Expedient synthesis of substituted imidazoles from nitriles

Article abstract of DOI:10.1016/j.tetlet.2005.09.153

Expedient and practical new methodology for the synthesis of substituted imidazoles was developed to provide a rapid access to a variety of 2-substituted, 1,2-disubstituted and 1,2,4-trisubstituted imidazoles by the direct CuCl-mediated reaction of nitriles with α-amino acetals in an intermolecular as well as intramolecular fashion.

Full text of DOI:10.1016/j.tetlet.2005.09.153

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8369–8372
Expedient synthesis of substituted imidazoles from nitriles
Rogelio P. Frutos,* Isabelle Gallou, Diana Reeves, Yibo Xu,
Dhileepkumar Krishnamurthy and Chris H. Senanayake
Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd./POBox 368,
Ridgefield, CT 06877-0368, USA
Received 8 September 2005; revised 26 September 2005; accepted 26 September 2005
Available online 13 October 2005
Abstract—Expedient and practical new methodology for the synthesis of substituted imidazoles was developed to provide a rapid
access to a variety of 2-substituted, 1,2-disubstituted and 1,2,4-trisubstituted imidazoles by the direct CuCl-mediated reaction of
nitriles with a-amino acetals in an intermolecular as well as intramolecular fashion.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
OMe
3
N
H
NH2Cl
HCl
OMe
Imidazoles are common scaffolds in many compounds
of significant biological activity1 and have attracted
the attention of synthetic chemists for over a century.2
Recently, we needed rapid access to a variety 1,2-
disubstituted imidazoles to support pre-clinical activities
in one of our therapeutic areas. Despite their apparent
simplicity, a survey of the literature procedures revealed
a lack of general methodologies for the expedient syn-
thesis of these types of heterocycles. Elegant methods
employing TosMic3 derivatives were not suitable for
the preparation of imidazoles with the required substitu-
tion pattern. At first glance, the classic method reported
by Lawson4 for the formation of 1,2-disubstituted imi-
dazoles from imidate salts and a-amino acetals appeared
well suited for this purpose, and the synthesis of imidaz-
ole 5c5 from imidate hydrochloride 2c6 and a-amino ace-
tal 3 using such methodology is illustrated in Scheme 1.
However, after synthesizing a number of 1,2-disubsti-
tuted imidazoles in this manner, it became obvious the
above protocol suffered from a number of limitations:
for example, synthesis of the required imidazoles took
two to three steps from commercially available nitriles
(1), formation of the imidate salts (2) often required
prolonged reaction times (up to weeks), the yields of
CN
1c
OEt
2c
Et2O, HCl
(74%)
EtOH
(79%)
N
AcOH
NH2Cl
N
N
OMe
OMe
HCl
(50%)
4c
5c
Scheme 1. Synthesis of imidazole 5 from imidate 2.5
the imidate salts varied widely and these intermediates
were hygroscopic and prone to decomposition.
Since the reaction of imidates (2) and a-amino acetal 3
give rise to amidine intermediates such as 4, we reasoned
it should be possible to arrive at the amidine intermedi-
ates directly from the corresponding nitriles (1) and
a-amine-acetals like 3 avoiding the formation of imidate
salts like 2 and the problems associated with them.
Moreover, we intended to carry out the cyclization to
imidazoles 5 without isolation of the intermediate ami-
dines (4). The relatively mild Cu(I)-induced addition of
amines to nitriles reported by Capdevielle and co-work-
ers7 seemed promising for the synthesis of the required
amidines (4), even though the amines previously used
for this transformation lacked functionality such as the
acetal present in 3. Satisfyingly, after minimal optimiza-
tion of the reaction conditions we were able to obtain
good to fair yields of the desired imidazoles. Best results
Keywords: Heterocycles; Substituted imidazoles; Nitriles; a-Amino
acetals; Copper-mediated.
Corresponding author. Tel.: +1 203 798 4681; fax: +1 203 791
6130; e-mail: rfrutos@rdg.boehringer-ingelheim.com
*
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.153

