Novel protocol for the synthesis of octahydropyrano- and thiopyrano[4,3-a]carbazole derivatives via Prins/Friedel-Crafts cyclization

Article abstract of DOI:10.1016/j.tetlet.2012.12.113

A novel Prins/Friedel-Crafts cyclization of (Z)-6-(1-methyl-1H-indol-3-yl) hex-3-en-1-ol with aldehydes has been achieved using a catalytic amount of BF₃·OEt₂ under mild reaction conditions to produce the corresponding octahydropyrano[4,3-a]carbazole derivatives in good yields with high diastereoselectivity. The cross-coupling of (Z)-6-(1-methyl-1H-indol- 3-yl)hex-3-ene-1-thiol with aldehydes affords the corresponding octahydrothiopyrano[4,3-a]carbazole derivatives under similar conditions. Copyright

Full text of DOI:10.1016/j.tetlet.2012.12.113

Tetrahedron Letters 54 (2013) 1392–1396
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Novel protocol for the synthesis of octahydropyrano- and
thiopyrano[4,3-a]carbazole derivatives via Prins/Friedel–Crafts cyclization
B. V. Subba Reddy a, , P. Sivaramakrishna Reddy a, J. S. Yadav a, B. Sridhar b
⇑
a Natural Product Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
b Laboratory of X-ray Crystallography, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel Prins/Friedel–Crafts cyclization of (Z)-6-(1-methyl-1H-indol-3-yl)hex-3-en-1-ol with aldehydes
has been achieved using a catalytic amount of BF3ÁOEt2 under mild reaction conditions to produce the
corresponding octahydropyrano[4,3-a]carbazole derivatives in good yields with high diastereoselectivity.
The cross-coupling of (Z)-6-(1-methyl-1H-indol-3-yl)hex-3-ene-1-thiol with aldehydes affords the corre-
sponding octahydrothiopyrano[4,3-a]carbazole derivatives under similar conditions.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 5 October 2012
Revised 26 December 2012
Accepted 27 December 2012
Available online 8 January 2013
Keywords:
Prins/Friedel–Crafts reaction
Acid catalysis
Aldehydes
Pyrano[4,3-a]carbazole
The carbazole core is often found in various natural products.1 In
particular, pyranocarbazole alkaloids are very attractive due to their
fascinating structural features and potential biological activity.2
Furthermore, pyranocarbazole core is present in several alkaloids
such as heptazolicine, euchrestifoline, cis-dihydroxygirinimbine,
clausine-T, and many others (Fig. 1).3 Some of these alkaloids are
known to exhibit antidiarrheal and antitumor activities.4,5
In recent years, the Prins cyclization has received special atten-
tion because of its versatility for the construction of tetrahydropyran
scaffolds.6 In particular, intramolecular version of Prins cyclization
is very useful for the stereoselective construction of fused heterobi-
cycles and tricycles.7,8 Inspired by inherent biological properties of
carbazoles, we were interested to develop a novel strategy for the
synthesis of octahydropyrano- and thiopyrano[4,3-a]carbazole
derivatives. However, to the best of our knowledge, there have been
no reports on the preparation of thiopyrano[4,3-a]carbazole deriva-
tives via a tandem Prins/Friedel–Crafts cyclization.
Me
CHO
O
O
N
N
H
HO
H
O
Euchrestifoline
Heptazolicine
Me
CHO
O
HO
O
N
H
N
H
HO
OH
OH
cis-Dihydroxygirinimbine
Clausine-T
Figure 1. Naturally occurring pyrano[3,2-a]carbazole alkaloids.
dropyrano[4,3-a]carbazole 3a was isolated in 87% yield with cis-
selectivity (Scheme 1).
In continuation of our research findings on Prins cyclization,9
we herein report a novel strategy for the synthesis of octahydro-
pyrano- and thiopyrano[4,3-a]carbazole derivatives via Prins-
and thia-Prins/Friedel–Crafts cyclization, respectively. Accordingly,
we first attempted the cross-coupling of (Z)-6-(1-methyl-1H-indol-
3-yl)hex-3-en-1-ol (1) with benzaldehyde (2) using BF3ÁOEt2 in
dichloromethane. The reaction went to completion within 10 min
at room temperature and the desired product, 4-phenyl-octahy-
The cis-stereochemistry of 3a was established by 1H NMR
experiments. The coupling between Ha–Hb (JHa–Hb = 1.9 Hz) and
Hb–Hc (JHb–Hc = 4.5 Hz) indicates that Ha, Hb, and Hc are in cis-ori-
entation. This is further confirmed by the presence of nOe cross
peaks between Ha–Hb, Hb–Hc, and Ha–Hc as depicted in Figure 2.
The geometry of the olefin controls the stereoselectivity of the
reaction. It is known that cis-olefin gives the cis-fused product
exclusively whereas the trans-olefin provides the trans-fused prod-
uct predominantly.8d Unlike, classical Prins cyclization, no forma-
tion of 4-fluoro- or 4-hydroxytetrahydropyrans was observed in
⇑
Corresponding author. Fax: 91 40 27160512.
E-mail address: basireddy@iict.res.in (B.V. Subba Reddy).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.113

B. V. Subba Reddy et al. / Tetrahedron Letters 54 (2013) 1392–1396
1393
this reaction. Inspired by the above results, we extended this
process for other substituted aldehydes. The scope of the reaction
is illustrated with respect to various aldehydes and the results are
summarized in Table 1. The cross-coupling of (Z)-6-(1-methyl-
1H-indol-3-yl)hex-3-en-1-ol (1) with p-bromobenzaldehyde under
the above conditions gave the corresponding cis-fused octahydro-
pyrano[4,3-a]carbazole (3c) in 83% yield (Table 1, entry c).
The structure of 3c was confirmed by X-ray crystallography
(Fig. 3).10
HO
O
H
BF3OEt2
H
O
+
DCM, rt, 10 min
N
CH3
H
N
CH3
1
2
3a
Scheme 1. Reaction of (Z)-6-(1-methyl-1H-indol-3-yl)hex-3-en-1-ol with
benzaldehyde.
Various substituted aromatic aldehydes such as p-chloro-,
p-nitro-, p-methyl-, p-methoxy-, p-fluoro-, and p-cyano-benzalde-
hydes participated well in this reaction. As seen from Table 1, both
electron-rich and electron-deficient aldehydes gave the desired
products in good yields (Table 1). Furthermore, acid sensitive
furan-2-carboxaldehyde also underwent a smooth coupling with
(Z)-6-(1-methyl-1H-indol-3-yl)hex-3-en-1-ol (1) to give the
corresponding cis-4-furanyl-octahydropyrano[4,3-a]carbazole in
δ 2.48
Ph
O
Hb
N
H
δ 4.77
Ha
δ 3.23
Hc
85% yield (Table 1, entry i). Notably, a sterically hindered
a-naph-
JHa-Hb = 1.9 Hz; JHb-Hc = 4.5 Hz
thaldehyde also gave the product 3l in excellent yield (Table 1,
Figure 2. Characteristic nOes of 3a.
Table 1
BF3ÁOEt2 catalyzed tandem Prins/Friedel–Crafts cyclization
Entry
Alcohol (1)
Aldehyde (2)
Product (3)a
Time (min)
Yieldb (%)
CHO
OH
H
H
H
H
O
a
10
87
N
N
H
CHO
Cl
Br
OH
Cl
b
10
85
N
H
O
N
H
CHO
OH
Br
c
d
e
f
15
20
10
10
83
85
90
N
N
N
H
O
N
N
H
CHO
CHO
NO2
OH
O2N
H
H
O
H
Me
OH
Me
H
H
H
O
N
N
H
H
CHO
OMe
OH
MeO
87
N
H
O
(continued on next page)

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B. V. Subba Reddy et al. / Tetrahedron Letters 54 (2013) 1392–1396
Table 1 (continued)
Entry
Alcohol (1)
Aldehyde (2)
Product (3)a
Time (min)
Yieldb (%)
CHO
OH
H
H
g
10
90
N
O
N
H
CHO
OH
H
H
h
10
87
N
N
O
N
H
OH
OH
O
H
CHO
O
H
O
i
j
10
10
85
90
N
N
H
H
CHO
H
H
O
N
N
CHO
F
OH
F
H
H
k
10
10
87
90
H
O
N
H
H
CHO
OH
OH
H
l
N
N
O
N
CHO
CN
NC
H
H
m
10
10
89
80
H
O
N
N
H
H
CHO
OH
H
n
O
N
a
All products were characterized by 1H NMR, IR, and mass spectrometry.
Yield refers to pure products after chromatography.
b
entry l). The structure of 3l was confirmed by X-ray crystallogra-
phy (Fig. 4).10
This method works well not only with aromatic aldehydes but
also with aliphatic aldehydes like cyclohexanaldehyde, n-hexanal,
n-propanal, and n-butanal. In case of aliphatic aldehydes, the cor-
responding alkyl-substituted octahydropyrano[4,3-a]carbazole
derivatives were obtained in good yields (Table 1, entries g, h, j,
and n). Thus, it provides a diverse range of cis-fused octahydropyr-
ano[4,3-a]carbazole derivatives in a single-step operation.
Next attempt was made to examine the reactivity of (Z)-4-
methyl-N-(6-(1-methyl-1H-indol-3-yl)hex-3-enyl)benzenesulfon-
amide (4) and (Z)-6-(1-methyl-1H-indol-3-yl)hex-3-ene-1-thiol
(5). Surprisingly, (Z)-4-methyl-N-(6-(1-methyl-1H-indol-3-yl)hex-
3-enyl)benzenesulfonamide (4) failed to give the desired product
Figure 3. ORTEP diagram of 3c.

B. V. Subba Reddy et al. / Tetrahedron Letters 54 (2013) 1392–1396
1395
O
BF3
+
N
N
R
H
R
OH
O
..
N
R
O
Scheme 3. A plausible reaction pathway.
dichloroethane. However, the cross-coupling of (Z)-6-(1-methyl-
1H-indol-3-yl)hex-3-ene-1-thiol (5) with benzaldehyde in the
presence of BF3ÁOEt2 at room temperature gave the corresponding
octahydrothiopyrano[4,3-a]carbazole (6d) in 75% yield (Scheme 2,
Table 2).
Figure 4. ORTEP diagram of 3l.
The scope of thia-Prins cyclization with various aldehydes like
n-butanal, p-nitrobenzaldehyde, and p-bromobenzaldehyde is
illustrated in Table 2 (entries a–d).11 The structure of the products
was established by NMR, IR, and mass spectroscopy. The effect of
various Lewis acids such as Sc(OTf)3, In(OTf)3, La(OTf)3, and InBr3
as well as Bronsted acids such as p-TSA and CSA were screened
for this conversion. Of these, BF3ÁOEt2 was found to give the best
results in Prins- and thia-Prins/Friedel–Crafts cyclization. As a sol-
vent, dichloromethane gave the best results.
HS
O
H
BF3.OEt2
H
S
+
DCM, rt, 35 min
N
CH3
H
N
CH3
5
2
6d
The reaction was expected to proceed via the formation of
oxocarbenium ion from hemi-acetal which is formed in situ from
an aldehyde and a homoallylic alcohol, likely after activation
through BF3ÁOEt2. This is followed by the attack of an internal ole-
fin resulting in the formation of carbocation which is simulta-
neously trapped by an indolyl group leading to the formation of
octahydropyrano[4,3-a]carbazole as depicted in Scheme 3.
Scheme 2. Reaction of (Z)-6-(1-methyl-1H-indol-3-yl)hex-3-ene-1-thiol with
benzaldehyde.
under the influence of acid catalysts such as Sc(OTf)3, Sc(OTf)3/p-
TSA, InCl3, In(OTf)3, InBr3, and BF3ÁOEt2 in various amounts ranging
from catalytic to stoichiometric even at reflux temperature in
Table 2
BF3ÁOEt2 catalyzed tandem thia-Prins/Friedel–Crafts cyclization
Entry
Thiol (5)
Aldehyde (2)
Product (6)a
Time (min)
45
Yieldb (%)
CHO
SH
H
H
S
a
80
N
N
H
CHO
NO2
SH
O2N
H
b
40
75
N
N
N
H
S
N
H
CHO
Br
SH
SH
Br
H
c
30
35
83
75
H
S
N
N
H
H
CHO
H
H
S
d
a
All products were characterized by 1H NMR, IR, and mass spectrometry.
Yield refers to pure products after chromatography.
b

