Sultam synthesis via Cu-catalyzed intermolecular carboamination of alkenes with N -fluorobenzenesulfonimide

Article abstract of DOI:10.1021/ol4009848

Cu-catalyzed intermolecular carboamination of alkenes is described. The reaction of terminal alkenes and an internal alkene with N- fluorobenzenesulfonimide was promoted by 2.5 mol % of a Cu(I)-salt at 60 C, and six-membered ring sultams were obtained in 91-44% yields.

Full text of DOI:10.1021/ol4009848

ORGANIC
LETTERS
2013
Vol. 15, No. 10
2502–2505
Sultam Synthesis via Cu-Catalyzed
Intermolecular Carboamination of Alkenes
with N‑Fluorobenzenesulfonimide
Keiichi Kaneko,† Tatsuhiko Yoshino,† Shigeki Matsunaga,*,‡ and Motomu Kanai*,†
Graduate School of Pharmaceutical Sciences, the University of Tokyo, Hongo 7-3-1,
Bunkyo-ku, Tokyo 113-0033, Japan, and ACT-C, Japan Science and Technology
Agency (JST), Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
smatsuna@mol.f.u-tokyo.ac.jp; kanai@mol.f.u-tokyo.ac.jp
Received April 9, 2013
ABSTRACT
Cu-catalyzed intermolecular carboamination of alkenes is described. The reaction of terminal alkenes and an internal alkene with
N-fluorobenzenesulfonimide was promoted by 2.5 mol % of a Cu(I)-salt at 60 °C, and six-membered ring sultams were obtained in 91ꢀ44% yields.
The sultam subunit is an important structural motif
found in many biologically active compounds, such as a
carbonic anhydrase inhibitor brinzolamide, which is used
clinically to lower intraocular pressure, an anticonvulsant
agent sultiame, a potent HIV integrase inhibitor, and a
calpain I selective inhibitor (Figure 1).1 Various divergent
but multistep synthetic methods for sultams have been
reported, including transition-metal catalyzed processes.2
The current strong demand for environmentally benign
synthetic processes makes the development of a new step-
economical3 method for sultam synthesis highly desirable.
The catalytic aminative difunctionalization of alkenes4,5 is
an attractive straightforward approach for producing
sultams. Dauban, Dodd and co-workers reported a Cu(I)-
catalyzed intramolecular aziridination of sulfonamides in
the presence of a hypervalent iodine reagent, followed by
nucleophilic ring opening of aziridines (eq 1).6 Chemler
and co-workers reported an efficient and stereoselective
Cu(II)-catalyzedcarboamination ofalkenesfor theconcise
synthesis of sultams (eq 2). These methods, however, focused
† The University of Tokyo.
‡ ACT-C, Japan Science and Technology Agency (JST).
(1) (a) Ingram, C. J.; Brubaker, R. F. Am. J. Opthalmol. 1999,
128, 292. (b) Doherty, A. M. Annu. Rep. Med. Chem. 1999, 34, 317. (c)
Wells, G. J.; Tao, M.; Josef, K. A.; Bihovsky, R. J. Med. Chem. 2001, 44,
3488. (d) Zhuang, L.; Wai, J. S.; Embrey, M. W.; Fisher, T. E.;
Egbertson, M. S.; Payne, L. S.; Guare, J. P., Jr.; Vacca, J. P.; Hazuda,
D. J.; Felock, P. J.; Wolfe, A. L.; Stillmock, K. A.; Witmer, M. V.;
Moyer, G.; Schleif, W. A.; Gabryelski, L. J.; Leonard, Y. M.; Lynch,
J. J., Jr.; Michelson, S. R.; Young, S. D. J. Med. Chem. 2003, 46, 453.
(2) For reviews including a topic on sultam synthesis, see: (a)
Majumdar, K. C. RSC Adv. 2011, 1, 1152. (b) Katrizky, A. R.; Wu, J.;
Rachwal, B.; Macomber, D. W.; Smith, T. P. Org. Prep. Proc. Int. 1992,
24, 463. (c) The Chemistry of Sulphonic Acids, Esters and Derivatives;
Patai, S., Rappoport, Z., Eds.; Wiley: New York, 1991; Chapter 19. For
selected examples of divergent multistep sultam synthesis via transition-
metal-catalyzed intramolecular cyclization, see: (d) Hanson, P. R.; Probst,
D. A.; Robinson, R. E.; Yau, M. Tetrahedron Lett. 1999, 40, 4761. (e)
Hanessian, S.; Sailes, H.; Therrien, E. Tetrahedron 2003, 59, 7047. (f)
(3) Wender, P. A.; Miller, B. L. Nature 2009, 460, 197.
(4) Reviews on catalytic carboamination of alkenes: (a) Schultz,
D. M.; Wolfe, J. P. Synthesis 2012, 44, 351. (b) Wolfe, J. P. Eur. J. Org.
Chem. 2007, 571.
(5) Reviews on various oxidative aminations of alkenes: (a) de
Figueiredo, R. M. Angew. Chem., Int. Ed. 2009, 48, 1190. (b) Cardona,
F.; Goti, A. Nat. Chem. 2009, 1, 269. (c) Chemler, S. R. Org. Biomol.
Chem. 2009, 7, 3009. (d) Kotov, V.; Scarborough, C. C.; Stahl, S. S.
Inorg. Chem. 2007, 46, 1910. (e) Bodkin, J. A.; McLeod, M. D. J. Chem.
Soc., Perkin Trans. 1 2002, 2733. For early works, see also: (f) Cardillo,
G.; Orena, M. Tetrahedron 1990, 46, 3321. (g) Tamaru, Y.; Yoshida,
Z.-i. J. Organomet. Chem. 1987, 334, 213. (h) Hegedus, L. S. Tetrahedron
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1984, 40, 2415. (i) Backvall, J.-E. Acc. Chem. Res. 1983, 16, 335.
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347, 754. (g) Liu, X.-Y.; Li, C.-H.; Che, C.-M. Org. Lett. 2006, 8, 2707.
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(h) Jimenez-Hopkins, M.; Hanson, P. R. Org. Lett. 2008, 10, 2223. (i)
7707. For similar works under Rh-catalysis, see also: (c) Liang, J.-L.;
Yuan, S.-X.; Chan, P. W. H.; Che, C.-M. Org. Lett. 2002, 4, 4507.
(d) Padwa, A.; Flick, A. C.; Leverett, C. A.; Stengel, T. J. Org. Chem.
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K. C.; Mondal, S.; De, N. Synthesis 2009, 3127 and references therein.
r
10.1021/ol4009848
Published on Web 04/29/2013
2013 American Chemical Society

we selected N-fluorobenzenesulfonimide (NFSI), which
acts as both a nitrogen source and an oxidant. A Cu(I)-
salt (2.5 mol %)16 efficiently catalyzed the intermolecular
amino-arylation of unactivated alkenes with NFSI, giving
six-membered ring sultams in one step (eq 3).
Figure 1. Structures of biologically active sultams.
on the intramolecular amination of alkenes bearing a
tethered nitrogen nucleophile (eqs 1 and 2).6,7 Thus, the
development of a new catalytic system enabling intermo-
lecular carboamination of alkenes for sultam synthesis is in
high demand.
In contrast to recent advances in the intramolecular
carboamination of alkenes,4,6ꢀ12 the available methods
for catalytic carboamination of alkenes involving an inter-
molecular amination step are quite limited.13ꢀ15 To realize
the intermolecular carboamination of unactivated alkenes,
The optimization studies using NFSI and alkene 1a are
summarized in Table 1. CuOTf•1/2tol (2.5 mol %) pro-
moted the desired carboamination in CH3CN at 60 °C,
albeit in moderate yield (48%, entry 1). Solvent screening
revealed that a nitrile group in the solvent was essential to
obtain product 2a, and other solvents, such as CHCl3,
THF, and benzene, only afforded complex mixtures of
byproducts. The best yield of 2a, 59%, was achieved using
benzonitrileasthe solvent (entry 5). Cu(I)-salts affectedthe
reactivity to some extent, and Cu(CH3CN)4BF4 gave
product 2a in slightly better yield than other Cu-salts
(entry 10, 67%). Although strongly coordinating bipyridyl
and phenathroline-type ligands 3aꢀ3b(Figure2) adversely
affected the reactivity (entries 11ꢀ12), other coordinating
additives 3cꢀ3f bearing carbonyl groups were applicable
in the present reaction. The amounts of byproducts de-
creased when using 3f as an additive (entry 16, 68%), and
the best yield was obtained with 1.6 mol % of 3f (entry 17,
70% isolated yield).17 Further trials toimprovetheyield by
adding an inorganic base were not successful, and the
conditions in entry 17 were selected as optimum.
(7) (a) Zeng, W.; Chemler, S. R. J. Am. Chem. Soc. 2007, 129, 12948.
(b) Sherman, E. S.; Fuller, P. H.; Kasi, D.; Chemler, S. R. J. Org. Chem.
2007, 72, 3896. (c) Sherman, E. S.; Chemler, S. R.; Tan, T. B.; Gerlits, O.
Org. Lett. 2004, 6, 1573.
(8) For related Cu-catalyzed/promoted intramolecular carboamina-
tion, see: (a) Fuller, P. H.; Chemler, S. R. Org. Lett. 2007, 9, 5477. (b)
Sherman, E. S.; Chemler, S. R. Adv. Synth. Catal. 2009, 351, 467. (c)
Miao, L.; Haque, I.; Manzoni, M. R.; Tham, W. S.; Chemler, S. R. Org.
Lett. 2010, 12, 4739. (d) Liwosz, T. W.; Chemler, S. R. J. Am. Chem. Soc.
2012, 134, 2020. For other related Cu-catalyzed aminative difunction-
alization by Chemler and co-workers, see a review: (e) Chemler, S. R.
J. Organomet. Chem. 2011, 696, 150.
(9) Review: (a) Wolfe, J. P. Synlett 2008, 2913. For selected recent
reports by Wolfe and co-workers, see: (b) Hopkins, B. A.; Wolfe, J. P.
Angew. Chem., Int. Ed. 2012, 51, 9886. (c) Babij, N. R.; Wolfe, J. P.
Angew. Chem., Int. Ed. 2012, 51, 4128. (d) Ward, A. F.; Wolfe, J. P. Org.
Lett. 2011, 13, 4728. (e) Lemen, G. S.; Wolfe, J. P. Org. Lett. 2011, 13,
3218. (f) Schultz, D. M.; Wolfe, J. P. Org. Lett. 2011, 13, 2962. (g) Mai,
D. N.; Rosen, B. R.; Wolfe, J. P. Org. Lett. 2011, 13, 2932. (h) Neukom,
J. D.; Aquino, A. S.; Wolfe, J. P. Org. Lett. 2011, 13, 2196. (i) Mai, D. N.;
Wolfe, J. P. J. Am. Chem. Soc. 2010, 132, 12157. For selected early
works, see also: (j) Ney, J. E.; Wolfe, J. P. J. Am. Chem. Soc. 2005, 127,
8644. (k) Ney, J. E.; Wolfe, J. P. Angew. Chem., Int. Ed. 2004, 43, 3605.
(l) Nakhla, J. S.; Kampf, J. W.; Wolfe, J. P. J. Am. Chem. Soc. 2006, 128,
2893. (m) Giampietro, N. C.; Wolfe, J. P. J. Am. Chem. Soc. 2008, 130,
12907.
The substrate scope of alkenes in the present intermole-
cular carboamination reaction under the optimized reac-
tion conditions is summarized in Scheme 1. Not only
simple aliphatic terminal alkenes (1aꢀ1c) but also various
terminal alkenes 1dꢀ1l with functional groups were ap-
plicable. Although the yield varied depending on the
functional groups, products 2dꢀ2l bearing an imide, halo-
gen, nitro group, free-hydroxy group, benzyl ether, or ester
(10) (a) Rosewall, C. F.; Sibbald, P. A.; Liskin, D. V.; Michael, F. E.
J. Am. Chem. Soc. 2009, 131, 9488. (b) Sibbald, P. A.; Rosewall, C. F.;
Swartz, R. D.; Michael, F. E. J. Am. Chem. Soc. 2009, 131, 15945.
