A convenient synthesis of 4(5)-alkylacyl-1H-imidazoles from 4(5)-imidazolecarboxaldehyde

Article abstract of DOI:10.1055/s-2003-38067

A convenient synthesis of 4(5)-acyl-1H-imidazoles from 4(5)-imidazolecarboxaldehyde without N-protecting group is described. 4(5)-Cyanoimidazole could be synthesized from commercially available 4(5)-imidazolecarboxaldehyde in one-pot. Treatment of 4(5)-cyanoimidazole with various alkylmagnesium bromides followed by addition of aqueous sulfuric acid afforded 4(5)-acyl-1H-imidazoles in good yield.

Full text of DOI:10.1055/s-2003-38067

PAPER
677
A Convenient Synthesis of 4(5)-Alkylacyl-1H-imidazoles from
4
(5)-Imidazolecarboxaldehyde
S
J
ynthesis
uo f 4(5)-Alky
n
lacy-1
H
-imi
-
Chemical Development Laboratories, Takeda Chemical Industries, Ltd., 2-17-85 Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan
E-mail: Kawakami_Junichi@takeda.co.jp
Received 13 December 2002; revised 29 January 2003
We have therefore investigated a convenient synthesis of
Abstract: A convenient synthesis of 4(5)-acyl-1H-imidazoles from
4
(5)-acyl-1H-imidazoles 3 from commercially available
4
(5)-imidazolecarboxaldehyde without N-protecting group is de-
starting materials taking into account cost, practicability,
scribed. 4(5)-Cyanoimidazole could be synthesized from commer-
cially available 4(5)-imidazolecarboxaldehyde in one-pot. preparation time, simplicity of purification and waste dis-
Treatment of 4(5)-cyanoimidazole with various alkylmagnesium posal. We now report that acylimidazoles 3 can be effi-
bromides followed by addition of aqueous sulfuric acid afforded
ciently prepared from 4(5)-imidazolecarboxaldehyde (1)
without N-protection (Equations 1 and 2).
4
(5)-acyl-1H-imidazoles in good yield.
Key words: Grignard reaction, ketones, nitriles, alkylations
First, the synthesis of 4(5)-cyanoimidazole (2) was exam-
ined. Few examples of the synthesis of 2 from other start-
ing materials have been reported. Although 4(5)-
cyanoimidazole (2) can be prepared from 4(5)-trifluorom-
ethylimidazole, the use of trifluomethyl group makes this
The imidazole ring is an important structure in biological
and industrial chemistry; 4(5)-acyl-1H-imidazoles are
useful intermediates in organic synthesis. For example,
9
process costly. The synthesis of 2 from 4(5)-imidazole-
1
several compounds of the HIV-1 protease inhibitor, inter-
carboxylate has also been reported, however, the process
consists of two steps and the reaction time of the first step
is 1–7 days. Hence, this method is impractical for large-
2
mediates of the P-450 enzyme aromatase inhibitor, and
3
an adreno receptor agonist contain 4(5)-acylimidazoles.
Anticardiac, cerebral, and tissular ischemic active com-
10
scale preparation.
4
pounds are also prepared from acylimidazoles.
To explore a convenient synthesis of cyanoimidazole 2, it
was started with the commercially available 4(5)-imida-
zolecarboxaldehyde (1). Cyanoimidazole 2 could be pre-
pared from 1 in an one-pot reaction. A pyridine solution
containing 1 and hydroxylamine hydrochloride was
stirred at room temperature for 2 hours, then treated with
acetic anhydride, and stirred again at 110 °C for 2 hours
Although 4(5)-acyl-1H-imidazoles 3 are simple com-
pounds, a convenient synthesis of acylimidazoles 3 is still
not available because of the impossibility of direct
5
Friedel–Crafts acylation of imidazoles. Therefore, other
strategies must be employed to synthesize C-acylimida-
zoles. However, these have the following drawbacks:
1
. The synthesis of acylimidazoles 3 can be achieved by (Equation 1). After usual workup and recrystallization,
the metalation chemistry. This generally requires that the cyanoimidazole 2 was obtained in 88% yield.11
-position is suitably blocked by a protecting group or by
2
6
1) NH2OH HCl
an unreactive substituent in addition to N-protection.
OHC
N
NC
N
2
. Acylimidazoles 3 can also be prepared from 4-ami-
NH
2) Ac O
NH
2
noisoxazoles, however, these are not commercially avail-
able.
7
1
2
3
. Recently the solid-phase synthesis of 4-substituted im- Equation 1
8
idazoles was described, which is not acceptable for large-
scale manufacture. It was not satisfactory with respect to
yield either.
Most investigations have demonstrated that imidazoles
should be protected in their reaction with organometallic
4
. The synthesis of acylimidazoles 3 from 4(5)-imidazole- compounds. Therefore, we examined the reaction of 2
4
carboxaldehyde (1) has been reported. But, this route in- with triphenylmethyl chloride to protect the N-1 position
volves four steps; N-protection, alkylation, oxidation, and in the next step (Scheme 1). The products were a mixture
N-deprotection. In the case of alkylacylimidazoles, espe- of N-1 protected and N-3 protected cyanoimidazole. The
cially, alkylation or oxidation of imidazole derivatives desired N-1 protected compound 4 was obtained in only
suffers from low yield. In the oxidation step, manganese 49% yield. As the N-1 protected product was obtained in
dioxide, which changes to industrial waste, is used.
low yield and this route was not advantageous, we tried a
direct Grignard reaction of cyanoimidazole
Equation 2). As a result, it was found that 1-[1H-imida-
zol-4(5)-yl]-2-methylpropan-1-one (3a) could be synthe-
sized in 69% yield by using 2.2 equivalents of Grignard
2
(
Synthesis 2003, No. 5, Print: 01 05 2003.
Art Id.1437-210X,E;2003,0,05,0677,0680,ftx,en;F10102SS.pdf.
©
Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

6
78
J.-i. Kawakami et al.
PAPER
reagent. Moreover, the use of an excess of Grignard re- Table 1 Conversion of 4(5)-Cyanoimidazole 2 to 4(5)-Acyl-1H-
imidazoles 3
agent (3 equiv) in this reaction successfully afforded 3a in
good yield. For example, when the Grignard reaction of
Entry
1
Grignard Reagent
Product
Yield (%)a
82
cyanoimidazole 2 with isopropylmagnesium bromide (3
equiv) was carried out at room temperature for 3 hours, 3a
was obtained in a 82% yield (Scheme 1, Table 1). It was
reported that the use of excess Grignard reagent in the re-
action with nitrile compounds afforded amine products.12
Interestingly, however, the alkylation of non-protected
cyanoimidazole 2 with excess Grignard reagent takes
place selectively to provide 3 in high yield.
i-PrMgBr
O
N
iPr
NH
3
a
2
3
4
5
6
7
PrMgBr
O
83
79
96
85
90
92
N
nPr
NH
3
b
EtMgBr
O
N
Et
NH
3
c
Equation 2
BuMgBr
O
O
N
nBu
O
i
NC
N
1) PrMgBr
N
NH
iPr
NH
3d
2) H2SO4 aq.
NH
s-BuMgBr
i-BuMgBr
c-C H MgBr
3a
2
82%
N
sBu
TritylCl
NC
49%
deprotection
NH
3
e
O
N
iPrMgBr
O
N
iBu
N
iPr
N
NH
Trityl
N
5
3f
4
Trityl
6
12
O
Scheme 1
N
NH
Table 1 shows the results of the reaction using various
alkylmagnesium bromides with cyanoimidazole 2. The
reaction with alkyl Grignard reagents such as i-Pr-, Pr-,
Et-, Bu-, s-Bu-, i-Bu-, and c-C H MgBr proceeded
3
g
a
Yield of isolated product.
6
12
smoothly to give the corresponding products 3 in good
yields, respectively. This procedure allows for large-scale
production without the need for oxidation by manganese
dioxide and chromatographic purification.
sumed to proceed via an intermediate of 4 or 5 as shown
in Scheme 2.
In summary, we have found that acylimidazoles 3 could
be synthesized in good yields using 3 equivalents of Grig-
nard reagent without the troublesome processes of protec-
Although elucidation of the precise mechanism requires
further detailed investigation, this reaction may be as-
XMg
N
N
R
O
N
NC
N
2RMgX
H3O+
4
or
N
MgX
R
NH
N
NH
Mg
2
R
3
N
N
5
Scheme 2
Synthesis 2003, No. 5, 677–680 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 4(5)-Alkylacyl-1H-imidazoles
679
SO
tion and deprotection. Although most investigations have ture was stirred at r.t. for 1 h. H
demonstrated that imidazoles were protected in the reac-
tion of imidazoles with organometalic compounds, this
reaction does not need N-protection. We have developed
O (100 mL) and 6.7% aq H
2
2
4
(
16.4 kg) were added dropwise, and the mixture was stirred for 30
6
min and then brought to pH 8 with 30% aq NaOH solution. After
the organic layer was separated, the aqueous layer was extracted
with EtOAc (2 × 3.8 kg). The organic layers were combined, and the
a new process for the large-scale preparation of 4(5)-acyl-
mixture was washed with aq NaHCO (5.5 kg) and brine (5.5 kg),
3
1
H-imidazoles from 4(5)-imidazolecarboxaldehyde in
and concentrated under reduced pressure. The crystals formed were
good yield without using a protective group and purifica- collected by filtration and washed with diisopropyl ether (4.8 kg).
tion by chromatography.
The crystals were dried in vacuo (40 °C) to give 3a (631.7 g, 78%).
1
-[1H-Imidazol-4(5)-yl]-2-methylpropan-1-one (3a)
Mp 106–108 °C.
4
(5)-Cyanoimidazole (2)
–
1
IR (KBr): 1664 (C=O) cm .
1H NMR (300 MHz, CDCl
): δ = 1.25 (d, J = 6.9 Hz, 6 H), 3.31–
To a solution of 4(5)-imidazolecarboxaldehyde (1; 50 g, 0.52 mol)
in pyridine (150 mL) was added hydroxylamine hydrochloride
3
(
40.5 g, 0.585 mol). After stirring the mixture for 2 h at r.t., the mix-
3.41 (m, 1 H), 7.81 (s, 1 H), 7.87 (s, 1 H), 11.39 (br s, 1 H).
ture was heated to 80 °C, and Ac O (92.3 mL, 0.978 mol) was added
13
2
C NMR (75 MHz, CDCl ): δ = 197.9, 138.5, 135.9, 127.9, 36.7,
3
dropwise at 80–110 °C. The mixture was further stirred until the
temperature reached r.t., and then the pH of the mixture was brought
to 7.9 with 30% aq NaOH solution. EtOAc (380 mL) was added for
extraction, and the aqueous layer was extracted with EtOAc (250
mL). The organic layers were combined, washed with brine (2 ×),
and concentrated under reduced pressure. Toluene was added to the
residue and the mixture was concentrated under reduced pressure
1
9.2.
MS (EI): m/z = 138 (M+).
Anal. Calcd for C H N O: C, 60.85; H, 7.30; N, 20.28. Found: C,
60.83; H, 7.44; N, 20.21.
7
10
2
1-[1H-Imidazol-4(5)-yl]butan-1-one (3b)
Mp 121–124 °C.
(
twice). The crystals formed were collected by filtration and washed
with diisopropyl ether. The crystals were dried in vacuo (40 °C) to
–
1
IR (KBr): 1678 (C=O) cm .
9
give 2 (42.7 g, 88%).
1
H NMR (300 MHz, CDCl ): δ = 0.90 (t, J = 7.4 Hz, 3 H), 1.60 (q,
1
3
H NMR (300 MHz, DMSO-d ): δ = 7.91 (s, 1 H), 8.10 (s, 1 H).
6
J = 7.3 Hz, 2 H), 3.34 (q, J = 7.1 Hz, 2 H), 7.77 (s, 1 H), 7.85 (s, 1
H), 11.35 (br s, 1 H).
+
+
MS (EI): m/z = 93 (M ·), 66 (M · – HCN).
1
3
C NMR (75 MHz, CDCl ): δ = 193.9, 138.4, 137.0, 128.1, 40.9,
3
1
-[1H-imidazol-4(5)-yl]-2-methylpropan-1-one (3a); Typical
1
8.1, 13.8.
Procedure
MS (EI): m/z = 138 (M+).
A solution of 4(5)-cyanoimdazole (2; 42.7 g, 0.458 mol) in THF
(
500 mL) was added dropwise over 30 min to a solution of 1.1 M of
isopropylmagnesium bromide in THF (1.4 L, 1.47 mol) below 10
C under N2.13 The mixture was stirred at r.t. for 3 h, H O (430 mL)
Anal. Calcd for C H N O: C, 60.85; H, 7.30; N, 20.28. Found: C,
7
10
2
6
0.76; H, 7.58; N, 20.23.
°
2
and 10% aq H SO (860 mL) were added dropwise, and the mixture
2
4
1-[1H-Imidazol-4(5)-yl]propan-1-one (3c)
Mp 155–158 °C.
was stirred at 30 min and then brought to pH 8 with 30% aq NaOH
solution. After the organic layer was separated, the aqueous layer
was extracted with EtOAc (2 × 300 mL). The organic layer was
–
1
IR (KBr): 1660 (C=O) cm .
1
combined, and the mixture was washed with aq NaHCO and brine,
H NMR (300MHz, CDCl ): δ = 1.06 (t, J = 7.4 Hz, 3 H), 2.86 (q,
3
3
and concentrated under reduced pressure. The crystals formed were
collected by filtration and washed with diisopropyl ether. The crys-
tals were dried in vacuo (40 °C) to give 3a (51.9 g, 82%).
J = 7.4 Hz, 2 H), 7.81 (s, 1 H), 7.84 (s, 1 H), 10.63 (br s, 1 H).
1
3
C NMR (75 MHz, CD OD): δ = 196.0, 139.2, 138.2, 128.3, 33.0,
3
8
.7.
MS (EI): m/z = 124 (M+).
1
-[1H-imidazol-4(5)-yl]-2-methylpropan-1-one (3a); Large-
Scale Procedure
To a solution of 4(5)-imidazolecarboxaldehyde (1; 635 g, 6.61 mol)
in pyridine (1.85 kg) was added hydroxylamine hydrochloride
+
HRMS: m/z Calcd for C H N O (M ): 124.0637. Found: 124.0631.
6
8
2
1
-[1H-Imidazol-4(5)-yl]pentan-1-one (3d)
(516.4 g, 7.43 mol). After stirring the mixture for 2 h at 27–43 °C,
Mp 119–121 °C.
the solution was heated to 78 °C, and Ac O (1.27 kg, 12.4 mol) was
2
–
1
IR (KBr): 1674 (C=O) cm .
added dropwise at 78–110 °C. The mixture was further stirred until
r.t. was attained, and brought to pH 7.9 with 30% aq NaOH solution.
EtOAc (4.3 kg) was added for extraction and the aqueous layer was
extracted again with EtOAc (2.9 kg). The organic layers were com-
bined, washed with brine (2 × 3.8 kg), and concentrated under re-
duced pressure. Toluene (1.0 kg) was added to the residue and the
mixture was concentrated under reduced pressure (twice). The crys-
tals formed were collected by filtration and washed with diisopropyl
ether (1.86 kg). The crystals were dried in vacuo (40 °C) to give
1
H NMR (300 MHz, CDCl ): δ = 0.95 (t, J = 7.3 Hz, 3 H), 1.35–
1.47 (m, 2 H), 1.68–1.78 (m, 2 H), 2.86 (t, J = 7.0 Hz, 3 H), 7.79 (s,
1 H), 7.85 (s, 1 H), 11.33 (br s, 1 H).
3
13
C NMR (75 MHz, CDCl ): δ = 193.9, 138.4, 136.4, 128.4, 38.8,
3
2
6.8, 22.4, 13.8.
MS (EI): m/z = 152 (M+).
Anal. Calcd for C H N O: C, 63.13; H, 7.95; N, 18.41.Found: C,
8
12
2
4
(5)-cyanoimidazole (2) (545.2 g, 89%).
A Grignard reagent was prepared from isopropyl bromide (2.31 kg,
8.8 mol), Mg (479 g, 19.7 mol), and I (0.48 g, 1.88 mmol) in THF
6
2.97; H, 8.18; N, 18.56.
1
-[1H-Imidazol-4(5)-yl]-2-methylbutan-1-one (3e)
1
2
Mp 102–104 °C.
IR (KBr): 1657 (C=O) cm–1.
(15.9 kg). A solution of 4(5)-cyanoimdazole (2; 545 g, 5.85 mol) in
THF (5.7 kg) was added dropwise over 35 min to the solution of iso-
propylmagnesium bromide in THF below 15 °C under N . The mix-
2
Synthesis 2003, No. 5, 677–680 ISSN 0039-7881 © Thieme Stuttgart · New York

6
80
J.-i. Kawakami et al.
PAPER
1
H NMR (300 MHz, CDCl ): δ = 0.93 (t, J = 7.4 Hz, 3 H), 1.22 (d, References
3
J = 6.9 Hz, 3 H), 1.47–1.61 (m, 1 H), 1.77–1.91 (m, 1 H), 3.17 (br
s, 1 H), 7.81 (s, 1 H), 7.88 (s, 1 H), 11.65 (br s, 1 H).
(
1) Thompson, S. K.; Murthy, K. H. M.; Zhao, B.; Winborne, E.;
Green, D. W.; Fisher, S. M.; DesJarlais, R. L.; Tomaszek, T.
A. Jr.; Meek, T. D.; Gleason, J. G.; Abdel-Meguid, S. S. J.
Med. Chem. 1994, 37, 3100.
1
3
C NMR (75 MHz, CDCl ): δ = 197.6, 138.7, 136.0, 129.0, 43.7,
3
2
6.8, 17.0, 11.8.
MS (EI): m/z = 152 (M+).
(2) Smith, H. J.; Nicholls, P. J.; Simons, C.; Lain, R. L. Exp.
Opin. Ther. Patents 2001, 11, 789.
+
HRMS: m/z Calcd for C H N O (M ): 152.0950. Found: 152.0943.
8
12
2
(
3) Cordi, A. A.; Persigand, T.; Lecouve, J.-P. Synth. Commun.
996, 26, 1585.
1
1
-[1H-Imidazol-4(5)-yl]-3-methylbutan-1-one (3f)
(4) (a) Cossement, E.; Geerts, J.-P.; Gobert, J.; Michel, P. US
Mp 118–119 °C.
Patent 4814343, 1989; Chem. Abstr. 1988, 109, 231016.
–
1
IR (KBr): 1672 (C=O) cm .
(
b) Kelly, J. L.; Miller, C. A.; McLean, E. W. J. Med. Chem.
1
1977, 20, 721.
H NMR (300 MHz, CDCl ): δ = 1.00 (d, J = 6.7 Hz, 6 H), 2.23–
3
(
(
5) Grimmett, M. R. In Advances in Heterocyclic Chemisry,
Vol. 12; Katritzky, A. R.; Boulton, A. J., Eds.; Academic
Press: New York, 1970, 179.
6) (a) Iddon, B. Heterocycles 1985, 23, 417. (b) Kirk, K. L. J.
Heterocycl. Chem. 1985, 22, 57. (c) Iddon, B.; Khan, N.
Tetrahedron Lett. 1986, 27, 1635. (d) Carpenter, A. J.;
Chadwick, D. J. Tetrahedron 1986, 42, 2351.
7) Reiter, L. A. J. Org. Chem. 1987, 52, 2714.
8) Gelens, E.; Koot, W. J.; Menge, W. M. P. B.; Ottenheijm, H.
C. J.; Timmerman, H. Bioorg. Med. Chem. Lett. 2000, 10,
2
1
.37 (m, 1 H), 2.74 (d, J = 7.0 Hz, 2 H), 7.79 (s, 1 H), 7.88 (s, 1 H),
1.82 (br s, 1 H).
1
3
C NMR (75 MHz, CDCl ): δ = 197.9, 138.5, 135.9, 127.9, 36.7,
3
1
9.2.
MS (EI): m/z = 152 (M+).
Anal. Calcd for C H N O: C, 63.13; H, 7.95; N, 18.41. Found: C,
6
8
12
2
(
(
2.88; H, 8.12; N, 18.56.
Cyclohexyl[1H-imidazol-4(5)-yl]methanone (3g)14
Mp 177–178 °C.
1935.
(
9) Matthews, D. P.; Whitten, J. P.; McCarthy, J. R. J. Org.
Chem. 1986, 51, 3228.
–
1
IR (KBr): 1664 (C=O) cm .
1
(10) Leone-Bay, A.; Glaser, L. Synth. Commun. 1987, 17, 1409.
H NMR (300MHz, CDCl ): δ = 1.20–1.92 (m, 10 H), 2.98 (br s, 1
3
(
11) Pierce, M. E.; Carini, D. J.; Huhn, G. F.; Wells, G. J.; Arnett,
J. F. J. Org. Chem. 1993, 58, 4642.
H,), 7.77 (s, 1 H), 7.83 (s, 1 H), 10.76 (br s, 1 H).
1
3
C NMR (75 MHz, CD OD): δ = 198.7, 139.4, 137.0, 128.2, 47.8,
3
(
(
12) Alvernhe, G.; Laurent, A. Tetrahedron Lett. 1973, 13, 1057.
13) During the dropwise addition of isopropylmagnesium
bromide in THF to a solution of 4(5)-cyanoimdazole(2) in
THF, the reaction mixture solidified to a cake and could not
be stirred. This procedure is unsuitable for large-scale
synthesis.
3
0.5, 27.0, 26.7.
MS (EI): m/z = 178 (M+).
Anal. Calcd for C H N O: C, 67.39; H, 7.92; N, 15.72. Found: C,
6
10
14
2
7.16; H, 8.20; N, 15.74.
(14) Iwasaki, S. Helv. Chim. Acta 1976, 59, 2738.
Acknowledgments
The authors express their gratitude to Takeda Analytical Research
Laboratories, Ltd. for MS and elemental analyses.
Synthesis 2003, No. 5, 677–680 ISSN 0039-7881 © Thieme Stuttgart · New York