Direct functionalization of indoles: Copper-catalyzed malonyl carbenoid insertions

Article abstract of DOI:10.1021/ol1020948

Indoles, when treated with dimethyl diazomalonate under catalysis by Cu(acac)₂, undergo C-H insertion reactions regioselectively depending on the substitution pattern on the indole moiety. Indoles where the 3-position is substituted give high yields of the C2-H insertion product. Microwave conditions are also disclosed which show comparable yields with reduced reaction times.

Full text of DOI:10.1021/ol1020948

ORGANIC
LETTERS
2010
Vol. 12, No. 21
4956-4959
Direct Functionalization of Indoles:
Copper-Catalyzed Malonyl Carbenoid
Insertions
Michael B. Johansen and Michael A. Kerr*
Department of Chemistry, The UniVersity of Western Ontario,
London, Ontario, Canada N6A 5B7
makerr@uwo.ca
Received September 2, 2010
ABSTRACT
Indoles, when treated with dimethyl diazomalonate under catalysis by Cu(acac)2, undergo C-H insertion reactions regioselectively depending
on the substitution pattern on the indole moiety. Indoles where the 3-position is substituted give high yields of the C2-H insertion product.
Microwave conditions are also disclosed which show comparable yields with reduced reaction times.
Indole derivatives permeate pharmaceutical, agrochemical,
and functional material sciences, and as such the development
of mild, selective, and efficient derivatization protocols for
the synthesis of useful indoles remains a burgeoning field
of synthetic research.1 Effective C-H bond activation and
transition metal catalyzed cross coupling reactions continue
to grow in prominence as proficient modes of derivatization,
often excelling in efficiency.2 Since the early investigations3
on the decomposition of R-diazo esters to generate carbenes
or metal-stabilized carbenoids, their reactivity with indoles
has garnered attention as a unique method of functionaliza-
tion.4 More recently Qin has demonstrated the capability of
this mode of reactivity in the synthesis of a number of
(3) For representative examples see: (a) Jackson, R. W.; Manske, R. H.
Can. J. Res. 1935, 13B, 170. (b) Welstead, W. J. J.; Stauffer, H. F.; Sancilio,
L. F. J. Med. Chem. 1974, 17, 544. (c) Wenkert, E.; Alonso, M. E.; Gottlieb,
H. E.; Sanchez, E. L.; Pellicciari, R.; Cogolli, P. J. Org. Chem. 1977, 42,
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9608. (b) Humphrey, G. R.; Kuethe, J. T. Chem. ReV. 2006, 106, 2875. (c)
Cacchi, S.; Fabrizi, G. Chem. ReV. 2005, 105, 2873. (d) SundbergR. J.,
Indoles; Academic: New York, 1996.
(4) (a) Chan, W.-W.; Yeung, S.-H.; Zhou, Z.; Chan, A. S. C.; Yu, W.-
Y. Org. Lett. 2010, 12, 604. (b) Lian, Y.; Davies, H. M. L. Org. Lett. 2010,
12, 924. (c) Lian, Y.; Davies, H. M. L. J. Am. Chem. Soc. 2010, 132, 440.
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Trebbin, M.; Uggerud, E.; Hansen, T. Tetrahedron Lett. 2009, 50, 6506.
(f) Zhang, X.-J.; Liu, S.-P.; Yan, M. Chin. J. Chem. 2008, 26, 716. (g)
Zhang, B.; Wee, A. G. H. J. Chem. Soc., Chem. Commun. 2008, 39, 4837.
(h) Muthusamy, S.; Gnanaprakasam, B. Tetrahedron Lett. 2009, 49, 475.
(i) Song, H.; Yang, J.; Chen, W.; Qin, Y. Org. Lett. 2006, 8, 6011. (j)
Cuevas-Yan˜ez, E.; Muchowski, J. M.; Cruz-Almanza, R. Tetrahedron 2004,
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45, 4277. (l) Yadav, J. S.; Reddy, B. V. S.; Satheesh, G. Tetrahedron Lett.
2003, 44, 8331. (m) Muthusamy, S.; Gunanathan, C.; Babu, S. A.; Suresh,
E.; Dastidar, P. J. Chem. Soc., Chem. Commun. 2002, 824. (n) Jung, M. E.;
Slowinski, F. Tetrahedron Lett. 2001, 42, 6835. (o) Salim, M.; Capretta,
A. Tetrahedron 2000, 56, 8063. (p) Wood, J. L.; Stoltz, B. M.; Dietrich,
H.-J.; Pflum, D. A.; Petsch, D. T. J. Am. Chem. Soc. 1997, 119, 9641. (q)
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J. Org. Lett. 2010, 12, 1052. (b) Yang, L.; Zhao, L.; Li, C.-J. J. Chem.
Soc., Chem. Commun. 2010, 46, 4181. (c) Dudnik, A. S.; Gevorgyan, V.
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10.1021/ol1020948  2010 American Chemical Society
Published on Web 10/11/2010

impressive natural products.5 Herein, we report an economi-
cal, high yielding, and technically simple method for the
installation of a malonyl unit on the pyrrole portion of the
indole ring system.
the more facile C3 insertion. The results are summarized in
Table 1. Conditions adapted from our original study (entry
In 2002 we disclosed the reaction of dimethyl diazoma-
lonate 6 with a variety of indoles under dirhodium tetraac-
etate catalysis to give N1, C2, or C3 malonyl indoles,
depending on original substrate substitution patterns.6 Our
interest in this type of reaction was driven by a desire to
access, by total synthesis, indole natural products bearing
an acetyl (or malonyl) moiety at the indole 2-position. Figure
1 illustrates some representative compounds which have
piqued our interest.
Table 1. Optimization Studies
entry solvent temp
time
catalyst (mol %) 6:5a 7aa
1
2
3
CH2Cl2 rt
CH2Cl2 rt
CH2Cl2 rt
7.5 h
24 h
24 h
Rh2(OAc)4 (10) 1:1
37%
NR
NR
Cu(acac)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:2
4
toluene reflux 1 h
NDb
64%
75%
76%
82%
90%
5
6
toluene reflux 40 min Cu(acac)2 (10)
benzene reflux 75 min Cu(acac)2 (10)
7
8
9
10
benzene reflux 2 h
benzene reflux 6 h
benzene reflux 4 h
benzene reflux 6 h
Cu(acac)2 (5)
Cu(acac)2 (1)
Cu(acac)2 (1)
Cu(acac)2 (1)
1:1.5 88%
a Yield of isolated products. b Yield not determined. Complex mixture
1
resulted with 7a as a minor component as observed by H NMR.
1) gave moderate amounts of 7a after 7.5 h. Substituting
copper catalysts known to promote carbenoid formation gave
no desired product after extended reaction times at room
temperature (entries 2 and 3).10
When more vigorous reaction conditions were employed
(entries 4 and 5) the copper catalysts began to display
reactivity in carbenoid formation and C2-H insertion in
reduced reaction times, though Cu(OTf)2 (entry 4) provided
an intractable mixture of compounds with 7a formed in small
amounts. Entry 5 showed the most promise with Cu(acac)2
providing 7a in the highest yield observed thus far. By
utilizing a lower boiling solvent (entry 6) a moderate increase
in yield was again observed.
Decreasing the catalyst loading to 1% provided another
increase in yield of 7a to 82% with only a slight increase in
reaction time. Upon adjusting the ratio of dimethyl diaz-
omalonate 6 to N-methyl skatole 5a to 1:2 a maximum yield
of 7a was observed. Adjusting the ratio of the indole
component once more showed negligible change in the
reaction, and we chose these conditions as optimal for the
insertion of the malonyl carbenoid into the C2-H position
of 3-substituted indoles (entry 10).
With optimal conditions in hand, we surveyed indole
substrates which bore substitution at the various positions
of the indole ring system (Table 2). We first examined the
effects of substitution at the 2- and 3-positions (indole
numbering) and were pleased to find, in general, that the
new conditions provided the desired malonyl indoles in
greatly increased yields in comparison to those previously
observed by us. The lowest yield (while still acceptable) was
observed for a substrate bearing an electron-withdrawing
Figure 1. Indole natural products containing a 2 and/or 3 acetate
moiety.
In addition to their presence in natural products, the
2-malonyl indole has been integral as an important interme-
diate as demonstrated by total syntheses completed by
Overman7 and Fukuyama.8 They have also appeared in
biosynthetic proposals of natural products.9
At the outset of our 2002 study, a few limitations became
clear. While the reaction excelled at the installation of a
malonate moiety in the 3-position of unsubstituted indoles,
moderate or low yields were obtained from 2- and 3-sub-
stituted indoles to give the corresponding 3- or 2-malonyl
indoles, respectively.
We commenced our study by screening reaction conditions
for the carbenoid insertion of dimethyl diazomalonate 6 into
the 2-position of N-methyl skatole 5a. We selected this indole
substrate since we expected C2 insertion to be the more
difficult process (with respect to C3 insertion) and an optimal
set of conditions with this substrate would likely excel at
(5) (a) Zhang, M.; Huang, X.; Shen, L.; Qin, Y. J. Am. Chem. Soc.
2009, 131, 6013. (b) Shen, L.; Zhang, M.; Qin, Y. Angew. Chem., Int. Ed.
2008, 47, 3618. (c) He, B.; Song, H.; Qin, Y. J. Org. Chem. 2009, 74, 298.
(d) Yang, J.; Wu, H.; Shen, L.; Qin, Y. J. Am. Chem. Soc. 2007, 129, 13794.
(6) Gibe, R.; Kerr, M. A. J. Org. Chem. 2002, 67, 6247.
(7) Martin, C. L.; Overman, L. E.; Rhode, J. M. J. Am. Chem. Soc.
2010, 132, 4894.
(8) Kaburagi, Y.; Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2004,
126, 10246.
(10) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds: From Cyclopropanes to
Ylides; John Wiley & Sons: New York, 1998.
(9) For example see: Lim, K.-H.; Kam, T.-S. Org. Lett. 2006, 8, 1733.
Org. Lett., Vol. 12, No. 21, 2010
4957

Table 2. Scope of Malonyl C-H Insertion
a Yield of isolated products. b Reaction run on 0.6 mmol scale. c Reaction run on 8.7 mmol scale.
ester moiety at the 2-position (entry 7). This is likely due to
the attenuated reactivity of the electron-poor indole toward
the electrophilic carbenoid.
Next, the effects of N-substitution were examined. Sur-
prisingly, N-tosyl and N-Boc indole (entries 8 and 9) gave
appreciable yields of products. This may be considered
4958
Org. Lett., Vol. 12, No. 21, 2010

unusual since N-tosylation greatly limits the nucleophilic
reactivity of indoles. As expected substitution occurs at the
3-position of the indole where possible (entries 8-12);
however, in cases where this position is occupied, 2-sub-
sitution occurs in a facile fashion (entry 13). It is interesting
to note that in contrast to our previously reported Rh-
catalyzed process where N-H insertion was a major product
when unprotected skatole was the substrate, little N-substitu-
tion was observed under the present copper-catalyzed condi-
tions (entry 13).11
Table 3. Microwave-Promoted C-H Insertions
Substitution on the benzenoid portion of the indole was
surprisingly well tolerated in most cases. Both electron-
withdrawing (entries 14-16) and electron-donating moieties
(entries 17 and 18) were well behaved. The low yield
observed for entry 17 is anamolous, but greater than 85%
of the unreacted indole starting material could be recovered
from the reaction, suggesting that multiple reaction cycles
could provide higher yields.12
In an effort to decrease reaction times, we explored the
carbenoid insertion reaction under microwave irradiation
conditions. By adjusting the reaction temperature to 100 °C
and employing microwave conditions we found that the
desired malonyl indoles could be obtained in comparable
yields in only 2 h (Table 3).
In summary, we have developed conditions for the
Cu(acac)2-catalyzed malonyl carbenoid insertion into
indole substrates, which excels for a variety of substitution
patterns and functional groups. The reaction proceeds with
a high degree of regiocontrol and can be accelerated under
microwave irradiation conditions. Applications of this
reaction in total synthesis endeavors are currently under-
way in our laboratories, and will be presented in due
course.
Acknowledgement. We thank the Natural Sciences and
Engineering Research Council of Canada for funding. We
thank Mr. Doug Hairsine of the University of Western
Ontario mass spectrometry facility for performing MS
analyses. M.B.J. is a NSERC CGS-D awardee.
Supporting Information Available: Full experimental
procedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL1020948
(11) Less than 10% N-H carbenoid insertion as observed by 1H
NMR.
a Yield of isolated products.
(12) 85% recovered 5q based on expected return, given 55% 7q iso-
lated.
Org. Lett., Vol. 12, No. 21, 2010
4959