Sonogashira coupling and Garratt-Braverman cyclization in tandem: Formation of four C-C bonds leading to the synthesis of aryl dihydro isofurans and isoindoles

Article abstract of DOI:10.1016/j.tetlet.2015.02.093

Abstract In this Letter we report an interesting one pot synthesis of aryl dihydro isofurans and isoindoles, naturally occurring privileged skeletons, in excellent yields from easily accessible starting materials. The process involved carrying out three reactions in a tandem manner leading to 4 C-C bond formations, namely two Sonogashira couplings (2 × 1 C-C bond) followed by Garratt-Braverman Cyclization (2 C-C bond).

Full text of DOI:10.1016/j.tetlet.2015.02.093

Tetrahedron Letters 56 (2015) 1964–1967
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Tetrahedron Letters
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Sonogashira coupling and Garratt–Braverman cyclization in tandem:
formation of four C–C bonds leading to the synthesis of aryl dihydro
isofurans and isoindoles
⇑
Debaki Ghosh, Paramita Pal, Amit Basak
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
In this Letter we report an interesting one pot synthesis of aryl dihydro isofurans and isoindoles, naturally
occurring privileged skeletons, in excellent yields from easily accessible starting materials. The process
involved carrying out three reactions in a tandem manner leading to 4 C–C bond formations, namely
two Sonogashira couplings (2 Â 1 C–C bond) followed by Garratt–Braverman Cyclization (2 C–C bond).
Ó 2015 Elsevier Ltd. All rights reserved.
Received 10 January 2015
Revised 17 February 2015
Accepted 18 February 2015
Available online 24 February 2015
Keywords:
Sonogashira
Garratt–Braverman
Cyclization
Tandem
Isofurans
Isoindoles
The Garratt–Braverman cyclization,1 discovered nearly 40 years
ago, has drawn active interest in the past few years. The recent ini-
tiatives have been aimed toward addressing the mechanistic
issues2 and also to explore the synthetic potential3 of the reaction.
The substrates for GB cyclization are the bis-propargyl systems,
namely, sulfones, ethers, and sulfonamides. These, under basic
conditions, are thought to undergo isomerization to bis-allenes,
which then cyclize to the hetero-fused arylnaphthalenes via the
involvement of diradical and subsequent H-shifts (Scheme 1).4
The final outcome of GB cyclization is the efficient formation of
two C–C bonds in a single reaction. The precursor bis-propargyl
systems (for ethers and sulfonamides) are usually obtained by
Sonogashira coupling5 of bromo/iodo arenes with propargyl alco-
hol or sulfonamide followed by O/N-propargylation and another
round of Sonogashira coupling. Thus the complete synthesis of aryl
dihydro isofuran (also called phthalan) and isoindole (also known
as isoindoline) derivatives requires three steps. It would be nice
if all the three reactions can be clubbed together and executed with
the same set of reagents. In this Letter we report the one pot con-
version of bromo/iodo arene and bis-propargyl ether/sulfonamide
to aryl dihydro isofurans or isoindoles in excellent yields, sig-
nificantly better in comparison with the overall yield by the usual
route. The reaction sequence involved two consecutive Pd (0)-
mediated Sonogashira couplings followed by GB cyclization to lead
to the products (Scheme 2).
The idea of combining all the reactions using the same set of
reagents occurred to us considering the fact that both alkyne–
allene isomerization and subsequent cyclization take place under
basic condition6 whereas ene-yne coupling also requires an
YH
X
Y
R
R
R
C
A
B
Y
C
C
Y
R
R
R
R
E
D
Y
R
Y
R
R
F
G
R
⇑
Corresponding author.
E-mail address: absk@chem.iitkgp.ernet.in (A. Basak).
Scheme 1. Usual route to accomplish the synthesis of aryl dihydro furan/isoindole.
http://dx.doi.org/10.1016/j.tetlet.2015.02.093
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

D. Ghosh et al. / Tetrahedron Letters 56 (2015) 1964–1967
1965
Y
X
Y
R
R
R
R
Y
H
A
D
G
R
Scheme 2. The route proposed and followed in the present work.
Table 1
Results of one pot synthesis of naphthoisofurans
O
X
A
O
O
+
A
A
A
A
2a-g
3
4a-g
1a-g
Substrate
Base
Solvent and condition
Product/yield (%)
Overall yield (%) via usual
route as depicted in Scheme 1
Br
DBU
DBU
Toluene, reflux, 8 h
Toluene, reflux, 10 h
1a/80
1b/84
60
2a
Br
61
62
MeO
2b
Br
DBU
Toluene, reflux, 10 h
Toluene, reflux, 9 h
1c/85
2c
Br
DBU
DBU
1d/80
1e/70
55
55
OHC
NC
2d
I
Toluene, rt, 6 h, then reflux, 8 h
Toluene, rt, 8 h, then reflux, 10 h
Toluene, reflux, 20 h
2e
I
DBU
DBU
1f/70
1g/65
52
51
MeO2C
2f
Br
CH3
2g
equivalent of base along with Pd (0) and CuI. The latter reagents
are expected not to interfere with the subsequent isomerization
cum cyclization.
work up and chromatography led to the isolation of the GB product
in 82% yield. Considering that 4 new C–C bond formations
have taken place in a single pot, the yield can be regarded as
excellent.
With the optimum conditions in hand, we next examined the
reaction scope. Thus several bromoarenes were similarly treated
[Pd(PPh3)2Cl2, propargyl ether, toluene, reflux]. In all cases, the
dihydro isofurans were isolated in good to excellent yields.
Interestingly, the reaction also worked well in case of iodoarenes
with an electron withdrawing group (substrates 2e and 2f).
Iodoarenes with electron donor groups, however, failed to work.
The results are shown in Table 1.
We initiated the study by carrying out the reaction of iodoben-
zene with Pd(PPh3)2Cl2 in the presence of DBU. Toluene was
selected as the solvent in view of the high temperature required
in effecting the alkyne-allene isomerization. The temperature
was initially maintained at 30 °C because of high reactivity of
iodoarenes7 toward the coupling reaction. Upon completion of
the two ene-yne coupling reactions as monitored by 1H NMR, the
reaction mixture was refluxed for 8 h. However, to our dismay,
the final arylnaphthalene was isolated in low yields. We then
replaced the iodo with less reactive bromo benzene and the reac-
tion temperature was maintained at 110 °C throughout. Usual
Following the success with the ether system, we then explored
whether the same protocol works for the sulfonamides. Thus a

1966
D. Ghosh et al. / Tetrahedron Letters 56 (2015) 1964–1967
Table 2
Result of one pot synthesis of isoindole derivatives
Ts
N
X
A
NTs
NTs
+
A
A
A
2a, 2c, 2h
7
A
6a, 6c, 6h
5a, 5c, 5h
Substrate
Base
DBU
DBU
Solvent and condition
Toluene, reflux, 6 h
Toluene, reflux, 8 h
Product/yield (%)
5a/82
Overall yield (%) via usual
route as depicted in Scheme 1
Br
60
62
2a
Br
5h/84
2h
Br
DBU
Toluene, reflux, 8 h
5c/85
62
2c
Sonogashira coupling and then DBU for the cyclization. On the
other hand, our method leads to the formation of 4 C–C bonds in
a single pot requiring the use of DBU as a single base. Moreover,
the reaction leads to both isobenzofuran and isoindole derivatives
and the yields are also better than the reported ones.7
R3
I
R3
35-76%
R1
NTs
R1
NTs
+
i
9
10
8
i = Pd(PPh3)2Cl2, CuI, THF, Et3N, rt, 0.5 h, then DBN, 60 oC, 8h
Regarding the possibility of synthesizing dihydro isobenzofuran/
isoindole from unsymmetrical propargyl systems, we attempted the
reactions of several haloarenes with bis-propargyl ether 3 or
sulfonamide 7. The reaction was carried out by performing the first
ene-yne coupling with 1.0 equiv of the haloarene. Then the second
haloarene (1.0 equiv) was added and the reaction was continued till
the completion of GB cyclization. However, in spite of our best
efforts, we failed to stop the bis eneyne coupling even with 1.0 equiv
of haloarene and the reaction became complicated. Except in case
where the first and the second haloarenes were methyl 4-iodo
benzoate (2f) and iodobenzene, (2i), we could obtain the final
dihydroisobenzofuran as a mixture (1h and 1i) from bispropargyl
ether 3 (Scheme 4).
In conclusion, we have successfully brought down the synthesis
of aryl naphthalenes via successive Sonogashira coupling and
Garratt–Braverman Cyclization to a single pot protocol.9 The
method is simple, high yielding and works well for the synthesis
of dihydro isobenzofurn and isoindole systems. Future research
activity will aim toward solving the problem of synthesis involving
unsymmetrical systems.
Scheme 3. Reported work by Zhu et al.8
solution of bromobenzene and sulfonamido bis-propargyl amine in
toluene was refluxed in the presence of Pd(PPh3)2Cl2 and DBU.
Gratifyingly, after usual workup (vide experimental) and chro-
matography, we could isolate the dihydro isoindoles in excellent
yields (Table 2). It may be mentioned here that recently, Zhu et al.8
have reported the synthesis of dihydro isoindoles starting from an
N-bis-propargyl sulfonamide in which one arm already has an
N-aryl propargyl moiety. The method involved one Pd(0)-mediated
ene-yne coupling followed by the formation of dihydro isoindoles
via, according to the authors, an intramolecular [4+2] cycloaddition
cum aromatization. The method reported 3 new C–C bond forma-
tions (Scheme 3) involving iodoalkenes; aryl iodides with electron
withdrawing groups also gave the target isoindoles. With simple
iodobenzene and iodobenzene with electron donor groups like
methoxy, the reaction stopped after the Sonogashira step. Also,
the method involved the use of two different bases, first Et3N for
i: 2f, Pd(PPh3)2Cl2, CuI, DBU,
toluene, rt, 15 min
O
O
O
MeO2C
3
ii:
2i, Pd(PPh3)2Cl2, CuI, rt, 2 h
+
iii: Reflux, 10 h
I
I
1h
CO2Me
1i
MeO2C
2i
2f
Scheme 4. Synthesis of aryl dihydroisobenzofuran from mixed haloarenes.

D. Ghosh et al. / Tetrahedron Letters 56 (2015) 1964–1967
1967
Jemmis, E. D. Chem. Asian J. 2012, 7, 957; (c) Ghosh, D.; Jana, S.; Panja, A.; Anoop,
A.; Basak, A. Tetrahedron 2013, 69, 8724.
Acknowledgements
3. (a) Mitra, T.; Das, S.; Basak, A. Tetrahedron Lett. 2009, 50, 5846; (b) Mondal, S.;
Maji, M.; Basak, A. Tetrahedron Lett. 2011, 52, 1183; (c) Mukherjee, R.; Basak, A.
Synlett 2012, 877; (d) Mitra, T.; Jana, S.; Pandey, S.; Bhattacharya, P.; Khamrai, U.
K.; Anoop, A.; Basak, A. J. Org. Chem. 2014, 79, 5608; (e) Das, J.; Mukherjee, R.;
Basak, A. J. Org. Chem. 2014, 79, 3789.
4. (a) Iwai, I.; Ide, J. Chem. Pharm. Bull. 1964, 12, 1094; (b) Bartlett, A. J.; Laird, T.;
Ollis, W. D. J. Chem. Soc. Perkin I 1975, 1315; (c) Kudoh, T.; Mori, T.; Shirahama,
M.; Yamada, M.; Ishikawa, T.; Saito, S.; Kobayashi, H. J. Am. Chem. Soc. 2007, 129,
4939.
Author A.B. is grateful to DST, Govt. of India, for funding and for
the JC Bose fellowship. D.G. 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.
Supplementary data
5. (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467; (b)
Tykwinski, R. R. Angew. Chem., Int. Ed. 2003, 42, 1566; (c) Negishi, E.; Anastasia,
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093.
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9. General experimental procedure:
References and notes
To a solution of aryl bromide/iodide (2.0 mmol) and the alkyne 3/7 (1.0 equiv) in
toluene, DBU (5 equiv) was added followed by PdCl2(PPh3)2 (6 mol %) and CuI
(10 mol %). For aryl bromide, the mixture was refluxed at 110 °C for 8–20 h. For
aryl iodide, the reaction mixture was stirred at room temperature for 6–8 h and
then at 110 °C for 8–10 h. The reaction mixture was evaporated under vacuo and
then diluted with water and the aqueous phase was extracted with EtOAc
(3 Â 50 mL). The combined organic layers were dried over Na2SO4, filtered and
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evaporated using
a rotavap. The crude product was purified by column
chromatography on silica gel.