Copper-catalyzed annulation of α-substituted diazoacetates with 2-ethynylanilines: The direct synthesis of C2-functionalized indoles

Article abstract of DOI:10.1039/c3ob42350f

Copper-catalyzed direct annulation of α-substituted diazoacetates with 2-ethynylanilines leading to C2-functionalized indoles was achieved under mild reaction conditions. The C2-(carboxylate methyl) substituted indoles were obtained in moderate to high yi

Full text of DOI:10.1039/c3ob42350f

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
COMMUNICATION
Copper-catalyzed annulation of α-substituted
diazoacetates with 2-ethynylanilines: the direct
synthesis of C2-functionalized indoles†
Cite this: Org. Biomol. Chem., 2014,
12, 1387
Received 25th November 2013,
Accepted 13th January 2014
Gang Liu, Guangyang Xu, Jian Li, Dong Ding and Jiangtao Sun*
DOI: 10.1039/c3ob42350f
www.rsc.org/obc
Copper-catalyzed direct annulation of α-substituted diazoacetates heterocyclics5 including indole has been reported recently.6 In
with 2-ethynylanilines leading to C2-functionalized indoles was 2010, Yu et al. reported a ruthenium-catalyzed C2-selective car-
achieved under mild reaction conditions. The C2-(carboxylate benoid functionalization of indoles by α-aryldiazoesters
methyl) substituted indoles were obtained in moderate to high (Scheme 1, route a).7 At nearly the same time, Kerr et al.
yields. In addition, this procedure tolerates a series of N-substi- reported copper-catalyzed malonyl carbenoid insertion toward
tuted and free substituted 2-ethynylanilines.
the synthesis of C2 functionalized indoles (Scheme 1, route
b).8 However, those approaches need two steps of synthesis
toward the C2-(carboxylate methyl) substituted indole scaffold,
namely the pre-synthesis of indole substrates and the follow-
ing metal-catalyzed C2-functionalization. Clearly, it is of sig-
nificance to develop a straightforward pathway to access this
C2-(carboxylate methyl) functionalized nucleus.
In 2004, Fu et al. described the CuI-catalyzed coupling reac-
tion of terminal alkynes with diazoacetates, which delivered
the alkynoates under mild reaction conditions.9 Later, Fox
et al. reported the Cu(II) (trifluoroacetylacetonate)2/3,6-di-
(2-pyridyl)-s-tetrazine-catalyzed method for coupling of diazo
compounds with terminal alkynes to give substituted alleno-
ates in the presence of potassium carbonate.10 Based on the
previous reports and our own investigations,11 we postulated
that the combination of copper-catalyzed coupling of terminal
alkynes with α-aryl-diazo compounds followed by intramolecu-
lar cyclization would probably give the C2-(carboxylate methyl)
substituted indoles in one step. Herein, we report the
The indole nucleus is one of the most common motifs found
in bioactive natural products and numerous pharmaceuti-
cals.1,2 Among the functionalized indoles, the C2-substituted
indoles have attracted much attention since they are good can-
didates for various transformations.3 Moreover, the C2-(carboxy-
late methyl) substituted indole motifs have been found in
many biologically active natural products (Fig. 1).4 And thus
many efforts have been made toward simple and selective
methods to access this type of indoles. In another part, the
utilization of α-diazo compounds as precursors to access the
Fig. 1 Natural products containing the 2-(carboxylate methyl)-indole
moiety.
School of Pharmaceutical Engineering & Life Science, Changzhou University,
Changzhou 213164, P. R. China. E-mail: jtsun08@gmail.com;
Fax: +86 519 86334598; Tel: +86 519 86334597
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3ob42350f
Scheme 1 Previous pathways and our design plan leading to C2-(car-
boxylate methyl) substituted indole.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 1387–1390 | 1387

View Article Online
Communication
Organic & Biomolecular Chemistry
Table 1 Optimization of reaction conditionsa
Entry
[Cu] (mol%)
R (alkyne)
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
CuI (5)
CuI (5)
CuI (5)
CuI (5)
CuBr (5)
CuCl (5)
Cu(OAc)2 (5)
Cu(OTf)2 (5)
Cu(acac)2 (5)
CuI (5)
CuI (5)
CuI (10)
CuI (5)
H (1a)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
DMF
50 (1aa)
70 (2aa)
72 (3aa)
54 (4aa)
63 (3aa)
62 (3aa)
<5 (3aa)
<5 (3aa)
<5 (3aa)
52 (3aa)
23 (3aa)
74 (3aa)
30 (3aa)
25 (3aa)
Ts (2a)
Ac (3a)
Boc (4a)
Ac (3a)
Ac (3a)
Ac (3a)
Ac (3a)
Ac (3a)
Ac (3a)
Ac (3a)
Ac (3a)
Ac (3a)
Ac (3a)
9
10c
11d
12e
13
14
CuI (5)
a Reaction conditions: to
a 10 mL Schlenk tube was added
ethynylphenylamine (1.0 mmol), copper catalyst (0.05 mmol) and
CH3CN (2 mL) under a nitrogen atmosphere. Then the diazo substrate
(1.1 mmol) in CH3CN (1 mL) was added into the reaction mixture and
was stirred at 60 °C for 3 hours. b Isolated yield. c Reaction temperature
is 80 °C. d Reaction temperature is 25 °C. e Reaction time is 1 hour.
Scheme 2 Substrate scope. To a 10 mL Schlenk tube was added ethynyl-
phenylamine (1.0 mmol), CuI (0.05 mmol) and CH3CN (2 mL) under a
nitrogen atmosphere. Then 5a (1.1 mmol) in CH3CN (1 mL) was added
and the whole mixture was stirred at 60 °C for 3 hours. Isolated yield.
utilization of this strategy to access this type of compound
under mild reaction conditions.
Initially, we tested the reaction of α-phenyl diazoacetate 5a
with amines (Table 1, 1a to 4a) in the presence of CuI (5 mol%)
in acetonitrile at 60 °C. Treatment of ethynylaniline 1a with 5a
gave the indole in moderate yield (Table 1, entry 1), while N- electron-withdrawing substitutes had a negative effect and the
protected ethynylanilines (2a to 4a) afforded the corresponding indoles were obtained in moderate yields (Scheme 2, 3fa to
indoles in higher yields (Table 1, entries 2–4). CuBr displayed 3ia).
a similar catalytic reactivity compared with CuI but with a
Next, the reaction of various amines and diazo compounds
lower yield (Table 1, entry 5). Other copper catalysts gave very was examined under the optimized reaction conditions
low yields (Table 1, entries 7 to 9). High reaction temperature (Scheme 3). As observed, the free substituted anilines gave the
resulted in low isolated yield (Table 1, entry 10). The reaction corresponding indoles in lower yields compared with N-pro-
was sluggish when it had been conducted at room temperature tected ones (Scheme 3, 1ab–1ad vs. others). For the α-aryl
(Table 1, entry 11, 23% yield). Higher catalyst loading (10 mol% diazo substrates, the indoles were obtained in moderate to
CuI) gave slightly higher yield and shorter reaction time high yields for all the cases. Generally, the ethynylanilines
(Table 1, entry 12). For the solvents examined, DMF and bearing strong electron-withdrawing substitutes gave the
dichloromethane gave the product in a much lower yield indoles in lower yields compared with electron-donating or
(Table 1, entries 13 and 14). So we chose CuI (5 mol%) in weak electron-withdrawing substituted anilines (Scheme 3, 3ib
acetonitrile at 60 °C as the optimized reaction condition for vs. others). In addition, the α-benzyl diazoacetate also gave the
further investigations.
indoles in high yields (Scheme 3, 2af and 3af). Moreover, the
With the optimized reaction conditions in hand, the chiral diazoesters were also examined in the reaction. 3ag was
different substituted ethynylanilines for this cyclization were obtained in 71% yield with two isomers in a 1 : 1 ratio and 3ah
studied. As expected, both electron-donating and electron- was obtained in 76% yield with a 1.5 : 1 ratio.
withdrawing substituted ethynylanilines tolerated well under
Although the mechanism remains unclear currently, based
this procedure (Scheme 2). The N-Ac-protected ethynylanilines on the pioneering studies of Fu, Fox and ourselves, a proposed
gave higher yields than the N-Ts-protected ethynylanilines mechanism was outlined in Fig. 2. As mentioned by Fu et al.,
(Scheme 2, 3ca vs. 2ba). For the N-Ac-protected ethynylanilines, the reaction of alkynes with diazoesters catalyzed by CuI in
the electron-donating substitutes had a positive effect on the acetonitrile delivered the alkynoates as major products (Fig. 2,
reaction reactivity and the corresponding indoles were route a).9 Fox et al. examined the reaction of copper acetylide
obtained in high yields (Scheme 2, 3ba to 3ea). In contrast, the with phenyl diazoacetate, which did not give any allenoate
1388 | Org. Biomol. Chem., 2014, 12, 1387–1390
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Communication
Fig. 2 Proposed reaction mechanism.
We gratefully acknowledge the National Natural Science
Foundation of China (21172023), the Jiangsu Yabang Pharma-
ceutical Group and a project funded by the Priority Academic
Program Development of Jiangsu Higher Education Insti-
tutions (PAPD) for their financial support.
Scheme 3 Substrate scope. To a 10 mL Schlenk tube was added ethy-
nylphenylamine (1.0 mmol), CuI (0.05 mmol) and CH3CN (2 mL) under a
nitrogen atmosphere. Then 5 (1.1 mmol) in CH3CN (1 mL) was added
and the whole mixture was stirred at 60 °C for 3 hours. Isolated yield.
The d.r. ratio was determined by NMR analysis of crude compounds for
3ag and 3ah. The absolute configuration was not assigned.
Notes and references
1 (a) M. Somei and F. Yamada, Nat. Prod. Rep., 2004, 21, 278;
(b) T. Kawasaki and K. Higuchi, Nat. Prod. Rep., 2005, 22,
73; (c) A. J. Kochanowska-Karamyan and M. T. Hamann,
Chem. Rev., 2010, 110, 4489; (d) M. Ishikura, T. Abe,
T. Choshi and S. Hibino, Nat. Prod. Rep., 2013, 30, 694;
(e) M. Inman and C. J. Moody, Chem. Sci., 2013, 4, 29.
product (Fig. 2, route b).10 So their observation provided
support for the mechanism that did not involve initial for-
mation of copper acetylide. Our recent study also disclosed
that the presence of a base played an important role in the
selective formation of alkynoates and allenoates.11
For the plausible reaction mechanism, we postulated that
the reaction of CuI with α-diazoacetate generates carbenoid A
(Fig. 2, route c). Subsequent reaction with ortho-alkyne-aniline
affords the formation of intermediate B, which undergoes the
leaving of the copper complex accompanied by hydrogen
migration to give the intermediate C. Subsequent copper-cata-
lyzed annulation delivers the indole product.
In conclusion, we have developed a simple and efficient
approach to access the C2-(carboxylate methyl) substituted
indoles with good functional group tolerance under mild reac-
tion conditions. The indoles were obtained in moderate to
high isolated yields. Efforts to expand the strategy to new reac-
tions and to elucidate the mechanism in detail are underway.
2 For recent reviews on indole synthesis, see: (a) S. Cacchi
and G. Fabrizi, Chem. Rev., 2005, 105, 2873;
(b) G. R. Humphrey and J. T. Kuethe, Chem. Rev., 2006, 106,
2875; (c) S. Cacchi and G. Fabrizi, Chem. Rev., 2011, 111,
PR215; (d) R. Vicente, Org. Biomol. Chem., 2011, 9, 6469;
(e) D. F. Taber and P. K. Tirunahari, Tetrahedron, 2011, 67,
7195; (f) M. Shiri, Chem. Rev., 2012, 112, 3508; Selected
examples on indole synthesis, see:
(g) W. Geng,
W.-X. Zhang, W. Hao and Z. Xi, J. Am. Chem. Soc., 2012,
134, 20230; (h) D. R. Stuart, M. Bertrand-Laperle,
K. M. N. Burgess and K. Fagnou, J. Am. Chem. Soc., 2008,
130, 16464; (i) S. P. Breazzano, Y. B. Poudel and
D. L. Boger, J. Am. Chem. Soc., 2013, 135, 1600;
( j) A. Porcheddu, M. G. Mura, L. De Luca, M. Pizzetti and
M. Taddei, Org. Lett., 2012, 14, 6112; (k) D. Shu,
G. N. Winston-McPherson, W. Song and W. Tang, Org. Lett.,
2013, 15, 4162; (l) W. Gati, F. Couty, T. Boubaker,
M. M. Rammah, M. B. Rammah and G. Evano, Org. Lett.,
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 1387–1390 | 1389

View Article Online
Communication
Organic & Biomolecular Chemistry
2013, 15, 3122; (m) T. Nanjo, C. Tsukano and Y. Takemoto,
Org. Lett., 2012, 14, 4270; (n) D. McAusland, S. Seo,
D. G. Pintori, J. Finlayson and M. F. Greaney, Org. Lett.,
2011, 13, 3667; (o) G. Qiu, Q. Ding, H. Ren, Y. Peng and
J. Wu, Org. Lett., 2010, 12, 3975; (p) B. M. Trost and
A. McMlory, Angew. Chem., Int. Ed., 2007, 46, 2074.
3 (a) H. Ohno, Y. Ohta, S. Oishi and N. Fujii, Angew. Chem.,
Int. Ed., 2007, 46, 2295; (b) S. Cacchi, G. Fabrizi,
A. Goggiamani, A. Perboni, A. Sferrazza and P. Stabile, Org.
Lett., 2010, 12, 3279; (c) Z. Chen, D. Zheng and J. Wu, Org.
Lett., 2011, 13, 848; (d) S. Pan, N. Ryu and K. Shibata, J. Am.
Chem. Soc., 2012, 134, 17474; (e) Y. Ohta, S. Oishi, N. Fujii
and H. Ohno, Org. Lett., 2009, 11, 1979; (f) H. Song, Y. Liu
and Q. Wang, Org. Lett., 2013, 15, 3274; (g) S. Cacchi,
G. Fabrizi, A. Goggiamani, C. Molinaro and R. Verdiglione,
J. Org. Chem., 2014, 79, 401.
4 (a) Y. Kaburagi, H. Tokuyama and T. Fukuyama, J. Am.
Chem. Soc., 2004, 126, 10246; (b) C. L. Martin,
L. E. Overman and J. M. Rhode, J. Am. Chem. Soc., 2010,
132, 489; (c) H. Gotoh, J. E. Sears, A. Eschenmoser and
D. L. Boger, J. Am. Chem. Soc., 2012, 134, 13240.
5 (a) Z. Guo, M. Cai, J. Jiang, L. Yang and W. Hu, Org. Lett.,
2010, 12, 652; (b) Y. Zhu, C. Zhai, L. Yang and W. Hu,
Chem. Commun., 2010, 46, 2865; (c) H. Wang, J. R. Denton
and H. M. L. Davies, Org. Lett., 2011, 13, 4316; (d) M. Li,
L. Zan, D. Prajapati and W. Hu, Org. Biomol. Chem., 2012,
10, 8808; (e) X. Xu, P. Y. Zavalij, W. Hu and M. P. Doyle,
Chem. Commun., 2012, 48, 11522; (f) X. Zhang, J. Ji, Y. Zhu,
C. Jing, M. Li and W. Hu, Org. Biomol. Chem., 2012, 10,
Y.-M. Liang, Chem. Commun., 2013, 49, 561; ( j) X. Xu,
P. Y. Zavalij, W. Hu and M. P. Doyle, J. Org. Chem., 2013, 78,
1583; (k) S. Liu, B. Ren, X. Ma, X. Guo, F. Lv, X. Wu and
W. Hu, Angew. Chem., Int. Ed., 2013, 52, 1539; (l) C. Qin
and H. M. L. Davies, J. Am. Chem. Soc., 2013, 135, 14516;
(m) H. Wang, G. Li, K. M. Engle, J.-Q. Yu and
H. M. L. Davies, J. Am. Chem. Soc., 2013, 135, 6774;
(n) W.-W. Chan, T.-L. Kwong and W.-Y. Yu, Org. Biomol.
Chem., 2012, 10, 3749; (o) J. M. Fraile, K. Le Jeune,
J. A. Mayoral, N. Ravasio and F. Zaccheria, Org. Biomol.
Chem., 2013, 11, 4327; (p) L. Qiu, X. Guo, J. Zhou, S. Liu,
L. Yang, X. Wu and W. Hu, RSC Adv., 2013, 3, 20065.
6 (a) Y. Nakamura and T. Ukita, Org. Lett., 2002, 4, 2317;
(b) L. Zhou and M. P. Doyle, J. Org. Chem., 2009, 74,
9222; (c) S.-L. Cui, J. Wang and Y.-G. Wang, J. Am. Chem.
Soc., 2008, 130, 13526; (d) M. A. Honey, A. J. Blake,
I. B. Campbell, B. D. Judkins and C. J. Moody, Tetrahe-
dron, 2009, 65, 8995; (e) B. V. S. Reddy, M. R. Reddy,
Y. G. Rao, J. S. Yadav and B. Sridhar, Org. Lett., 2013,
15, 464; Selected examples for the use of N-tosylhydra-
zone as the diazo precursor, see: (f) L. Zhou, Y. Shi,
Q. Xiao, Y. Liu, F. Ye, Y. Zhang and J. Wang, Org. Lett.,
2011, 13, 968; (g) T. Xiao, X. Dong and L. Zhou, Org.
Biomol. Chem., 2013, 11, 1490.
7 W.-W. Chan, S.-H. Yeung, Z. Zhou, A. S. C. Chan and
W.-Y. Yu, Org. Lett., 2010, 12, 604.
8 M. B. Johansen and M. A. Kerr, Org. Lett., 2010, 12, 4956.
9 A. Suárez and G. C. Fu, Angew. Chem., Int. Ed., 2004, 43,
3580.
2133; (g) X. Guo and W. Hu, Acc. Chem. Res., 2013, 46, 2427; 10 M. Hassink, X. Liu and J. M. Fox, Org. Lett., 2011, 13, 2388.
(h) Y. Qian, P. Y. Zavalij, W. Hu and M. P. Doyle, Org. Lett., 11 (a) J. Li, D. Ding, L. Liu and J. Sun, RSC Adv., 2013, 3,
2013, 15, 1564; (i) P.-X. Zhou, Z.-Z. Zhou, Z.-S. Chen,
Y.-Y. Ye, L.-B. Zhao, Y.-F. Yang, X.-F. Xia, J.-Y. Luo and
21260; (b) G. Liu, J. Li, L. Qiu, L. Liu, G. Xu, B. Ma and
J. Sun, Org. Biomol. Chem., 2013, 11, 5998.
1390 | Org. Biomol. Chem., 2014, 12, 1387–1390
This journal is © The Royal Society of Chemistry 2014