8370
R. P. Frutos et al. / Tetrahedron Letters 46 (2005) 8369–8372
were obtained when the Cu(I)-promoted formation of
the amidine intermediates was carried out in the absence
of solvent followed by cyclization with TFA or HCl in
MeOH. The cyclization could be done after removing
the Cu salts from the mixture (Method A) or more con-
veniently in a Ôone-potÕ procedure in which the Cu salts
are removed after cyclization (Method B). This
approach gave us quick access to the required imidazoles,
and even when the yield of the reaction was moderate in
some cases, the reaction mixtures were virtually free of
organic side-products facilitating the isolation of the
products.
2. Experimental section
2.1. General methods
Unless otherwise specified, all reactions were carried out
in oven-dried glassware under an atmosphere of nitro-
gen. NMR spectra were recorded on a Bruker DPX-400
NMR spectrometer. Shifts are reported in ppm relative
to tetramethylsilane; coupling constants (J) are reported
in Hertz, and refer to apparent peak multiplicities, and
may not necessarily be true coupling constants. The
commercially available starting materials were used as
received without further purification and all solvents
were dried by standard methods prior to use. All melting
points are recorded using a Fisher–Johns melting point
apparatus and are uncorrected.
The results from our expedient synthesis of imidazoles
from nitriles and a-amino acetals are summarized in
Table 1. The reaction conditions that afforded the best
yields varied slightly for the different substrates investi-
gated; in some cases the Ôone-potÕ procedure gave better
results, but in other cases it was advantageous to remove
the copper salts at the amidine stage. Similarly, HCl was
the acid of choice in some instances while TFA worked
better for the cyclization of other amidine intermediates.
Regardless of the specific reaction conditions, a variety
of 1,2-disubstituted imidazoles were prepared by the
intermolecular as well as the intramolecular reaction
of nitriles and a-amino acetals. Good results were
obtained upon the reaction of fluoroacetonitrile (1a) or
cyclopropropanecarbonitrile (1b) with (methylamino)-
acetaldehyde dimethyl acetal (3a) (entries 1 and 2).
The yield decreased with bulkier nitriles (entries 3–5)
such as benzyl cyanide (1c) and benzonitrile (1e), or
when nitriles with short aliphatic chains such as propio-
nitrile (1f) or butyronitrile (1g) were employed (entry 6).
The presence of electron-withdrawing groups on the
starting nitrile was beneficial to the reaction, as it can
be seen by the higher yield of 5d (entry 4)8 compared
with 5e (entry 5).9 The synthesis of imidazoles with sub-
stituents at the 2-position other than methyl was also
demonstrated by the synthesis of 2-substituted imidazole
5h from primary amine 3b (entry 7) and the synthesis of
N-benzyl imidazole 5i from 1a and 3c (entry 8). Our pro-
tocol also worked well for the intramolecular version of
the reaction (entries 9 and 10) to afford bicyclic imidaz-
oles 5j10,11 and 5k.10,11 The formation of 5j is notewor-
thy because a non-copper catalyzed, two step approach
to this compound was reported to take over four weeks
to give 5j in 11% yield.12 Finally, the synthesis of 1,2,4-
trisubstituted imidazoles was demonstrated, albeit in
modest yield, by the synthesis of 5l (entry 11).
2.1.1. Method A. (Methylamino)acetaldehyde di-
methyl acetal 3a (2.0 mL, 15.56 mmol) was charged into
a round-bottomed flask followed by benzyl cyanide 1c
(2.25 mL, 19.45 mmol) and CuCl (1.93 g, 19.45 mmol).
The mixture was then stirred at 85 ꢁCfor 12 h. The mix-
ture was allowed to reach ambient temperature and a 3:1
mixture of MTBE/THF (12 mL) was charged. The
resulting mixture was placed over an ice bath and 50%
aq NaOH (3.2 g) was added keeping the temperature be-
low 20 ꢁC. The mixture was stirred for 5 min and filtered
over a Celite pad. The solids were rinsed with MTBE/
THF 3:1 (2 · 15 ml). The combined organic portions
were concentrated under reduced pressure and taken
up in neat TFA (5 mL). The mixture was heated to
75 ꢁCfor 1 h, cooled to ambient temperature and con-
centrated to afford 5c (67% yield by GCassay).
2.1.2. Method B. (Methylamino)acetaldehyde dimethyl
acetal 3a (2.0 mL, 15.56 mmol) was charged into a
round-bottomed flask followed by fluoroacetonitrile 1a
(1.08 mL, 19.45 mmol) and CuCl (1.93 g, 19.45 mmol).
The mixture was then stirred at 85 ꢁCfor 8 h. The mix-
ture was allowed to reach ambient temperature and
methanol (12 mL) was charged followed by conc. HCl
(3.24 mL). The resulting mixture was refluxed for 4 h
and concentrated under reduced pressure to remove
MeOH. The mixture was placed over an ice bath and
50% aq NaOH (5.0 g) was added keeping the temperature
below 20 ꢁC. MTBE (30 mL) was added, the mixture was
stirred for 5 min and decanted. The solids were rinsed
with MTBE (2 · 15 mL). The combined organic portion
was dried (Na2SO4) and concentrated under reduced
pressure to afford 1.89 g (90% purity by HPLC) of 5a.
In conclusion, to support pre-clinical activities in one of
our therapeutic areas we developed methodology for the
synthesis of substituted imidazoles that provides the
desired targets in a more expedient way and in higher
yield than previously reported approaches. Our protocol
provides practical and rapid access to a variety of
2-substituted, 1,2-disubstituted and 1,2,4-trisubstituted
imidazoles by the direct CuCl-mediated reaction of
nitriles with a-amino acetals in an intermolecular as well
as intramolecular fashion. Our methodology is compli-
mentary to existing approaches to imidazoles and
should prove a valuable addition to the existing Ôtool-
boxÕ available for the synthesis of these heterocycles.
2.1.3.
2-Fluoromethyl-1-methyl-1H-imidazole
(5a).
Imidazole 5a was obtained in 96% yield using the exper-
imental procedure B. H NMR (400 MHz, CDCl3) d
1
2
3.75 (s, 3H), 5.43 (d, JF–H = 52 Hz, 2H), 6.95 (s, 1H),
7.04 (s, 1H); 13C NMR (100 MHz, CDCl3) d 32.2, 75.1
(d, J = 164 Hz), 122.5, 127.4, 142.2; HRMS calcd for
115.0671 (MH+), found 115.0679.
2.1.4. 2-Cyclopropyl-1-methyl-1H-imidazole (5b). Imid-
azole 5b was obtained in 79% yield using the procedure
1
B. H NMR (400 MHz, CDCl3) d 0.91–1.01 (m, 4H),
1.74–1.81 (m, 1H), 3.67 (s, 3H), 6.77 (d, J = 1.0 Hz,

