Synthesis of indolines via a domino Cu-catalyzed amidation/cyclization reaction

Article abstract of DOI:10.1021/ol8008792

(Chemical Equation Presented) A highly efficient one-pot procedure for the synthesis of indolines and their homologues based on a domino Cu-catalyzed amidation/nucleophilic substitution reaction has been developed. Substituted 2-iodophenethyl mesylates and related compounds afforded the corresponding products in excellent yields. No erosion of optical purity was observed when transforming enantiomerically pure mesylates under the reaction conditions.

Full text of DOI:10.1021/ol8008792

ORGANIC
LETTERS
2008
Vol. 10, No. 13
2721-2724
Synthesis of Indolines via a Domino
Cu-Catalyzed Amidation/Cyclization
Reaction
Ana Minatti and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
sbuchwal@mit.edu
Received April 16, 2008
ABSTRACT
A highly efficient one-pot procedure for the synthesis of indolines and their homologues based on a domino Cu-catalyzed amidation/nucleophilic
substitution reaction has been developed. Substituted 2-iodophenethyl mesylates and related compounds afforded the corresponding products
in excellent yields. No erosion of optical purity was observed when transforming enantiomerically pure mesylates under the reaction conditions.
The indoline moiety1 can be found in numerous biologically
active alkaloid natural products2 and pharmaceuticals.3
Recently, highly efficient indoline-based organic dyes for
dye-sensitized solar cells have also been developed.4
Since our previous reports on the Pd-catalyzed intramo-
lecular amination reactions for the formation of indolines,5
a variety of intramolecular transition metal-catalyzed ami-
nation and amidation processes have emerged for the
synthesis of N-protected indolines (Scheme 1, eq 1).6–8 More
versatile routes toward the synthesis of the indoline core
incorporate an intermolecular Pd-catalyzed amidation or
amination reaction as part of a sequential or domino process
(3) For selected examples, see: (a) Gruenfeld, N.; Stanton, J. L.; Yuan,
A. M.; Ebetino, F. H.; Browne, L. J.; Gude, C.; Huebner, C. F. J. Med.
Chem. 1983, 26, 1277. (b) Bromidge, S. M.; Duckworth, M.; Forbes, I. T.;
Ham, P.; King, F. D.; Thewlis, K. M.; Blaney, F. E.; Naylor, C. B.;
Blackburn, T. P.; Kennett, G. A.; Wood, M. D.; Clarke, S. E. J. Med. Chem.
1997, 40, 3494. (c) Hobson, L. A.; Nugent, W. A.; Anderson, S. R.;
Deshmukh, S. S.; Haley, J. J., III; Liu, P.; Magnus, N. A.; Sheeran, P.;
Sherbine, J. P.; Stone, B. R. P.; Zhu, J. Org. Process Res. DeV. 2007, 11,
(1) For recent examples of indoline syntheses based on non-metal-
catalyzed or radical processes, see: (a) Nicolaou, K. C.; Roecker, A. J.;
Pfefferkorn, J. A.; Cao, G.-Q. J. Am. Chem. Soc. 2000, 122, 2966. (b) Sanz
Gil, G.; Groth, U. M. J. Am. Chem. Soc. 2000, 122, 6789. (c) Dunetz, J. R.;
Danheiser, R. L. J. Am. Chem. Soc. 2005, 127, 5776. (d) Correa, A.; Tellitu,
I.; Dom´ınguez, E.; SanMartin, R. J. Org. Chem. 2006, 71, 8316. (e) Fuwa,
H.; Sasaki, M. Org. Lett. 2007, 9, 3347. (f) Wang, Z.; Wan, W.; Jiang, H.;
Hao, J. J. Org. Chem. 2007, 72, 9364. (g) Gilmore, C. D.; Allan, K. M.;
Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 1558. (h) Viswanathan, R.;
Smith, C. R.; Prabhakaran, E. N.; Johnston, J. N. J. Org. Chem. 2008, 73,
3040. (i) Clive, D. L. J.; Peng, J.; Fletcher, S. P.; Ziffle, V. E.; Wingert, D.
J. Org. Chem. 2008, 73, 2330.
985
(4) Kuang, D.; Uchida, S.; Humphry-Baker, R.; Zakeeruddin, S. M.;
Gra¨tzel, M. Angew. Chem., Int. Ed. 2008, 47, 1923
.
.
(5) (a) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 1348. (b) Wolfe, J. P.; Rennels, R. A.; Buchwald,
S. L. Tetrahedron 1996, 52, 7525
.
(6) For Pd-catalyzed processes, see: (a) Wagaw, S.; Rennels, R. A.;
Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 8451. (b) Yang, B. H.;
Buchwald, S. L. Org. Lett. 1999, 1, 35. (c) Kitamura, Y.; Hashimoto, A.;
Yoshikawa, S.; Odaira, J.-i.; Furuta, T.; Kan, T.; Tanaka, K. Synlett 2006,
115. For a Pd-catalyzed C-H activation approach, see: (d) Watanabe, T.;
(2) For selected examples, see: (a) Boger, D. L.; Boyce, C. W.;
Garbaccio, R. M.; Goldberg, J. A. Chem. ReV. 1997, 97, 787. (b) 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. (c) Dounay,
A. B.; Overman, L. E.; Wrobleski, A. D. J. Am. Chem. Soc. 2005, 127,
10186.
Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2008, 10, 1759.
(7) For Cu-catalyzed processes, see: (a) Klapars, A.; Huang, X.;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 7421. (b) Yamada, K.; Kubo,
T.; Tokuyama, H.; Fukuyama, T. Synlett 2002, 231. (c) Zhang, H.; Cai,
Q.; Ma, D. J. Org. Chem. 2005, 70, 5164. (d) Shafir, A.; Buchwald, S. L.
J. Am. Chem. Soc. 2006, 128, 8742
.
10.1021/ol8008792 CCC: $40.75
Published on Web 06/04/2008
2008 American Chemical Society

