0-%I-F)&0-+ JKL+

1"$)*(')*"++,+(&1+(-%2+'3"+5.%I-F)&0-#32%#3)&"++-:+/2I-1+(/'+)&+(+%),)-($+,(&&"$+(%+'3"+%I-F2M)1".

#32%#3)&"+-)H(&1+I%"1+40+B)(2+#&*%85+N2$+'3)%+$"(%2&:+E"+'"%'"1+'3"+(11)')2&+2F+D=O#)&7=+'2+;.D2/+

(-1),)&"+ ,.+ I%)&H+ 2I$+ -)H(&1%+ OP/3","+ Q9=R79+ NI--+ /2&*"$%)2&%+ E"$"+ (/3)"*"1+ I%)&H+ 42'3+

1)(%'"$"2,"$%+2F+'3"+&#"&.4I'0-%I-F)&0-+JKL+1"$)*(')*"++,+(%+/3)$(-+-)H(&1%9+K3"+1)(%'"$"2,"$++,/0+

-"1+ '2+ (+ $(/",)/+ ,)M'I$"+ 2F+ '3"+ 5.(,)&2+ 42$2&)/+ "%'"$+ O*17:+ E3"$"(%+ I%)&H+ '3"+ 2'3"$+

1)(%'"$"2,"$++,/)+'3"+"&(&')2%"-"/')*)'0+E(%+A=S+""+O)&+F(*2I$+2F+'3"+<+"&(&')2,"$79+T%)&H+'3"+

'E2+ 1)(%'"$"2,"$%+ 2F+ 5.%I-F)&0-#32%#3)&"+ +-2+ /2&*"$%)2&%+ E"$"+ (-%2+ /2,#-"'":+ 32E"*"$+ '3"+

(%0,,"'$)/+ )&1I/')2&+E(%+*"$0+#22$+ O-"%%+ '3(&+UCS+"":+ )&+ F(*2I$+2F+ '3"+<+ "&(&')2,"$+ )&+42'3+

/(%"%79+ V'+ %32I-1+ 4"+ &2'"1+ '3(':+ 1I"+ '2+ '3"+ $"($$(&H","&'+ '3('+ +-+ /(&+ %IFF"$+ ('+ $22,+

'",#"$('I$"+ '2+ H)*"+ '1+ O%""+ (42*"7:+ E"+ /(&&2'+ "&%I$"+ '3('+ '3"+ -)H(&1+ %'$I/'I$"+ 2F+ +-+ E(%+

#$"%"$*"1+1I$)&H+'3"+/('(-0%)%9+

b) Morken's approach

R

O

H

LiHMDSTMSCl

R

N

H

TMS

Pt(dba)3/chiral ligand

R

N

Bpin

TMS

B2(pin)2

Bpin

PivClPivOH

*R

HN

Bpin*

O

tBu

a) Ellman's approach

R

N

H

S(R)(R)

O

tBu

B2(pin)2

[Cu(ICy)OtBu]

R

HN

Bpin

S(R)(R)

O

tBu

*

high dr

c) Liao's approach

Ar

N

H

BocCuCl/chiral ligand

KOtBu Ar

HN

Bpin

Boc

B2(pin)2*

high ee OMeMeO

S

P

tBuO

iPriPr

NN

CuOtBu

[Cu(ICy)OtBu]

CuCl

CuCl S

P

O

OMeOMeiPr iPr

tBu

OP

OO

OPh

MeMe

R

R

R

R

R

R R

R

R = H, Me, F, Et, iPr, Ph, tBuchiral ligand

!"#$%&'()*(

!

!"#$!

!!"#$%$&'()*&!""#$#%&'%(')*+,#&-*'$%'+.)%/'01"#2#&3'++,-'45#&6'%47'89!.:053"'1#60&"5;'+0-'9<3'"35#73"'730/$#%&'

,7%"4/$',07$#011='"3/%2,%535'"47#&6'/<7%20$%670,<#/',47#(#/0$#%&;!

