Stereoselective radical bromination of α-chloro hydrocinnamic acid derivatives

Article abstract of DOI:10.1016/S0040-4039(00)00220-3

Reaction of (S)-2-chloro-3-phenylpropanoic acid derivatives with NBS gave the corresponding 3-bromo-2-chloro derivatives with a preference for the formation of the (2R,3S) isomers over the (2R,3R) isomers. The stereoselectivity was affected by the nature

Full text of DOI:10.1016/S0040-4039(00)00220-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2671–2674
Stereoselective radical bromination of α-chloro hydrocinnamic
acid derivatives
Leh See Wong, Bun Chan and Eng Wui Tan ∗
Department of Chemistry, University of Otago, PO Box 56, Dunedin, New Zealand
Received 15 December 1999; accepted 3 February 2000
Abstract
Reaction of (S)-2-chloro-3-phenylpropanoic acid derivatives with NBS gave the corresponding 3-bromo-2-
chloro derivatives with a preference for the formation of the (2R,3S) isomers over the (2R,3R) isomers. The
stereoselectivity was affected by the nature of the carboxylic acid derivative. Reaction of ester derivatives was
highly stereoselective while the reaction of amide derivatives showed varied stereoselectivity which depended on
the nature of the amide. Theoretical studies at UHF/3-21G* level showed that the intermediate benzylic radical
of the methyl ester, the methyl amide and the diisopropyl amide derivatives had different energy profiles with
respect to rotation of the C2–C3 bond. The different stereoselectivity observed from reaction of the various acid
derivatives could be attributed, at least in part, to different distribution of conformers of the radical intermediate.
© 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
It has been reported that radical bromination of methyl (S)-2-chloro-3-phenylpropanoate 1a gave
predominantly the methyl (2R,3S)-3-bromo-2-chloro-3-phenylpropanoate 2a (Scheme 1).1 The result
was attributed to the formation of a chloro bridge in the radical intermediate.2 In this article we report
experimental and theoretical studies of radical bromination of α-chloro carboxylic acid derivatives
analogous to 1a, as part of a detailed study of stereoselective radical bromination of α-chloro carboxylic
acid derivatives.
2. Results and discussion
α-Chloro hydrocinnamic acid derivatives 1a–j were prepared by converting the carboxylic acid3 to
the acid chloride, and reacting the acid chloride with the appropriate alcohol or amine.4 Bromination
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00220-3
tetl 16500

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Scheme 1.
of the α-chloro acid derivatives was carried out with NBS in refluxing CCl4, with irradiation from a
1
160 W mercury gas discharge lamp.5 The reaction mixture was analysed by H NMR spectroscopy to
determine the extent of reaction and diastereomeric excess. In all cases, the crude mixture contained
only the corresponding α-chloro β-bromo acid derivatives 2 and 3 and succinimide. The ratio of the
two diastereomers 2 and 3 was determined from the relative integration of the α-proton and/or β-
proton signals of the two isomers. The stereochemical configuration of the α-chloro β-bromo esters was
assigned by comparing their 1H NMR spectra to that of 2a and 3a. The major isomers from the reactions
of the p-nitrophenyl amide 1f and the diisopropyl amide 1j were identified to be 2f and 2j, respectively,
by X-ray crystallography.6 The configuration of products from bromination of other amides was assigned
by comparing their NMR spectra to the spectra of 2f and 2j. The diastereoselectivity observed is shown
in Table 1.
Table 1
Ratio of diastereomeric α-chloro β-bromo acid derivatives 2 and 3 from NBS bromination of α-chloro
acid derivative 1
Bromination of different α-chloro esters showed no significant difference in the diastereomeric ratio of
the products. In contrast to the reported high diastereoselectivity of bromination of 1a, the reaction of the
corresponding methyl amide 1d gave a low preference for the formation of the (2R,3S) isomer 2d. The
stereoselectivity achieved from the reaction of other amides remained close to that of the methyl amide.
However, replacing a primary amide with a secondary amide significantly raised the preference for the
formation of the (2R,3S) isomer 2, and the selectivity increased with the bulkiness of the substituents.

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Theoretical studies were carried out to determine the energy profile of C2–C3 bond rotation of the
radical intermediates of 1a (ester), 1d (primary amide) and 1j (secondary amide). Geometry optimisations
were carried out on MacSpartan Plus™.7 The dihedral angle 1 (DA1=C1–C2–C3–CPh) was fixed at a
specific angle (0, 30, 60...330°) and the dihedral angle 2 (DA2=O(carbonyl)–C1–C2–C3) was changed
from 0 to 330° with an interval of 30°. The energy of different conformers with a specific DA1 was
obtained at SYBYL level to determine the preferred conformation of each DA1-fixed conformer. The
geometry of each DA1-fixed conformer was then optimised at AM1 level and refined at UHF/3-21G*
level. The results are shown in Fig. 1.
Fig. 1. Energy versus dihedral angle (Cl–C2–C3–CPh). Profile of the intermediate radical of the methyl ester 1a, methyl amide
1d and diisopropyl amide 1j. Calculated at UHF/3-21G* level
The energy profile for the radical intermediate of the α-chloro methyl ester 1a showed two local
minima (DA1=60, 270°) (Fig. 2). The global minimum (DA1=270°) places the phenyl group and the
ester in an anti configuration and the chlorine parallel to the p-orbital of the benzylic radical. Presumably,
this conformation minimises steric interactions and maximises any potential stabilisation of the radical
by neighbouring chlorine. Bromine atom transfer is more likely to occur on the less hindered si face. This
leads to the formation of the (2R,3S) isomer. The local minimum at DA1=60° has the si face hindered
by the chlorine and the re face hindered by the ester. There is no clear facial preference for bromine
atom transfer. The α-chloro methyl amide 1d showed three minima in its energy profile (DA1=60, 210
and 270°), and the minimum with DA1=210° was the global minimum. In this conformation, the amide
is parallel to the p-orbital of the radical. In a related system, an amide neighbouring group effect has
been suggested which could account for this preferred conformation.8 Bromine atom transfer to this
conformer would occur preferentially from the re face to give the (2R,3R) product and hence lower the
overall preference for the formation of the (2R,3S) product. The energy profile of the α-chloro diisopropyl
amide 1j showed three local minima (DA1=60, 210 and 270°). However, while the global minimum of
the methyl amide occurred at DA1=210°, that of the diisopropyl amide occurred at DA1=270°. This can
be attributed to the bulkier amide experiencing more severe non-bonding interactions with the phenyl
group, thus favouring an anti arrangement.
Fig. 2. Minimum energy C2–C3 rotation conformers of the intermediate radical

