Pd-free Sonogashira coupling: One pot synthesis of phthalide via domino Sonogashira coupling and 5-exo-dig cyclization

Article abstract of DOI:10.1039/c4ra07639g

Phthalides have been synthesized exclusively in one pot via Pd-free Sonogashira coupling. A Cu-catalyzed domino Sonogashira coupling and 5-exo-dig cyclization between suitable substituted ortho-bromobenzoic acids and terminal alkynes afforded phthalides in good yields under mild reaction conditions.

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Graphical Abstract
Pd-free Sonogashira Coupling: One pot synthesis of Phthalide via domino
Sonogashira coupling and 5-exo-dig cyclization
Shubhendu Dhara, Raju Singha, Munmun Ghosh, Atiur Ahmed, Yasin Nuree, Anuvab
Das and Jayanta K. Ray*
Corresponding author: Tel.: +91 3222283326; fax: +91 3222282252.
E-mail address: jkray@chem.iitkgp.ernet.in

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Pd-free Sonogashira Coupling: One pot Synthesis of
Phthalide via domino Sonogashira Coupling and 5-exo-
dig Cyclization
Cite this: DOI: 10.1039/x0xx00000x
Shubhendu Dhara,a Raju Singha,a Munmun Ghosh,a Atiur Ahmed,a Yasin Nuree,a
Anuvab Dasa and Jayanta K. Ray*a
Received 00th 2014,
Accepted 00th
2014
DOI: 10.1039/x0xx00000x
www.rsc.org/
In literature there are few reactions involving Pd-free Sonogashira
coupling for the synthesis of heterocycles and carbocycles. We
envisaged that regio-selectively 3-substituted phthalides could be
obtained by domino Sonogashira coupling and 5-exo-dig cyclization
(Scheme 1).
Phthalides have been synthesized exclusively in one pot via
Pd-free Sonogashira coupling.
A Cu-catalyzed domino
Sonogashira coupling and 5-exo-dig cyclization between
suitable substituted ortho-bromobenzoic acids and terminal
alkynes afforded phthalides in good yields under mild
reaction condition.
Phthalides are the core structural subunit of enormous drug
candidates.1 Though, many phthalide derivatives are used as clinical
medicine, two most important marketed drugs are antiarthritic agent
talniflumate2 and the immunosuppressant drug mycophenolate
mofetil.3 Particularly C3-substituted phthalides are exemplified by
Scheme 1: Retro-synthetic analysis
the natural products cytosporone
E
(1)4, fuscinarin (2)5,
cryphonectric acid (3)6 (Fig.1) and important intermediate in
synthesis of complex natural products.7
Consequently, in this report we have described an interesting method
for one-pot synthesis of 3-substituted phthalides exclusively starting
from o-bromobenzoic acid and terminal alkyne (Scheme 2).
Therefore, owing to their pharmacological importance and synthetic
utility in organic synthesis development of efficient and economic
method of preparation is of considerable interest for last few
decades.
Scheme 2: Synthesis of phthalides
The precursor 2-bromobenzoic acids were prepared in moderate to
good yields via Pinnick oxidation12 from the corresponding
aldehydes. We started the investigation of the domino process with
simple 2-bromobenzoic acid (1mmol) and phenylacetylene (0.1
mmol) (Table 1). While screening with different Cu-salt, we
identified CuI (10 mmol %) as a convenient and inexpensive catalyst
that is more effective over the other. DMF gave the better yields of
the product compared to other solvents. Addition of ligands (such as,
1, 10-phenanthroline) did not have marked effect on the reaction
yields (Table 1, entry 6). Amine base triethylamine have prominent
Fig 1: Bioactive phthalide derivatives
A number of methods for the synthesis of 3-substituted phthalide
have been developed, most of them involved the cyclization of
ortho-substituted arylaldehydes8 or C3-alkylation of phthalides.9
Recently, several transition-metal mediated syntheses of phthalide
such as, Ru-catalysed cross-dehydrogenative coupling10 and and Ru-
or Rh-catalyzed intramolecular hydroacylation11 have been reported.
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effect on reaction among the organic and inorganic bases. Some The scope and generality of the reaction was demonstrated by
synthesizing a number of structurally diverse phthalide derivatives
with varying substituents (Table 2). Results described in the Table 2
shows that our synthetic protocol has a wide range functional group
tolerance, including amine, alkyl, halogens, methoxy and primary
alcoholic OH. Influence of the electron-donating and withdrawing
functional groups on both the coupling partner is quite clear from the
results in Table 2. Electron withdrawing group such as F and pyridyl
ring in combination with COOH in the 2-bromobenzoic acid part
increase the reactivity of the C-Br bond producing good yields of
phthalides (3b, 3l). In contrast, electron-donating group methyl,
methoxy, tBu in both acids and alkyne part decrease the reactivity of
alkyne moiety as well as C-Br bond resulting lower yields of
phthalides (3c, 3d, 3f). A steric factor may be operating in the o-
chloro substituent and the bulky aryl group in the alkyne part which
afforded quite lower amount the phthalide formation (3g, 3i, 3j).
increment of the product yields was resulted with elevation of
temperature from 60 °C to 80 °C (Table 1, entry 7). Further elevation
temperature to 100 °C did not affect the yields of the reaction.
Table 1: Optimization of reaction conditions for the domino
processb
Entry Catalyst Base Solvent Temp.(°C) Time (h) Yield (%)c
1
2
3
4
CuI
Et3N DMF
Et3N DMF
Et3N DMF
60
60
60
60
60
60
80
80
80
3
3
3
3
3
75
45
30
25
0
Table 2: Synthesis of phthalide derivativesd,†
CuBr
CuCl
Cu(OTf)2 Et3N
Cu(OAc)2 Et3N
DMF
DMF
DMF
DMF
DMF
DMA
5
6
7
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
Et3N
Et3N
Et3N
Et3N
Et3N
3
74*
90
65
65
53
50
41
44
90
3
8
5
9
3
3
3
3
3
3
10
11
12
13
14
DMSO 80
NaOAc DMF
Na2CO3 DMF
K2CO3 DMF
80
80
80
Et3N
DMF
100
bReaction conditions: o-bromobenzoic acids (1 mmol), phenylacetylene (0.1
mmol), base ( 3.0 mmol), Cu-salt (10 mol %), solvent (3 mL). cIsolated
yield. *With 1,10-phenanthroline ligand.
We found that prolonged reaction time did not give better conversion
of phthalides. Optimal conditions for the domino reaction were
finalized to be CuI (10 mol %), Et3N (3.0 mmol), DMF (3mL), 80
°C, 3 h.
Exclusive formation of the phthalide was unambiguously confirmed
by the single crystal structure analysis of the product formed with an
exo-cyclic double. CCDC of the compound 3a is 1000643 and
ORTEP of the compound is shown in Fig 2.
Fig 2: The X-ray crystal structure of compound 3a
2 | J. Name., xxxx, xx, x-x
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Table 2 : Continued.
In conclusion, we have developed a very short and efficient
methodology for the regio-selective synthesis of 3-substituted
phthalide using very cheap starting materials and under mild reaction
conditions. Our methodology is a very convenient one to be applied
in the total synthesis of complex molecules of prevalent
pharmacological values.
Products(% yields)e
Alkyne
Entry
Substrate
N
H
Br
HN
O
O
10
COOH
Br
3j ( 56 %)
Ph
Ph
11
12
Notes and references
O
a
COOH
Department of Chemistry, Indian Institute of Technology, Kharagpur-
O
3k ( 72 %)
721302, India
O
COOH
Br
E-mail: jkray@chem.iitkgp.ernet.in
Ph
O
Electronic Supplementary Information (ESI) available: See
DOI: 10.1039/c000000x/
†General procedure of the preparation of 3-substituted phthalides:
N
N
3l ( 80 %)f
Ph
Ph
COOH
Br
o-bromobenzoic acids (1mmol), terminal alkyne (0.1 mmol), Et3N (3.0
mmol), CuI (10 mol %) and 3mL of DMF were taken in a 25 ml round
bottomed flask in argon atmosphere. The mixture was heated to 80 oC
temperature for 3 h. The completion of the reaction was monitored by TLC
checking. After completion of the reaction mixture was cooled to room
temperature and diluted with water. It was then extracted with ethyl acetate
(3×50 ml). Combined organic layer was washed with brine and evaporated to
dryness under reduced pressure. The desired phthalide was isolated by usual
column chromatography with a mixture of ethyl acetate and petroleum ether
O
14
Ph
O
Ph
3m ( 65 %)
Br
O
MeO
COOH
MeO
O
Ph
15
(1:20) as eluent
.
Spectral data of the representative compound 3-
3n ( 60 %)
benzylideneisobenzofuran-1(3H)-one (3a): White Solid; mp: 84-86 oC;
1
Yield: 90 %; H NMR (200 MHz, CDCl3) : 6.40 (1H, s), 7.29-7.44 (3H, m),
eReaction conditions: o-bromobenzoic acids (1 mmol), terminal alkyne (0.1
mmol), Et3N ( 3.0 mmol), CuI (10 mol %), DMF (3 mL), 80 oC, 3 h.
Isolated yield in parenthesis. fIsocumarin (10 %) was isolated.
7.48-7.56 (1H, m), 7.66-7.76 (2H, m), 7.82-.792 (3H, m); 13C NMR (50
MHz, CDCl3): 107.2, 120.0, 123.4, 125.6, 128.5, 128.9 (2C), 129.8, 130.2
(2C), 133.2, 134.6, 140.7, 144.7, 167.2; Elemental Analysis: C: 81.07 %; H:
4.54%; Found: C: 81.00%; H: 4.49%; HRMS of C15H11O2 [M+ H+]:
+
We propose that the reaction proceeds via domino reaction of Cu-
mediated Sonogashira coupling and intramolecular 5-exo-dig
cyclization (Scheme 3). Firstly, CuI in presence of Et3N base formed
Cu-acetylide which undergoes a Sonogashira type coupling with the
C-Br bond to afford the o-alkynylcarboxylate (I). Intramolecular
attack of the carboxylate on the Cu(I) co-ordinated electrophilic o-
alkyne moiety in a 5-exo-dig fashion to gave the intermediate II. The
intermediate II finally produced our desired compound III and Cu(I)
which enters into the catalytic cycle.
223.0754; Observed : 223.0750.
1
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3
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