! >37&?&"3@' &%( #,;ABCD' ,7%E#"3"' 0&' %760&%/0$01=$#/' E375#%&' $%' 3&0&$#%5313/$#E31=' 0((%7"'+.

0/=1.F.02#&%':%7%&#/'35$375;'9<3'&4/13%,<#1#/':%7%&'0""#$#%&'$%'+.$%5=101"#2#&35'G05'/%&"4/$3"'

#&'$<3',7353&/3'%('/<#701',<%5,<#&35'05'1#60&"5'+H/<323'C;*I-;'

!!"#$%$&'(),&!""#$#%&'%(')*+,#&-*'$%'+.$%5=101"#2#&35'"3E31%,3"':='>37&?&"3@'3$'01;ABCD&

Ph

N

H

Boc

CuCl (10 mol%)PTA-based ligand (12 mol%)

KOtBu (12 mol%)

Ph

HN

Bpin

Boc

B2(pin)2 *tBuOMe, 16 h, rt

NN

N

P

HN

Ph

35-1

Ph

S(R)(R)O

tBu

35-2

NN

N

P

HN

PhPh

S(R)(R)O

tBu

59 60

100% conv. 93% isolated yield(a)

rac


32% ee (R)

NN

N

P S(S)(S)O

38-1 38-2

p-Tol

NN

N

P S(S)(S)O

p-Tol

100% conv.15% ee (R)


7% ee (R)

R

N

H

Ts

MeOH, Cs2CO3chiral phosphine (4 mol%)

THF, 45 ºC

R

HN

Bpin

TsB2(pin)2

*

PPh2

Fe

P

Me

F3CCF3

CF3

CF3

N

PPh2

(R,R)-Walphos (S)-Quinap

!"#$%"%&'()*(+*)#,*#)%)&'($-"#*!./01%2#3*3#"'4%&'4#25*6(7#*%$$8'9%&'()2*')*#)%)&'(2#8#9&'4#*9%&%8:2'25*

!

! "#"!

! !"#$%#$&%'()*"#"()+%(,%#$"+%-(./0%-&%#&+#&*%12+(%#$&%3&.,(.41)'&%(,%(5.%678%*&."91#"9&+%

1+%(.:1)('1#12;+#+%<='$&4&%>?@AB?%C),(.#5)1#&2;0%#$&%3.('&++%*"*%)(#%-(./?%

!!"#$%$&'()*&D.:1)('1#12;+&*%1**"#"()%(,%E@<3")B@%#(%;F#(+;212*"4")&%+,?!

!'(-&!.%%/01&/23&4.56447&&% G)%#$"+%'$13#&.0%-&%$19&%3.&31.&*%#$&%,".+#%&)1)#"(4&."'122;%35.&%678FH1+&*%'(43(5)*+?%

7$&% 678% '1:&% $1+% H&&)% ,5)'#"()12"+&*% ")% #$&% 533&.F."4% 4&#$;2&)&% 3(+"#"()0% :&)&.1#"):% 1%

+#&.&(:&)"'%'1.H()%'&)#.&%")%%8$<%%3(+"#"()%#(%#$&%3$(+3$(.5+%1#(4?%7$"+%2":1)*%#(3(2(:;%3&.4"#%

#$&% 4()(F% (.% H"*&)#1#&% '((.*")1#"()% #(% 1% 4&#12% '&)#.&% :"9"):% '$".12% 4&#12FH1+&*% '1#12;#"'%

3.&'5.+(.+%(.%#$&%'((.*")1#"()%#(%1%+5H+#.1#&%1'#"):0%")%#$"+%'1+&0%1+%1)%(.:1)('1#12;+#?%%

% 7$&% 3.&31.1#"()% (,% #$&% &)1)#"(35.&% 678FH1+&*% IF3$(+3$")(% 12'($(2% <)+B% 1)*% IF

3$(+3$")(%+52,")14"*&%<-8B%-1+%+5''&++,522;%(3#"4"+&*%(H#1")"):%H(#$%*&."91#"9&+%")%:((*%;"&2*+?%

7$&%+#.1#&:;%#(%3.&31.&%H(#$%678FH1+&*%*&."91#"9&+%'()+"+#+%()%#$&%+&2&'#"9&%2"#$"1#"()%(,%678%#(%

1,,(.*% #$&% )5'2&(3$"2"'% 678JK"% #$1#% .&1'#+% -"#$% H&)L12*&$;*&% (.% 1)% &)1)#"(35.&% &#"&F

H5#;2+52,");2"4")&0%.&+3&'#"9&2;0%#(%.&)*&.%#$&%*&+".&*%'(43(5)*+?%%

% 7$&%MF+52,");23$(+3$")&%678%*&."91#"9&%<-9B%-1+%12+(%+;)#$&+"+&*%1)*%,522;%'$1.1'#&."+&*?%

G)% #$"+% '1+&0% #$&% .&1'#"()% (5#'(4&% '$1):&*%-"#$% .&+3&'#% #(% #$&% 3.&9"(5+% "4")&?%!$&.&1+% #$&%

1**"#"()%(,%678JK"%#(%1)%&)1)#"(35.&%&#"&FH5#;2+52,");2"4")&%3.('&&*&*%()%#$&%NOP%*(5H2&%H()*0%

#$&% 1**"#"()% #(% 1% $F#(2;2+52,");2"4")&% -&)#% ()% #$&% =OD% 4("&#;% <)5'2&(3$"2"'% 1**"#"()% 325+%

&2"4")1#"()B?%!&% #."&*% #(% (3#"4"+&% #$&% 3.&31.1#"()% (,% #$"+% ")#&.&+#"):% 678% *&."91#"9&% 5+"):% 1+%

&2&'#.(3$"2&%&)1)#"(35.&%4&)#$;2%$F#(2;2+52,")1#&%H5#%#$&%;"&2*+%*"*%)(#%"43.(9&?%C),(.#5)1#&2;0%

#$&+&% '(43(5)*+% -&.&% ,(5)*% #(% H&% 5)+#1H2&0% +5,,&."):% ,.(4% 1)% 5)&Q3&'#&*% .&1..1):&4&)#%

2&1*"):%#(%1%.1'&4"'%#$"(&#$&.%3$(+3$")&%(Q"*&%<',B0%1+%-&%'(52*%3.(9&%H;%RF.1;%*",,.1'#"()?%

*

Ph

N

H

Ts

Ph

HN

Bpin

Ts

*

NN

N

P

HN

Ph

35-1

Ph

S(R)(R)O

tBu

61 62

no reaction

MeOH, Cs2CO3chiral phosphine (4 mol%)

THF, 45 ºC

B2(pin)2

!"#$%&'()*(

!

!"#$!

! "#$! %&$'(')$! *+! ,#$! %&'%-./,0&1/&+230&! '/42&2'50! )5*/6! *+! 7-6#*16#23*! 1/&+23'829$! :!";!

6$582,,$9!,#$!65$6'5',2*3!*+!'3!$3'3,2*6/5$!<"=-.'1$9!6528'50!'823*6#*16#23$!:#$;!'39!+5*8!

,#$!&'1,!*3$>!'!<"=-.'1$9!,#2*/5$'!:##;?!"#$1$!9$52(',2($1!%*/&9!.$!6*,$3,2'&!*5)'3*%','&01,1!+*5!

'1088$,52%!5$'%,2*31?!"#$!65$6'5',2*3!*+!.*,#!9$52(',2($1!1#*/&9!.$!*6,2821$9!23!,#$!+/,/5$?!

