Copper-catalyzed intermolecular hydroamination of alkenes

Article abstract of DOI:10.1021/ol061355b

Regioselective additions of arylsulfonamides to vinylarenes, norbornene, and cyclohexadiene were achieved using a copper-diphosphine catayst under mild reaction conditions. These processes appear to be ligand-accelerated.

Full text of DOI:10.1021/ol061355b

ORGANIC
LETTERS
2006
Vol. 8, No. 16
3561-3564
Copper-Catalyzed Intermolecular
Hydroamination of Alkenes
Jason G. Taylor, Neil Whittall,† and King Kuok (Mimi) Hii*
Department of Chemistry, Imperial College London, Exhibition Road, South
Kensington SW7 2AZ, United Kingdom
mimi.hii@imperial.ac.uk
Received June 2, 2006
ABSTRACT
Regioselective additions of arylsulfonamides to vinylarenes, norbornene, and cyclohexadiene were achieved using a copper
−diphosphine
catayst under mild reaction conditions. These processes appear to be ligand-accelerated.
The addition of N-H bonds across alkenes (the hydroami-
nation reaction) is an extremely attractive process for the
production of amines. The uncatalyzed reaction is prohibited
by a large activation energy barrier under ambient conditions,
especially with electronically neutral alkene and/or non-
nucleophilic NH substrates. With unsymmetrical alkenes, the
reaction also poses additional regio- and stereoselectivity
issues. Despite these considerable challenges, research in
hydroamination catalysis has intensified significantly in
recent years and has evolved into a highly competitive area
of research.1
catalyst employed: anti-Markovnikov addition of aryl/
alkylamines occurs in the presence of strong Brønsted bases,2
organolanthanide,3 rhodium,4 or ruthenium5 catalysts to
furnish the linear product. Conversely, branched regioisomers
result from the addition of aromatic amines effected by Pd-
(II)-diphosphine/triflic acid6 or TiCl4.7 Thus far, general
catalyzed additions of non-nucleophilic sulfonamides to
vinylarenes are rare. Recently, Pt(II) and Au(I)/Ag(I) com-
plexes have been reported to catalyze these additions, but
only in low to moderate yields (45 and 51%).8,9
To the best of our knowledge, intermolecular hydroami-
nation reactions catalyzed by copper complexes were only
reported for reactions with alkenes containing electron-
Among the number of intermolecular hydroamination
reactions reported to date, the intermolecular addition of
N-H to vinylarenes has been widely studied. These reactions
can proceed with different regioselectivity, depending on the
(2) Kumar, K.; Michalik, D.; Castro, I. G.; Tillack, A.; Zapf, A.; Arlt,
M.; Heinrich, T.; Bo¨ttcher, H.; Beller, M. Chem. Eur. J. 2004, 10, 746.
(3) Ryu, J. S.; Li, G. Y.; Marks, T. J. J. Am. Chem. Soc. 2003, 125,
12584.
(4) Utsunomiya, M.; Kuwano, R.; Katwatsura, M.; Hartwig, J. F. J. Am.
Chem. Soc. 2003, 125, 5608.
(5) Utsunomiya, M.; Hartwig, J. F. J. Am. Chem. Soc. 2004, 126, 2702.
(6) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2000, 122, 9546.
(7) Kaspar, L. T.; Fingerhut, B.; Ackermann, L. Angew. Chem., Int. Ed.
2005, 44, 5972. Competing hydroarylation was observed using this catalyst.
(8) Qian, H.; Widenhoefer, R. A. Org. Lett. 2005, 7, 2635.
(9) Zhang, J.; Yang, C. G.; He, C. J. Am. Chem. Soc. 2006, 128, 1798.
† Present address: Process R&D, GlaxoSmithKline, Old Powder Mills,
Nr. Leigh, Tonbridge, Kent TN11 9AN, U.K.
(1) For selected reviews within the last two years, see: (a) Hazari, N.;
Mountford, P. Acc. Chem. Res. 2005, 38, 839. (b) Hultzsch, K. C. AdV.
Synth. Catal. 2005, 347, 367. (c) Hultzsch, K. C. Org. Biomol. Chem. 2005,
3, 1819. (d) Xu, L. W.; Xia, C. G. Eur. J. Org. Chem. 2005, 633. (e) Hong,
S.; Marks, T. J. Acc. Chem. Res. 2004, 37, 673. (f) Beller, M.; Tillack, A.;
Seayad. J. In Transition Metals for Organic Synthesis, 2nd ed.; Beller, M.,
Bolm, C., Eds.; VCH: Weinheim, 2004; Vol. 2, pp 403-414.
10.1021/ol061355b CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/08/2006

withdrawing substituents (Michael acceptors).10 Following
our recent discovery of copper(II) triflate as an effective
catalyst for the addition of O-H bonds to norbornene,11 we
initiated a study to develop the corresponding hydroamination
reactions. Herein, we provide the first examples of the
copper-catalyzed addition of arylsulfonamides to vinyl are-
nes, norbornene, and 1,3-cyclohexadiene.
An excess of TsNH2 is needed for the high yieldsusing
an equivalent/excess of styrene leads to a lower yield of 1a,
although the formation of the dimer 2 remained negligible
(<5%) under these reaction conditions. Significantly, in-
creased stoichiometry of styrene has very little effect (entries
11-13), implying that the alkene is not involved in the rate-
determining step.
Initially, 10 mol % of copper(II) triflate was used in the
reaction between toluenesulfonamide and styrene. Gratify-
ingly, product formation was observable at 75 °C (Table 1,
The scope of the reaction was subsequently examined by
introducing electronically different substituents to the sub-
strates (Table 2). 4-Nitrobenzenesulfonamide (NsNH2) was
employed in this part of the study, as the nosyl (Ns) moiety
is often used as a protecting and activating group in the
synthesis of secondary amines.13
Table 1. Reactions between Styrene and Toluenesulfonamidea
Using 5 mol % catalytic loading, the addition proceeded
smoothly to afford the branched regioisomer with moderate
to excellent yields in most cases. The reactions of TsNH2
with styrene and electron-deficient 4-fluorostyrene gave fast
and high-yielding reactions (entries 1 and 2), while the
reaction of 4-chlorostyrene was somewhat slower (entry 3).
The introduction of methyl groups has a retarding effect
(entries 4 and 5), although moderate yields can be obtained
by prolonging the reaction time. Similarly, the addition of
TsNH2 to 2-vinylnaphthalene also proceeded with an ac-
ceptable yield (entry 7). In comparison, the addition of the
less nucleophilic NsNH2 is generally slower, although the
relative activity remained broadly similar: Best yields were
obtained with the unsubstituted and 4-fluoro-styrenes (entries
8 and 9), and moderate yields with 4-chloro- and 4-meth-
ylstyrenes (entries 10 and 12).
entry
catalyst (loading/mol %)
TsNH2/styrene 1a:2b (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
Cu(OTf)2 (10)
CuSO4 (10)
Cu(OAc)2 (10)
[Cu(NCMe)4]PF6 (10)
CuBr (10)
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
1:1
1:2
1:4
42c
-
-
-
-
CuI (10)
TfOH (20)
-
14:15
98c
97c
93c
70c
72c
75c
Cu(OTf)2/(()-BINAP (10)
Cu(OTf)2/(()-BINAP (5)
Cu(OTf)2/(()-BINAP (1)
Cu(OTf)2/(()-BINAP (10)
Cu(OTf)2/(()-BINAP (10)
Cu(OTf)2/(()-BINAP (10)
Additions to electron-rich 4-methoxystyrene are notewor-
thy. The reactions were very sluggish, and competitive
dimerization of the vinylarene was observed, leading to
mixtures of products (entries 6 and 13). Interestingly,
attempted addition of NsNH2 to vinylnaphthalene led ex-
clusively to the formation of the dimer (entry 14).
a Typical procedure: TsNH2 (number of equivalents indicated), styrene
(1 mmol), solvent (1 mL), 75 °C, 18 h. b Isolated yield after purification
by column chromatography, duplicated to within (3%. c Dimer 2 was not
detected in the reaction mixture (1H NMR).
Despite these limitations, the performance of the copper
catalyst still surpasses other catalysts reported for the same
reaction, such as the aforementioned platinum and gold
catalysts, and NBS.14
entry 1)sa lower temperature than that required by other
catalysts. Despite the modest yield (42%), the branched
1-phenethyltosylamide 1a was obtained as the only product.
To validate the unique reactivity of the catalyst, a set of
control experiments were conducted in the presence of other
copper salts, as well as triflic acid. The results show that
the combination of the triflate counteranion (entries 2 and
3) and the +2 oxidation state (entries 4-6) is crucial for
catalytic activity. Notably, triflic acid alone gave a very low
yield of 1a under these conditions, with concomitant forma-
tion of a styrene dimer 2 (entry 7). Hence, we rule out a
process catalyzed solely by the Brønsted acid.12
Significantly, ligand screening revealed that the copper-
catalyzed process is greatly enhanced by the addition of
BINAP ligand (entry 8). Consequently, the catalyst loading
can be reduced to 1 mol % before any adverse effect became
noticeable (entries 9 and 10).
The overall reactivity and the regioselectivity of the system
suggest the reaction between a benzylic cation intermediate
and nucleophilic arylsulfonamide. In the absence of the
sulfonamide, either Cu(OTf)2 or triflic acid can catalyze the
formation of styrene dimer 2 at 75 and 85 °C, respectively.
Thus, the involvement of a Brønsted acid in the catalytic
cycle cannot be completely ruled out. This is further
supported by the fact that the reaction between styrene and
TsNH2 is sequested in the presence of noncoordinating bases
such as CuCO3 and K2CO3 (10 mol %).
On the basis of these observations, a catalytic cycle is
tentatively proposed (Scheme 1). We assume ligand exchange
occurs between the catalyst and arylsulfonamide to generate
a copper-sulfonamide intermediate 4. This releases triflic
acid that protonates the vinylarene, furnishing a benzylic
(10) For example, see: Munro-Leighton, C.; Blue, E. D.; Gunnoe, T. B.
J. Am. Chem. Soc. 2006, 128, 1446.
(11) Taylor, J. G.; Whittall, N.; Hii, K. K. Chem. Commun. 2005, 5103.
(12) Strong Brønsted acids catalyze competitive hydroamination and
hydroarylation reactions between styrene and aniline at 135 °C: Anderson,
L. L.; Arnold, J.; Bergman, R. G. J. Am. Chem. Soc. 2005, 127, 14542.
(13) (a) Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353. (b)
Fukuyama, T.; Jow, C. K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373.
(14) NBS (20 mol %) catalyzes the addition of sulfonamides to activated
styrenes containing OMe or SMe groups only: Talluri, S. K.; Sudalai, A.
Org. Lett. 2005, 7, 855.
3562
Org. Lett., Vol. 8, No. 16, 2006

Table 2. Cu-Catalyzed Hydroamination of Vinylarenes with Arylsulfonamidesa
a General reaction conditions: Cu(OTf)2 (0.05 mmol), (()-BINAP (0.05 mmol), Ar2SO2NH2 (2.0 mmol), vinylarene (1.0 mmol), 1,4-dioxane, 75 °C, 36
h. b Isolated yield (based on vinylarene) after purification by column chromatography, duplicated to within (3%. c Reaction time ) 18 h. d Calculated by
1H analysis of reactions mixtures. Value in parentheses corresponds to the yield of dimer (based on vinylarene).
cation. The TfO- anion is envisaged to play an important
role in the bond formation; for example, by enhancing the
nucleophilicity of the amide through hydrogen bonding and/
or stabilizing the cationic intermediate through ion pairing.
In this catalytic model, formation of styrene dimer 2 results
from the reaction of 5 with vinylarene, which becomes
competitive when the sulfonamide addition (rate-determining
step) is slow, as is the case when an electron-deficient
sulfonamide and/or electron-rich vinylarene (weaker nucleo-
phile and electrophile, respectively) were employed.
Thus far, reactions performed with optically pure R-
BINAP did not lead to any significant enantiomeric excess
in the product under these conditions (<5%). This led us to
speculate that the reaction may be reversible. To verify the
reversibility of the C-N bond formation,15 the configura-
tional stability of optically pure (S)-1a16 was examined with
and without added (()-BINAP ligand (Scheme 2).17 Surpris-
ingly, while the stereointegrity of (S)-1a was retained in the
latter case, it deteriorated slowly in the presence of the
Scheme 1. Proposed Catalytic Cycle
(15) Results of crossover experiments were inconclusive: With or without
added ligand, a mixture of 3a/TsNH2 showed very little (<1%) crossover
product, whereas 1a/NsNH2 showed a mixture of crossover products (CI-
MS). This could be the result of substitution reactions.
Org. Lett., Vol. 8, No. 16, 2006
3563

Ph3PAuCl/AgOTf at 85 °C (89%).19 Furthermore, additions
of electron-deficient 4-nitrophenylsulfonamide and N-benzyl-
4-toluenesulfonamide can also be realized, giving products
6b and 6c in good yields. As was the case with O-H
additions,11 the reactions favor the exclusive formation of
the exo-isomer (NMR spectroscopy).20
Scheme 2. Product Racemization Study
Following recent reports of the addition of carbamates and
sulfonamides to 1,3-dienes catalyzed by bimetallic systems
21
Bi(OTf)3/[Cu(CH3CN)4]PF6 and Ph3PAuCl/ AgOTf,22 the
effectiveness of the copper catalyst in these additions was
examined. Preliminary studies show a dramatic ligand
acceleration effect. While Cu(OTf)2 alone is ineffective for
the addition of TsNH2 to 1,3-cyclohexadiene at 55 °C, the
presence of dppe induced catalytic turnovers to furnish the
product 7a in 92% yield. This observation emphasizes the
importance of ligand in this catalytic system.
diphosphine (84% ee after 24 h). These experiments suggest
that the ligand lowers the energy barrier of the copper-
catalyzed process, rendering it reversible at 75 °C.
Preliminary studies have shown that the copper catalyst
can also effect the addition of TsNH2 to norbornene (Scheme
3). For example, the addition to the strained olefin furnished
In summary, using a catalyst generated from copper(II)
trifluoromethanesulfonate/diphosphine, regioselective addi-
tions of arylsulfonamides to vinylarenes, norbornene, and
1,3-cyclohexadiene can be achieved. The copper(II) catalyst
was procured cheaply from commercial sources and stored
and handled in air without recourse to gloveboxes. All these
reactions can also be performed in air, using unpurified
reagent-grade solvent. These practical simplicities provide
ample justification of further explorations of its application
in hydroamination and other olefin heterofunctionalization
processes.
Scheme 3. Addition of Arylsulfonates to Norbornene and
1,3-Cyclohexadiene
Acknowledgment. We are grateful to GSK and EPSRC
for studentship support (J.G.T.).
Supporting Information Available: Experimental pro-
cedures, characterization data, and NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
the hydroamination product 6a in excellent yield. The
efficiency of the system compares favorably with recent
reports where 10 mol % of [(COD)Pt(OTf)2] was employed
under similar conditions (>95% GC yield)18 or 5 mol % of
OL061355B
(19) Four equivalents of styrene were needed for the Au-catalyzed
reaction, which proceeded with 51% yield in 14 h (ref 9).
(20) Coupling between H-1 and its adjacent bridgehead methine proton
is conspicuously absent (COSY spectrum of 6a provided in the Supporting
Info). This 3J coupling is typically <1 Hz for an endo-proton and 4 Hz for
an exo-proton. See: (a) Laszlo, P.; Schleyer, P. v. R. J. Am. Chem. Soc.
1964, 86, 1171-1179. (b) Franz, J. E.; Osuch, C.; Dietrich, M. W. J. Org.
Chem. 1964, 29, 2922-2927.
(16) Prepared by the tosylation of commercially available S-(-)-1-
phenylethylamine.
(17) Enantiopurity of 1a was assessed by chiral HPLC (Conditions:
Chiralcel OD-H, i-PrOH/hexane 10: 90, flow rate 0.6 mL/min, tR ) 16.8
min, tS ) 20.4 min).
(18) Karshtedt, D.; Bell, A. T.; Tilley, T. D. J. Am. Chem. Soc. 2005,
127, 12640.
(21) Qin, H.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. J. Am. Chem.
Soc. 2006, 128, 1611.
(22) Brouwer, C.; He, C. Angew. Chem., Int. Ed. 2006, 45, 1744.
3564
Org. Lett., Vol. 8, No. 16, 2006