Lewis Acid Catalyzed Three-Component [3+2] Cycloaddition Reaction Using Pentafulvene as 2π Component: An Easy Way to Construct Pentaleno(1,2-b)indoles

Article abstract of DOI:10.1055/s-0036-1588696

A facile route toward the synthesis of pentaleno(1,2-b)indoles via multicomponent reaction of indole, aldehyde, and pentafulvene is realized. The reaction proceeds through Lewis acid catalyzed [3+2] cycloaddition of in situ generated indolylmethanol and pentafulvene. This methodology provides an easy access to biologically relevant indole derivatives.

Full text of DOI:10.1055/s-0036-1588696

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©
Georg Thieme Verlag Stuttgart · New York
2017, 28, A–F
A
letter
Synlett
P. V. Santhini et al.
Letter
Lewis Acid Catalyzed Three-Component [3+2] Cycloaddition Reac-
tion Using Pentafulvene as 2π Component: An Easy Way to Con-
struct Pentaleno(1,2-b)indoles
R3
P. V. Santhinia,b
S. Sarath Chanda,b
Jubi Johna,b
R. Luxmi Varmaa,b
Florian Jaroschikc
Ph
O
Ph
Ph
H
Ph
Lewis acid
+
H
+
N
R1
R2
R2
R3
N
R1
H
K. V. Radhakrishnan*a,b
1
2
R3 = H, Cl, Br, F
17 examples
R
R
= H, Me
= H, Me, F
a
Organic Chemistry Section, National Institute for Interdisciplinary Science
and Technology (CSIR), Trivandrum 695019, India
radhu2005@gmail.com
b
Academy of Scientific and Innovative Research (AcSIR), New Delhi
110001, India
c
Institut de Chimie Moléculaire de Reims and Université de Reims, BP
039, 51687 Reims Cedex, France
1
9
Received: 14.10.2016
Accepted after revision: 09.01.2016
Published online: 03.02.2017
try of cross-conjugated trienes, we were intrigued to study
the reaction outcome by replacing the diene component of
the reaction by replacing it with pentafulvene.
DOI: 10.1055/s-0036-1588696; Art ID: st-2016-b0693-l
Abstract A facile route toward the synthesis of pentaleno(1,2-b)in-
doles via multicomponent reaction of indole, aldehyde, and pentaful-
vene is realized. The reaction proceeds through Lewis acid catalyzed
CN
H
H
HN
OH
Cl
H
H
[
3+2] cycloaddition of in situ generated indolylmethanol and pentaful-
H
H
N
vene. This methodology provides an easy access to biologically relevant
indole derivatives.
N
H
H
N
H
H
H
Fischer indole L
Keywords fulvene, indole, cycloaddition, multicomponent reaction,
cyclopentaleno indoles
Yuehchkene
Polyveoline
H
F
Ring-fused indoles, ubiquitous to many structurally
H
OH
O
COOH
O
N
complex natural products and bioactives, have acquired
considerable scientific attention over the years (Figure 1).1
A number of synthetic procedures including Friedel–Crafts
O
O
S
N
,2
O
H
O
MK-0524
Shearinine A
Cl
3
4
5
reactions, transition-metal /Lewis/Brønsted acid catalysis
Figure 1 Biologically important fused indole derivatives1
and catalytic asymmetric synthetic strategies5 have been
developed for such fused indole scaffolds. The 3- or 2-indo-
lylmethanols formed by the acid-catalyzed condensation of
indole and aldehyde were utilized as the three-carbon syn-
thons in a variety of [3+2], [3+3], and [4+3] intermolecular
cycloaddition reactions providing fused indole derivatives.6
In line with the report of Yonemitsu on the three-compo-
nent reaction of indole, aldehydes, and meldrums acid, di-
verse indole scaffolds, in particular, 2,3-disubstituted/ring-
Pentafulvenes have been utilized as a valuable synthons
for the synthesis of many natural products and biologically
10
11
12
active molecules due to its ability to act as a 2π, 4π , or
13
6π component in diverse cycloaddition reactions. New en-
docyclic ring functionalization of fulvenes based on transi-
tion-metal or FLP system mediated reactions have also
emerged.14 Very recently, we have utilized pentafulvene as
an unsymmetrical alkene for the Lewis acid catalyzed regi-
7
fused indoles were synthesized. Inspired by the report of
15
Winne et al. on the [4+3] cycloaddition reaction of furfuryl
cations to 1,3-diene, Wu and co-workers adopted a similar
protocol for the gallium(III)-catalyzed regio- and diastereo-
selective three-component [4+3] cycloaddition reaction of
in situ generated indolyl methanol to 1,3-diene toward the
oselective hydroheteroarylation reaction (Figure 2, b).
Herein we report a Lewis acid catalyzed three-component
cycloaddition reaction involving indole, aldehyde, and pen-
tafulvene in which one of the endocyclic double bonds of
pentafulvene acts as a 2π component towards the synthesis
of cyclopenta-annulated indole derivatives (Figure 2, c).
8
synthesis of cyclohepta[b]indoles (Figure 2, a). Motivated
by these results and our continuing interest in the chemis-
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

B
Synlett
P. V. Santhini et al.
Letter
(
a) Previous work by Wu and co-workers
HRMS. Furthermore, the stereochemistry of compound 4ad
was unambiguously confirmed by single-crystal X-ray anal-
ysis (Figure 3).
Cyclopentadiene as 4π componet in (4+3) cycloaddition reaction
R3
R2
O
Lewis acid
+
+
R2
R3
N
Ref. 8a
R1
N
R1
(
b) Hydroheteroarylation of fulvene
Ph
Ph
Ph
Ph
Lewis acid
Ref. 15
+
N
R1
N
R1
R3
Figure 3 Single-crystal X-ray structure of 4ad (CCDC 1488241)16
(
c) This strategy
Pentafulvene as 2π component in [3+2] cycloaddition reaction
Ph
We then turned our attention to optimize the reaction
conditions with 1a, 2a, and 3a as substrates. Lewis acids
such as Sc(OTf) , Cu(OTf) , Fe(OTf) , BF ·OEt , and Sn(OTf)
O
Ph
Ph
Lewis acid
H
Ph
+
H
+
3
2
3
3
2
2
N
R2
R2
were able to furnish the desired product 4aa along with
R1 R3
N
R1
H
1
2
4aa and 4aa . The expected cycloaddition product 4aa was
not observed with Yb(OTf) , Zn(OTf) , and La(OTf) , and in
3
2
3
Figure 2 New strategy toward the synthesis of cyclopentaleno[1,2-
b]indoles
these cases the reaction was found to halt at the stage of the
1
intermediate indolyl methanol 4aa . However, the AgOTf-
Anticipating a three-component cycloaddition reaction,
we initiated our experiments by treating an equimolar mix-
ture of indole 1a, aldehyde 2a, and diphenylfulvene 3a in
MeCN at room temperature in the presence of catalytic
catalyzed reaction was found to furnish the hydroheteroa-
rylated product 4aa in addition to 4aa . To determine the
2
1
Table 1 Optimization studies
amount of Sc(OTf) for 12 hours (Scheme 1). Interestingly,
3
the reaction afforded the [3+2] cycloadduct 4aa in 40% yield
Entry
1a
Catalyst
Sc(OTf)
Solvent
Yield (%)
(instead of the established [3+4] cycloaddition product for
4
aa
4aa1
4aa2
other dienes (Figure 2, a) along with minor amounts of hy-
2
droheteroarylated product (4aa ) and indolyl methanol
3
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
CH Cl
40
45
–
15
12
45
43
52
32
18
–
18
20
–
1
(
4aa ). The structural assignment of the fused indole scaf-
2
a
Cu(OTf)2
La(OTf)
fold 4aa was done with the aid of various spectroscopic
3a
3
1
13
techniques such as H NMR and C NMR spectroscopy and
4a
5a
6a
7a
8a
9a
Yb(OTf)
Zn(OTf)
–
–
3
2
–
-
HO
Ph
Ag(OTf)
Fe(OTf)
AlCl
BF ·OEt
–
23
22
15
18
8
3
35
43
45
52
10
35
35
–
N
H
3
aa1 (15%)
3
2
14
12
–
4
Ph
10
a
Sn(OTf)2
TfOH
O
Ph
Ph
Ph
H
Ph
11a
12b
13b
15
14
8
Sc(OTf)3
H
N
MeCN
rt, 12 h
Sn(OTf)2
Sn(OTf)2
Sn(OTf)2
–
2
2
H
N
H
1a
2a
3a
H
DCE
–
4aa (40%)
14
b
THF
35
33
31
–
Ph
Ph
1
5b
Sn(OTf)
Sn(OTf)
Sn(OTf)
2
2
2
toluene
DMF
–
25
32
1
6b
–
1
7b,c
MeCN
62
trace
trace
N
H
a
All reactions were carried out with 2 mol% catalyst, 1 equiv of 1a, 1 equiv
4
aa2 (18%)
of 2a, 1 equiv of 3a in 2 mL of solvent at r.t. for 4 h.
b
Equivalents of 2a and 3a increased to 1.5 equiv in 2 mL of toluene at r.t.
Scheme 1 Multicomponent reaction of indole, aldehyde, and diphenyl
fulvene
for 2 h.
c
Trace amount of the byproduct alcohol was observed.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

C
Synlett
P. V. Santhini et al.
Letter
effect of Brønsted acid on the present reaction, a reaction
was performed with catalytic amounts of HOTf, from which
the product 4aa was obtained in poor yield. We then
checked the feasibility of various solvents for the exclusive
formation of the cycloaddition product. The use of solvents
such as toluene, CH Cl , DCE, and THF was less effective in
delivering the expected product. Finally, MeCN turned out
as the best reaction medium for the present multicompo-
nent reaction. The use of Sn(OTf) as Lewis acid in MeCN (2
2
mL) decreased the reaction time to two hours with a better
yield of cycloaddition product 4aa (62%).1
6,17
In addition,
the yield of the reaction was found to improve with the in-
2
2
R3
Ph
O
R
R
Sn(OTf)2
Ph
H
R2
R3
MeCN
rt, 2 h
N
R2
H
N
H
1a–d
2a–g
3a, b
4aa–5ad
Cl
Ph
Ph
Ph
Br
Ph
Ph
Ph
N
N
H
N
H
H
4
aa (62%)
4ab (55%)
4ac (56%)
F
Br
OMe
Ph
Ph
Ph
Ph
Ph
Ph
N
N
N
H
H
H
4ad (55%)
4ae (58%)
4af (0%)
Cl
Br
Cl
Ph
Ph
Ph
Me
Ph
Ph
Me
Ph
N
H
N
N
H
H
4ag (40%)
4bd (66%)
4ca (54%)
Cl
Br
Ph
Ph
Ph
Ph
Ph
Ph
Br
Me
Me
N
N
H
N
H
H
F
4cc (55%)
4cd (57%)
4da (35%)
Me
Me
Me
Me
N
N
H
H
5aa (52%)
5ad (45%)
Scheme 2 Scope of the reaction with various indoles and aldehydes. All reactions were carried out with 2 mol% catalyst, indole (1 equiv), aldehyde (1.5
equiv), pentafulvene (1.5 equiv) in 2 mL of toluene at r.t. for 2 h.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

D
Synlett
P. V. Santhini et al.
Letter
crease in the equivalents of fulvene and aldehyde (Table 1,
entry 17). From the detailed optimization, the standard
conditions for the reaction was found to be a combination
of indole (1 equiv), aldehyde (1.5 equiv), fulvene (1.5 equiv),
R3
Ph
O
Ph
Sn(OTf)2
H
and Sn(OTf) (2 mol %) affording [3+2] cycloaddition prod-
2
R3
R2
3a
uct 4aa in 62% yield in MeCN within two hours.
Under the optimal reaction conditions, the scope of the
reaction was explored with various aldehydes and ketones.
N
R1
MeCN
rt, 2 h
R2
N
R1
1e–g
2a–d
4ea–ga
Cl
Aromatic aldehydes bearing electron-withdrawing groups
3
(
R = Cl, Br, F) were tolerated well under the reaction condi-
tions, and afforded the cycloaddition products 4aa–ag in
Ph
Br
Ph
Ph
moderate to good yields. However, aldehydes with elec-
Ph
Ph
Ph
3
tron-rich substituents (R = 2,4-OMe, Me) were unable to
take part in the cycloaddition reaction.
N
N
N
In addition, aliphatic aldehydes and ketones also failed
to undergo multicomponent [3+2] cycloaddition reaction
resulting in a complex reaction mixture. Pentafulvenes
with alkyl, dialkyl, and unsymmetrical substituents at the
exocyclic position did not afford the expected products 4aa,
instead hydroarylated and polymerized products were
Me
Me
Me
4ea (70%)
4eb (65%)
4ec (56%)
Br
Ph
Ph
Ph
Ph
Ph
Ph
1
formed as evident from H NMR analysis of the reaction
mixture. The scope of the reaction was then explored with
N
N
N
6
,6′-diaryl pentafulvene 3b (derived from 4,4′-dimethyl-
Me
ed (68%)
Bz
Boc
benzophenone), which afforded the product 5aa–ad in
moderate yields. Further reactions were performed to ex-
tend the scope of reaction to indole substrates bearing elec-
tron-donating and electron-withdrawing substituents; all
of which afforded the corresponding products in good
yields (Scheme 2).
4
4fa (0%)
4ga (0%)
Scheme 3 Scope of the reaction with various N-substituted indoles. All
reactions were carried out with 2 mol% catalyst, indole (1 equiv), alde-
hyde (1.5 equiv), pentafulvene (1.5 equiv) in 2 mL of toluene at r.t. for 2 h.
Scheme 3 delineates the scope of the reaction with re-
spect to the substituents on the indole nitrogen. The reac-
tions with N-methyl indole delivered the expected fused in-
dole derivatives 4ea in good yield (70%) compared to the
unprotected indoles. On the other hand, electron-deficient
N-protecting groups (Boc, Bz, Ts) failed to afford the desired
cyclopentalenoindole derivatives.
In conclusion, we have developed a Lewis acid mediated
three-component reaction for the synthesis of fused poly-
cyclic indole skeleton in which fulvene acts as a 2π cycload-
dition partner. This Schlenk-free strategy tolerates a variety
of aryl aldehydes and indoles to furnish various pentale-
no[1,2-b]indoles. Studies on the scope of the reaction with
pentafulvenes other than diphenylfulvenes and various 3π
components are currently under way.
A mechanistic proposal for the Lewis acid catalyzed
three-component reaction on the basis of our experimental
8
results and previous reports is shown in Scheme 4. The
Acknowledgment
process involves an intial Lewis acid catalyzed formation of
carbocation intermediate A or the vinyliminium intermedi-
ate B from indole 1 and aldehyde 2 which can undergo ei-
ther a concerted or a stepwise reaction to realize the cy-
cloadduct. The initial [2+2] cycloaddition of the intermedi-
ate A/B with the pentafulvene 3 is followed by a ring
expansion, by 1,2-migration analogous to the mechanism
proposed for [3+2] cycloaddition reported by Moody et al.
furnishing cyclopentalenoindoles III in a concerted man-
P.V.S. and S.C.S. thank UGC for a research fellowship. Financial assis-
tance from Indo-French Centre for Promotion of Advanced Research
[IFCPAR/CEFIPRA (Project 4505-1)] and Council of Scientific and In-
dustrial Research, New Delhi (12th FYP project, ORIGIN-CSC-0108)
are greatly acknowledged. The authors also thank Mrs. Saumini
Mathew, Mrs. S. Viji, Ms. Aathira S., and Mr. Saran P. Raveendran of
CSIR-NIIST, Trivandrum for recording NMR and mass spectra. Thanks
are due to Dr. Sunil Varghese of CSIR-NIIST, Trivandrum, for single-
crystal X-ray analysis.
6a
ner. The stepwise pathway involves endocyclic functional-
ization of fulvene 3, with the indole core A/B to deliver the
intermediate C in a regioselective manner and followed by
proton loss to yield cyclopentalenoindole III from the inter-
Supporting Information
Supporting information for this article is available online at
6b
mediate D.
http://dx.doi.org/10.1055/s-0036-1588696.
S
u
p
p
ortioIgnfmr oaitn
S
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p
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rm oaitn
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Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

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Synlett
P. V. Santhini et al.
Letter
R2
R2
R2
H
OH
LA
+
N
R1
N
R1
N
R1
2
I
A
B
Ph
Ph
N
1
R1
Ph
Ph
3
LA
Path A
Path B
Concerted
Stepwise
3
Ph
Ph
R2
H
Ph
Ph
Ph
Ph
R2
N
R1 II
C
N
R1
N
R1
R2
Ph
R2
Ph
H
Ph
H
Ph
– H+
N
R1
H
N
R1
H
D
III
Scheme 4 Plausible reaction pathways
References and Notes
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8) (a) Han, X.; Li, H.; Hughes, R. P.; Wu, J. Angew. Chem. Int. Ed.
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c) Laplace, D. R.; Verbraeken, B.; Hecke, K. V.; Winne, J. M.
(
Chem. Eur. J. 2014, 20, 253.
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9) (a) Sarath Chand, S.; Jijy, E.; Prakash, P.; Szymoniak, J.;
Preethanuj, P.; Dhanya, B. P.; Radhakrishnan, K. V. Org. Lett.
2013, 15, 3338. (b) Sarath Chand, S.; Saranya, S.; Preethanuj, P.;
Dhanya, B. P.; Jijy, E.; Prakash, P.; Sasidhar, B. S.; Szymoniak, J.;
Santhini, P. V.; Radhakrishnan, K. V. Org. Biomol. Chem. 2014,
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L.; Radhakrishnan, K. V. RSC Adv. 2015, 5, 38075.
(
10) (a) Little, R. D.; Carroll, G. L. Tetrahedron Lett. 1981, 22, 4389.
b) Little, R. D.; Miller, G. W.; Venegas, M. G.; Carroll, G. L.;
Bukhari, A.; Patton, L.; Stone, K. Tetrahedron 1981, 33, 4371.
(15) Sarath Chand, S.; Greeshma, G.; Santhini, P. V.; Preethanuj, P.;
Jubi, J.; Harakat, D.; Jaroschik, F.; Radhakrishnan, K. V. Org. Lett.
2016, 18, 9646.
(
(
(
8
c) Lei, B.; Fallis, A. G. J. Am. Chem. Soc. 1990, 112, 4609.
d) Goering, B. K.; Li, J.; Ganem, B. Tetrahedron Lett. 1995, 36,
905. (e) Ebner, C.; Carreira, E. M. Angew. Chem. Int. Ed. 2015,
(16) Typical Experimental Procedure for 4aa
A mixture of indole 1a (50 mg, 0.427 mmol), pentafulvene 3a
(147 mg, 0.640 mmol), aldehyde 2a (70 mg, 0.640 mmol), and
54, 11227.
Sn(OTf) (4 mg, 0.008 mmol) were weighed in to a reaction tube
2
(
11) (a) Arai, K. Synthesis 1989, 501. (b) Nair, V.; Anilkumar, G.;
Radhakrishnan, K. V.; Nandakumar, M. V.; Kumar, S. Tetrahe-
dron 1997, 53, 15903. (c) Nair, V.; Kumar, S.; Williard, P. G. Tet-
rahedron Lett. 1995, 36, 1605. (d) Nair, V.; Anilkumar, G.;
Radhakrishnan, K. V.; Sheela, K. C.; Rath, N. P. Tetrahedron 1997,
and dry MeCN (2 mL) was added and allowed to stir at r.t. for 2
h. The solvent was evaporated in vacuo and the residue on silica
gel (100–200 mesh) column chromatography with mixture of
hexane–EtOAc yielded the products.
(17) Spectral Data of Compound 4aa
53, 17361. (e) Nair, V.; Nandakumar, M. V.; Maliakal, D.;
Yield 115 mg, 62%; off-white solid, mp 155–160 °C; R = 0.43
f
Mathen, J. S.; Rath, N. P. Tetrahedron 2000, 56, 8001. (f) Nair, V.;
Mathew, B.; Menon, R. S.; Mathew, S.; Vairamani, M.;
Prabhakar, S. Tetrahedron 2002, 58, 3235. (g) Hong, B.-C.; Shri,
Y.-J.; Liao, J.-H. Org. Lett. 2002, 4, 663. (h) Boger, D. L.; Huter, O.;
Mbiya, K.; Zhang, M. J. Am. Chem. Soc. 1995, 117, 11839.
(hexane–EtOAc = 9:1). IR (neat) νmax = 3402, 3056, 3026, 2923,
–1
1710, 1603, 1489, 1449, 1361, 1224, 1060, 1028, 750, 701 cm
.
1
H NMR (500 MHz, CDCl , TMS): δ = 7.84 (s, 1 H), 7.27–7.7.25
3
(m, 3 H), 7.23–7.21 (m, 1 H), 7.19–7.17 (m, 2 H), 7.14–7.13 (m, 5
H), 7.05–7.01 (m, 2 H), 7.00–6.97 (m, 3 H), 6.89 (t, J = 8 Hz, 1 H),
6.50–6.48 (m, 2 H), 6.44–6.43 (m, 1 H), 6.33 (d, J = 8.5 Hz, 1 H),
(
12) (a) Lonergan, D. G.; Deslongchamps, G. Tetrahedron 1998, 54,
13
14041. (b) Warrener, R. N.; Butler, D. N. Aldrichimica Acta 1997,
4.74–4.66 (m, 2 H), 4.20 (s, 1 H). C NMR (125 MHz, CDCl ): δ =
3
3
0, 119. (c) Radhakrishnan, K. V.; Nandakumar, M. V.; Rath, N. P.
148.0, 146.3, 143.6, 143.4, 142.9, 141.4, 136.8, 135.1, 134.8,
130.2, 129.7, 128.6, 127.9, 127.7, 126.9, 126.8, 126.7, 125.3,
124.3, 122.3, 121.1, 119.7, 118.9, 111.4, 61.5, 51.6, 50.8. ESI-
Synlett 1997, 767. (d) Nzabamwita, G.; Kolani, B.; Jousseaume, B.
Tetrahedron Lett. 1989, 30, 2207. (e) Manikandan, S.;
Shanmugasundaram, M.; Raghunathan, R. Tetrahedron 2002, 58,
+
HRMS: m/z calcd for C23H25N [M + H] : 436.20652; found:
597. (f) Bhojgude, S. S.; Kaicharla, T.; Bhunia, A.; Biju, A. T. Org.
436.20610.
Lett. 2012, 14, 4098.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F