Highly regio- and stereoselective asymmetric bromoazidation of chiral α,β-unsaturated carboxylic acid derivatives: Scope and limitations

Article abstract of DOI:10.1021/jo061593k

(Chemical Equation Presented) Lewis acid catalyzed asymmetric bromoazidation of chiral α,β-unsaturated carboxylic acid derivatives was performed using N-bromosuccinimide (NBS) and trimethylsilyl azide (TMSN ₃) as the bromine and azide sources. Among the Lewis acids, Yb(OTf)₃ was found to be the best catalyst. Regio- and anti-selectivity of 100% and moderate to good diastereoselectivity (up to 89:11) with good yields were obtained when Oppolzer's bornane sultam chiral auxilairy was used. Diastereoselectivity of > 95:05 was observed when (2S,5S)-2,5-diphenylpyrrolidine was used as the chiral auxiliary.

Full text of DOI:10.1021/jo061593k

12
NaN3 mostly under noncatalytic conditions. The above
Highly Regio- and Stereoselective Asymmetric
Bromoazidation of Chiral r,â-Unsaturated
Carboxylic Acid Derivatives: Scope and
Limitations
11
methods except IPy2BF4/TMSN3 have not been utilized for
the haloazidation of R,â-unsaturated carbonyl compounds.
R,â-Unsaturated carbonyl compounds represent a syntheti-
cally useful class of substrate for various alkene oxidative
reactions. In particular, haloazidation of R,â-unsaturated car-
bonyl compounds would provide the functionalized azidohalo-
genated compounds, which can be transformed to various useful
organic compounds by replacing the halogen atom with a series
of nucleophiles, where the azido functionality would serve as a
protected amino group. However, little attention has been paid
to haloazidation of R,â-unsaturated carbonyl compounds. Asym-
metric haloazidation reaction has also not been explored. Herein,
we report a Lewis acid catalyzed asymmetric bromoazidation
of chiral R,â-unsaturated carboxylic acid derivatives using
N-bromosuccinimide (NBS) and trimethylsilyl azide (TMSN3)
as the bromine and azide sources, in which 100% regioselectivity
and high diastereoselectivity (>95:5) of the anti-R-bromo-â-
azido carbonyl compounds are demonstrated with good yields.
A current interest in our laboratory is to develop asymmetric
1,2-halofunctionalization of alkenes, especially R,â-unsaturated
carbonyl compounds.13 A reliable possibility for exerting
stereochemical control in the stereogenic centers is the use of
the chiral auxiliary methodology. Recently we have found
that Lewis acid activates NBS to facilitate the formation of
bromonium ion intermediate from alkenes.13a Accordingly, we
anticipated that a suitable Lewis acid might catalyze the
bromoazidation of chiral R,â-unsaturated carboxylic acid deriva-
tives containing a suitable chiral auxiliary with NBS and
TMSN3. Initially, asymmetric bromoazidation was investigated
on cinnamic acid derivatives containing two well-known chiral
auxiliaries such as Evans oxazolidinone14 and Oppolzer’s
sultam.15 N-Cinnamoyl-2-oxazolidinone 1a was selected as a
model substrate for the screening of the Lewis acids as catalysts
for bromoazidation with NBS and TMSN3 (Table 1). The metal
halides and acetates, such as CuCl2, Co(OAc)2, Cu(OAc)2, Mn-
(OAc)2, and Ni(OAC)2, showed poor to moderate catalytic effect
for the bromoazidation of 1a (entries 2-6). The metal triflates
Zn(OTf)2, La(OTf)3, Y(OTf)3, Sm(OTf)3, and Yb(OTf)3 as
Saumen Hajra,* Manishabrata Bhowmick, and
Debarshi Sinha
Department of Chemistry, Indian Institute of Technology,
Kharagpur 721 302, India
shajra@chem.iitkgp.ernet.in
ReceiVed August 1, 2006
Lewis acid catalyzed asymmetric bromoazidation of chiral
R,â-unsaturated carboxylic acid derivatives was performed
using N-bromosuccinimide (NBS) and trimethylsilyl azide
(TMSN3) as the bromine and azide sources. Among the
Lewis acids, Yb(OTf)3 was found to be the best catalyst.
Regio- and anti-selectivity of 100% and moderate to good
diastereoselectivity (up to 89:11) with good yields were
obtained when Oppolzer’s bornane sultam chiral auxilairy
was used. Diastereoselectivity of >95:05 was observed when
(2S,5S)-2,5-diphenylpyrrolidine was used as the chiral aux-
iliary.
1,2-Haloazidation of alkenes is an important oxidative reac-
tion in organic chemistry. These vicinal haloazides are versatile
chemical intermediates for the synthesis of numerous function-
alized compounds such as vinyl azides,1 amines,2 heterocycles,3
and particularly aziridines.4 The study of catalytic highly regio-
and stereoselective haloazidation of alkenes, especially R,â-
unsaturated carbonyl compounds, still remains a challenging task
to organic chemists.
(5) (a) Hassner, A.; Boerwinkle, F. J. Am. Chem. Soc. 1968, 90, 216-
218. (b) Boerwinkle, F.; Hassner, A. Tetrahedron Lett. 1968, 3921-3924.
(c) Hassner, A.; Boerwinkle, F. Tetrahedron Lett. 1969, 3309-3312.
(6) Hantzsch, A.; Schu¨mann, M. Ber. Dtsch. Chem. Ges. 1900, 33, 522.
(7) (a) Hassner, A.; Levy, L. A. J. Am. Chem. Soc. 1965, 87, 4203-
4204. (b) Fowler, F. W.; Hassner, A.; Levy, L. A. J. Am. Chem. Soc. 1967,
89, 2077-2082.
(8) Olah, G. O.; Wang, Q.; Li, X.-Y.; Prakash, G. K. S. Synlett 1990,
487-489.
(9) Kirschning, A.; Hashem, Md. A.; Monenschein, H.; Rose, L.;
Scho¨ning, K.-U. J. Org. Chem. 1999, 64, 6522-6526.
(10) Nair, V.; George, T. G.; Sheeba, V.; Augustine, A.; Balagopal, L.;
Nair, L. G. Synlett 2000, 1597-1598.
(11) Barluenga, J.; Alvarez-Perez, M.; Fananas, F. J.; Gonzales, J. M.
AdV. Synth. Catal. 2001, 343, 335-337.
(12) Curini, M.; Epifano, F.; Marcotullio, M. C.; Rosati, O. Tetrahedron
Lett. 2002, 43, 1201-1203.
(13) (a) Hajra, S.; Bhowmick, M.; Karmakar, A. Tetrahedron Lett. 2005,
46, 3073-3077. (b) (b) Hajra, S.; Karmakar, A.; Bhowmick, M. Tetrahedron
2005, 61, 2279-2286. (c) Hajra, S.; Karmakar, A.; and Bhowmick, M.
Tetrahedron: Asymmetry 2006, 17, 210-222.
(14) (a) Evans, D. A. Aldrichimica Acta 1982, 15, 23. (b) Evans, D. A.;
Shaw, J. T. Actual. Chim. 2003, 35.
In the literature, 1,2-haloazides are usually prepared by
addition of Br2/NaN3,5 NBS/NaN3,4 I2/AgN3,6 and ICl/NaN3
7
onto alkenes. Although no problems have been reported,
bromine azide and iodine azide are potentially explosive. There
are also a few methods for the haloazidation of alkenes using
NBS/TMSN3/Nafion-H resin (cat.),8 PhI(OAc)2/Et4NX/TMSN3,9
CAN/NaI/NaN3,10 IPy2BF4/TMSN3,11 and Oxone/wet-Al2O3/KI/
(1) Hassner, A.; Fowler, F. W. J. Org. Chem. 1968, 33, 2686-2691.
(2) Wasserman, H. H.; Brunner, R. K.; Buynak, J. D.; Carter, C. G.;
Oku, T.; Robinson, R. P. J. Am. Chem. Soc. 1985, 107, 519-521.
(3) For the synthesis of tetrazoles via Hassner-Ritter reaction: (a)
Ranganathan, S.; Ranganathan, D.; Mehrotra, A. K. Tetrahedron Lett. 1973,
14, 2265-2268. (b) Moorthy, S. N.; Devaprabakara, D. Tetrahedron Lett.
1975, 16, 257-260.
(4) (a) Van Ende, D.; Krief, A. Angew. Chem., Int. Ed. Engl. 1974, 13,
279-280. (b) Denis, J. N.; Krief, A. Tetrahedron 1979, 35, 2901-2903.
(15) Vandewalle, M.; Van, der Eycken, J.; Oppolzer, W.; Vullioud, C.
Tetrahedron 1986, 42, 4035-4043.
10.1021/jo061593k CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/27/2006
J. Org. Chem. 2006, 71, 9237-9240
9237

TABLE 1. Screening of Lewis Acids as Catalysts for the
Bromoazidation of 1 with NBS and TMSN3
TABLE 2. Yb(OTf)3-Catalyzed Bromoazidation of
(2R)-N-Enoylbornanesultams 5
t
T
(˚C)
dra
(6:7)
yieldb
(%)
entry
substrate
Ar
(h)
1
2
3
4
5
6
7
8
9
5a
5a
5b
5b
5c
5c
5d
5e
5f
C6H5
C6H5
24
4
2
4
1
rt
45
rt
-20
rt
-20
45
45
45
45
NR
NR
86
85
87
88
sub-
entry strate
T
(h)
conva
ratioa
dr of yielda
(%)
70:30
86:14
60:40
89:11
65:35
NR
NR
75:25
73:27
MLn
none
CuCl2
(%) (2+3):(4+4′) (2:3)a
4-MeOC6H4
4-MeOC6H4
3,4-MeOC6H3
3,4-MeOC6H3
2-ClC6H4
2-NO2C6H4
4-ClC6H4
4-NO2C6H4
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
24
24
<5
60
75
ND
ND
71:29
88:12
72:28
77:23
87:13
85:15
87:13
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
57:43 70
55:45 47
57:43 54
57:43 62
57:43 65
53:47 44
53:47 33
56:44 77
57:43 59
57:43 53
55:45 52
59:41 90 (87)
55:45 97 (93)
2
84
Cu(OAc)2 24
Co(OAc)2 24
Mn(OAc)2 12
Ni(OAc)2 10
Mg(OTf)2 24
Cu(OTf)2 24
24
24
36
36
NR
NR
85c
89d
66
100
100
16
10
5g
a Determined by HPLC. NR: no reaction. b Combined isolated yields
of 6 and 7 after column chromatography. NR: no reaction. c Combined
isolated yield of 6f and 7f along with 17% of undesired compounds.
d Combined isolated yield of 6g and 7g along with 24% of undesired
compounds.
78
9
Zn(OTf)2
La(OTf)3
Y(OTf)3
Sm(OTf)3
Yb(OTf)3
Yb(OTf)3
5.5 100
12
3.5 100
6
4
2
10
11
12
13
14
100
100
100
100
diastereomers16 (entries 9 and 10). The bromoazidation of 5f
and 5g required an excess of reagents (0.15 equiv of Yb(OTf)3,
1.8 equiv of NBS, and 2.0 equiv of TMSN3) and longer reaction
time for 100% of conversion. Steric effect along with electronic
effect might be responsible for substrates 5d and 5e not
undergoing the bromoazidation reaction. Stereochemistry of the
bromoazides 6 and 7 were assigned by analogy with our earlier
work.13a
It was found that oxazolidinone chiral auxiliary provided poor
diastereoselectivity (Table 1) and sultam showed moderate to
good diastereoselectivity (Table 2) for the Yb(OTf)3-catalyzed
bromoazidation of 1 and 5, respectively. We further investigated
the bromoazidation reaction of R,â-unsaturated carboxylic acid
derivatives possessing C2-symmetry with 2,5-diphenylpyrroli-
dine17 as a chiral auxiliary. When cinnamide 8a was treated
with Yb(OTf)3 (0.10 equiv), TMSN3 (1.5 equiv), and NBS (1.2
equiv) in CH2Cl2 at -20 °C, it provided anti-R-bromo-â-azido
carbonyl compound 9a with high diastereoselectivity (dr >95:
05) and in good yield (Table 3; entry 1). However, bromoazi-
dation of 8a at room temperature or at 0 °C showed poor
diastereoselectivity of 50:50 and 62:38, respectively.
This bromoazidation reaction was further studied using other
cinnamoyl substrates containing electron-donating and
-withdrawing substituents on the aromatic ring as well as
alkenoyl substrates. It was found that the â-(2-naphthyl)-enoyl
substrate 8b smoothly underwent bromoazidation (entry 2) with
high diastereoselectivity (94:06) at -20 °C. The more electron-
rich cinnamoyl substrate 8c also efficiently underwent bro-
moazidation reaction with slightly lower diastereoselectivity (85:
15; entry 3). The electron-deficient cinnamoyl substrates 8d and
a Determined by 1H NMR spectrum analysis of the crude reaction mixture
with succinic anhydride as an internal standard. Yields in the parentheses
refer to the isolated yields. ND: not determined.
catalysts showed good results (entries 9-13). Among these, Yb-
(OTf)3 was found to be the best catalyst. It should be noted
that in the absence of Lewis acid the substrate 1a did not
undergo the bromoazidation reaction (entry 1). When 1a was
treated with TMSN3 (1.5 equiv) and NBS (1.2 equiv) in CH2-
Cl2 in the presence of the Yb(OTf)3 catalyst (10 mol %) and
MS 4Å at room temperature (25 °C), within 4 h it gave the
desired bromoazides 2a and 3a in good yield (entry 13). Without
MS 4Å, 10-15% of halohydroxylated product13a was observed.
The electron-rich cinnamoyl substrate 1b also underwent the
clean bromoazidation under the same reaction conditions.
However, the diastereoselectivities of the above bromoazidation
reactions were rather low.
Yb(OTf)3-catalyzed bromoazidation of (2R)-N-cinnamoyl-
bornanesultam 5a did not occur at room temperature (Table 2;
entry 1), but at 45 °C it provided the clean bromoazides 6a and
7a with moderate diastereoselectivity in good yield (entry 2).
This Yb(OTf)3-catalyzed bromoazidation reaction was further
studied with other cinnamoyl substrates. Electron-rich cinnamoyl
substrates 5b and 5c smoothly underwent the bromoazidation
reaction at room temperature and afforded the bromoazides with
good diastereoselectivity and yields (entries 3 and 5). Substrates
5b and 5c also responded to the bromoazidation reaction even
at lower temperature such as -20 °C; however, diastereose-
lectivity went down (entries 4 and 6). The ortho-substituted
electron-deficient cinnamoyl substrates 5d and 5e did not
undergo the bromoazidation reaction even at 45 °C. However,
substrates 5f and 5g containing the same electron-withdrawing
groups at the para position underwent the bromoazidation
reaction at 45 °C and provided a nonseparable mixture of
(16) In addition, a minor amount (17-24%) of nonseparable undesired
compounds was obtained.
(17) Aldous, D. J.; Dutton, W. M.; Steel, P. G. Tetrahedron: Asymmetry
2000, 11, 2455-2462.
9238 J. Org. Chem., Vol. 71, No. 24, 2006

TABLE 3. Yb(OTf)3-Catalyzed Bromoazidation of 8
In summary, we have developed a Lewis acid catalyzed
asymmetric bromoazidation reaction of chiral R,â-unsaturated
carbonyl compounds with NBS and TMSN3 as the bromine and
azide sources. The metal halides and acetates showed poor to
moderate catalytic effect for the bromoazidation reaction, but
metal triflates were found to be good catalysts. Among the metal
triflates, Yb(OTf)3 was found to be the best catalyst. Regio-
and anti-selectivity of 100% and moderate to good diastereo-
selectivity (up to 89:11) with good yields were observed when
bornanesultam was used as the chiral auxiliary. Use of the
(2S,5S)-2,5-diphenylpyrolidine as a chiral auxiliary provided
very high diastereoselectivity (>95:05) depending upon the
reaction conditions. Alkenoyl, cinnamoyl, and electron-rich
cinnamoyl substrates smoothly underwent the Yb(OTf)3-
catalyzed bromoazidation reactions with NBS and TMSN3. The
cinnamoyl substrates possessing electron-withdrawing substit-
uents at the para position also responded to the reaction at higher
temperature, but the cinnamoyl substrates containing electron-
withdrawing substituents at the ortho position did not. This
methodology offers an efficient method for the synthesis of
chiral anti-R-bromo-â-azido carboxylic acid derivatives using
commercially available NBS and TMSN3 as the bromine and
azide sources.
t
T
yieldb
(%)
entry
substrate
R
(h)
(˚C)
dra
1
2
8a
8b
8c
8d
8e
8f
8g
8h
8i
C6H5
10
8
2
24
24
30
30
6
-20
-20
-20
25
25
35
35
-20
25
>95:05
94:06
85:15
NR
80
91
71
NR
NR
90c
85e
87
2-naphthyl
3,4-MeOC6H3
2-ClC6H4
2-NO2C6H4
4-ClC6H4
4-NO2C6H4
CH3
3
4c
5c
6
NR
60:40
50:50d
>95:05
>95:05
7
8
9
C6H13
24
75
a Determined from the 1H NMR spectrum of the crude reaction mixture.
NR: no reaction. b Isolated yields of pure 9 after column chromatography.
NR: no reaction. c Combined isolated yield of 9f diastereomers along with
15% of undesired compounds. d Determined by HPLC. e Combined isolated
yield of 9g diastereomers along with 24% of undesired compounds.
SCHEME 1
Experimental Section
General Procedure for the Bromoazidation of Compounds
1, 5, and 8. To a well-stirred suspended solution of substrate 1, 5,
or 8 (0.50 mmol) and MS 4Å (0.100 g) in dry CH2Cl2 (2.5 mL; for
the substrates 8, 20% of THF was used when the reaction was
performed at -20 °C) was added Yb(OTf)3 (0.031 g, 0.05 mmol)
under argon atmosphere. The temperature of the reaction mixture
was maintaied as specified in Tables 1, 2, and 3. TMSN3 (0.1 mL,
0.75 mmol) and NBS (0.107 g, 0.60 mmol) were successively
added. Reaction was monitored by TLC, quenched with saturated
NaHCO3, and extracted with CH2Cl2 (3 × 30 mL). The combined
organic layers were washed with water, dried over Na2SO4, and
concentrated under vacuum. Flash column chromatography of the
crude mixture using petroleum ether-EtOAc as an eluent gave pure
R-bromo-â-azido carbonyl compounds 2/3, 6, and 9. Minor isomers
7 and of 9 could not be isolated in pure form.
8e, similar to 5f and 5g, did not undergo any bromoazidation
reaction under the same reaction conditions, even with the use
of excess reagents at room temperature (25 °C) and at 45 °C
gave mixture of uncharacterized products. However, the sub-
strates 8f and 8g containing the same electron-withdrawing
groups at the para position yielded the bromoazides18 9f and
9g at 35 °C (entries 6 and 7). It is to be noted that bromoazi-
dation of substrates 8f and 8g also required, similar to substrates
5f and 5g, an excess of reagents (0.15 equiv of Yb(OTf)3, 1.8
equiv of NBS, and 2.0 equiv of TMSN3) and longer reaction
time for 100% of conversion. The crotonyl substrate 8h
underwent bromoazidation reaction at -20 °C and yielded the
anti-R-bromo-â-azido carbonyl compound 9h with >95:05
diastereoselectivity and 100% regioselectivity (entry 8). How-
ever, alkenoyl substrate 8i showed the reactivity only at room
temperature (25 °C) and provided the bromoazide compound
9i with high diastereoselectivity and moderate yield (entry 9).
The stereochemistry of 9 was confirmed from the single-crystal
X-ray analysis of major compound 9c (see Supporting Informa-
tion).
Removal of the chiral auxiliary of the bromoazides would
provide enantiomerically pure anti-R-bromo-â-azido carboxylic
acids. As example, an aqueous THF (10:1) solution of com-
pound 6b was treated with LiOH (1.5 equiv) and 30% of H2O2
(10 equiv) at -4 °C. Within 6 h, it produced the anti-R-bromo-
â-azido carboxylic acid 10b in 61% yield along with a minor
amount (25%) of parent cinnamic acid 11b (Scheme 1), which
might have been produced by retro-bromoazidation reaction
under the alkaline condition. Sultam chiral auxiliary was
recovered in 88% yield, and its optical purity was the same as
that of the parent sultam.
anti-(2R,2′R,3′R)-N-[3′-Azido-2′-bromo-3′-(4-methoxyphenyl)-
propionyl]-bornanesultam (6b). White solid, mp 144-146 °C;
[R]25 ) -116.57 (c 0.29, CHCl3). IR (KBr, cm-1): 500, 532,
D
547, 668, 831, 1026, 1116, 1136, 1177, 1215, 1255, 1294, 1314,-
1329, 1384,1459, 1515, 1613, 1693 (CO), 2104 (N3), 2342, 2361,
1
2961. H NMR (200 MHz, CDCl3): δ 0.99 (s, 3H), 1.17 (s, 3H),
1.20-1.55 (m, 3H), 1.85-2.05 (m, 2H), 2.10-2.25 (m, 2H), 3.55
(s, 2H), 3.82 (s, 3H), 4.04 (m, 1H), 4.90-5.10 (m, 2H), 6 94 (d, J
) 8.6 Hz, 2H), 7.31 (d, J ) 8.6 Hz, 2H). 13C NMR (50 MHz,
CDCl3): δ 19.8, 20.6, 26.4, 32.7, 37.5, 44.5, 45.2, 47.9, 48.8, 52.9,
55.2, 65.0, 65.9, 114.2 (2C), 127.1, 129.4 (2C), 160.3, 166.3. Anal.
Calcd for C20H25BrN4O4S: C, 48.29; H, 5.07; N, 11.26. Found:
C, 48.67; H, 5.06; N, 11.06. Diastereomeric ratio was determined
by HPLC [ZORBAX Eclipse XBD-C18 column, acetonitrile/water
(80/20 v/v), 1 mL/min, 250 nm].
anti-(2′R,3′R,2S,5S)-1-[3′-Azido-2′-bromo-3′-phenyl-propionyl]-
2,5-diphenyl-pyrrolidine (9a). White solid, mp 167-169 °C; [R]25
D
) -248.30 (c 0.94, CHCl3). IR (KBr, cm-1): 466, 536, 570, 604,
612, 668, 702, 755, 767, 802, 900, 1002, 1028, 1077, 1168, 1205,
1308, 1359, 1418, 1452, 1493, 1583, 1660 (CO), 2111 (N3), 2342,
1
2361, 2961, 3028, 3057. H NMR (200 MHz, CDCl3): δ 1.60-
2.05 (m, 2H), 2.35-2.75 (m, 2H), 4.12 (d, J ) 10.5 Hz, 1H), 4.94
(d, J ) 10.5 Hz, 1H), 5.36 (d, J ) 7.7 Hz, 1H), 5.60 (d, J ) 7.7
Hz, 1H), 6.75-6.90 (m, 2H), 7.00-7.65 (m, 13H). 13C NMR (50
MHz, CDCl3): δ 30.6, 32.9, 45.5, 62.4 (2C), 66.2, 125.1 (2C),
(18) In addition, a minor amount (15-24%) of nonseparable undesired
compounds was obtained.
J. Org. Chem, Vol. 71, No. 24, 2006 9239

125.6 (2C), 126.9, 127.8 (2C), 128.0, 128.4 (2C), 128.5 (2C), 128.8,
129.2 (2C), 136.1, 142.1, 142.9, 166.0. Anal. Calcd for C25H23-
BrN4O: C, 63.16; H, 4.88; N, 11.79. Found: C, 63.46; H, 5.25;
N, 11.47.
and D.S. would like to thank IIT, Kharagpur and CSIR, New
Delhi, respectively, for their fellowships.
Supporting Information Available: General experimental
details, characterization data of other bromoazides 2/3, 6, 9 and
1
10b; H, 13C, and DEPT-135 NMR spectra of bromoazides 6, 9,
and 10b; HPLC traces of crude reaction mixture; ORTEP diagram
and file for the single-crystal X-ray analysis of compound 9c in
CIF format. This material is available free of charge via the Internet
at http://pubs.acs.org.
Acknowledgment. We wish to thank DST, New Delhi for
providing financial support (project no. SR/S1/OC-13/2004) and
for providing XRD facility to the Department of Chemistry,
IIT Guwahati under FIST programme (sanction no. SR/FST/
CSII-007/2003) for extending support for single XRD data. M.B.
JO061593K
9240 J. Org. Chem., Vol. 71, No. 24, 2006