=&,#*/)#!8*1,! *+! ,#21! 6'5,! *+! ,#$! <#@! 65*A$%,! B'1! 9$(*,$9! ,*! ,#$! 103,#$121>! B$! '&1*!

,$1,$9! ,#$! %#25'&! <"=! 9$52(',2($1! '1! &2)'391! *5! *5)'3*%','&01,1! 23! 1*8$! 8*9$&! '1088$,52%!

,5'31+*58',2*31?!"#$!7-6#*16#23*!'&%*#*&1!)'($!)**9!%*3($512*31!23!,#$!*5)'3*%','&01$9!CDE!

5$'%,2*3>!#*B$($5!,#$0!929!3*,!239/%$!$3'3,2*1$&$%,2(2,0?!%&'%-D/,0&1/&+230&!<"=!9$52(',2($1!)'($!

&*B$5! %*3($512*31! 23! ,#21! 5$'%,2*3>! 65*.'.&0! 9/$! ,*! ,#$! #2)#$5! 1,$52%! #2395'3%$?! "#$!

*5)'3*%','&01$9! 'F252923',2*3! /123)! */5! %&'%-./,0&1/&+230&! <"=! 9$52(',2($1! *5! ,#$! 6528'50!

'823*6#*16#23$!929!3*,!B*5G?!"#$!H-'823',2*3!5$'%,2*3!B'1!,$1,$9!/123)!,#$!%&'%-./,0&1/&+230&!

<"=!9$52(',2($1!'1!*5)'3*%','&01,1!'39!'&1*!'1!&2)'391!23!,#$!65$1$3%$!*+!'!%*66$5:II;!1'&,?!J**9!

%*3($512*31!B$5$!*.,'23$9!23!,#$!&'1,!%'1$>!B#$5$'1!,#$!$3'3,2*1$&$%,2(2,0!B'1!($50!&*B?!I,!%*/&9!

.$!23,$5$1,23)!23!,#21!%'1$!,*!%'550!*/,!'!1%5$$323)!*+!%*392,2*31!'39!8$,'&!1'&,1!'99$9!'1!K$B21!

'%291! 23! *59$5! ,*! 2865*($! ,#$! 5$1/&,1?! "#$! '&G030&',2*3! *+! *3$! L-MNO-1/.1,2,/,$9! 21',23!B*5G$9!

*3&0! /123)! *3$! *+! ,#$! 92'1,$5$*8$51! *+! %&'%-./,0&1/&+230&! <"=! 9$52(',2($! &$'923)! ,*! '! 5'%$82%!

824,/5$?! N23'&&0>! *3$! *+! ,#$! 8*1,! 65*82123)! 5$1/&,1! B'1! *.,'23$9! 23! ,#$! M/-%','&01$9!

#095*.*5',2*3!*+!+-D*%-65*,$%,$9!2823$1!/123)!%&'%-./,0&1/&+230&!<"=!9$52(',2($1!'1!&2)'391?!"#21!

5$'%,2*3!1#*/&9!.$!1,/92$9!9$$6&0!,*!,50!,*!2865*($!,#$!5$1/&,1?!

! N*&&*B23)! */5! *.A$%,2($>! ,#',! 21! ,*! /1$! ,#$1$! 8*&$%/&$1! 23! )&0%$5*&! 8$92/8>! 1*&/.2&2,0!

,$1,1!1#*/&9!.$!9*3$!23!,#$!+/,/5$?!I+>!&2G$!<"=>!,#$0!'5$!3*,!1*&/.&$!23!,#21!1*&($3,>!,#$0!%*/&9!.$!

+-'&G0&',$9!'1! %*88$3,$9! 23! ,#$! 23,5*9/%,2*3! 23!*59$5! ,*!8'G$! ,#$8!1*&/.&$!.0! +*58',2*3!*+!

,#$!%*55$16*3923)!P/',$53'50!'88*32/8!1'&,1?!

#%#&'()*+,-*./01&2*3/,4.&

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