Direct and Regioselective Introduction of Acetals into Imidazoles at the 2-Position by an Iridium-Catalyzed Reaction with Formates in the Presence of Hydrosilanes

Article abstract of DOI:10.1002/ejoc.201700125

The iridium-catalyzed reaction of imidazoles with formates in the presence of hydrosilanes as coreactants led to the production of 2-[(alkoxy)(siloxy)methyl]imidazoles. Dimethyl acetylenedicarboxylate was the additive of choice for the reaction in terms of reaction efficiency. No reaction was observed in the absence of the hydrosilanes. Whereas substituents at the 1- and 5-positions on the imidazole ring did not affect the reaction, substituents at the 4-position greatly retarded the reaction. The regioselective reaction of 1-methyl-1,2,4-triazole occurred at the carbon atom between the sp³ and sp² nitrogen atoms of the ring but not between two sp² nitrogen atoms. The products were converted into imidazole 2-carbaldehydes by hydrolysis under acidic conditions.

Full text of DOI:10.1002/ejoc.201700125

A Journal of
Accepted Article
Title: Direct And Regioselective Introduction of Acetals into Imidazoles
at the 2-Position by the Iridium-Catalyzed Reaction with Formates
in the Presence of Hydrosilanes
Authors: Yoshiya Fukumoto, Yasuaki Iyori, and Naoto Chatani
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700125
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700125
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COMMUNICATION
Direct And Regioselective Introduction of Acetals into Imidazoles
at the 2-Position by the Iridium-Catalyzed Reaction with Formates
in the Presence of Hydrosilanes
[
a]
[a]
[a]
Yoshiya Fukumoto,* Yasuaki Iyori, and Naoto Chatani
Abstract: The iridium-catalyzed reaction of imidazoles with formates
in the presence of hydrosilanes as co-reactants, leading to the
production of 2-[(alkoxy)(siloxy)methyl]imidazoles, is described.
Dimethyl acetylenedicarboxylate (DMAD) was the additive of choice
for the reaction, in terms of reaction efficiency. No reaction was
observed in the absence of the hydrosilanes. While substituents at
the 1- and 5-positions on the imidazole ring did not affect the
reaction, substituents at the 4-position greatly retarded the reaction.
The regioselective reaction of 1-methyl-1,2,4-triazole occurred at the
catalyst with a stoichiometric amount of a hydrosilane as a co-
reactant (Scheme 1). To the best of our knowledge, this is the
first report on the direct catalytic introduction of acetal groups
into imidazoles.
3
2
Scheme 1. Iridium-catalyzed reaction of imidazoles with formates and
hydrosilanes.
carbon atom between the sp and sp nitrogen atoms of the ring, but
2
not between two sp nitrogen atoms The products were converted
into imidazole 2-carbaldehydes by hydrolysis under acidic conditions.
Results and Discussion
Introduction
Following the success of the development of the related reaction
10
with aldehydes, we started our studies by optimizing the
reaction conditions for model reaction consisting of 1-
butylimidazole (1a, 1 mmol) with benzyl formate (3 mmol) and
HSiEt Me (3 mmol) in the presence of Ir (CO)12 (0.02 mmol) and
DMAD (0.16 mmol) in toluene (3 mL) at 110 ˚C. As shown in
Table 1, the reaction for 24 h gave 2a in 59%, which was
isolated in 56% yield by NH -modified silica-gel column
2
chromatography (entry 1). On the other hand, the reaction in the
absence of DMAD resulted in decrease in the product yield to
Imidazoles are important structural components that are widely
1
a
distributed in various molecules such as natural products,
2
3
biologically active compounds, and functional materials. As a
consequence, an extensive array of new methods for the
2
4
4
preparation of imidazole derivatives has been developed.
Among these synthetic methodologies, transition metal-
catalyzed direct C-H functionalizations have attracted particular
attention as an efficient tool for the synthesis of highly
5
substituted imidazoles. Considerable efforts have been made to
14%, along with the recovery of the starting 1a in 83% (entry 2).
develop new methods for C-C bond formation with aryl and
alkenyl halides or pseudohalides catalyzed by various transition
Other alkynes such as diphenylacetylene (entry 3) and 4-octyne
(entry 4) were ineffective as additives. Under the reaction
conditions at 140 ˚C for 48 h, 2a was produced in 70% yield
(entry 6). In this run, however, 2a could not be isolated in pure
6
2
2
metal complexes. The oxidative C(sp )-H/C(sp )-H coupling of
imidazoles at the C-2 position with aromatic compounds has
7
also been reported. The catalytic addition of imidazole C-H
8
8c,9
form
because
1-butyl-2-[(diethylmethylsilyl)oxy]methyl-1H-
bonds at the 2-position to C-C double and triple bonds
has
imidazole (2a’) was produced in 4% yield as a by-product, which
could not be separated from 2a. Other transition-metal
been developed for the introduction of alkyl and alkenyl groups,
respectively, without the formation of any side products.
Aldehydes have also been reported to function as a coupling
partner with imidazoles in the presence of hydrosilanes to
produce 2-(1-siloxyalkyl)imidazoles under conditions of
complexes, such as IrCl(CO)(PPh
also showed catalytic activity for the present reaction (entries 7-
). Lastly, some control experiments with no catalyst (entry 12)
and no HSiEt Me (entry 13) were performed, and no detectable
3 2 2 4
) , [IrCl(cod)] , and Rh (CO)12,
9
2
4
Ir (CO)12/DMAD
catalysis
(DMAD
=
dimethyl
10
formation of the product was observed in both cases. The former
result rules out the possibility that the reaction proceeds via the
acetylenedicarboxylate). The addition of a catalytic amount of
DMAD was sufficient for the reaction in terms of reaction
efficiency, suggesting that DMAD acts as a ligand, and not a
hydrogen acceptor. The addition of a hydrosilane was crucial for
the reaction to proceed. We report herein the direct C2-
functionalization of imidazoles with formates to produce 2-
formation of 1-butyl-3-vinylimidazol-2-ylidene as
a
key
intermediate, which could be generated by the nucleophilic
attack of the nitrogen atom at the 3-position in 1a at the alkyne
carbon in DMAD and the subsequent 1,4-transfer of hydrogen at
11
the 2-position.
[
4
(alkoxy)(siloxy)methyl]imidazoles by using Ir (CO)12/DMAD as a
We next examined some hydrosilanes and carbonyl
compounds in the reaction of 1a, and the results are shown in
Table 2. Using triethylsilane, 3a was produced in 70% yield, with
no siloxymethylated compound at the 2-position, corresponding
to 2a’, being produced. Therefore, pure 3a was isolated in 60%
yield (entry 2). When dimethyloctylsilane was used in the
[
a]
Dr. Y. Fukumoto, Y. Iyori, Prof. Dr. N. Chatani
Department of Applied Chemistry, Faculty of Engineering
Osaka University
Suita, Osaka 565-0871 (Japan)
E-mail: fukumoto@chem.eng.osaka-u.ac.jp
Web: http://www.chem.eng.osaka-u.ac.jp/~chatani-lab/
reaction, 4a was produced in 49% yield (entry 3). The yield of 5a
t
was decreased to 11% when the bulkier HSi BuMe
2
was used,
Supporting information for this article is available on the WWW
under http://dx.doi.org/@@@.
with 1a being recovered in 64% yield (entry 4). The use of
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European Journal of Organic Chemistry
10.1002/ejoc.201700125
COMMUNICATION
2
HSiPhMe , which possesses an electron-withdrawing substituent
of phenyl ring, in the reaction led to the formation of a complex
mixture of products, with 6a being produced in 16% yield (entry
5). Although hexyl formate was employed as a coupling partner
for producing 7a in 53% yield (entry 6), the use of other carbonyl
compounds such as DMF and benzyl acetate resulted in the
recovery of 1a (entries 7-8), due to the less-electrophilic
character of DMF and the more sterically demanding benzyl
acetate, respectively.
Scheme 2. Acid hydrolysis of 3a to the aldehyde 8a.
Table 1. Optimization of reaction conditions using 1a
Table 2. Screening of hydrosilanes and carbonyl compounds with 1a.
[
a]
Entry
Catalyst
Additive
Time Temp. Yield of
Remaining
[b]
1a [%]
[b]
[
h]
[ºC]
2a [%]
[
a]
[b]
[
c]
Entry
R
R’
HSiR”
HSiEt
3
Product
Yield [%]
70
1
2
3
4
5
6
7
8
9
1
1
1
1
Ir
Ir
Ir
Ir
Ir
Ir
4
4
(CO)12
(CO)12
DMAD
none
24
24
110
110
110
110
140
140
140
140
140
140
140
140
140
59
14
19
15
62
70
42
53
21
0
29
83
1
2
3
4
5
6
7
8
H
H
OBn
OBn
OBn
OBn
OBn
2
Me
2a
3a
4a
5a
6a
7a
[
c]
4
4
4
4
(CO)12
(CO)12
(CO)12
(CO)12
PhC≡CPh 24
75
73
16
4
HSiEt3
70 (60)
49 (39)
[
d]
PrC≡CPr
DMAD
DMAD
DMAD
DMAD
DMAD
DMAD
DMAD
DMAD
DMAD
24
24
48
48
48
48
48
48
48
48
H
HSiOctMe
2
t
[c]
H
HSi BuMe
2
11 (8)
[
d]
H
HSiPhMe2
HSiEt3
16 (14)
[
[
d]
e]
[c]
IrCl(CO)(PPh
[IrCl(cod)]
Rh (CO)12
[RhCl(cod)]
Ru (CO)12
none
Ir (CO)12
3
)
2
52
6
H
OC H
53 (41)
6
13
2
H
NMe2
HSiEt3
0
0
4
38
62
79
88
85
CH3
OBn
HSiEt3
0
1
2
3
2
[
f]
3
0
[a] Reaction conditions: 1a (1 mmol), ester or DMF (3 mmol), hydrosilane (3
mmol), Ir (CO)12 (0.02 mmol), DMAD (0.16 mmol), toluene (3 mL) at 140 ºC for
48 h. [b] Yield of the products was determined from H NMR spectrum with
,1,1,2-tetrachloroethane as an internal standard. [c] The value in parenthesis
0
4
1
[
g]
4
0
1
refers to an isolated yield of the acetal. [d] The value in parenthesis refers to
an isolated yield of 8a after the in situ acid hydrolysis of the product acetals.
[
a] Reaction conditions: 1a (1 mmol), benzyl formate (3 mmol), HSiEt
2
Me (3
mmol), catalyst (0.02 mmol), additive (0.16 mmol), toluene (3 mL). [b] Yields
1
of 1a and 2a were determined from
tetrachloroethane as an internal standard. [c] 2a was isolated by NH
silica-gel column chromatography in 56% yield. [d] Catalyst (0.08 mmol). [e]
Catalyst (0.04 mmol). [f] Catalyst (0.027 mmol). [g] No addition of HSiEt Me.
H
NMR spectrum with 1,1,1,2-
2
-modified
2
With the optimized reaction conditions in hand, the scope of
the catalytic reaction with respect to imidazole substrates was
then investigated (Table 3). The reaction of 1-methylimidazole
resulted in a higher product yield of 3b in 73% (entry 2).
Imidazoles bearing other substituents on the nitrogen such as
benzyl, methoxymethyl, and phenyl groups also reacted to afford
the corresponding coupling products 3c-3e (entries 3-5),
although no desired product was formed when 1-
ethoxycarbonylimidazole was used as a substrate. Both alkyl
The product acetals were susceptible to hydrolysis under
acidic conditions to give the corresponding aldehydes, which are
frequently used for the synthesis of materials such as
12
13
topsentins, vitronectin receptor antagonist SB223245, and
14
ZIF-90. A one-pot reaction involving the present iridium-
catalyzed coupling reaction of 1a with benzyl formate and HSiEt
followed by acid hydrolysis, resulted in 8a being produced in
1% yield (Scheme 2). Due to instability of 4a and 6a during
3
,
(entries 6-7) and aryl (entries 8-10) subtituents at the 5-position
did not affect the reaction. On the other hand, substituents
located at the 4-position caused the reaction to be greatly
retarded, with starting materials being recovered (entries 11-13).
6
attempted chromatographic separation, the hydrolysis method
was also applied, with isolated yields of 8a in 39% and 14%,
respectively.
2
These interesting results indicate that the sp nitrogen atom at
the 3-position in the imidazole ring appears to play an important
role in the catalytic reaction, but is not simply a spectator. The
reaction of benzene-fused imidazoles, including imidazo[1,5-
a]pyridine and 1-methylbenzimidazole, also led to the production
of 3l and 3m, respectively (entries 14 and 15). However,
benzoxazole and benzothiazole derivatives were not applicable
for use in the present catalytic reaction. These results might be
15
due to lower basicity of benzoxazole (pK
a
= -0.13) and
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European Journal of Organic Chemistry
10.1002/ejoc.201700125
COMMUNICATION
15
benzothiazole (1.2) compared with 1-methylbenzoimidazole Conclusions
1
6
(
5.67). The regioselective reaction of 1-methyl-1,2,4-triazole
3
2
occurred at the carbon atom between the sp and sp nitrogen
atoms of the ring to yield 3n, but not between two sp nitrogen
We report herein the iridium-catalyzed reaction of imidazoles
with formates in the presence of hydrosilanes leading to the
production of 2-[(alkoxy)(siloxy)methyl]imidazoles. The presence
of a hydrosilane in the reaction mixture was crucial for the
reaction to proceed. DMAD was the additive of choice for the
reaction, in terms of reaction efficiency. The products underwent
acid hydrolysis to afford imidazole 2-carbozyaldehyde
derivatives. Further study on the reaction mechanism, especially,
for the role of hydrosilanes and DMAD, is currently underway in
our groups.
2
atoms (entry 16).
Table 3. Scope of azoles.
[
a]
[b]
Entry
Product
Yield [%]
Experimental Section
1
2
3
4
5
R = Bu (3a)
= Me (3b)
= Bn (3c)
60
73
71
54
4
General Procedure for the Ir (CO)12-Catalyzed Reaction of
Imidazoles with Formates in the Presence of Hydrosilanes: A 25 mL
Schlenk tube was flame-dried and then cooled to room temperature
2
= CH OMe (3d)
[
c]
= Ph (3e)
27
2 4
under N . Ir (CO)12 (22.1 mg, 0.02 mmol), hydrosilane (3 mmol), toluene
(
3 mL), imidazole (1 mmol), formate (3 mmol), and DMAD (22.4 mg, 0.16
6
7
8
9
1
R = Me (3f)
= tBu (3g)
= Ph (3h)
= 4-MeOC
62
46
57
62
53
mmol) were added to the tube. The reaction mixture was then heated at
140 °C for 48 h. After cooling the mixture to room temperature, the
volatiles were removed in vacuo. Product yields were determined by
NMR spectroscopy with 1,1,1,2-tetrachloroethane as an internal standard.
1
6
H
4
(3i)
(3j)
H
0
= 4-F
3
CC
6
H
4
The products were isolated by flash column chromatography on NH
modified silica-gel.
2
-
1
1
2
R = tBu
0
0
1
= Ph
General Procedure for the Hydrolysis of the Product Acetals to
Aldehydes: After the reaction described above was carried out, the
volatiles were removed in vacuo. THF (5 mL) was then added to the
residue and the mixture was cooled to 0 ºC. 12N HCl (0.5 mL) was added
dropwise to the mixture and the mixture was stirred at room temperature
for 2 h. The resulting reaction mixture was quenched by the addition of
sat. NaHCO3 aq. (50 mL). The aqueous layer was extracted with CHCl3
13
3k
7
(
2 4
50 mL x 3) and the combined organic layers were dried over Na SO .
After removing the solids by filtration, the filtrate was concentrated in
vacuo and the products were isolated by flash column chromatography
on silica-gel.
[
c]
1
4
5
3l
24
Acknowledgements
1
3m
38
We wish to thank Osaka University for providing financial
assistance. We also thank the Instrumental Analysis Center,
Faculty of Engineering, Osaka University, for assistance with
HRMS and the elemental analyses.
16
3n
22
Keywords: C-H functionalization• Iridium Catalysis • Imidazole •
Formate • Hydrosilane
[
a] Reaction conditions: 1 (1 mmol), benzyl formate (3 mmol), HSiEt
Ir (CO)12 (0.02 mmol), DMAD (0.16 mmol), toluene (3 mL) at 140 ºC for 48 h.
b] Isolated Yields. [c] Isolated yield as the corresponding aldehyde 8 after the
in situ acid hydrolysis of 3.
3
(3 mmol),
[1]
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Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
Acetal Introduction
Yoshiya Fukumoto,* Yasuaki Iyori,
Naoto Chatani
Page No. – Page No.
Direct And Regioselective
Introduction of Acetals into
Imidazoles at the 2-Position by the
Iridium-Catalyzed Reaction with
Formates in the Presence of
Hydrosilanes
The iridium-catalyzed reaction of imidazoles with formates in the presence of
hydrosilanes as co-reactants produces 2-[(alkoxy)(siloxy)methyl]imidazoles.
Dimethyl acetylenedicarboxylate (DMAD) is the sole effective additive for the
reaction. The addition of hydrosilanes is crucial for the reaction to proceed. The
product acetals undergo hydrolysis under acidic conditions to yield the
corresponding imidzole 2-carboxaldehydes.
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