Scheme 1
.
Known and Envisioned Strategies for the Synthesis
of Indolines
Table 1. Optimization of the Domino Cu-Catalyzed Amidation/
Cyclization Reaction
yield of yield of yield of
entry
Y
base
solvent
3aa (%) 4a (%) 5a (%)
1b
2
I (1a)
1a
Cs2CO3 THF
Cs2CO3 THF
Cs2CO3 1,4-dioxane
Cs2CO3 toluene
Cs2CO3 THF
K3PO4 THF
K2CO3 THF
Cs2CO3 THF
6
37
35
3
-
23
11
-
31
23
-
14
-
3
1a
6
4
1a
11
-
5c
6
1a
40
9
1a
14
33
-
7
1a
-
8
Cl (1b)
87
-
-
9
OMs (1c) Cs2CO3 THF
89d
-
a GC yield with dodecane as an internal standard; 99% conversion of
1, unless indicated otherwise. b Experiment performed at rt; 41% conversion
of 1a. c Racemic trans-1,2-N,N′-dimethylcyclohexanediamine was used as
a ligand. d Isolated yield.
(Scheme 1, eqs 2 and 3).9Although this strategy represents a
significant improvement in the modular synthesis of indolines,
several drawbacks limit the reported methods. Specifically,
certain methods only allow access to 3-substituted,9a 2-subs-
tituted,9c or nonsubstituted9d,e indolines, and the Pd-catalyzed
C-C/C-N coupling of bromoalkylamines with an aryl
iodide requires ortho-substituted aryl iodides and a p-
nitrophenyl-protected amine.9f We felt that a one-pot pro-
cedure for the synthesis of indolines that overcomes these
limitations would be highly desirable.
solvent, base, and diamine-ligand did not increase the yield
of the desired product, although varying amounts of the
products 4a and 5a were observed (Table 1, entries 1-7).
Variation of the nucleofuge proved to be crucial. Switching
from the phenethyl iodide 1a to the phenethyl chloride 1b
or the phenethyl mesylate 1c resulted in exclusive formation
of the desired product 3a in high yields (87% and 89%,
respectively).
Herein, we report the development of a general domino
Cu-catalyzed amidation/nucleophilic substitution process for
the synthesis of substituted indolines and their homologues
(Scheme 1, eq 4).10
Under the optimized reaction conditions 2-iodophenethyl
mesylate (1c) reacted equally efficiently with other com-
monly used carbamates 2b,c and amides 2d and yielded the
corresponding N-protected indolines 3b-d in comparably
high yields without formation of any side products (Table
2).
Encouraged by these results, we investigated the substrate
scope of this reaction sequence. Various 2-iodophenethyl
mesylates were subjected to the domino amidation sequence
(Table 3).
A wide variety of functional groups, such as ethers, acetals,
halogens, esters, and siloxy or alkyl groups were tolerated
on the aryl ring (entries 1-3) and in positions R2 and R3
(entries 4-8). In all cases, the reaction proceeded smoothly
and the corresponding substituted indolines were obtained
in excellent yield. This method was further applied to the
synthesis of indoline homologues, which are difficult to
access using the previously reported domino processes.8 The
corresponding mesylates gave access to N-Boc-tetrahydro-
quinoline (3n), -benzoxazine (3o), and -3-methyl-2,3,4,5-
tetrahydro-1H-1-benzazepine (3p) in yields up to 76%
(entries 9-11).
Three distinct mechanistic pathways for this domino
process can be envisioned for the formation of the indoline
structure (Scheme 2): (1) base-promoted formation of 2-iodo-
styrene followed by intermolecular Cu-catalyzed C-N
coupling and intramolecular hydroamidation of styrene I
We began our investigation with 1-iodo-2-(2-iodoethyl)-
benzene (1a) and tert-butyl carbamate (2a) as the model
substrates to examine the reaction conditions, which we
previously reported for the Cu-catalyzed amidation of aryl
halides (Table 1) [5 mol % CuI, 20 mol % N,N′-dimethyl-
ethylenediamine (DMEDA), Cs2CO3 in THF].7a,11 Only low
conversion of 1a was observed at room temperature after
16 h. At 80 °C, however, full conversion and up to 37% of
the N-Boc-protected indoline 3a were obtained, along with
23% of 2-N-Boc-styrene (4a). Systematic variation of the
(8) For a Ni-catalyzed process, see: Omar-Amrani, R.; Thomas, A.;
Brenner, E.; Schneider, R.; Fort, Y. Org. Lett. 2003, 5, 2311.
(9) (a) Aoki, K.; Peat, A. J.; Buchwald, S. L. J. Am. Chem. Soc. 1998,
120, 3068. (b) Deboves, H. J. C.; Hunter, C.; Jackson, R. F. W. J. Chem.
Soc., Perkin Trans. 1 2002, 733. (c) Lira, R.; Wolfe, J. P. J. Am. Chem.
Soc. 2004, 126, 13906. (d) Ganton, M. D.; Kerr, M. A. Org. Lett. 2005, 7,
4777. (e) Ganton, M. D.; Kerr, M. A. Org. Lett. 2007, 72, 574. In this
case, the Pd-catalyzed amination proceeds intramolecularly: (f) Thansandote,
P.; Raemy, M.; Rudolph, A.; Lautens, M. Org. Lett. 2007, 9, 5255.
(10) For recent reviews on Cu-catalyzed C-N bond forming reactions,
see: (a) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428. (b) Ley, S. V.;
Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400. (c) Beletskaya,
I. P.; Cheprakov, A. V. Coord. Chem. ReV. 2004, 248, 2337. (d) Monnier,
F.; Taillefer, M. Angew. Chem., Int. Ed. 2008, 47, 3096.
(11) (a) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am.
Chem. Soc. 2001, 123, 7727. (b) Mart´ın, R.; Rodr´ıguez Rivero, M.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45, 7079
.
2722
Org. Lett., Vol. 10, No. 13, 2008

Table 2. Synthesis of N-Protected Indolines via Domino
Cu-Catalyzed Amidation/Cyclization Reaction
Table 3. Substrate Scope of the Cu-Catalyzed Domino
Amidation Reaction
a Yields of the isolated products are an average of two runs and the
products are estimated to be over 95% pure by 1H NMR spectroscopic and
GC analysis.
(pathway A),12 (2) intermolecular Cu-catalyzed or uncata-
lyzed substitution of the alkyl mesylate and subsequent Cu-
catalyzed intramolecular C-N coupling with the aryl iodide
II (pathway B), and (3) initial intermolecular Cu-catalyzed
amidation of the aryl iodide, followed by an intramolecular
SN2 reaction of the carbamate or amide III onto the alkyl
mesylate (pathway C).
To elucidate the reaction mechanism, we synthesized
compounds 1q, 1r, 4, and 5 (Scheme 3).
Under the reaction conditions, racemic trans-mesylate 1q
yielded the racemic cis-fused hexahydrocarbazole 3qsas
confirmed by an NOE experimentsas a single diastereosi-
omer in 94% yield, and the enantiomerically pure mesylate
1r afforded indoline 3r in excellent yield and with 99% ee.13
On the basis of these results, pathway A is unlikely to be
the operative mechanism, since hydroamidation of the achiral
intermediate I would lead to a mixture of cis and trans14
products in the case of 3q and to racemization of the
stereocenter in position 2 in the case of 3r. Furthermore,
pathway B can be ruled out, since no substitution at the alkyl
mesylate took place in model systems 4 and 5 under our
reaction conditions. Finally, the fact that complete stereo-
chemical inversion was observed in cases 1q and 1r strongly
suggests a nucleophilic displacement of the mesylate group
a Yields of the isolated products are an average of two runs, and the
products are estimated to be over 95% pure by 1H NMR spectroscopic and
GC analysis.
via an SN2 mechansim (pathway C in Scheme 2). Attempts
to isolate reaction intermediate III were unsuccessful. Only
the final product and remaining starting material could be
detected by GC or NMR in various ratios over the course of
the reaction.
In summary, we have developed a highly efficient domino
Cu-catalyzed amidation/nucleophilic substitution reaction for
the synthesis of indolines and their homologues from ortho-
(12) For evidence of intramolecular Cu-catalyzed hydroamidation of an
unsaturated moiety, see ref 11b.
(13) (a) For recent examples of the synthesis of enantiomerically enriched
indolines, see: Arp, F. O.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 14265.
(b) Kuwano, R.; Kashiwabara, M. Org. Lett. 2006, 8, 2653. (c) Yamamoto,
H.; Pandey, G.; Asai, Y.; Nakano, M.; Kinoshita, A.; Namba, K.; Imagawa,
H.; Nishizawa, M. Org. Lett. 2007, 9, 4029.
(14) For examples of trans-1,2,3,4,4a,9a-hexahydrocarbazoles, see: (a)
Smolinsky, G. J. Am. Chem. Soc. 1961, 83, 2489. (b) Sundberg, R. J.
Tetrahedron Lett. 1966, 7, 477.
Org. Lett., Vol. 10, No. 13, 2008
2723

Scheme 2. Possible Mechanistic Pathways
Scheme 3
.
Experiments Conducted To Elucidate the Reaction
Mechanism
iodophenalkyl mesylates. The mild reaction conditions and
the broad substrate scope render this method attractive and
complementary to existing methods for the synthesis of
indolines. Finally, this approach also allows the synthesis
of enantiomerically pure indolines, since the second step
proceeds with complete stereochemical inversion and there-
fore no erosion of optical purity.
experiment. The Bruker Advance 400 MHz used in this work
was purchased with funding from the National Institutes of
Health (GM 1S10RR13886-01). The Varian NMR instru-
ments used for this publication were supported by the
National Science Foundation (CHE 9808061 and DBI
9729592). We are also indebted to Merck for unrestricted
support.
Supporting Information Available: Experimental pro-
cedures and characterization data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. Generous financial support from the
National Institutes of Health (GM 58160) is gratefully
acknowledged. A.M. thanks the Alexander von Humboldt
Stiftung for a Feodor Lynen postdoctoral Fellowship. We
thank Alison E. Ondrus (MIT) for assistance with the NOE
OL8008792
2724
Org. Lett., Vol. 10, No. 13, 2008