Electroreductive intermolecular coupling of 3-methoxycarbonylindoles with ketones

Article abstract of DOI:10.1021/ol4010799

The electroreductive coupling of 1-alkoxycarbonyl-3-methoxycarbonylindoles with aromatic ketones in the presence of chlorotrimethylsilane gave cis-adducts stereoselectively. The cis-adducts were readily transformed to trans-adducts by treatment with catal

Full text of DOI:10.1021/ol4010799

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Electroreductive Intermolecular
Coupling of 3‑Methoxycarbonylindoles
with Ketones
Naoki Kise,* Akinori Sueyoshi, Shin-ichirou Takeuchi, and Toshihiko Sakurai
Department of Chemistry and Biotechnology, Graduate School of Engineering,
Tottori University, 4-101, Koyama-cho Minami, Tottori 680-8552, Japan
kise@bio.tottori-u.ac.jp
Received April 19, 2013
ABSTRACT
The electroreductive coupling of 1-alkoxycarbonyl-3-methoxycarbonylindoles with aromatic ketones in the presence of chlorotrimethylsilane
gave cis-adducts stereoselectively. The cis-adducts were readily transformed to trans-adducts by treatment with catalyst DBU. On the other hand,
the electroreductive coupling of 1-methyl-3-methoxycarbonylindole with aliphatic ketones in isopropanol afforded trans-adducts exclusively.
The adducts are the precursors for the synthesis of 2-substituted 3-methoxycarbonylindoles and indolines.
To date, a variety of reductive cross-couplings of un-
saturated groups with ketones have been developed using
SmI2 as a reducing agent, and they have been exploited
for the synthesis of a number of natural products and
physiologically active substances.1 Recently, Reissig and
co-workers have reported the SmI2-promoted reductive
intra-2 and intermolecular3 couplings of indole deriva-
tives with ketones to synthesize indolidine heterocycles
stereoselectively. On the other hand, we disclosed that
the reductive intramolecular coupling of indole derivatives
with ketones was also realized by electroreduction in
isopropanol4 and trans-cyclized products were stereoselec-
tively formed similarly to the SmI2-promoted cyclization2a
(Scheme 1). In this context, we report herein the electro-
reductive intermolecular coupling of N-substituted
3-methoxycarbonylindoles with aromatic and aliphatic
ketones, since the coupled products are expected to be
useful precursors for the synthesis of 2-substituted
3-methoxycarbonylindoles5 and indolines. The electrore-
duction of 1-alkoxycarbonyl-3-methoxycarbonylindoles
with aromatic ketones in the presence of chlorotrimethyl-
silane (TMSCl)6 gave intramolecularly coupled products
(1) For recent reviews on the reductive coupling with SmI2:
(a) Kagan, H. B. Tetrahedron 2003, 59, 10351. (b) Berndt, M.; Gross,
S.; Hoelemann, A.; Reissig, H.-U. Synlett 2004, 422. (c) Edmonds, D.;
Johnston, D.; Procter, D. J. Chem. Rev. 2004, 104, 3371. (d) Gopalaiah,
K.; Kagan, H. B. New J. Chem. 2008, 32, 607. (e) Rudkin, I. M.; Miller,
L. C.; Procter, D. J. Organomet. Chem. 2008, 34, 19. (f) Nicolaou, K. C.;
Ellery, S. P.; Chen, J. S. Angew. Chem., Int. Ed. 2009, 48, 7140.
(g) Beemelmanns, C.; Reissig, H.-U. Chem. Soc. Rev. 2011, 40, 2199.
(2) (a) Gross, S.; Reissig, H.-U. Org. Lett. 2003, 5, 4305. (b) Blot, V.;
Reissig, H.-U. Eur. J. Org. Chem. 2006, 4989. (c) Beemelmanns, C.; Blot,
V.; Cross, S.; Lentz, D.; Reissig, H.-U. Eur. J. Org. Chem. 2010, 2716.
(d) Beemelmanns, C.; Reissig, H.-U. Amgew. Chem., Int. Ed. 2010, 49,
8021. (e) Beemelmanns, C.; Lentz, D.; Reissig, H.-U. Chem.;Eur. J.
2011, 17, 9720.
(5) For recent reports on the synthesis of 2-substituted 3-alkoxycar-
bonylindoles, see: (a) Cui, S.-L.; Wang, J.; Wang, Y.-G. J. Am. Chem.
Soc. 2008, 130, 13526. (b) Zhou, L.; Doyle, M. P. J. Org. Chem. 2009, 74,
9222. (c) Huestis, M. P.; Chan, L.; Stuart, D. R.; Fagnou, K. Angew.
€
Chem., Int. Ed. 2011, 50, 1338. (d) Neumann, J. J.; Rakshit, S.; Droge,
€
T.; Wurtz, S.; Glorius, F. Chem.;Eur. J. 2011, 17, 7298. (e) He, Z.; Liu,
W.; Li, Z. Chem.;Asian. J. 2011, 6, 1340. (f) Bunescu, A.; Wang, Q.;
Zhu, J. Synthesis 2012, 44, 3811. (g) Nguyen, H. H.; Kurth, M. J. Org.
Lett. 2013, 15, 364.
(6) For our recent reports on the electroreductive coupling in the
presence of TMSCl, see: (a) Kise, N.; Isemoto, S.; Sakurai, T. Org. Lett.
2009, 11, 4902. (b) Kise, N.; Sakurai, T. Tetrahedron Lett. 2010, 51, 70.
(c) Kise, N.; Isemoto, S.; Sakurai, T. J. Org. Chem. 2011, 76, 9856.
(d) Kise, N.; Isemoto, S.; Sakurai, T. Tetrahedron 2012, 68, 8805.
(3) Blot, V.; Reissig, H.-U. Synlett 2006, 2763.
(4) Kise, N.; Mano, T.; Sakurai, T. Org. Lett. 2008, 10, 4617.
r
10.1021/ol4010799
XXXX American Chemical Society

with cis-stereoselectivity. The cis-adducts could be com-
pletely isomerized to the trans-adducts by treatment
with catalyst (cat.) DBU. In contrast, the electroreductive
coupling of 1-methyl-3-methoxycarbonylindole with alipha-
tic ketones in isopropanol using an undivided cell afforded
trans-adducts exclusively. We investigated the reaction me-
chanisms of these reactions and found that the mechanisms
of the electroreductive couplings with aromatic and aliphatic
ketones are different.
the yield of 4g was low (30%) owing to the formation of
pinacolsfrom 2dand unreacted1awas recovered (>60%).
Bulkier ketones 2e and 2f brought about 4h (48%) and 4i
(54%) in somewhat higher yields.
Scheme 2. Electroreductive Coupling of 1-Alkoxycarbonyl-
3-methoxycarbonylindoles with Diaryl Ketonesa
Scheme 1. Electroreductive Intramolecular Coupling of Indole
Derivatives with Ketones
First, we attempted the electroreductive coupling
of 3-methoxycarbonylindoles 1aꢀd with benzophenone
(2a) as a representative of aromatic ketones (Scheme 2).
Unfortunately, 1aꢀd were recovered and benzhydrol was
produced from 2a by the electroreduction in isopropanol.4
Therefore, we explored other conditions for the electro-
reductive coupling and found that the electroreduction
of 1-alkoxycarbonyl-3-methoxycarbonylindoles 1a and 1b
with 2a (2 equiv) in the presence of TMSCl (5 equiv)
in THF solvent gave coupled products 3a and 3b in 88%
and 72% yields, respectively (Scheme 2, runs 1 and 2).
These products were formed with high stereoselectivity,
and the major isomer of 3a was determined to be cis
by X-ray crystallography (Supporting Information). The
cis-isomers of 3a and 3b could be completely converted
to the corresponding trans-isomers by treatment with a
catalytic amount of DBU in THF at room temperature.
Desilylation of the trans-isomers of 3a and 3b by treatment
with 0.1 M HCl in methanol at 0 °C gave alcohols trans-4a
and trans-4b. The relative configuration of trans-4b was
confirmed by X-ray crystallography. When the electrore-
ductive coupling of 1-methyl-3-methoxycarbonylindoles
(1c) with 2a was carried out under the same conditions,
no coupled product was obtained and trimethylsilyl ether
of benzhydrol was produced. In place of 2a, 4,40-difluoro-
and 4,40-dimethoxybenzophenones (2b and 2c) were em-
ployed as aromatic ketones, and the results were summar-
ized in Scheme 2 (runs 3ꢀ6). Although the cis-selectivity
in the reductive coupling of 2b was somewhat lower (runs 3
and 4) than in that of 2a, similar yields of the coupled
products 3cꢀf were obtained. Isomerization of the cis-
isomers of 3cꢀf withcat. DBU gavetrans-3cꢀf exclusively.
Next, the electroreduction of 1a with phenyl alkyl
ketones 2dꢀf was carried out under the same conditions
as above (Scheme 3). Since coupled products were formed
as complex mixtures of diastereomers, the crude products
were treated with cat. DBU in THF and 0.1 M HCl in
methanol successively to facilitate product isolation. All
products 4gꢀi seemed to be obtained as two diastereomers
of trans-isomers. In the reaction with acetophenone (2d),
a Isolated yield.
Scheme 3. Electroreductive Coupling of 1,3-Dimethoxycarbo-
nyllindole with Phenyl Alkyl Ketones
In addition, we attempted the electroreductive coupling
of 1-alkoxycarbonyl-3-methoxycarbonylindoles 1a and
1b with acetone (5a) as an aliphatic ketone. However, no
coupled product was obtained and hydrogenated indolines
were formed from 1a,b. After the survey of substrates and
conditions for the electroreductive coupling with 5a, we
found that 1-methyl-3-methoxycarbonylindole (1c) gave
the expected product 6a in 73% yield as a sole stereoisomer
together with a small amount of hydrogenated indoline 7
(10%) by the electroreduction with 5a (5 equiv) in iso-
propanol using an undivided cell4 (Scheme 4). The stereo-
configuration of the obtained 6a seemed to be trans, since
NOE could not be observed between 2-H and 3-H protons
1
in the H NMR analysis of 6a. Other aliphatic cyclic
ketones 5b and 5c also afforded the coupled products 6b
(60%) and6c (58%), respectively. The relative configuration
of 6b was confirmed to be trans by X-ray crystallographic
analysis.
B
Org. Lett., Vol. XX, No. XX, XXXX

