Strategies for the synthesis of 2-substituted indoles and indolines starting from acyclic α-phosphoryloxy enecarbamates

Article abstract of DOI:10.1021/ol071312a

Strategies have been developed for the synthesis of 2-substituted indoles and indolines starting from acyclic α-phosphoryloxy enecarbamates. A highly chemoselective cross-coupling of N-(o-bromophenyl)-α- phosphoryloxyenecarbamates with boron nucleophiles

Full text of DOI:10.1021/ol071312a

ORGANIC
LETTERS
2007
Vol. 9, No. 17
3347-3350
Strategies for the Synthesis of
2-Substituted Indoles and Indolines
Starting from Acyclic
Enecarbamates
r-Phosphoryloxy
Haruhiko Fuwa* and Makoto Sasaki*
Laboratory of Biostructural Chemistry, Graduate School of Life Sciences,
Tohoku UniVersity, 1-1 Tsutsumidori-amamiya, Aoba-ku, Sendai 981-8555, Japan
hfuwa@bios.tohoku.ac.jp; masasaki@bios.tohoku.ac.jp
Received June 3, 2007
ABSTRACT
Strategies have been developed for the synthesis of 2-substituted indoles and indolines starting from acyclic
r-phosphoryloxy enecarbamates.
A highly chemoselective cross-coupling of N-(o-bromophenyl)-r-phosphoryloxyenecarbamates with boron nucleophiles enabled the efficient
preparation of various N-(o-bromophenyl)enecarbamates, which served as useful precursors for subsequent Heck-type cyclization or 5-endo-
trig aryl radical cyclization to furnish 2-substituted indoles or indolines, respectively.
Utilization of alkenyl phosphates in palladium(0)-catalyzed
reactions, pioneered by Oshima and co-workers,1 has recently
gained much attention among organic chemists due to their
potential as substitutes for triflate counterparts.2 Alkenyl
phosphates are easy to prepare and handle because they are
more stable than the corresponding triflates. In addition,
reagents for phosphorylation, such as diphenylphosphoryl
chloride, are less expensive than conventional triflating agents
[e.g., trifluoromethanesulfonic anhydride or N-phenyl bis-
(trifluoromethanesulfonimide)]. However, the reactivity pro-
file of alkenyl phosphates remains largely unexplored despite
their potential to expand the scope of palladium(0)-catalyzed
processes. An understanding of the reactivity difference
between alkenyl phosphates and other functionalities, such
as aryl bromides/chlorides, is essential for the successful
design of sequential or cascade processes involving pal-
ladium(0)-catalyzed reactions.
(1) (a) Takai, K.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1980, 21,
2531. (b) Sato, M.; Takai, K.; Oshima, K.; Nozaki, H. Tetrahedron Lett.
1981, 22, 1609. (c) Takai, K.; Sato, M.; Oshima, K.; Nozaki, H. Bull. Chem.
Soc. Jpn. 1984, 57, 108. (d) Fugami, K.; Oshima, K.; Utimoto, K. Chem.
Lett. 1987, 2203.
(2) (a) Nicolaou, K. C.; Shi, G.-Q.; Gunzner, J. L.; Ga¨rtner, P.; Yang,
Z. J. Am. Chem. Soc. 1997, 119, 5467. (b) Nicolaou, K. C.; Shi, G.-Q.;
Namoto, K.; Bernal, F. Chem. Commun. 1998, 1757. (c) Buon, C.; Chacun-
Lefevre, L.; Rabot, R.; Bouyssou, P.; Coudert, G. Tetrahedron 2000, 56,
605. (d) Lepifre, F.; Clavier, S.; Bouyssou, P.; Coudert, G. Tetrahedron
2001, 57, 6969. (e) Lo Galbo, F.; Occhiato, E. G.; Guarna, A.; Faggi, C. J.
Org. Chem. 2003, 68, 6360. (f) Mousset, D.; Gillaizeau, I.; Hassan, J.;
Lepifre, F.; Bouyssou, P.; Coudert, G. Tetrahedron Lett. 2005, 46, 3703.
(g) Occhiato, E. G.; Lo Galbo, F.; Guarna, A. J. Org. Chem. 2005, 70,
7324. (h) Hansen, A. L.; Ebran, J.-P.; Ahlquist, M.; Norrby, P.-O.;
Skrydstrup, T. Angew. Chem., Int. Ed. 2006, 45, 3349. (i) Ebran, J.-P.;
Hansen, A. L.; Gogsig, T. M.; Skrydstrup, T. J. Am. Chem. Soc. 2007,
129, 6931.
We reported that Suzuki-Miyaura coupling with cyclic
R-phosphoryloxy enol ethers is a powerful process for the
convergent synthesis of marine polycyclic ether natural
products.3,4 However, acyclic R-phosphoryloxy enamides/
(3) (a) Sasaki, M.; Fuwa, H.; Ishikawa, M.; Tachibana, K. Org. Lett.
1999, 1, 1075. (b) Sasaki, M.; Ishikawa, M.; Fuwa, H.; Tachibana, K.
Tetrahedron 2002, 58, 1889. (c) Sasaki, M.; Fuwa, H. Synlett 2004, 1851.
10.1021/ol071312a CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/21/2007

enecarbamates have not been used in palladium(0)-catalyzed
processes despite their potential utility in the synthesis of
nitrogen heterocycles.5 We recently reported the first suc-
cessful application of acyclic R-phosphoryloxy enecarbam-
ates to the synthesis of indole-2,3-quinodimethanes and 2-(N-
alkoxycarbonylamino)-1,3-dienes and demonstrated their
versatility in the Heck reaction.6 As part of our studies on
the exploitation of R-phosphoryloxy enamides/enecarbamates
in the palladium(0)-catalyzed synthesis of nitrogen hetero-
cycles,7 we describe herein strategies for the synthesis of
2-substituted indoles and indolines starting from acyclic
R-phosphoryloxy enecarbamates based on a highly chemo-
selective Suzuki-Miyaura coupling.
Table 1. Chemoselective Cross-Coupling of 2 with
Phenylboronic Acida
% yield
entry substrate
solvent
1,4-dioxane
temp (°C) 6a
7
1
2
2
2
2
2
60
50
50
50
rt
47 24
2
3
1,4-dioxane/H2O (10:1)
THF/H2O (10:1)
72
85
90
52
0
0
0
0
4
5b
DMF/H2O (10:1)
DMF/H2O (10:1)
a All reactions were performed with 10 mol % of Pd(PPh3)4, 1.1 equiv
of PhB(OH)2, and 3 equiv of Cs2CO3. Yields are overall from 1. b Na2CO3
was used as a base.
Scheme 1. Concept of the Present Work
with 2, phenylboronic acid, Pd(PPh3)4, and Cs2CO3 in
dioxane at 60 °C, the desired enecarbamate 6a was isolated
in 47% yield (from 1) along with a considerable amount of
indole 7 (entry 1). To suppress the formation of 7, we
surveyed a series of reaction conditions and found that the
addition of H2O as a cosolvent dramatically increased the
yield of 6a. Thus, employing Pd(PPh3)4 catalyst and Cs2-
CO3 in 10:1 dioxane/H2O at 50 °C, the cross-coupling
proceeded smoothly and without incident, giving 6a in 72%
overall yield from 1 (entry 2). Further examination revealed
that 10:1 DMF/H2O is the best solvent for the cross-coupling;
a remarkable chemoselectivity was attained under these
conditions, and 6a was isolated in 90% yield (entry 4). On
the other hand, when the reaction was performed at room
temperature, the yield of 6a declined (entry 5). Thus, under
the aqueous Suzuki-Miyaura conditions, the reactivity order
R-phosphoryloxy enecarbamate > aryl bromide is estab-
lished.
Scheme 1 illustrates our strategies for the synthesis of
2-substituted indoles and indolines starting from acyclic
R-phosphoryloxy enecarbamates. Thus, a highly chemose-
lective cross-coupling of R-phosphoryloxy enecarbamate 2,
readily derived from the corresponding imide 1 by treatment
with KHMDS and (PhO)2P(O)Cl, in the presence of an aryl
bromide would give N-(o-bromophenyl)enecarbamate 3. The
Heck-type cyclization of 3 would afford 2-substituted indole
derivative 4. On the other hand, 5-endo-trig aryl radical
cyclization of 3 would furnish 2-substituted indoline 5,
although this type of cyclization is generally disfavored
according to Baldwin’s rules.8
We then investigated the Heck-type cyclization of 6a as
summarized in Table 2. Although there are reports on the
Table 2. Screening of Conditionsa
We first examined a chemoselective cross-coupling of
R-phosphoryloxy enecarbamate 2 with 1.1 equiv of phenyl-
boronic acid9 (Table 1). When the reaction was performed
(4) (a) Fuwa, H.; Sasaki, M.; Satake, M.; Tachibana, K. Org. Lett. 2002,
4, 2891. (b) Fuwa, H.; Kainuma, N.; Tachibana, K.; Sasaki, M. J. Am. Chem.
Soc. 2002, 124, 14983. (c) Tsukano, C.; Sasaki, M. J. Am. Chem. Soc. 2003,
125, 14294. (d) Tsukano, C.; Ebine, M.; Sasaki, M. J. Am. Chem. Soc.
2005, 127, 4326. (e) Fuwa, H.; Ebine, M.; Sasaki, M. J. Am. Chem. Soc.
2006, 128, 9648. (f) Fuwa, H.; Ebine, M.; Bourdelais, A. J.; Baden, D. G.;
Sasaki, M. J. Am. Chem. Soc. 2006, 128, 16989.
entry
base (equiv)
solvent
temp (°C)
% yield
1
K2CO3 (3)
K2CO3 (3)
Et3N (10)
Et3N (10)
i-Pr2NEt (10)
PMP (5)
DMF
CH3CN
DMF
DMF
DMF
DMF
100
80
100
100
100
100
48
71
76
94
38
18
2b,c
3b,c
4b
5b
6
(5) For leading reviews on palladium(0)-catalyzed synthesis of hetero-
cycles see: (a) Zeni, G.; Larock, R. C. Chem. ReV. 2006, 106, 4644. (b)
Humphrey, G. R.; Kuethe, J. T. Chem. ReV. 2006, 106, 2875. (c) Cacchi,
S.; Fabrizi, G. Chem. ReV. 2005, 105, 2873.
(6) Fuwa, H.; Sasaki, M. Chem. Commun. 2007, 2876.
(7) (a) Fuwa, H.; Kaneko, A.; Sugimoto, Y.; Tomita, T.; Iwatsubo, T.;
Sasaki, M. Heterocycles 2006, 70, 101. (b) Fuwa, H.; Sasaki, M. Org.
Biomol. Chem. 2007, 5, 1849.
(8) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
(9) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
a All reactions were carried out for 20-24 h unless otherwise noted.
Yields are overall from 1. b Reactions performed in a sealed tube.
c n-Bu4NCl (1 equiv) was used as an additive.
3348
Org. Lett., Vol. 9, No. 17, 2007

Heck-type cyclization of related enamines and enamino-
nes,10,11 its application to the synthesis of 2-substituted
indoles has been less explored and, to the best of our
knowledge, the use of N-alkoxycarbonyl derivatives in such
reactions has not been reported. We initially performed the
cyclization of 6a using 10 mol % of Pd(PPh3)4 and K2CO3
as a base in DMF at 100 °C (Table 2, entry 1). The desired
N-Boc-2-phenylindole 7 was isolated in 48% yield, and the
major byproduct was the dehalogenated 6b (22%). On the
other hand, under the Jeffery conditions,12 the desired product
7 was cleanly obtained in an improved 71% yield, and the
formation of 6b was completely suppressed (entry 2).
Employing Et3N as a base, further enhancement of the yield
was attained (entries 3 and 4). Thus, exposure of 6a to
catalytic Pd(PPh3)4 and Et3N in DMF at 100 °C afforded 7
in 94% yield. Changing the base to i-Pr2NEt or 1,2,2,6,6-penta-
methylpiperidine (PMP) was found to be detrimental due to
the significant dehalogenation as a side reaction (entries 5
and 6).
reactions of 8-12 were efficiently achieved, affording 2-aryl
and 2-heteroaryl indoles 13-17 in good to excellent yields.13
We next investigated a cross-coupling/cyclization cascade
starting from R-phosphoryloxy enecarbamate 2, exploiting
its unique reactivity profile (Scheme 2). In the previous
Scheme 2. Suzuki-Miyaura Coupling/Heck-Type Cyclization
Cascade
experiment, we unexpectedly isolated indole 7 as a byproduct
in 24% yield when cross-coupling of 2 with phenylboronic
acid was performed in anhydrous dioxane at 60 °C (see Table
1, entry 1). Under these conditions, however, further conver-
sion of enecarbamate 2 to indole 7 stalled after ca. 24 h.
Elevation of temperature (100 °C) and/or prolonged reaction
time proved to be ineffective. After several attempts, we
found that consecutive cross-coupling/cyclization could be
realized using 10 mol % of Pd(PPh3)4, Cs2CO3 (3 equiv),
arylboronic acid (1.1 equiv), and n-Bu4NBr (1 equiv)12 in
10:1 DMF/H2O at 50-70 °C. Under these conditions, we
isolated N-Boc-2-substituted indole derivatives 7, 13, and
14 in good yields.
Having secured reliable conditions for the cross-coupling
and cyclization processes, application of the present strategy
to a variety of substrates was investigated, and the results
are summarized in Table 3. Suzuki-Miyaura cross-coupling
Table 3. Application to a Variety of Substratesa
Finally, 5-endo-trig aryl radical cyclization of enecarbam-
ates 6a and 8-11 was examined. It is well-known that 5-exo-
trig radical cyclization is a powerful strategy for the
construction of 3-substituted indoline derivatives.14 To the
best of our knowledge, however, there has been no report
of the application of 5-endo-trig radical cyclization for the
synthesis of an indoline system.15,16 To our delight, treatment
(10) For early examples see: (a) Iida, H.; Yuasa, Y.; Kibayashi, C. J.
Org. Chem. 1980, 45, 2938. (b) Kasahara, A.; Izumi, T.; Murakami, S.;
Yanai, H.; Takatori, M. Bull. Chem. Soc. Jpn. 1986, 59, 927. (b) Sakamoto,
T.; Nagano, T.; Kondo, Y.; Yamanaka, H. Synthesis 1990, 215.
(11) (a) Michael, J. P.; Chang, S.-F.; Wilson, C. Tetrahedron Lett. 1993,
34, 8365. (b) Koerber-Ple´, K.; Massiot, G. Synlett 1994, 759. (c) Chen,
L.-C.; Yang, S.-C.; Wang, H.-M. Synthesis 1995, 385. (d) Latham, E. J.;
Stanforth, S. P. J. Chem. Soc., Perkin Trans. 1 1997, 2059. (e) Edmondson,
S. D.; Mastracchio, A.; Parmee, E. R. Org. Lett. 2000, 2, 1109. (f) Yamazaki,
K.; Nakamura, Y.; Kondo, Y. J. Org. Chem. 2003, 68, 6011. (g) Watanabe,
T.; Arai, S.; Nishida, A. Synlett 2004, 907. (h) Nazare´, M.; Schneider, C.;
Lindenschmidt, A.; Will, D. W. Angew. Chem., Int. Ed. 2004, 43, 452. (i)
Lachnace, N.; April, M.; Joly, M.-A. Synthesis 2005, 2571. (j) Barluenga,
J.; Fernandez, M. A.; Aznar, F.; Valdes, C. Chem. Eur. J. 2005, 11, 2276.
(k) Baran, P. S.; Hafensteiner, B. D.; Ambhaikar, N. B.; Guerrero, C. A.;
Gallagher, J. D. J. Am. Chem. Soc. 2006, 128, 8678. (l) Jia, J.; Zhu, J. J.
Org. Chem. 2006, 71, 7826.
a Cross-coupling reactions: Pd(PPh3)4 (0.1 equiv), Cs2CO3 (3 equiv),
boron nucleophile (1.1 equiv) in 10:1 DMF/H2O at 50 °C. Cyclization
reactions: Pd(PPh3)4 (0.1 equiv), Et3N (10 equiv) in DMF at 100 °C.
b Yields in parentheses are the corresponding N-deprotected indole.
(12) Jeffery, T. Tetrahedron 1996, 52, 10113.
(13) Although the present reaction affords 5-endo-trig Heck cyclization-
type products, it is believed that it proceeds via a 6-membered palladacycle
intermediate. For discussions on the mechanism, see refs 10a and 11d.
(14) (a) Boger, D. L.; Yun, W.; Teegarden, B. R. J. Org. Chem. 1992,
57, 2873. (b) Boger, D. L.; McKie, J. A. J. Org. Chem. 1995, 60, 1271. (c)
Patel, V. F.; Andis, S. L.; Enkema, J. K.; Johnson, D. A.; Kennedy, J. H.;
Mohamadi, F.; Schultz, R. M.; Soose, D. J.; Spees, M. M. J. Org. Chem.
1997, 62, 8868.
of 2 with a range of arylboronic acids proceeded without
incident to give enecarbamates 8-12 without touching the
aryl bromide. Under the established conditions, cyclization
(15) For reviews see: (a) Ishibashi, H.; Sato, T.; Ikeda, M. Synthesis
2002, 695. (b) Ishibashi, H. Chem. Rec. 2006, 6, 23.
Org. Lett., Vol. 9, No. 17, 2007
3349

of 6a and 8-11 with Bu3SnH in the presence of catalytic
AIBN in toluene at 100 °C (method A) gave a series of
2-substituted indolines 18-22 in moderate to good yields
(Table 4). Furthermore, we found that radical cyclization
in the presence of t-BuOH in THF/HMPA17 at room
temperature (method B). The latter method affords 2-sub-
stituted indolines in somewhat better yields and eliminates
the need for tedious chromatographic separation of tin
byproducts.
In conclusion, the present study clearly demonstrates the
synthetic utility of acyclic R-phosphoryloxy enecarbamates
as novel versatile precursors in the synthesis of 2-substituted
indoles and indolines. We found that the addition of water
as a cosolvent in the Suzuki-Miyaura reaction of R-phos-
phoryloxy enecarbamates with aryl or heteroaryl boronic
acids allowed for a highly chemoselective cross-coupling,
giving a series of N-(o-bromophenyl)enecarbamates in excel-
lent yields. The establishment of the reactivity order R-phos-
phoryloxy enecarbamate > aryl bromide under aqueous
Suzuki-Miyaura conditions is noteworthy. The Heck-type
cyclization of N-(o-bromophenyl)enecarbamates was suc-
cessfully employed in the synthesis of 2-substituted indole
derivatives. Consequently, the Suzuki-Miyaura cross-
coupling/Heck-type cyclization cascade was developed based
on the established reactivity difference between R-phospho-
ryloxy enecarbamate and aryl bromide functional groups. We
have also succeeded in the 5-endo-trig aryl radical cyclization
of N-(o-bromophenyl)enecarbamates, which is an unprec-
edented example of the successful application of generally
disfavored 5-endo-trig cyclization to the synthesis of indoline
derivatives.18
Table 4. 5-endo-trig Aryl Radical Cyclization
Acknowledgment. This work is supported in part by a
Grant-in-Aid for Scientific Research by the Ministry of
Education, Culture, Sports, Science and Technology, Japan
(MEXT).
a Method A: n-Bu3SnH, AIBN, toluene, 100 °C. Method B: SmI2,
t-BuOH, HMPA, THF, room temperature. b Reaction performed in the
absence of t-BuOH.
Supporting Information Available: Representative ex-
perimental procedures and spectroscopic data for new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
could also be performed under mild conditions using SmI2
OL071312A
(16) For a theoretical study see: Chatgilialoglu, C.; Ferreri, C.; Guerra,
M.; Timokhin, V.; Froudakis, G.; Gimisis, T. J. Am. Chem. Soc. 2002, 124,
10765.
(17) (a) Inanaga, J.; Ishikawa, M.; Yamaguchi, M. Chem. Lett. 1987,
1485. (b) Hasegawa, E.; Curran, D. P. J. Org. Chem. 1993, 58, 5008.
(18) To expand the scope of the present strategies, we are currently
investigating the use of a propionyl imide instead of 1 as the starting
material, which would provide 2,3-disubstituted indoles or indolines. The
results will be reported in due course.
3350
Org. Lett., Vol. 9, No. 17, 2007