N-Heterocyclic carbene (NHC)-catalyzed intramolecular benzoin condensation-oxidation

Article abstract of DOI:10.1039/d0ob02606a

NHC-Catalyzed intramolecular benzoin condensation-oxidation is developed for the expedient synthesis of diverse cyclic 1,2-diketones incorporated in dibenzo-fused seven-membered heterocycles in good to excellent yields, under ambient conditions. The prese

Full text of DOI:10.1039/d0ob02606a

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N-Heterocyclic carbene (NHC)-catalyzed
intramolecular benzoin condensation–oxidation†
Cite this: Org. Biomol. Chem., 2021,
19, 1488
Killari Satyam,a,b Jakkula Ramaraoa,b and Surisetti Suresh
*
a,b
Received 31st December 2020,
Accepted 14th January 2021
DOI: 10.1039/d0ob02606a
rsc.li/obc
NHC-Catalyzed intramolecular benzoin condensation–oxidation is noxalines.10 The conventional approaches to access 1,2-dike-
developed for the expedient synthesis of diverse cyclic 1,2-dike- tones include the oxidation of alkenes, alkynes,
tones incorporated in dibenzo-fused seven-membered hetero- α-hydroxyketones and 1,2-diols.11 Although there exist several
cycles in good to excellent yields, under ambient conditions. The methods to access 1,2-diketones, those methods rely on the
presented carbene-catalyzed transformation appears to proceed use of transition metal compounds, toxic reagents, stoichio-
through the benzoin intermediate followed by aerobic oxidation.
metric oxidants, long reaction times, harsh reaction con-
ditions, and lengthy synthetic protocols.11–13 Besides, however,
those reported approaches are limited to access acyclic 1,2-
diketones while straightforward methods to access cyclic 1,2-
diketones are very scarce. Wong and co-workers described a
cyanide catalyzed intramolecular benzoin reaction for the syn-
thesis of the dibenzo[b,f]oxepine-10,11-dione derivative (22%
yield) along with the benzoin derivative (25% yield). This
method provides very low yields and uses substoichiometric
amounts of toxic cyanide (Scheme 1a).13a Enders and co-
workers reported an example of the α-diketone product by
employing aromatic dialdehyde under NHC catalysis and
obtained α-hydroxy ketone. During the work-up process, the
product underwent oxidation to obtain the six-membered
α-diketone, an ortho-quinone derivative (Scheme 1b).13b
N-Heterocyclic carbene (NHC)-organocatalyzed umpolung reac-
tions have gained considerable attention for C–C bond for-
mation involving various potentially useful unconventional
organic transformations for synthesizing diverse building
blocks and also have been elegantly applied in target-oriented
organic syntheses.1 Among these, NHC-catalyzed benzoin con-
densation is the earliest and
a
well-established
transformation.1,2 The intramolecular benzoin condensation is
of particular interest to access carbo- and heterocycles.2,3
However, NHC-catalyzed intramolecular benzoin condensation
is mostly limited to constructing more feasible five-membered
and six-membered rings while the construction of seven-mem-
bered rings is not known, to best of our knowledge.
Continuing our interest in NHC catalysis4 and the synthesis of
fused heterocyclic systems,5 we became interested to construct
dibenzo-fused seven-membered heterocycles by using intra-
molecular benzoin condensation as a strategy. Dibenzo-fused
seven-membered heterocycles such as dibenzoxepines,
dibenzothiepines and dibenzazepines constitute valuable
therapeutics that are useful in the treatment of several diseases
and possess a wide range of biological profiles.6–9
On the other hand, 1,2-diketones are important precursors
that are useful in the straightforward synthesis of biologically
valuable heterocycles such as imidazoles, pyrazines and qui-
aDepartment of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of
Chemical Technology (CSIR-IICT), Hyderabad 500 007, India.
E-mail: surisetti@iict.res.in, suresh.surisetti@yahoo.in
bAcademy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, spectral data, and copies of NMR spectra for products. See DOI:
10.1039/d0ob02606a
Scheme 1 Prior work and present work.
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Furthermore, it is a challenging task to access cyclic 1,2-dike- The use of other bases, instead of DBU, such as K2CO3 and
tones incorporated in medium-sized rings such as seven-mem- NaH, proved to be less efficient in this transformation
bered rings under mild conditions obviating the use of tran- (Table 1, entries 6 and 7). Probably, DBU combines well in
sition metal compounds/toxic reagents. Herein, we describe an THF and also as a strong base it promotes efficient conversion
NHC-catalyzed intramolecular benzoin condensation–oxi- of the NHC pre-catalyst to NHC. Furthermore, DBU may also
dation protocol to access cyclic 1,2-diketones incorporated in enhance the oxidation of the corresponding benzoin inter-
dibenzo-fused seven-membered heterocycles (Scheme 1c).
mediate to the diketone product. We also performed the reac-
We reasoned that an intramolecular benzoin condensation tion of 1a in various solvents under NHC catalysis conditions
between two aldehyde groups could provide cyclic α-sec-hydro- (Table 1, entries 8 and 9) and THF was found to be the best
xyketone that could undergo oxidation of the secondary medium to provide the desired product 3a in an excellent yield
hydroxyl group to eventually furnish the cyclic 1,2-diketone (Table 1, entry 4). Product 3a was not observed when we con-
functionality. We envisaged that an intramolecular benzoin ducted the reaction of 1a in the absence of NHC or a base.
reaction of readily available 2,2′-oxydibenzaldehyde 1a, by These results suggest the essentiality of an NHC precatalyst
using NHC catalysis, would provide access to a dibenzo-fused and a base for this transformation (see the ESI† for an exten-
oxepine core. Accordingly, 1a was subjected to NHC catalysis sive optimization survey).
using a readily accessible NHC precatalyst A1 5f in the presence
By choosing the optimal conditions from Table 1 (entry 4),
of DBU as a base. Interestingly, under the reaction conditions, we intended to examine the generality of this transformation.
we isolated the corresponding cyclic 1,2-diketone dibenzo[b,f] We subjected 2,2′-oxydibenzaldehydes, bearing EDGs on one
oxepine-10,11-dione 3a, and the benzoin derivative 2a was not of the benzene rings at different positions, to the optimized
observed (Table 1, entry 1). In order to obtain higher yields of NHC catalysis conditions to give the corresponding products
the cyclic 1,2-diketone 3a, we performed an optimization assay 3b–i in high yields (Scheme 2). The dialdehydes comprising
using different NHC precatalysts, bases and reaction the phenyl and naphthyl groups are also well tolerated for this
conditions.
transformation to afford the corresponding diketones 3j and
The commercially available imidazolium-based NHC pre- 3k in 80% and 75% yields, respectively (Scheme 2). The dialde-
catalyst A2 delivered the cyclic 1,2-diketone 3a in a high yield hydes, having halogen substituents, worked efficiently to
(Table 1, entry 2). The imidazolinium-based NHC precatalyst provide the corresponding diketones 3l–v in good to excellent
B1 provided a moderate yield of 3a (Table 1, entry 3). The thia- yields (Scheme 2). The dialdehyde bearing an EWG such as
zolium-based NHC precatalyst C1 was found to be a superior
catalyst to give 3a in an excellent yield (Table 1, entry 4). It was
reported that thiazolium-derived NHCs are efficient for certain
benzoin condensation reactions.14 Note that with C1 the reac-
tion could be scaled up to the gram scale in a high yield. The
triazolium-based NHC precatalyst D1 was also effective for this
study to afford 3a, albeit in a moderate yield (Table 1, entry 5).
Table 1 Optimization studya
Entry
NHC precatalyst
Base
Solvent
%Yield of 3a b
1
2
3
4
5
6
7
8
9
A1
A2
B1
C1
D1
C1
C1
C1
C1
DBU
DBU
DBU
DBU
DBU
K2CO3
NaH
DBU
DBU
THF
THF
THF
THF
THF
THF
THF
DMSO
EtOAc
42
85
48
92 (82%)c
58
45
35
85
31
a Reaction conditions: 1a (0.25 mmol), NHC precatalyst (20 mol%),
base (0.3 mmol), solvent (2.5 mL). b Yields are of isolated products.
c 82% yield (1.84 g) on a 10 mmol scale.
Scheme 2 Scope of the NHC-catalyzed intramolecular benzoin con-
densation–oxidation.
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CF3 also served well in this transformation to afford the
respective cyclic 1,2-diketone 3w in 83% yield (Scheme 2).
However, our efforts to access the dialdehyde starting material
bearing a strong EWG such as NO2 using an SNAr reaction were
not successful. We were also interested in investigating the scope
of dialdehyde 1 bearing substituents on both the benzene rings
(Scheme 2). The dialdehyde, bearing EDGs on the benzene rings,
served as a good substrate to deliver the corresponding diketone
3x in 78% yield. The dialdehyde containing halo substituents
such as –Br and –Cl on the benzene rings gave the corresponding
diketone 3y in 85% yield. The dialdehydes bearing an EDG and
halo groups on the benzene rings afforded the corresponding
products 3z and 3aa in good yields.
Later, we thought of examining the scope of the heteroatom
connection in dialdehyde 1. We performed the reaction of 2,2′-
thiodibenzaldehyde 4 under the optimized NHC catalysis con-
ditions and observed the formation of the corresponding
benzoin derivative 5 in 60% yield instead of the expected
dibenzo[b,f]thiepine-10,11-dione 6 (Scheme 3, LHS). When the
reaction time was prolonged to 1 hour, the 1,2-diketone
product 6 was formed in 65% yield (Scheme 3, RHS). We also
treated benzoin 5 with DBU (1.2 equiv.), in the absence of
NHC, in THF at room temperature in open air for 30 minutes
to furnish 6 in 90% yield (Scheme 3). We then performed the
reaction of 2,2′-azanediyldibenzaldehyde 7 under the optimal
NHC-catalyzed conditions and isolated the corresponding
benzoin 8 in 75% yield (Scheme 3, LHS). Prolonging the reac-
tion time to 1 hour provided the cyclic 1,2-diketone 5H-
dibenzo[b,f]azepine-10,11-dione 9 in 78% yield (Scheme 3,
RHS). The reaction of 8 with DBU in open air, in the absence
of NHC, furnished 9 in an excellent yield (Scheme 3).
To probe the reaction mechanism of the present transform-
ation, we decided to isolate the benzoin intermediate 2a. We
treated 1a with the NHC C1 (20 mol%) in the presence of DBU
(1.2 equiv.) in THF and stirred the reaction mixture for
15 minutes. However, we failed to obtain the corresponding
benzoin intermediate 2a. When the reaction was conducted
with a reduced amount of DBU (30 mol%), we isolated the
benzoin derivative 2a in 51% yield (Scheme 4).
These results indicate that the sequential transformation
proceeds through the benzoin intermediate (Schemes 3 and 4).
Subsequently, the benzoin derivative 2a was treated with DBU
(1.2 equiv.) in THF under an open air atmosphere to obtain
the diketone 3a in 85% yield. Note that in the absence of DBU
also the desired diketone 3a was observed in 80% yield
(Scheme 4a). The reaction of 1a with NHC was not successful
under an oxygen/open air atmosphere (Scheme 4b, LHS),
Scheme 4 Control experiments.
which may suggest that the reaction does not proceed through
intramolecular oxidative coupling of the dialdehyde. By using
degassed THF, under an argon atmosphere, the yield of 3a
drastically dropped, which may suggest that the oxidation of
the benzoin intermediate is assisted by the dissolved oxygen in
THF15 (Scheme 4b, RHS). It turns out that the first step, i.e.
benzoin condensation needs an inert atmosphere;2 sub-
sequently, the secondary hydroxyl group undergoes
oxidation with molecular oxygen dissolved in the reaction
solvent.15
From the control experiments and previous literature
reports,2 we postulated a plausible mechanism for the NHC-
catalyzed intramolecular benzoin condensation–oxidation to
access dibenzo[b,f]oxepine-10,11-dione derivatives (Scheme 5).
The catalytic cycle could be initiated by the abstraction of the
proton from carbene precursor C1 to generate the free NHC I,
which would add to one of the electrophilic carbonyl carbons
of dialdehyde 1a to give intermediate II. Subsequently, a
proton shift might take place on intermediate II to lead to the
formation of the Breslow intermediate III. The Breslow inter-
mediate’s nucleophilic carbon would intramolecularly add to
the other electrophilic carbonyl centre of aldehyde to
provide intermediate IV. Expulsion of NHC would take place
from intermediate IV to provide the corresponding benzoin
derivative 2a. The benzoin derivative would undergo an
aerial oxidation13b process to furnish the desired diketone
derivative 3a.
To demonstrate the synthetic utility of the cyclic 1,2-dike-
tones, we subjected the 1,2-diketone functionality to various
organic transformations. The cyclic 1,2-diketones 3a and 3m
were treated with sodium borohydride to give the corres-
Scheme 3 NHC-catalyzed intramolecular benzoin condensation–oxi-
dation of 4/7.
Scheme 5 Plausible mechanism.
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Acknowledgements
We thank the Science & Engineering Research Board (SERB),
Department of Science and Technology (DST), India, for the
Extramural Research grant (EMR/2017/002601). K.S. thanks
the CSIR, New Delhi, and J.R. thanks the UGC, New Delhi, for
their fellowships. We thank the Director, CSIR-IICT, for the
support (communication No. IICT/Pubs./2020/143).
Notes and references
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Scheme 6 Synthetic transformation of the cyclic 1,2-diketones 3a and
3m.
ponding 1,2-diols 10 and 11, respectively, in high yields
with excellent diastereoselectivity (Scheme 6). The cyclic
1,2-diketones 3a and 3m were treated with ammonium acetate
and paraformaldehyde to furnish the corresponding imid-
azole-fused dibenzoxepine derivatives 12 and 13, respectively,
in very good yields (Scheme 6). The –NH group of imidazole 13
was methylated using methyl iodide to give compound 14
(Scheme 6). The tetracyclic compounds 12–14 can be con-
sidered as the imidazole congeners of asenapine,7 which is
used as an antipsychotic drug. Also these kinds of imidazole-
fused dibenzoxepine derivatives were shown to have anti-
inflammatory activities.16
To further demonstrate the synthetic utility of the cyclic 1,2-
diketones, 3m was treated with o-phenylenediamine 15 in the
presence of 10 mol% of I2 in CH3CN at room temperature for
1 h to afford 7-chlorodibenzo[2,3 : 6,7]oxepino[4,5-b]quinoxa-
line 17 in 78% yield (Scheme 6). We also performed the reac-
tion of 3m and ethylenediamine 16 in the presence of
10 mol% of I2 in CH3CN at room temperature for 1 h to
furnish the respective 6-chloro-2,3-dihydrodibenzo[2,3 : 6,7]
oxepino[4,5-b]pyrazine 18 in 65% yield (Scheme 6).
Subsequently, compound 18 was subjected to DDQ oxidation
to furnish 6-chlorodibenzo[2,3 : 6,7]oxepino[4,5-b]pyrazine 19
in 80% yield (Scheme 6).
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Conflicts of interest
There are no conflicts to declare.
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