Nucleophilic addition of grignard reagents to 3-acylindoles: Stereoselective synthesis of highly substituted indoline scaffolds

Article abstract of DOI:10.1021/ol301750b

3-Acylindoles undergo nucleophilic-type reactions with Grignard reagents to efficiently afford either cis- or trans-substituted indolines, depending on the different quenching procedures. The enolate intermediate could be trapped by aryl acyl chlorides to provide indolines bearing a quaternary carbon center with high stereoselectivity. In contrast, the use of benzyl bromide as an electrophile results in the fragmentation of the indole ring. The indoline products could be easily transformed into indoles through oxidation with DDQ in a one-pot manner.

Full text of DOI:10.1021/ol301750b

ORGANIC
LETTERS
2012
Vol. 14, No. 15
3978–3981
Nucleophilic Addition of Grignard
Reagents to 3ꢀAcylindoles:
Stereoselective Synthesis of Highly
Substituted Indoline Scaffolds
Lu Wang,† Yushang Shao,‡ and Yuanhong Liu*,†
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, People’s
Republic of China, and Department of Chemistry, East China Normal University, 3663
North Zhongshan Road, Shanghai 200062, People’s Republic of China
yhliu@mail.sioc.ac.cn
Received June 26, 2012
ABSTRACT
3-Acylindoles undergo nucleophilic-type reactions with Grignard reagents to efficiently afford either cis- or trans-substituted indolines,
depending on the different quenching procedures. The enolate intermediate could be trapped by aryl acyl chlorides to provide indolines
bearing a quaternary carbon center with high stereoselectivity. In contrast, the use of benzyl bromide as an electrophile results in the
fragmentation of the indole ring. The indoline products could be easily transformed into indoles through oxidation with DDQ in a one-pot manner.
The indole ring widely occurs as a key structural subunit
in numerous natural products and also represents one of
the most important building blocks in organic synthesis.1
Indoles usually act as nucleophiles to engage in electro-
philic substitution reactions, mainly at the C-3 position,
due to the π-excessive nature of the indolyl aromatic ring.2
However, when indoles are substituted with electron-with-
drawing groups or there is a leaving group on the indole
nitrogen, they can also react with nucleophiles, leading to
highly functionalized indole or indoline derivatives.3 Com-
pared with the well-established electrophilic substitu-
tion reactions, much less attention has been paid to
nucleophilic-type reactions of indoles. As early as 1962,
it was reported that phenylmagnesium bromide adds
to 1-methyl- or 1,2-dimethyl-3-benzoylindole to give a
Michael adduct of 2,3-substituted indolines.4 However, only
those two examples wereexamined, and the stereochemical
information of the indoline products was not provided.
In addition to an acyl substituent, the nitro group has
been used to activate the indole ring toward nucleophilic
reactions.5 Gribble et al. showed that addition of the
enolates of diethyl malonate to 3-nitro-1-(phenylsulfonyl)-
indole forms trans-3-nitro-2-substituted indoline.5c The
studies by Somei’s6 and Gribble’s5dꢀf research groups
† Shanghai Institute of Organic Chemistry.
‡ East China Normal University.
(1) For reviews, see: (a) Indoles; Sundberg, R. J., Ed.; Academic Press:
San Diego, 1996. (b) Indole Alkaloids; Rahman, A., Basha, A., Eds.;
Harwood Academic: Amsterdam, 1998. (c) Kochanowska-Karamyan,
A. J.; Hamann, M. T. Chem. Rev. 2010, 110, 4489.
(2) (a) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48,
9608. (b) Sundberg, R. J. Top Heterocycl. Chem. 2010, 26, 47.
(3) (a) Kishbaugh, T. L. S. Top Heterocycl. Chem. 2010, 26, 117.
(b) Gribble, G. W. Pure Appl. Chem. 2003, 75, 1417.
(4) Szmuszkovicz, J. J. Org. Chem. 1962, 27, 511.
r
10.1021/ol301750b
Published on Web 07/25/2012
2012 American Chemical Society

indicated that employing a leaving group such as a 1-hy-
droxy-, 1-methoxy, or phenylsulfonyl group on the indole
nitrogen can facilitate a formal SN20 reaction to generate
substituted free NꢀH indoles. Although much progress
has been achieved in this field, the development of a highly
stereoselective process allowing ready access to 2,3-sub-
stituted indolines,5c,7 a ubiquitous scaffold found in nat-
ural products and pharmaceutically active compounds,8 is
quite rare. In the course of our studies on indole-based
transformations,9 we accidently found that 3-acyl indoles
could react with Grignard reagents in a Michael addition
fashion, leading to dearomatization of the indole nucleus
and formation of highly substituted indolines with high
levels of stereochemical control. In this communication, we
describe a general and mild method for stereoselective
synthesis of either trans- or cis-indolines using Grignard
reagents, as well as a detailed study for further transforma-
tions of the magnesium enolate intermediates with electro-
philes (Scheme 1).
We initially investigated the reaction of 1-methyl-
3-benzoylindole 1a with the commercially available
Grignard reagent phenylmagnesium bromide. To our de-
light, treatment of 1a with 2.0 equiv of PhMgBr in THF at
0 °C followed by warming to rt and stirring for only 10 min
cleanly afforded the cis-2-phenyl-3-benzoylindoline 2a in
81% yield after quenching with MeOH, together with 7%
of trans-2a (Scheme 2).10 Further optimization of the
quenching procedures indicated that when the reaction
was first quenched by MeOH, followed by addition of
Et3N and stirring at 50 °C for 1 h, the cis-2a could convert
completely to the trans-isomer to afford trans-2a in 82%
yield. Obviously, the cisꢀtrans isomerization occurs under
basic conditions. The results indicated that a high degree of
stereoselectivity for both cis- and trans-diastereomers
could be achieved by choosing the appropriate quenching
methods. The 1H NMR shows similar coupling constants
of the vicinal protons in cis-2a and trans-2a (10.4 and
10.0 Hz, respectively). The stereochemistry of cis- or trans-
indolines 2 was confirmed by X-ray crystal analyses of
compounds cis-2g, trans-2a, and trans-2e (vide infra).11
Scheme 1
Scheme 2
The presented procedure via Michael-type addition of
Grignard reagents to indoles provides the indoline scaffold
in only one step and with high stereoselectivity. Therefore,
we were interested in the scope and limitations of this
reaction. We first investigated the reactions of PhMgBr
with various 3-acylindoles under the conditions for the
trans-isomers of indoline 2, and the results are shown in
Figure 1. An N-benzyl-protected indole reacted smoothly
to afford indoline 2b in 73% yield. The presence of
electron-withdrawing groups such as Boc or CONMe2
on the indole nitrogen did not influence the reaction,
leading to 2c and 2d in 92% and 79% yields, respectively.
However, an Ac-protected indole gave 2e in a lower yield
of58%. The functionality of 5-Br, 5-CN, and5-BnO on the
indole ring could also be incorporated into the reaction
procedures, furnishing the Michael adducts 2fꢀ2h in high
yields of 84ꢀ88%. Especially, the sensitive cyano group
was also well tolerated (2g). As for carbonyl substituents
(R2) on the acyl moiety, a furanyl or alkenyl group as R2
was found to be compatible for this reaction (2i and 2j).
(5) (a) Pelkey, E. T.; Chang, L.; Gribble, G. W. Chem. Commun.
1996, 1909. (b) Pelkey, E. T.; Gribble, G. W. Chem. Commun. 1997, 1873.
(c) Pelkey, E. T.; Gribble, G. W. Synthesis 1999, 1117. (d) Pelkey, E. T.;
Barden, T. C.; Gribble, G. W. Tetrahedron Lett. 1999, 40, 7615. (e) Roy,
S.; Gribble, G. W. Tetrahedron Lett. 2007, 48, 1003. (f) Qian, D. C.;
Alford, P. E.; Kishbaugh, T. L. S.; Jones, S. T.; Gribble, G. W.
ARKIVOC 2010, No. iv, 66. (g) Alford, P. E.; Kishbaugh, T. L. S.;
Gribble, G. W. Heterocycles 2010, 80, 831.
(6) (a) Somei, M.; Kawasaki, T.; Fukui, Y.; Yamada, F.; Kobayashi,
T.; Aoyama, H.; Shinmyo, D. Heterocycles 1992, 34, 1877. (b) Yamada,
F.; Fukui, Y.; Shinmyo, D.; Somei, M. Heterocycles 1993, 35, 99.
(c) Somei, M. Heterocycles 1999, 50, 1157. (d) Yamada, K.; Yamada,
F.; Somei, M. Heterocycles 2002, 57, 1231. (e) Yamada, K.; Yamada, F.;
Shiraishi, T.; Tomioka, S.; Somei, M. Heterocycles 2009, 77, 971.
(7) For stereoselective synthesis of indolines by other methods, see:
(a) Viswanathan, R.; Smith, C. R.; Prabhakaran, E. N.; Johnston, J. N.
J. Org. Chem. 2008, 73, 3040. (b) Hasegawa, K.; Kimura, N.; Arai, S.;
Nishida, A. J. Org. Chem. 2008, 73, 6363. (c) Liu, Y.; Xu, W.; Wang, X.
Org. Lett. 2010, 12, 1448. (d) Schammel, A. W.; Boal, B. W.; Zu, L.;
Mesganaw, T.; Garg, N. K. Tetrahedron 2010, 66, 4687. (e) Cera, G.;
Crispino, P.; Monari, M.; Bandini, M. Chem. Commun. 2011, 47, 7803.
(f) Nguyen, Q.; Sun, K.; Driver, T. G. J. Am. Chem. Soc. 2012, 134, 7262.
(8) (a) Boger, D. L.; Boyce, C. W.; Garbaccio, R. M.; Goldberg, J. A.
Chem. Rev. 1997, 97, 787. (b) Horton, D. A.; Bourne, G. T.; Smythe,
M. L. Chem. Rev. 2003, 103, 893.
(10) We found that cis-2a is not so stable in the air, which can convert
to indole slowly. The indole product might be formed through air
oxidation. It is recommended column chromatography be performed
immediately after the reaction is complete.
(11) X-ray crystal structures of cis-2g, trans-2a, trans-2e, and 4a are
given in the Supporting Information.
(9) (a) Wang, L.; Li, G.; Liu, Y. Org. Lett. 2011, 13, 3786. (b) Xie, X.;
Du, X.; Chen, Y.; Liu, Y. J. Org. Chem. 2011, 76, 9175. (c) Li, G.; Liu, Y.
J. Org. Chem. 2010, 75, 3526. (d) Li, H.; Yang, J.; Liu, Y.; Li, Y. J. Org.
Chem. 2009, 74, 6797. (e) Lu, Y.; Du, X.; Jia, X.; Liu, Y. Adv. Synth.
Catal. 2009, 351, 1517. (f) Li, G.; Wang, E.; Chen, H.; Li, H.; Liu, Y.;
Wang, P. G. Tetrahedron 2008, 64, 9033.
Org. Lett., Vol. 14, No. 15, 2012
3979

Figure 2. Synthesis of indolines through the reactions with
various Grignard reagents. All yields are isolated yields.
aGrignard reagent was prepared by iodineꢀmagnesium ex-
change reaction.12 bGrignard reagent was prepared by the
reaction of aryl halide with Mg.
Figure 1. Synthesis of indolines through the reactions with
PhMgBr. All yields are isolated yields. Reaction time is 1 h
for the first step.
2-pyridylmagnesium bromide12 were also accommodated
(2t and 2u).
a
Under the optimized reaction conditions for cis-isomers,
cis-indolines could also be obtained smoothly. Represen-
tative results are shown in Figure 3. In these reactions, only
5ꢀ6% of trans-isomers were isolated.
t
When R2 is a bulky Bu group, a mixture of two diaste-
reomers were obtained, in which cis-2k was predominant,
indicating the cis to trans isomerization could not complete
under the standard reaction conditions. The less hindered
iPr group (R2) provided an excellent yield of 2l. However,
the smaller size methyl group as the R2 substituent gave a
mixture of 1,4- and 1,2-adducts (2m and 3), which may be
due to the steric and/or electronic effects of the 3-Ac group.
Next, we examined the reactions of 3-acylindoles with
various Grignard reagents to produce trans-indolines 2. As
shown in Figure 2, a variety of Grignard reagents are
compatible with this transformation. Vinyl- as well as
substituted vinylmagnesium bromides were suitable nu-
cleophiles, giving rise to 2n and 2o in 58ꢀ60% yields.
Employing ethylmagnesium bromide afforded 2p in a
lower yield of 44%. Aromatic Grignard reagents bearing
electron-withdrawing or -donating groups were all proven
to be efficient in inducing the nucleophilic addition reac-
tion, and the corresponding trans-indolines 2qꢀ2s were
obtained in 79ꢀ93% yields. In the cases of Grignard
reagents with electron-withdrawing groups,12 the reactions
became slower (2q and 2r), probably due to the lower
nucleophilicity of these Grignard reagents. Heter-
oaryl Grignard reagents such as 3-benzothienyl and
Figure 3. Typical examples for cis-indolines 2.
It is well-known that the enolate intermediates of con-
jugate addition reactions can be trapped by various
electrophiles.13 We envisioned that the magnesium enolate
might be formed in our reaction system, which may react
with electrophiles to produce more complex derivatives.
Along this line, the magnesium enolate generated by the
reaction of 1a and PhMgBr was trapped with aryl acyl
chlorides, giving the corresponding diacyl-indoline prod-
ucts 4 with a quaternary carbon center in good yields
(Scheme 3). Interestingly, in all cases, only one diastereo-
mer was formed. The relative stereochemistry is confirmed
(12) (4-(Ethoxycarbonyl)phenyl)magnesium bromide and 2-pyridyl-
magnesium bromide were prepared by iodineꢀmagnesium exchange
(13) (a) Teichert, J. F.; Feringa, B. L. Angew. Chem., Int. Ed. 2010, 49,
2486. (b) Rathgeb, X.; March, S.; Alexakis, A. J. Org. Chem. 2006, 71,
5737. (c) Howell, G. P.; Fletcher, S. P.; Geurts, K.; ter Horst, B.; Feringa,
B. L. J. Am. Chem. Soc. 2006, 128, 14977.
€
reactions; see: (a) Boymond, L.; Rottlander, M.; Cahiez, G.; Knochel, P.
Angew. Chem., Int. Ed. 1998, 37, 1701. (b) Furukawa, N.; Shibutani, T.;
Fujihara, H. Tetrahedron Lett. 1987, 28, 5845.
3980
Org. Lett., Vol. 14, No. 15, 2012

Scheme 3
Scheme 4
by X-ray crystal analysis of compound 4a,11 which clearly
shows that the ꢀCOAr group derived from acyl chloride
and the phenyl group are in a trans configuration.
Scheme 5
We propose the following mechanism for the observed
stereoselectivity (Scheme 4). First, enolate 5 is formed
through a nucleophilic addition reaction. Protonation or
reaction with electrophiles proceeds preferentially from the
less hindered side of 5, i.e., trans to the larger R3 group,
leading to cis-2 or 4. To our surprise, when benzyl bromide
was used as an electrophile, a ring-opening reaction occurred
to generate 1,2-difunctionalized benzene 6 in 50% yield as a
mixture of alkene isomers (Scheme 5, eq 1). In this case, the
enolate intermediate may attack the electrophile through its
nitrogen atom, leading to fragmentation of the indole ring. It
should be noted that ring-opening reactions of indoles are
quite rare.14 Finally, we tried to apply the method for the
synthesis of 2,3-disubstituted indoles in a one-pot procedure.
After screening various oxidants, we found that addition of
2.0 equiv of DDQ to the reaction mixture could produce
indole 7 in 89% yield (Scheme 5, eq 2).
addition, the indoline product could be easily transformed
into indoles through oxidation with DDQ in a one-pot
manner. The resulting indoline and indole derivatives are
attractive building blocks for further synthetic manipulations.
Further studies to expand the reaction scope are in progress.
In conclusion, we have developed an efficient process for
the stereoselective synthesis of either cis- or trans-indolines via
nucleophilic addition of Grignard reagents to 3-acylindoles.
The enolate intermediates could be trapped efficiently by aryl
acyl chlorides to afford indolines bearing a quaternary carbon
center with high stereoselectivity. The use of benzyl bromide
as an electrophile resulted in the ring opening of indoles. In
Acknowledgment. We thank the National Natural
Science Foundation of China (Grant Nos. 21125210,
21121062), Chinese Academy of Science and the Major
State Basic Research Development Program (Grant No.
2011CB808700) for financial support.
Supporting Information Available. Experimental de-
tails, spectroscopic characterization of all new com-
pounds, and X-ray crystallography of compounds cis-
2g, trans-2a, trans-2e, and 4a are given in the Supporting
Information. This material is available free of charge via
the Internet at http://pubs.acs.org.
(14) For the fragmentation of indole rings, see: (a) Gribble, G. W.;
Saulnier, M. G. J. Org. Chem. 1983, 48, 607. (b) Johnson, D. A.; Gribble,
G. W. Heterocycles 1986, 24, 2127. (c) Reference 5a, 5b. (d) Kolotaev,
A. V.; Belen’kii, L. I.; Kononikhin, A. S.; Krayushkin, M. M. Russ.
Chem. Bull. Int. Ed. 2006, 55, 892. (e) Lee, S.; Park, S. B. Org. Lett. 2009,
11, 5214. (f) Vecchione, M. K.; Sun, A. X.; Seidel, D. Chem. Sci. 2011, 2,
2178. (g) Knepper, I.; Iaroshenko, V. O.; Vilches-Herrera, M.; Domke,
L.; Mkrtchyan, S.; Zahid, M.; Villinger, A.; Langer, P. Tetrahedron
2011, 67, 5293.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 15, 2012
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