N-Heterocyclic Carbene Catalyzed Oxidative Coupling of Alkenes/ α-Bromoacetophenones with Aldehydes: A Facile Entry to α,β-Epoxy Ketones

Article abstract of DOI:10.1002/anie.201507363

A novel, N-heterocyclic carbene (NHC) catalyzed direct oxidative coupling of styrenes with aldehydes has been described for the synthesis of α,β-epoxy ketones in good yields. This unprecedented regioselective oxidative coupling employs NBS/DBU/DMSO (DBU=1,8-diazabicyclo [5.4. 0] undec-7-ene, DMSO=dimethylsulfoxide, NBS=N-bromosuccinimide) as an oxidative system at ambient conditions. Additionally, first NHC-catalyzed Darzens reaction of α-bromoketones and aldehydes under mild reaction conditions has also been described. Interestingly, mechanistic studies have revealed the preferred reactivity of NHC with alkene/α-bromoketone rather than aldehydes, thus proceeding via the ketodeoxy Breslow intermediate.

Full text of DOI:10.1002/anie.201507363

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Angewandte
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International Edition: DOI: 10.1002/anie.201507363
German Edition: DOI: 10.1002/ange.201507363
Carbenes
N-Heterocyclic Carbene Catalyzed Oxidative Coupling of Alkenes/
a-Bromoacetophenones with Aldehydes: A Facile Entry to a,b-Epoxy
Ketones
Rambabu N. Reddi, Pragati K. Prasad, and Arumugam Sudalai*
Abstract: A novel, N-heterocyclic carbene (NHC) catalyzed
direct oxidative coupling of styrenes with aldehydes has been
described for the synthesis of a,b-epoxy ketones in good yields.
This unprecedented regioselective oxidative coupling employs
NBS/DBU/DMSO (DBU = 1,8-diazabicyclo [5.4. 0] undec-7-
ene, DMSO = dimethylsulfoxide, NBS = N-bromosuccini-
mide) as an oxidative system at ambient conditions. Addition-
ally, first NHC-catalyzed Darzens reaction of a-bromoketones
and aldehydes under mild reaction conditions has also been
described. Interestingly, mechanistic studies have revealed the
preferred reactivity of NHC with alkene/a-bromoketone rather
than aldehydes, thus proceeding via the ketodeoxy Breslow
intermediate.
nucleophilicity, are limited to reactions with carbonyl com-
pounds and electron-deficient alkenes only,[6] and their
reactions with other electrophiles remain elusive.[7] In con-
tinuation of our earlier studies on NHC-catalyzed reactions,[7]
we envisioned that the Breslow intermediate from the
aldehyde 1 and NHC 5 could regioselectively open the
bromonium ion A (for structure see Scheme5), formed in situ
from the alkene 2 and NHC, to afford, after HBr elimination,
the corresponding a,b-unsaturated ketone 3 (Scheme 1).
E
poxy ketones are among the most versatile building blocks
in organic synthesis because of their dense functionalization.
Further, they can be reliably functionalized to provide
numerous products (e.g. pharmaceuticals, natural products,
agricultural chemicals, fragrances, and inhibitors of cytosolic
epoxide hydrolases) including a- and b-carbonyls, a,b-epoxy
alcohols, 1,3-diols, etc.[1] In general, a,b-epoxy ketones can be
prepared either by the Darzens reaction of a-halocarbonyl
compounds with aldehydes under strong basic conditions[2] or
epoxidation of a,b-unsaturated ketones, with various oxi-
dants, catalyzed by Lewis acids or phase-transfer catalysts.[3]
An alternative method of oxidative coupling of aldehydes
with styrenes catalyzed by base, with TBHP as an oxidant, has
also been reported for its synthesis.[4] However, these methods
require either prefunctionalized starting materials, costly
metal catalysts, or often employ a large excess of aldehydes
and oxidants (TBHP, H2O2) at high temperatures, thus
resulting in low atom economy of the process.
Scheme 1. NHC-catalyzed oxidative coupling of alkenes with alde-
hydes. DBU=1,8-diazabicyclo [5.4. 0] undec-7-ene, DMSO=dimethyl-
sulfoxide, NBS=N-bromosuccinimide.
Surprisingly, the reaction took a different course, thus
affording the epoxy ketones 4 in high yields. To the best of
our knowledge, the direct coupling of aldehydes with alkenes
under NHC catalysis has not been reported. Herein, we
describe NHC-catalyzed oxidative coupling of styrenes and
aldehydes to afford the corresponding a,b-epoxy ketones in
good yields and in a highly regio- and diastereoselective
manner, by using NBS/DBU/DMSO as an oxidative system
under an N2 atmosphere.
To begin with, when styrene (2a; 1 mmol) was treated
Organocatalyzed reactions represent an attractive alter-
native to metal-catalyzed processes because of their low cost
and benign environmental impact in comparison to organo-
metallic catalysis. As organocatalysts, N-heterocyclic car-
with
a
mixture containing p-nitrobenzaldehyde (1e;
1.1 mmol), NBS (1 mmol), and Et3N (1.2 mmol) in the
presence of the NHC catalyst 5a (10 mol%; for structure
see Figure 1) at 258C in DMSO under a completely inert
atmosphere, the a,b-epoxy ketone 4e was obtained in 56%
yield upon isolation, with an excellent diastereomeric ratio
(trans/cis = 98:2; Table 1). It is unusual that the ketone group
in 4e is formed from the styrenic counterpart by benzylic
oxidation while the epoxide moiety is obtained from the
aldehydic coupling partner. To improve the yield of 4e, other
NHC catalysts were examined (Figure 1). Among the cata-
lysts screened, the thiazolium-based catalysts 5d and 5e were
found to be quite efficient for the oxidative coupling reaction
(up to 66% yields), while the imidazolium-based precatalysts
gave only moderate yields (up to 45%; Table 1; entries 1–5).
Surprisingly, the triazolium-based NHC catalysts 5 f and 5g
gave extremely low yields (18 and 13%, respectively) of the
À
À
À
benes (NHCs) catalyze a wide range of C C, C O, and C N
bond-forming reactions involving umpolung of the functional
group, with the carbonyl carbon atom acting as a transient
nucleophile.[5] NHC catalysts, because of their moderate
[*] R. N. Reddi,[+] P. K. Prasad,[+] Dr. A. Sudalai
Chemical Engineering and Process Development Division
National Chemical Laboratory
Pashan Road, Pune, 411008 (India)
E-mail: a.sudalai@ncl.res.in
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201507363.
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Table 2: NHC-catalyzed oxidative coupling of styrenes with aldehydes:
Substrate scope.[a]
Entry
Aldehyde (1)
Styrene (2)
Yield [%][b,c]
1
2
3
4
5
6
7
8
benzaldehyde (1a)
4-BrC6H4CHO (1b)
4-ClC6H4CHO (1c)
4-CNC6H4CHO (1d)
4-NO2C6H4CHO (1e)
2-NO2C6H4CHO (1 f)
1-heptanal (1g)
isovaleraldehyde (1h)
ethyl glyoxalate (1i)
4-NO2C6H4CHO (1e)
4-NO2C6H4CHO (1e)
benzaldehyde (1a)
styrene (2a)
styrene
styrene
styrene
styrene
styrene
styrene
styrene
styrene
4a
4b
4c
4d
4e
4 f
4g
4h
4i
61
58
63
66
72
68
51
62
65
64
69
16
Figure 1. Some of the NHC precatalysts used. Mes=2,4,6-trimethyl-
phenyl.
Table 1: NHC-catalyzed oxidative coupling of 4-nitrobenzaldehyde (1e)
and styrene (2a): Optimization studies.[a]
9
10
11
12
4-methylstyrene (2b) 4j
4-bromostyrene (2c)
4k
4l
1-octene (2d)[d]
[a] For the reaction conditions, see the footnote [a] of Table 1. [b] Yield of
product isolated after column chromatographic purification. [c] Diaste-
reomeric ratios were found to be about 95:5 in each case as determined
by HPLC and 1H NMR analysess of the crude reaction mixture.
[d] 3 equiv of 2d were used and the reaction time was 34 h.
Entry
5 (10 mol%)
Base
Yield [%][b]
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5 f
5g
5e
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
NaH
Cs2CO3
KOtBu
DBU
DBU
56
45
37
58
66
18
13
54
4a–f were obtained (entries 1–6). Notably, aliphatic alde-
hydes such as heptanal (1g) and isovaleraldehyde (1h)
afforded the corresponding epoxy ketones 4g (51%) and 4h
(62%; entries 7 and 8). Remarkably, ethyl glyoxalate (1i)
gave ethyl 3-benzoyloxirane-2-carboxylate (4i) in moderate
yield (65%; entry 9). Additionally, styrene-type substrates,
having Br and Me groups on the benzene nucleus, were
subjected to coupling with 1e under the optimized reaction
conditions and gave good yields of the corresponding a,b-
epoxy ketones 4j (64%) and 4k (69%; entries 10 and 11). In
the case of 1-octene (2d), the desired epoxy ketone 4l was
formed in 16% yield. However, internal alkenes and terminal
disubstituted alkenes failed to undergo this oxidative coupling
reaction.
9
5e
5e
5e
24
61
10
11
12
72 (51)[c] (15)[d]
41 (70)[e]
5e (5 mol%)
[a] Reaction conditions: styrene (1 mmol), p-nitrobenzaldehyde
(1.1 mmol), NHC precatalyst (5a–e; 10 mol%), base (1.2 mmol), and
NBS (1 mmol) in DMSO at 258C for 18 h. [b] Yield of isolated product
after column chromatographic purification. [c] NIS was used instead of
NBS. [d] NCS was used as halogen source. [e] 20 mol% of catalyst 5e
was used.
desired product 4e. Other solvents such as THF, CH3CN,
CH2Cl2, 1,4-dioxane, and DMF were unsuitable for the
reaction. Also, DBU was found to be an excellent base for
the reaction (72% yield) while inorganic bases were only
moderately active (up to 61% yield; entries 8–11). Other N-
halosuccinimides (halogen = I, Cl) were also screened to give
4e in 51 and 15% yields, respectively (entry 11). In addition,
either lowering of the catalyst concentration or increase of the
reaction temperature did not significantly improve the yield
(entry 12).
With this optimized yield in hand, the NHC catalytic
system consisting of 5e (10 mol%), NBS (1 equiv), and DBU
(1.2 equiv) in DMSO under an inert atmosphere was chosen
for the study of the substrate scope. Accordingly, a variety of
aromatic aldehydes (1a–f), having different groups such as
bromo, chloro, methyl, and NO2, etc. at various positions on
the aromatic nucleus, were subjected to oxidative coupling
(Table 2) with styrenes. For all the substrates studied,
moderate to good yields (58–72%) of the epoxy ketones
To probe the reaction mechanism, the following control
experiments were conducted: a) no epoxy ketone product was
formed in the absence of either the NHC catalyst or NBS;
thereby establishing the fact that both of them are critical in
this coupling reaction; b) when the NHC precatalyst 5e was
treated with NBS and DBU in DMSO in the absence of
styrene and aldehyde, the NHC dimer 8 was isolated[11] in
40% yield, and it was also formed in the absence of NBS. This
result explains the fact that no reaction occurs between NBS
and NHC; c) in the absence of aldehyde and NHC catalyst,
with 2a as a substrate, the phenacyl bromide 6a and styrene
epoxide 7a were formed in 34% and 36% yields, respectively
(Scheme 2); d) additionally, treatment of 6a with 1e, in the
presence of 5e and DBU under a N2 atmosphere, afforded the
desired product 4e in 78% yield, whereas 7a, under similar
reaction conditions did not undergo any reaction. Thus, it is
proven that the coupling reaction proceeds through the
respective a-bromoketones 6, which subsequently react with
aldehydes: indeed a conventional Darzens reaction.
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Scheme 2. Control experiments to probe the mechanism.
Consequently, it was of interest to explore the first NHC-
catalyzed Darzens reaction to see if it could overcome the
disadvantages associated with the conventional reagent
system (e.g. strong basic conditions, use of sulfur compounds
and phase-transfer reagents). The results are presented in
Table 3. Accordingly, various aromatic aldehydes having
Scheme 3. NHC-catalyzed enantioselective Darzens reaction.
and the trans-product, once formed, is thermodynamically
more stable. Kinetic experiments revealed that an NHC-
catalyzed Darzens reaction proceeds faster than the forma-
tion of the phenacyl bromide under the reaction conditions
(see the Supporting Information for details).
Table 3: NHC-catalyzed oxidative coupling of a-bromoacetophenones
with aldehydes: Substrate scope.[a]
To probe mechanistic details further, the following
stoichiometric control experiments were carried out
(Scheme 4): a) when 2a was treated with 1 equivalent of 5e,
Entry Aldehyde (1)
Ar (6)
Yield [%][b,c]
1
2
3
4
5
6
7
8
9
benzaldehyde (1a)
Ph (6a)
Ph
Ph
4a 71
4b 74
4c 75
4d 72
4-BrC6H4CHO (1b)
4-ClC6H4CHO (1c)
4-CNC6H4CHO (1d)
4-NO2C6H4CHO (1e) Ph
1-heptanal (1g) Ph
4-NO2C6H4CHO (1e) 4-MeC6H4 (6b) 4j 71
4-NO2C6H4CHO (1e) 4-BrC6H4 (6c)
benzaldehyde (1a) C6H11 (6d)
Ph
4e 78 (15)[d] (66)[e,f]
4g 68
Scheme 4. Stoichiometric experiments.
4k 69
in the absence of an aldehyde, under standard reaction
conditions, the ketodeoxy Breslow intermediate 9 was
isolated[8] in 48% yield. It was also formed (78%) when 6a
was treated with 5e under basic conditions, irrespective of
whether or not aldehyde is present; b) Furthermore, when 9
was treated with 1e in DMSO, the corresponding epoxy
ketone 4e was isolated in 64% yield. This leads us to believe
that NHC preferentially reacts with phenacyl bromide rather
than aldehyde under the optimized reaction conditions,
although one cannot rule out the possibility of reaction
between the aldehyde and NHC, which may be reversible and
hence unproductive.
Based on the aforementioned results and previous
reports,[9] a probable catalytic cycle for this NHC-catalyzed
oxidative functionalization of styrenes is outlined in
Scheme 5. To begin with, styrene reacts with NBS to form
the bromonium ion A, which undergoes regioselective ring
opening with DMSO and subsequent Me2S elimination to
provide the phenacyl bromide 6. The NHC then reacts with 6
to form the intermediate salt B, which eliminates HBr to give
the ketodeoxy Breslow intermediate 9. Finally, 9 reacts with
aldehyde followed by liberation of the NHC catalyst and
furnishes the thermodynamically stable trans-a,b-epoxy
ketones 4.
4l 54[g]
[a] Reaction conditions: a-bromoacetophenones (1 mmol), aldehyde
(1.1 mmol), NHC precatalyst 5e (10 mol%), and DBU (20 mol%) in
DMSO at 258C, for 12 h under N2 atm. [b] Yield of product isolated after
column chromatographic purification. [c] Diastereomeric ratios were
found to be >95:5 for all the case studied, as determined by 1H NMR
spectroscopy and HPLC analysis. [d] a-Chloroacetophenone was used
instead of a-bromoacetophenone. [e] The NHC catalyst 5 f was used.
[f] No product was observed in the absence of an NHC catalyst.
[g] Reaction time 18 h.
groups such as Cl, Br, CN, and NO2 on the aromatic nucleus
were subjected to the NHC-catalyzed Darzens reactions with
the phenacyl bromides 6 and afforded the corresponding a,b-
epoxy ketones (4a–e) in high yields (entries 1–5). Also, 1-1-
heptanal (1g) gave the corresponding epoxy ketone 4g in
68% yield. Further, the substituted a-bromoacetophenones
6b and 6c gave 4j (71%) and 4k (69%), respectively
(entries 7 and 8). Interestingly, the aliphatic bromoketone 6d
gave the corresponding epoxy ketone 4l in 54% yield.
Remarkably, for its asymmetric version, the chiral NHC
catalyst 5h was used, and gave the corresponding chiral epoxy
ketone 4e in 62% yield with 56% enantiomeric excess
(Scheme 3). The absolute configuration (2S, 3R) of (+)-4e
was assigned based on comparison of its specific rotation with
the reported value.[3h]
In summary, we have described, for the first time, a novel
organocatalytic process in which oxidative coupling of
styrenes with aldehydes take place, thus leading to a facile
synthesis of the a,b-epoxy ketones 4a–l in moderate to good
yields with excellent d.r. values (> 95%). The procedure
employs NHC in catalytic amounts (10 mol%) in combina-
tion with NBS/DBU/DMSO as the oxidative system. An
When a cis-epoxide (cis-4c) was subjected to the opti-
mized reaction conditions, it remained a cis isomer. Also, the
Darzens reaction of the a-bromoketone 6a and 1e at low
temperature (À40 to À108C) did not produce the cis-epoxy
ketone. These results suggest that the reaction is irreversible
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Scheme 5. Probable catalytic cycle for oxidative coupling of aldehydes
with styrenes/a-bromoketones.
unconventional mechanistic course has been proposed based
on the isolated ketodeoxy Breslow intermediate 9. Further,
the a,b-epoxy ketones 4 were obtained by the reaction of a-
bromoacetophenones with aldehydes (Darzens reaction
including its asymmetric version) using an NHC catalyst
under mildly basic conditions. The salient features of the
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Acknowledgements
R.B.R and P. K.P thank CSIR, New Delhi for the award of
research fellowships and thank CSIR, New Delhi, India
(Indus MAGIC project CSC-0123) and DST-SERB (no. SB/
S1/OC-42/2014), for financial support. The authors are also
thankful to Dr. V. V. Ranade, Chair, Chem. Engg. & Process
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[11]
Keywords: aldehydes · epoxidation · N-heterocyclic carbenes ·
oxidation · synthetic methods
How to cite: Angew. Chem. Int. Ed. 2015, 54, 14150–14153
Angew. Chem. 2015, 127, 14356–14359
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Received: August 7, 2015
Published online: September 21, 2015
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