Catalyst-Free Three-Component Tandem CDC Cyclization: Convenient Access to Isoindolinones from Aromatic Acid, Amides, and DMSO by a Pummerer-Type Rearrangement

Article abstract of DOI:10.1002/chem.201600865

A catalyst-free multicomponent CDC reaction is rarely reported, especially for the intermolecular tandem CDC cyclization, which represents an important strategy for constructing cyclic compounds. Herein, a three-component tandem CDC cyclization by a Pumme

Full text of DOI:10.1002/chem.201600865

DOI: 10.1002/chem.201600865
Communication
&
Cross-Coupling
Catalyst-Free Three-Component Tandem CDC Cyclization:
Convenient Access to Isoindolinones from Aromatic Acid, Amides,
and DMSO by a Pummerer-Type Rearrangement
Peng-Min Wang,[a] Fan Pu,[a] Ke-Yan Liu,[a] Chao-Jun Li,[b] Zhong-Wen Liu,[a] Xian-Ying Shi,*[a]
Juan Fan,[a] Ming-Yu Yang,[a] and Jun-Fa Wei[a]
syntheses, have seen considerably less progress. Moreover, it is
of high interest to develop efficient and practical synthetic pro-
tocols by tandem CDC to construct important cyclic com-
pounds.
Abstract: A catalyst-free multicomponent CDC reaction is
rarely reported, especially for the intermolecular tandem
CDC cyclization, which represents an important strategy
for constructing cyclic compounds. Herein, a three-com-
ponent tandem CDC cyclization by a Pummerer-type rear-
rangement to afford biologically relevant isoindolinones
from aromatic acids, amides, and DMSO, is described. This
intermolecular tandem reaction undergoes a C(sp2)ÀH/
C(sp3)ÀH cross-dehydrogenative coupling, CÀN bond for-
mation, and intramolecular amidation. A notable feature
of this novel protocol is avoiding a catalyst and additive
(apart from oxidant).
Isoindolinones and their derivatives have gained extensive
attention due to their profound physiological and chemothera-
peutic properties.[4] The N-substituted isoindolinones are found
in many natural and synthetic drug molecules possessing vari-
ous biological activities, for example, indoprofen (anti-inflam-
matory), deoxythalldomide (anti-tumor activity), triazol-isoindo-
linone (MGR-1 antagonist), and DWP201190 (TNF-a production
inhibitor).[5] Their great importance in chemistry and biology
has consistently stimulated the development of novel methods
for their preparation.[6] Although the selective monoreduction
of phthalimides (Scheme 1a) and intramolecular cyclization of
2-alkyl-N-substituted benzamides (Scheme 1b) provide the
most straightforward routes to isoindolinone heterocycles,
although these methods require commercially unavailable
starting materials.[7] Intermolecular cyclizations, such as
transition-metal-catalyzed cyclization reactions through CO
insertion (Scheme 1c),[8] reductive CÀN coupling, and intra-
molecular amidation of 2-carboxybenzaldehyde and amines
Direct cross-dehydrogenative-coupling (CDC) reactions, which
combine two CÀH bonds to form new CÀC and CÀX (X=
heteroatom) bonds avoiding the requirement for preparing
prefunctionalized reagents, have emerged as powerful and en-
vironmentally friendly alternatives in organic syntheses.[1] It can
provide a step- and atom-economical strategy for the synthesis
of complex molecules from simple materials through CÀH
functionalization. Although many efforts have been made to
develop CDC methodologies to access useful motifs,[1] there
are still some major challenges that need to be addressed in
this field. Most of these reactions involve catalysts, especially
metal catalysts, such as Pd, Ru, Ag, Cu, and so forth.[1] From
the viewpoint of atomic economy and green chemistry,[2] the
development of a catalyst-free method under simpler reaction
conditions is highly desirable. The CDC reactions between two
compounds have been extensively investigated.[3] However, in
sharp contrast, tandem multicomponent CDC reactions, which
represent efficient and rapid alternatives to traditional stepwise
[a] P.-M. Wang, F. Pu, K.-Y. Liu, Prof. Dr. Z.-W. Liu, Dr. X.-Y. Shi, J. Fan,
Dr. M.-Y. Yang, Prof. Dr. J.-F. Wei
Key Laboratory of Applied Surface and Colloid Chemistry (Ministry of Edu-
cation), Key Laboratory for Macromolecular Science of Shaanxi Province,
School of Chemistry and Chemical Engineering, Shaanxi Normal University,
Xi’an 710062 (P.R. China)
E-mail: shixy@snnu.edu.cn
[b] Prof. Dr. C.-J. Li
Department of Chemistry, McGill University, Montreal, QC, H3A 0B8
(Canada)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201600865.
Scheme 1. Strategies for the construction of isoindolinones framework.
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(Scheme 1d),[9] have also been developed for the construction
of isoindolinone core. However, most of these methods utilize
halogenated substrates, costly transition-metal catalysts, toxic
CO, or flammable H2 gas. Therefore, an efficient route, which is
transition-metal-free, catalyst-free, and employs commercially
available substrates and reagents, would be highly desirable
for the construction of N-substituted isoindolinones.
Table 1. Selected results for optimizing the reaction conditions.[a]
Entry
Oxidant (equiv)
Solvent
Yield [%][b]
1
2
3
4
DDQ (2.0)
DDQ (2.0)
DDQ (2.0)
DDQ (2.0)
C6H5Cl
1,4-dioxane
DMSO
toluene
DCE
74
trace
32
67
37
We recently demonstrated several rhodium-catalyzed cas-
cade cyclizations with easily available aromatic acids through
the CÀH activation,[10] which provide atom economical alterna-
tives to construct important heterocycle frameworks in a single
step. On our continuous effort to explore the cyclization reac-
tions with aromatic acids, an unexpected three-component
tandem CDC cyclization between benzenesulfonamide, di-
methyl sulfoxide (DMSO), and 3,4,5-trimethoxybenzoic acid oc-
curred without catalyst to afford 4,5,6-trimethoxy-2-(phenylsul-
fonyl)isoindolin-1-one (3a; Scheme 1e), in which DMSO served
as a carbon bridge to construct a five-membered ring. The
structure of 3a was unambiguously identified by single-crystal
X-ray diffraction analysis (Figure 1). It is worth noting that
although DMSO is increasingly employed as a building block in
transition-metal-catalyzed CÀH bond activations, such as
-SCH3,[11] -CH2SCH3,[12] -CN,[13] -SO2CH3,[14] -CHO,[15] and -CH3,[16] it
is rarely used as a methylating reagent.[17]
5
DDQ (2.0)
6
7
DDQ (2.0)
DDQ (2.0)
CH3CN
DME
28
27
8
9
K2S2O8 (2.0)
(NH4)2S2O8 (2.0)
PhI(CF3CO2)2 (2.0)
PhI(OAc)2 (2.0)
Ag2O (2.0)
AgOAc (2.0)
Ag2CO3 (2.0)
benzoquinone (2.0)
DDQ (1.0)
DDQ (1.5)
DDQ (2.5)
DDQ (3.0)
DDQ (2.0)
C6H5Cl
C6H5Cl
C6H5Cl
C6H5Cl
C6H5Cl
C6H5Cl
C6H5Cl
C6H5Cl
C6H5Cl
C6H5Cl
C6H5Cl
C6H5Cl
C6H5Cl
C6H5Cl
12
18
52
45
trace
trace
trace
ND[c]
73
68
74
70
80
10
11
12
13
14
15
16
17
18
19
20[d]
21[e]
DDQ (2.0)
81
[a] Reactions were carried out with 3,4,5-trimethoxybenzoic acid
(0.1 mmol), benzenesulfonamide (0.2 mmol), DMSO (30 mL), oxidant, and
solvent (0.6 mL) at 1308C for 24 h under argon in pressure tubes. [b] De-
termined by 1H NMR analysis of the crude reaction mixture using mesity-
lene as internal standard. [c] ND=Not detected. [d] Run for 12 h. [e] Run
at 110 8C for 12 h.
the present cyclization reaction. Among the oxidants tested,
DDQ appeared to be the most effective, whereas other oxi-
dants, such as K2S2O8, (NH4)2S2O8, PhI(CF3CO2)2, PhI(OAc)2, as
well as some transition-metal salts proved to be less effective
(entries 8–14). Benzoquinone failed to give the desired product
(entry 15). Subsequently, various conditions concerning the
amount of oxidant, reaction time, and reaction temperature
were examined to further optimize the formation of the cycli-
zation product with C6H5Cl as solvent. The yield of 3a could be
enhanced to 81% by decreasing the reaction time and reac-
tion temperature (entry 21).
Figure 1. X-ray crystal structure of 3a.[19]
With the optimized reaction conditions in hand, we set to
explore the generality of this transformation regarding sulfona-
mides and 3,4,5-trimethoxybenzoic acid. We were pleased to
find that a variety of substituted benzenesulfonamides were
successfully converted into the desired cyclization products in
moderate to good yields (Table 2). Different substituents on
the phenyl ring, either electron-withdrawing or -donating
groups, were all compatible, which implies that the electronic
effect is not critical for this transformation. For example, benze-
nesulfonamides with 2-CH3, 4-CH3, 4-C2H5, 4-tBu, all smoothly
underwent the process to provide the products in synthetically
acceptable yields (3b–3e). Substrates possessing halogenated
functional groups, such as bromo and chloro, which allow easy
further functionalizations, were well tolerated and generated
the cyclization products in good yields (3 f–3k). The presences
After the surprising formation of N-substituted isoindolinone
from 3,4,5-trimethoxybenzoic acid (1a), benzenesulfonamide
(2a), and DMSO by C(sp2)ÀH/C(sp3)ÀH cross coupling, CÀN
bond formation, and intramolecular amidation in the presence
of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) without
any catalyst, we set out to optimize the reaction conditions
(Table 1). In view that the choice of solvent is crucial for the
success of this transformation, several commonly used solvents
were tested, and C6H5Cl appeared to be the best choice for
the cyclization. Other solvents, such as 1,4-dioxane, DMSO, tol-
uene, DCE, CH3CN, and DME can also be used in this reaction
to furnish a lower yield of 3a (entries 2–7). Control experi-
ments demonstrated that 3a was not formed in the absence
of DDQ, indicating that the oxidant plays an important role in
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nately, no desired product was detected. These results suggest
that the catalyst-free cyclization reaction has a high require-
ment for the electron density of aromatic acid and transition-
metal catalysts could potentially extend this method in future.
Apart from sulfonamides, amides can also undergo this
transformation to afford the desired cyclization products,
although the reaction conditions needed to be adjusted slight-
ly to obtain satisfying results (see the Supporting Information).
By employing the mixture oxidants of DDQ and (NH4)2S2O8, the
satisfied yield of 5a can reach up to 70%. With the establish-
ment of the optimal conditions, the scope and limitation of
this cyclization system were explored subsequently. A variety
of electron-donating and -withdrawing substituents, as well as
halogens on the benzamides were well tolerated and provided
the isolated yields ranging from 50 to 70% (Table 3). The posi-
tion of substituents on the benzamide has little influence on
the reaction efficiency (5g–5i). The reaction also tolerated dis-
ubstituents, for example, 3-chloro-2-fluorobenzamide (5k,
70%), 2,6-difluorobenzamide (5k, 70%), and 5-chloro-2- fluoro-
benzamide (5m, 60%). Aliphatic formamides were also effec-
tive in this transformation and the steric effect on the reaction
appeared to be negligible (5n and 5o); almost the same yield
of products was obtained employing both acetamide and pro-
pionamide.
Table 2. Substrate scope for the tandem CDC cyclization of 1a, sulfona-
mides, and DMSO.[a]
To gain mechanistic insights, additional experiments were
performed. When 3,4,5-trimethoxybenzoic acid was reacted
with N-methylbenzamide, a trace amount of 5pa was ob-
served in absence of 5pb from the 1H NMR analysis of the
crude reaction mixture (Scheme 2a), which implies that the in-
tramolecular amination probably is the last step in this trans-
formation. Furthermore, the reaction of 3,4,5-trimethoxybenzo-
ic acid and DMSO without the amide afforded isobenzofuran-
1(3H)-one 5q (Scheme 2b). The structure of 5q was confirmed
by single-crystal X-ray analysis (Figure 2).
[a] Reactions were carried out with 3,4,5-trimethoxybenzoic acid
(0.2 mmol), sulfonamides (0.4 mmol), DMSO (60 mL), DDQ (0.4 mmol), and
C6H5Cl (1.2 mL) at 110 8C for 12 h under argon in pressure tubes. Yields of
isolated products are reported. [b] Run at 1308C.
of strong electron-withdrawing groups in benzenesulfona-
mides worked also well and provided the target products in
satisfied yields (3l–3o). Moreover, a heterocyclic aromatic sul-
fonamide could also be converted into the corresponding
products with a slightly lower yield (3p). In addition to aromat-
ic sulfonamides, an aliphatic sulfonamide delivered the corre-
sponding cyclization product in excellent yield (3q).
To further explore the substrate scope and limitations of this
three-component tandem CDC cyclization, we tested the reac-
tion of 2-fluorobenzenesulfonamide with various aromatic
acids. When other aromatic acids with electron-withdrawing or
-donating groups were used for this transformation, unfortu-
Scheme 2. Preliminary mechanism studies.
Although the mechanistic details of this cascade cyclization
are not very clear at the moment, based on related research
studies[16,18] and our preliminary experimental results, a tenta-
tive mechanism is proposed in Scheme 3. The three-compo-
nent CDC cyclization reaction may proceed by an acid-mediat-
ed Pummerer-type rearrangement. The reaction likely starts
with DMSO being attacked by the carboxylic group to form
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Table 3. Substrate scope for the tandem CDC cyclization of 1a, amides,
and DMSO.[a]
Figure 2. X-ray crystal structure of 5q.[19]
Scheme 3. Proposed mechanism.
In summary, a catalyst- and additive-free three-component
tandem CDC reaction has been successfully developed by
Pummerer-type rearrangement to offer a convenient approach
for the preparation of biologically relevant isoindolinones. This
one-step intermolecular tandem CDC undergoes a formal
C(sp2)ÀH/C(sp3)ÀH cross-dehydrogenative coupling, CÀN bond
formation, and intramolecular amidation. The method utilizes
commercially available aromatic acid and amine derivatives
using DMSO as methylene donor and exhibits broad substrate
scopes with respect to sulfonamides and amides. An additional
notable feature is that the novel protocol is catalyst- and addi-
tive-free (apart from oxidant). Further studies to expand the
substrate scope regarding the aromatic acids by transition-
metal catalysis as well as detailed mechanistic investigations
are currently in progress in our laboratory.
[a] Reactions were carried out with 3,4,5-trimethoxybenzoic acid
(0.2 mmol), amides (0.4 mmol), DMSO (60 mL), DDQ (0.5 mmol), (NH4)2S2O8
(0.3 mmol), and solvent (1.2 mL) at 1308C for 24 h under argon in pres-
sure tubes. Yields of isolated product are reported.
a sulfoxide ester, releasing one equivalent OHÀ at the same
time. Then, with the assistance of OHÀ, the elimination thioni-
um CH2 =S+CH3 is generated that is then attacked by the aryl
through a Friedel-Crafts alkylation in situ to give intermediate
B. The process of Friedel-Crafts alkylation can explain why this
cyclization reaction has a high requirement for the electron
density of aromatic acids. Intermediate C is formed by the oxi-
dation with DDQ. Subsequently, C could proceed in two direc-
tions: a) intramolecular attack by the oxygen atom of carboxyl
on the a-carbon of sulfoxide to afford product 5q; b) intermo-
lecular attack by the amide and subsequently CÀS cleavage to
afford D. Finally, the intramolecular amidation of D affords the
desired cyclization product.
Experimental Section
An oven-dried reaction vessel was charged with 3,4,5-trimethoxy-
benzoic acid (0.2 mmol), sulfonamide (0.4 mmol), DMSO (60 mL),
and DDQ (0.4 mmol). After the tube was evacuated and purged
with argon three times, chlorobenzene (1.2 mL) was added to the
system by syringe. The mixture was stirred at 110 8C for 12 h. When
the reaction was completed, the resulting mixture was cooled to
room temperature and filtered through a short silica gel pad. Then,
the mixture was concentrated in vacuo to give a residue, which
was purified by preparative TLC to afford the corresponding prod-
uct.
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Acknowledgements
The authors are grateful to the National Science Foundation of
China (Grant No. 21572122 and 21572124), Shaanxi Innovative
Team of Key Science and Technology (2013KCT-17), the 111
Project (B14041), the Fundamental Research Funds for the Cen-
tral Universities (Grant GK201503030 and GK201601005), and
the Innovation Foundation of Graduate Cultivation of Shaanxi
Normal University (2015CXS042) for providing financial sup-
ports.
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Keywords: annulation
isoindolinone · Pummerer-type rearrangement
· dehydrogenation · heterocycles ·
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by The Cambridge Crystallographic Data Centre
Received: February 24, 2016
Published online on March 21, 2016
Chem. Eur. J. 2016, 22, 6262 – 6267
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim