A simple and efficient method for regioselective and stereoselective synthesis of vicinal bromohydrins and alkoxybromides from an olefin

Article abstract of DOI:10.1021/jo0600611

(Chemical Equation Presented) A very rapid and efficient method has been developed for the synthesis of vicinal bromohydrins and alkoxybromides directly from an olefin without any catalyst. The reaction was performed in CH ₃CN-water (4:1) or alcohol using N,N-dibromo-p-toluenesulfonamide (TsNBr₂) as the brominating agent. Excellent yields and regio- and stereoselectivities have been obtained. Bromohydrins are formed instantaneously, whereas formation of alkoxybromides takes 30-60 min.

Full text of DOI:10.1021/jo0600611

A Simple and Efficient Method for Regioselective and
Stereoselective Synthesis of Vicinal Bromohydrins and
Alkoxybromides from an Olefin
Prodeep Phukan,* Pranita Chakraborty, and Dolly Kataki
Department of Chemistry, Gauhati UniVersity, Guwahati 781014, Assam, India
pphukan@yahoo.com
ReceiVed January 11, 2006 (ReVised Manuscript ReceiVed April 20, 2006)
A very rapid and efficient method has been developed for the synthesis of vicinal bromohydrins and
alkoxybromides directly from an olefin without any catalyst. The reaction was performed in CH3CN-
water (4:1) or alcohol using N,N-dibromo-p-toluenesulfonamide (TsNBr2) as the brominating agent.
Excellent yields and regio- and stereoselectivities have been obtained. Bromohydrins are formed
instantaneously, whereas formation of alkoxybromides takes 30-60 min.
Introduction
additions of water and halogen to an olefinic bond. One involves
the use of molecular halogen or N-halosuccinimide for halo-
genation,5 and the other uses metal halide along with an
oxidizing agent.6 N-Halosuccinimide is a better choice over
hazardous molecular halogens for such transformations, but this
method suffers the drawback of low yield and longer reaction
time. Moreover, this protocol does not work well with electron-
deficient alkenes. Recently, Yadav et al. reported a modified
The vicinal fictionalization of an olefin is a powerful synthetic
tool for organic chemists, especially when the reaction is carried
out in regio- and stereoselective fashion. In particular, selective
introduction of two different functional groups, such as hydroxy
or alkoxy and halogen, has attracted sustained attention in
organic synthesis.1 The resulting halohydrins and alkoxyhalides
are important building blocks in organic, medicinal, as well as
industrial chemistry.2 Halohydrins are usually synthesized by
ring opening of epoxides3 or cyclic sulfate4 by hydrogen halides
or metal halides. However, these procedures are associated with
the formation of Vic-dihalides and 1,2-diols as byproducts.3a,b
Second, these procedures require prior synthesis of epoxide or
cyclic sulfate. There are two general approaches for heterolytic
(3) (a) Majetich, G.; Hicks, R.; Reister, S. J. Org. Chem. 1997, 62, 4321-
4326. (b) Bonini, C.; Righi, G. Synthesis 1994, 225-238. (c) Smith, J. G.;
Fieser, M. Fieser and Fieser’s Reagent for Organic Synthesis; John Wiley
and Sons: New York, 1990; Vols. 1-12. (d) Reddy, M. A.; Surendra, K.;
Bhanumathi, N.; Rama Rao, K. Tetrahedron 2002, 58, 6003-6008. (e)
Sharghi, H.; Niknam, K.; Pooyan, M. Tetrahedron 2001, 57, 6057-6064.
(f) Ranu, B. C.; Banerjee, S. J. Org. Chem. 2005, 70, 4517-4519. (g)
Shimizu, M.; Yoshida, A.; Fujisawa, T. Synlett 1992, 204-206. (h) Ciaccio,
J. A.; Heller, E.; Talbot, A. Synlett 1991, 248-250.
(4) Nandanan, E.; Phukan, P.; Sudalai, A. Ind. J. Chem. 1999, 38B, 283-
286.
* To whom correspondence should be addressed. Tel: +91-361-2570535 (O).
Fax: +91-361-2700311.
(1) (a) Tenaglia, A.; Pardigon, O.; Buono, G. J. Org. Chem. 1996, 61,
1129-1132. (b) Haruyoshi, M.; Kiyoshi, T.; Masahiro, N.; Akira, H.;
Yutaka, N.; Yasutaka, I. J. Org. Chem. 1994, 59, 5550-5555. (c) Rodriguez,
J.; Dulcere, J.-P. Synthesis 1993, 1177-1205. (d) Block, E.; Schwan, A.
L. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I.,
Semmelhack, M. F., Eds.; Pergamon Press: Oxford, 1991; Vol. 4, pp 344-
347.
(2) (a) Christophersen, C. Acta Chem. Scand. 1985, 39B, 517-529. (b)
Erickson, R. E. In Marine Natural Products; Scheuer, P. J., Ed.; Aca-
demic: New York, 1986; Vol. V, p 131. (c) Ueda, Y.; Maynard, S. C.
Tetrahedron Lett. 1988, 29, 5197-5200. (d) Konopelski, J. P.; Boehler,
M. A.; Tarasow, T. M. J. Org. Chem. 1989, 54, 4966-4970. (e) Ullmann’s
Encyclopedia of Industrial Chemistry, 6th ed.; Electronic Release, 1998.
(f) Cabanal-Duvillard, I.; Berrier, J. F.; Royer, J.; Husson, H. P. Tetrahedron
Lett. 1998, 39, 5181-5184.
(5) (a) Comprehensive Organic Transformation: A Guide to Functional
Group Preparation, 2nd ed.; Larock, R. C., Ed.; Wiley-VCH: New York,
1999; pp 629-640. (b) Damin, B.; Garapon, J.; Silion, B. Synthesis 1981,
362-363. (c) Rolston, J. H.; Yates, K. J. Am. Chem. Soc. 1969, 91, 1469-
1476. (d) Dalton, D. R.; Dutta, V. P.; Jones, D. C. J. Am. Chem. Soc. 1968,
90, 5498-5501. (e) Langman, A. W.; Dalton, D. R. Org. Synth. 1979, 59,
16-19. (f) Chamberlin, A. R.; Dezube, M.; Dussalt P.; McMills, M. C. J.
Am. Chem. Soc. 1983, 105, 5819. (g) Barluenga, J.; Marco-Arias, M.;
Gonzalez-Bobes, F.; Ballesteros, A.; Gonzalez, J. M. Chem.sEur. J. 2004,
10, 1677-1682. (h) Masuda, H.; Takase, K.; Nishio, M.; Hasegawa, A.;
Nishiyam, Y.; Ishii, Y. J. Org. Chem. 1994, 59, 5050-5055. (i) Yadav, J.
S.; Reddy, B. V. S.; Baishya, G.; Harshavardhan, S. J. Tetrahedron Lett.
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Sons: New York, 1988; Collect. Vol. 6, pp 560-564. (k) Vishwakarma,
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10.1021/jo0600611 CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/07/2006
J. Org. Chem. 2006, 71, 7533-7537
7533

Phukan et al.
TABLE 2. Synthesis of Bromohydrin from Various Olefins
SCHEME 1. Synthesis of Bromohydrins and -ethers
TABLE 1. Bromination of Ethylcinnamatea
brominating
entry
solvent
agent
time
7 min
instantaneous
25 min
25 min
6 h
yieldb
1
2
3
4
5
MeCN-H2O (4:2)
MeCN-H2O (4:1)
CHCl3- H2O (4:1)
CH2Cl2- H2O (4:1)
MeCN-H2O (4:1)
TsNBr2
TsNBr2
TsNBr2
TsNBr2
NBS
90
92
82
85
56
a Reaction conditions: olefin (1.1 mmol), solvent (5 mL), TsNBr2 (1.2
mmol), rt. b Isolated yield after chromatographic purification.
procedure for hydrobromination of olefins using NBS in ionic
liquid.5i The disadvantage of this method is that ionic liquids
are expensive, and in some cases, bromohydrin formation takes
longer time. The oxidative halogenation methods6 require a
metal salt as the halogen source, an oxidizing agent, and a
catalyst to carry out the transformation. Sudalai et al.6d reported
a method for such transformation using metal salts, such as LiX
(X ) Cl, Br) and NaX, as a halogenating agent in the presence
of NaIO4 as catalyst. The major drawback of this method is the
use of a high amount (25%) of the catalyst and a stoichiometric
amount of 30% H2SO4 along with the metal halide (1.2 equiv).