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B. V. Subba Reddy et al. / Tetrahedron Letters 54 (2013) 1392–1396
5. Cui, C.-B.; Yan, S.-Y.; Cai, B.; Yao, X.-S. J. Asian Nat. Prod. Res. 2002, 4, 233.
In summary, we have developed a novel strategy for the synthe-
6. (a) Olier, C.; Kaafarani, M.; Gastaldi, S. S.; Bertrand, M. P. Tetrahedron 2010, 66,
413. and references cited therein; (b) Pastor, I. M.; Yus, M. Curr. Org. Chem.
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8316; (d) Borkar, P.; van de Weghe, P.; Reddy, B. V. S.; Yadav, J. S.; Gree, R.
Chem. Commun. 2012, 48, 9316.
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sis of octahydropyrano- and thiopyrano[4,3-a]carbazole deriva-
tives in a highly diastereoselective manner via a cascade of Prins
cyclization using a catalytic amount of BF3ÁOEt2. This method pro-
vides a rapid access to the synthesis of a wide range of pyrano- and
thiopyrano[4,3-a]carbazole derivatives in good yields with excel-
lent selectivity.
Acknowledgment
8. (a) Yadav, J. S.; Chakravarthy, P. P.; Borkar, P.; Reddy, B. V. S.; Sarma, A. V. S.
Tetrahedron Lett. 2009, 50, 5998; (b) Yadav, J. S.; Borkar, P.; Chakravarthy, P. P.;
Reddy, B. V. S.; Sarma, A. V. S.; Sridhar, B.; Grée, R. J. Org. Chem. 2010, 75, 2081;
(c) Reddy, B. V. S.; Borkar, P.; Chakravarthy, P. P.; Yadav, J. S.; Grée, R.
Tetrahedron Lett. 2010, 51, 3412; (d) Reddy, B. V. S.; Borkar, P.; Yadav, J. S.;
Sridhar, B.; Grée, R. J. Org. Chem. 2011, 76, 7677.
P.S.R.K.R. thanks CSIR, New Delhi for the award of a fellowship.
Supplementary data
9. (a) Reddy, B. V. S.; Ganesh, A. V.; Krishna, A. S.; Kumar, G. G. K. S. N.; Yadav, J. S.
Tetrahedron Lett. 2011, 52, 3342; (b) Reddy, B. V. S.; Anjum, S. R.; Reddy, G. M.;
Yadav, J. S. Tetrahedron Lett. 2012, 53, 1790; (c) Reddy, B. V. S.; Jalal, S.; Borkar,
P.; Yadav, J. S.; Reddy, P. P.; Kunwar, A. C.; Sridhar, B. Org. Biomol. Chem. 2012,
10, 6562; (d) Reddy, B. V. S.; Borkar, P.; Yadav, J. S.; Reddy, P. P.; Kunwar, A. C.;
Sridhar, B.; Gree, R. Org. Biomol. Chem. 2012, 10, 1349.
10. CCDC-909200 (3c) and CCDC-909201 (3l) contain the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Supplementary data (spectral data and NMR spectra) associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2012.12.113.
References and notes
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Knolker, H.-J. Pure Appl. Chem. 2010, 82, 1975; (b) Knolker, H.-J.; Reddy, K. R.
Chem. Rev. 2002, 102, 4303; (c) Knolker, H.-J. Top. Curr. Chem. 2005, 244, 115;
(d) Knolker, H.-J.; Reddy, K. R. In The Alkaloids; Cordell, G. A., Ed.; Academic
Press: Amsterdam, 2008; Vol. 65, pp 1–430.
3. (a) Wu, T.-S.; Huang, S.-C.; Wu, P.-L. Heterocycles 1997, 45, 969; (b) Furukawa,
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11. General procedure: To
homoallylic alcohol, or thiol (1 mmol) in anhydrous dichloromethane
(5 mL) was added catalytic amount of BF3.OEt2 (10 mol %). The
a
stirred solution of aldehyde (1 mmol),
a
resulting mixture was stirred at room temperature under nitrogen
atmosphere for the specified time (Table 1). After completion of the
reaction as indicated by TLC, the mixture was quenched with saturated
NaHCO3 and extracted with dichloromethane (2 Â 15 mL). The combined
organic layers were concentrated in vacuo and the resulting residue was
purified by column chromatography on silica gel (Merck, 60–120 mesh,
ethyl acetate/hexane, 1:9) to afford the pure product.
4. Mandal, S.; Nayak, A.; Kar, M.; Banerjee, S. K.; Das, A.; Upadhyay, S. N.; Singh, R.
K.; Banerji, A.; Banerji, J. Fitoterapia 2010, 81, 72.