NBS-catalyzed hydroamination and hydroalkoxylation of activated styrenes

Article abstract of DOI:10.1021/ol047402m

(Chemical Equation Presented) N-Bromosuccinimide efficiently catalyzes the hydroamination and hydroalkoxylation of activated styrenes using tosylamides, carbamates, and alcohols as the nucleophiles to afford amino and ether derivatives, respectively. Both

Full text of DOI:10.1021/ol047402m

ORGANIC
LETTERS
2005
Vol. 7, No. 5
855-857
NBS-Catalyzed Hydroamination and
Hydroalkoxylation of Activated Styrenes
Siva Kumar Talluri and Arumugam Sudalai*
Chemical Engineering & Process DeVelopment DiVision,
National Chemical Laboratory, Pashan Road, Pune, India 411008
sudalai@dalton.ncl.res.in
Received December 17, 2004
ABSTRACT
N-Bromosuccinimide efficiently catalyzes the hydroamination and hydroalkoxylation of activated styrenes using tosylamides, carbamates, and
alcohols as the nucleophiles to afford amino and ether derivatives, respectively. Both the processes give good to excellent yields of the
products with 100% regioselectivity (Markovnikov fashion).
The catalytic addition of organic amines and their derivatives
to alkenes or alkynes (hydroamination) to produce nitrogen-
containing organic molecules is of great importance for
synthetic chemists in basic research as well as for the
chemical industry.1 While a variety of protocols exist for
the functionalization of alkynes,2 relatively few reports
describe the hydroamination of alkenes.3 Hydroaminations
are generally catalyzed by transition metals (d- and f-block),4
alkali metals,5 and Bronsted and Lewis acids.6 However,
many of these catalysts are difficult to synthesize, expensive,
sensitive to air and moisture, or highly toxic. Further,
hydroamination of alkenes with weaker nucleophiles such
as sulfonamides and carbamates as amine sources has been
carried out generally under intramolecular fashion only.6a,7
Recently, we have reported a high-yielding preparative
procedure for the aminobromination of a variety of olefins
to give vicinal haloamine derivatives 2 by using Cu, Mn, or
V catalysts with stoichiometric p-toluenesulfonamide (TsNH2)
and N-bromosuccinimide (NBS) as nitrogen and bromine
sources, respectively.8
(4) (a) Coulson, D. R. Tetrahedron Lett. 1971, 12, 429. (b) Casalnuovo,
A. L.; Calabrese, J. C.; Milstein, D. J. Am. Chem. Soc. 1988, 110, 6738.
(c) Gagne´, M. R.; Marks, T. J. J. Am. Chem. Soc. 1989, 111, 4108. (d)
Beller, M.; Eichberger, M.; Trauthwein, H. Angew. Chem., Int. Ed. Engl.
1997, 36, 2225. (e) Dorta, R.; Egli, P.; Zu¨rcher, F.; Togni, A. J. Am. Chem.
Soc. 1997, 119, 10857. (f) Kawatsura, M.; Hartwig, J. F. J. Am. Chem.
Soc. 2000, 122, 9546. (g) Lo¨ber, O.; Kawatsura, M.; Hartwig, J. F. J. Am.
Chem. Soc. 2001, 123, 4366. (h) Utsunomiya, M.; Hartwig, J. F. J. Am.
Chem. Soc. 2001, 123, 14287. (i) Beller, M.; Breindl, C.; Eichberger, M.;
Hartung, C. G.; Seayed, J.; Thiel, O. R.; Tillack, A.; Trauthwein, H. Synlett
2002, 1579. (j) Lo¨ber, O.; Kawatsura, M.; Hartwig, J. F. J. Am. Chem.
Soc. 2003, 125, 4366. (k) Utsunomiya, M.; Kuwano, R.; Kawatsura, M.;
Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 5608. (l) Fadini, L.; Togni, A.
Chem. Commun. 2003, 30. (m) Ryu, J.-S.; Li, G. Y.; Marks, T. J. J. Am.
Chem. Soc. 2003, 125, 12584. (n) Hong, S.; Tian, S.; Metz, M. V.; Marks,
T. J. J. Am. Chem. Soc. 2003, 125, 14768. (o) Brunet, J.-J.; Cadena, M.;
Chu, N. C.; Diallo, O.; Jacob, K.; Mothes, E. Organometallics 2004, 23,
1264. (p) Utsunomiya, M.; Hartwig, J. F. J. Am. Chem. Soc. 2004, 126,
2702. (q) Ackermann, L.; Kaspar, L. T.; Gschrei, C. J. Org. Lett. 2004, 6,
2515.
(1) (a) Mu¨ller, T. E.; Beller, M. Chem. ReV. 1998, 98, 675. (b) Norbis,
M.; Ho¨lscher, B. D. Angew. Chem., Int. Ed. 2001, 40, 3983. (c) Roesky, P.
W.; Mu¨ller, T. E. Angew. Chem., Int. Ed. 2003, 42, 2708. (d) Hartwig, J.
F. Pure Appl. Chem. 2004, 76, 507. (e) Beller, M.; Seayad, J.; Tillack, A.;
Jiao, H. Angew. Chem., Int. Ed. 2004, 43, 3368.
(2) (a) Haak, E.; Bytschkov, I.; Doye, S. Angew. Chem., Int. Ed. 1999,
38, 3389. (b) Pohlki, F.; Doye, S. Chem. Soc. ReV. 2003, 32, 104 and
references therein. (c) Bytschkov, I.; Doye, S. Eur. J. Org. Chem. 2003,
935.
(3) (a) Transition Metals in Organic Synthesis; Mueller, T. E., Beller,
M., Eds.; Wiley-VCH: Weinheim, 1998; p 316. (b) Taube, R. In Applied
Homogeneous Catalysis of Organometallic Compounds; Cornils, B., Her-
mann, W. A., Eds.; Wiley-VCH: Weinheim, 1996; p 507.
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A: Chem. 2002, 182-183, 489 and references therein.
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10.1021/ol047402m CCC: $30.25
© 2005 American Chemical Society
Published on Web 02/08/2005

While screening various olefinic substrates for the amino-
bromination process, we found that 4-methoxystyrene took
a different course and furnished the unexpected hydroami-
nated product 3 in a Markovnikov fashion instead of the
bromoaminated product 2. In continuation of this work, we
present herein NBS-catalyzed intermolecular hydroamination
of activated styrenes using sulfonamides and carbamates as
mild nucleophiles to produce hydroaminated products 3 and
4, respectively (Scheme 1).
ride, as other solvents were found to be less effective. An
increase in temperature (50 °C), for enhancing the rate, had
a deleterious effect on the yield and selectivity of the process.
Other catalysts such as ZnBr2, I2, etc. have failed to give
the hydroaminated products. In the absence of NBS, no
product formation was observed even after 78 h of stirring.
We have applied the optimized procedure of NBS-
catalyzed hydroamination to a variety of electron-rich
styrenes to determine the scope of the hydroamination
process, and the results are presented in Table 2. As can be
a
Scheme 1
Table 2. NBS-Catalyzed Hydroamination of Activated
Styrenes Using Sulfonamides and Carbamatesa
a Conditions: (i) TsNH2 (2 mmol), NBS (2.2 mmol), Cul/MnSO4/
V2O5 (5 mol %), CH2Cl2, 25 °C. (ii) TsNH2 or NHCO2R1, NBS
(20 mol %), CH2Cl2, 25 °C.
entry
R
R1
R2
R3NH2
TsNH2
CbzNH2
MeOCONH2
TsNH2
CbzNH2
TsNH2
TsNH2
MeOCONH2
TsNH2
TsNH2
MeOCONH2
TsNH2
TsNH2
yield (%)b
1
2
3
4
5
6
7
8
9c
10
11
12
13
OMe
OMe
OMe
OEt
H
H
H
H
H
H
H
H
H
Cl
Cl
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
82
80
74
75
60
78
83
80
60
78
80
66
62
When 4-methoxystyrene was treated with either TsNH2
or benzyl carbamate (1.0 equiv) in the presence of a catalytic
amount of NBS (20 mol %) at 25 °C in CH2Cl2, the
corresponding hydroaminated product 3 or 4 was obtained
in good yields with excellent regioselectivity (Markovnikov
fashion). Encouraged by this result, a systematic study was
undertaken to screen various bromine-based catalytic systems
for the hydroamination process. The data presented in Table
1 show the effect of the catalyst and solvent on the efficiency
OEt
OBn
SMe
SMe
OMe
OMe
OMe
OiPr
OCpd
a All reactions were performed at 25 °C for 24 h unless otherwise
mentioned. b Isolated yield after column chromatographic purification.
c Reaction was performed for 48 h. d Cp ) cyclopentyl.
Table 1. Effect of Catalyst on Hydroamination of
4-Methoxystyrene with TsNH2 at 25 °Ca
yield of 3b
entry
catalyst (mol %)
solvent
(%)
seen, both sulfonamides and carbamates were successfully
employed as the amine sources to produce the corresponding
amino derivatives in high yields.
1
2
3
4
5
6
7
8
N-bromosuccinimide (10)
N-bromosuccinimide (20)
N-bromosuccinimide (20)
N-bromosuccinimide (20)
N-bromoacetamide (20)
N-chlorosuccinimide (20)
CH2Cl2
CH2Cl2
CH3CN
THF
CH2Cl2
CH2Cl2
60
82
68
18
65
25
70
0
However, the reaction of 2-methyl-4-methoxystyrene with
TsNH2 proceeded slowly (48 h), yielding 60% of the
hydroaminated product (entry 9). Surprisingly, the methodol-
ogy fails in the case of aliphatic olefins, electron-deficient
styrenes, as well as with more nucleophilic amines.
We further extended the scope of this methodology by
subjecting a variety of alcohols as nucleophiles for the
hydroalkoxylation of electron-rich styrenes (Table 3).
Remarkably, even allyl and propargyl alcohols readily
underwent hydroalkoxylation with activated styrenes using
20 mol % NBS, under ambient conditions, to produce the
corresponding ethers in high yields (entries 6 and 7).
However, in the case of aliphatic and less activated styrenes,
the bromoalkoxylated products were obtained as expected
under stoichiometric NBS conditions.9 Generally, olefin
hydroalkoxylation is catalyzed by Bronsted acids as well as
transition metal complexes.10
pyridinium bromide perbromide (20) CH2Cl2
zinc bromide (20) CH2Cl2
a General Procedure: To a mixture of 4-methoxystyrene (2 mmol) and
p-toluenesulfonamide (2 mmol) in 4 mL of solvent was added catalyst (20
mol %) at 25 °C. After stirring for 24 h, the reaction mixture was
concentrated and purified using silica gel (ethyl acetate/petroleum ether).
b Isolated yield after column chromatographic purification.
of the hydroamination process. Although pyridinium bromide
perbromide and N-bromoacetamide have displayed compa-
rable activity, the activity of NBS is found to be superior,
as it provides excellent yields of the hydroaminated product.
Lowering the NBS concentration below 20 mol % led to a
decline in the yield (entry 1).
The NBS-catalyzed hydroamination reactions were gener-
ally conducted at ambient temperatures in methylene chlo-
(9) Rodriguez, J.; Dulce`re, J.-P. Synthesis 1993, 1177.
Org. Lett., Vol. 7, No. 5, 2005
856

takes place by the reaction of intermediate A with TsNH2,
thereby giving the hydroaminated product. Further, involve-
ment of radical species in the reaction was ruled out, as the
reaction proceeded smoothly in the presence of TEMPO. The
mechanism for the hydroalkoxylation is not yet clearly
understood.
Table 3. NBS-Catalyzed Hydroalkoxylation of Activated
Styrenes Using Alcohols as Nucleophilesa
entry
R
R1
R2
benzyl
methyl
benzyl
methyl
benzyl
allyl
yield of 5 (%)b
1
2
3
4
5
6
7
8
OMe
OMe
SMe
SMe
OMe
OMe
OMe
OMe
H
H
H
H
Cl
H
H
H
81
84
85
86
83
85
76
70
propargyl
1-phenethylc
a General Procedure: To a mixture of 4-methoxystyrene (2 mmol) and
alcohol (2 mmol) in CH2Cl2 (4 mL) was added NBS (20 mol %) at 25 °C.
After stirring for 36 h, the reaction mixture was concentrated and purified
using silica gel (5% ethyl acetate/petroleum ether). b Isolated yield after
column chromatographic purification. c Dr ) 1:1.
Figure 1. Proposed mechanism for the hydroamination of activated
styrenes catalyzed by NBS.
In conclusion, we have developed, for the first time, a new,
practical, and “metal-free” procedure for the hydroamination
and hydroalkoxylation of activated styrenes catalyzed by
NBS under ambient conditions using sulfonamides, carbam-
ates, and alcohols as nucleophiles. Further work to expand
this catalytic process to an asymmetric version is under
investigation.
The proposed mechanistic pathway for the NBS-catalyzed
hydroamination process is shown in Figure 1 and is based
on the following observations. The species TsNHBr was
isolated (as characterized by 1H and 13C NMR and MS) when
TsNH2 was reacted with NBS (in equimolar proportions).8
Subsequently, the interaction between TsNHBr and 4-meth-
oxystyrene leads to the protonation of a styrenic double bond
in Markovnikov fashion [as evidenced by the in situ UV
studies, which showed a λmax at 590 nm typical of benzylic
carbocation species11 and by in situ 1H NMR studies, which
showed a doublet at δ 1.39 (J ) 6.6 Hz) for the methyl
group].12 Finally, the regeneration of the species TsNHBr
Acknowledgment. T.S.K. thanks CSIR, New Delhi, for
the award of a fellowship. The authors are thankful to Dr.
B. D. Kulkarni, Head, CE-PD Division, for his constant
encouragement.
Supporting Information Available: Spectral data for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(10) (a) Stewart, I. C.; Bergman, R. G.; Toste F. D. J. Am. Chem. Soc.
2003, 125, 8696 and references therein. (b) Qian, H.; Han, X.; Widenhoefer,
R. A. J. Am. Chem. Soc. 2004, 126, 9536 and references therein.
(11) Rao, V. J.; Prevost, N.; Ramamurthy, V.; Kojima, M.; Johnston, L.
J. Chem. Commun. 1997, 2209 and references therein.
OL047402M
(12) See Supporting Information for spectra.
Org. Lett., Vol. 7, No. 5, 2005
857