Oxidative hydrohalogenation with hypohalous acid or bromates
suffers the drawback of longer reaction time and low yield.7 In
recent years, haloperoxidases have also been studied extensively
for oxidative halogenations, to understand the biosynthesis of
many halogenated marine natural products.8 We wish to report
herein a very simple and efficient method for direct synthesis
of bromohydrins and alkoxybromides from an olefin using N,N-
dibromo-p-toluenesulfonamide (TsNBr2) as the bromine source
under mild conditions (Scheme 1).
a Isolated yield after chromatographic purification. Products are char-
acterized by IR, 1H NMR, 13C NMR, mass and elemental analysis. b From
refs 7b and 12. c From ref 6d.
N,N-Dibromo-p-toluenesulfonamide was used first by Khara-
sch for the synthesis of 1-phenyl-2-(p-toluenesulfonamido)-1-
bromoethane.9 The same reagent was also used by Paul et al.
for the synthesis of 3,5-dihydroxy-1-substituted piperidines from
1,4-pentadiene.10 The yield of the intermediate methoxy bromide
synthesized for this purpose was found to be very low. In both
the cases, the reagent was not studied expeditiously. N,N-
Dihalosulfonamides were also used for the preparation of
haloamines and azidins.11 In the recent past, several procedures
haveappearedintheliteratureforthesynthesisofbromohydrins.3-7,12
Understanding the importance of this subject, we have carried
out a study to generalize the utility of TsNBr2 as a bromine
source for the synthesis of bromohydrins and alkoxybromides.
(6) (a) Vijay, N.; Sreeletha, B. P.; Anu, A.; Tesmot, G. G.; Siji, T.;
Vairamani, M. Tetrahedron 2001, 57, 7417-7422. (b) Kabalka, G. W.;
Yang, K.; Reddy, N. K.; Narayana, C. Synth. Commun. 1998, 28, 925-
929. (c) Dieter, R. K.; Nice, L. E.; Sadanandan, E. V. Tetrahedron Lett.
1996, 37, 2377-2380. (d) Dewkar, G. K.; Narina, S. V.; Sudalai, A. Org.
Lett. 2003, 5, 4501-4504.
(7) (a) Masuda, H.; Takase, K.; Nishio, M.; Hasegawa, A.; Nishiyama,
Y.; Ishii, Y. J. Org. Chem. 1994, 59, 5550-5555. (b) Anand N.; Kapoor,
M.; Koul, S.; Taneja, S. C.; Sharma, R. L.; Qazi, G. N. Tetrahedron:
Asymmetry 2004, 15, 3131-3138.
(8) (a) Carter-Franklin, J. N.; Parrish, J. D.; Tschirret-Gutt, R. A. S.;
Little, R. D.; Butler, A. J. Am. Chem. Soc. 2003, 125, 3688-3689. (b)
Butler, A.; Walker, J. V. Chem. ReV. 1993, 93, 1937-1944. (c) de la Rosa,
R. I.; Clague, M. J.; Butler, A. J. Am. Chem. Soc. 1992, 114, 760-761. (d)
Sels, B. F.; De Vos, D. E.; Jacobs, P. A. J. Am. Chem. Soc. 2001, 123,
8350-8359. (e) Espenson, J. H.; Zhu, Z.; Zauche, T. H. J. Org. Chem.
1999, 64, 1191-1196. (f) Sels, B.; De Vos, D.; Buntinx, M.; Pierand, F.;
Mesmaeker, A. K.; Jacobs, P. A. Nature 1999, 400, 855-857. (g) Walker,
J. V.; Morey, M.; Carlsson, H.; Davidson, A.; Stucky, G. D.; Butler, A. J.
Am. Chem. Soc. 1997, 119, 6921-6922.
(9) Kharasch, M. S.; Priestley, H. N. J. Am. Chem. Soc. 1939, 61, 3425-
3432.
(10) Paul, R.; Tchelitcheff, S. Bull. Soc. Chim. France 1948, 896-900
(AN 1949:10930).
