Synthesis of substituted indoles from 2-azidoacrylates and ortho-silyl aryltriflates

Article abstract of DOI:10.1021/ol101934v

2-Azidoacrylates react with benzynes in the presence of PPh₃ and CsF to afford substituted indoles in good yields. The reaction involves the formation of iminophosphorane and benzyne and a subsequent double cyclization/hydrolysis/air-oxidation cascade. This methodology was utilized to synthesize 10H-indolo[1,2-a]indol-10-ones.

Full text of DOI:10.1021/ol101934v

ORGANIC
LETTERS
2010
Vol. 12, No. 20
4608-4611
Synthesis of Substituted Indoles from
2-Azidoacrylates and ortho-Silyl
Aryltriflates†
Deng Hong, Zhengbo Chen, Xufeng Lin,* and Yanguang Wang*
Department of Chemistry, Zhejiang UniVersity, Hangzhou 310027, P. R. China
orgwyg@zju.edu.cn; lxfok@zju.edu.cn
Received August 16, 2010
ABSTRACT
2-Azidoacrylates react with benzynes in the presence of PPh3 and CsF to afford substituted indoles in good yields. The reaction involves the
formation of iminophosphorane and benzyne and a subsequent double cyclization/hydrolysis/air-oxidation cascade. This methodology was
utilized to synthesize 10H-indolo[1,2-a]indol-10-ones.
Indoles constitute an important class of alkaloids and are
common building blocks for a number of bioactive natural
products and marketed drugs.1 Consequently, many methods
have been developed for the construction of indoles,2
including the Fischer synthesis,3 hetero-annulations,4 reduc-
tive cyclization,5 and metal-catalyzed processes.6 Still, the
development of more efficient routes to substituted indoles
is of great importance.
synthesis.7 Additionally, aryne cyclizations have proved to
be an exceptional method for gaining metal-free access to
heterocyclic molecules.8 Inspired by these works and our
recent findings around the synthesis of indoles9 and the
reactions of iminophosphoranes,10 we assumed that cycload-
dition of arynes with vinyl iminophosphoranes would lead
to the formation of indoles since the iminophosphorane
nitrogen bears a partial negative charge and thus exhibits
considerable nucleophilicity.
Recently, much attention has been attracted to applying
ortho-silyl aryltriflates as the benzyne precursors in organic
(5) (a) Rutherford, J. L.; Rainka, M. P.; Buchwald, S. L. J. Am. Chem.
Soc. 2002, 124, 15168. (b) Wong, A.; Kuethe, J. T.; Davies, I. W.; Hughes,
D. L. J. Org. Chem. 2004, 69, 7761.
† Dedicated to Professor Henry N. C. Wong on the occasion of his 60th
birthday.
(6) (a) Dunetz, J. R.; Danheiser, R. L. J. Am. Chem. Soc. 2005, 127,
5776. (b) Jensen, T.; Pedersen, H.; Bang-Andersen, B.; Madsen, R.;
Jørgensen, M. Angew. Chem., Int. Ed. 2008, 47, 888. (c) Leogane, O.; Lebel,
H. Angew. Chem., Int. Ed. 2008, 47, 350. (d) Barluenga, J.; Jime´nez-Aquino,
A.; Valde´s, C.; Aznar, F. Angew. Chem., Int. Ed. 2007, 46, 1529. (e) Fayol,
Fang, Y. Q.; Lautens, M. Org. Lett. 2006, 8, 4203–4206. (f) Coleman, C. M.;
O’Shea, D. F. J. Am. Chem. Soc. 2003, 125, 4054. (g) Kothandaraman, P.;
Rao, W.; Foo, S.; Chan, P. W. H. Angew. Chem., Int. Ed. 2010, 49, 4619.
(h) Okamoto, N.; Miwa, Y.; Minami, H.; Takeda, K.; Yanada, R. Angew.
Chem., Int. Ed. 2009, 48, 9693. (i) Barluenga, J.; Aquino, A.; Aznar, F.;
Valdes, C. J. Am. Chem. Soc. 2009, 131, 4031.
(1) (a) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003,
103, 893. (b) Somei, M.; Yamada, F. Nat. Prod. Rep. 2004, 21, 278. (c)
Somei, M.; Yamada, F. Nat. Prod. Rep. 2005, 22, 73.
(2) (a) Humphrey, G. R.; Kuethe, J. T. Chem. ReV. 2006, 106, 2875.
(b) Cacchi, S.; Fabrizi, G. Chem. ReV. 2005, 105, 2873.
(3) (a) Wagaw, S.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc.
1999, 121, 10251. (b) Alex, K.; Tillack, A.; Schwarz, N.; Beller, M. Angew.
Chem., Int. Ed. 2008, 47, 2304. (c) Ko¨hling, P.; Schmidt, A. M.; Eilbracht,
P. Org. Lett. 2003, 5, 3213.
(4) (a) Barluenga, J.; Trincado, M.; Rubio, E.; Gonza´lez, J. Angew.
Chem., Int. Ed. 2003, 42, 2406. (b) Arcadi, A.; Cacchi, S.; Fabrizi, G.;
Marinelli, F.; Parisi, L. M. J. Org. Chem. 2005, 70, 6213. (c) Trost, B. M.;
McClory, A. Angew. Chem., Int. Ed. 2007, 46, 2074. (d) Li, G. T.; Huang,
X. G.; Zhang, L. M. Angew. Chem., Int. Ed. 2008, 47, 346. (e) Carious,
K.; Ronan, B.; Mignani, S.; Fensterbank, L.; Malacria, M. Angew. Chem.,
Int. Ed. 2007, 46, 1881. (f) Nakamura, I.; Yamagishi, U.; Song, D.; Konta,
S.; Yamamoto, Y. Angew. Chem., Int. Ed. 2007, 46, 2284. (g) Ohno, H.;
Ohta, Y.; Oishi, S.; Fujii, N. Angew. Chem., Int. Ed. 2007, 46, 2295.
(7) (a) Pen˜a, D.; Pe´rez, D.; Guitia´n, E. Angew. Chem., Int. Ed. 2006,
45, 3579. (b) Liu, Z.; Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2005,
127, 15716. (c) Liu, Z.; Larock, R. C. J. Am. Chem. Soc. 2005, 127, 13112.
(d) Jin, T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2007, 46, 3323. (e) Liu,
Z.; Larock, R. C. Angew. Chem., Int. Ed. 2007, 46, 2535. (f) Henderson,
J. L.; Edwards, A. S.; Greaney, M. F. J. Am. Chem. Soc. 2006, 128, 7426.
(g) Jayanth, T. T.; Jeganmohan, M.; Cheng, M.-J.; Chu, S.-Y.; Cheng, C.-
H. J. Am. Chem. Soc. 2006, 128, 2232.
10.1021/ol101934v  2010 American Chemical Society
Published on Web 09/15/2010

The reaction of ethyl 2-azido-3-phenylacrylate 1a (1
equiv), 2-(trimethylsilyl)-phenyl triflate 2a (1.5 equiv), PPh3
(1 equiv), and CsF (3 equiv) under air was used to screen
the reaction conditions (Table 1). It is noteworthy that the
Since ethyl 2-azidoacrylates are readily available,12 the
prospect of vinyl iminophosphorane generation from them
is highly appealing. We, therefore, extended the substrate
scope to various ethyl 2-azidoacrylates 1 using the optimized
reaction conditions. As shown in Table 1, aryl-substituted
vinylazides 1a∼1i (Table 2, enties 1-9) and aryl-substituted
Table 1. Optimization of Reaction Conditionsa
Table 2. Azidoacrylate Scope in Indole Synthesisa
entry
temp (°C)
solvent
t (h)
yieldb (%)
1
2
3
4
5
6
7
8
50
50
50
50
50
50
50
50
50
80
25
50
50
THF
DCE
MeCN
10
10
10
10
10
10
10
5
25
0
0
entry
R1
product
yieldb (%)
1
2
3
4
5
6
7
8
Ph (1a)
4-MeC6H4 (1b)
4-ClC6H4 (1c)
4-BrC6H4 (1d)
4-MeOC6H4 (1e)
3-NO2C6H4 (1f)
4-PhC6H4 (1g)
4-PhCH2OC6H4 (1h)
2-naphthyl (1i)
PhCHdCH (1j)
3a
3b
3c
3d
3e
3f
3g
3h
3i
81
79
84
82
76
89
82
74
80
72
73
70
76
PhMe
0
MeCN/PhMe (1:2)
MeCN/PhMe (2:1)
MeCN/PhMe (1:1)
MeCN/PhMe (1:1)
MeCN/PhMe (1:1)
MeCN/PhMe (1:1)
MeCN/PhMe (1:1)
MeCN/PhMe (1:1)
MeCN/PhMe (1:1)
73
66
81
81
50
70
60
17c
80d
9
2
10
11
12
13
10
10
15
10
9
10
11
12
13
3j
3k
3l
2-ClC6H4CHdCH (1k)
2-MeOC6H4CHdCH (1l)
2-NO2C6H4CHdCH (1m)
a Reaction conditions: 1a (0.5 mmol), 2a (0.75 mmol), PPh3 (0.5 mmol),
CsF (1.5 mmol), solvent (10 mL), air. b Yield of the isolated product. c cat.
PPh3 (0.1 mmol, 0.2 equiv) was used. d Under N2.
3m
a Reaction conditions: 1 (0.5 mmol), 2a (0.75 mmol), PPh3 (0.5 mmol),
CsF (1.5 mmol), toluene/CH3CN (1:1, 10 mL), 50 °C, air, 5 h. b Yield of
the isolated product.
solvent system is crucial to the success of this annulation
chemistry (Table 1, entries 1-7). By using MeCN/toluene
as the cosolvent, we could control the release rate of
benzyne,11 consequently prevent the formation of benzot-
riazole, and improve the yield of product 3a. We found that
the cosolvent with a 1:1 ratio of MeCN/toluene was the most
suitable solvent (Table 1, entry 7). A screening of the
temperature and time of this reaction showed that 50 °C and
5 h were the best choices for this transformation (Table 1,
entries 7-11). When the PPh3 loading was reduced to 20
mol %, low yield (17%) of 3a was obtained (Table 1, entry
12). Interestingly, when the reaction was conducted under
inert conditions at 50 °C for 10 h, the product 3a also was
isolated in 80% yield (Table 1, entry 13). Thus, the most
suitable reaction conditions for the formation of 3a were
established (Table 1, entry 8).
dienyl azides 1j-1m (Table 2, entries 10-13) afforded
indoles 3 in good yields (70-89%). Furthermore, the
structure of compound 3g was unambiguously confirmed by
single-crystal X-ray analysis (Figure 1).
(8) (a) Yoshida, H.; Fukushima, H.; Ohshita, J.; Kunai, A. Angew. Chem.,
Int. Ed. 2004, 43, 3935. (b) Sha, F.; Huang, X. Angew. Chem., Int. Ed.
2009, 48, 3458. (c) Biehl, E. R.; Khanapure, S. P. Acc. Chem. Res. 1989,
22, 275. (d) Yoshida, H.; Shirakawa, E.; Honda, Y.; Hiyama, T. Angew.
Chem., Int. Ed. 2002, 41, 3247. (e) Yoshida, H.; Fukushima, H.; Ohshita,
J.; Kunai, A. J. Am. Chem. Soc. 2006, 128, 11040. (f) Liu, Z. J.; Shi, F.;
Martinez, P. D. G.; Raminelli, C. R.; Larock, C. J. Org. Chem. 2008, 73,
219. (g) Gilmore, C. D.; Allan, K. M.; Stoltz, B. M. J. Am. Chem. Soc.
2008, 130, 1558. (h) Yoshida, H.; Watanabe, M.; Fukushima, H.; Ohshita,
J.; Kunai, A. Org. Lett. 2004, 6, 4049.
Figure 1. Crystal structure of compound 3g.
To extend this protocol, several substituted ortho-silyl
aryltriflates 2b-2f were used as the substrates to perform
the reaction (Table 3). We were delighted to find that the
substituted arynes could also furnish the desired indoles
3n-3z in good yields (64-88%). It is noteworthy that 1,2-
naphthalyne (from 2d) and ortho-methoxy benzyne (from
(9) Cui, S. L.; Wang, J.; Wang, Y. G. J. Am. Chem. Soc. 2008, 130,
13526.
(10) (a) Chen, Z. B.; Hong, D.; Wang, Y. G. J. Org. Chem. 2009, 74,
903. (b) Yang, Y. Y.; Shou, W. G.; Chen, Z. B.; Wang, Y. G. J. Org.
Chem. 2008, 73, 3928. (c) Yang, Y. Y.; Shou, W. G.; Hong, D.; Wang,
Y. G. J. Org. Chem. 2008, 73, 3574.
(11) Liu, Z. J.; Larock, R. C. J. Org. Chem. 2007, 72, 223.
Org. Lett., Vol. 12, No. 20, 2010
4609

Table 3. Aryne Scope in Indole Synthesisa
Figure 2. Crystal structure of compound 3x.
Figure 3. Crystal structure of compound 3y.
form vinyl iminophosphorane A via the Staudinger-Meyer
reaction. A subsequently reacts with the in situ generated
benzyne to yield intermediate B by a nucleophilic double
cyclization. The reactive B is easily hydrolyzed to dihy-
a 1 (0.5 mmol), 2 (0.75 mmol), PPh3 (0.5 mmol), CsF (1.5 mmol),
toluene/CH3CN (1:1, 10 mL), 50 °C, air, 5 h. b Isolated yield refers to azide.
c Mixture of meta- and para-regioisomers (2.5:1).
Scheme 1. Possible Mechanism for the Formation of 3
2e) provided a single product, respectively (Table 3, entries
11 and 12). Furthermore, the complete regioselectivity of
the products 3x (Figure 2) and 3y (Figure 3) was unambigu-
ously confirmed by X-ray analysis. In the case of meta-
methyl benzyne (from 2f), the product 3z was observed as
a mixture of two isomers (2.5:1) in 84% yield (Table 3, entry
13).
On the basis of these results and the known chemistry of
arynes,13 a possible mechanism for this cascade process is
proposed (Scheme 1). First, azide 1a reacts with PPh3 to
(12) The 2-azidoacrylates employed herein were synthesized by the
condensation of an aromatic or cinnamic aldehyde with ethyl azidoacetate.
Indoles were produced by thermolysis or Rh2(II)-catalyzed decomposition
of 2-azidoacrylates. See: (a) Stokes, B. J.; Dong, H.; Leslie, B. E.; Pumphrey,
A. L.; Driver, T. G. J. Am. Chem. Soc. 2007, 129, 7500. (b) Hemetsberger,
H.; Knittel, D.; Weidmann, H. Monatsh. Chem. 1970, 101, 16.
(13) (a) Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127,
5340. (b) Huang, X.; Liu, Y.; Liang, Y.; Pi, S.; Wang, F.; Li, J. Org. Lett.
2008, 10, 1525. (c) Tambar, U. K.; Ebner, D. C.; Stoltz, B. M. J. Am. Chem.
Soc. 2006, 128, 11752. (d) Yoshida, H.; Watanabe, M.; Ohshita, J.; Kunai,
A. Chem. Commun. 2005, 3292.
4610
Org. Lett., Vol. 12, No. 20, 2010

