Phosphorus Heterocycles II

2tTopics in Heterocyclic Chemistry

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Phosphorus Heterocycles II

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J. Drabowicz D. D. Enchev . D. Gudat . N. GuptaT. S. A. Heugebaert . G. Keglevich . D. KrasowskaA. tr opusiriski , S. Sasaki . C. V. Stevens

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h"

Preface

The success of the ongoing series "Topics in Heterocyclic Chemistry', beingpublished by Springer verlag motivated the publisher and the then chief

'Editor to

bring out two special volumes on "phosphorus Heterocycles,', and I was invited toshoulder this responsibility in the capacity ol the Guest Editor.

The special volume "Phosphorus Heterocycres I" was published last year whichincluded the following critical review articles:

Anellated AzaphospholesBiological Activity of Aminophosphonic Acids and rheir Short peptidesPhosphinine Derivatives and theirUse as Versatile Intermediates in P-HeterocyclicChemistrySpiro- and Tricyclic Phosphoranes with Six- and Higher_MemberedThe Chemistry of PhosphininesSynthe tic Approaches to I,2-Heteraphosphacyclates,Phosphorus-Containi ng Cali x arenes

Rings

From Phosphorus-containing Macrocycles to phosphorus-containingDendrimers.

After receiving an enthusiastic and active response and support from the aca_demic comm,nity, particularly the organophosphorus chemists, we intensified oureffons to bring out the special volume, "phosphorus Heterocycles II,' at the earliestand now it is in your hands.

This volume includes six chapters.The lust chapter "Heterophenes Carrying phosphorus Functional Groups as Key

structures" presents a detailed description ofthe recent advances made in ir,i, n"lo.The recent studies of all-phosphorus-substituted aromatic compound.s have revealedsome unique properties of these heterocycles.

, The second chapter "synthesis and Biological Activity of 2,5-Dihydro-1,2-oxaphosphole-2-oxide Derivatives" deals with the recent synthetic methods, par-ticularly [hose using phosphorytated alienes as the starting materials, of thesecompounds which show interesting biological properties.

The third chapter "Recent Developments in the chemistry of N-HeterocyclicPhosphines" presents a survey on fir,e- and six-membered phosphorus-nitrogenheterocyclic compounds whose rings combine a phosphazene or pirosphazane unit

ix

Prc'1ace

r:-rntCntS in:i:'.:. hetetO-

I e:.'rtrcvclesi iirhciis and

: Flatteneda thr.ie ccnr-:i!nlatropic

.if'le.

:horpholes"nJ r ersatile

rt Springer,r dedicated

r K. Bansaliuest Editor

Contents

Heterophenes Carrying phosphorus Functional Groupsas Key Structures...Shigeru Sasaki

Synthesls and Biological Activity of 2,S-Dihydro-1,2-Oxaphosphole-2-Oxide Derivatives,Dobrontir D. Enchcv

Recent Developments in the Chemistryof N- Heterocyclic PhosphinesDietrich Gudat

Selected Five-Nlembered phosphorus HeterocyclesContaining a Stereogenic phosphorus

)1

63

r03J6zef Drabowjcz, Dorota Krasowska. Anclrzej Lopusifiski,Thomas S.A. Heugebaerr, ancl Christian V. Stevens

l-{2,4,6-Trialkylphenyl)-1l1-phospholes with a FlattenedP-Pyramid: Synthesis and ReactivityGyrirgy Keglevich

Recent Advances in the Chemistry of DiazaphospholesNeelima Gupta

lndex

149

t75

207

Top Heterocycl Chem (2010) 2l:23-62DOI 10. 1007 t7081 _2009 _4@ Springer-Verlag Berlin Heidelberg 2009Published online: 18 September 2009

Synthesis and Biological Activityof 2,5 -Dihyd r o-1,2 -Oxaphosphole- 2- OxideDerivatives

Dobromir D. Enchev

Abstract This chapter deals with the methods for the syntheses of 2,5-dihydro-1,2-oxaphosphole-2-oxide derivatives, and some recent rlsults of their biologicalactivity testing. The electrophilic addition to I,2-alkadiene- and alkatrienephospho-nate derivatives is one of the easiest and fruitful synthetic strategies for obtainingthese compounds in preparative amounts.

Keywords 1,2-Alkadienephosphonates . 1,2-Alkatrienephosphonates .1,2-Oxaphosphole . Oxaphospholic cyclization

Contents

I Introduction...............2 Methods for Synthesis of 2,5-Dihydro-1,2-oxaphosphole-2-oxide Derivatives................

2.1 HistoricalOverview2.2 Elecrrophilic Addition to 1,2-Alkadienephosphonates............2.3 Electrophilic Addition to 1,2-Alkatrienephosphonares ...........3 Electrophilic Addition to Allenesubstituted-1,3,2-iioxaphospholanes

4 Electrophilic Addition to 1,3-Alkadienephosphonates ............4.1 Electrophilic Addition ro 1,3-Alkadienephosphonic Dichrorides.................4.2 Electrophilic Addition to 1,3-Alkadienephosphonic Dialkyl Esters .........5 Conclusion...............

References..

I Introduction

Organophosphorus compounds are important intermediates in organic synthesis andhave been widely used as pharmaceutical [1-6], agricultural [7], and chemical agenrs[8-14]' Recently phosphorus heterocycles [15, 16] have received considerable interesr

D.D. EnchevDepartment of organic chemistry and rechnology, Konstantin preslavskyUniversity of Shumen, Shumen 9712,Butgariae-mail : enchev @ shu-bg.net

23

2424

305l545656575858

24 D.D. Enchev

because of their unique biological activities as hydrolytic enzyme inhibitors [17] andtheir anticancer effects [18-20], as well as because of their wide-ranging utilitiesas synthetic intermediates in organic syntheses. Consequently, much attention hasbeen directed to the synthesis of these compounds l2l-28]. Among them, particularinterest was paid to the oxaphosphole derivatives. Numerous methods and syntheticprotocols for synthesis of these compounds have been described. The literatureoverview shows that, among the other promising substrates for the preparation ofoxaphosphole derivatives, the most fruitful ones are the phosphorylated allenes.

The unique combination of double bonds in the molecules of those compounds,each with different reactivity along with the easy preparation, makes phosphor-ylated allenes useful substrates for the synthesis of different cyclic and noncyclicorganophosphorus compounds. Recent investigations increase the scope of applica-tion of phosphorylated allenes as precursors in organic syntheses. Most of them areaccompanied by the formation of five- or six-membered phosphorus heterocycles,which in many cases demonstrate certain biological activity.

The subject matter of the present work is summarizing most useful methods forthe preparative synthesis of the titled compounds, as well as submitting some recentdata about their biological activity.

There are a number of other compounds with similar structure however; they areoutside the scope of this review.

2 Methods for Synthesis of 2,s-Dihydro-1,2-oxaphosphole-2-Oxide Derivatives

2.1 Historical Overview

The reaction of diacetone alcohol I with alkyldichlorophosphines afforded3-chloro- 1,2-oxaphospholane-2-oxide 2. The latter undergo isomerization followedby dehydrochlorination to the corresponding l,2-oxaphosphole derivatives 3(Scheme l) t291.

RPCr2

YY -'.....>>a\dro- aaP o-o-o

itR ,/:\

L_ --\ / \c,r\ <,^ 11. v-f)r<) -HC' _)'<)- +,<; -=--->_HCI

scheme I Synthesis of 2-alkyl-3,5,5-trimethyl-5H-[1,2]-oxaphosphole-2-oxide 3

,at

F

:

,:

:

{r*f#ft.B

n

,&

,t,

:

tl!

it**,i[#{+

i4

?,&

4

!

l'h,

ll$

**,*$[]

+

t

i

!r

s.Ir

YYoHO

Synthesis and Biological Activity of 2,5-Dihydro-1,2-Oxaphosphole-2-Oxide Derivarives 25

Civunin et al. [30-32] described synthesis of similar compounds, from the reac-tion of phosphorus pentachloride with divinyl ether (Scheme2).

