Diastereoselective intramolecular friedel-crafts cyclizations of substituted methyl 2-(1 H-indole-1-carbonyl)acrylates: Efficient access to functionalized 1 H-pyrrolo[1,2-a]indoles

Article abstract of DOI:10.1021/ol202431x

A general, catalytic method for the diastereoselective synthesis of functionalized 1H-pyrrolo[1,2-a]indoles via an intramolecular Friedel-Crafts alkylation of N-acyl indoles is reported. Products were obtained in excellent yields (up to 98%) with high diastereoselectivities (up to >25:1 dr).

Full text of DOI:10.1021/ol202431x

ORGANIC
LETTERS
2011
Vol. 13, No. 21
5820–5823
Diastereoselective Intramolecular
FriedelÀCrafts Cyclizations of
Substituted Methyl 2-(1H-indole-
1-carbonyl)acrylates: Efficient Access to
Functionalized 1H-Pyrrolo[1,2-a]indoles
Dadasaheb V. Patil, Marchello A. Cavitt, and Stefan France*
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta,
Georgia 30332, United States
stefan.france@chemistry.gatech.edu
Received September 7, 2011
ABSTRACT
A general, catalytic method for the diastereoselective synthesis of functionalized 1H-pyrrolo[1,2-a]indoles via an intramolecular FriedelÀCrafts
alkylation of N-acyl indoles is reported. Products were obtained in excellent yields (up to 98%) with high diastereoselectivities (up to >25:1 dr).
[a]-Annelated indoles are unique structural features
present in a wide range of heterocyclic compounds that
play important roles in medicinal chemistry and organic
synthesis.1 Among [a]-annelated systems, the pyrrolo[1,2-a]-
indole scaffold is a primary target for synthetic chemists
due to its structural diversity (Figure 1).2 For example,
pyrrolo[1,2-a]indoles are primarily characterized by three
isomeric structures (the 9H-pyrrolo[1,2-a]indoles 1, the
3H-pyrrolo[1,2-a]indoles 2, and the 1H-pyrrolo[1,2-a]-
indoles 3) or by the two reduced forms 4 and 5. Moreover,
compounds specifically containing a 1H-pyrrolo[1,2-a]-
indole core demonstrate interesting physiological and
therapeutic properties.3 For example, mitomycin C (6)4
exhibits strong antitumor activity; yuremamine (7)5 shows
hallucinogenic and psychoactive effects; isatisine A (8)6
possesses antiviral activity; and flinderole C (9)7 acts as a
selective antimalarial agent (Figure 2).
(1) (a) Aygun, A.; Pindur, U. Curr. Med. Chem. 2003, 10, 1113. (b)
Pindur, U.; Lemster, T. Curr. Med. Chem. 2001, 8, 1681. (c) Ishikura,
M.; Terashima, M. Tetrahedron Lett. 1992, 33, 6849. (d) Kozikowski,
A. P.; Ma, D. Tetrahedron Lett. 1991, 32, 3317.
Figure 1. Representative pyrrolo[1,2-a]indole frameworks.
(2) For a representative example, see: Hao, L.; Pan, Y.; Wang, T.;
Lin, M.; Chen, L.; Zhan, Z.-p. Adv. Synth. Catal. 2010, 352, 3215.
(3) (a) Kakadiya, R.; Dong, H.; Lee, P.-C.; Kapuriya, N.; Zhang, X.;
Chou, T.-C.; Lee, T.-C.; Kapuriya, K.; Shah, A.; Su, T.-L. Bioorg. Med.
Chem. 2009, 17, 5614. (b) Tanaka, M.; Sagawa, S.; Hoshi, J.-I.;
Shimoma, F.; Yasue, K.; Ubukata, M.; Ikemoto, T.; Hase, Y.; Takahashi,
M.; Sasase, T.; Ueda, N.; Matsushita, M.; Inaba, T. Bioorg. Med. Chem.
2006, 14, 5781.
Numerous routes to the pyrrolo[1,2-a]indoles have been
reported in recent years,8 underlining the continued im-
portance of this framework to the synthetic community.
(6) Liu, J.-F.; Jiang, Z.-Y.; Wang, R.-R.; Zheng, Y.-T.; Chen, J.-J.;
Zhang, X.-M.; Ma, Y.-B. Org. Lett. 2007, 9, 4127.
(7) Fernandez, L. S.; Buchanan, M. S.; Carroll, A. R.; Feng, Y. J.;
(4) Wolkenberg, S. E.; Boger, D. L. Chem. Rev. 2002, 102, 2477.
(5) Vepsalainen, J. J.; Auriola, S.; Tukiainen, M.; Ropponen, N.;
Callaway, J. C. Planta Med. 2005, 71, 1053.
Quinn, R. J.; Avery, V. M. Org. Lett. 2009, 11, 329.
r
10.1021/ol202431x
Published on Web 10/11/2011
2011 American Chemical Society

these reactions are prevalent in the literature,11 the lesser
studied intramolecular variants offer tremendous utility for
the synthesis of complex indole-containing polycycles.12
We recently reported an efficient synthesis of hydropyrido-
[1,2-a]indole-6(7H)-ones via an In(III)-catalyzed tandem
cyclopropane ring-opening/intramolecular FC alkylation
sequence.13 Encouraged by this previous work, we reaso-
ned that an intramolecular FC reaction should occur if the
corresponding methyl 2-(1H-indole-1-carbonyl)acrylates
12 were employed as the cyclization precursors.
Adding credence to this hypothesis, Hadjipavlou-Litina
and Papaioannou recently reported the unexpected forma-
tion of a 1H-pyrrolo[1,2-a]indole-3(2H)-one from treatment
of a N-cinnamoyl indole derivative with an excess of TFA
in dichloromethane.14 This reaction only occurred when
the aryl portion of the cinnamate had electron-donating
ortho- and para-methoxy substituents. When no methoxy
group was present or if the aryl ring had only one methoxy
group in the ortho- or para-position, no cyclization
occurred.15 In hopes of circumventing this limitation and
given that alkylidene malonates have been shown to offer
enhanced reactivity as Michael acceptors in comparison to
simple R,β-unsaturated alkenes,16 we synthesized N-acylated
indoles 12 according to Scheme 2. Treatment of an indole
with methyl malonyl chloride afforded the β-ester-amide
11, and Knovenagel condensation with a suitable aldehyde/
ketone furnished the desired acrylates 12.
Figure 2. Representative examples of biologically active
1H-pyrrolo[1,2-a]indole-based natural products.
However, a general and efficient method that allows for
a variety of functionality to be incorporated about the
1H-pyrrolo[1,2-a]indole skeleton has yet to be achieved.9
Scheme 1. Intramolecular FriedelÀCrafts Alkylations of
Methyl 2-(1H-Indole-1-carbonyl)acrylates
Scheme 2. Substrate Synthesis
Toward this end, we report an efficient and diastereo-
selective approach to functionalized 1H-pyrrolo[1,2-a]-
indole-3(2H)-ones via an In(OTf)3-catalyzed intramole-
cular FriedelÀCrafts (FC) alkylations of methyl 2-(1H-
indole-1-carbonyl)acrylates (Scheme 1). The Michael-type
FC reaction of indoles with R,β-unsaturated carbonyl
compounds is a powerful strategy in the total synthesis of
complex products.10 While intermolecular examples of
With a facile method in hand to prepare the acrylates,
we chose the 4-methoxyphenyl derivative 12a (from
p-anisaldehyde) as the test substrate to develop and opti-
mize the reaction conditions. After several experimental
iterations, the conditions for efficient and timely conver-
sion were determined to be 10 mol % In(OTf)3 in 1,
2-dichloroethane at reflux.17
Table 1 shows the scope and limitations of the cycliza-
tion when aromatic groups are present on the acrylate.
Using the optimized conditions, the 1H-pyrrolo[1,2-a]indole
product 13a (derived from our test substrate 12a) was
formed in 95% yield with a 15:1 trans/cis dr18 (entry 1).19
(8) For a seminal review on pyrrolo[1,2-a]indoles, see: Verboom, W.;
Reinhoudt, D. N. Recl. Trav. Chim. Pays-Bas 1986, 105, 199.
(9) For recent syntheses of pyrrolo[1,2-a]indoles, see: (a) Li, L.; Du,
D.;Ren, J.;Wang, Z. Eur. J. Org. Chem. 2011, 614. (b) Hong, L.;Sun, W.;
Liu, C.; Wang, L.; Wang, R. Chem.;Eur. J. 2010, 16, 440. (c) Wood, K.;
Black, D. S.; Kumar, N. Aust. J. Chem. 2010, 63, 761. (d) Schultz, D. M.;
Wolfe, J. P. Org. Lett. 2010, 12, 1028. (e) He, W.; Yip, K.-T.; Zhu, N.-Y.;
Yang, D. Org. Lett. 2009, 11, 5626. (f) Huang, X.; Zhu, S.; Shen, R. Adv.
Synth. Catal. 2009, 351, 3118. (g) Enders, D.; Wang, C.; Raabe, G.
Synthesis 2009, 4119. (h) Cui, H.-L.; Feng, X.; Peng, J.; Lei, J.; Jiang, K.;
Chen, Y.-C. Angew. Chem., Int. Ed. 2009, 48, 5737. (i) Wood, K.; Black,
D. S.; Kumar, N. Tetrahedron Lett. 2009, 50, 574.
(10) For a seminal reference, see: Zhuang, W.; Hansen, T.; Jorgensen,
K. A. Chem. Commun. 2001, 347.
(11) For recent reviews, see: (a) Blay, G.; Pedro, J. R.; Vila, C. Catal.
Asymmetric Friedel-Crafts Alkylations 2009, 223. (b) Poulsen, T. B.;
Jorgensen, K. A. Chem. Rev. 2008, 108, 2903.
(12) For some representative examples of intramolecular FriedelÀ
Crafts alkylations with indoles, see: (a) Medeiros, M. R.; Schaus, S. E.;
Porco, J. A., Jr. Org. Lett. 2011, 13, 4012. (b) Zhou, J.-L.; Ye, M.-C.;
Sun, X.-L.; Tang, Y. Tetrahedron 2009, 65, 6877. (c) Cincinelli, R.;
Dallavalle, S.; Merlini, L.; Nannei, R.; Scaglioni, L. Tetrahedron 2009,
65, 3465. (d) Malona, J. A.; Colbourne, J. M.; Frontier, A. J. Org. Lett.
2006, 8, 5661. (e) Bergman, J.; Venemalm, L.; Gogoll, A. Tetrahedron
1990, 46, 6067.
(13) Patil, D. V.; Cavitt, M. A.; France, S. Chem. Commun. 2011, 47,
10278.
(14) Hadjipavlou-Litina, D.; Magoulas, G. E.; Krokidis, M.;
Papaioannou, D. Eur. J. Med. Chem. 2010, 45, 298.
(15) The corresponding N-cinnamoyl indoles were synthesized, but
no cyclization was observed when heated in DCE or toluene in the
presence of Lewis acid catalysts (10 to 30 mol %).
(16) Evans, D. A.; Rovis, T.; Kozlowski, M. C.; Downey, C. W.;
Tedrow, J. S. J. Am. Chem. Soc. 2000, 122, 9134.
(17) For reaction optimization details, see Supporting Information.
(18) For rationale behind trans/cis dr assignment, see Supporting
Information.
(19) The high diastereoselectivity presumably arises from a postcy-
clization thermodynamic equilibration of the β-amidoester.
Org. Lett., Vol. 13, No. 21, 2011
5821

To determine whether the substituent on the aryl group
conveys an effect upon product formation, the phenyl sub-
strate 12b and the electron-withdrawing 4-bromophenyl
12c, 4-trifluoromethylphenyl 12d, and the 4-nitrophenyl
substrates 12e were synthesized. The phenyl derivative
cyclized to form 13b in 97% yield with a 16:1 dr (entry 2).
Similarly, the electron-deficient arenes 12cÀe also effi-
ciently afforded products 13cÀe in high yields (84À93%)
with >16:1 dr (entries 3À5). Therefore, no discernible elec-
tronic effect of aryl substitution was observed.
Electron-rich heteroaromatics, such as the 2-substituted
furanyl derivative 12f and 2-thienyl derivative 12g, proved
to be suitable substrates, providing 1H-pyrrolo[1,2-a]indole
products 13f and 13g in 97% and 98% yield, respectively, with
highdr(entries6 and 7). Incontrast, the2-pyridylsubstrate
12h did not undergo any appreciable cyclization (entry 8).
This lack of reactivity may be attributed to inductive effects,
given that the 2-pyridyl group prefers to serve as an elec-
tron acceptor. Moreover, the nitrogen of the pyridine could
serve to deactivate the In catalyst by forming a stable complex.
when the phthalimide-protected tryptamine derivative 12i
was subjected to the reaction conditions, 1H-pyrrolo[1,2-a]-
indole product 13i was generated in 96% yield with 14:1 dr
(entry 9). Moreover, 13i can then be readily deprotected
to provide the free amine, which is important for several
natural product targets, such as the flinderoles 9. The
3-(2-bromoethyl)-1H-indole derivative 12j also provided
its cyclization product 13j in 69% yield with a 25:1 dr (entry10).
The methyl acetate substituted indole derivative 12k gen-
erates its cyclized product 13k in 93% yield with 13:1 dr
(entry 11). Finally, when 12l (derived from indole) was em-
ployed, cyclization readily occurred to afford 13l in 98%
yield and 10:1 dr (entry 12).
While pleased with the performance of the aromatic
substrates, we were determined to expand the substrate
scope to include nonaromatic substrates (Table 2). In
particular, we were interested in systems derived from
alkyl aldehydes and cinnamaldehyde. The ethyl substi-
tuted acrylate 12m was the first nonaromatic substrate
synthesized. Unfortunately, subjecting 12m to the opti-
mized reaction conditions only led to long reaction times
(>24h) withoutanyconversionto thedesired 1H-pyrrolo-
[1,2-a]indole. After some optimization, we found that the
cyclization could be achieved more efficiently at a slightly
higher catalyst loading (15%) in toluene at reflux. Under
these new conditions, the cyclized product 13m was furn-
ished in 89% yield as the trans isomer (entry 1). Similar
reactivity was observed for the corresponding propyl sub-
stituted derivative 12n (entry 2). The parent compound,
methyl 2-(1H-indole-1-carbonyl)acrylate 12o (derived
from formaldehyde), gave the 1H-pyrrolo[1,2-a]indole
product 13o in 47% yield. Cinnamate 12p (from cinna-
maldehyde) afforded its product 13p in 71% yield with 8:1
dr (entry 4). We were extremely pleased to find that the 2,
2-disubstituted acrylate 12q (derived from 3-pentanone)
cyclized to generate product 13q, which now contains a
quaternary carbon, in 98% yield (entry 5). Thus, this method
is amenable to substrates derived from ketones and offers a
powerful method to generate a functionalized quaternary
carbon, particularly, if an unsymmetric ketone is used.
An interesting result was obtained when acrylate 12r
(derived from isobutyraldehyde) was subjected to the same
conditions. While we formed the anticipated trans-1H-
pyrrolo[1,2-a]indole product 13r in 86% yield, we also
observed a small amount of the hydropyrido[1,2-a]-
indole product 14 (Scheme 3). This product seemingly
arises from a putative carbocationic intermediate I that
undergoes a 1,2-hydride shift to generate carbocation
II, an intermediate observed in our tandem cyclopro-
pane ring-opening/intramolecular FC cyclization.13 II
then undergoes an intramolecular FC reaction to gen-
erate the six-membered ring in 14. Frontier recently
noted this type of transformation for alkenyl 2-furyl
and alkenyl 2-benzofuryl ketones in the presence of a
highly Lewis acidic IrIII catalyst.20 Both examples high-
light the existence of two possible pathways that depend
Table 1. FriedelÀCrafts Alkylation with Aromatic Acrylatesa
a Reactions run with substrate (1 equiv) and In(OTf)3 (10 mol %) in
1,2-dichloroethane at reflux. b Isolated yields after column chromato-
graphy. c Diastereoselectivities determined from 1H NMR of the crude
reaction mixture and represent trans/cis diastereomeric ratio.
The cyclization is also amenable to substituent changes
about the 3-position of the indole moiety. For example,
(20) Vaidya, T.; Manbeck, G. F.; Chen, S.; Frontier, A. J.; Eisenberg,
R. J. Am. Chem. Soc. 2011, 133, 3300.
5822
Org. Lett., Vol. 13, No. 21, 2011

Given that the cyclization readily occurs with indoles, we
anticipated that pyrroles would behave similarly under the
reaction conditions to form 1H-pyrrolizin-3(2H)-ones.
Pyrrolizine derivatives, many of which are naturally occur-
ring, have attracted considerable attention from both
synthetic and medicinal chemists for their interesting bio-
logical activities and therapeutic potential.21 To our satis-
faction, when N-acyl pyrrole 15 was treated with In(OTf)3
in 1,2-dichloroethane at reflux, the expected pyrrolizine
product 16 was obtained in 54% yield22 (unoptimized)
with 13:1 dr (Scheme 4).
Table 2. Reaction Scope with Nonaromatic Acrylatesa
Scheme 4. Pyrrole as an Effective Substrate
a Reactions run with substrate (1 equiv) and In(OTf)3 (15 mol %) in
toluene at reflux. b Isolated yields after column chromatography. c Dia-
stereoselectivities determined from 1H NMR of the crude reaction
mixture and represent trans/cis diastereomeric ratio. d Only one diaster-
eomer observable by crude NMR.
In summary, we have developed a diastereoselective,
Lewis acid-catalyzed intramolecular FriedelÀCrafts reac-
tion that efficiently generates functionalized 1H-pyrrolo-
[1,2-a]indole-3(2H)-ones in high yields (up to 98%) with
high diastereoselectivities (up to >25:1 dr) from simple,
readily available starting materials. Efforts to employ
chiral catalyst complexes to promote enantioselectivity as
well as further examination of the cationic rearrangement
pathway are currently underway. Future application of
this reaction toward the synthesis of natural products will
be reported in due course.
on both the aromatic character of the heteroaryl moiety
and the Lewis acid catalyst.
Scheme 3. An Alternative Reaction Pathway
Acknowledgment. S.F. thanks the National Science
Foundation (CAREER award CHE-1056687) and Geor-
gia Tech for financial support of this work. M.A.C. thanks
the Ford Foundation (Diversity Fellowship), the NSF
(Graduate Research Fellowship), and Georgia Tech
(Presidential Fellowship) for generous support.
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Finally, to expand the scope of this synthetic approach,
we performed a preliminary test on a different substrate.
(22) Under the reaction conditions, some degradation of 15 was
observed resulting in decreased isolated yields.
(21) Hall, G.; Sugden, J. K.; Waghela, M. B. Synthesis 1987, 10.
Org. Lett., Vol. 13, No. 21, 2011
5823