droindole F and releases Ph3PO during the conventional
workup. Finally, the resulting F is immediately oxidized by
air to afford indole 3a. In our reactions, we isolated Ph3PO
as a byproduct. The reactive intermediate B was detected
by both HRMS (ESI) and 31P NMR trapping experiments
under N2 (see Supporting Information).
two-step strategy for access to 10H-indolo[1,2-a]indol-10-
ones, which are useful scaffolds for the synthesis of
biologically active compounds, is concise and highly ef-
ficient.
In conclusion, we demonstrated a mild and efficient
procedure for the synthesis of substituted indoles. In the
presence of CsF and PPh3, 2-azidoacrylates reacted with
ortho-silyl aryltriflates to afford the corresponding indole
derivatives in good yields. The reaction involves the forma-
tion of iminophosphorane and benzyne intermediates and a
subsequent double cyclization/hydrolysis/air-oxidation cas-
cade. Furthermore, the indole products could be easily
converted into 10H-indolo[1,2-a]indol-10-ones. The further
synthetic application of this methodology in more complex
settings is currently in progress.
A demonstration of the synthetic utility for this method
was shown in Scheme 2. Thus, treatment of indoles 3a, 3b,
Scheme 2. Synthesis of Indole-indolone 4
Acknowledgment. We thank the National Natural Science
Foundation of China (No. 20872128 and 20702047) and the
Fundamental Research Funds for the Central Universities
(2009QNA3011) for financial support.
and 3e with benzyne 2a in the presence of Cs2CO3 under
mild conditions afforded 10H-indolo[1,2-a]indol-10-ones 4a
(93% yield), 4b (85% yield), and 4c (82% yield), respec-
tively. The reaction is believed to proceed via a [3 + 2]
annulation of aryne and ethyl indole-2-carboxylates.14 This
Supporting Information Available: Detailed experimen-
1
tal procedures, characterizaton data, copies of H, 13C, and
31P NMR spectra, and crystallographic information file (CIF)
for compounds 3g, 3x, and 3y. This material is available
free of charge via the Internet at http://pubs.acs.org.
(14) (a) Giacometti, R.; Ramtohul, Y. Synlett 2009, 2010. (b) Rogness,
D.; Larock, R. C. Tetrahedron Lett. 2009, 50, 4003.
OL101934V
Org. Lett., Vol. 12, No. 20, 2010
4611