attacks 5a to give intermediate D, and then further reduc-
tion of D followed by protonation produces 6a. In the pro-
tonation of the enolate anion in D, cis-6a may be produced
preferentially. However, it is likely that cis-6a readily iso-
merized to thermodynamically more stable trans-6a under
the basic conditions near the cathode. The DFT calcula-
tions suggest this assumption: trans-6a is lower in energy
(3.46 kcal/mol in isopropanol) than cis-6a.
Scheme 4. Electroreductive Coupling of 1-Methyl-3-methoxy-
carbonylindoles with Aliphatic Ketonesa
Scheme 5. Presumed Reaction Mechanism of Electroreductive
coupling of 1,3-Di(methoxycarbonyl)indole with
Benzophenone
a Isolated yield.
The cyclic voltamograms of aromatic ketones 2a and 2d
in 0.03 M Bu4NClO4/DMF on a platinum cathode showed
a first reduction peak at ꢀ1.87 and ꢀ2.14 V vs SCE, res-
pectively, while those of 1-alkoxycarbonyl 3-methoxycar-
bonylindoles 1a and 1b under the same conditions revealed
no reduction peak from 0 to ꢀ2.50 V vs SCE. These results
suggest that 2a and 2d are more reducible than 1a and 1b.
Therefore, the electroreductive coupling of 1a with 2a
was supposed to be initiated by the reduction of 2a and
the reaction mechanism can be presumed as illustrated
in Scheme 5. Carbanion A is formed by the two-electron
transfer to 2a and O-silylation with TMSCl. Since the
electroreduction of 1c with 2a gave no coupled product as
described above, it is likely that the active species is not an
O-silylated radical but anion A. The nucleophilic addition
of A to the 2-position of 1a and subsequent O-silylation
of the resulting enolate anion give silyl ketene acetal B. The
labile B is readily desilylated to ester 3a during workup. In
this desilylation, protonation at the 3-position of B occurs
from the less bulky side, that is the opposite side of
the substituent at the 2-position, to produce cis-3a stereo-
selectively. The kinetically controlled product cis-3a was
completely transformed to trans-3a by treatment with
DBU. This result indicates that trans-3a is thermodyna-
mically more stable than cis-3a. The DFT calculations
(Supporting Information) also support this presumption,
since trans-3a is much more stable (8.39 kcal/mol in THF)
than cis-3a.
Scheme 6. Presumed Reaction Mechanism of Electroreductive
Coupling of 1-Methyl-3-methoxycarbonylindole with Acetone
The obtained coupled products 4 and 6 are promising as
the precursors for the synthesis of 2-substituted 3-methox-
ycarbonylindoles and indolines. The preliminary results
of our ongoing study are shown in Scheme 7. Dehydration
of trans-4a by refluxing in toluene in the presence of cat.
p-TsOH gave 2-diphenylmethylindole 8 (78%). Deprotec-
tion of 8 was effected by treatment with TBAF7 to give 9
(94%). The N-unsubstituted 2-diphenylmethylindole 9
On the other hand, the electroreductive intermolecular
coupling of 1c with aliphatic ketone 5a is presumed to be
promoted by the reduction of 1c as the already reported
intramolecular coupling,4 in which one-electron transfer to
the 3-methoxycarbonyl moiety in the substrate takes place
(Scheme 6). DFT calculations of radical anion C generated
by the one-electron transfer to 1c show the highest spin
density exists at the C2 carbon and a negative charge
is delocalized at the oxygen atoms. The radical anion C
ꢀ ꢀ ꢀ
(7) Jaxquemard, U.; Beneteau, V.; Lefoix, M.; Routier, S.; Merour,
J.-Y.; Coudert, G. Tetrahedron 2004, 60, 10039.
Org. Lett., Vol. XX, No. XX, XXXX
C

