Copper(II) acetate promoted oxidative cyclization of arylsulfonyl-o- allylanilines

Article abstract of DOI:10.1021/ol049702+

Tosyl-o-allylaniline 1 undergoes oxidative cyclization to produce tetracycle 2 upon treatment with Cu(OAc)₂ and Cs₂CO ₃ at 120°C. The scope of the reaction was extended to other N-sulfonylated aromatic systems.

Full text of DOI:10.1021/ol049702+

ORGANIC
LETTERS
2004
Vol. 6, No. 10
1573-1575
Copper(II) Acetate Promoted Oxidative
Cyclization of Arylsulfonyl-o-allylanilines
Eric S. Sherman, Sherry R. Chemler,* Tai Boon Tan, and Oksana Gerlits†
Department of Chemistry, Rm. 618 Natural Sciences Complex, UniVersity at Buffalo,
The State UniVersity of New York, Buffalo, New York 14260
schemler@buffalo.edu
Received February 19, 2004
ABSTRACT
Tosyl-o-allylaniline 1 undergoes oxidative cyclization to produce tetracycle 2 upon treatment with Cu(OAc)2 and Cs2CO at 120 °C. The scope
3
of the reaction was extended to other N-sulfonylated aromatic systems.
The pursuit of concise methods to assemble chemical
complexity is a major focus of the synthetic organic and
organometallic chemical community. Reactions that do not
require excessive functionalization of the substrates are
especially attractive. In this communication we report a direct
method for the rapid assembly of heterocyclic systems via a
simple oxidative cyclization procedure.
We chose to initiate studies with the o-allyl aniline
substrate 1 because of its excellent previous performance in
aminopalladation reactions.1 Specific reactions under inves-
tigation in our labs include intramolecular aminohalogena-
tion, diamination, and aminocarbonation of olefins. Wacker-
type experimental procedures were initially adopted, wherein
a catalytic amount of expensive group 10 transition metal,
e.g., PdII or PtII, would be used in conjunction with less
expensive stoichiometric CuII salts (commonly used to
reoxidize Pd0 to PdII). In the course of our studies (by
carrying out control experiments) we found that the CuII
oxidants are themselves capable of promoting additions of
heteroatoms to double bonds.
of these salts to promote the additions of unfunctionalized
nitrogens to olefins to form sp3 carbon centers have previ-
ously been reported.
We have recently found that N-tosyl-o-allylaniline 1
undergoes efficient oxidative cyclization when treated with
Cu(OAc)2 (3 equiv) and Cs2CO3 in CH3CN or DMF at 120
°C. This transformation (cf., 1 f 2) represents a highly
concise heterocycle formation. Conversely, when olefin 1
was treated with catalytic amounts (0.1 equiv) of Pd(OAc)2
in the presence of Cu(OAc)2, the indole product 3, the result
of aminopalladation and subsequent â-hydride elimination,
was obtained, in keeping with results reported by Hegedus
and others (Scheme 1).1
The oxidative cyclization reaction is best performed at 120
°C in a pressure tube in polar solvents such as CH3CN and
DMF (Table 1, entries 4 and 7). The reaction of 1 in THF
was incomplete after 24 h (entry 8). The reaction was also
much less efficient upon removal of the base (entry 5).
Addition of DMSO (4 equiv) neither aided nor impeded the
Reports on the oxidizing powers of CuII salts have
previously appeared,2 but no examples examining the abilities
(2) (a) Rajesawaran, W. G.; Srinivansan, P. C. Synthesis 1994, 270-
272. (b) Noto, R.; Gruttadauria, M.; Lo Meo, P.; Frenna, V.; Werber, G. J.
Heterocycl. Chem. 1995, 32, 1277. (c) Tsuji, J.; Kezuka, H.; Toshida, Y.;
Takayanagi, H.; Yamamoto, K. Tetrahedron 1983, 39, 3279-3282. (d)
Coda, A. C.; Desimoni, G.; Monaco, H. L.; Quadrelli, P.; Righetti, P. Gazz.
Chim. Ital. 1989, 119, 13-17. (e) Bisiacchi, P.; Coda, A. C.; Desimoni,
G.; Righetti, P. P.; Tacconi, G. Gazz. Chim. Ital. 1985, 115, 119-123. (f)
Barun, O.; Ila, H.; Junjappa, H.; Singh, O. M. J. Org. Chem. 2000, 65,
1583-1587. (g) Wang, S.-F.; Chuang, C.-P.; Lee, J.-H.; Liu, S.-T.
Tetrahedron 1999, 55, 2273-2288.
† Assigned the structure of 2 by X-ray crystallography.
(1) (a) Hegedus, L. S. In ComprehensiVe Organic Synthesis; Permagon;
New York, 1991; Vol. 4, Chapter 3.1. (b) Hegedus, L. S.; Allen, G. F.;
Bozell, J. J.; Waterman, E. L. J. Am. Chem. Soc. 1978, 100, 5800-5807.
(c) Fix, S. R.; Brice, J. L.; Stahl, S. S. Angew. Chem., Int. Ed. 2002, 41,
164-166.
10.1021/ol049702+ CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/07/2004

Table 2. Substrate Scopea
Scheme 1. Divergent Product Formation
progress of the reaction with this substrate. No reaction
occurred at 23 or 70 °C in CH3CN (entries 1 and 2). A 26%
yield of 2 was obtained at 90 °C in CH3CN (entry 3).
Table 1. Effect of Reaction Conditions
entrya
solvent
temp (°C)
isolated yield (%)
1
2
3
4
5c
6d
7
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
23
70
90
120
120
120
120
120
nrb
nr
26
73
19
71
69
51
8
THF
a Cu(OAc)2 (3 equiv), Cs2CO3 (1 equiv). b No reaction. c No Cs2CO3
was used. d DMSO (4 equiv) additive.
a Conditions. A: Substrate in DMF (0.08 M) was treated with Cu(OAc)2
(3 equiv) and Cs2CO3 (1 equiv). The mixture was heated 24 h at 120 °C in
a pressure tube. B: DMSO (4 equiv) was added to the reaction mixture.
b Reaction was run in CH3CN. c Yields refer to the sum of products isolated
by chromatography on SiO2. The remainder of the material was either
starting olefin or olefin-isomerized starting material. The structures of the
products (e.g., regioisomer) were assigned by analysis of the aromatic region
The substrate scope was expanded to other arylsulfonyl-
o-allylaninines in an effort to collect data on the effects of
steric and electronic changes on the reaction (Table 2).
We found that the yield and selectivity vary considerably
depending upon the electronic nature of the aryl substituent.
In general, the reactions of electron-rich substrates 1, 4, 7,
and 9 proceeded in good yield. meta-Substitution generally
led to mixtures of regioisomeric products (see entries 2, 4,
and 8). Substrates with electron-withdrawing groups on the
sulfonylated aromatic ring reacted more sluggishly, and DMF
proved a better solvent than CH3CN. Addition of DMSO (4
equiv) increased the yields of these reaction, sometimes with
significant affect.3 Neither added HMPA nor pyridine
1
of the H NMR spectra.
provided such yields enhancements. Interestingly, the reac-
tion of the meta-substituted nitrosulfonamide 14 provided
the o-adduct as the sole cyclization product, albeit in low
yield (entry 6, Table 2). In the case of the p-bromophenyl-
sulfonyl-o-allylaniline substrate 16, the oxidative cyclization
to 17 was accompanied by loss of the bromide.
Potential mechanistic sequences for the reaction are
proposed in Scheme 2. Thus, one-electron oxidation of the
nitrogen (1 f 24) followed by 5-exo-trig intramolecular ring
closure generates 25. Subsequent addition of the primary
carbon-based radical onto the aromatic ring, followed by loss
of hydrogen radical, would provide 2. An alternative mech-
anism would involve nitrogen-copper (II) bond formation
(3) For studies on the rate-enhancing effects of DMSO in PdII-catalyzed
reactions, see: (a) Larock, R. C.; Hightower, T. R. J. Org. Chem. 1993,
58, 5298-5300. (b) Ro¨nn, M.; Ba¨ckvall, J.-E.; Andersson, P. G. Tetrahedron
Lett. 1995, 36, 7749-7752. (c) Larock, R. C.; Hightower, T. R.; Hasvold,
L. A.; Peterson, K. P. J. Org. Chem. 1996, 61, 3584-3585. (d) Steinhoff,
B. A.; Fix, S. R.; Stahl, S. J. Am. Chem. Soc. 2002, 124, 766-767. (e)
Steinhoff, B. A.; Stahl, S. S. Org. Lett. 2002, 4, 4179-4181.
1574
Org. Lett., Vol. 6, No. 10, 2004

In support of this mechanism, we note that cyclizations
initiated by the formation of nitrogen radicals, though
uncommon, do exist.5 In particular, independent work by
Zard,5d using N-(O-ethyl thiocarbonylsulfanyl)amides, and
Broka,5e using N-halogenated substrates, have established that
nitrogen radical initiated cascades are useful methods for the
synthesis of heterocycles. Nicolaou has also published a
recent study using o-iodoxybenzoic acid (IBX) to generate
Scheme 2. Proposed Reaction Mechanism
5f
nitrogen radicals.
Further work to expand the substrate scope and to
differentiate between the possible mechanistic pathways
shown in Scheme 2 will be the subject of future reports.
Acknowledgment. We thank Dr. Alice Bergmann for
mass spectral analysis and the NSF for providing funds for
the mass spectrometers (CHE0091977). Financial support for
this work was provided by the University at Buffalo (start-
up funds for S.R.C.).
(cf., 21) followed by intramolecular migratory insertion and
subsequent addition to the aromatic ring, possibly via a
radical process. The ortho-addition preference shown in
substrates 4, 9, and 14 seems to indicate radical character
may be present in the aromatic addition step.4
Supporting Information Available: Experimental condi-
1
tions and characterization data, including H NMR spectra
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
The correlation of substrate reactivity with electron density
at nitrogen summarized in Table 2 may indicate either
varying degrees of ease of one-electron oxidation in the
initiating step or an electrophilic component to the aromatic
addition step.
OL049702+
(5) (a) Bowman, W. R.; Bridge, C. F.; Brookes, P. J. Chem. Soc., Perkin
Trans. 1 2000, 1-14. (b) Zard, S. Z. Synlett 1996, 1148-1154. (c) Fallis,
A. G.; Brinza, I. M. Tetrahedron 1997, 53, 17543-17594. (d) Gagosz, F.;
Moutrille, C.; Zard, S. Z. Org. Lett. 2002, 4, 2707-2709. (e) Broka, C. A.;
Eng., K. K. J. Org. Chem. 1986, 51, 5043-5045. (f) See also a recent
report using IBX: Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Barluenga,
S.; Hunt, K. W.; Kanich, R.; Vega, J. A. J. Am. Chem. Soc. 2002, 124,
2233-2244. (g) Studer, A.; Bossart, M. Tetrahedron 2001, 57, 9649-9667.
(4) (a) Ito, R.; Migita, T.; Morikawa, N.; Simamura, O. Tetrahedron
1965, 21, 955. (b) Pryor, W. A.; Davis, W. H., Jr.; Gleaton, J. H. J. Org.
Chem. 1975, 40, 2099-2102.
Org. Lett., Vol. 6, No. 10, 2004
1575