Lewis acid catalyzed asymmetric halohydrin reactions of chiral α,β-unsaturated carboxylic acid derivatives with N-halosuccinimide (NXS) as the halogen source

Article abstract of DOI:10.1016/j.tetlet.2005.03.014

Lewis acid catalyzed asymmetric halohydrin reactions-(halohydroxylation as well as halomethoxylation) of chiral α,β-unsaturated carboxylic acid derivatives were performed using N-halosuccinimide (NXS; X = Br, I) as the halogen source. Regio- and anti-sele

Full text of DOI:10.1016/j.tetlet.2005.03.014

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3073–3077
Lewis acid catalyzed asymmetric halohydrin reactions of
chiral a,b-unsaturated carboxylic acid derivatives with
N-halosuccinimide (NXS) as the halogen source
Saumen Hajra,* Manishabrata Bhowmick and Ananta Karmakar
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
Received 20 January 2005; revised 21 February 2005; accepted 1 March 2005
Available online 18 March 2005
Abstract—Lewis acid catalyzed asymmetric halohydrin reactions—(halohydroxylation as well as halomethoxylation) of chiral a,b-
unsaturated carboxylic acid derivatives were performed using N-halosuccinimide (NXS; X = Br, I) as the halogen source. Regio-
and anti-selectivity of 100% and moderate to good diastereoselectivity with good yields were observed when OppolzerÕs sultam
was used as the chiral auxiliary. Among the Lewis acids, Yb(OTf)3 was found to be the best catalyst. Alkenoyl and cinnamoyl
substrates smoothly underwent bromohydrin reactions and the more electron-rich cinnamoyl substrates preferred to undergo
iodohydrin reactions. However, electron-deficient cinnamoyl substrates did not respond to this Lewis acid catalyzed halohydrin
reaction with NXS (X = Cl, Br, I).
Ó 2005 Elsevier Ltd. All rights reserved.
The 1,2-halo functionalization of olefins, for example,
halohydrination, (halohydroxylation and haloalkoxyl-
ation) is an important transformation in organic chemis-
try.1 The product halogen-containing compounds are
versatile for the synthesis of pharmaceuticals, dyes,
flame retardants, agrochemicals and speciality chemi-
cals.2 The study of catalytic, highly regioselective and
asymmetric halohydrin forming reactions of olefins,
especially of electron-deficient olefins, still remains an
important challenge to organic chemists.3
derivatives,6 we describe in this Letter, a Lewis acid cat-
alyzed asymmetric halohydrin reaction, a halohydroxy-
lation as well as halomethoxylation, of chiral
a,b-unsaturated carboxylic acid derivatives using N-
halosuccinimide (NXS; X = Br, I) as the halogen source,
in which 100% regioselectivity and with diastereoselec-
tivities of up to 82:18 of the anti-a-halo-b-hydroxy/
methoxy carbonyl compounds are demonstrated with
good yields.
It is known in the literature that a,b-unsaturated car-
bonyl compounds undergo halohydrin forming reac-
tions with NBS/NIS in the presence of H2SO4.5b,d,7
Initial studies of halohydroxylation of N-cinnamoyl-2-
oxazolidinone 1a8 with NBS/NIS in different aqueous
organic solvents such as CH3COCH3, CH3CN, THF,
1,4-dioxane, DME, DMF and DMSO at 25 °C (rt)
showed that in aqueous CH3CN only, 1a underwent
bromohydroxylation. It gave a mixture of the carboxy-
bromohydrins 2a and 2a0 and the dibromocarbonyl
compounds 3a/3a0 after 26 h when an excess of NBS
(2.5 equiv) was used and the same reaction in the pres-
ence of H2SO4 gave a mixture of products within 6 h.
These observations prompted us to search for an effec-
tive catalyst for the asymmetric halohydrin forming
reactions of chiral a,b-unsaturated carbonyl compounds
with NBS. We screened different Lewis acids as catalysts
for this halohydrin forming reaction (Table 1). The
Regioselective and asymmetric halohydrin formation of
a,b-unsaturated carboxylic acid derivatives can provide
chiral carboxyhalohydrins and a-halo-b-hydroxy/alkoxy
carboxylic acid derivatives. These are versatile and use-
ful synthetic intermediates because of their transform-
ations to a variety of important compounds. These
moieties are also either present in or are precursors to
biologically active compounds.4,5 In our efforts to pro-
vide new asymmetric methods for the halohydrin
forming reactions of a,b-unsaturated carboxylic acid
Keywords: Lewis acid; Catalyst; Asymmetric; Halohydrin; Halohydr-
oxylation; Halomethoxylation; N-Halosuccinimide (NXS); (2R)-N-
Enoylbornanesultam; a-Halo-b-hydroxy/methoxycarboxylic acid
derivatives.