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The difference in stereoselectivity of bromination cannot be explained solely by these bond conformer
distributions. For instance, if bromine atom transfer to the radical intermediate of the α-chloro amide
1d only occurred at the preferred face of each minimum energy C2–C3 rotation conformer at the same
rate, the (2R,3R) isomer 3d is expected to be the major product, in contrast to observation. It has been
suggested that in addition to the relative population of minimum energy conformers, the relative energy
of the transition states for atom transfer to the two prochiral faces of each minimum energy conformer
is also important in determining the product distribution.9 The calculation of transition state energies is
beyond the scope of this communication.
3. Conclusion
The stereoselectivity of radical bromination of α-chloro hydrocinnamic acid derivatives was found to
be affected by the nature of the acid derivative. α-Chloro esters consistently showed high preference
for formation of the (2R,3S) α-chloro β-bromo derivative. Primary amide analogues showed low
stereoselectivity. Bromination of secondary amides showed higher stereoselectivity than the primary
amides, and the selectivity generally increased with the bulkiness of the amide. The difference in the
outcome can be partly attributed to the different distribution of C2–C3 rotation conformers of the radical
intermediate for each class of compound.
References
1. Shaw, J. P.; Tan, E. W. J. Org. Chem. 1996, 61, 5635.
2. For an overview, see: Skell, P. S.; Shea, K. J. In Free Radicals; Kochi, J. K., Ed. Bridged free radicals. John Wiley & Sons:
New York, 1973; Vol. II, pp. 809–852.
3. For example, see: (a) Fisher, E.; Schoeller, W. Liebigs Ann. Chem. 1907, 357, 1. (b) Renard, M. Bull. Soc. Chim. Biol. 1946,
28, 497. (c) Karrer, P.; Reschofsky, H.; Kasse, W. Helv. Chim. Acta 1947, 30, 271.
4. Typical procedure for preparation of α-chloro acid derivatives 1. A mixture of (S)-2-chloro-3-phenylpropanoic acid (4.0 g,
21.7 mmol) and PCl5 (9.0 g, 43.4 mmol) in benzene (100 ml) was heated under reflux under an anhydrous atmosphere for
2 h. The resulting solution was cooled and washed with ice-water (1×50 ml). After drying (Na2SO4), aniline (2.0 g, 21.7
mmol) and triethylamine (4.4 g, 43.4 mmol) were added to the solution and the mixture was left stirring under an anhydrous
atmosphere for 2 days. The solution was washed with 1 M HCl, satd NaHCO3 and water and was then dried over Na2SO4.
The solvent was removed under reduced pressure and the crude product recrystallised from hexane/ethyl acetate to give pure
1e in 24% yield. All new compounds were fully characterised.
5. Typical procedure for bromination. A mixture of phenyl (S)-2-chloro-3-phenylpropanamide 1e (20 mg, 77 mmol) and NBS
(13 mg, 77 mmol) in CCl4 (5 ml) was heated at reflux under nitrogen. The reaction was initiated by irradiation with a 160 W
mercury lamp. After 2 h the mixture was cooled and the solvent was removed under reduced pressure. The composition of
the crude product was determined by NMR spectroscopy. All new compounds were fully characterised.
6. Simpson, J.; Chan, B.; Wong, L. S.; Tan, E. W. Acta Crystallogr., in preparation. Compound 2f had 1H NMR (CDCl3) δ 4.94
(1H, d, J=8.2 Hz), 5.57 (1H, d, J=8.2 Hz), 7.33–7.42 (3H, m), 7.42–7.52 (2H, m), 7.71 (2H, d, J=9.2 Hz), 8.02 (1H, bs), 8.25
(2H, d, J=9.2 Hz) ppm. Compound 2j had 1H NMR (CDCl3) δ 1.35 (6H, d, J=6.8 Hz), 1.48 (6H, d, J=6.8 Hz), 3.65 (1H, m),
4.16 (1H, m), 5.04 (1H, d, J=10.7 Hz), 5.55 (1H, d, J=10.7 Hz), 7.20–7.40 (5H, m) ppm.
7. MacSpartan Plus™, Wavefunction, Inc., 18401 Von Karman, Suite 370, Irvine, California, 92612, USA.
8. Easton, C. J.; Merrett, M. C. J. Am. Chem. Soc. 1996, 118, 3035.
9. Caramella, P.; Rondan, N. G.; Paddon-Row, M. N.; Houk, K. N. J. Am. Chem. Soc. 1981, 103, 2438.