7534 J. Org. Chem., Vol. 71, No. 20, 2006

Synthesis of Vicinal Bromohydrins and Alkoxybromides
TABLE 3. Values of Coupling Constants for Protons of R-C(OH)H1-CH2BrX
compound
R
X
(δH1) JH1 (Hz)
reported JH1 (Hz)
(δ H2) JH2 (Hz)
reported JH2 (Hz)
ref
7b
1b
2b
3b
4b
5b
7b
10b
Ph-
Ph-
-COOEt
-COOMe
-COOEt
-COOEt
-COOEt
-H
(5.07, dd) 8.1, 3.3
(5.05, d) 8.4
(5.05, d) 7.8
(5.03, d) 8.3
(5.04, d) 8.2
(5.08, d) 8.1
(5.07, d)/(5.08, d) 8.2/8.3
(4.36, d) 8.1
(4.35, d) 8.4
(4.29, d) 8.1
(4.34, d) 8.4
(4.28, d) 8.2
(3.48-3.67, m) -
(4.36, dd) 5.4, 7.5
(4.36, d) 8.1
(4.38, d) 8.2/8.3
7b/12
(4-Cl)-Ph-
(4-Me)-Ph-
(4-Br)-Ph-
Ph-
-
-
-
(4.91, dd) 8.7, 3.3
(4.05, dd) 7.2, 12.0
(4.95, dd) 8.1, 4.0
-
(3.55-3.70, m)
6d
H-
-COOMe
Results and Discussion
TABLE 4. Synthesis of Alkoxybromides
The brominating agent TsNBr2 employed for this purpose
was prepared from Chloramine-T by the following literature
procedure.13 Initially, a systematic study for the synthesis of
bromohydrin was carried out using ethylcinnamate as substrate.
The reaction was carried out by adding TsNBr2 (1.1 equiv) to
a solution of the organic substrate in acetonitrile-water at room
temperature. Use of a stoichiometric amount of the reagent
resulted in slightly lower yield. Various solvents, such as MeCN,
CH2Cl2, and CHCl3, in combination with water were studied
(Table 1). A mixture of acetonitrile and water in a 4:1 ratio
was found to be the best solvent for halohydrin formation. The
reaction takes a relatively longer time for lower acetonitrile-
water ratio, which is due to poor solubility of the substrate. We
observed that, after addition, the yellow color of TsNBr2
disappears instantaneously along with the olefin. Disappearance
of yellow color is indicative of the completion of the reaction,
which was further confirmed by monitoring the reaction by TLC.
The reaction mixture was stirred for another 10 min. After the
usual workup, the corresponding hydrobromide was obtained
in excellent yield. The reagent is much faster than NBS for the
bromination reaction. For example, when bromination of ethyl
cinnamate was carried out with NBS under the same conditions,
the respective bromo alcohol was formed in 56% yield in 6 h
(Table 1, entry 5). We are pleased to find that both regioselec-
tivity and stereoselectivity were controlled very well in this
reaction. Only the erythro-â-hydroxy-R-bromo isomer was
observed as evident by the analysis of 1H NMR data. The mass
spectra showed prominent peaks corresponding to [ArCHOH]+
and [BrCHCOOEt]+ ion fragments. The anti configuration was
further confirmed by structural analysis of X-ray crystallography
data of the compound 1b.
After optimizing the reaction conditions, we have extended
the process to a variety of olefins, which are summarized in
Table 2. The present method works well for all kinds of olefins,
such as cinnamates, styrenes, cyclohexene, and methyl acrylate,
to produce bromohydrins in excellent yield. In all cases, the
rate of the reaction is very fast, and the reaction occurs
instantaneously; anti-selectivity of the products was determined
by analysis of the coupling constant data of protons attached to
the carbons bearing -OH and -Br groups of the bromo alcohol.
A comparative result of the coupling constants with the reported
value is presented in Table 3.
(11) (a) Daniher, F. A.; Butler, P. E. J. Org. Chem. 1968, 33, 4336-
4340. (b) Terauchi, H.; Kowata, K.; Minematsu, T.; Takemura, S. Chem.
Pharm. Bull. 1977, 25, 556-562. (c) Hegedus, L. S.; McKearin, J. M. J.
Am. Chem. Soc. 1982, 104, 2444-2451. (d) Li, G.; Wei, H.-X.; Kim, S.
H.; Neighbors, M. Org. Lett. 1999, 1, 395. (e) Li, G.; Wei, H.-X.; Kim, S.
H. Org. Lett. 2000, 2, 2249. (f) Wei, H.-X.; Kim, S. H.; Li, G. Tetrahedron
2001, 57, 3869. (g) Wei, H.-X.; Kim, S. H.; Li, G. Tetrahedron 2001, 57,
8407. (h) Xu, X.; Kotti, S. R. S. S.; Liu, J.; Cannon, J. F.; Headley, A. D.;
Li, G. Org. Lett. 2004, 6, 4881-4884.
a Isolated yield after chromatographic purification. Products are char-
acterized by IR, 1H NMR, 13C NMR, mass and elemental analysis. b From
ref 6d.
