Synthesis of enantiomerically enriched-bromonitriles from amino acids

Article abstract of DOI:10.1080/00397911.2011.608142

Two methods were investigated for the preparation of six chiral-bromonitriles with different optic purities. The nitrous deamination of amino acids gives-bromoacids, which react with chlorosulfonyl isocyanate followed by triethylamine to afford-bromonitriles with moderate enantiomeric excess. However, the dehydration of corresponding-bromoamids using thionyl chloride gives-bromonitriles with good enantiomeric excess up to 94%. The use of phosphoryl chloride instead of thionyl chloride results in more than 30% racemization as determined by high-performance liquid chromatograpic analysis.

Full text of DOI:10.1080/00397911.2011.608142

This article was downloaded by: [Linkopings universitetsbibliotek]
On: 28 February 2013, At: 13:15
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Synthesis of Enantiomerically Enriched
α-Bromonitriles from Amino Acids
Najeh Tka a , Jamil Kraïem a & Béchir Ben Hassine a
a Laboratoire de Synthèse Organique Asymétrique et Catalyse
Homogène, Faculté des Sciences de Monastir, Monastir, Tunisia
Accepted author version posted online: 22 Feb 2012.Version of
record first published: 13 Nov 2012.
To cite this article: Najeh Tka , Jamil Kraïem & Béchir Ben Hassine (2013): Synthesis of
Enantiomerically Enriched α-Bromonitriles from Amino Acids, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 43:5, 735-743
To link to this article: http://dx.doi.org/10.1080/00397911.2011.608142
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary
sources. The publisher shall not be liable for any loss, actions, claims, proceedings,
demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

Synthetic Communications1, 43: 735–743, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.608142
SYNTHESIS OF ENANTIOMERICALLY ENRICHED
a-BROMONITRILES FROM AMINO ACIDS
´
Najeh Tka, Jamil Kra¨ıem, and Bechir Ben Hassine
Laboratoire de Synthese Organique Asymetrique et Catalyse Homogene,
`
´
`
´
Faculte des Sciences de Monastir, Monastir, Tunisia
GRAPHICAL ABSTRACT
Abstract Two methods were investigated for the preparation of six chiral a-bromonitriles
with different optic purities. The nitrous deamination of amino acids gives a-bromoacids,
which react with chlorosulfonyl isocyanate followed by triethylamine to afford a-bromoni-
triles with moderate enantiomeric excess. However, the dehydration of corresponding
a-bromoamids using thionyl chloride gives a-bromonitriles with good enantiomeric excess
up to 94%. The use of phosphoryl chloride instead of thionyl chloride results in more than
30% racemization as determined by high-performance liquid chromatograpic analysis.
Keywords a-Bromoamids dehydration; chiral a-bromoacids; enantiomerically enriched
a-bromonitriles
INTRODUCTION
Bromonitriles are potentially useful intermediates used for the synthesis of
biologically active compounds.[1–2] Recently, the addition of Grignard reagents
to bromonitriles was found to be an efficient route to prepare heterocyclic systems
in particular functionalized cyclic imines used for alkaloid natural product syn-
thesis.[3–5] Although they have shown important synthetic utilities, bromonitriles
have not been well studied. Furthermore, the described methods often afford pro-
ducts in unsatisfactory way. Methods based on radical processes lead to a mixture
of isomers,[6–8] and most of methods based on nucleophilic substitution of the
hydroxyl group give poor yields or are time-consuming multistage processes.[9,10]
Somewhat frustratingly, the literature is bereft of reports concerning the prep-
aration of a-bromonitriles in an enantiomerically enriched form. To our knowledge,
only two examples have been described in the literature with no indication of the
Received March 31, 2011.
Address correspondence to Bechir Ben Hassine, Laboratoire de Synthese Organique Asymetrique
´
et Catalyse Homogene (01 UR 1201), Faculte des Sciences de Monastir, Avenue de l’Environnement,
`
´
`
5019, Monastir, Tunisia. E-mail: bechirbenhassine@yahoo.fr
´
735

€
N. TKA, J. KRAIEM, AND B. BEN HASSINE
736
products’ optical purity. Recently, Matveeva et al.[11] used the 2,4,4,6-tetrabromocy-
clohexa-2,5-dienone complex with triphenylphosphine for the synthesis of bromoni-
triles by nucleophilic substitution of optically active cyanodrins. The second
described method is the dehydration of optically active amide which affords
a-bromonitriles with moderate yields.[12–14] Therefore, there is further scope to
explore more efficient synthetic methods, giving a-bromonitriles in the combined
terms of quantitative yields and enantiomeric purity.
As part of our work aimed at the synthesis of new enantiomerically pure
nitriles from amino acids[15] and investigation of the synthesis of new biologically
active heterocyclic compounds,[16–18] herein we report the synthesis of new optically
active a-bromonitriles using inexpensive and readily available (L)-amino acids fol-
lowing two methods, leading to products with different enantiomeric excesses and
chemical yields.
RESULTS AND DISCUSSION
[19]
Larcheveque and Petit have described the enantiospecific transformation of
ˆ
(L)-serine to the corresponding 2-bromo-3-hydroxypropano€ꢀc acid. The reaction
occurred with retention of the configuration, which can be explained by the forma-
tion of lactone as intermediate. Following the some procedure, we have prepared
a-bromoacids 1a–f by nitrous deamination of commercially available (L)-amino
acids (Scheme 1). The reaction occurred with high stereospecificity as determined
by high-performance liquid chromatography (HPLC) using a chiral column. Opera-
tiing conditions were adjusted by injecting racemic a-bromoacids prepared from
(D, L)-amino acids.
Desired a-bromoacids were obtained with excellent chemical yields ranging
from 84% to 93% and were used as key products. We decided to use the (2S,3S)-2-
bromo-3-methylpentanoic acid 1d first to measure easily using 1H NMR the epimer-
ization of the asymmetric carbon C2, giving two diastereoisomers (2S,3S) and
(2 R,3S) (Scheme 2).
The first synthetic method is the most economical and allows direct access to
a-bromonitrile 2d. The (2S,3S)-2-bromo-3-methylpentanoic acid 1d react’s with
chlorosulfonyl isocyanate to give the N-chlorosulfonylamides, which can be con-
verted by equivalent amounts of triethylamine to their corresponding nitriles 2d.
This method[20] provides a-bromonitrile 2d in one step but with poor chemical yield
Scheme 1. Synthesis of enantiomerically pure a-bromoacids 1a–f from the corresponding natural a-amino
acids. a: R = Me; b: R = i-Pr; c: R = i-Bu; d: R = sec-Bu; e: R = Bn; f: R = Ph.

ENANTIOMERICALLY ENRICHED a-BROMONITRILES
737
Scheme 2. Synthesis of a-bromonitrile 2d from (2S,3S)-2-bromo-3-methylpentano€ꢀc acid 1d.
1
and epimerization exceeding 36% as detected by H NMR of compound 2d and
confirmed by gas-phase chromatography (GPC).
This result prompted us to try another approach to obtain nonracemic
a-bromonitriles. Perhaps the most efficient described method is the dehydration of
amids with different agents in particular phosphorus pentoxide.[21–23] Chiral
a-bromoamids 3a–f were prepared in good yields by simple treatment of
a-bromoacids 1a–f with thionyl chloride followed by ammonia.
According to the HPLC studies, chiral a-bromoamids 3a–f were formed with-
out significant racemization. Operatory conditions were adjusted by injecting
racemic a-bromoamids prepared from (D, L)-amino acids. The (2S,3S)-2-bromo-3-
methylpentane amide 3d containing two asymmetric carbons was first dehydrated
by phosphoryl chloride. Dehydration occurred using POCl3 as solvent and reagent
at a temperature of 40 ꢀC for 3 h (Scheme 3). Chemical yield of obtained 2-bromo-3-
methylpentane nitrile 4d was acceptable; however, an important epimerization
around 30% has been detected.
1
This epimerization was measured by H NMR according to the signal relative
to the proton linked to the asymmetric carbon bearing the nitrile group, which reso-
nates in different positions for each pair of diasteromers. As shown in Fig. 1, the sig-
nal of this proton appeared as two doublets: a first doublet at 4.44 ppm (J ¼ 4.8 Hz)
corresponding to the diastereomer (2S,3S) and a second doublet at 4.45 ppm
(J ¼ 4.2 Hz) corresponding to the diastereomer (3S,2 R) relative to the partial epi-
merization of carbon C2. This eventual epimerization can be explained by the
Scheme 3. Dehydration of a-bromoamids 3d using POCl3 and SOCl2.

€
N. TKA, J. KRAIEM, AND B. BEN HASSINE
738
Scheme 4. Synthesis of a-bromonitriles 4a–f from the corresponding a-bromoamids 3a–f. a: R = Me; b:
R = i-Pr; c: R = i-Bu; d: R = sec-Bu; e: R = Bn; f: R = Ph; g: R = i-Pr (racemic).
electron-withdrawing effect of the cyano group which makes the proton of the asym-
metric carbon somewhat acidic. POCl3 frees POCl2 (OH) during the reaction and,
then the presence of such a basic site would catalyze the racemization process by
interaction with the acidic proton. We decided then to use thionyl chloride as
dehydrating agent, which was expected to give better results (Scheme 3). Unlike
POCl3, by-products from the dehydration by SOCl2 are HCl (g) and SO2 (g), which
is convenient to avoid the racemization, because there is no possible acid–base inter-
action between the acidic proton of a-bromonitrile. As expected, the dehydration
of (2S,3S)-2-bromo-3-methylpentane amide 3d is accompanied by only a slight epi-
1
merization, which was not detected by H NMR (see Fig. 1). This unavoidable epi-
merization was measured by GPC and did not exceed 4% (see Fig. 2).
We applied thionyl chloride to dehydrate the other a-bromoamides 3a–f leading to
the corresponding a-bromonitriles 4a–f with good yields (Scheme 4). Enantiomeric
ratios were measured by HPLC using a chiral Chirobiotic V column and did not change
significally for the series of compounds. As shown in Table 1, partial racemization was
still evident in all cases. This eventual racemization is the result of heating the mixture of
a-bromoamide and thionyl chloride for 2 h at 79 ꢀC. We note that a-bromonitrile 4a–f
Figure 1. Signal of the Cꢁ-H proton of a-bromonitrile 4d dehydrated with phosphoryl chloride (a) and
thionyl chloride (b).

ENANTIOMERICALLY ENRICHED a-BROMONITRILES
739
Figure 2. GPC of a-bromonitrile 4d dehydrated by phosphoryl chloride (a) and thionyl chloride (b).
Table 1. Synthesis of a-bromonitriles 4a–f from the corresponding a-bromoamids 3a–f
using thionyl chloride
Amino acids
a-Bromonitriles
R
Yields (%)
Ee (%)
Alanine
Valine
Leucine
4a
4b
4c
4d
4e
4f
Me
90
88
92
90
86
77
94
93
91
92
90
88
i-Pr
i-Bu
sec-Bu
Bn
Isoleucine
Phenylalanine
Phenylglycine
Ph
are colorless liquids and could be chromatographed on a flash neutral alumina-gel
column with no detectable changes in enantiomeric enrichment.
CONCLUSION
To conclude, the preparation of enantiomerically enriched a-bromonitriles from
their corresponding amino acids has been achieved for the first time by investigating
two synthetic methods. Dehydration of chiral a-bromoamides using thionyl chloride
gave the best results in the combined terms of quantitative yields and enantiomeric
purity. The study of the synthetic features of these products to prepare new chiral bio-
logically active heterocyclic compounds is under investigation in our laboratory.
EXPERIMENTAL
Typical Procedure for the Preparation of a-Bromonitrile from
Corresponding a-Bromoacid
a-Bromo acid (5 mmol) was dissolved in 40 mL of anhydrous dichloromethane,
and then chlorosulfonyl isocyanate (CSI) (5 mmol) was added dropwise. The mixture

€
N. TKA, J. KRAIEM, AND B. BEN HASSINE
740
was stirred for 1 h at room temperature and then refluxed for 2 h until the end of car-
bon dioxide evolution. The mixture was cooled in an ice bath (0 ꢀC) and 5 mmol of
freshly distilled triethylamine was added dropwise. The mixture is stirred again for
1 h at room temperature until the end of HCl evolution and then washed once with
50 mL of saturated NaHO3 and twice with 100 mL of water. The aqueous phase were
then extracted with 2 ꢂ 100 mL of dichloromethane. The combined organic layers
were dried over MgSO4, filtered, and concentrated under reduced pressure. The resi-
due obtained was purified by column chromatography on neutral alumina [cyclohex-
ane–ethylacetate (80:20)].
Typical Procedure for the Preparation of a-Bromoamides
A mixture of a-bromoacid (5 mmol), SOCl2 (20 mmol), and three drops of dry
DMF in anhydrous dichloromethane was stirred overnight at room temperature.
After removal of the excess of SOCl2 under vacuum, the residue was added slowly
to a cold solution of aqueous ammonium hydroxide and was allowed to warm slowly
to room temperature with stirring. The mixture was filtered, and the resultant solid
was dissolved in boiling ethanol. The solution was then filtered while hot, and water
was added dropwise to the cloud point. After cooling, the pure a-bromoamides 3a–f
were collected.
(2S)-2-Bromopropanamide 3a. Yield 82%; mp 63–65 ꢀC; [a]D ꢃ20.0 (c
0.33%, CHCl3): ee > 99.5% [HPLC analysis using a Chirobiotic V column
(4.6 mm ꢂ 250 mm) under the following conditions: heptane=isopropanol as mobile
phase, rt, (¼254 nm, flow rate ¼ 0.6 mL=min, retention time: 30.88 min]; IR (cmꢃ1):
1
nCO ¼ 1716; nN-H ¼ 3432; H NMR (300 MHz, CDCl3): d 1.88 (d, 3H, J ¼ 6.9 Hz),
3.79 (q, 1H, J ¼ 6.9 Hz), 6.14 (s, 1H), 6.44 (s, 1H); 13C NMR (75 MHz, CDCl3), d
21.47, 39.52, 175.71 (CO). Anal. calcd. for C3H6BrNO, 151.99: C, 23.71, H, 3.98,
N, 9.22. Found: C, 23.76; H, 4.02; N, 9.25.
(2S)-2-Bromo-3-methylbutanamide 3b. Yield ¼ 88%; mp 92–94 ꢀC; [a]D
ꢃ25.0 (c 0.33%, CHCl3): ee > 99.5% [HPLC analysis using a Chirobiotic V column
(4.6 mm ꢂ 250 mm) under the following conditions: heptane=isopropanol as mobile
phase, rt, k¼254 nm, flow rate ¼ 0.6 mL=min, retention time: 32.96 min]; IR (cmꢃ1):
1
nCO ¼ 1712, nN-H ¼ 3435; H NMR (300 MHz, CDCl3): d 1.07 (d, 3H, J ¼ 6.6 Hz),
1.12 (d, 3H, J ¼ 6.9 Hz), 2.26 (m, 1H), 4.08 (d, 1H, J ¼ 7.5 Hz), 6.22 (s, 1H); 6.52(s,
1H); 13C NMR (75 MHz, CDCl3); d19.77, 20.14, 32.15, 54.11, 173.01 (CO). Anal.
calcd. for C5H10BrNO, 180.05: C, 33.36; H, 5.60; N, 7.78. Found: C, 33.39; H,
5.64; N, 7.81.
(2S)-2-Bromo-4-methylpentanamide 3c. Yield ¼ 82%; mp 73–75 ꢀC; [a]D
ꢃ30.0 (c 0.33%, CHCl3): IR (cmꢃ1): nCO ¼ 1719, nN-H ¼ 3439; 1H NMR
(300 MHz, CDCl3): d 0.90 (d, 3H, J ¼ 6.3 Hz), 0.96 (d, 3H, J ¼ 6.3 Hz), 1.90 (m,
3H), 4.37 (dd, 1H, J1 ¼ 5.7 Hz, J2 ¼ 5.7 Hz), 6.20(s, 1H), 6.32 (s, 1H); 13C NMR
(75 MHz, CDCl3), d 21.02, 22.71, 26.35, 44.50, 49.13, 172.08 (CO).
(2S,3S)-2-Bromo-3-methylpentanamide 3d. Yield ¼ 90%; mp 83–85 ꢀC;
[a]D ꢃ35.0 (c 0.33%, CHCl3): IR (cmꢃ1): nCO ¼ 1724, nN-H ¼ 3430; 1H NMR
(300 MHz, CDCl3): d 0.94 (t, 3H, J ¼ 7.2 Hz), 1.11 (d, 3H, J ¼ 6.6 Hz), 1.32 (m,

ENANTIOMERICALLY ENRICHED a-BROMONITRILES
741
1H), 1.81 (m, 1H), 2.09 (m, 1H), 4.18 (d, 1H, J ¼ 8.1 Hz), 6.04 (s, 1H), 6.44 (s, 1H);
13C NMR (75 MHz, CDCl3), d11.01, 16.64, 26.58, 38.46, 52.91, 170.96 (CO). Anal.
calcd. for C6H12BrNO, 194.07: C, 37.13; H, 6.23; N, 7.22. Found: C, 37.17; H, 6.26;
N, 7.26.
(2S)-2-Bromo-3-phenylpropanamide 3e. Yield ¼ 85%; mp 103–105 ꢀC;
[a]D ꢃ40.0 (c 0.33%, CHCl3); IR (cmꢃ1): nCO ¼ 1714, nN-H ¼ 3432; 1H NMR
(300 MHz, CDCl3): d 3.54 (d, 1H), 3.41 (d, 1H), 4.52 (t, 1H), 6.22 (s, 1H), 6.52 (s,
1H), 7.07–7.65 (m, 5H), 13C NMR (75 MHz, CDCl3), d 33.58, 60.09, 126.62,
127.22, 128.31, 129.16, 129.75, 35.53, 137.35, 143.68, 177.98. Anal. calcd. for
C9H10BrNO, 228.09: C, 47.39; H, 4.42; N, 6.14. Found: C, 47.42; H, 4.47; N, 6.19.
(2S)-2-Bromo-2-phenylethanamide 3f. Yield ¼ 79%; [a]D ꢃ45.0 (c 0.33%,
CHCl3); IR (cmꢃ1): ee > 99.5% [HPLC analysis using a Chirobiotic V column
(4.6 mm ꢂ 250 mm) under the following conditions: heptane=isopropanol as mobile
phase, rt, k¼254 nm, flow rate ¼ 0.6 mL=min, retention time: 28.52 min]; nCO ¼ 1711,
1
nN-H ¼ 3433; H NMR (300 MHz, CDCl3): d 4.25 (s, 3H), 6.02 (s, 1H), 6.32 (s, 1H),
7.18–7.71 (m, 5H); 13C NMR (75 MHz, CDCl3), d 40.47, 128.74, 129.55, 130.16,
134.75, 171.13 (CO).
Typical Procedure for the Dehydration of a-Bromoamides
The a-bromoamide (4 mmol) was dissolved in 20 mL of freshly distilled thionyl
chloride. The mixture was refluxed for 2 h until the amide was consumed (as moni-
tored by thin-layer chromatography, TLC). The excess of thionyl chloride was
removed under vacuum using a rotary evaporator, and the reaction residue was then
mixed with crushed ice and extracted with ethylacetate (3 ꢂ 50 mL). The organic
layers were combined, washed sequentially with a saturated aqueous NaHCO3 sol-
ution and water, and dried with anhydrous MgSO4. After that, the solvent was
removed under vacuum and the crude product was purified by column chromato-
graphy on a neutral alumina gel, using [cyclohexane–ethylacetate (8:2)], to afford
pure a-bromonitriles 4a–f.
(2S)-2-Bromopropanenitrile 4a. Yield ¼ 90%; [a]D ꢃ50.0 (c 0.25%, CHCl3);
HRMS-ESI calcd. for C3H4BrN 132.95274; found 132.95279; ee ꢄ94% [HPLC
analysis using a Chirobiotic V column (4.6 mm ꢂ 250 mm) under the following con-
ditions: heptane=isopropanol as mobile phase, rt, k¼254 nm, flow rate ¼ 0.6 mL=
min, retention time: 15.25 min, 17.94 min]; IR (cmꢃ1): nCN ¼ 2249; 1H NMR
(300 MHz, CDCl3): d 1.97 (d, 3H, J ¼ 7.2 Hz), 4.38 (q, 1H, J ¼ 6.9 Hz); 13C NMR
(75 MHz, CDCl3), d 21.21, 23.91, 118.26 (CN).
(2S)-2-Bromo-3-methylbutanenitrile 4b. Yield ¼ 88%; [a]D ꢃ55.0 (c 0.25%,
CHCl3); HRMS-ESI calcd. for C5H8BrN 160.98403; found 160.98408; ee ꢄ93%
[HPLC analysis using a Chirobiotic V column (4.6 mm ꢂ 250 mm) under the follow-
ing conditions: heptane=isopropanol as mobile phase, rt, k¼254 nm, flow rate -
¼ 0.6 mL=min, retention time: 17.66 min, 19.54 min]; IR (cmꢃ1); nCN ¼ 2239; 1H
NMR (300 MHz, CDCl3): d1.15 (d, 3H, J ¼ 2.4 Hz), 1.18 (d, 3H, J ¼ 2.4 Hz), 2.16
(m, 1H), 4.24 (d, 1H, J ¼ 5.1 Hz); 13C NMR (75 MHz, CDCl3), d 19.09, 19.59,
33.89, 35.75, 116.60 (CN).

€
N. TKA, J. KRAIEM, AND B. BEN HASSINE
742
(2S)-2-Bromo-4-methylpentanenitrile 4c. Yield ¼ 92%; [a]D ꢃ60.0 (c
0.25%, CHCl3); HRMS-ESI calcd. for C6H10BrN 174.99969; found 174.99972; ee
ꢄ91% [HPLC analysis using a Chirobiotic V column (4.6 mm ꢂ 250 mm) under the
following conditions: heptane=isopropanol as mobile phase, rt, k¼254 nm, flow rate
¼ 0.6 mL=min, retention time: 19.01 min, 22.66 min]; IR (cmꢃ1): nCN ¼ 2242; 1H
NMR (300 MHz, CDCl3): d 0.93 (m, 6H), 1.87–2.02 (m, 3H), 4.29 (m, 1H); 13C
NMR (75 MHz, CDCl3), d 21.64, 25.66, 26.63, 45.17, 52.65, 117.66 (CN).
(2S,3S)-2-Bromo-3-methylpentanenitrile 4d. Yield ¼ 90%; [a]D ꢃ65.0 (c
0.25%, CHCl3); HRMS-ESI calcd. for C6H10BrN 174.99969; found 174.99974; ee
ꢄ92% [HPLC analysis using a Chirobiotic V column (4.6 mm ꢂ 250 mm) under the
following conditions: heptane=isopropanol as mobile phase, rt, k¼254 nm, flow rate
¼ 0.6 mL=min, retention time: 21.81 min, 23.27 min]; IR (cmꢃ1), nCN ¼ 2240; 1H
NMR (300 MHz, CDCl3): d 0.97 (t, 3H, J ¼ 7.5 Hz), 1.17 (d, 3H, J ¼ 6.6 Hz), 1.48
(m, 1H), 1.69 (m, 1H), 1.97 (m, 1H), 4.33 (d, 1H, J ¼ 4.8 Hz), 13C NMR (75 MHz,
CDCl3), d11.38, 16.03, 26.98, 34.22, 40.39, 116.43 (CN).
(2 s)-2-Bromo-3-phenylpropanenitrile 4e. Yield ¼ 86%; [a]D ꢃ70.0 (c
0.25%, CHCl3); ee ꢄ90% [HPLC analysis using a Chirobiotic V column
(4.6 mm ꢂ 250 mm) under the following conditions: heptane=isopropanol as mobile
phase, rt, k¼254 nm, flow rate ¼ 0.6 mL=min, retention time: 22.65 min, 25.33 min];
1
IR (cmꢃ1); nCN ¼ 2245; H NMR (300 MHz, CDCl3): d 3.38 (d, 1H), 3.42 (d, 1H),
4.43 (dd, 1H, J1 ¼ 7.2 Hz, J2 ¼ 7.5 Hz), 7.28–7.45 (m, 5H); 13C NMR (75 MHz,
CDCl3), d 27.75, 43.07, 117.35 (CN), 128.71, 129.41, 129.74, 135.00.
(2S)-2-Bromo-2-phenylethanenitrile 4f. Yield ¼ 77%; [a]D ꢃ45.0 (c 0.33%,
CHCl3); ee ꢄ88% [HPLC analysis using a Chirobiotic V column (4.6 mm ꢂ 250 mm)
under the following conditions: heptane=isopropanol as mobile phase, rt, k¼254 nm,
flow rate ¼ 0.6 mL=min, retention time: 20.64 min, 22.87 min]; IR (cmꢃ1);
1
nCN ¼ 2238; H NMR (300 MHz, CDCl3): d 4.25 (s, 1H), 7.18–7.61 (m, 5H); 13C
NMR (75 MHz, CDCl3), d 40.47, 118.11 (CN), 128.74, 129.55, 130.16, 134.75.
ACKNOWLEDGMENT
´ ´
The authors thank the Direction Generale de la Recherche Scientifique of the
Tunisian Ministry of Higher Education and Scientific Research for the financial
support of this research.
REFERENCES
1. Sarges, R.; Hank, R. F.; Blake, J. F.; Bordner, J.; Bussolotti, D. L.; Hargrove, D. M.;
Treadway, J. L.; Gibbs, E. M. Glucose transport-enhancing and hypoglycemic activity
of 2-methyl-2-phenoxy-3-phenylpropanoic acids. J. Med. Chem. 1996, 39, 4783–4803.
2. Geies, A. A. Bromonitriles in heterocyclic synthesis: Synthesis and reactions of thiazo-
lo[3,2-a]pyrimidines (III). Collect. Czech. Chem. Commun. 1992, 57, 1565–1569.
3. Monterde, M. I.; Brieva, R.; Gotor, V. Stereocontrolled chemoenzymatic synthesis of
2,3-disubstituted piperidines. Tetrahedron: Asymmetry 2001, 12, 525–528.

ENANTIOMERICALLY ENRICHED a-BROMONITRILES
743
4. Fry, D. F.; Brown, M.; McDonald, J. C.; Dieter, R. K. Synthesis of functionalized cyclic
imines by addition of Grignard reagents to x-bromonitriles and c,d-unsaturated nitriles.
Tetrahedron Lett. 1996, 37, 6227–6230.
5. Thibonnet, J.; Knochel, P. Preparation of functionalized alkenylmagnesium bromides via
a bromine-magnesium exchange. Tetrahedron Lett. 2000, 41, 3319–3322.
6. Couvreur, P.; Bruylants, A. Reaction of N-bromosuccinimide with nitriles, II: 2,3-
Aliphatic nitriles. J. Org. Chem. 1953, 18, 501.
7. Couvreur, P. Bruylants, A. Les nitriles et les amides bromcrotoniques III action de la
`
N-Bromsuccinimide sur les butenes-nitriles. Bull. Soc. Chim. Belg. 1952, 61, 253.