(11) Zhang, G.; Cui, L.; Wang, Y.; Zhang, L. J. Am. Chem. Soc. 2010,
132, 1474.
(12) Hayashi, S.; Yorimitsu, H.; Oshima, K. Angew. Chem., Int. Ed.
2009, 48, 7224.
(13) Pd(II)-catalyzed aerobic oxidative carboamination: Scarborough,
C. C.; Stahl, S. S. Org. Lett. 2006, 8, 3251.
(16) For selected recent reports from our group on Cu-catalyzed
oxidative functionalizations, see: (a) Takemura, N.; Kuninobu, Y.;
Kanai, M. Org. Lett. 2013, 15, 844. (b) Sonobe, T.; Oisaki, K.; Kanai, M.
Chem. Sci. 2012, 3, 3249. (c) Hashizume, S.; Oisaki, K.; Kanai, M.
Chem.;Asian J. 2012, 7, 2600. (d) Hashizume, S.; Oisaki, K.; Kanai, M.
Org. Lett. 2011, 13, 4288.
(17) Although the reason is not clear, the optimum reactivity was
observed when the amount of additive 3f was in the range of 1.25ꢀ2.0 mol %.
Greater than 2.5 mol % of 3f had slightly adverse effects on the
reactivity.
(14) For Pd-catalyzed intermolecular 1,2-carboamination of dienes
involving intramolecular CꢀN bond formation as the second step, see:
ꢀ
Houlden, C. E.; Bailey, C. D.; Ford, J. G.; Gagne, M. R.; Lloyd-Jones,
G. C.; Booker-Milburn, K. I. J. Am. Chem. Soc. 2008, 130, 10066.
(15) Cu(I)-catalyzed aminocyanation of alkenes with NFSI: (a)
Zhang, H.; Pu, W.; Xiong, T.; Li, Y.; Zhou, X.; Sun, K.; Liu, Q.; Zhang,
Q. Angew. Chem., Int. Ed. 2013, 52, 2529. For related work on allylic
CꢀH amination of alkenes with NFSI, see: (b) Xiong, T.; Li, Y.; Mao,
L.; Zhang, Q.; Zhang, Q. Chem. Commun. 2012, 48, 2246.
Org. Lett., Vol. 15, No. 10, 2013
2503

the diamination adduct 4o instead of an amino-arylation
adduct (eq 4).19
Table 1. Optimization Studies
Scheme 1. Cu-Catalyzed Intermolecular Carboamination of
Alkenes 1aꢀ1n with NFSIa
time
additive
(mol %)
yielda
(%)
entry
Cu cat. (mol %)
(h)
solvent
1
CuOTf•1/2tol
CuOTf•1/2tol
CuOTf•1/2tol
CuOTf•1/2tol
CuOTf•1/2tol
CuOAc
10
10
10
10
1
CH3CN
CHCl3
THF
none
none
none
48
2
0
3
0
4
benzene none
0
5
PhCN
PhCN
PhCN
PhCN
PhCN
PhCN
PhCN
PhCN
PhCN
PhCN
PhCN
PhCN
PhCN
none
59
60
55
60
61
67
0
6
1
none
7
CuTC
1
none
8
CuCl
1
none
9
Cu(CH3CN)4ClO4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
1
none
10
11
12
13
14
15
16
17
1
none
1
3a (2.5)
3b (2.5)
1
0
1
3c (2.5) 56
3d (2.5) 67
3e (2.5) 63
1
1
1
3f (2.5)
3f (1.6)
68
74 (70)b
1
a Determined by H NMR analysis of crude mixture using 1,1,2,2-
tetrabromoethane as an internal standard. b Number in parentheses is
the isolated yield of 2a after purification by silica gel column
chromatography.
1
a Reaction was run using alkene 1 (0.20 mmol), NFSI (0.30 mmol),
Cu(CH3CN)4BF4 (2.5 mol %), 3f (1.6 mol %) in PhCN (0.4 M) at 60 °C.
Isolated yield of products 2 after purification by silica gel column
chromatography are shown.
Figure 2. Structures of additives 3aꢀ3f.
were obtained in 44ꢀ91% yield. Vinylsilane also gave
product 2m in 56% yield. Not only terminal alkenes but
also internal alkene 1n were applicable in the present
system, giving cis-adduct 2n in 53% yield.18 On the other
hand, the desired sultam was not obtained from styrene 1o,
because benzonitrile reacted as a nitrogen source to give
The postulated catalytic cycle of the intermolecular
carboamination reaction basedon earlier reports ofrelated
Cu-catalyzed reactions7,15 is shown in Figure 3. Oxidation
of Cu(I) with NFSI affords Cu(III) species A,20 which
would exist in equilibrium with Cu(II)-stabilized nitrogen-
centered radical species B.15a,21 Amino-cupration from
Cu(III) species A followed by homolysis of the CuꢀC
(18) Acyclic E- or Z-disubstituted internal alkenes and geminal
disubstituted alkenes were not applicable in the present system, showing
much less satisfactory reactivity.
(19) Cu(I)-catalyzed diamination of styrenes with NFSI and nitriles
as the second nitrogen source to give 4 was recently reported by Zhang
and co-workers; see ref 15a.
(20) A review on Fþ oxidant in transition metal catalysis: Engle,
K. M.; Mei, T.-S.; Wang, X.; Yu, J.-Q. Angew. Chem., Int. Ed. 2011, 50,
1478.
2504
Org. Lett., Vol. 15, No. 10, 2013

straightforward access to sultams. The reaction of terminal
and internal alkenes with NFSI was efficiently promoted
by 2.5 mol % of a Cu(I)-salt at 60 °C, giving sultams in
91ꢀ44% yield. Further studies to expand the scope of the
alkenes and nitrogen reactants are ongoing in our group.
Acknowledgment. This work was supported in part by
the ACT-C program from JST and a Grant-in-Aid for
Scientific Research on Innovative Areas “Molecular Acti-
vation Directed toward Straightforward Synthesis” from
MEXT. T.Y. thanks JSPS for fellowships.
Supporting Information Available. Experimental pro-
cedures, and spectral data of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(21) Reviews on nitrogen-centered radicals: (a) Zard, S. Z. Chem.
Soc. Rev. 2008, 37, 1603. (b) N-Centered Radicals; Alfassi, Z. B., Ed.;
Wiley, New York, 1998. A review on metal complexes of aminyl radicals:
(c) Hicks, R. G. Angew. Chem., Int. Ed. 2008, 47, 7393. For selected
examples of intermolecular addition of amidyl radicals with alkenes, see:
(d) Tsuritani, T.; Shinokubo, H.; Oshima, K. Org. Lett. 2001, 3, 2709.
(e) Tsuritani, T.; Shinokubo, H.; Oshima, K. J. Org. Chem. 2003, 68,
Figure 3. Postulated catalytic cycle of Cu(I)-catalyzed intermo-
lecular carboamination of alkenes.
€
3246. (f) Guin, J.; Frohlich, R.; Studer, A. Angew. Chem., Int. Ed. 2008,
bond or the reaction of a nitrogen-centered radical B with
alkene provided the carbon radical intermediate C. Intra-
molecular addition of the carbon radical to the neighbor-
ing aromatic ring, followed by oxidation of D with Cu(II)
and rearomatization, afforded sultam 2 and regenerated
the Cu(I) catalyst. Studies to clarify the reaction mecha-
nism will be reported in due course.22
€
47, 779. (g) Chou, C.; Guin, J.; Muck-Lichtenfeld, C.; Grimme, S.;
Studer, A. Chem.;Asian J. 2011, 6, 119 and references therein. For
examples of intramolecular carboamination of alkenes with amidyl
radicals, see: (h) Moutrille, C.; Zard, S. Z. Chem. Commun. 2004,
1848. (i) Hoang-Cong, X.; Quiclet-Sire, B.; Zard, S. Z. Tetrahedron
Lett. 1999, 40, 2125. (j) Lin, X.; Stien, D.; Weinreb, S. M. Tetrahedron
Lett. 2000, 41, 2333.
(22) Preliminary trials on “radical clock” experiments did not afford
clear results, giving complex mixtures of byproducts.
In summary, we succeeded in developing an intermole-
cular aminoarylation of aliphatic alkenes that provides
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 10, 2013
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