Copper(I)-catalyzed cascade dearomatization of 2-substituted tryptophols with arylidonium salts

Article abstract of DOI:10.1021/ol301939w

Copper(I)-catalyzed dearomative arylation and vinylation of 2-substituted tryptophols were realized with a subsequent cyclization reaction. The cascade dearomatization sequence provided versatile furoindoline derivatives with two quaternary carbon centers

Full text of DOI:10.1021/ol301939w

ORGANIC
LETTERS
2
012
Vol. 14, No. 17
525–4527
Copper(I)-Catalyzed Cascade
Dearomatization of 2‑Substituted
Tryptophols with Arylidonium Salts
4
Chuan Liu, Wei Zhang, Li-Xin Dai, and Shu-Li You*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
slyou@sioc.ac.cn
Received July 12, 2012
ABSTRACT
Copper(I)-catalyzed dearomative arylation and vinylation of 2-substituted tryptophols were realized with a subsequent cyclization reaction. The
cascade dearomatization sequence provided versatile furoindoline derivatives with two quaternary carbon centers in good to excellent yields.
Furoindolines are frequently existing structural frag-
ments innatural products (Figure 1). However, substituted
furoindolines with a quaternary carbon center at the C-3
position represent a synthetic challenge and still mainly
with the fully developed synthesis of pyrrolidinoindolines
with a quaternary carbon center at the C-3 position utiliz-
3
ing various cascade dearomatization sequences, the ap-
plication of cascade dearomatization oftryptopholsfor the
1
4
construction of furoindoline derivatives still needs further
rely on Fischer indole synthesis. We recently developed an
3
d,5
efficient cascade dearomatization protocol of N-substi-
tuted tryptophols to synthesize functionalized furoindo-
lines via a Lewis acid catalyzed Michael addition reaction
exploration.
2
and a subsequent iminium ion trapping step. Compared
(
1) (a) ElAzab, A. S.; Taniguchi, T.; Ogasawara, K. Org. Lett. 2000,
, 2757. (b) Schammel, A. W.; Boal, B. W.; Zu, L.; Mesganaw, T.; Garg,
2
N. K. Tetrahedron 2010, 66, 4687. (c) Zu, L.; Boal, B. W.; Garg, N. K.
J. Am. Chem. Soc. 2011, 133, 8877.
(2) For a cascade dearomatization of N-substituted tryptophols via a
Lewis acid catalyzed Michael reaction, see: Liu, C.; Zhang, W.; Dai
L.-X.; You, S.-L. Org. Biomol. Chem. 201210.1039/C2OB26139A.
(
3) For selected dearomatization reaction of indoles: (a) L ꢀe vy, J.; Sapi, J.;
Figure 1. Representative furoindoline natural products.
Laronze, J.-Y.; Royer, D.; Toupet, L. Synlett 1992, 601.(b) Schkeryantz,
J. M.; Woo, J. C. G.; Siliphaivanh, P.; Depew, K. M.; Danishefsky, S. J.
J. Am. Chem. Soc. 1999, 121, 11964. (c) Austin, J. F.; Kim, S.-G.; Sinz,
C. J.; Xiao, W.-J.; MacMillan, D. W. C. Proc. Natl. Acad. Sci. U.S.A.
Transition-metal-catalyzed direct arylation of aromatic
6
rings with diarylidonium salts have made significant progress.
2004, 101, 5482. (d) Trost, B. M.; Quancard, J. J. Am. Chem. Soc. 2006,
128, 6314. (e) Repka, L. M.; Ni, J.; Reisman, S. E. J. Am. Chem. Soc.
2010, 132, 14418. (f) Jones, S. B.; Simmons, B.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2009, 131, 13606. (g) Knowles, R. R.; Carpenter, J.;
Blakey, S. B.; Kayano, A.; Mangion, I. K.; Sinz, C. J.; MacMillan,
D. W. C. Chem. Sci. 2011, 2, 308.
(5) For selected cascade dearomatization reaction of tryptophols: (a)
Sunazuka, T.; Hirose, T.; Shirahata, T.; Harigaya, Y.; Hayashi, M.;
Komiyama, K.; Omura, S.; Smith, A. B., III. J. Am. Chem. Soc. 2000,
122, 2122. (b) Sunazuka, T.; Yoshida, K.; Kojima, N.; Shirahata, T.;
Hirose, T.; Handa, M.; Yamamoto, D.; Harigaya, Y.; Kuwajima, I.;
Omura, S. Tetrahedron Lett. 2005, 46, 1459. (c) Lozano, O.; Blessley, G.;
Martinez del Campo, T.; Thompson, A. L.; Giuffredi, G. T.; Bettati, M.;
Walker, M.; Borman, R.; Gouverneur, V. Angew. Chem., Int. Ed. 2011,
50, 8105.