PCrs --.,q(-.PpcLP I "1of ____________> ,rr,,) :_::j! [,,u.

4

__Jorl,\

I'/ -i .,n

| -r.,v

-,/ \6

o... fl AcoH

.,) l. oF *^"-' cl3P\o

5

scheme 2 synthesis of 2-chloro-5-methyrene-5 H-[1,2]-oxaphosphole-2-oxide 5

Later Pudovik et al. synthesized 2,5-dihydro-1,2-oxaphosphole-2-oxidederivatives from the reaction of propynoic acid with ethyldichlorophosphine(Scheme 3) t331.

t'l.@,r--\- P -/-LO

et/ I /^ct o(,

/-)\Y '{o,/'/t-t ,/-'\@f- 13 ----->Et- P O"ct/

Scheme 3 Synthesis of 2-ethyl-2-oxo-2H -2?vs -[ 1,2]-oxaphosphol-5-one 7

The same authors also reported the preparation of 1,2-oxaphosphole derivativesfrom the reaction of alkyl(phenyl)dichlorophosphines with unsaturated ketones(Scheme 4) 1331.

o

OH

EtPC12

-------.-.-_>

26

o

il

,"^,_ + RPCr2

wt"/ 8cr

q. a!**"---------')'-..X.;

D.D. Enchev

o\

R,,.

Me_Jtr \-I

-

\o/9

Me

o ):\\1 VPh/ 'o/

11

Scheme 4 Synthesis of 2-alkyl-4-methyl-5-methylene-5F1-[1,2]-oxaphosphole-2-oxides 9

The1,2-oxaphosphole derivatives were also obtained from the reaction of alkyl(aryl)phosphonic acids with Gpunsaturated ketones or aldehydes (Scheme 5) [34,35].

R

).top*rH._-_________>

-Hzo

Ph\ prorortH"__-__________>

-Hzo

t2 13

Scheme 5 Synthesis of 5-alkyl-3-methyl-2-phenyl-SH-fl,2l-oxaphosphole-2-oxides 1l and of4-alkyl-Z,5 -diphenyl-5H- [ 1,2] -oxaphosphole-2-oxides 13

The same authors described obtaining similar compounds from the reaction ofthe chloride of methyl-B-chloroformylvinylphosphonic acid with acetic anhydride(Scheme 6) [36,37].

cl.\ ,/ \ (Aco)ro

EL/ .'o cl/ -2AcoCl

t4

-J(Aco)2o oo ./ \ -. ,. Crz---------------> .e. Y ------_____>-AcOH R'' \o/

---------_->_2HCI

R,/

o.... /:1 - Ph'P \,.'Ph/ to/

Scheme 6

CHCI./CCI4, -8o - -10"C to room

,n---\:o,/

l0

Synthesis and Biological Activity of 2,5-Dihydro-1,2-Oxaphosphole-2-Oxide Derivatives 2'7

Macomber and coworkers [38, 39] found that the reaction of 2,2,6,6-tetrame-thyl-4-heptyn-3-ol with phosphorus tribromide led to 3,5-disubstituted-2,5-dihy-dro- 1,2-oxaphosphole -2- oxide derivatives (Scheme 7).

,Bu-----:---------r= gu, PBrr- tBu-----E- BurI ....."............-- i

OH -HBr I

OPBr,

t6

[u'.. --l

..........->l ->,,, 1

l_ Br,P- o

__l ,,.n

tBu

o.. la- P. z)- Bul

Br' O'

ItBu Y

\_o/-\Br2P-

o,}- But

,P

Hzo<_-

-HBr

t7

CHCI3/CCI4, -8'- -10"C to room

Scheme 7

These authors also reported the synthesis of 1,2-oxaphosphole derivatives fromthe reaction of hypophosphoric acid with a,B-unsaturated aldehydes (Scheme 8)1341.

RPh^

-/ \,

,1:\._ o HzP(o)oH, il os/:!.-,n-Hzo /Y',-o/18 l"D

Scheme 8 Synthesis of 2-alkyl- I (2-oxo-5-phenyl-2,5-dihy dro-2Ls-lt,2l-oxaphosphol-2-yl)-3-phenylprop-2-en- I -oles 19

Mashida and Sato [40] developed a method for the synthesis of the target com-pounds, based on the intramolecular rearrangement of the butyl esters of 3-hydrox-ipropene- 1-phosphonic acid (Scheme 9).

,-\ ,ro F\ zoHO- -p.

----J> \ _p, ---------->Buno/ aorrrn -BunoH \o/- aorun

F\zo\ .P.tot toH

222t

Scheme 9 Synthesis of 2-butoxy- 5H-11,21-oxaphosphole-2-oxide 21 and 2-oxo-2,5-dlhydro-2fu5-[ 1,2] -oxapho sphol-2- o1 22

i

28 D.D. Enchev

a-Acylallylphosphonates 23, on reacting with ru-chloroperbenzoic acid(z-CPBA) in presence of magnesium sulfate, afforded 2,5-dihydro-1,2-oxaphosphole-2-oxide derivatives 24. The subsequent reaction of the latter with lithiocuprateproduced 1,2-oxaphospholanes stereoselectively (Scheme 10) lT4l _

oil

(EtO)rP..- _-^\,,RrY v mCPBA|

-6/tx,

MgSoo

o

o uto-[-q

*,)-\Ap,

oEto_$_o

Rs,culi o / \

R2/ i,

2423

Scheme 10 Synthesis of 1-(5-alkyl-2-ethoxy-2-oxo-2,5-dihydro-2i,5-[1,2]-oxaphosphol-3-yl)-alkanones 24

Petrov and coworkers [41] showed that the reaction of dibromides of alkenephos-phonic acids with acetylenic alcohols involved an acetylene-allene rearrangement.The products so formed hydrolyzed easily to the corresponding phosphinic acids.The latter on heterocyclization afforded 2,5-dihydro-1,2-oxaphosphole-2-oxidederivatives (Scheme 1 1 ).

PB12

25

R

J"oX*'{- o.. ^/-o.-(RrP

:/ to,28 27

Et2O, -5o - -8oC to room, isomerization, hydrolysis, cyclization

Scheme 11

All the synthetic protocols described above have limitations to some extent andthe yields of the products were modest. In some cases the formation of l,2-alkadi-enephosphonate derivatives is essential for obtaining the final cyclic products. Thisis the reason why many authors have used the higher reactivity of 1,2-alkadi-enephosphonates, discovered by Mark $21in 1962 for the preparation of 2,5-dihy-dro-1,2-oxaphosphole-2-oxide derivatives. Since then, the oxaphospholic cyclizationof l,2-alkadienephosphonate system of double bonds has become the easiestmethod for the synthesis of these compounds. The special structure of phosphorylatedallenes is responsible for their special properties, which has attracted the attentionof chemists for a long time 143461.

o\_/

R

r ---.-L-^rr

-

^R

-r/P... RI

or\ _R' pl

_/Rl

26

Synthesis and Biological Activity of 2,5-Dihydro- 1,2-Oxaphosphole-2-Oxide Derivatives 29

The synthesis of 2,5-dihydro- 1,2-oxaphospholes via multicomponent or catalyticreactions has been published recently. For example, it was shown that the reac-tion of ethyl propiolate with triphenylphosphine in the presence of N-alkylisatinsleads to spiroindole-derivatives of 1,2-oxaphosphpole-2-oxide (Scheme lz) L4ll.

corEtt-I

Ph,P .lll +

-"->

29CHzClz, room toC, 24h column chromatography

Scheme 12

A very interesting method for the preparation of 1,2-oxaphosphole-2-oxide deriva-tives, bearing 4-alkenyl- or 4-allyl-substituents in one pot tandem Pd(II) and pd(0)catalytic reactions, was reported by Ma and coworkers (Scheme 13) [27,2g].

R

Pd(rr) o__)-

I

HO

EtO "EtOP

3130

i,II+i

Y

*\ ,R' zRs

'o.^2:"4*, * 1*o_P.p.td *o

Pd(0)_---__--

pa

psBl

ot\.P

EtO

p2

Scheme 13

30 Pd(cat), CaH(cat.)/N al(cat.)/ O 2, Be(leqiv.)

toR3

30 D.D. Enchev

2.2 Electrophilic Addition to l,2-Alkadienephosphonates

Phosphorylated allenes have been widely used as building blocks for the synthesisof five- and six-membered phosphorus heterocycles [48-52].

2.2.1 Electrophilic Addition to l,2-Alkadienephosphonic Acids

In 1911 Braverman and Reisman [53] reported the preparation of 2,5-dihydro-l,Z-oxaphosphole-2-oxide derivatives from the reaction of allenylphosphinic and alle-nylphosphonic acids with bromine (Scheme l4).

HO ,-.--n'*')r.1 '*.

R- ..o

33

Br

o* /:( - r"*,'toX*.

34

R2=R3=Alk n\ Br

P..x r\ft1ABr"

Brz--------r-

HBr

R=Ph,OH CHCI3/CCI4, -10.C to room, 24h

Scheme 14

Macomber, using monosubstituted at C3 atom of the alkadienephosphonatesystem substrates [54], employed the same reaction (scheme 15).

nl

,a,*\- ---JB2 Brz - ,,1't', o'Y.F"1,R% rq):!:l*,x' " o x' "o *A*'

35 Br"

Rl=H,Alk;R2=HR3=Alk 1rill

n\ Br\,/Ho.ol-\... R2

P X" oAR3

I

l-Hnrnivr.\_,--l

o.. /-\ . n2

,'t'oA p:

(BrHo X.oo,x'P" o $n'

I _,,.ni{r.o. ):{ n,

* t'oX*'

3736

CHCI3/CCI4, -10"C to room,24h

Scheme 15

Synthesis and Biological Activity of 2,5-Dihydro- 1,2-oxaphosphole-2-oxide Derivatives 31

In this context, it was suggested [53] that the reaction involved a tertiary carbocationintermediate that was in equilibrium with quasiphosphonium salt. The elimination ofHCI from the latter, reads to the formation oi 2,5-dihydro_1,2_oxaphospholederivatives' Macombet [54], however, has shown that bromination of optically pure1,2-alkadienephos-phonic acids occurred with 4lzo stereoselectivity. This fact hasbeen taken in consideration as evidence that, by the bromination of 3-monosubstituted-1,2-alkadienephosphonic acids, the intermediates of the reaction were presumablybromonium ion or nonplanar secondary carbocation.

The brominarion :f ,!: optically pure arkadienephosphonic acids proceeds withsimilar stereoselectivity [55], while in the case of arienic alcohols complete racemi-zation of the product occurred (Scheme 16) t561.

HO "J\,,P\

o

HB.z

--------->But

o.\

j

HOHO

38 CHCI3/CCI4, -l0oc to room, 24h 39

Scheme 16

In 1989 Macomber and coworkers showed that theenephosphonic acids with different kinds of electrophilicphosphole derivatives (Scheme 17) t51.).

reaction of 1,2-alkadi-reagents gave I ,2-oxa-

Ho ,-1<\,/\

HO

P.\

," P*.P*

-HNuMe

-Joo /-\ ,tvteP.XHo/ 'ot - M.

4ttBu

o 40

1Bu ooE Nu-

_______>

But -HNu

o42CHCIj/CCI4, -10"C to room,

43

24h, E-Nu=Clz, Brz

,t\

os

HOHO

Scheme 17

It was suggested that the reaction of 3-methyl-l,2-butadienephosphinic acidwith bromine in water involved oxaphospholic cyclization and oxidation of thesubstrate (Scheme 18) t581.

32

Me

D.D. Enchev

Br__/ox / -\ ,.''.P Y

Hol \o/ -M"

oo fl ,vt'PX-/

tot -Ma

Hor,r:'-<,'\ Me

Br2lH2O______>

o44 CHCI3/CCI4, -10.C to room, 24h 45

Scheme 18

The same substrate reacted with carbonyl compounds [59, 60] and with azome-thines [60, 61] to afford 2,5-dihydro-1,2-oxaphorphol" derivatives. compounds 49could also be produced by the use of rhe conesponding amides 4g (Schemi g fozl.

Me

46

HPhN

P

Me

Me

RCHO-.--.------->

HO.MeRN. *1 V-tot-M'

R/ 47

PhN. MeHO.dVYJ -'o/ - M.

R49

Me

Me

R

\HCI o... .Me

--------------> "d v,/ -O/ -M"H

5150

HO Fo< RCHO -

gg -\': / - \ L_-,, P.t MeHo44o/

HO48

Scheme 19 Synthesis of 2-substituted-2,5-dihydro- 1,2-oxaphosphole-2-oxides 46, 47 and 49

The reaction of 3,3-disubstituted-1,2-alkadienephosphinic acids with HCI was alsoused to prepare the corresponding l,2-oxaphosphole derivatives (Scheme 20) [63,64].

RCH=NR

Scheme 20

R=H, Alk CHCI3/CCI4, -10"C to room, 24h

t.

i

i,1'

t,ssplr

IIFfF{*P3,|

6-

)rb,

it1

iIf'

?

h

t

Synthesis and Biological Activity of 2,5-Dihydro- 1,2-Oxaphosphole-2-Oxide Derivatives 33

Compounds 53 could be obtained from an acid-promoted oxaphospholic cyclizationof phosphinic acid 52 in the presence of mineral acid and heating ,p to 100"C(Scheme 2l) [4ll

H@ oo /:\ .Me___:i___+ )X X,/ Y)- -Me

Rt' 'p253

Me -Ju:u,, _ oo1-V*.

Me -HBr ,( - O, - Me

Me

Me

R=H, Alk

Scheme 21 Synthesis of 5,5-dimethyl-2-(l,Z-dialkyletenyl) - 5H-11,Z1-oxaphosphole-2-oxides 53

The synthesis of 55 has been accomprished as shown in Scheme 22 t651.

,,P\PKO54 CHC13/CCI4, -lOoc to room, 24h Ss

Scheme 22

On the other hand, the bromination of 3-methyl-1,2-butadienephosphonic acid56 leads to the cyclic acid 57 (Scheme 23) t651.

Ho. u-"{,Ptxo

56

Scheme 23

MeB.,

------l>Me @"--Me

- 10"C to room, 24h

B, -l,/l

Ho efl .Me I op Y l----------->x'-ot -nae | -unt x

--l ",o

The reaction of 1,Z-alkadienephosphonic acids with an electrophile E. [H*, Br*/cHCli, Hg(oAc)r/AcoHl leads to 2,5-dihydro-1,2-oxaphosphole-2-oxides(Scheme 24) 166-691.

4f,f

*,fi',lF

t*lltjl.tilt$,Ita*tl!

$rd

:ir,F

34 D.D. Enchev

Rlr P2\- ./ E*

^. _,/ \^,Rr

or(HO),P:'-\ B2 (HO)2P\

R\ E +- \_Jol\1 \-*',

H& -ot t *, H@

59 CHCI3/CCI4, -10.C to room,24h

Scheme 24

The reaction occurs with high regio- and stereoselectivity.Macomber has described the oxidation of 3-methyl-1,2-butadienephosphonic

acid with 3-chloroperbenzoic acid to the corresponding cyclic allenic oiide, whichundergoes realTangement to produce the corresponding unstable 2,5-dihydro-l,Z-oxaphosphole-2-oxide derivarive (Scheme 25) 1661.

p3p2

o.a\

Hd Me

Scheme 25 Synthesis of 5,5-dimethyl-2-oxo-2,5-dihydro-2t 5-[1,2]-oxaphosphol-2,4-diol 59

2.2.2 Electrophilic Addition to l,2-Alkadienephosphonic Dichlorides

The halogenation of 1,2-alkadienephosphonic dichlorides leads to tetrahalogeno-2,5-dihydro- 1,2-oxaphospholederivatives ortothecorrespondingquasiphosphoniumsalts [70-79].These compounds are stable in nonpolar solvents for several days,but decompose to 1,3-alkadienephosphonates on keeping for a longer time[71,73-801.

A detailed investigation of the reaction shows that, in the case of chlorine asreagent, the compounds with phosphorane structure were isolated, whereas in

(HO)2P\o

M" .-CPBA_-_____>

Me

OH

--o '/, o.'. /:1 Me(HO)z( x ------->' 'P v"^"'z^\o */- r. Hd 'o/ - M"

60 6t

**'$E

Ft

I

##*#*#t$*s+fftlB$*,t

Synthesis and Biological Activity of 2,5-Dihydro-1,2-oxaphosphole-2-oxide Derivatives 35

the case of bromine, only compounds with phosphonium structure were obtained.Both products (with phosphorane or prrosprronlum structures) are unstable anddecompose to the corresponding phosphorylated 1,3-dienes (Scheme 26) 170,73,741.

l-". _l

I :-_.. IlMe- / \ OIlr"X .,-'PCt'Ir__l

65

i

Br*\_

:1-),.,,C;,

66

Br, /<F- :,r'-",a'nP cl2P,r

o62

,rClMe ctz ^, 1:]-r.

,. -

t"t.'otKr.

63

I

I,l .,-

.,//-\_

CI,P.

oCHCI3/CCI4, -10"C to room, 24h

Scheme 26

1,2-Alkadienephosphonates with bulky substituents at the allene moiety reactwith chlorine with formation of 1,2-oxaphosphole-2-oxide intermediate 69(Scheme 27) [78,79].

MeI

tBu

\_CI,P.

o

Me cr:

CH.CI

tBr. ,C-- CH2CI

\._=a Cl,/\CI,P.. CI

o68

tBu cl\- -//-\@/ \ vreCI.P V'^- d -cH,cr

cls'69

67

tBu cl\-/---------+ ,/-\ Me

_HCl cl2P\\ Yo tncr70

Scheme 27

The reaction ofinterhalogenides gave(Scheme 28) i811.

CHCI3/CCI4, -10"C to room,24h

1,2-alkadienephosphonic dichlorides with iodine and4-iodo-2,5-dihydro- 1,2-oxaphosphole-2-oxide derivatives

36

[,-('.1L'""'^.:l

Rl12, rx

----------> 2ROH_____-_____> RO\

Ao"*:

D.D. Enchev

R2

Rr

p2o-

727l

Rl, R2=AlkRl+R2= Cyclohexyl

Scheme 28

CCl4, 50"C, 24h, IX=ICI, IBr

I,/

Ho.. f1 -RlP. .Yo" 'c/ \ R2

73

On reacting the same substrates with phenylsulphenyl- and with phenylselenenylbromides, relatively stable cyclic phosphonium salts 74 were obtained (Scheme 29)1821.

YPhBt

t- ,,,\I ./:1 n' I

l-cl,P"o'K { ,:,/

clrP.r pz

7l

Y=S, Se

Rl, R2 =AlkRl+R2 =Cyclohexyl

Scheme 29

PhYBr__=__> A.------.---->.

-HBrcl^P..,\

74

C2H4Clz, -20C to room, 24h, boiling

75

The possibility of obtaining the desired compounds is due to the higher stabiliza-tion of the phosphonium intermediate. Heating of the compounds 74 leads to thecorresponding 1,3-dienephosphonates 75 [82].

The cyclic phosphoranes so obtained demonstrate properties typical for thecompounds with pentacoordinated phosphorus atom (Scheme 30) [7g, g3].

d+*J&

*d,lt

#*

il*

Synthesis and Biological Activity of 2,5-Dihydro-1,2-oxaphosphole-2-oxide Derivatives 3t

S.

RS/

x

-J/-\ p,t" o'K p'

AI

I viii

lx,-//\prP \-/'toAR'

i

XX,:( o ,-(cL{ )< ^l ,, -

".' p/ - \- *'

i_' o/\R'

-*or'

r o,,'\qzx/t

,"i \ l1"".i ". r-<okn o' \,- *'

vii cll 'ol\R'Rl k"-

S

\\

ct/

x__J

o..... /-\ -n,'P )<'s{ \o"/ \

R2

x

.o.'. /:( Br

=- tr3ro..orK *,

p2

i=2RSH, ii=2ROH, iii=RSH, iv=2HrO,v=HrO/ROH/SO, vi=ROH/SOCI2, vii=HzO, viii=RSH/B-R.RI,R2=AIk ' z

Rl +R2=Cyclohexyl

Scheme 30 Transformation of the cyclic phosphoranes

The phosphorus atom in the cyclic acids obtained from reaction IV is achiralbecause of rapid proton exchange between two oxygen atoms (scheme 31) tg4l.

HO\-r---

o//Scheme 31 Cyclic acids equilibrium

On the basis of X-ray analysis of l,2-oxaphosphole derivatives authors sug-gested [68] that these compounds have planar symmetry or that there is a processof rapid conformational equilibrium.

Similar compounds were prepared by the same method, from the reaction ofsulfuryl chloride and dichlorides of 1,2-alkadienephosphonic acids. It is noteworthyto emphasi ze that, in this case, 2,5-d rhy dro-L,2-oxaphosphole-2-oxide derivativeswere isolated, even when 3-monosubstituted allenephosphonate were used as sub-strates (Scheme 32) [39, 85].

pt

p2

$iFpp,&

*B+,tf},6

l|F$F

rttrilN

F

I1t

I

Ii.

38

,/CI.P..\

o76

s02cl2---_---->

Me Crz

-------+Me

._-.----->p2

CI__J

@l-\ n,cl.P )/.//o'\ (.)

o--

\ -oct/

D.D. Enchev

CI,/

o... /1 Rl.P \,/ct/ \{

77

------>-socl2

Hzorj) --------->

Ci- SO:

R'sorcr, ct

RI

H

Rl=AIk

Scheme 32

CzH4Cl2, -5o - -8"C to room, 24h

A synthetic strategy as described above was employed [39, 79] for the preparationof 79 and 81 (Scheme 33).

P.Ph- \to

78

cl ,-.-1\,/\P.

z\\Y'o80

CI,/

;c,../:{ ,"1

Lnt"x*]o1\

p(

Rr

8l

R, Rl= Alk

Scheme 34

o 7t

o ,-(''__-_-______> .t 1 t-*'-socl2 7 \'ozl -'-Pz

Rl, R2 = Alk

Scheme 33

ct/C2H4C11, -5o - -8'C to room, 24h

'Macomber et al. achieved formation of cyclic phosphoranes 82 [86]. The latteron treatment with water or with alcohols gave the corresponding oxaphospholederivatives (Scheme 34).

o\

HO

HCt / \-RCI.P Yr \o"' \Rl

82

/.:::::1/ \ -RPxo,/(n,

83

o..'. /:\ - R

Rd Pto/<R'

84CzH4Cl2, -5o - -8oC to room, 24h


The reaction of the 3,3-disubstituted-1,2-alkadienephosphonic dichlorides withalkylsulphenyl chlorides afforded, along with 2,5-dihydro-1,2-oxaphosphole-2-oxide derivatives, 1,2-adducts also. The use of sulfur dioxide in this reaction pro-moted the formation of the oxaphosphole product (Scheme 35) lzz, 44,7l-73,87-921.

R'.o

a,t ,". , R'

,/-'.XozClz(' IolI

vRS. Rl\-/

CtzpJ Rr

O

R(\-CI,P.

o

RSCI , R,

;-o-\Cl:P' R'

oI

Rr=R2=H lnscrI

Y

-.4,/------\ ;oClzP' 5-

ooR

Ro,

ClSo

oo

I -,,ct,1r^sn

\n'=n'=g \

x'=x'z=t2r/

u

o ^/-\ R'cr cizp V'ot - R2

SR

-/cr'ql:\M"ollC2HaC12, -5o - -8"C to room, 24h

o

CI,

| ,o,

tsn

"-V *:

'o'-R'

Scheme 35

2,4'Drchloro-2-oxo-1,2-oxaphosphol-2-oxide derivatives could be producedfrom the reaction of dialkylphosphorylsulphenyl chloride with 1,2-alkadienephos-phonic dichlorides (Scheme 36) [87, 89].

.+Me .-

Me

i ,Cr

rd-\) P-.OrK

Me

Me

87

l=(R2O)2P (O)SCl

Rl=H, AlkR=Alk

R\-/croo;\-''

cl/ .oa - M.

88

C2H4CI2, -5'- -SnC to room, 24h

-1n2o;rn1s;ct

Scheme 36

86

D.D. Enchev

2.2.3 Electrophilic Addition to l,2-Alkadienephosphonic Dialkyl Esters

2,5 -Dihydr o - 1,2- oxaphosphole-2-oxide derivatives were the main products obtainedfrom halogenation of dialkyl esters of 1,2-alkadienephosphonic acids (Scheme 37)153, 69, 79, 81, 93-1001.

R, Rl,R2=Alk, Rl+R2= CyclohexylX=Cl, Br

Scheme 37

_ _,/p' xz;-------->

tno)z( 'R''o

89

,,R,,"--ta*z

(RO)2P\o

,, R,__/^ ^. -/ \R'

(RO)2P\o89

C2H4C12, -5o - -8oC to room, 24h

x

------,-

o.. /:(,- *lxO -RX-RO/ -OA*'

90

CI. RI+ \:./,/\(R'

(Ro),|-- 93--o

X

F"***l

It is important to emphasize that in this reaction a spontaneous elimination of alkyl-halide takes place. Detection of the eliminated allrylhalide is an additional evidence forthe mechanism of the formation of 2,5-dihydro-1,2-oxaphosphole-2-oxide derivatives.

As underlined above, formation of these compounds by halogenation of dialkylesters of 1,2-alkadienephosphonic acids is the major direction of the reaction. Evenin the case of dialkyl esters of propadienephosphonic acid, some 1,2-oxaphospholederivatives could be detected [86]. On using sulfuryl chloride as electrophilic rea-gent, only 3,3-disubstituted- and 3-monosubstituted substrates could be transformedin oxaphosphole derivatives [39]. Thus, the main role of the substituent at the C3atom of the allenephosphonate system, for the formation of 2,5-dihydro-1,2-oxa-phosphole-2-oxide derivatives, was demonstrated.

A similarprocedure was employed [81, 101] forthe synthesis of iodine-substituted1,2-oxaphospholes (Scheme 38).

89

R, Rl, R2=Alk, Rl+R2= Cyclohexyl

I

Ir, ICl, IBr oo /{ -*'

-

P. ,<Rd -o/ \R2

-J,o /-\KICI:. "rr;1. \-*'Hzo Rd 'o/ \ R2

92

9t

Scheme 38

CC14, 50"C, 24h or CHCl.,, room, 20min

Synthesis and Biological Activity of 2,5-Dihydro-1,2-Oxaphosphole-2-Oxide Derivatives 4l

Early studies carried out by Angelov et al. [102] esrablished the herbicidal activityof 4-iodo-2,5-dihydro- 1,2-oxaphosphole-2-oxide derivatives 91. Some of the testedcompounds showed promising properties for further application as herbicides infarming.

Compounds 95 could be produced from the reaction of 94 with potassiumdichloroiodate as well as with inrerhalides (Scheme 39) I1011.

KIClj, ICl, IBr----------------

EtO/

CHCI3, room,20min

Scheme 39

The hydrohalogenation of phenyl(3-methyl-1,2-butadienyl) phosphinic esrersinvolved protophilic attack of the reagent, followed by heterocycliiation of theallenephosphonate system (Scheme 40) [103, 104].

<"*(Eto)rP(-

94

RO ,,-.-*4tP' t R',,\Pho

96

RI o\

P{HCI______>

_RCI

RI

R2

97

R, Rl, R2=Alk CHCl.r/CCl4, -10.C to room, 24h

Scheme 40

On using 3,3-disubstituted-1,2-alkadienephosphonic dialkyl esters as the sub-strates in the above discussed reaction, a mixture of dialkyl esters of the 1,2-oxa-phospholic acid and l,2-adducts was obtained. The products ratio depends onnature of the substituents at the substrate, and on the polarity of the solvent(Scheme 41) [03, 104].

oil

nr(no).pcux ,R'+..>-<P2 ci 'R2

o\\

RO

HCI

nonpolarsolvent

o\\

RO

ptHCI

polarsolvent

o

99

Scheme 41 Influence of the solvent polarity

f;

t

$

ft)r

I

I

ILh

Ii,t,,

It,

42 D.D. Enchev

Similar compounds were prepared via the same method, from the reaction of thesame substrates with phenylsulphenyl- and phenylselenenyl bromides (Scheme 42)

t1Osl.

, *' tn"',-:\

-

(RO)rP-rO R2 F

ZPh

-,/),P( "\-e-

prIuR2

ZPh,/

X.I:V-,R-i- o' 'o- t

R2

\:7BrrI -RBrI

t zpn__JRo. /-\ -RrP.Y

o" u o' tR2

101

;*rP/

\89

Z=S, Se

C2H4C|2, -20"C to room,24h

Scheme 42

It was established that the reaction of dialkyl esters

acids with phosphorus dithio acids gave small amountoxaphosphole-2-oxide derivatives (Scheme 43) [106].

of 1,2-alkadienephosphonic(5-67o) of 2,5-dihy dro- 1,2-

,*o,.rf'o

o.il

(n'or.P(s)su (R'o)'P\

- /*'

-

/:\,/ 'R:I

P(OR)"

&

6o).n.( -":*"

102 l0,l

Scheme 43 Synthesis of 2-alkoxy-5,5-dialkyl-5H-11,2l-oxaphosphole-2-oxides 104

1,2-Oxaphospholic derivatives were also prepared from the reaction of 3-monosub-stituted alkadienephosphonates with alkylsulphenyl chlorides (Scheme 44) ll}]-l.

"'R'Altscttnlo).p1. rrO

105

AlkS R2\_,/+ )>-rcl-< ,

P(OR'),

{,

o.\ntd

SAIK

/-\.R2P\r-o-

106

R1, R2=Rtt

Scheme 44

c2H4cl2, -20"C to room, 24h

t#*fifi,s*

$

##*s#

**$tffi

,**#*,

$

Synthesis and Biological Activity of 2,5-Dihydro-1,2-Oxaphosphole-2-Oxide Derivatives 43

It has been reported that same reaction gave a complex mixture of products,r.e.,|,2-oxaphosphole derivatives,1,2- and2,3-adducts in 1:1:4 ratio t107].

On reacting 3,3-disubstituted-1,2-alkadienephonic diatkyl esters with methyl-sulphenyl chloride, 1,2-oxaphosphole derivatives and 1,2-adducts were isolatedt1081. In the case of dialkyl esters of 3-methyl-1,2-butadienephosphonic acid, theformation of dialkyl esters of l,3-butadienylphosphonic acid was also detected(Scheme 45).

(RO),P(-\o

SR3

o\\

RrO' P(ORr)"

o"108 109

C2H4CI2, -20"C to room, 24h

Scheme 45

The analogous reaction with SCl, leads to1,2-oxaphosphole-2-oxide derivativesin high yields t1091. The cyclic compounds prepared in this manner react withnucleophilic reagents easily, allowing incorporation of oxaphosphole ring in manyorganic substrates (Scheme 46) [109, 110].

Ph SCI

t''... -

,*' * oo){- ve . SCrz Ph,. ,M. M.scr Ph.. , SMetP-.<4,\<:Nae Etd'

ro"^'''--,..,,4"-r.*,e,otref! rr,,.cl' P(oEt), o 'z -o ../\

Or; '- -'2 v Ma Cl

113 lll

CH2CI2, -20.C to room,24h

Scheme 46

It has been established that alkadienephosphonates bearing bridge-substituent atC3 atom of the alenephosphonate system on reaction with alkyl(aryl)sulphenylchlorides lead to the formation of spyrocompounds t1l1l.

The reaction of diethyl ester of 3-methyl-1,2-butadienephosphonic acid withPhscl/sbcl' leads to oxaphosphonium salt 115 (Scheme 47) lllz).

il0107

tt4 lt2

Rr Phscr_--_---_>

B2 Sbcls L;*l]115

(,SbCI-t

Scheme 47

89

CHCI,/CCI4, -10"C to room,24h

rIt

;Ilhh

t

44 D.D. Enchev

Compounds 118 could be produced from the reaction of dialkyl esters of3-monosubstituted-1,2-alkadienephosphonic acids with methylselenenyl chlo-ride. It was established that, along with 118, z,3-adducts were also formed[113]. Use of phenylsulphenyl chloride in this reaction leads exclusively to theformation of 2,5-dihydro- 1,2-oxaphosphole-2-oxide derivatives 117 (Scheme 48)[113,114].

-/ _ /-_<

rnolr( 'cHCt rnolr( ts"M.

ob.oEZ

ll9R=Alk

Scheme 48

Compounds 120 were usedlectivity of the reaction of(Scheme 49) [Il4].

SeMe

__J* o.. 1- ler.MeSecr

nd - d (Ro)2p.

ll8

SePh

,P' Phs.cr o.r (-r,

Pr

I

CHCI

o

ll6

C2H4CI2, -20oC to room, 24h

as the starting material for establishing the stereose-allenephosphonates with phenylselenenyl chloride

H 'X"\-tt"tn '1"\- 'sePh

l,-.-\' Phsecl Krl-I-, oo^):/(Ro)2P\ u,'-*d'tfi;;' .*)1t'f,,''

o:r,oR=Alk

l2tC2H4CI2, -20oC to room,24h

122

phosphinic acids2,5-dihydro-1,2-

the molecules ofleads to the for-

Scheme 49

The reaction of dialkyl esters of 1,2-alkadienylphosphonic andwith methyl and phenylsulphenyl chloride, leads excrusively tooxaphosphole-2-oxide derivatives [1 l3-1 15].

Regardless of the nature of the ester groups at phosphorus inthe 1,2-alkadienephosphonic substrate, the electrophilic additionmation of 1,2-oxaphosphole derivatives (Scheme 50) tl16l.

I

t-.ro.' ENu loro'. _o.o.ro-"=*=( *Pl*d'

Aro' -o L

123


Ar=Ph, PhCH2

C2H4CI2, -20'C to room,24h ENu = Clz,

Scheme 50

The synthesis of 4-phenylseleno-2,5-dihydro- 1 ,2-oxaphosphole-2-oxide derivatives125 is shown below (Scheme 51) t871.

,RI

-r/

o< \n,PhSeNEt, \

(RO\^P/,\o F(O/

-20oC to room,24h

Scheme 51

The 1,2-alkadienephosphonic dialkyl esters react smoothly with dialkoxyphos-phonylsulphenyl chlorides, affording 2,5-dihydro- 1,2-oxaphosphole-2-oxide deriva-tives 126 (Scheme 52) l1lll.

Ph

Rr

>2

c2H4cl2,

Rl (RO)2P(O)SCt -J sP(oxoR)2

o.., /-\ -Rr\/'RO" -o/ \ R'

126

- -/,_o ___{

-^ -,/ \R2(RO)2P\

o

R,R,,Rr=Alk

Scheme 52

C2H4CL2, -20"C to room, 24h

Christov et al. Il l8-120] have described the synthesis of oxaphosphole derivatives128 and 130 from bromination of bifunctionalized allenes (Scheme 53).

46 D.D. Enchev

134

,o,//RSo

,//RS,

OH

pt

(M.o)2Pa

,/tR2

oE,LO< ,,RI

)-.-(tMeO)rP( Rz'o

rzg

Me oEt\./,o----y

(R):.-(

n' .

(EtO;rPo Me''o 132

B.r_______=_-_>

cH2ct2

o\ pt

p2

Rl

R2

)'-..MeO

127

B.,---------+-

cH2c12

Rl, R2=Alk

130

C}{zclz, -20"C to room,24h

Scheme 53

A similar procedure was followed for the preparation of 2,5-dihydro-1,2-oxa-phosphole-2-oxide derivatives 134 possessing CHrOH group at C3 atom of theoxaphosphole ring. The oxaphosphole products were obtained as EIZ mixture fromthe reaction of 1-substituted-1,2-alkadienephosphonic diethyl esters 135 with halo-gens (Scheme 54) 1121,1221.

Me oEro-f/

o'

128o

pl+

p2

(MeO)rPO131

R -tr* o\

Me prd

o1\

Bt{

o'

361

Me

135

R

Me

x2**__--_-_>

rnMeOH, Hv

o\

EtO

R=Alk

Scheme 54

P

'o

CHzCl2, -20"C to room, 24h

o..... / -M.o/P\o'

Synthesis and Biological Activity of 2,5-Dihydro- 1,2-Oxaphosphole-2-Oxide Derivarives 4j

The synthesis of oxaphosphole derivatives 138 has been reported from the reactionof allenephosphonic dialkyl esrers with phenylteluryl halides (Scheme 55) ll23l.

*'\ ., R, phreX

,_4T --------------l>

xalos.Y / \ R3.\ol:7

Rl, R2, R3, R4= Alk CH3OH, 55.C,2h

*'\ ,TePh

o\/ L- n'z

poo/ -\o/ \ R3

138

Scheme 55

A mechanism similar to that proposed for the reaction ofdialkyl esters with halogens has been suggested.

It is noteworthy that compounds 138 are good precursors inbecause oftheir good leaving phenylteluro group tl2,3l.

allenephosphonic

further synthesis,

2.2.4 Electrophilic Addition to l,2-Alkadienephosphonic oxides

The chlorination of dimethyl(3-methyl-1,2-butadienyl)phosphine oxide has beenreported to produce 2,5-dihydro-1,2-oxaphosphonium salts 140 (Scheme 56) t1131.

Me Cr,--._-----__>

Me

"or_6)

CIO Fr

f-cr IlrH Meli '"rt',. ,< I

loMelet_ lcr

/-Me^P

l\

o139

C2H4CI2, -10. - -15"C to room, 24h

Scheme 56

Hydrochlorination of the same substrate leads to the cyclic unstable phospho-nium salt 141 (Scheme 57) t1031.

u.,e.(-'-'oMeMe"P Y

I Hd -M'

142

Me HCr [-..- ,J-________r> tMe p

,Xn " iMe L", It4t

Scheme 57

139

C2H4CI2, -10" - -15"C to room, 24h

D.D. Enchev

The substrate 139 reacts with phenylsulphenyl chloride, affording cyclic phos-phonium salt 143 which decomposes on heating to the corresponding 1,3-diene(Scheme 58) [107].

M" pnsct

- -,/-------r>

MerP( Meo P

f sPh-ll__JlI @i \ Mel

I *"o'.oX *. IL __l

743139

SPhMe----------)-

HCI M",

C2H4CI2, -10" - -15'C to room,24h

Scheme 58

The |,Z-alkadienephosphine oxides react smoothly with dialkoxyphosphonyl-sulphenyl-chlorides affording 2,5-dihydro-1,2-oxaphosphonium salts 145 and 146(Scheme 59) U 171.

, srrolton'1,

Me Rr(o) P(o)scr ^d, Me......"...."...- Krr. ,,^\ -Me '."'o' Mecl-

145

.o ,-(tt1n'orrn'(g _@l \_M.- \'^ R.P x5 --z-\O'l \

14a

146

R^Pl\\ o 139

R=Me, R1=Alk

Scheme 59

C2H4C|2, -10'- -15'C to room, 24h

The cyclic phosphonium salts 140,141, L43,145, and 146 so obtained are evi-dence for the mechanism of the oxaphospholic cyclization and especially for themain role of the tertiary carbocation formation during the process. The additionaldata which support this assumption, come from the investigation of the same reac-tion, but with different substrate, i.e., dimethyl(1,2-hexadienyl)phosphine oxidel47.In this case, the reaction mechanism involved formation of secondary carboca-tion that gives oxaphosphole product 148 only tn llVo yield (Scheme 60) 11241.

EOCI O

MerP(o Pr-M%t6oAo*'Xa, *':!r.147 r4B 149 br

oov.rfl-1 .,Cl - M.,[---y ,P,t'crXpr+-crXcr

Scheme 60

ls0 C2H4CI2, -10" - -15'C to room, 24h

#

*pt,**fr.

#

fr'

m

I


The mechanism of oxaphospholic cyclization was confirmed by isolating 152 inthe reaction of N-methyl-N-propargylamine with dialkylchlorophosphite(Scheme 61) U25}

(RO)2PC1HN-\

---->t\:Me

151

R=Alk

Scheme 61

CHzClz, -5" -0oC, lh boiling

*"**o'01o"'N'

*rr*_a/-- ^eY-"kliNuo y' *-o

\.\\Nu- |

| -RNu

,1, u

', ,:(*,2".1_ \--*,

ozz \o'l\P2

TH--l

| ,*o,,.- f\ _ l ---- Re e:\L Me --_l cP

,r_Eo. 1u/(cP MeI

Me

152

Other authors followed similar synthetic sequence U26,1271.

2.2.5 Electrophilic Addition to l,2-Alkadienephosphonic Amidoesters

Enchev et al. [128, l29lhas reported the synthesis of 1,2-oxaphosphole derivatives,bearing N,N-dialkylamido-group at phosphorus 154 (Scheme 62).

Rl,/RO /r-c----1- pi.- 'R,

R3zN' - o153

R. Rl, R2. R3=ark

C2H4CI2, -5o --8oC, to room, 24h 154

Scheme 62

This synthetic strategy makes the synthesis of amino derivatives of 2,5-dihydro-1,2-oxaphospholes possible.

Furthermore, these compounds were found to possess growth-regulating activity[130, 131]. The same compounds were tested for their cytotoxic and cytomutageniceffects. As a result, only weak mutagenic and mytostatic properties of the compoundshave been detected [132].

Authors employed similar method to prepare compounds 156 (Scheme 63)t I 331.

FF

?)IPt.

$

T*msbFrI

50 D.D. Enchev

I Br _l .H .r''

Br: l*o, I *'*.af1 _ R,#l .'( Y*' l-_*r?'.oX*,lR3NoD2 lo/

LH r\ __l Br ( ,r"

I

l-ner*s,

H,/nrN. fl Rr

o"'oX*,C2H4C12, -5o --8oC, to room,24h 156

Rl./

- P-- 'R2_ , _o

RJNH 155

R, Rl, R2, R3= Alk

Scheme 63

The synthetic strategy described allowed the synthesis of N-morpholino-1,2-oxaphosphole derivatives [34], as well as 1,2-oxaphosphole derivatives, bearingN-2-chloroethyl group at phosphorus (Scheme 6a) [135].

158

plRO- t-.4.-'-- p, . R2

R3N' -oH 1s9

R, Rl, R2=AlkR3=-CHzCHzCl

u*, l*o .-<t I.-.*Eu'q Y.J -- ^r$T.

NP /"-\ Bro

C2H4Clz, -5o --8"C to room, 24h

Scheme 64

Compounds 160 are still under investigation for their biological activity, as theyare expected to exhibit such activity, because of their structure similarity to phos-phorus amides bearing 2-chloroethyl substituent at nitrogen. It is well known that

{ls,f <I-u*H'att.l

\-/ tsl

R, Rl, R2=AlkRl+R2=6r"lohexyl

Synthesis and Biological Activity of 2,5-Dihydro- 1,2-Oxaphosphole-2-Oxide Derivatives 5l

the latter have wide application as chemosterilizing insecticides or cytostatic agents

lt36-t441.The evaluation of antimicrobial activity of 1,2-oxaphosphole-2-oxides was

reported by Haranath et al. t1451.

2.3 Electrophilic Addition to l,2-Alkatrienephosphonates

2.3.1 Electrophilic Addition to l,2-Alkatrienephosphonic Acids

It was shown that 1,3,4-hexatrienephosphonic acid 161 reacted with hypophos-phoric acid and air to give the corresponding 3-vinyl-2,5-dihydro-1,2-oxaphosp-hole-2-oxide derivatives 162 (Scheme 65) 1641.

,r*"Ho...

,( Me

HO161

6lo,l, Fr----+

:\_

\(-\-*'H' 'o- t

Ma

162

Scheme 65 Synthesis of 5,5-dimethyl-3-vinyl-511-[ 1,2]-oxaphosphole-2-oxide 162

2.3.2 Electrophilic Addition to l,2-Alkatrienephosphonic Dichlorides

Compounds 168 and 169 were synthesized from the reaction of dichlorides of1,2,4-pentatriene- and 1,3,4-hexatrienephosphonic acids with sulfurilchloride(Scheme 66) 1146).

R=-CH=CH,Rl=u

,,CIo

.)t'' "{165R

Me

so2c12-----------*

Rl cl\.//_\/\Rcl3P. ^,rKoMe

164163

R(

cLPoo

Scheme 66

C2HaCl2, -5o --8oC to room, 24h

p*,*;

$

####

$

$

#f,r

$tr

*

il

M}

52

The reactivity of the chlorinereaction of these compounds with

R=Alk

Scheme 68

D.D. Enchev

atom at phosphorus was demonstrated in the

methanol (Scheme 61) 1146).

CI

,. ,-(MeOH ".../ \ --165,166 ---------> ''p- .Y

Meo/ 'o' 'M"

167

CzH4Cl2, -5o --0"C to room, 24h

Scheme 67

2.3.3 Electrophilic Addition to l,2-Alkatrienephosphonic Dialkyl Esters

The above results encouraged authors 195,991to examine the reactivity of dialkylesters of 1,2,4- and 1,3,4-alkatrienephosphonic acids 169 and L70. These substrates

on halogenation gave 3- or 5-vinylsubstituted-2,5-dihydro-1,2-oxaphosphole-2-oxide derivatives 171 and 172 (Scheme 68). Spectral investigations of this reaction

show that, formation of oxaphosphole ring starts immediately after adding of the

reagsnt.

172170

x(cr)

.Me x.(so"cl.) o'/L-LZ'\\

,/\/(RO)rP( -RX(RCI+SO2) RO

,Me X?(SO?CI))\_,/-

---'

-

(Ro)rPa t Mt -Rx(RCl+so2)

CCl4, -5o --SoC to room, 24h

Dialkyl esters of 1,3,4-hexatrienephosphonic acid react with alkyl(phenyl)sul-phenyl halides, to form mixture of 2,5-dihydro-1,2-oxaphosphole-2-oxide derivativesand thiophene derivatives (Scheme 69) fla7-la9\

oI--P

RO

t

IrI]hrr,1-

+flIT*-f,

I


,*"(RO),P:. Me- r\o

173

Scheme 69

ottrloRy,

-J( \-*-s'

177

Me(Ph)SX ,S(Ph)Me€ o.rf:{-r. +

'P )<Ro/ -o/ -M"

CCl4, -5" --8oC to ,o#, ron

The same substrate 170 reacts with alkyl(phenyl)selenenyl chlorides to givepredominantly 2,5-dihydro-1,2-oxaphosphole-2-oxide derivatives 175 (Scheme 70)[1s0].

,*"rnolrn( Me

P(OR)2

Me

MeSeCl -:\ SeMe____> \_/o. /-\ rur.'P X*,Rd 'o

o" a1o*;,

-J( \-..,

Se'

176

o

o\\

170 t7s

ooR.P// 'o clH2c

\

178

CCl4, -5o --8oC to room, 24h

Scheme 70

The same substrates react with phenylselenenyl bromide to give only 2,5-dihy-dro-1,2-oxaphosphole-2-oxide derivatives (Scheme 7 I) U4gl.

Me

Me

179177

,M. phSeBr\-/,/-.:\

--->(Ro)2P( Me

--\ SePh

o,..):( -r,.*o)n- i*,o

170

R=Alk C2H4CI2, -10"

180

--15'C to room,24h

Scheme 71

54

3 Electrophilic Addition to Allenesubstituted-L,3,2-Dioxaphospholanes

D.D. Enchev

The halogenation of the allenesubstituted 2-oxo-1,3,Z-dioxaphospholanes alsoleads to 2,5-dihydro-1,2-oxaphosphole-2-oxide derivatives 182 (Scheme72) 1991.

pl f-xlr-""11..Lto'"o l'

x-l-o.ot4 R l

l- o)t'oX*, I- --l

*"

,/

I )r( p2

\o o

nl. n2 = ett

x)-----3

181

x_-/q. /-\ - nr.P Y

xcH2cH2o 'o' - R2

182

C2H4C12, -5o --8oC to room, 24h

Scheme 72

The mechanism of the reaction involves oxaphosphole ring closure followed by1,3,2- dioxaphospholane rind opening.

The reaction of 181 with sulfuric acid was then employed for establishing thepostulated reaction intermediate (Scheme 73) [151].

.-'ot /-":<I ).( 'p2

=\d o

H2so4- [ *-J* I€ lro..'efl -R'| I

l[/"oX*, 1 oL 183 _t HSO4

Rr

181

Rl, R2 = elt

Scheme 73

CCl4, -5o --8oC to room,24h

Compounds 181 react with alkylsulphenyl chlorides to form a mixture of1,2-oxaphosphole derivatives and I,2-adducts in 4:1 ratio. Decreasing the reactiontemperature favored formation of oxaphosphole product. The same substratesreacted with phenylsulphenyl- and phenylselenenyl bromides to give only 1 ,2-oxa-phosphole derivatives [133].

Similar to the reaction pathway discussed above, 181 reacts with dialkoxyphos-phonyl-sulphenyl chlorides affording 184 (Scheme 1 4) [ll7).


Rl (RO)2P(O)SCl

c2H4c12, -70

184

--15'C to room,24h

In another synthetic strategy allenesubstituted-1,3,2-oxazaphospholanes 185 onreacting with electrophilic reagents afforded 160 (Scheme 75) t1351.

E

.o .rRt ENu o- 4 pr

( )'<- *' ,.io,,N)i'ox:'\N' rg5 H

H 160

Rl, R2 = Alk C2H4Clz, -5" --0oC to room, 24h

Scheme 75

An attempt to obtain other evidence for the mechanism of the oxaphospholiccyclization has been made and is shown in Scheme j6 tl12).

Br

q . /-( ;,-l*)r. ox*,

I

H --l sf

187

plo __./l-. _--____--.1

\P' 'p2*'ooH 186

t-^

[q

oBr

Br

| ).( \R'

t--d' 'o lgl

R, R', R2=Alk

Scheme 74

Rl. n2=e.tk

Scheme 76

oR',.:- 9 F.--4I \p1 'R2

)-ol "oMe' 188

o. o --r*'Y \p1. '- n,)-{"oPh' l9o

C2H4C12, -5" --0oC to room, 24h

sP(oxoR)2

pt

p2

56

4

D.D. Enchev

Electrophilic Addition to l,3-Alkadienephosphonates

4.1 Electrophilic Addition to 1,3-AlkadienephosphonicDichlorides

On chlorination of dialkyl esters of 2-chloro-3-methyl-1,3-butadienephosphonicacid in non-polar media, a mixture of five- and six-membered heterocycli. .o*-pounds was obtained (Scheme 77) [153, 154).

CI

Cr, o... /:( v.€ p v-RCl nd' \O/ \-

61

193

C2H4CI2, -5o --0oC to room, 24h

CIo_J\,/-\ ,.M.+PK / \ / \,xd \o---/ -cl

ty

o\ t(o*,"

cl/ 'Me

x2---------+-

RCI

or\/'P.

RO/ 'o'

Me

Me

19s D6R=Alk C2H4CI2, -5o --0oC to room, 24h

Scheme 78

A similar procedure was followed for the synthesis of 198 (Scheme 19) 1156l.

cl"Me -----t--->.

_RCI

CI

.Me

r98

,:< Me

1RO;,e/ Y'iltgz ll

R=Alk

Scheme 77

The 2,5-dihydro-1,2-oxaphosphole-2-oxide derivatives 196 were also obtainedfrom the reaction of esters of 3-chloro-4-methyl- 1,3-pentadiene-2-phosphonic acidwith halogens (Scheme 78) [155, 156].

Scheme 79

C2H4CL2, -5'- -0'C to room, 24h

rI

1b

$I

$i#*F*k

h

F

rh

nr.Fl[',FFFIIH

Synthesis and Biological Activity of 2,5-Dihydro- 1,2-oxaphosphole-2-oxide Derivatives 57

4.2 Electrophilic Addition to l,3-ArkadienephosphonicDialkyl Esters

The reaction of 2-chloro- 1,3-alkadienephosphonates with arenesulphenylchloridesgave 2,5-dihydro-1,2-oxaphosphole derivatives in good to exceillnt yields(Scheme 80) [157].

^ ArSCIRr -__>-MeCl

ptpz

200


RsArSCI_cr I o=

-MeCl no/I

R4

p3

p2

obtained from the reaction of 2-chloro-1,3-with areneselenenyl chlorides (Scheme 82)

Scheme 80

The reaction of 1,3-dienephosphonic-1,3,2-droxaphospholanes with arenesul-phenyl chlorides followed the mechanism discussed earlieito give 202 (Scheme g l )t1s8l.

201

Rl, R2, R3, R4, R5=n, Rtt<

Scheme 81


o\v"{

pt

199

Rl, R2, R3=g, ett

The target compounds were alsoalkadienephosphonic dialkyl esters

tlsel.

202

miFr*Bs.,

rF

t

58

(MeO)2P\

203

Rl. n2, R3=H, ett

Scheme 82

, ArSCIcH2R' ----------)-MeCl

p2

os

rtedcHrn3 o

rl

(MeO)rP

D.D. Enchev

205

SAr

204


R2

5 Conclusion

The submitted methods for preparation of target compounds based on the electrophilicaddition reactions of 1,2-alkadiene- and alkatrienephosphonates show that they arevery promising from synthetic point of view.

1'2-Alkadiene- and alkatrienephosphonates are available from acetylene-allenereaffangement of acetylene phosphites which could easily be prepaied from thereaction of carbonyl compounds and l-alkynes.

In this context the described methods for preparation of 2,5-dihydro-1,2-oxa-phosphole-2-oxide derivatives have to be considered as synthetic protocols fortransformation of carbonyl compounds in to p-containing heterocyclei.

All the reactions are environmental friendly and proceed with almost total atomeconomy.

It is important to emphasize that all of theactive substances.

tested compounds are biologically

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99. Angelov ChM, Christov ChZh (1983) Heterocycles 20:219

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Phosphorus Heterocycles II

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