(56%). Incontrast, dehydration of trans-6a under the same
conditions produced 2-isopropenylindoline 10. Dehydro-
genation of10 with DDQ and the following hydrogenation
of resulting 11 afforded 2-isopropylindole 12.8 Unexpect-
edly, chloride 13 prepared from trans-6a was rearranged to
1,2,3,4-tetrahydroquinoline 14 by treatment with t-BuOK
inTHF (Scheme8). The ring expansion of13to14seems to
be promoted by the formation of cyclopropane intermedi-
ate E and its ring opening due to the reaction with water
through iminium ion F. Although the stereoconfiguration
wasnot determined, 14was formedasasingle stereoisomer
Scheme 7. Transformations of trans-4a and trans-6a
1
according to H and 13C NMR analyses. Further trans-
formations of the adducts 4 and 6 to other indoles and
indolines are in progress.
Inconclusion, theelectroreductionof1-alkoxycarbonyl-
3-methoxycarbonylindoles 1a and 1b with benzophenones
2aꢀc in the presence of TMSCl in THF gave intermole-
cularly coupled products 3aꢀf with cis-stereoselectivity.
The cis-isomers of 3aꢀf were readily transformed to trans-
isomers quantitatively by treatment with cat. DBU in
THF. Desilylation of trans-3aꢀf afforded the correspond-
ing alcohols trans-4aꢀf. The electroreduction of 1a and 1b
with phenyl alkyl ketones 2dꢀf under the same condi-
tions and subsequent isomerization followed by desilyla-
tion yielded trans-4gꢀi as mixtures of two diastereomers.
The electroreduction of 1-methyl-3-methoxycarbonylin-
dole (1c) with aliphatic ketones 5aꢀc in isopropanol gave
intermolecularly coupled products trans-6aꢀc exclusively.
The products 4 and 6 are the precursors for the synthesis of
2-substituted 3-methoxycarbonylindoles and indolines.
Scheme 8. Transformation of trans-6a to 14
Supporting Information Available. Experimental proce-
dures; characterization data for products; 1H and 13CNMR
spectra of products; X-ray crystallographic data (ortep)
of cis-3a, trans-4b, and trans-6b; and the results of DFT
calculations for 3a, 6a, and C. Crystallographic CIF files for
cis-3a, trans-4b, and trans-6b. This material is available free
of charge via the Internet at http://pubs.acs.org.
was also obtained from trans-4b by treatment with 1 M
HCl in methanol at 25 °C, although the yield decreased
(8) Suresh, J. R.; Syam Kumar, U. K.; Ila, H.; Junjappa, H. Tetra-
hedron 2001, 57, 781.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX