A three-component reaction toward the synthesis of 1-carboxamido-isoindoles

Article abstract of DOI:10.1021/ol302460s

An efficient three-component reaction toward the facile synthesis of structurally diverse 1-carboxamido-isoindoles has been developed. The resultant isoindoles can be used in Diels-Alder reactions.

Full text of DOI:10.1021/ol302460s

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
A Three-Component Reaction toward the
Synthesis of 1‑Carboxamido-isoindoles
Yanfeng Zhang, Chi Lung Lee, Han Liu, and Xuechen Li*
Department of Chemistry, The University of Hong Kong, Hong Kong, China
xuechenl@hku.hk
Received September 6, 2012
ABSTRACT
An efficient three-component reaction toward the facile synthesis of structurally diverse 1-carboxamido-isoindoles has been developed. The
resultant isoindoles can be used in DielsÀAlder reactions.
Isoindoles are interesting skeletons because of their
fluorescent properties and potential medicinal value.1
Recently, numerous synthetic strategies have been re-
ported to prepare various isoindole moieties.2 For in-
stance, Suginome and co-workers used a palladium-cat-
alyzed reaction of isoindolines to prepare 1-borylisoindoles.3
Sole et al.4 reported a Pd-catalyzed intramolecular R-arylation
of amino acid esters to produce 1-isoindolecarboxylic acid
esters. Stevens et al.5 have synthesized 1-cyanoisoindoles
and phosphorylated isoindoles. Multicomponent coupling
reactions (MCRs), which enable several reacting partners
to join together in a sequential manner under mild and
robust conditions, have been shown to be a powerful
approach to preparing structurally diverse compounds.6
Herein, we consider the possibility of exploiting an
MCR strategy to synthesize the isoindole derivatives.
Identification of suitable partners is the key to achieving
such a goal. We are attracted by the rich chemistry of
ortho-phthalaldehyde (OPA), which has long been
known to react with some nucleophiles7 and widely
used to detect the amino group during Edman degrada-
tion of peptides.8 To the best of our knowledge, iso-
nitriles have not been reported to react with OPAs.
Herein, we report a three-component reaction toward the
synthesis of 1-carboxamido-isoindoles with OPA, amines,
and isonitriles.
We envisioned that the monoimine A, formed by a
reaction between OPA and 1 equiv of amine, can be
attacked by the “soft” nucleophile isonitrile as in the
Ugi reaction.9 Then, the thus generated nitrilium
cation B can be trapped by water to form intermediate
C via a Ritter-type mechanism.10Finally, dehydration-
mediated aromatization produces the isoindole product
D (Figure 1).
According to our proposed mechanism, a model study
was initiated with ortho-phthalaldehyde 1, benzylamine 2,
and cyclohexyl isonitrile 3a or glycine isonitrile 3b as
substrates to explore the working reaction conditions.
Disappointingly at the time, initial attempts with a variety
of conditions with different solvents (Table 1, entries 1À7)
produced no desired product. The major or sole product
(1) (a) Wainaina, M.; Shibata, T.; Smanmoo, C.; Kabashima, T.;
Kai, M. Anal. Biochem. 2008, 374, 423. (b) Diana, P.; Martorana, A.;
Barraja, P.; Montalbano, A.; Dattolo, G.; Cirrincione, G.; Dall’Acqua,
F.; Salvador, A.; Vedaldi, D.; Basso, G.; Viola, G. J. Med. Chem. 2008,
51, 2387.
(2) Heugebaert, T. S. A.; Roman, B. I.; Stevens, C. V. Chem. Soc.
Rev. 2012, 41, 5626.
(3) Ohmura, T.; Kijima, A.; Suginome, M. J. Am. Chem. Soc. 2009,
131, 6070.
(7) (a) Takahashi, K.; Suenobu, K.; Ogura, K.; Iida, H. Chem. Lett.
1985, 14, 1487. (b) Zuman, P. Chem. Rev. 2004, 104, 3217.
(8) Zuman, P. Anal. Lett. 2005, 38, 1213.
(4) Sole, D.; Serrano, O. Org. Biomol. Chem. 2009, 7, 3382.
(5) Heugebaert, T. S. A.; Stevens, C. V. Org. Lett. 2009, 11, 5018.
Dieltiens, N.; Stevens, C. V. Org. Lett. 2007, 9, 465.
(6) (a) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown,
S. D.; Keating, T. A. Acc. Chem. Res. 1996, 29, 123. (b) Ugi, I. Pure Appl.
€
(9) (a) Ugi, I.; Meyr, R.; Fetzer, U.; Steinbruckner, C. Angew. Chem.
€
1959, 71, 386. (b) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39,
3169.
ꢀ
Chem. 2001, 73, 187. (c) Zhu, J.; Bienayme, H. Multicomponent Reac-
€
tions; Wiley-VCH: Weinheim, Germany, 2005. (d) Domling, A. Chem. Rev.
(10) (a) Ritter, J. J.; Kalish, J. J. Am. Chem. Soc. 1948, 70, 4048.
(b) Krimen, L. I.; Cota, D. J. Org. React. 1969, 17, 213.
2006, 106, 17.
r
10.1021/ol302460s
XXXX American Chemical Society

Figure 1. Three-component reaction toward the synthesis of isoindole compounds.
obtained was the N-substituted isoindolin-1-ones (cf. F),
whose formation has been observed and proposed in the
Table 1. Optimization of the Reaction Conditionsa
literature through a 1,3-hydride shift via the hydroxyimi-
nium species (cf. E) (Figure 1).11 The undesired reaction
can be attributed to the low electrophilicity of the imine in
A and the strong driving force for the lactam formation. In
other words, the isonitrile moiety seemed unable to join in
the reaction. To increase the electrophilicity of the imine,
various Lewis acids/Brønsted acids (entries 8À12) includ-
ing triflic acid, Zn(OTf)2, and BF3OEt2 were tested, but
in vain.
temp
time
(h)
yield
(%)b
entry
3
solvent
THF
(°C)
additive
Considering the key role of intermediate E in the un-
desired reaction pathway, another possible tactic was to
suppress its formation. Sodium bisulfiteisknowntoforma
bisulfite adduct with aldehyde groups;7 thus it probably
helped to slow down the formation of the hydroxyiminium
species E. Gratifyingly, when sodium bisulfite (NaHSO3)
was used as the additive, the desired product was obtained
in 10À16% yield after 40 h (Table 1, entry 13). Further
optimizations revealed that the mixed solvent (DMSO/
H2O) can accelerate the reaction, enabling the completion
at room temperature within 8 h to produce a 70% yield
(Table 1, entry 15). Furthermore, the reaction temperature
was also investigated at 50 and 100 °C; heating the reaction
mixture can also help drive the reaction (Table 1, entries
16À17). For a comparison, the reaction at 50 °C without
NaHSO3 still failed to produce any desired product,
revealing the importance of NaHSO3 (Table 1, entry 18).
Thus, the optimal conditions were found, in which ortho-
phthalaldehyde was mixed with 2 equiv of NaHSO3
sodium bisulfite in DMSO/H2O (1/1 v/v) for 0.5 h to
obtain a homogeneous solution at room temperature,
followed by the addition of 1 equiv of amine and 2 equiv
of isonitriles. It is noteworthy that, during the process of
the reaction, some white solid precipitated out from the
reaction mixture, and the simple filtration produced the
pure desired compound 4b in 55% yield. Further chroma-
tography of the mother liquid gave an additional 15%
product.
1
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
50
100
50
8
0
2
H2O
12
9
0
3
MeOH
CH2Cl2
DMF
0
4
9
0
5
9
0
6
AcCN
9
0
7
TFE
9
0
8
CH2Cl2
CH2Cl2
CH2Cl2
DMF
9
TfOH
0
9
9
Zn(OTf)2
BF3OEt2
TfOH
0
10
11
12
13
14
15
16
17
18
9
0
9
0
DMF
9
Zn(OTf)2
NaHSO3
NaHSO3
NaHSO3
NaHSO3
NaHSO3
0
H2O
40
40
8
10
16
70
41
65
0
H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
2
2
2
a All reactions were carried out with 0.41 mmol of OPA. b Isolated
yield.
To probe the role of NaHSO3 during the reaction,
we mixed OPA and NaHSO3 in d-DMSO/d-H2O
and recorded the NMR spectrum of the resulting
intermediate. The disappearance of the aldehyde pro-
ton signal indicated the formation of a bisulfite adduct
G (Figure 2). It is likely that the adduct G could
condense with amines, followed by the attack of iso-
nitriles to give J (or via H and J). The Ritter-type
reaction converted the nitrilium ion into the carboxa-
mide, and the resultant amine expelled the sodium
(11) (a) Grigg, R.; Gunaratne, H. Q. N.; Sridharan, V. J. Chem. Soc.,
Chem. Commun. 1985, 1183. (b) Aubert, T.; Farnier, M.; Guilard, R.
Can. J. Chem. 1990, 68, 842.
B
Org. Lett., Vol. XX, No. XX, XXXX

sulfite group to yield C. Then, aromatization resulted in
the desired isoindole compound.
commercially available tert-butylisonitrile, cyclohexyl isoni-
trile, and glycine isonitrile. As shown in Figure 3, the desired
isoindole compounds (4aÀ4l) were obtained in modest to
good yields (52À85%). Even with the very hindered tert-
butyl isonitrile, the reaction still worked well. Due to the
limited solubility of 3,4-dimethoxy ortho-phthalaldehyde in
the mixture of DMSO and H2O, the addition of acetonitrile
leading to the reacting solvent as DMSO/H2O/CH3CN
(4/4/1) was needed for the reaction to proceed effectively
to produce isoindoles (5aÀ5j) in good yields (55À90%).
Further derivatization of the resultant isoindole prod-
uct was also explored. Considering the electron-rich diene
Figure 2. Proposed role of NaHSO3 during the isoindole
formation.
Next, we set out to explore the scope and limita-
tions of this reaction, using the optimized conditions. Both
ortho-phthalaldehyde and 3,4-dimethoxy ortho-phthalal-
dehyde were used, together with benzyl amine derivatives
and aniline derivatives. Isonitriles were selected from
Figure 4. 1-Carboxamido-isoindoles in DielsÀAlder reaction.
Figure 3. Scope of the multicomponent reaction.
Org. Lett., Vol. XX, No. XX, XXXX
C

structure in the isoindole molecules, the DielsÀAlder
reaction with electron-deficient dienophile dimethyl acet-
ylenedicarboxylate (DMAD) and isoindoles (4c, 4f, and
4g) was conducted in CH2Cl2 at room temperature for 1 h.
As expected, the cycloadducts 6aÀc were smoothly formed
in 90À95% yields to generate a fused-ring heterocycle
(Figure 4).
In summary, we reported herein a three-component
reaction toward the synthesis of 1-carboxamido-isoindoles
under mild conditions. The generated isoindoles can be
used for the preparation of fused-ring heterocycles via
DielsÀAlder reactions.
Acknowledgment. Financial support for this research
from General Research Fund (HKU703811P) and a seed
grant from the University of Hong Kong (201111159010)
are gratefully acknowledged. We thank Prof. Patrick Toy
of The University of Hong Kong for his help with this
manuscript.
Supporting Information Available. Experimental proce-
dures, spectroscopic data and copies of 1H and 13C NMR
spectra of all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX