Site-Selective Addition of Maleimide to Indole at the C-2 Position: Ru(II)-Catalyzed C-H Activation

Article abstract of DOI:10.1021/acs.orglett.5b01809

Synthesis of 3-(indol-2-yl)succinimide derivatives is presented using a directing group strategy. Selective functionalization of C-2 in the presence of highly reactive C-3 in indole derivatives has been achieved. A conjugate addition product instead of He

Full text of DOI:10.1021/acs.orglett.5b01809

Letter
pubs.acs.org/OrgLett
Site-Selective Addition of Maleimide to Indole at the C‑2 Position:
Ru(II)-Catalyzed C−H Activation
Veeranjaneyulu Lanke, Kiran R. Bettadapur, and Kandikere Ramaiah Prabhu*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, Karnataka, India
S
* Supporting Information
ABSTRACT: Synthesis of 3-(indol-2-yl)succinimide deriva-
tives is presented using a directing group strategy. Selective
functionalization of C-2 in the presence of highly reactive C-3
in indole derivatives has been achieved. A conjugate addition
product instead of Heck-type product has been brought about
by careful selection of the alkene partner (maleimides and
maleate esters) such that a β-hydride elimination is avoided.
he succinimide class of organic molecules are important
intermediates in large molecule synthesis.1 Derivatives of
Scheme 1. Directing Group Mediated Conjugate Addition
T
succinimide rings are structural units found in many natural
products and clinical drug candidates, indicating that molecules
of this class possess a wide range of biological and pharmaceutical
activities (see Figure 1).2 Moreover, succinimides can be easily
Many examples of directing groups and various catalytic
systems to effect such transformations are well-known in the
literature;9 however, applications toward selective functionaliza-
tion of indole moieties remain rare.10 When used as coupling
partners with Ru(II) catalysts, alkenes typically result in Heck-
type product formation by a β-hydride elimination.11 We
hypothesized that alkenes that do not furnish a “syn planar” β-
hydrogen to the metal would not have the ability to undergo β-
hydride elimination and, therefore, would lead to conjugate
addition products.12 In continuation of our previous work13 on
the selective functionalization of indole, herein we report the C-2
succinimidation of N-benzoylindole derivatives using [Ru(p-
cymene)Cl2]2 catalyst.
Figure 1. Succinimide rings in various natural products, drug candidates,
and pharmaceutically active compounds.
reduced into 5-membered pyrrolidine rings, γ-lactams and
lactims, which by themselves are useful natural product motifs.3
The indole ring is abundant among natural products,
pharmacologically active compounds, and many commercially
marketed drugs.4 The importance of developing methods to
synthesize indole derivatives can never be overestimated, as
indicated by the large number of reports appearing consistently
in journals from the past several decades.5
Synthesis of succinimides, via conjugate addition using the
high reactivity of C-3, is known in the literature.6 However, such
conjugate addition at the C-2 position of indole in the presence
of an unblocked C-3 position is difficult to achieve. To overcome
this problem, we envisaged the use of C−H activation
methods.7,8 Such selective functionalization is possible by using
a directing group strategy with transition-metal catalysts
(Scheme 1).9
The optimization studies began with N-benzoylindole (1a)
and N-benzylmaleimide (2a) as the model substrates. The first
reaction between 1a (0.2 mmol) and 2a (2 equiv) was performed
in the presence of 5 mol % of [Ru(p-cymene)Cl2]2 catalyst, 20
Received: June 23, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01809
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Letter
mol % of AgSbF6, and 1.0 equiv of Cu(OAc)2·H2O in DCE (2
mL) at 80 °C to yield the desired product 3aa in 44% NMR yield
(entry 1, Table 1). By decreasing the amount of 2a to 1.5 equiv,
derivatives (1) as well as maleimide derivatives (2) (Scheme 2).
Halogenated derivatives of N-benzoyl indole (1b, 1c, and 1d)
a,b
Scheme 2. Substrate Scope with Maleimides
a
Table 1. Optimization Studies
a
Reaction conditions: N-benzoylindole derivative (1 equiv), mal-
eimide (2 equiv), [Ru(p-cymene)Cl2]2 (5 mol %), AgSbF6 (20 mol
%), Cu(OAc)2·H2O (1 equiv), AcOH (10 equiv), DCE (2 mL), 120
°C, 24 h. Isolated yields. [Rh(C5Me5)Cl2]2 was used instead of
[Ru(p-cymene)Cl2]2.
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), [Ru(p-
cymene)Cl2]2 (5 mol %), AgSbF6 (20 mol %), Cu(OAc)2·H2O (1
equiv), DCE (2 mL), 24 h. NMR yields using terephthaldehyde as
internal standard. 1.5 equiv of 2a. 10 mol % of Ru. Under argon
b
b
c
c
d
e
atmosphere for 24 h. nd, not detected.
we found that the yield of 3aa dropped to 40%. Increasing the
temperature of the reaction to 100 °C led to a yield of 62% (entry
3, Table 1). Further increase of the temperature to 120 °C
resulted in a marginal increase in the yield to 65% (entry 4). In
order to improve the yield of the product 3aa, the effect of
various additives was examined. Use of pivalic acid (10 equiv) led
to a decrease in the yield (40%, entry 5) of the product, whereas
use of acetic acid (10 equiv) led to an increase in the yield to 80%
(entry 6). A decrease in the amount of AcOH to 5 equiv also led
to a decrease of the yield of 3aa (60%, entry 7). Using AcOH as a
cosolvent was detrimental to the outcome of the reaction (56%,
entry 8), whereas water as an additive in place of AcOH resulted
in decreased yields (62%, entry 9). Increasing the catalyst loading
to 10 mol % decreased the yield to 70% (entry 10). The reaction
conditions of entry 6 were found to give an inconsistent yield.
This problem was circumvented by performing the reaction
under inert conditions and refraining from opening the reaction
vial until 24 h had passed (84%, entry 11). Screening a variety of
solvents such as CH3CN, DMF, DCM, or CHCl3 did not result
in any improvement (entries 12−14). A few control studies
(entries 15−17) indicate that Cu(OAc)2·H2O is essential for this
redox-neutral reaction. However, its role is uncertain, and we
believe it is a source of acetate ion and also activates the
electrophile by Lewis acid catalysis.
when reacted with N-benzylmaleimide (2a) furnished the
requisite products (3ba, 3ca, and 3da) in good yields without
any loss of the halogen atom. Electron-rich 5-methoxy derivative
1e underwent the reaction with 2a in a smooth manner to furnish
the desired product 3ea in 66% yield. The electron-neutral
derivative (5-phenyl) of N-benzoylindole, 3f, also reacted with 2a
to yield the corresponding product 3fa in moderate yield (50%).
The electron-deficient (5-methoxycarbonyl) derivative of N-
benzoylindole (1g) also underwent a smooth reaction to form
the corresponding product (3ga) in good yields without any
trace of product obtained by the competing reaction with the
ester as directing group. Changing the maleimide derivative from
N-benzyl to N-ethyl (2b) and N-phenyl (2c) also furnished the
corresponding products 3ab and 3ac in good yields (68% and
62%, respectively). However, the 1,4-addition reaction of
maleimide derivatives (2a, 2b, and 2c) with N-benzoylpyrrole
derivatives resulted in poor yields under the optimal conditions.
This problem was overcome by modifying the optimal
conditions, wherein [Rh(C5Me5)Cl2]2 was used instead of
[Ru(p-cymene)Cl2]2, and the corresponding C-2-substituted
products (3ha, 3hb, and 3hc) were obtained in moderate yields
(54%, 44%, and 47%, respectively). In cases of low yields, we
found extensive decomposition of the starting material under the
reaction conditions.
On the basis of these screening studies, the standard reaction
condition was established (entry 11, Table 1), and an exploration
of substrate scope was undertaken with a variety of indole
The scope of this reaction was further extended by performing
a reaction of a variety of indole derivatives with n-butyl and
methyl esters of maleic acid (2d, 2e) under the optimal
B
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Letter
a
conditions (Scheme 3). In these reactions, we were pleased to
find the corresponding adducts were obtained in good yields.
Scheme 5. Synthetic Applications
a,b
Scheme 3. Substrate Scope with Maleate Esters
a
Conditions: 3aa/3ad (0.37 mmol), LAH (1.1 mmol), THF (2 mL),
room temperature. Values in parentheses indicate isolated yields.
observed that the benzoyl group was cleaved in situ by reduction
with LAH, thereby saving a further deprotection step.
In order to gain some understanding of the mechanism,
methyl acrylate was used instead of maleimide or maleate under
the optimal conditions, and it furnished the Heck coupled
product (6, Scheme 6). The terminal step of a Heck reaction is β-
Scheme 6. Maleimide and Maleate vs Acrylate
a
Reaction conditions: N-benzoylindole derivative (1 equiv), maleate
ester (2 equiv), [Ru(p-cymene)Cl2]2 (5 mol %), AgSbF6 (20 mol %),
Cu(OAc)2·H2O (1 equiv), AcOH (10 equiv), DCE (2 mL), 120 °C,
b
24 h. Isolated yields.
Halogenated, electron-rich, electron-neutral, as well as electron-
deficient N-benzoylindole derivatives reacted in a smooth
manner with dibutylmaleate (2d) to yield the corresponding
diester adducts (3ad, 3bd, 3cd, 3dd, 3ed, 3fd, and 3gd) in good
to excellent yields (68%, 81%, 77%, 62%, 75%, 62%, and 78%,
respectively). The reaction was found to be equally efficient
when 2d was replaced with dimethylmaleate (2e), leading to the
formation of the products 3ae and 3be in good yields (67% and
79%, respectively).
Succinimide rings can be cleaved by using selective reagents to
generate a wide variety of useful functional groups like
dicarboxylic acids, diamides, diols, hydrazides, etc. (Scheme
4).14 They can be reduced to form useful pyrrodinyl rings using
hydride elimination leading to the formation of an alkene.
Moreover, the β-hydride has to be in a syn-periplanar orientation
with the metal center. Therefore, we propose that maleimide and
maleate do not provide this β-hydrogen atom in a syn-periplanar
fashion. Although this is easy to visualize in the case of maleimide
(rigid 5-membered ring, int1a)15 it is counterintuitive in maleate
ester, which is expected to possess conformational flexibility.
However, a proposed formation of int1b leads to the formation
of a conformationally rigid ring wherein the β-hydrogen is not
syn-periplanar to the Ru(II) center (Scheme 7).
Scheme 4. Opening of Succinimide Ring14
In conclusion, we have herein presented a novel regioselective
addition reaction of the indole C-2 position to maleimide leading
Scheme 7. Proposed Mechanism
strong reducing agents such as LAH. Since such applications have
not been reported with the indole moiety attached at third
position of the succinimide ring, we have demonstrated the
formation of 2-(1-benzylpyrrolidin-3-yl)-1H-indole (4), which
was obtained in very high yields (Scheme 5, 85%). Similarly, the
product 3ad was also subjected to reduction to form 1,4-diol with
indole ring attached at the second position (Scheme 5, 2-(1H-
indol-2-yl)butane-1,4-diol (5)). In both the cases, it was
C
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Fujiwara, Y. Science 2000, 287, 1992. (d) Labinger, J.; Bercaw, J. Nature
2002, 417, 507. (e) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Angew.
Chem., Int. Ed. 2012, 51, 8960.
(9) Review for directing group strategy with transition-metal catalysts:
(a) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (b) Engle,
K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788.
(c) Mewald, M.; Schiffner, J. A.; Oestreich, M. Angew. Chem., Int. Ed.
2012, 51, 1763. (d) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem.
Rev. 2012, 112, 5879.
to the formation of 3-substituted succinimide derivatives. This
distinction of regioselectivity has been achieved by employing
Ru(II) catalyst and a directing group strategy. Succinimides and
indole derivatives are useful moieties in the field of organic
chemistry, and many of them are synthetic drugs or natural
products.
ASSOCIATED CONTENT
* Supporting Information
■
(10) (a) Zhang, Y.; Zheng, J.; Cui, S. J. Org. Chem. 2014, 79, 6490.
(b) Ikemoto, H.; Yoshino, T.; Sakata, K.; Matsunaga, S.; Kanai, M. J. Am.
Chem. Soc. 2014, 136, 5424. (c) Lanke, V.; Prabhu, K. R. Org. Lett. 2013,
15, 6262. (d) Liu, X.; Li, X.; Liu, H.; Guo, Q.; Lan, J.; Wang, R.; You, J.
Org. Lett. 2015, 17, 2936. (e) Song, Z. Q.; Samanta, R.; Antonchick, A. P.
Org. Lett. 2013, 15, 5662. (f) Li, B.; Ma, J.; Xie, W.; Song, H.; Xu, S.;
Wang, B. J. Org. Chem. 2013, 78, 9345. (g) Sollert, C.; Devaraj, K.;
Orthaber, A.; Gates, P.; Pilarski, L. Chem. - Eur. J. 2015, 21, 5380.
(h) Yang, L.; Zhang, G.; Huang, H. Adv. Synth. Catal. 2014, 356, 1509.
(i) Yang, X.-F.; Hu, X.-H.; Feng, C.; Loh, T.-P. Chem. Commun. 2015,
51, 2532. (j) Tang, C.-Y.; Tao, Y.; Wu, X.- Y.; Sha, F. Adv. Synth. Catal.
2014, 356, 609. (k) Gong, B.; Shi, J.; Wang, X.; Yan, Y.; Li, Q.; Meng, Y.;
Xu, H. E.; Yi, W. Adv. Synth. Catal. 2014, 356, 137. (l) Shi, J.; Yan, Y.; Li,
Q.; Xu, H. E.; Yi, W. Chem. Commun. 2014, 50, 6483. (m) Zhang, L.;
Qiu, R.; Xue, X.; Pan, Y.; Xu, C.; Wang, D.; Wang, X.; Xu, L.; Li, H.
Chem. Commun. 2014, 50, 12385. (n) Zhang, L.-Q.; Yang, S.; Huang, X.;
You, J.; Song, F. Chem. Commun. 2013, 49, 8830.
(11) Some selected publications: (a) Kozhushkov, S. I.; Ackermann, L.
Chem. Sci. 2013, 4, 886. (b) Ueyama, T.; Mochida, S.; Fukutani, T.;
Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2011, 13, 706. (c) Padala, K.;
Jeganmohan, M. Org. Lett. 2012, 14, 1134. (d) Graczyk, K.; Ma, W.;
Ackermann, L. Org. Lett. 2012, 14, 4110. (e) Ma, W.; Mei, R.; Tenti, G.;
Ackermann, L. Chem. - Eur. J. 2014, 20, 15248. (f) Reddy, M.;
Jeganmohan, M. Eur. J. Org. Chem. 2013, 2013 (6), 1150.
(12) (a) Yang, L.; Huang, H. Chem. Rev. 2015, 115, 3468. (b) Kakiuchi,
F.; Murai, S. Acc. Chem. Res. 2002, 35, 826. (c) Murai, S.; Kakiuchi, F.;
Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda, M.; Chatani, N. Nature
1993, 366, 529. (d) Rouquet, G.; Chatani, N. Chem. Sci. 2013, 4, 2201.
(e) Zhou, B.; Yang, Y.; Lin, S.; Li, Y. Adv. Synth. Catal. 2013, 360.
(f) Yang, L.; Correia, C.; Li, C.-J Org. Biomol. Chem. 2011, 9, 7176.
(g) Schinkel, M.; Marek, I.; Ackermann, L. Angew. Chem., Int. Ed. 2013,
52, 3977. (h) Martinez, R.; Chevalier, R.; Darses, S.; Genet, J. Angew.
Chem., Int. Ed. 2006, 45, 8232. (i) Trost, B.; Imi, K.; Davies, I. J. Am.
Chem. Soc. 1995, 117, 5371. (j) Pan, S.; Ryu, N.; Shibata, T. J. Am. Chem.
Soc. 2012, 134, 17474.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b01809.
Experimental procedures; characterization data for all new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: prabhu@orgchem.iisc.ernet.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by SERB (NO.SB/S1/OC-56/2013),
New Delhi, Indian Institute of Science and RL Fine Chem. We
thank Dr. A. R. Ramesha (RL Fine Chem) for useful discussions.
V.L. and K.R.B. thank CSIR, New Delhi, for fellowships.
REFERENCES
■
(1) Fredenhagen, A.; Tamura, S. Y.; Kenny, P. T. M.; Komura, H.;
Naya, Y.; Nakanishi, K.; Nishiyama, K.; Sugiura, M.; Kita, H. J. Am.
Chem. Soc. 1987, 109, 4409. (b) Yang, H.-M.; Park, C.; Lim, S.; Park, S.-
I.; Chung, B.; Kim, J.-D. Chem. Commun. 2011, 47, 12518. (c) Chou, T.-
C.; Wu, R.-T.; Liao, K.-C.; Wang, C.-H. J. Org. Chem. 2011, 76, 6813.
(d) Robert, F.; Gao, H. Q.; Donia, M.; Merrick, W. C.; Hamann, M. T.;
Pettetier, J. RNA 2006, 12, 717.
(2) Crider, A. M.; Kolczynski, T. M.; Yates, K. M. J. Med. Chem. 1980,
23, 324. (b) Isaka, M.; Rugseree, N.; Maithip, P.; Kongsaeree, P.;
Prabpai, S.; Thebtaranonth, Y. Tetrahedron 2005, 61, 5577. (c) Uddin,
J.; Ueda, K.; Siwu, E. R. O.; Kita, M.; Uemura, D. Bioorg. Med. Chem.
2006, 14, 6954. (d) Cho, H.; Engers, D.; Venable, D.; Niswender, C.;
Lindsley, C.; Conn, P.; Emmitte, K.; Rodriguez, A. ACS Chem. Neurosci.
(13) Lanke, V.; Prabhu, K. R. Org. Lett. 2013, 15, 2818.
(14) (a) Katritzky, A. R.; Yao, J.; Qi, M.; Chou, Y.; Sikora, D. J.; Davis,
S. Heterocycles 1998, 48, 2677. (b) Shemchuk, L.; Chernykh, V.;
Arzumanov, P.; Levashov, D.; Shemchuk, L. Russ. J. Org. Chem. 2007, 43,
615. (c) Gali, H.; Prabhu, K. R.; Karra, S. R.; Katti, K. V. J. Org. Chem.
2000, 65, 676.
(15) For detailed mechanistic DFT studies of maleimide addition
reaction, see the following paper in this issue: Bettadapur, K. R.; Lanke,
V.; Prabhu, K. R. Org. Lett. 2015, DOI: 10.1021/acs.orglett.5b01810.
2014, 5, 597. (e) Filho, V.; Correa
Pinheiro, T.; Andricopulo, A.; Yunes, R., Il Farmaco 1998, 53, 55.
(f) Kuran, B.; Kossakowski, J.; Cieslak, M.; Kazmierczak-Baranska, J.;
Krolewska, K.; Cyranski, M.; Stępien, D.; Krawiecka, M. Heterocycl.
Commun. 2013, 19, 287.
̂
, R.; Vaz, Z.; Calixto, J.; Nunes, R.;
́
́
́
́
́
(3) (a) Hubert, J. C.; Wijnberg, J. B. P. A.; Speckamp, W. N.
Tetrahedron 1975, 31, 1437. (b) Wijnberg, J. B. P. A.; Schoemaker, H. E.;
Speckamp, W. N. Tetrahedron 1978, 34, 179.
(4) Kochanowska-Karamyan, A. J.; Hamann, M. T. Chem. Rev. 2010,
110, 4489.
(5) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873. (b) Shiri, M.
Chem. Rev. 2012, 112, 3508. (c) Lancianesi, S.; Palmieri, A.; Petrini, M.
Chem. Rev. 2014, 114, 7108.
(6) Bogza, S.; Kobrakov, K.; Zubritskii, M.; Suikov, S.; Dulenko, V.
Chem. Heterocycl. Compd. 1997, 33, 74.
(7) Selected reviews for C−H activation: (a) Wencel-Delord, J.;
Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011, 40, 4740.
̈
(b) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174.
(c) Ackermann, L. Chem. Rev. 2011, 111, 1315. (d) McMurray, L.;
O’Hara, F.; Gaunt, M. J. Chem. Soc. Rev. 2011, 40, 1885. (e) Trost, B. M.
Acc. Chem. Res. 2002, 35, 695.
(8) (a) Trost, B. M. Science 1991, 254, 1471. (b) Murai, S.; Kakiuchi, F.;
Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda, M.; Chatani, N. Nature
1993, 366, 529. (c) Jia, C.; Piao, D.; Oyamada, J.; Lu, W.; Kitamura, T.;
D
DOI: 10.1021/acs.orglett.5b01809
Org. Lett. XXXX, XXX, XXX−XXX