*
Corresponding author. Tel.: +91 3222 283340; fax: +91 3222
255303; e-mail: shajra@chem.iitkgp.ernet.in
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.014

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S. Hajra et al. / Tetrahedron Letters 46 (2005) 3073–3077
Table 1. Lewis acid catalysts for the halohydroxylation of 1 with NBSa
OH
Ar
Br
O
O
OH
Ar
O
O
O
MLn (15 mol%), NBS (1.5 equiv)
N
Ar
N
N
N
Ar
+
+
°
Br
5% aqueous CH3CN (v/v), 25 C
O
O
O
B
r
O
Br
O
O
O
1
2
2'
anti-3/3'
1a: Ar = C6H5
1b: Ar = 4-MeOC6H4
Entry
Substrate
MLn
t (h)
Ratiob (2+20:3/30)
drb (2:20)
Yieldc (%)
80
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1a
1b
None
InCl3
26
1
63:37
50:50
Mixture of products
In(OTf)3
MgBr2
1.5
9
Mixture of products
ND
<05:95
78:22
78:22
72:28
87:13
>99:01
91
92
Zn(OTf)3
Y(OTf)3
Sm(OTf)3
Yb(OTf)3
Yb(OTf)3
6
55:45
54:46
52:48
55:45
58:42
5
90
78
92 (89)d
97 (98)
7
2
0.5
a Lewis acid catalyzed halohydroxylation was performed with 1.5 equiv of NBS and 0.15 equiv of metal salts in 5% aqueous CH3CN at rt (25 °C).
b Determined from the 1H NMR spectrum of the crude reaction mixture; well separated CHBr 1H NMR signals were used to assign the ratio of 2/20
and 3/30 and the dr of 2 and 20.
c Combined yields of halohydroxy- and dibromo-carbonyl compounds, determined by 1H NMR analysis of the crude reaction mixture with
naphthalene as internal standard. Yields in parenthesis refer to the combined isolated yields of the bromohydroxy- and dibromo-carbonyl
compounds.
d Isolated yields of the bromohydroxycarbonyl compounds 2a (42%) and 2a0 (36%) and the dibromocarbonyl compounds 3a/3a0 (11%). ND: Not
determined.
metal halides and acetates, such as CuCl2, NiCl2, CoCl2,
Co(OAc)2, Ni(OAc)2 and Cu(OAc)2 did not show any
catalytic effect for the halohydroxylation of 1a with
NBS. The metal triflates, such as Zn(OTf)2, Y(OTf)3,
Sm(OTf)3 and Yb(OTf)3 as catalysts, showed good re-
sults (entries 5–8). Among these, Yb(OTf)3 was found
to be the best catalyst for the halohydroxylation of 1a.
When 1a was treated with NBS (1.5 equiv) in 5% aque-
ous acetonitrile (v/v) in the presence of the Yb(OTf)3
catalyst (15 mol %) at rt it gave the desired bromohyd-
rins 2a and 2a0 in good yield within 2 h, along with a
minor amount of the dibromocarbonyl compounds
3a/3a0 (entry 8).9,10 Similarly the electron-rich cinnamoyl
substrate 1b underwent clean bromohydroxylation with
NBS (1.2 equiv) in the presence of the Yb(OTf)3 cata-
lyst.11 In this case no dibromocarbonyl compound 3b/
3b0 was observed (entry 9). However, the diastereoselec-
tivities of the above bromohydroxylations were rather
low.
E-4g and the b-(2-naphthyl)enoyl substrate 4h smoothly
underwent bromohydroxylation (entries 2, 3, 7 and 8)
under the same reaction conditions.13 The more elec-
tron-rich cinnamoyl substrates 4d, 4e and 4f14 preferred
to undergo iodohydroxylation efficiently with NIS
(entries 4–6) and yielded the electrophilic bromination
product of the aromatic moiety as the major product
with NBS. However, the electron-deficient cinnamoyl
substrates 4i and 4j did not undergo halohydroxylation
under the same reaction conditions, even with the use of
excess reagents under different reaction conditions using
either NCS, NBS or NIS as the halogen source. The
alkenoyl substrates 4k and 4l and also the E-a-methyl
alkenoyl substrate E-4m responded to the bromohydr-
oxylation with 100% regioselectivity in contrast to the
Ag(I)-promoted halohydrin reactions of N-alkenoyl-2-
oxazolidinone.6 It is important to note that the sub-
strates 4k, 4l and E-4m did not undergo any halohydr-
oxylation in the absence of Lewis acid.
Since the oxazolidinone chiral auxiliary gave low diaste-
reoselectivity for the Yb(OTf)3 catalyzed bromohydr-
oxylation of 1a and 1b, we examined the Yb(OTf)3
catalyzed bromohydroxylation of a,b-unsaturated car-
boxylic acid derivatives possessing OppolzerÕs sultam
chiral auxiliary.12 When the Yb(OTf)3 catalyzed bro-
mohydroxylation of (2R)-N-cinnamoylbornanesultam
4a was performed under the same reaction conditions,
moderate diastereoselectivity was observed with good
yields (Table 2; entry 1). This Yb(OTf)3 catalyzed halo-
hydroxylation reaction was further studied using a
variety of cinnamoyl substrates containing electron-
donating and -withdrawing substituents on the aromatic
ring as well as different alkenoyl substrates. It was found
that the electron-rich cinnamoyl substrates 4b, 4c and
The pure a-halo-b-hydroxycarbonyl compounds 5 and 6
1
were fully characterized by H and 13C NMR and ele-
mental (CHN) analysis13 and their configurational
assignments were made by confirming the stereochemis-
try of the major isomer 5b. Pure 5b was transformed to
the epoxide 7b (Scheme 1) and the optical rotation of 7b
(½aꢀ
22:4
D
+212.2, (c 1.0, MeOH)) was compared with the
24
D
literature data (½aꢀ ꢁ205 (c 1.0, MeOH)).15
b-Methoxy-a-amino acids are unusual amino acid con-
stituents of many biologically active cyclic peptide and
depsipeptide antibiotics such as callipeltines,16 papu-
amides,17 cyclomarins18 and discokiolide.19 a-Halo-b-
methoxycarboxylic acid derivatives are important
precursors to b-methoxyamino acids.6a The Yb(OTf)3

S. Hajra et al. / Tetrahedron Letters 46 (2005) 3073–3077
Table 2. Yb(OTf)3 catalyzed halohydroxylation of (2R)-N-enoylbornanesultams 4
3075
O
O
OH
R1
O
OH
R1
X
Yb(OTf)3 (15 mol%), NBS (1.5 equiv)
R1
N
+
N
N
R2
°
X
R2
5% aqueous CH3CN (v/v), 25 C
R2
S
S
S
O
O
O
O
O
O
4
6
5
Entry
Substrate
R1
C6H5
R2
t (h)
X
dra (5:6)
Yieldb(%)
1
4a
4b
H
8
Br
Br
Br
I
64:36
72:28
74:26
75:25
76:24
78:22
82:18
65:35
80 (12)
93
91
2
4-MeOC6H4
4-BnOC6H4
3,4-MeOC6H3
4-BnO-3-MeOC6H3
3,4,5-MeOC6H2
4-MeOC6H4
2-Naphthyl
2-ClC6H4
H
2
3
4c
4d
H
3
4
H
1.5
3
94
5
4e
4f
H
I
90
6
H
3
I
71c
95
7
E-4g
4h
CH3
H
6
10
Br
Br
8
88
9
4i
H
48
48
36
36
36
Cl/Br/I
Cl/Br/I
Br
NR
NR
10
11
12
13
4j
2-NO2C6H4
CH3
C6H13
H
4k
4l
H
72:28
68:32
70:30
78 (20)
81 (10)
80 (12)
H
CH3
Br
Br
E-4m
C6H13
Yields in parentheses refer to the isolated yield of dibromocarbonyl compounds. NR: No reaction.
a Determined from the 1H NMR spectrum of the crude reaction mixture.
b Combined isolated yields of pure 5 and 6 after column chromatography.
c Isolated yield of isomer 5f.14
O
OH
O
O
°
i) K2CO3, acetone, 25 C, 14 h
N
MeO
Br
S
OMe
°
OMe
ii) MeOH, n-BuLi, -78 C, 10 min.
O
O
7b
[α]D22.4 = +212.2 (c 1.0, MeOH)
81%
5b
Scheme 1.
Table 3. Yb(OTf)3 catalyzed halomethoxylation of 4
O
OMe
R1
O
O
OMe
R1
(15 mol%), NBS (1.5 equiv)
Yb(OTf)3
R1
+
N
N
N
°
MeOH, 25 C
X
X
S
S
S
O
O
O
O
O
O
9
4
8
Entry
Substrate
R1
t (h)
X
dra (8:9)
Yieldb(%)
1
4a
4a
4b
4c
4d
4e
4h
4i
C6H5
C6H5
7
8
Br
I
65:35
67:33
78:22
75:25
79:21
75:25
63:37
52
87
98
91
97
90
90
2
3
4-MeOC6H4
4-BnOC6H4
3, 4-MeOC6H3
4-BnO-3-MeOC6H3
2-Naphthyl
2-ClC6H4
2-NO2C6H4
CH3
3
Br
Br
I
4
4
5
2
6
2
I
Br
7
9
8
48
48
24
24
Cl/Br/I
Cl/Br/I
Br
NR
NR
9
4j
10
11
4k
4l
66:34
62:38
71 (10)
78 (8)
C6H13
Br
Yields in parentheses refer to the dibromocarbonyl compounds. NR: No reaction.
a Determined from the 1H NMR spectrum of the crude reaction mixture.
b Combined isolated yields of pure 8 and 9 after column chromatography.
catalyzed asymmetric halohydrination, therefore, was fur-
ther applied to the catalytic asymmetric halomethoxy-
lation of different (2R)-N-enoylbornanesultam substra-
tes 4 (Table 3). It was found that when a methanolic

3076
S. Hajra et al. / Tetrahedron Letters 46 (2005) 3073–3077
solution of substrate 4a was treated with NBS
(1.5 equiv) in the presence of the Yb(OTf)3 catalyst
(15 mol %) at rt, it gave the desired bromomethoxycar-
bonyl compounds in 52% yield (entry 1). The iodometh-
oxylation of 4a under the same reaction conditions using
NIS instead of NBS provided the iodomethoxycarbonyl
compounds in 87% yield with moderate diastereoselec-
tivity (entry 2). The stereochemistry of the major isomer
8a was assigned by analogy with the above halohydr-
oxylation reactions. The compound 8a could easily be
transformed into the N-protected syn-b-methoxy-
phenylalanine, the unusual amino acid component of
cyclomarins.14,6a The electron-rich cinnamoyl substrates
4b, 4c and the b-(2-naphthyl)enoyl substrate 4h re-
sponded to the bromomethoxylation with moderate to
good diastereoselectivities (entries 3, 4 and 7) and the
more electron-rich cinnamoyl substrates 4d and 4e pre-
ferred to undergo iodomethoxylation with NIS (entries
5 and 6). Similar to the halohydroxylation, the elec-
tron-deficient cinnamoyl substrates 4i and 4j did not un-
dergo any halomethoxylation even under more vigorous
reaction conditions. We also studied the halomethoxyla-
tion of alkenoyl substrates 4k and 4l under the same
reaction conditions, which showed 100% regioselectiv-
ity, with moderate diastereoselectivity, in good yields.
pur and A.K. thanks CSIR, New Delhi for their
fellowships.
References and notes
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In summary, we have developed a Lewis acid catalyzed
asymmetric halohydrination, (halohydroxylation as well
as halomethoxylation) of chiral a,b-unsaturated car-
bonyl compounds with NXS (X = Br, I) as the halogen
source. Regio- and anti-selectivity of 100% and moder-
ate to good diastereoselectivity with good yields was
observed when bornanesultam was used as the chiral
auxiliary. Most of the metal halides and acetates did
not catalyze the halohydrin reactions, but metal triflates
showed good catalytic activity for the halohydrination
of a,b-unsaturated carbonyl compounds. Among the
metal triflates, Yb(OTf)3 was found to be the best cata-
lyst. Alkenoyl, cinnamoyl and moderately electron-rich
cinnamoyl substrates smoothly underwent the Yb(OTf)3
catalyzed bromohydrin reactions with NBS whilst the
more electron-rich cinnamoyl substrates preferred to un-
dergo iodohydrin reactions with NIS. The cinnamoyl
substrates possessing electron-withdrawing substituents
on the aromatic ring did not respond to the Lewis acid
catalyzed halohydrin reaction with either NCS, NBS
or NIS. This methodology offers an alternative method
for the synthesis of chiral a-halo-b-hydroxy/methoxy
carboxylic acid derivatives using easily available N-halo-
succinimide as the halogen source. A better understand-
ing of Lewis acid catalyzed halohydrin reactions may
provide a catalytic and enantioselective method for the
halohydrination of olefins. We are currently attempting
to improve the diastereoselectivity of this process and we
are applying this concept to other catalytic 1,2-halo
functionalizations of olefins.
5. (a) Ishihara, T.; Mima, K.; Konno, T.; Yamanaka, H.
Tetrahedron Lett. 2002, 43, 3493; (b) Guindon, Y.;
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9. Pure compounds 2a and 2a0 were fully characterized and
their stereochemistry was assigned in our earlier report.6b
10. The dr of 3a/3a0 was also the same as for the halohydrins.
It was determined by 13C NMR spectral analysis because
no separated 1H NMR signal was found for the diaste-
1
reomers of dibromocarbonyl compound 3a/3a0 in the H
NMR spectrum in CDCl3.
11. Representative spectral data of 2b: H NMR (200 MHz,
1
CDCl3) d 7.35 (d, J = 6.6 Hz, 2H), 6.90 (d, J = 6.7 Hz,
2H), 5.88 (d, J = 8.3 Hz, 1H), 5.13 (d, J = 8.3 Hz, 1H),
4.49–4.45 (m, 1H), 4.28–4.23 (m, 2H), 3.80 (s, 3H), 2.71–
2.25 (m, 2H), 0.93 (d, J = 7.0 Hz, 3H), 0.92 (d,J = 7.0 Hz,
3H);13C NMR (50 MHz, CDCl3) d 168.9, 159.6, 153.0,
131.3, 128.4, 113.7, 74.2, 63.5, 58.3, 55.1, 45.1, 28.0, 17.6,
14.7. 2b0: 1H NMR (200 MHz, CDCl3) d 7.36 (d, J =
6.7 Hz, 2H), 6.90 (d, J = 6.7 Hz, 2H), 6.00 (d, J = 7.5 Hz,
1H), 5.10 (d, J = 7.7 Hz, 1H), 4.52–4.39 (m, 1H), 4.26–
4.17 (m, 2H), 3.80 (s, 3H), 2.45–2.20 (m, 1H), 0.89 (d,
Acknowledgements
We thank DST, New Delhi and CSIR, New Delhi for
providing financial support. M.B. thanks IIT, Kharag-

S. Hajra et al. / Tetrahedron Letters 46 (2005) 3073–3077
3077
J = 6.9 Hz, 3H), 0.71 (d, J = 6.9 Hz, 3H); 13C NMR
(50 MHz, CDCl3) d 169.2, 159.6, 153.1, 131.3, 128.1,
113.8, 75.0, 63.4, 58.9, 55.1, 44.6, 28.2, 17.7, 14.3.
65.2, 55.1, 52.6, 48.3, 47.5, 46.3, 44.4, 37.7, 32.6, 26.1, 20.1,
19.6. Anal. Calcd for C20H26BrNO5S: C, 50.85; H, 5.55;
N, 2.97%. Found: C, 51.14; H, 5.20; N, 2.83%.
12. Vandewall, M.; Van der Eycken, J.; Oppolzer, W.;
Uullioud, C. Tetrahedron 1986, 42, 4035.
14. The minor isomer 6f, from the iodohydroxylation of 4f,
could not be obtained in pure form due to its instability
during silica gel column chromatography.
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Chem. 2002, 67, 4599.
13. Diastereomers of halohydrins 5 and 6 were isolated in
pure form and fully characterized by 1H and 13C NMR
and elemental (CHN) analysis. Representative spectral
1
data for 5b: H NMR (200 MHz, CDCl3) d 7.35 (d, J =
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19. Haruhiko, T.; Takehiko, T.; Yoshihiro, T.; Fumiaki, H.
Chem. Lett. 1992, 431.
6.3 Hz, 2H), 6.90 (d, J = 6.7 Hz, 2H), 5.11 (d, J = 8.1 Hz,
1H), 5.05–4.92 (br d, J = 8.0 Hz, 1H), 4.05–3.88 (m, 1H),
3.80 (s, 3H), 3.50 (d, J = 4.6 Hz, 2H), 2.28–2.00 (m, 3H)
2.00–1.25 (m, 4H), 1.17 (s, 3H), 0.91 (s, 3H); 13C NMR
(50 MHz, CDCl3) d 167.7, 159.6, 130.9, 128.2, 113.7, 74.5,
64.7, 55.0, 52.7, 48.6, 47.7, 46.5, 44.3, 37.4, 32.5, 26.2, 20.5,
19.7. Anal. Calcd for C20H26BrNO5S: C, 50.85; H, 5.55;
N, 2.97%. Found: C, 51.18; H, 5.61; N, 2.66%. 6b: 1H
NMR (200 MHz, CDCl3) d 7.32 (d, J = 8.5 Hz, 2H), 6.88
(d, J = 8.6 Hz, 2H), 5.07 (quasi q, J = 2.8 Hz, 2H), 3.82
(m, 1H), 3.79 (s, 3H), 3.45 (s, 2H), 2.20–1.75 (m, 5H),
1.75–1.10 (m, 3H), 0.91 (s, 3H), 0.77 (s, 3H); 13C NMR
(50 MHz, CDCl3) d 167.2, 159.6, 130.9, 127.7, 113.7, 75.9,