(4) (a) Kim, S.-G. Bull. Korean Chem. Soc. 2009, 30, 2519. (b) Liu, Y.;
Xu, W.; Wang, X. Org. Lett. 2010, 12, 1448. (c) Cera, G.; Crispino, P.;
Monari, M.; Bandini, M. Chem. Commun. 2011, 47, 7803. (d) Noey,
E. L.; Wang, X.; Houk, K. N. J. Org. Chem. 2011, 76, 3477. (e) Cera, G.;
Chiarucci, M.; Mazzanti, A.; Mancinelli, M.; Bandini, M. Org. Lett.
2012, 14, 1350. (f) Fan, F.; Xie, W.; Ma, D. Org. Lett. 2012, 14, 1405.
1
0.1021/ol301939w r 2012 American Chemical Society
Published on Web 08/14/2012

In 2008, Gaunt et al. reported a copper-catalyzed aryla-
We began our exploration by testing model substrate 1a
with diphenylidonium salt (2a) under the catalysis of
various copper sources. To our great delight, the reaction
proceeded smoothly in dichloromethane at room tempera-
ture to afford the desired dearomative product 3a in
satisfactory yields (entries 1À6, Table 1). Among these
tested copper sources, (CuOTf) PhMe performed best
6
c
tion of indoles with a favorable C-3 selectivity. Inspired
by this pioneering work, we envisioned that a copper-
catalyzed cascade dearomatization reaction of 2-substi-
tuted tryptophols including the direct arylation at the
indole C-3 position and a subsequent iminium ion trapping
would afford the furoindoline derivatives with two qua-
ternary carbon centers (Scheme 1). Herein, we report the
preliminary results on such a copper-catalyzed dearoma-
tization reaction of 2-substituted tryptophols affording
2
3
(94% yield, entry 4, Table 1). To further explore this
cascade sequence, several frequently used Lewis acids were
also examined. However, none of them could catalyze this
reaction efficiently (entries 7À11, Table 1).
7
,8
furoindoline derivatives.
With (CuOTf) PhMe as the catalyst, the catalyst load-
2
3
ing was then examined. With2.5 or1 mol % of the catalyst,
the reaction could also proceed smoothly but with a
prolonged reaction time (entries 12À13, Table 1). With
Scheme 1. Proposed Cascade Dearomatization of 2-Substituted
Tryptophols via Copper-Catalyzed Arylation Reaction with
Diarylidonium Salts
5
mol % of (CuOTf) PhMe, the reaction conditions were
2
3
further optimized. Various solvents (CHCl , DCE, tol-
3
uene, Et O, THF, and CH CN) were tested, and all led
2
3
to the formation of the desired product 3a except for
CH CN (entries 14À19, Table 1). The reaction in CH Cl
3
2
2
gave the best yield (entry 4, Table 1). The syn stereochemistry
of product 3a was established by an X-ray crystallographic
analysis (see the Supporting Information for details).
Under the optimized reaction conditions (5 mol % of
(
CuOTf) PhMe in CH Cl , rt), the scope of the reaction
2 2 2
3
was explored. The results are summarized in Scheme 2.
First, the substituent at the C-2 position of tryptophol was
9
tested. The phenyl group could be tolerated, and 3b was
obtained in 87% yield after refluxing for 48 h. Second,
Table 1. Evaluation of Catalysts and Reaction Conditions
(
6) For recent reviews on diaryliodonium salts, see: (a) Deprez,
N. R.; Sanford, M. S. Inorg. Chem. 2007, 46, 1924. (b) Merritt, E. A.;
Olofsson, B. Angew. Chem., Int. Ed. 2009, 48, 9052. For selected
Cu-catalyzed arylation with diaryliodonium salts: (c) Phipps, R. J.;
Grimster, N. P.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 8172.
(
d) Phipps, R. J.; Gaunt, M. J. Science 2009, 323, 1593. (e) Ciana, C.-L.;
Phipps, R. J.; Brandt, J. R.; Meyer, F. M.; Gaunt, M. J. Angew. Chem.,
Int. Ed. 2011, 50, 458. (f) Duong, H. A.; Gilligan, R. E.; Cooke, M. L.;
Phipps, R. J.; Gaunt, M. J. Angew. Chem., Int. Ed. 2011, 50, 463.
time
(h)
yield
a
b
entry
catalyst
solvent
(%)
(
g) Bigot, A.; Williamson, A. E.; Gaunt, M. J. J. Am. Chem. Soc.
2
011, 133, 13778. (h) Allen, A. E.; MacMillan, D. W. C. J. Am. Chem.
1
2
3
Cu(OTf)
Cu(OAc)
2
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
2
2
2
2
2
2
2
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
2
2
2
2
2
2
2
2
1
1
91
Soc. 2011, 133, 4260. (i) Harvey, J. S.; Simonovich, S. P.; Jamison, C. R.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2011, 133, 13782. (j) Phipps,
R. J.; McMurray, L.; Ritter, S.; Duong, H. A.; Gaunt, M. J. J. Am.
Chem. Soc. 2012, 134, 10773. For selected Pd-catalyzed arylation with
diaryliodonium salts: (k) Kalyani, D.; Deprez, N. R.; Desai, L. V.;
Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 7330. (l) Deprez, N. R.;
Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 11234. (m) Xiao, B.; Fu, Y.;
Xu, J.; Gong, T.-J.; Dai, J.-J.; Yi, J.; Liu, L. J. Am. Chem. Soc. 2010, 132,
468. For an organic base promoted C-3 arylation of 3-substituted indole
with diaryliodonium salts: (n) Eastman, K.; Baran, P. S. Tetrahedron
2
82
Cu(ClO
(CuOTf)
4
)
2
6H
2
O
28
1
80
3
c
4
2
PhMe
94
3
5
6
7
8
9
6
CuPF (CH
CuCl
3
CN)
4
20
18
48
48
48
48
48
12
12
24
24
48
3
90
75
Sc(OTf)
3
<5
N.R.
<5
N.R.
<5
90
Zn(OTf)
Sn(OTf)
2
3
2
009, 65, 3149.
7) For recent reviews on dearomatization reaction, see: (a) Pouys ꢀe gu,
1
0
Bi(OTf)
Pd(OAc)
2
3
(
11
L.; Deffieux, D.; Quideau, S. Tetrahedron 2010, 66, 2235. (b) Roche, S. P.;
Porco, J. A., Jr Angew. Chem., Int. Ed. 2011, 50, 4068. (c) Zhang, D.; Song,
H.; Qin, Y. Acc. Chem. Res. 2011, 44, 447. For selected dearomatization
reactions from our group, see: (d) Wu, Q.-F.; He, H.; Liu, W.-B.; You, S.-L.
J. Am. Chem. Soc. 2010, 132, 11418. (e) Wu, Q.-F.; Liu, W.-B.; Zhuo, C.-X.;
Rong, Z.-Q.; Ye, K.-Y.; You, S.-L. Angew. Chem., Int. Ed. 2011, 50, 4455.
(f) Cai, Q.; Zheng, C.; You, S.-L. Angew. Chem., Int. Ed. 2011, 50, 8665.
(g) Zhuo, C.-X.; Liu, W.-B.; Wu, Q.-F.; You, S.-L. Chem. Sci. 2012, 3, 205.
(h) Wu, Q.-F.; Zheng, C.; You, S.-L. Angew. Chem., Int. Ed. 2012, 51, 1680.
(i) Cai, Q.; You, S.-L. Org. Lett. 2012, 14, 3040. (j) Wu, K.-J.; Dai, L.-X.;
You, S.-L. Org. Lett. 2012, 14, 3772.
d
e
c
c
c
c
c
c
12
13
14
15
16
17
18
19
(CuOTf)
(CuOTf)
(CuOTf)
(CuOTf)
(CuOTf)
(CuOTf)
(CuOTf)
(CuOTf)
2
2
2
2
2
2
2
2
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
3
3
3
3
3
3
3
3
84
2
Et O
80
THF
63
toluene
DCE
71
86
CHCl
CH CN
3
3
73
3
48
N.R.
(
8) During the preparation of the manuscript, Zhu and MacMillan
a
Reaction conditions: 1a (0.3 mmol), 2a (0.36 mmol), catalyst (0.03
mmol) in solvent (3 mL) at rt. Isolated yield. 5 mol % of (CuOTf)
reported an enantioselective copper-catalyzed construction of aryl-
pyrroloindolines via an arylationÀcyclization cascade; see: Zhu, S.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2012, 134, 10815.
(9) Under the optimized reaction conditions, 2-(2-phenyl-1H-indol-
-yl)ethanol was isolated in 86% yield when tryptophol was used.
b
c
2
3
d
PhMe was used. 2.5 mol
mol % of (CuOTf)
2
%
of (CuOTf)
2
3 PhMe
was used.
e
1
3 PhMe was used.
3
4
526
Org. Lett., Vol. 14, No. 17, 2012

Scheme 2. Substrate Scope for Cu(I)-Catalyzed Arylation
Scheme 3. Substrate Scope for Cu(I)-Catalyzed Vinylation
withdrawing group (4-Cl, 4-Br, 4-F, 3-Br, 3-CF ) could
3
be employed. In most cases, good to excellent yields were
achieved (81À95%, 3h to 3k, and 3n). However, 3l (3-Br),
3
m (3-CF ), and 3o (2-Me) were obtained in only moder-
3
ate yields, due to either the strong meta-electron-with-
drawing groups or the steric hindrance.
Finally, to further broaden the substrate scope, vinyla-
tion of 2-methyl tryptophol (1a) was also explored. The
results are summarized in Scheme 3. To our great delight,
1
0
various vinylphenylidonium salts were good partners for
this cascade sequence (3p to 3s, Scheme 3). In general, the
vinylphenylidonium salts display higher reactivity com-
pared to the diarylidonium salts. The reactions with vinyl-
phenylidonium salts proceed to completion in 2 h at room
temperature.
In summary, we have developed an efficient method to
provide functionalized furoindolines via Cu(I)-catalyzed
arylation or vinylation of 2-substituted tryptophols and
the subsequent cyclization reaction. This cascade dearo-
matization sequence of tryptophols provided versatile
furoindoline derivatives with two quaternary carbon cen-
ters in excellent yields under mild conditions. Further
development of an enantioselective version of this reaction
is currently underway in our laboratory.
2
-methyl tryptophols with various substituents on the
indole core all reacted with diphenylidonium salt (2a)
smoothly. The substrates bearing either an electron-donating
group (5-Me, 5-MeO) or an electron-withdrawing group
(5-Cl, 5-Br, 5-F) were found suitable to afford dearomative
products in 80À95% yield (3c to 3g, Scheme 2). Further
exploration of the substrate scope involved various diaryli-
donium salts. Diarylidonium salts having either an electron-
donating group (2-Me, 3-Me, 4-Me) or an electron-
Acknowledgment. We thank the National Basic Re-
search Program of China (973 Program 2009CB825300)
and the National Natural Science Foundation of China
(21025209, 20932008, 21102160, 21121062) for generous
financial support.
(
10) For selected reactions of vinylphenylidonium salts, see: (a)
Beringer, F. M.; Galton, S. A. J. Org. Chem. 1965, 30, 1930. (b) Ochiai,
M.; Sumi, K.; Takaoka, Y.; Kunushima, M.; Nagao, Y.; Shiro, M.;
Fujita, E. Tetrahedron 1988, 44, 4095. (c) Ochiai, M.; Oshima, K.;
Masaki, Y. J. Am. Chem. Soc. 1991, 113, 7059. (d) Zefirov, N. S.;
Kozmin, A. S.; Kasumov, T.; Potekhin, K. A.; Sorokin, V. D.; Brel,
V. K.; Abramkin, E. V.; Struchkov, Y. T.; Zhdankin, V. V.; Stang, P. J.
J. Org. Chem. 1992, 57, 2433. (e) Ochiai, M.; Shu, T.; Nagaoka, T.;
Kitagawa, Y. J. Org. Chem. 1997, 62, 2130. (f) Skucas, E.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2012, 134, 9090.
Supporting Information Available. Detailed experimen-
tal procedures and spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 17, 2012
4527