Garratt-Braverman cyclization on basic alumina: A green protocol with improved selectivity

Article abstract of DOI:10.1016/j.tetlet.2014.05.033

A green protocol (compared to the existing methodology) for carrying out Garratt-Braverman cyclization has been developed. The method involves stirring a pre-absorbed bispropargyl sulfone/ether/sulfonamide over basic alumina. The reaction with sulfones wa

Full text of DOI:10.1016/j.tetlet.2014.05.033

Accepted Manuscript
Garratt-Braverman cyclization on basic alumina: A green protocol with im-
proved selectivity
Debaki Ghosh, Subhanip Biswas, Koena Ghosh, Amit Basak
PII:
S0040-4039(14)00822-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.05.033
TETL 44624
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
27 February 2014
6 May 2014
7 May 2014
Please cite this article as: Ghosh, D., Biswas, S., Ghosh, K., Basak, A., Garratt-Braverman cyclization on basic
alumina: A green protocol with improved selectivity, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/
j.tetlet.2014.05.033
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Garratt-Braverman cyclization on basic
alumina: A green protocol with improved
selectivity
Debaki Ghosh, Subhanip Biswas, Koena Ghosh and Amit Basak*
A simple green protocol for carrying out the GB reaction on basic alumina support is described. The reaction
proceeded in high yields and with significantly higher selectivity in case of ethers and sulfonamides with
dissimilar aryl groups.
X
Al2O3
A2
X
A1
X
+
O
O
O
A1
A2
A1
A2
Basic Al2O3
For X = SO2, r.t. 10-15 min, 90-95% For X = O, NSO2Ar, 130 oC, 6-8 h, 80-90%

Garratt-Braverman cyclization on basic alumina: A green protocol with improved
selectivity
Debaki Ghosh, Subhanip Biswas, Koena Ghosh and Amit Basak*+
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
+ absk@chem.iitkgp.ernet.in
Abstract: A green protocol (compared to the existing methodology) for carrying out Garratt-Braverman cyclization has been developed.
The method involves stirring a pre-absorbed bispropargyl sulfone/ether/sulfonamide over basic alumina. The reaction with sulfones was
o
over within 10-15 min at room temperature whereas for the ether/sulfonamide the reaction took 6-8 h at 130 C. The products, aryl
naphthalene derivatives, are obtained by simple filtration through Si-gel, in excellent yields.
Organic reactions on porous solid support under
solvent-free conditions offer many advantages over
traditional solution phase synthesis.1 These include
product yields, reaction time, benign conditions, ease of
purification and recyclability of the support2 which are
essential attributes of green chemistry. In addition, the
solid supports have cavities/ channels or large surface
area with highly porous exteriors available to substrates.3
These pores can act as micro reactors where the reactant
can bind and undergo the transformation. This can lead
to higher selectivity4 and less side reactions as compared
to the same reaction under solution phase. Amongst the
many solid supports that have been used, alumina is an
important member due to its surface property and well
defined porosity.5 It is also available in basic, neutral and
acidic forms and the choice of selection depends upon
the nature of the reaction. Some of the examples of
reactions on alumina include oxidation, alkylation,
addition, heterocycle synthesis etc.6 Recently, we have
developed interest in expanding the synthetic scope of
Garratt-Braverman (GB) cyclization,7 a reaction of
importance as it involves formation of two C-C bonds
(Scheme 1). The usual substrates for GB reaction are bis-
propargyl sulfones/ethers/sulfonamides. While triethyl
amine can bring about the rearrangement of the sulfones,
stronger bases like KOBut, NaH or DBN8, are required
for ethers and sulfonamides. We were interested in
finding a suitable alternative but simple protocol for GB
cyclization. Since it is widely believed that the
rearrangement proceeds via the formation of a bis-allene,
for which one needs the base, it occurred to us that basic
alumina could be a possible alternative. The latter has a
pH of 9-10 which should be enough to cause the required
isomerization of propargyl to allene that subsequently
undergoes the GB reaction. This is indeed found to be
true and herein we report successful GB reaction on
basic alumina, the latter performing the dual role as a
solid support as well as a basic catalyst. The reaction
proceeds in solvent-free conditions leading to the
synthesis of easily isolable aryl naphthalenes in high
yields. To the best of our knowledge, this is the first
example of GB reaction on a solid support under solvent-
free condition.
Initially a series of bis-propargyl sulfones 1a-e were
prepared following the literature procedure.9 These were
pre-absorbed on basic alumina (0.5 mmol substrate: 500
mg alumina) and then stirred at room temperature for 10-
15 min. The product aryl naphthalene sulfones were

2
o
substrates was stirred at 130 C for 6-8 h (Table 2-3).
isolated pure in high yields simply by extraction with
DCM filtration and evaporation followed by
crystallization. The results are compiled in Table 1.
O
The products were isolated following the same procedure
as adapted for the sulfones.
The known GB products were characterized by
comparing with those reported in the literature9 while the
structures of the unknown products were determined by
extensive NMR and mass spectral analysis. Thus for the
major product 6n from the GB reaction of 3n, the 13C
NMR showed 9 aryl C-H signals (Figure 1). For the
other isomer 5n, 11 aryl C-H signals were expected.
O
O
O
S
S
S
C
O
O
C
.
R
R
.
R
O
O
O
O
S
S
New C-C bond
R
R
O
New C-C bond
A1
A2
O
O
+
Scheme 1: GB cyclization of bis-propargyl systems
A2
A1
A2
A1
O
O
S
5m-r
6n-r
3m-r
O
O
A
S
SM
A1
A2
phenyl
Product Yield
(%)
A
A
A
phenyl
phenyl
80
3m
3n
5m
1a-e
2a-e
6-methoxy-
2-naphthyl
85
5n & 6n
SM
1a
A
Product
2a
% yield
95
phenyl
2-naphthyl
88
3o
5o & 6o
phenyl
93
2-naphthyl
1b
1c
2b
phenyl
2-pyridyl
85
86
3p
3q
6p only
95
2,4-dimethoxy phenyl
2c
4-anisyl
2-naphthyl
5q & 6q
90
5-methoxy N-ethoxy
carbonyl
1d
2d
3r
2-naphthyl
9-
phenanthryl
5r & 6r
85
3-indolyl
N-methoxy carbonyl
3-indolyl
90
1e
2e
Table 2: Results of GB reaction of bis-propargyl ethers
over basic alumina
Table 1: Results of GB reaction of bis-propargyl sulfones
over basic alumina
Apart from the operational simplicity, one other
interesting feature of this alumina-based protocol is the
significantly higher selectivity in case of unsymmetrical
ethers and sulfonamides as compared to solution phase
(Table 4, entries 1-3, 5) except for 3r (entry 4), for which
the selectivity remained nearly the same. For
sulfonamides 4k and 4l, reversal of selectivity was
observed (entry 6-7).
Encouraged by the success with sulfones, we focused
on the possible extension of this protocol to GB reaction
of propargyl ethers and sulfonamides. We realized that
because of lower acidity of the propargylic hydrogens in
ethers/sulfonamides as compared to that in sulfones, it
may be necessary to raise the temperature which was
found to be true. Thus when the ether or the sulfonamide
(0.5 mmol) was pre-absorbed on the solid surface of
basic alumina (500 mg) and stirred at room temperature
for up to 48 h, no product was obtained; only the starting
material was recovered. However, high yields of the
dihydro isobenzofuran/dihydro isoindole derivatives
were obtained when the alumina with pre-absorbed
Thus it appears that the reaction possibly follows
different mechanisms on alumina and in solution. The
generally accepted mechanism of GB reaction in solution
involves the formation of an intermediate diradical; so

3
far, nothing is known about the mechanism when carried
out on solid phase. Although knowledge of the latter
needs deeper investigation, at this stage, it appears that
the loss of resonance energy during formation of product
(see mechanism shown in Scheme 1) plays a key role. As
the resonance energy per benzene ring is less in
naphthalene compared to benzene, the former
preferentially participates. Although it is difficult to
explain the reversal of selectivity as observed in the
reaction of 4k and 4l under solid phase conditions, it
may be that the bis-allene conformation leading to the
The remarkable ability of basic alumina can be ascribed
to the presence of Al–O- groups on the alumina surface
that acts as a base to assist the isomerization of propargyl
to allene system. Once the bis-allene is formed, it
undergoes spontaneous cyclization via the diradical10 or
any other reactive intermediate (to be investigated) to
lead to the products11,12 (Scheme 2). The basic centres
also played an important role in facilitating the H+ shifts
required in order to regain aromaticity. Regarding
recyclability, the solid support after the reaction of
sulfones could be reused at least 5 times without
significant loss of activity. However, in case of ether or
sulfonamide, the recovered alumina could not be reused
because of use of prolonged heating at high temperature.
major product has a better adaptation in the micro pores.
R
N
R
N
A2
R
N
A1
Entry Substrate
Products Ratio in Product ratio
the existing In solution
+
A2
A1
A2
A1
protocol
1:11
phase
1.25:1
g-l
4
-l
7g
g-k, R = 4-methylbenzenesulfonyl, for l R=4-nitrobenzenesulfonyl
h-l
8
5n & 6n
5o & 6o
5q & 6q
5r & 6r
7j & 8j
7k & 8k
7l & 8l
1
2
3
4
5
6
3n
3o
3q
3r
4j
1:10
1:11
1:1.2
1:3
1:1.6
1:6
SM
4g
A1
A2
Product
7g
% yield
87
phenyl
phenyl
1:1.3
1:1
4h
2-naphthyl
2-naphthyl
85
7h
4i
9-
9-
89
7i
4k
1:5
3.3:1
4.5:1
phenanthryl
phenyl
phenanthryl
2-naphthyl
7
4l
1:1.75
4j
90
85
7j & 8j
Table 4: Selectivity comparisons for solid and solution
phases
4k
phenyl
Phenyl
4-anisyl
4-anisyl
7k & 8k
85
4l
7l & 8l
A
A
O
O
H
O
OH
Al2O3
Al2O3
X
X
II
Table 3: Results of GB reaction of bis-propargyl
sulfonamides on basic alumina
O
O
I
A
A
O
H
A
O
A
C
C
O H
Al2O3
O
Al2O3
X
X
H
O
O
III
A
IV
A
H
A
X
O
O
O
C
C
C
X
MeO
A
X
O
Al2O3
6n
A
A
5n
C
A
VII
O
MeO
11 Aryl C-H signals expected in DEPT-
135
A
9 Aryl C-H signals expected in
DEPT-135
H
VI
V
Scheme 2: Proposed mechanism for alumina mediated GB.
In conclusion we have developed a green and high
yielding method for carrying out the GB reaction of
various bis-propargyl sulfones, ethers and sulfonamides
Figure 1: 13C NMR DEPT 135 and H-decoupled of 6n

4
A. Tetrahedron Lett. 2012, 53,19. (i) Basak, A.; Das, S.;
Mallick, D.; Jemmis, E. D. J. Am. Chem. Soc. 2009, 131,
15695. (j) Mohamed, R. K.; Peterson, P. W.; Alabugin, I. V.
Chem. Rev. 2013, 113, 7089 and references therein.
using basic alumina. The selectivity shown by the
unsymmetrical ethers is also very high. Our current
efforts aim is directed towards bringing down the
temperature for GB reaction of ethers or sulfonamides.13
8. Kudoh, T.; Mori, T.; Shirahama, M.; Yamada, M.; Ishikawa,
T.; Saito, S., and Kobayashi, H. J. Am. Chem. Soc. 2007,
129, 4939.
Acknowledgement
9. Mondal, S.; Maji, M.; Basak, A. Tetrahedron Lett. 2010, 52,
1183. (b) Mitra, T.; Das, J.; Maji, M.; Das, R.; Das, U. K.;
Chattaraj, P. K.; Basak, A. RSC Advances 2013, 3, 19844.
10. Maji, M.; Mallick, D.; Mondal, S.; Anoop, A.; Bag, S, S.;
Basak, A.; Jemmis, E. D. Org. Lett. 2011, 13, 888.
The author AB is grateful to DST, Govt. of India, for
funding and for the JC Bose fellowship. DG thanks
CSIR, Govt. of India for a research fellowship (NET).
DST is also thanked for the funds for a 400 MHz facility
under the IRPHA program.
11. Experimental procedure: A solution of compounds 1a-e
(0.50 mmol) in dichloromethane (5 mL) was added to basic
alumina (500 mg) and the contents thoroughly mixed and
dried under vacuum. For sulfones: the mixture was stirred
at r.t. for 10-15 mins after which it was extracted with ethyl
acetate. Filtration followed by evaporation afforded the
product which was crystallized from hexane and ethyl
acetate mixture. For ethers or sulfonamides, the contents
References and Notes
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o
was stirred at 130 C for 6-8 h, then cooled and proceeded
like sulfones.
3. Sanchez-Valente, J.; Hernandez-Beltran, F.; Guzman-
Castillo, M. L.; Fripiat, J. J.; Bokhimi, X. J. Mater. Res.
2004, 19, 1499. (b) Keshavarz, A. R.; Rezaei, M.; Yaripour,
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12. Spectral data: Compound 2c: δH (400 MHz, CDCl3): 8.12
(s, 1 H), 7.09 (d, J = 8.0 Hz, 1H), 6.63-6.61 (m, 2H), 6.54
(s, 1H) , 6.51 (s, 1H) , 4.58-4.54 (m, 2H), 4.25 (d, J = 16.0
Hz, 1H) , 4.07 (d, J = 16.0 Hz, 1H), 3.97 (s, 3H) , 3.91 (s,
3H), 3.71 (s, 3H), 3.69 (s, 3H); δC (100 MHz, CDCl3)
161.4, 158.9, 158.1, 156.7, 134.7, 132.1, 130.6, 125.3,
122.2, 119.1, 118.9, 105.2, 99.3, 98.3, 96.9, 57.8, 56.9,
56.0, 55.8, 55.7, 55.4. Mass: m/z 415 (MH+); Compounds
5r and 6r: δH (400 MHz, CDCl3): 8.86-8.83 (m, 1H, minor
and 1H, major), 8.66-8.62 (m, 3H, minor), 8.56-8.55 (m,
2H, major), 7.94-7.26 (m, 12H, major and 11H, minor),
6.92 (dt, J = 7.2, 1.2 Hz, 1H, major), 6.82 (t, J = 8.0 Hz,
1H, minor), 5.42 (m, 2H, minor and 2H, major), 5.17 (d, J
= 12.0 Hz, 1H, major), 4.93 (td, J = 13.2, 1.2 Hz, 1H, major
and 1H, minor) ,4.62 (d, J = 13.2 Hz, 1H, minor); δC (100
MHz, CDCl3) (major + minor) 141.0, 140.6 , 140.5 , 138.9,
138.5, 137.9, 134.2, 134.1, 134.0, 133.5, 132.8, 132.4,
131.9, 131.7, 131.3, 131.2, 130.8, 130.6, 130.5, 130.4,
130.3, 130.2, 129.9, 129.4, 129.3, 129.1, 128.7, 128.4,
128.3, 128.2, 128.0, 127.9, 127.7, 127.6, 127.5, 127.4,
127.3, 127.2, 127.1, 126.8, 126.7, 126.6, 126.5, 125.6,
124.6, 123.7, 123.5, 123.4, 123.3, 123.0, 121.1, 115.1, 74.6,
74.5, 74.2, 74.1; Mass (ESI): m/z 397 (MH+).
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McKillop A.; Young, K. W. 1979, 401. (c) Cornelis, A.;
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Chakraborty, R. Das, A. R.; Saha, M.; Sarkar, A. K.;
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M.; Ranu, B. C. J. Org. Chem. 2010, 75, 8533.
13. We have repeated the reaction with DBN pre-absorbed on
basic Al2O3 with one of the bis-propargyl ether 3n at three
7. Garratt, P. J.; Neoh, S. B. J. Org. Chem. 1979, 44, 2667. (b)
Cheng,Y. S. P.; Garratt, P. J.; Neoh, S. B.; Rumjanek, V. H.
Isr. J. Chem. 1985, 26, 101. (c) Braverman, S.; Duar, Y.;
Segev, D. Tetrahedron Lett. 1976, 17, 3181. (d) Zafrani, Y.;
Gottlieb, H. E.; Sprecher, M.; Braverman, S. J. Org. Chem.
2005, 70, 10166. (e) Mondal, S.; Mitra, T.; Mukherjee, R.;
Addy, P. S.; Basak, A. Synlett 2012, 23, 2582-2602. (f)
Mondal, S.; Basak, A.; Jana, S.; Anoop, A. Tetrahedron
2012, 68, 7202. (g) Mukherjee, R.; Mondal, S.; Basak, A.;
Mallick, D.; Jemmis, E. D. Chemistry - An Asian Journal
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o
o
temperature conditions, namely, r.t. (35 C), 50 C and 90
oC. There was no reaction at r.t. or at 50 oC. Prolonged
o
heating at 90 C led to decomposition. We have also tried
KF on basic Al2O3. In this case, the reaction of ethers could
be accomplished at 80 oC (with basic Al2O3 only, the
reaction temperature was 130 oC) but at the cost of
selectivity. For example, the reaction of unsymmetrical
ether 3n gave the products 5n and 6n in the ratio of ~1.15:1
as against 1:11 in basic Al2O3 only.