Encouraged by these results, we applied the procedure for
the synthesis of different alkoxybromides. Initially, when ethyl
cinnamate was subjected to bromination in methanol, corre-
sponding methoxy bromide was obtained in 45 min in excellent
(12) Urankar, D.; Rutar, I.; Modec, B.; Dolenc, D. Eur. J. Org. Chem.
2005, 2349-2353.
(13) Nair, C. G. R.; Indrasen, P. Talanta 1976, 23, 239.
J. Org. Chem, Vol. 71, No. 20, 2006 7535

Phukan et al.
TABLE 5. Values of Coupling Constants for Protons R-C(OMe)H1-CH2BrX
compound
R
X
(δH1) JH1 (Hz)
reported JH1 (Hz)
(δ H2) JH2 (Hz)
reported JH2 (Hz)
ref
6d
1c
2c
3c
7c
Ph-
Ph-
-COOEt
-COOMe
-COOEt
-H
(4.53, d) 10.0
(4.54, d) 10.0
(4.50, d) 10.0
(4.37, dd) 4.0, 8.4
(4.20, d) 11.6
(4.22, d) 10.0
(4.12, d) 10.0
(3.52, dd) 2.4, 10.8
(4-Cl)-Ph-
Ph-
(4.38, dd) 3.0, 9.0
(3.43-3.56, m)
SCHEME 2. Competitive Reaction between tert-BuOH and H2O
yield. Thereafter, we extended the procedure for various kinds
of olefins that are summarized in Table 4.
rest of the reactions because this is also consistent with our
assumed mechanistic pathway. This assumption can be realized
from the coupling constants of protons attached to the carbon
having OR and Br groups in the NMR spectra of the products
which match the reported values.
After a successful attempt at the synthesis of Vic-methoxy-
bromides, we sought to apply this method to more hindered
alcohols, such as tert-butyl alcohol. It is remarkable that all kinds
of olefins could be easily converted to corresponding vicinal
tert-butoxybromides in high yield (Table 4). Coupling constants
of a proton attached to the carbons bearing -OR and -Br
groups of the alkoxybromides are presented in Tables 5 and 6.
We have also carried out a study on the competitive
nucleophilicity of tert-butyl alcohol and water. It is interesting
to observe that when the reaction was carried out in a mixture
of tert-butyl alcohol and water (1:1 volume ratio) a mixture of
bromohydrin (1b) and tert-butoxybromide (1d) was obtained
in a 3:1 ratio (Scheme 2).
TABLE 6. Values of Coupling Constants for Protons
R-C(O-tert-Bu)H1-CH2BrX
compound
R
X
(δH1) JH1 (Hz)
(δ H2) JH2 (Hz)
1d
3d
7d
Ph-
(4-Cl)-Ph- -COOEt
Ph- -H
-COOEt (4.82, d) 9.9
(4.05, d) 9.9
(4.04, d) 9.6
3.32-3.44, m) -
(4.85, d) 9.6
(4.66, d) 8.0
When the same reagent was used by Kharasch9 for the
synthesis of bromoamines, the attacking nucleophile is a
sulfonamide. In this reaction, water or alcohol is present in
excess, and they are better nucleophiles than sulfonamide. So,
formation of bromohydrin or alkoxybromide was predominant
over that of amino bromides. We have carried out the reaction
in the absence of water or alcohol as a test case, taking ethyl
cinnamate as substrate. When ethyl cinnamate was subjected
to reaction with N,N-dibromo-p-toluenesulfonamide in dry
acetonitrile under inert atmosphere, corresponding bromoamine
12 was obtained in good yield (Scheme 4).
SCHEME 3. Probable Mechanism of Bromination
SCHEME 4. Synthesis of Bromoamine
A probable mechanistic pathway to explain the regio- and
stereoselectivity of the bromohydrins and bromoethers is
depicted in Scheme 3. A three-membered cyclic bromonium
ion intermediate 11 is formed at the initial stage of the reaction
due to electrophilic addition of the Br+ ion (generated from
TsNBr2) onto the olefin.14 The intermediate 11 undergoes ring
opening by the nucleophile via the SN2 pathway. The SN2
opening is responsible for high anti-stereoselectivity of the
bromo product. The regioselectivity can be explained by
considering the fact that the â-position is more positive than
the R-position due the presence of the aromatic ring. Nucleo-
philic opening of the cyclic bromonium intermediate is most
likely from the more positive â-position. Since analysis of the
product 1b using X-ray crystallography confirms the trans
addition, we assume that trans addition has occurred in all the
In conclusion, a regio- and stereoselective method for
hydrobromination and alkoxybromination of olefins has been
established by using N,N-dibromo-4-toluenesulfonamide as a
bromine source. The procedure is rapid, easy to perform at room
temperature, and applicable to different kinds of olefins, such
as cinnamates, styrenes, cyclohexene, and methyl acrylate, to
give corresponding brominated product in excellent yield.
Experimental Section
General Procedure for the Synthesis of Bromohydrins: To a
solution of olefin (1.1 mmol) in acetonitrile-water (4:1) (5 mL)
was added TsNBr2 (1.2 mmol). The color of TsNBr2 as well as the
olefin disappears immediately. After stirring for another 10 min,
sodium thiosulfate (200 mg approximately) was added and the
reaction mixture was stirred for 20 min. The reaction mixture was
taken up in ether, washed with brine, dried (Na2SO4), and
(14) Rodebaugh, R.; Fraser-Reid, B. Tetrahedron 1996, 52, 7663-7678.
7536 J. Org. Chem., Vol. 71, No. 20, 2006

Synthesis of Vicinal Bromohydrins and Alkoxybromides
concentrated. Purification of the crude product by flash chroma-
tography on silica gel (230-400 mesh) with petroleum ether-
EtOAc (5%) as eluent gave the pure product.
Ethyl-(2R*,3R*)-2-bromo-3-(tert-butoxy)-3-phenylpro-
panoate (1d): IR (neat, cm-1) ν 2977, 2929, 1744, 1267, 1054,
1
700, 603; H NMR (300 MHz, CDCl3) δ 1.0 (s, 9H), 1.28 (t, J )
Ethyl-(2R*,3R*)-2-bromo-3-(4-chlorophenyl)-3-hydroxypro-
7.5 Hz, 3H), 4.05 (d, J ) 9.9 Hz, 1H), 4.02-4.34 (m, 2H), 4.82
(d, J ) 9.9 Hz), 7.21-7.38 (m, 5H); 13C NMR (75 MHz, CDCl3)
δ 14.0, 28.6, 49.61, 61.8, 75.8, 76.2, 127.8, 128.0, 128.1, 141.0,
169.1. HRMS: calcd mass (M + Na) 351.0572; found 351.0598.
panoate (3b): IR (neat, cm-1) ν 3460, 2979, 2920, 1731, 1646,
1
1599, 1492, 1292, 1272, 1014, 537; H NMR (300 MHz, CDCl3)
δ 1.28 (t, J ) 6.9 Hz, 3H), 4.2-4.5 (m, 2H), 4.29 (d, J ) 8.1 Hz,
1H), 5.05 (d, J ) 7.8 Hz, 1H), 7.28-7.42 (m, 4 H); 13C NMR (75
MHz, CDCl3) δ 13.80, 47.46, 62.47, 128.36, 128.65, 134.48,
137.47, 169.25. Anal. Calcd for C11H12BrClO3: C 42.96%, H
3.93%. Found: C 42.58%, H 4.31%.
Ethyl-(2R*,3R*)-2-bromo-3-(tert-butoxy)-3-(4-chlorophenyl)-
propanoate (3d): IR (neat, cm-1) ν 2978, 2930, 1743, 1597, 1256,
1
737, 579; H NMR (400 MHz, CDCl3) δ 1.0 (s, 9H), 1.28-1.42
(m, 3H), 4.04 (d, J ) 9.6 Hz, 1H), 4.25-4.4 (m, 2H), 4.85 (d, J )
9.6 Hz, 1H), 7.22-7.44 (m, 5H); 13C NMR (100 MHz, CDCl3) δ
14.2, 28.7, 47.5, 49.7, 62.8, 76.5, 128.2, 129.1, 129.3, 130.6, 168.7.
Anal. Calcd for C15H20BrClO3: C 49.54%, H 5.54%. Found: C
49.25%, H 5.79%.
Ethyl-(2R*,3R*)-2-bromo-3-hydroxy-3-(4-methylphenyl)pro-
panoate (4b): IR (neat, cm-1) ν 3479, 2969, 2920, 1732, 1616,
1
1459, 1278, 1023, 817, 534; H NMR (400 MHz, CDCl3) δ 1.28
(t, J ) 6.8 Hz), 2.35 (s, 3H), 2.25 (q, J ) 1.8 Hz, 2H), 4.34 (d, J
) 8.4 Hz, 1H), 5.03 (d, J ) 8.3 Hz, 1 H), 7.18 (d, J ) 7.9 Hz,
2H), 7.27 (d, J ) 6.24 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ
13.9, 21.2, 47.8, 62.4, 75.1, 126.9, 129.2, 129.3, 136.1, 138.8, 169.5.
Ethyl-(2R*,3R*)-2-bromo-3-(4-bromophenyl)-3-hydroxypro-
panoate (5b): IR (neat, cm-1) ν 3450, 2970, 2920, 1739, 1594,
(()-1-[2-Bromo-1-(tert-butoxy)ethyl]benzene (7d): IR (neat,
1
cm-1) ν 3057, 2977, 1631, 1266; H NMR (400 MHz, CDCl3) δ
1.16 (s, 9H), 3.32-3.44 (m, 2H), 4.66 (d, J ) 8.0 Hz, 1H), 7.21-
7.45 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 28.7, 38.1, 74.6,
75.0, 126.3, 127.6, 128.2, 128.7. Anal. Calcd for C12H17BrO: C
56.05%, H 6.66%. Found: C 56.36%, H 6.37%.
1
1264, 739, 538; H NMR (400 MHz, CDCl3) δ 1.28 (J ) 7.1 Hz,
3H), 3.29 (br s, 1H), 4.25 (q, J ) 2.6 Hz, 2H), 4.28 (d, J ) 8.2 Hz,
1H), 5.04 (d, J ) 8.2 Hz, 1H), 7.27 (d, J ) 6.7 Hz), 7.50 (d, J )
6.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 13.9, 23.7, 28.9, 47.4,
62.5, 74.6, 122.8, 128.7, 131.7, 138.0, 169.3.
trans-1-Bromo-2-(tert-butoxy)cyclohexane (9d): IR (neat, cm-1
)
ν 3048, 2924, 1638, 1265, 740, 527; 1H NMR (400 MHz, CDCl3)
δ 1.0-1.4 (m, 13H), 1.66-1.75 (m, 2H), 1.75-1.90 (m, 1H), 1.98-
2.15 (m, 1H), 2.25-2.4 (m, 1H), 3.50-3.63 (m, 1H), 3.90-4.02
(m, 1H); 13C NMR (100 MHz, CDCl3) δ 22.6, 24.0, 28.8, 29.3,
33.9, 56.7, 72.6, 74.1.
Ethyl-(2R*,3R*)-2-bromo-3-hydroxy-5-phenylpentanoate (6b):
IR (neat, cm-1) ν 3481, 2976, 2926, 1742, 1601, 1451, 1261, 1154,
1029, 562; 1H NMR (300 MHz, CDCl3) δ 3.25 (t, J ) 3 Hz, 3H),
2.0-2.3 (m, 1H), 2.5-2.67 (m, 1H), 2.67-2.75 (m, 1H), 2.75-
3.05 (m, 1H), 4.1-4.55 (m, 4H), 7.1-7.6 (m, 5H); 13C NMR (75
MHz, CDCl3) δ 13.8, 32.5, 36.9, 47.9, 51.9, 62.4, 126.3, 128.3,
128.4, 128.5, 128.6, 140.0, 67.7. Anal. Calcd for C13H17BrO3: C
51.84%, H 5.69%. Found: C 52.02%, H 5.87%.
General Procedure for the Synthesis of Bromoamine. A two-
necked dry round-bottom flask fitted with a nitrogen inlet was
charged with ethyl cinnamate (1.1 mmol), dry acetonitrile (5 mL),
and freshly activated 4 Å molecular sieves (200 mg). The flask
was flashed with nitrogen, and TsNBr2 (1.21 mmol) was added
under a slow stream of nitrogen. The reaction mixture was allowed
to stir under nitrogen atmosphere for 2 h at room temperature.
Sodium thiosulfate (200 mg approximately) was added, and the
reaction mixture was stirred for 20 min. The reaction mixture was
filtered, solvent evaporated, and ether (50 mL) was added. The
ethereal layer was washed with brine, dried (Na2SO4), and
concentrated. Purification of the crude product by flash chroma-
tography on silica gel (230-400 mesh) with petroleum ether-
EtOAc (15%) as eluent gave the bromoamine 12: yield 68%; mp
174-176 °C; IR (Nujol, cm-1) ν 3450, 1743, 1669, 1527, 1343,
General Procedure for the Synthesis of Alkoxybromides. To
a solution of olefin (1.1 mmol) in alcohol (5 mL) was added TsNBr2
(1.21 mmol). The color of TsNBr2 as well as the olefin disappears
slowly. After the reaction was complete, sodium thiosulfate (200
mg approximately) was added, and the reaction mixture was stirred
for 20 min. After evaporation of the solvent, the reaction mixture
was extracted with ether, washed with brine, dried (Na2SO4), and
concentrated. Purification of the crude product by flash chroma-
tography on silica gel (230-400 mesh) with petroleum ether-
EtOAc (3-5%) as eluent gave the pure product.
Ethyl-(2R*,3R*)-2-bromo-3-methoxy-3-phenylpropanoate (1c):
1
IR (neat, cm-1) ν 2978, 2929, 1743, 1454, 1269, 1097, 602; H
1
1164, 1090, 559; H NMR (300 MHz, CDCl3) δ 1.14 (t, J ) 7.2
NMR (400 MHz, CDCl3) δ 1.33 (t, J ) 7.6 Hz, 3H), 3.21 (s, 3H),
4.20 (d, J ) 11.6 Hz, 1H), 4.23-4.32 (m, 2H), 4.53 (d, J ) 10
Hz, 1H), 7.30-7.40 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 14.0,
47.4, 57.5, 61.9, 84.1, 127.6, 127.9, 128.2, 128.4, 128.7, 136.7,
168.5. Anal. Calcd for C12H15BrO3: C 50.19%, H 5.27%. Found:
C 50.01%, H 5.52%.
Hz, 3H), 2.35 (s, 3H), 4.03-4.125 (m, 2H), 4.43 (d, J ) 5.4 Hz,
1H), 4.87 (dd, J ) 9.3, 5.4 Hz, 1H), 6.20 (d, J ) 9 Hz, 1H), 7.10-
7.24 (m, 7H), 7.58 (d, J ) 8.4 Hz, 2H); 13C NMR (75 MHz, CDCl3)
δ 13.6, 21.4, 46.6, 60.0, 62.5, 126.9, 127.0, 128.2, 128.5, 129.2,
136.3, 137.3, 143.1, 168.2. HRMS: calcd mass (M + Na) 448.0194;
found 448.0209.
Ethyl-(2R*,3R*)-2-bromo-3-(4-chlorophenyl)-3-methoxypro-
panoate (3c): IR (neat, cm-1) ν 2978, 2929, 1745, 1593, 1270,
1096, 556; 1H NMR (400 MHz, CDCl3) δ 1.3 (t, J ) 7.2 Hz, 3H),
3.19 (s, 3H), 4.12 (d, J ) 10 Hz, 1H), 4.19-4.32 (m, 2H), 4.50 (d,
J ) 10 Hz, 1H), 7.22-7.38 (m, 4H); 13C NMR (100 MHz, CDCl3)
δ 14.0, 47.2, 57.6, 62.1, 83.4, 128.4, 129.2, 134.5, 135.4, 168.3.
Anal. Calcd for C12H14BrClO3: C 44.82%, H 4.39%. Found: C
44.97% and H 4.04%.
Acknowledgment. Financial support from DST, New Delhi
(Grant No. SR/FTP/CSA/-11/2002) is gratefully acknowledged.
P.P. thanks the Indian National Science Academy for a visiting
fellowship, Prof. S. Chandrasekeran of IISc, Bangalore, for
laboratory facilities, and T. Vijay for X-ray crystallographic data
analysis.
trans-1-Bromo-2-methoxycyclohexane (9c): IR (neat, cm-1) ν
1
2939, 2861, 1452, 1189, 1097, 648; H NMR (400 MHz, CDCl3)
1
Supporting Information Available: Analytical data, H and
δ 1.19-1.41 (m, 3H), 1.62-1.88 (m, 3H), 2.10-2.24 (m, 1H),
2.24-2.39 (m, 1H), 3.18-3.28 (m, 1H), 3.42 (s, 3H), 3.92-4.01
(m, 1H); 13C NMR (100 MHz, CDCl3) δ 23.3, 25.5, 30.1, 35.5,
55.3, 57.1, 83.1.
13C NMR spectra, and crystal structure of the compound 1b. This
materialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
JO0600611
J. Org. Chem, Vol. 71, No. 20, 2006 7537