8. Seux, R.; Morel, G.; Foucaud, A. Action des phenylacetonitriles a-substitues sur les
tetrahalomethanes en milieu basique: Mecanismes de l’halogenation et de la duplication.
Tetrahedron 1975, 31, 1335–1341.
9. Tsuji, T.; Watanabe, Y.; Mukaiyama, T. One-step formation of alkynes from aryl ketones.
Chem. Lett. 1979, 5, 481–482.
10. Mukaiyama, T.; Kawata, K.; Sasaki, A.; Asami, M. A convenient method for the prep-
aration of a-chloronitriles. Chem. Lett. 1979, 9, 1117–1118.
11. Matveeva, E. D.; Podrugina, T. A.; Tishkovskaya, E. V.; Zefirov, N. S. 2,4,4,6-
Tetrabromocyclohexa-2,5-dienone in the presence of triphenylphosphine as a specific
reagent for nucleophilic substitution in cyanohydrins. Mendeleev Commun. 2003, 13,
260–261.
12. Ichimura, K.; Ohta, M. Umwandlung von Aldehyden in 2-monosubstituierte Aziridine:
Reduktion von a-Chlor, Brom- und Sulfonyloxynitilen mit Lithiumaluminiumhydrid.
Bull. Chem. Soc. Japan 1970, 43, 1443–1450.
13. Walborsky, H. M.; Motes, J. M. Cyclopropanes, XXV: The cyclopropyl anion. J. Am.
Chem. Soc. 1970, 92, 2445–2450.
14. Carlier, P. R.; Zhang, Y. The first enantioenriched metalated nitrile possessing macro-
scopic configurational stability. Org. Lett. 2007, 9, 1319–1322.
15. Tka, N.; Kraiem, J.; Kacem, Y.; Hajri, A.; Ben Hassine, B. Synthesis of new enantiomeri-
cally pure N-methyl-N-arylsulfonyl-a-aminonitriles from amino acids. C. R. Chimie. 2009,
12, 1066–1071.
16. Tka, N.; Jegham, N.; Ben Hassine, B. Synthesis, antibacterial, and antifungal activities of
new chiral 5-alkyl-3-(10-benzenesulfonylpyrrolidin-20-yl)-4,5-dihydro-1,2,4-oxadiazin-6-
ones. C. R. Chim. 2010, 13, 1278–1283.
17. Tka, N.; Ben Hassine, B. One-pot synthesis of new biologically active 3,5-disubstituted-1-
,2,4-oxadiazoles. Synth. Commun. 2010, 40, 3168–3176.
18. Tka, N.; Ben Hassine, B. New chiral aminoamidoximes: Syntheses and investigation of
heterocyclic compounds. Synth. Commun. 2012, 42, 828–835.
´
´
´
19. Larcheveque, M.; Petit, Y. Preparation d’ a-hydroxyesters et d’a-hydroxyaldehydes enan-
´
`
`
´
´
´
tiomeriquement purs: Application a la synthese enantiospecifique de la phermone sexuelle
de la cochenille Pseudococus comstoki. Bull. Soc. Chim. Fr. 1989, 1, 130.
20. Vorbruggen, H.; Krolikiewicz, K. The introduction of nitrile groups into heterocycles and
¨
conversion of carboxylic groups into their corresponding nitriles with chlorosulfonyliso-
cyanate and triethylamine. Tetrahedron 1994, 50, 6549–6558.
21. Oakes, F. T.; Leonard, N. J. Broadened scope of translocative rearrangements:
Substituted 1,2,3-triazolo[1,5-a]-1,3,5-triazines. J. Org. Chem. 1985, 50, 4986–4989.
22. Dowd, P.; Kaufman, C.; Kaufman, P. b-Methylene-DL-asparagine. J. Org. Chem. 1985,
50, 882–885.
23. Kaiser, D. A.; Kaye, P. T.; Pillay, L.; Roos, G. H. P. Preparation of nitriles by
dehydration of primary carboxawides with a supported phosphorus pentoxide reagent.
Synth. Commun. 1984, 14, 883–888.