N-Heterocyclic carbene-catalysed intramolecular hydroacylation to form basic nitrogen-containing heterocycles

Article abstract of DOI:10.1039/c6ob01956k

We report catalytic, intramolecular hydroacylations of N-allylimidazole-2-carboxaldehydes and N-allylbenzimidazole-2-carboxaldehydes. These exo-selective hydroacylations occur in the presence of a N-heterocyclic carbene catalyst to generate 5,6-dihydro-7H-pyrrolo[1,2-α]imidazol-7-ones and 1,2-dihydro-3H-benzo[d]pyrrolo[1,2-α]imidazol-2-ones in high yields (66-99%). In addition, hydroacylations of N-allylimidazole-2-carboxaldehydes in the presence of a chiral, non-racemic NHC catalyst occur, forming 5,6-dihydro-7H-pyrrolo[1,2-α]imidazol-7-ones in moderate-to-high yields (39-98%) with modest enantioselectivities (56-79% ee).

Full text of DOI:10.1039/c6ob01956k

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N-Heterocyclic Carbene-Catalysed Intramolecular Hydroacylation
to Form Basic Nitrogen-Containing Heterocycles
Received 00th January 20xx,
Accepted 00th January 20xx
James A. Walker Jr. and Levi M. Stanley*
DOI: 10.1039/x0xx00000x
www.rsc.org/
We report catalytic, intramolecular hydroacylations of N- selective hydroacylations. Building on reports from Glorius and
26-28
allylimidazole-2-carboxaldehydes and N-allylbenzimidazole-2- co-workers (scheme 1a)21,
and a recent study from our
carboxaldehydes. These exo-selective hydroacylations occur in laboratory29 on NHC-catalysed intramolecular hydroacylations
the presence of a N-heterocyclic carbene catalyst to generate 5,6- of unactivated alkenes, we now report NHC-catalysed, exo-
dihydro-7H-pyrrolo[1,2-α]imidazol-7-ones and 1,2-dihydro-3H- selective hydroacylations of N-allylimidazole- and N-
benzo[d]pyrrolo[1,2-α]imidazol-2-ones in high yields (66-99%). In allylbenzimidazole-2-carboxaldehydes to a form a variety of
addition, hydroacylations of N-allylimidazole-2-carboxaldehydes dihydropyrroloimidazolones
and
in the presence of a chiral, non-racemic NHC catalyst occur to form dihydrobenzopyrroloimidazolones in moderate to high yields
5,6-dihydro-7H-pyrrolo[1,2-α]imidazol-7-ones in moderate-to-high (Scheme 1b).
yields (39-98%) with modest enantioselectivities (56-79% ee).
Intramolecular hydroacylations of alkenes in the presence of
transition-metal catalysts are well-known processes to
generate a variety of valuable cyclic ketones.1-6 Transition
metal-catalysed alkene hydroacylations to form and
functionalize nitrogen-containing heterocycles, in many cases
with high yields and enantioselectivities, have been the focus
of recent studies to improve the synthetic utility of these
important C-C bond forming processes.7-11 However, alkene
hydroacylations to form nitrogen heterocycles containing a
basic nitrogen atom often do not occur in the presence of
rhodium, cobalt, and nickel complexes that are excellent
catalysts of alkene hydroacylation due to inhibition of the
Scheme
1 a) NHC-catalyzed enantioselective intramolecular hydroacylations of
catalyst in the presence of basic nitrogen atoms.11
unactivated alkenes and b) NHC-catalyzed, exo-selective hydroacylations of N-
allylimidazole and N-allylbenzimidazole-2-carboxaldehydes.
N-Heterocyclic carbenes (NHCs)12-16 are a widely utilized
class of organocatalysts and offer a promising alternative to
transition-metal catalysts for alkene hydroacylation
reactions.17-20 Key to our studies, NHCs have been shown to
tolerate additives containing basic nitrogen atoms.21
To identify general reaction conditions for the NHC-
catalysed hydroacylation of N-allylimidazole- and N-
allylbenzimidazole-2-carboxaldehydes, we evaluated the
model reaction of N-allylimidazole-2-carboxaldehyde 1a in the
The potential to further develop alkene hydroacylation
presence of triazolium chloride 2
30 and a variety of organic and
reactions as
heterocycles led us to investigate NHC-catalysed
intramolecular hydroacylations of N-allylimidazole-2-
a platform to generate polycyclic nitrogen
inorganic bases (Table 1). An initial survey of reaction
conditions showed that reaction temperature dramatically
impacts the yield of dihydropyrroloimidazolone 3a (entries 1-
5). Reactions of 1a run at 60 or 80 °C formed 3a in 96% and
95% yield when 20 mol% DBU was employed as the base
(entries 2 and 3). In contrast, reactions of 1a carried out at
room temperature and at or above 100 °C led to the formation
of 3a in low-to-moderate yield (entries 1, 4, and 5).
carboxaldehydes and N-allylbenzimidazole-2-carboxaldehydes.
