Practical synthesis of phthalimides and benzamides by a multicomponent reaction involving arynes, isocyanides, and CO2/H2O

Article abstract of DOI:10.1021/ol500403x

Transition-metal-free multicomponent reactions involving arynes and isocyanides with either CO₂ or H₂O have been reported. With CO₂ as the third component, the reactions resulted in the formation of N-substituted phthalimides. The utility of water as the third component furnished benzamide derivatives in moderate to good yields. These reactions took place under mild conditions with broad scope.

Full text of DOI:10.1021/ol500403x

Letter
pubs.acs.org/OrgLett
Practical Synthesis of Phthalimides and Benzamides by a
Multicomponent Reaction Involving Arynes, Isocyanides, and CO2/
H2O
Trinadh Kaicharla, Manikandan Thangaraj, and Akkattu T. Biju*
Organic Chemistry Division, CSIR-National Chemical Laboratory (CSIR-NCL), Dr. Homi Bhabha Road, Pune - 411008, India
S
* Supporting Information
ABSTRACT: Transition-metal-free multicomponent reactions involving arynes and isocyanides with either CO2 or H2O have
been reported. With CO2 as the third component, the reactions resulted in the formation of N-substituted phthalimides. The
utility of water as the third component furnished benzamide derivatives in moderate to good yields. These reactions took place
under mild conditions with broad scope.
reactions (MCRs),7 we envisioned that the isocyanide triggered
he amide bond is one of the most important functional
MCRs with highly electrophilic arynes8 could result in a
Tgroups present in various biologically important com-
transition-metal-free new route to the synthesis of amides.
Notably, the generation of a 1,3-zwitterionic intermediate from
isocyanide and aryne derived from 19 and its subsequent
interception with electrophiles such as aldehydes, and activated
imines leading to the formation of benzannulated heterocycles,
has been demonstrated by Yoshida, Kunai and co-workers (eq
2).10,11 Herein, we report the MCR involving isocyanides and
arynes, where the third component used is either CO2 or H2O.
When CO2 was used as the third component,12 the reaction
afforded N-substituted phthalimides, whereas the use of H2O as
the third component furnished benzamides (eq 3).
The synthesis of value-added products by the efficient
utilization of CO2 as a one-carbon source has been an
imperative subject in organic chemistry.13 Intriguingly, the
incorporation of CO2 in aryne reactions has received only
limited attention.12 In this context, we began our studies by
treating tert-butyl isocyanide 2a with the aryne formed in situ
from 2-(trimethylsilyl)aryl triflate 1a9 using CsF in MeCN at 30
°C under an atmosphere of CO2 (balloon). Although the
expected product was the iminoisobenzofuranone derivative 4a
formed by the interception of the 1:1 adduct between aryne
and isocyanide with CO2, delightfully, the N-tert-butyl
phthalimide 3a was isolated in 76% yield (Scheme 2).14 The
product 3a was likely formed by the fluoride induced ring
opening of 4a followed by the cyclization.
pounds including peptides and proteins, and this moiety is
present in more than 25% of the known drugs.1 Traditionally,
the construction of amide bonds has been achieved by the
coupling of carboxylic acids/derivatives with amines. However,
in most cases, the reaction requires coupling reagents and
produces a stoichiometric byproduct.2 Transition-metal-cata-
lyzed methods are possible alternatives, which expanded the
scope of amide synthesis by starting from various substrates
other than acids.3 Several reports to uncover efficient and
environmentally benign methods to amide synthesis have
appeared in the past few years.4 Very recently, the Grimaud and
Zhu groups independently disclosed an efficient and transition-
metal-free synthesis of aryl substituted carboxamides from aryl
diazonium salts and isocyanides, and the reaction proceeded via
a radical intermediate (Scheme 1, eq 1).5,6 Considering the
widespread applications of isocyanides in multicomponent
Scheme 1. Transition-Metal-Free Amide Bond-Forming
Reactions Involving Isocyanides
With this procedure in hand, we then studied the substrate
scope of this phthalimide forming aryne MCR (Scheme 3). A
variety of aliphatic isocyanides underwent a smooth aryne
MCR with incorporation of CO2 leading to the formation of N-
Received: February 7, 2014
Published: March 11, 2014
© 2014 American Chemical Society
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Letter
Scheme 2. MCR Involving Arynes, Isocyanides, and CO2
Scheme 4. Plausible Reaction Mechanism
Scheme 3. Substrate Scope of the MCR Involving
a
Isocyanides, Arynes, and CO2
generation of the 1,3-zwitterionic intermediate 5. The
nucleophilic aryl anion intermediate 5 can add to the
electrophilic carbonyl group of CO2 in a stepwise pathway
furnishing the zwitterion 6, which on ring closure results in the
formation of iminoisobenzofuranone derivative 7. Alternatively,
it is also likely that the addition of aryl anion 5 to CO2 and the
subsequent cyclization can proceed via a concerted manner to
form 7. It is probable that the fluoride induced ring opening of
7 generates the acid fluoride intermediate 8, and the latter on
further cyclization affords the phthalimide derivative 3. It is
interesting to note in this context that the rearrangement of
isoimide 7 to imide 3 has been documented in the literature.16
To shed light on the fluoride-induced rearrangement of
isoimide 7 to phthalimide 3, we have synthesized the N-tert-
butyl isoimide derivative 4a starting from phthalic anhydride in
three steps following the literature procedures.17 Gratifyingly,
treatment of 4a with CsF resulted in the formation of the
desired phthalimide derivative 3a in 97% yield (Scheme 5).
Scheme 5. Experiment to Confirm Fluoride-Induced
Rearrangement
a
General conditions: 1 (0.75 mmol), 2 (0.5 mmol), CsF (1.5 mmol),
MeCN (2.0 mL), under an atmosphere of CO2 (balloon), 30 °C, 24 h.
Yields of the isolated products are given. b Reaction was run at 60 °C
c
for 6 h. Reaction was run on 0.25 mmol scale.
alkyl phthalimides in moderate to good yields (3a−3d).
Moreover, relatively less nucleophilic aromatic isocyanides
reacted very slowly at 30 °C with arynes and CO2. However, at
a high temperature of 60 °C, these reactions afforded the
desired product in moderate yields (3e−3f). Then, we
evaluated the scope of this reaction with various aryne
precursors. As expected, electronically different 4,5-disubsti-
tuted symmetrical aryne precursors 1g−1i easily resulted in the
formation of phthalimides 3g−3i in moderate to good yields.
Additionally, the symmetrical naphthalyne derived from 1j as
well as the 3,6-dimethyl aryne derived from 1k furnished the
expected products in moderate yields (3j−3k). Interestingly,
the reaction of unsymmetrical aryne derived from 1l resulted in
the formation of the expected product 3l in 81% yield.
Furthermore, the monosubstituted aryne derived from 1m
delivered the phthalimide 3m in 87% yield, thereby expanding
the scope of the aryne MCRs. It may be noted in this context
that some of the N-substituted phthalimides are known to have
anticonvulsant and neurotoxic properties.15
This clearly indicates the fluoride-induced rearrangement of 7
to 3 as proposed in Scheme 4. Moreover, after filtration of the
reaction mixture and evaporation of solvent, the crude NMR of
the reaction (1H NMR in CDCl3 using CH2Br2 as an internal
standarad) mixture revealed an 80% yield of 3a indicating that
the rearrangement of 4a to 3a is not happening during
purification using silica gel column chromatography.
Inspired by the synthesis of phthalimides by the MCR of
isocyanides and arynes with CO2, we continued our studies
using other trapping agents instead of CO2. It was envisioned
that if the trapping agent used is water, this MCR can result in
the formation of aromatic amides under transition-metal-free
conditions. Notably, the synthesis of aromatic amides by the
reaction of isocyanides and water with an aryne generated from
aryldiazonium 2-carboxylate has been shown by Rigby and
Laurent.18 However, the scope of this reaction appears narrow
and the isolated yields of the product are moderate in most
cases. In a pilot experiment, treatment of tert-butyl isocyanide
2a with the aryne generated from 2-(trimethylsilyl)aryl triflate
1a9 using KF (in the presence of 18-crown-6) in THF at 30 °C
followed by the addition of water resulted in the formation of
N-(tert-butyl)benzamide 9a in 81% yield (Scheme 6). During
The proposed mechanism of this CO2 incorporated aryne
MCR leading to phthalimides is presented in Scheme 4.
Initially, the isocyanide undergoes a nucleophilic addition to an
aryne formed in situ from the precursor 1 leading to the
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the synthesis of indane-5-carboxamide (9n), tetrahydronaph-
thalene-2-carboxamide (9o), and phenanthrene-9-carboxamide
(9p) can be accomplished starting from suitably substituted
symmetrical aryne precursors.19
Scheme 6. MCR Involving Arynes, Isocyanides, and H2O
Not surprisingly, the reaction of tert-butyl isocyanide 2a with
unsymmetrical 3-methoxy benzyne derived from 1q and water
resulted in the formation of the aryl amide 9q in 83% yield as a
single isomer. The selective formation of 9q may be due to the
combined electron-withdrawing effect and steric effect induced
by the −OMe group, which directs the selective addition of
isocyanide at the meta-position (Scheme 8, eq 4). Moreover, 4-
optimization studies, it was found that the other fluoride
sources such as CsF (in MeCN) and tetrabutyl ammonium
fluoride (TBAF) in THF furnished the desired product in
reduced yields.
The scope of this transition-metal-free synthesis of aromatic
amides was found to be general with various isocyanides and
differently substituted arynes (Scheme 7). Diverse alkyl
Scheme 8. Regioselective Synthesis of Aromatic Amides
Scheme 7. Substrate Scope of the MCR Involving
a
Isocyanides, Arynes, and H2O
fluoro benzyne generated from 1r furnished a regioisomeric
mixture of aryl amides 9r and 9r′ in the ratio 12:1 in 64% yield
(eq 5). The preferential formation of 9r in this case may be due
to the enhanced stability of the intermediate (formed by the
addition of 2a on aryne generated from 1r), where the negative
charge is nearer to the electronegative fluorine atom.20
To gain insight into the mechanism of the aryl amide
forming reaction, an experiment has been performed with D2O
as the third component. This reaction resulted in the formation
of the expected product 9a-d in 84% yield (based on 1H NMR)
with 84% deuterium incorporation at the 2-position of the ring
(Scheme 8).14 In addition, 83% deuterium incorporation was
observed at the amide functionality. This indicates that the
initially formed aryl anion intermediate 5 (Scheme 4) is first
protonated and the subsequent hydrolysis of the resultant
iminium species results in the formation of the benzamide 9.
a
General conditions: 1 (0.75 mmol), 2 (0.5 mmol), KF (1.5 mmol),
18-crown-6 (1.5 mmol), H2O (1.0 mmol), and THF (2.0 mL), 30 °C,
Scheme 9. Reaction Using D2O as the Third Component
b
16 h. Yields of the isolated products are given. Reaction was run on
0.25 mmol scale. c The regioisomer ratio was determined by 1H NMR
analysis of the crude reaction mixture.
isocyanides were well tolerated leading to N-alkyl benzamides
in good yields (9a−9d). In addition, aromatic isocyanides also
underwent the reaction under the optimized conditions to
furnish the desired product (9e−9f). Moreover, a variety of
electronically diverse symmetrical arynes derived from
precursors 1g−1k afforded the expected product in good
yields (9g−9k). As anticipated, the unsymmetrical naphthalyne
generated from the precursor 1l underwent efficient MCR with
isocyanides and water to afford an inseparable mixture of
regioisomers 9l and 9l′ in a 1.2:1 ratio and in 79% yield.
Furthermore, the reaction of the unsymmetrical aryne derived
from 1m resulted in the formation of inseparable regioisomers
9m/9m′ in a 1.2:1 ratio. Finally, this method is not limited to
the synthesis of phenyl and naphthyl carboxamides, but instead,
In conclusion, we have reported the operationally simple and
transition-metal-free MCRs involving arynes and isocyanides
with either CO2 or H2O as the third component. When the
third component used was CO2, the reaction afforded N-
substituted phthalimides. The desired product was formed by
the construction of two new C−C bonds and a new C−N
bond. Additionally, the incorporation of water as the third
component resulted in the formation of aromatic amides in
moderate to good yields. Further studies on related aryne
MCRs are ongoing in our laboratory.
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Letter
Co. KGaA: Weinheim, Germany, 2009; p 401. (k) Sanz, R. Org. Prep.
Proced. Int. 2008, 40, 215.
(9) For the synthesis of 2-(trimethylsilyl)aryl triflates and the
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ASSOCIATED CONTENT
* Supporting Information
Detailed experimental procedures as well as characterization
data of all compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
■
S
́
the preparation of the triflate, see: (b) Pena, D.; Cobas, A.; Perez, D.;
̃
́
Guitian, E. Synthesis 2002, 1454.
(10) (a) Yoshida, H.; Fukushima, H.; Ohshita, J.; Kunai, A. Angew.
Chem., Int. Ed. 2004, 43, 3935. (b) Yoshida, H.; Fukushima, H.;
Ohshita, J.; Kunai, A. Tetrahedron Lett. 2004, 45, 8659. (c) Yoshida,
H.; Fukushima, H.; Morishita, T.; Ohshita, J.; Kunai, A. Tetrahedron
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: at.biju@ncl.res.in.
Notes
The authors declare no competing financial interest.
(11) For related isocyanide triggered aryne MCRs, see: (a) Allan, K.
M.; Gilmore, C. D.; Stoltz, B. M. Angew. Chem., Int. Ed. 2011, 50,
4488. (b) Yoshida, H.; Asatsu, Y.; Mimura, Y.; Ito, Y.; Ohshita, J.;
Takaki, K. Angew. Chem., Int. Ed. 2011, 50, 9676. (c) Sha, F.; Huang,
ACKNOWLEDGMENTS
■
Generous financial support by the Science and Engineering
Research Board, DST, Govt. of India (Grant No. SR/S1/OC/
12/2012) is gratefully acknowledged. T.K. and M.T. thank
CSIR-New Delhi for the award of an SPM Fellowship and JRF
respectively. We thank Mr. Digvijay Porwal (CSIR-NCL) for
the IR data, Dr. P. R. Rajamohanan (CSIR-NCL) for NMR
spectra, and Ms. B. Santhakumari (CSIR-NCL) for the HRMS
data.
X. Angew. Chem., Int. Ed. 2009, 48, 3458.
For a highlight on
transition-metal-free aryne MCRs, see: (d) Bhojgude, S. S.; Biju, A. T.
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initiated aryne MCRs, see: (e) Bhunia, A.; Roy, T.; Pachfule, P.;
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