Accepted Manuscript

Original article

Enantioselective Additions of Diethylzinc to Aldehydes Catalysed by tita‐

nate(IV) complex with chiral bidentate bis-amide ligands based on cyclopropane

backbone

Abdullah M.A. Al Majid, Mohammad Shahidul Islam, Zeid Abdullah Al-

Othman, Ahlam F. Al-Salhoob

PII: S1878-5352(13)00007-5

DOI: http://dx.doi.org/10.1016/j.arabjc.2012.12.036

Reference: ARABJC 825

To appear in: Arabian Journal of Chemistry

Received Date: 2 September 2012

Accepted Date: 30 December 2012

Please cite this article as: A.M.A. Al Majid, M.S. Islam, Z.A. Al-Othman, A.F. Al-Salhoob, Enantioselective

Additions of Diethylzinc to Aldehydes Catalysed by titanate(IV) complex with chiral bidentate bis-amide ligands

based on cyclopropane backbone, Arabian Journal of Chemistry (2013), doi: http://dx.doi.org/10.1016/j.arabjc.

2012.12.036

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Enantioselective Additions of Diethylzinc to Aldehydes Catalysed by titanate(IV) complex with chiral bidentate bis-amide ligands based on cyclopropane backbone

Abdullah M. A. Al Majid, Mohammad Shahidul Islam*, Zeid Abdullah Al-Othman and

Ahlam F. Al-Salhoob Department of Chemistry, Faculty of Science, King Saud University, P.O. Box 2455, Riyadh

11451, Saudi Arabia; E-Mail: amajid@ksu.edu.sa; zaothman@ksu.edu.sa; rhofy29@hotmail.com

* Author to whom correspondence should be addressed; E-Mail: mislam@ksu.edu.sa; Tel.:

+96614675884; Fax: +9661-4675992.

Abstract:

A set of chiral bis-amide ligands (4a-d and 5a-d) were obtained easily from readily available

starting materials in a straightforward manner via acid chloride reaction of the parent Feist's acid.

These ligands have been tested as chiral catalysts for the enantioselective addition of diethylzinc

to aromatic aldehydes in the presence of Ti(OiPr)4 as a co-additive. Very good enantioselectivity

was obtained for 4-bromobenzaldehyde while in case of 2,4-dichlorobenzaldehyde very low

enantioselectivity were observed. The influence of solvent, temperature and the alkyl group

substituents has been studied, and in the best case, an enantiomeric excess up to 95% has been

achieved by using only 10 mol % of the chiral bis-amides ligand 5b.

Graphical Abstract:

Keywords:

C2 symmetric Bis-amide Ligand, Diethylzinc Addition, Enantioselective Catalysis.

1. Introduction:

The enantioselective addition of organometallic reagents (Geng and Zhan, 2010) to prochiral

carbonyl compounds in the presence of chiral catalysts, has drawn a great deal of attention to the

synthetic organic chemists, because of its simple reaction conditions, low toxicity of the zinc

metal, and the huge number of functional group tolerance. Addition of organozinc is one of the

most reliable reactions for testing the effectiveness of newly developed chiral ligands (Pu and

Yu, 2001; Reetz, 1999; Noyori, 1994). It is also very useful reaction for the preparation of chiral

secondary alcohols and tert-alcohols, which are the key building blocks in the fine chemical and

pharmaceutical industries (Soai and Shibata, 1999). Furthermore, chiral alcohols are pervasive in

the skeleton of drug molecules, natural products, and also as an important organic precursors for

the preparation of many other functional organic entities (Ailing et al., 2006). Therefore an

asymmetric C–C bond construction, generation of stereogenic center in molecules have led to its

application in the preparation of optically active alcohols for the further synthesis of natural

products, drug molecules and biologically active molecules (Zhi-Long et al., 2009; Belén et al.,

2010 ). One of the most effective, convenient and useful methods for the asymmetric synthesis of

sec- and tert-alcohols is the enantioselective addition of dialkylzinc to carbonyl compounds in

the presence of a wide variety of chiral auxiliaries (Noyori and Kitamura, 1991; Soai and Niwa,

1992). A large number of chiral ligands have been reported in literature and successfully have

been employed in several asymmetric addition of diethylzinc to aldehydes, such as β-amino

alcohols (Andres et al., 2010; Le-sniak et al., 2009; Rodríguez-Escrich et al., 2008; Tanaka et al.,

2006), amino thiols and disulfides (Braga et al., 2008; Mellah et al., 2007; Braga et al., 2005),

aminonaphthols (Ko et al., 2002; Liu et al., 2001), imines (Mino et al., 2006; Qin et al., 2005),

diamines and their derivatives (Gao et al., 2010; Burguete et al., 2008; Mastranzo et al., 2006),

diols (Roudeau et al., 2006; Sarvary et al., 2002), Binols (Shaohua and Zaher, 2009; Yan et al.,

2008), diselenides, bisoxazolidines (Jacek et al., 2009; Devarajulu et al., 2007; Shen et al., 2000),

disulfonamides (Hirose et al., 2011; Huang et al., 2007), and diamide (Bateman et al., 2008; Blay

et al., 2007). Moreover, asymmetric addition of diethylzinc to aldehyde is the most successful

and still vigorously pursued area in asymmetric C-C bond formation (Manabu et al., 2006;

Noyori and Kitamura, 1991). Thus, addition of diethylzinc to aldehyde has become a classical

test in the design of new ligands for catalytic asymmetric synthesis. Thence forth, with the

development of diverse ligand structures and reaction conditions for the enantioselective

catalytic reactions, chiral bis-amides would be an attractive choice of catalysts, as a result of

their easy availability and simple reaction conditions.

Despite the enormous success of axial chiral ligands in asymmetric synthesis, a limited number

of chiral diamide type ligands have been reported (Umesh et al., 2012; Nallamuthu et al.,2009).

To the best of our knowledge, there are no reported ligands based on Feist's s acid in the long

catalyst list of the asymmetric addition of diethylzinc to aldehydes. Therefore, it would be the

great interest to explore the catalytic activity of C2 symmetric bis-amide ligands with a scaffold

of trans-3-methylenecyclopropane-1,2-dicarboxylic acid. Herein, we report the application of C2

symmetric bis-amide ligands obtained from Feist’s acid, for the catalytic enantioselective

addition of diethylzinc with 4-bromobenzaldehyde and 2,4-dichlorobenzaldehyde.

2. Experimental:

2.1. General

All the moisture and air sensitive reactions were carried out under an inert atmosphere using an

argon filled glove box and standard Schlenk-line techniques. All the reactions were monitored by

thin layer chromatography (TLC). Flash chromatography purifications were performed using

silica gel (100–200 mesh). Diethylzinc and Ti(OiPr)4 were purchased from Aldrich.

Triethylamine and diisopropylamine were dried over sodium hydroxide. Diethyl ether and

tetrahydrofuran were distilled from sodium benzophenone ketyl. Chloroform, dichloromethane,

benzene, toluene and dimethyformamide were dried using calcium hydride. Petroleum ether

(PE), hexane and ethyl acetate were distilled for column chromatography prior to use. 1H and 13C-NMR spectra were recorded on Jeol-400 spectrometer (1H 400 MHz, 13C 100 MHz): using

CDCl3 as solvent. The chemical shifts (δ in ppm) were referenced internally using residual non

deuterated solvent resonance shift and reported to trimethylsilane (TMS). Coupling constants (J)

are taken in Hertz (Hz). Optical rotation were recorded on a high sensitive automatic ‘A. KRÜSS

OPTRONOCS’ polarometer. Elemental analyses were performed on a Perkin Elmer 2400

Elemental Analyzer. Enantiomeric excess (ee) determination was carried out using HPLC with a

chiral Nucleosil® column; Solvent, 90:10 acetonitrile/water; Flow rate 0.5 mL.min-1; 220 nm UV

detection. IR spectra were recorded on a Model FTIR-800 Infrared FT-IR Spectrometer using

neat for liquids. Mass spectrometric analysis was conducted by using ESI mode on AGILENT

Technologies 6410-triple quad LC/MS instrument.

2.2. General procedure for enantioselective addition of diethylzinc to aromaticaldehydes

Ligand (10 mol%, 0.1 equiv.) and Ti(OiPr)4 (922 mg, 3.24 mmol, 1.2 equiv.) were dissolved in

dry toluene (5 ml) under argon atmosphere. The resulting mixture was heated at 60 oC for 20

min. Then it was cooled to 0 – 4 oC and a solution diethylzinc (5.4 ml, 5.4 mmol, 2 equiv., 1M in

hexane) was added drop wise to the reaction mixture. The resulting solution was stirred for 30

min at the identical condition. Aromaticaldehyde (2.7 mmol, 1 equiv.) dissolved in dry toluene (5

ml) was added slowly at this temperature. The reaction was stirred for the appointed time

mentioned in Table 1 and 2 for different condition. The reaction mixture was then quenched with

1M hydrochloric acid and extracted with ethyl acetate (3 × 10 ml). The combine organics were

extracts and dried over anhydrous Mg2SO4. The solvents were removed under reduced pressure

to afford crude product. The crude alcohol was purified by flash column chromatography on

silica gel (100-200 mesh) to afford the pure product. The enantiomeric excess was determined by

chiral HPLC ‘Nucleosil® chiral-1’ column.

2.3. Spectral data for 1-(4-bromophenyl) -1-propanol

IR (cm–1): 3359 (bs, OH str.), 2965 (s), 1486 (s), 1071 (s), 1009 (s), 820 (s), 542 (m); 1H-NMR

(CDCl3, 400 MHz) δ 0.88 (t, 3H, J = 7.32 Hz, CH3), 1.69 – 1.74 (m, 2H, CH2), 2.03 (s, 1H, OH),

4.54 (t, 1H, J = 6.60 Hz, CH), 7.18 – 7.20 (d, 2H, J = 8.04 Hz, ArH), 7.44 – 7.46 (d, 2H, J = 8.08

Hz, ArH); 13C-NMR (CDCl3, 100 MHz): δ 10.05 (CH3), 31.98 (CH2), 76.80 (CH), 121.25

(ArCBr), 127 (ArC), 131.52 (ArC); Anal. Calcd. for C9H11BrO: C, 50.26; H, 5.15; Br, 37.17;

Found: C, 50.38; H, 5.49; LC/MS (ESI): m/z = 215.12 {[M]+, for

79Br} and 217.1{ [M+2]+, for 81Br}.

1. [α]25D = + 23.25 (c = 0.31, CHCl3); % e.e. 60.69 (R) ; tR = 5.047 min for (S) and tR =

5.326 min for (R).

2. [α]25D = + 19.21 (c = 0.27, CHCl3); % e.e. 71.53 (R) ; tR = 5.073 min for (S) and tR =

5.376 min for (R).

3. [α]25D = + 23.25 (c = 0.31, CHCl3); % e.e. 71.70 (R) ; tR = 5.023 min for (S) and tR =

5.341 min for (R).

4. [α]25D = + 29.57 (c = 0.30, CHCl3); % e.e. 80.72 (R) ; tR = 5.034 min for (S) and tR =

5.378 min for (R).

5. [α]25D = + 33.26 (c = 0.28, CHCl3); % e.e. 84.69 (R) ; tR = 5.019 min for (S) and tR =

5.372 min for (R).

6. [α]25D = + 37.36 (c = 0.39, CHCl3); % e.e. 60.69 (R) ; tR = 5.040 min for (S) and tR =

5.369 min for (R).

7. [α]25D = + 22.79 (c = 0.29, CHCl3); % e.e. 58.63 (R) ; tR = 5.078 min for (S) and tR =

5.336 min for (R).

8. [α]25D = + 26.83 (c = 0.40, CHCl3); % e.e. 81.00 (R) ; tR = 5.036 min for (S) and tR =

5.378 min for (R).

2.4. Spectral data for 1-(2,4-dichlorophenyl)-1-propanol

IR (cm–1): 3351 (bs, OH str.), 2968 (s), 1467 (s), 1381 (s), 1097 (s), 1047 (s), 977 (s), 840 (s),

818 (s), 566 (s); 1H-NMR (CDCl3, 400 MHz) δ 0.95 (t, 3H, J = 7.32 Hz, CH3), 1.67 – 1.71 (m,

2H, CH2), 2.20 (s, 1H, OH), 4.98 (t, 1H, J = 2.20 Hz, CH), 7.31 – 7.32 (d, 2H, J = 2.2 Hz, ArH),

7.44 – 7.46 (d, 2H, J = 8.04 Hz, ArH); 13C-NMR (CDCl3, 100 MHz): δ 9.98 (CH3), 30.54 (CH2),

71.53 (CH), 127.39 (ArC), 128.22 (ArC), 129.10 (ArC), 132.54 (ArC), 133.37 (ArC), 140.69

(ArC); Anal. Calcd. for C9H10Cl2O: C, 52.71; H, 4.91; Cl, 34.57; O, 7.80; Found: C, 52.56; H,

5.18; LC/MS (ESI): m/z = 205.02 {[M]+, for 35Cl} and 207.2 {[M+2]+, for 37Cl}.

1. [α]25D = + 6.72 (c = 0.30, CHCl3); % e.e. 12.00 (R) ; tR = 5.191 min for (S) and tR = 7.441

min for (R).

2. [α]25D = + 3.80 (c = 0.28, CHCl3); % e.e. 16.44 (R) ; tR = 5.217 min for (S) and tR = 7.472

min for (R).

3. [α]25D = + 8.52 (c = 0.24, CHCl3); % e.e. 25.50 (R) ; tR = 5.206 min for (S) and tR = 7.434

min for (R).

4. [α]25D = + 7.94 (c = 0.31, CHCl3); % e.e. 9.13 (R) ; tR = 5.199 min for (S) and tR = 7.403

min for (R).

5. [α]25D = � 5.59 (c = 0.25, CHCl3); % e.e. 16.56 (S) ; tR = 5.208 min for (R) and tR = 7.416

min for (S).

6. [α]25D = � 4.79 (c = 0.41, CHCl3); % e.e. 17.00 (S) ; tR = 5.200 min for (R) and tR =

7.421 min for (S).

7. [α]25D = � 2.46 (c = 0.32, CHCl3); % e.e. 11.70 (S) ; tR = 5.214 min for (R) and tR =

7.408 min for (S).

8. [α]25D = � 6.08 (c = 0.25, CHCl3); % e.e. 10.30 (S) ; tR = 5.205 min for (R) and tR = 7.424

min for (S).

3. Result and Discussion

The reaction conditions and synthetic strategies, adopted in this work, have been described in

Schemes 1 and 2.

COOH

COOH

COOH

COOH

COOH

COOH

ONH

NHO R

R

(±)-Feist,s Acid(±)-1

R= a) tert-butylb) sec-butylc) iso-butyld) benzyl

(1R,2R)-(+)-2

(1S,2S)-(-)-3

(1R,2R)-(+)-4a-d

(1S,2S)-(-)-5a-d

NHO

NHO R

R

Scheme 1

Resolution(i)

(ii) & (iii)

(ii) & (iii)

Reagents and conditions:(i) alfa-Methylbenzylamine, isopropanol:water. (ii) CH2Cl2, (COCl)2,RT; (III) CH2Cl2, RNH2, DIPA.

Scheme 1. Outline for the synthesis of ligands (4a-d & 5a-d).

Scheme 1 shows the brief outline of synthetic routes leading to the formation of bis-amide

ligands (4a-b) and (5a-c) based on chiral cyclopropane backbone, which is to be used as base

catalysts. Synthesis of these chiral ligands initially require the preparation and the resolution of

chiral scaffold trans-3-methylene-1,2-dicarboxylic acid (Feist’s acid) reported by Almajid and

coworkers (Al-Majid et al., 2012a; Al-Majid et al., 2012b).19 The catalytic activity of these

ligand were investigated for the addition of diethylzinc to aldehydes (Scheme 2).

O

x x

i. Ligand (10 mol%), ii. Ti(iOPr)4 (1.2 eq.)

iii. Diethylzinc (2.0 eq.), iv. Toluene, r.t

y y OH

i. x = Br, y = Hii. x = y = Cl

% e.e 10-95%

Scheme 2. Addition of diethylzinc to aldehydes using ligand 4a-d & 5a-d (10 mol%).

Since the aromatic aldehydes are one of the most studied substrates in the enantioselective

addition of diethylzinc to aldehydes, we have employed these ligand as a base catalyst to find the

optimum reaction parameters such as the effect of solvents, the relative amount of catalyst

loading and the temperature, for the enantioselective addition of diethylzinc to 4-bromobenzal-

dehyde. The results of our initial investigation with (1R,2R)-4a and (1S,2S)-5a are shown in

Table 1.

Table 1. Enantioselective addition of diethylzinc to p-bromobenzaldehyde under different

conditions at 0 oC – RT. catalyzed by in situ-formed titanium(IV) complexes of ligands (1R,2R)-

4a and (1S,2S)-5a.

Entry Ligand Ti(OiPr)4/ ligand Et2Zn Solvent Time Yield (%)c e.e. (%)d

1 (1R,2R)-4a 1.0/0.05 1.2eq toluene 10 h 32 44

2 (1S,2S)-5a 1.0/0.05 1.2eq toluene 24 h 29 47

3 (1R,2R)-4a 1.0/0.05 1.2eq Benzene 30 h 15 13

4 (1S,2S)-5a 1.0/0.05 1.2eq THF 24 h 23 19

5 (1R,2R)-4a 1.0/0.05 1.2eq ether 36 h 19 17

6 (1R,2R)-4a 1.2/0.05 1.5eq toluene 24 h 48 51

7 (1S,2S)-5a 1.2/0.05 1.5eq CH2Cl2 24 h 13 67

8 (1R,2R)-4a 1.2/0.1 2.0eq toluene 24 h 63 61

9 (1S,2S)-5a 1.2/0.1 2.0eq toluene 24 h 70 85

10a (1R,2R)-4a 1.2/0.1 2.0eq toluene 30 h 30 78

11b (1R,2R)-4a 1.2/0.1 2.0eq toluene 6h 83 15

12 (1R,2R)-4a 1.2/0.1 2.0eq Benzen/Hexane 30 h 7 10

13 (1R,2R)-4a 1.2/0.1 2.0eq Toluene/Hexane 30 h 10 35

14 (1R,2R)-4a 1.2/0.1 2.0eq Toluene/ CH2Cl2 24 h 24 43

15 (1R,2R)-4a 1.2/0.1 2.0eq Toluene/THF 24 h 31 41 a Reaction was carried out at 0 – 4 oC for 3h then at r.t.; b Reaction was carried out at 80 oC for 6h.; c Isolated yield after column purification; d The e.e. values were determined by HPLC Nucleosil® chiral-1column.

Using different reaction parameters, moderate to good chemical and low to high enantiomeric

excesses were obtained. The optimum condition for both the chemical yields and enantiomeric

excesses were achieved with the combination of the substrate, Et2Zn, Ti(OiPr)4 and the ligand

(1:2:0.1.2:0.1) molar ratio in toluene at RT. for 24 hours (Table 1; entry 8 & 9). The reaction

carried out in different solvents such as benzene, Et2O, CH2Cl2 and THF, afforded low yield with

poor enantiomeric excess (Table 1; entries 3, 5, 7 and 4 accordingly). As compared to other

solvents, toluene gave better yield and enantiomeric excess in all cases (Table 1; entries 1, 2, 6, 8

& 9). For achieving better enantioselectivity, some reactions were carried out in a mixture (1:1

ratio) of two solvents and for longer time period (Table 1; entries 12-15), but neither

enantioselectivity nor chemical yields were improved. On increasing the loading percentage of

ligand from 5 to 10 mol% led to improve yield from 48 to 63% and 51% to 61% ee (Table 1;

entries 6 & 8). The yield of the reactions also could be improved on increasing the molar ratio of

diethylzinc (Table 1; entries 2, 6, 8). Significantly, the effect of temperature were also observed,

at lower temperature (0 - 10 oC for 3 hours and then for 21 hours at r.t.) high enantioselectivity

up to 78% and poor chemical yields were observed as expected. While at higher temperature

reaction took only 6 hours to complete and produced high chemical yield with poor enantiomeric

excess (Table 1; entries 10a & 11b). Optimum conditions were achieved, using 10 mol% of the

ligand, 2 eq. of diethylzinc, and 1.2 eq. of Ti(OiPr)4 in toluene (table 1; entry 8 & 9). Under the

optimum parameters, all the chiral bis-amide ligands 4a-d & 5a-d were employed for the

asymmetric addition of diethylzinc to 4-bromobenzaldehyde and 2,4-dichlorobenzaldehyd and

the corresponding results are shown in Table 2.

Table 2. Screening of Ligands 4a-d and 5a-d, complexed with Ti(OiPr)4 at room temperature in

catalytic enantioselective addition of diethylzinc to 4-bromobenzaldehyde and 2,4-dichloro

benzaldehyde in toluene.

R

O

H

i. ligand (4a-d & 5a-d)ii. Ti(OiPr)4(1.2 eq.)

R

OH

iii. Et2Zn (1M, 2 eq.)iv. toluene, 0oC-r.t.

R = 4-BrPh2,4-Cl2Ph

Entry Ligand %Mol Time Yield c (%) [α]25D; (in CHCl3) d e.e.e (%) Config.f

1a (1R,2R)-4a 10 24 h 63 + 23.25; (c, 0.31) 61 (R)

2 a (1R,2R)-4b 10 24 h 71 + 27.30; (c, 0.34) 72 (R)

3 a (1R,2R)-4c 10 24 h 76 + 19.21; (c, 0.27) 72 (R)

4 a (1R,2R)-4d 10 24 h 43 + 29.57; (c, 0.30) 81 (R)

5 a (1S,2S)-5a 10 24 h 70 + 33.26; (c, 0.28) 85 (R)

6 a (1S,2S)-5b 10 24 h 70 + 37.36; (c, 0.39) 95 (R)

7 a (1S,2S)-5c 10 24 h 58 + 22.79; (c, 0.29) 59 (R)

8 a (1S,2S)-5d 10 24 h 51 + 26.83; (c, 0.40) 81 (R)

9 b (1R,2R)-4a 10 24 h 65 + 6.78; (c, 0.30) 12 (R)

10 b (1R,2R)-4b 10 24 h 68 + 3.80; (c, 0.28) 16 (R)

11 b (1R,2R)-4c 10 24 h 64 + 8.52; (c, 0.24) 26 (R)

12 b (1R,2R)-4d 10 30 h 56 + 7.94; (c, 0.31) 9 (R)

13 b (1S,2S)-5a 10 24 h 60 - 5.59; (c, 0.25) 16 (S)

14 b (1S,2S)-5b 10 24 h 64 - 4.79; (c, 0.41) 17 (S)

15 b (1S,2S)-5c 10 24 h 52 - 2.46; (c, 0.32) 11 (S)

16 b (1S,2S)-5d 10 30 h 49 - 6.08; (c, 0.25) 10 (S) a 4-bromobenzaldehyde used as a substrate; b 2,4-dichlorobenzaldehyde used as a substrate; c Isolated yield after column purification; d Concentration of samples are in % and specific rotations values were taken at 21 oC; e The e.e. values were determined by chiral HPLC ‘Nucleosil® chiral-1’ column; 90:10 ACN/H2O; Flow rate 0.5 mL.min-1; λ = 220 nm); f Assigned by comparison of the specific rotation signs with those reported in the literature (Javier et al., 2006; Gonzalo et al., 2005; Ko et al., 2002).

The addition of diethylzinc to 4-bromobenzaldehyde under the optimized condition, all the

ligands produced (R)-1-(4-bromophenyl)-1-propanol with good yield and 95% ee (Table 2, entry

6a). But using the same parameters, in case of 2,4-dichlorobenzaldehyde afforded 1-(2,4-

dichlorophenyl)-1-propanol with very poor e.e (9-26%) and moderate chemical yield (52-65%).

The possible reason for low chemical yield and poor enantioselectivity is due to chlorine atom at

the ortho position of 2,4-dichloro benzalaldehyde. The proposed mechanism for the

enantioselective addition of diethylzinc to aldehyde in the presence of Ti(OiPr)4 has been shown

in Figure 1.

HNO

HNO

R

R

TiOiPr

NHO

NHO

R

R

O

OR

HO

RHR

Ti(OiPr)4

R

OHH

Ti(OiPr)4

TiiPrO

iPrOEtOiPr

Et2Zn

EtZnOiPr

TiiPrO

iPrO

iPrO

OiPr

ZnEt2Et2Zn + Ti(OiPr)4

OiPr

HNO

HNO

R

R

TiOiPr

Etre f acef avourable attack

NHHO

HNO

R

R

TiOiPr

HNO

HNO

R

R

TiOiPr

Et

R conf ig.

(A)

(B)

(C)

(D)(F)

Figure 1. Proposed mechanism for the enantioselective addition of Diethylzinc to aldehyde in

the presence of Ti(OiPr)4

The probable pathway has also been shown in Figure 2, for the formation of both enantiomers.

Figure 3 shows both the difficult and easy way of co-ordination for the oxygen atom towards

the metal center with proper orientation in case of both aldehydes.

Figure 2. Probable mechanism for the formation of opposite enantiomer

Cl

OH

TiN

N

Et

O

Cl

OH

TiN

N

Et

O

Br

dif ficult approach easy approach

Figure 3. Probable Transition States

4. Conclusions

This asymmetric alkylation approach provides a useful route for the synthesis of some chiral

secondary alcohols. We have conveniently applied the novel bis-amide ligands (4a-d & 5a-d) to

the catalytic asymmetric addition of diethylzinc to aldehydes under several conditions. The bis-

amide ligands provide excellent yield and good enantioselectivity. However, these ligands are

less effective in case of 2,4-dichlorobenzaldehyde. The oxygen atoms of aldehyde with ortho

substituents, thought to direct to the metal center of the complex, was difficult and led to a

decrease in both the yield and enantioselectivity. Further work is- in progress- in our laboratory

with the aim of expanding the use of these inexpensive chiral compounds to other

enantioselective processes.

Acknowledgment

The authors extend their appreciation to the Deanship of Scientific Research, at King Saud

University for funding the work through the research group project No. RGP-VPP-044.

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