The development of such reactions offers the potential to
rapidly generate dihydropyrroloimidazolone22,
23
and
dihydrobenzopyrroloimidazolone24, 25 derivatives through exo-
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Table 1 Identification of reaction conditions for NHC-catalysed hydroacylation of N-
allylimidazole-2-carboxaldehyde 1aa
The loading of catalyst and base and the identity of the
base are also important reaction variables that must be
controlled to generate 3a in high yield (Table 1, entries 6-12).
Lowering the loading of triazolium chloride
2 to 5 mol% (entry
6), DBU to 10 mol% (entry 7) or both (entry 8) was detrimental
to the yield of 3a. The model reaction formed 3a in low yield
when we replaced DBU with a relatively weak organic or
inorganic base, such as triethylamine, sodium acetate, or
potassium acetate (entries 9-11). However, the identity of the
base is not limited to DBU. The model reaction generates the
hydroacylation product 3a in nearly quantitative yield when
tribasic potassium phosphate is used as the base (entry 12).
Entry
1
Base
DBU
Temp (°C)
25
Conv (%)b
100
100
100
100
100
100
82
Yield 3a (%)c
14
96
95
45
0
2
DBU
60
Table 2 NHC-catalysed hydroacylation of N-allylimidazole-2-carboxaldehydes 1a-ja
3
DBU
80
4
DBU
100
120
60
5
DBU
6d
7e
8d,e
9
DBU
21
81
33
0
DBU
60
DBU
60
70
Et3N
60
100
100
100
100
10
11
12
NaOAc
KOAc
K3PO4
60
7
60
18
99
60
a
Entry
1
R1
R2
H
Yield 3 (%)b
96 (99)c
Reaction conditions: 1a (0.20 mmol), 2 (0.02 mmol), base (0.04 mmol), 1,4-
dioxane (0.4 mL), 12 h. Determined by 1H NMR spectroscopy of the crude
b
1
2
1a
1b
1c
1d
1e
1f
H
c
reaction mixture using dibromomethane as an internal standard. Isolated yield
C6H5
H
96
d
e
of 3a. Reaction run in the presence of 10 mol% DBU. Reaction run in the
presence of 5 mol% 2.
3
4-MeO-C6H4
H
85
4
4-Cl-C6H4
H
99
5
H
H
H
H
H
H
C6H5
99
The low yields of ketone 3a in reactions conducted at room
temperature and at or above 100 °C result from a benzoin
condensation that is the primary reaction pathway at room
temperature and deactivation of the NHC catalyst at or above
100 °C.27 The reaction of 1a conducted at room temperature
leads to the nearly quantitative formation of benzoin
condensation product 4a within minutes (Scheme 2). Heating
the reaction mixture containing benzoin condensation product
4a to 60 °C in the presence of the NHC catalyst generated from
6
4-MeO-C6H4
4-Cl-C6H4
4-F-C6H4
3-F-C6H4
2-F-C6H4
99 (88)c
95 (81)c
99
7
1g
1h
1i
8
9
99
10
1j
99
a
Reaction conditions: 1a-j (0.20 mmol), triazolium 2 (0.02 mmol), DBU (0.04
b
mmol) and 1,4-dioxane (0.4 mL).
Isolated yield of 3 after column
c
chromatography. Reaction run in the presence of 10 mol% 2 and 20 mol%
K3PO4.
triazolium chloride
2 leads to high yield of ketone 3a (See
A
summary
of
NHC-catalysed
intramolecular
Figure S2 in the Supporting Information). In contrast, heating
the reaction mixture containing 4a at 100 or 120 °C in the
presence of the NHC catalyst generated from triazolium
hydroacylations
of
N-allylimidazole-2-carboxaldehydes
containing a range of substituted allyl units is shown in Table 2.
The hydroacylation of N-allylimidazole-2-carboxaldehyde
forms 3a in high yield when either DBU or K3PO4 is used as the
base (Table 2, entry 1). Reactions of N-allylimidazole-2-
carboxaldehydes containing electron-neutral, electron-rich, or
electron-deficient aryl groups at the terminal position of the
chloride
2 did not lead to high yields of 3a, likely because the
NHC catalyst decomposes at these temperatures. The balance
of the mass in these reactions is composed of the benzoin
condensation product which is readily oxidized to the
corresponding diketone upon exposure of the reaction mixture
to air (see synthesis of S1 in the Supporting Information).31
allyl unit formed heterocyclic ketones 3b-3d in good to
excellent yields (85-99%, entries 2-4). Aryl substitution at the
internal position of the allyl unit is also well tolerated.
Hydroacylations
of
N-allylimidazole-2-carboxaldehydes
containing aryl groups with a variety of electronic properties
and substitution patterns at the internal position of the allyl
unit occur to form heterocyclic ketones 3e
quaternary carbon center in high yields (95-99%, entries 5-10).
The NHC-catalysed hydroacylations of N-
allylbenzimidazole-2-carboxaldehydes 5a also occur to form
heterocyclic ketone products 6a in moderate-to-high yields
-3j containing a
-f
Scheme 2 Rapid NHC-catalysed benzoin condensation of 1a at room temperature
-f
(59-97%, Scheme 3). N-Allylbenzimidazole-2-carboxaldehydes
2 | J. Name., 2012, 00, 1-3
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Table
carboxaldehydes 1e-ja
3 Enantioselective NHC-catalysed hydroacylation of N-allylimidazole-2-
containing unsubstituted allyl units, allyl units with terminal or
internal aryl substitution, and 5,6-dimethylbenzimidazole units
are all suitable substrates for the NHC-catalysed
hydroacylation reaction. The NHC-catalysed hydroacylation of
N-allylbenzimidazole-2-carboxaldehyde 5a formed the
corresponding ketone 6a in 97% yield. Hydroacylations of 5b
, substrates containing aryl substitution at the terminal
position of the allyl unit, generated ketones 6b in 83-87%
yield. Intramolecular hydroacylations of N-allylbenzimidazole-
2-carboxaldehydes 5d containing substitution at the internal
position of the allyl unit and on the benzimidazole backbone
formed ketones 6d in 66-93% yield.
-
c
-c
-f
Entry
1
R
Yield 3 (%)b
ee (%)c
71
-f
1
2
3
4
5
6
1e
1f
1g
1h
1i
C6H5
90
98
96
81
93
39
4-MeO-C6H4
4-Cl-C6H4
4-F-C6H4
3-F-C6H4
2-F-C6H4
79
67
75
67
1j
56
a
Reaction conditions: 1e-j (0.10 mmol), triazolium 7 (0.01 mmol), DBU (0.02
b
mmol) and 1,4-dioxane (0.2 mL).
chromatography. c Determined by chiral HPLC analysis.
Isolated yield of 3 after column
In conclusion, we have established exo-selective NHC-
catalyzed intramolecular hydroacylation of N-allylimidazole-
and N-allylbenzimidazole-2-carboxaldehydes as
approach to generate 5,6-dihydro-7H-pyrrolo[1,2-
7-ones and 1,2-dihydro-3H-benzo[d]pyrrolo[1,2-
a
practical
α
]imidazol-
α
]imidazol-2-
ones in high yields. This synthetic methodology represents a
new example of NHC-catalysed hydroacylation of unactivated
alkenes that enables efficient hydroacylations of nitrogen
heterocycles containing basic nitrogen atoms.
The authors thank the National Science Foundation (CHE-
CAREER 1353819) for financial support of this work.
Scheme 3 NHC-catalysed hydroacylation of N-allylbenzimidazole-2-carboxaldehydes.
Reaction conditions: 5a-g (0.20 mmol), triazolium 2 (0.02 mmol), DBU (0.04 mmol) and
1,4-dioxane (0.4 mL). Yields of 3 are isolated after column chromatography. Yields in
parentheses correspond to reactions run in the presence of 10 mol% 2 and 20 mol%
K3PO4.
Notes and references
1
2
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carboxaldehydes and N-allylbenzimidazole-2-carboxaldehydes
conducted in the presence of an achiral NHC catalyst, we
investigated enantioselective hydroacylations of N-
allylimidazole-2-carboxaldehydes 1e-j catalyzed by the chiral,
3
4
5
3
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(Table 3). The hydroacylations of N-allylimidazole-2-
carboxaldehydes 1e-i occur to form heterocyclic ketone
products 3e-i in high yields (81-98%, entries 1-5) with modest
enantioselectivities (67-79% ee). However, the hydroacylation
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