R. P. Frutos et al. / Tetrahedron Letters 46 (2005) 8369–8372
Table 1. Direct synthesis of imidazoles from nitriles and a-amino acetals
8371
OR
RO
HN
R2
OR
OR
N
N
CuCl
HCl
+
N
R1
N
N
H
R1
R1
R2
R2
4
5
3
1
Entry
1
Nitrile
a-Amine-acetal
Imidazole
Yield
H3C
OCH3
N
96%a,c
79%a,c
N
H
F
CN
CN
5a
1a
N
3a
3a
OCH3
F
CH3
N
N
H3C
OCH3
OCH3
5b
N
H
1b
2
3
4
CH3
N
H3C
H3C
OCH3
5c
1c
67%b
68%b
N
H
N
CN
3a
3a
OCH3
CH3
N
CN
OCH3
OCH3
N
H
5d
1d
N
F3C
F3C
CH3
N
CN
H3C
H3C
OCH3
5
6
7
47%a
32%a,b
58%b
N
H
5e
N
1e
3a
OCH3
CH3
N
OCH3
5f, n = 1
5g, n = 2
CN
( )n
1f, n = 1
1g, n = 2
N
H
N
CH3
( )n
3a
3b
OCH3
N
OCH3
1c
H2N
5h
NH
CN
OCH3
OEt
OEt
N
53%b
85%b
54%b
32%b
Ph
N
F
CN
8
1a
N
3c
H
5i
F
CN
1h
N
5j
9
—
N
OCH3
H
N
OCH3
1i
N
CN
OCH3
5k
10
11
—
H
N
N
OCH3
H3C
N
N
O
5l
F
CN
3d
1a
H
O
N
F
CH3
a HCl was used.
b TFA was used.
c One-pot (HCl).
1H), 6.85 (d, J = 1.0 Hz, 1H); 13CNMR (100 MHz,
CDCl3) d 6.36, 6.67, 32.1, 120.1, 126.4, 149.3; HRMS
calcd for C7H11N2 (MH+) 123.0916, found 123.0921.
A. The spectral data are consistent with the reported
literature values.5
2.1.6. 1-Methyl-2-(4-trifluoromethyl-phenyl)-1H-imidaz-
ole (5d). Imidazole 5d was obtained in 68% using
procedure A. H NMR (400 MHz, CDCl3) d 3.89 (s,
2.1.5. 2-Benzyl-1-methyl-1H-imidazole (5c). Imidazole
5c was obtained in 67% yield by following procedure
1

8372
R. P. Frutos et al. / Tetrahedron Letters 46 (2005) 8369–8372
3H), 7.78–8.04 (m, 6H); 13C NMR (100 MHz, CDCl3): d
35.4, 121.2, 122.4, 125.1, 125.9, 128.1, 130.3, 130.9,
131.2. HRMS C11H9F3N2 calcd for C11H10F3N2
(MH+) 227.20, found 227.08.
2.1.13. 6,7-Dihydro-5H-pyrrolo[1,2-a]imidazole (5k).
Imidazole 5k was obtained in 54% yield by following
the procedure A. The analytical data are consistent with
the literature values.11
2.1.7. 1-Methyl-2-phenyl-1H-imidazole (5e). Imidazole
5e was obtained in 47% yield by following the experi-
mental procedure B using HCl/MeOH for the cycliza-
tion of the amidine intermediate. The spectral data are
consistent with the reported literature values.9
2.1.14. 2-Fluoromethyl-1,4-dimethyl-1H-imidazole (5l).
Imidazole 5l was obtained in 32% yield by following
the procedure A. H NMR (400 MHz, CDCl3): d 2.30
(s, 3H), 3.85 (s, 3H), 5.62 (s, 1H), 5.74 (s, 1H), 7.12 (s,
1H); 13C NMR (100 MHz, CDCl3): d 9.6, 34.6, 70.3,
72.0, 121.1, 130.1, 138.8, 139.0; HRMS calcd for
C6H10N2F (M+H) 129.0822, found 129.0830.
1
2.1.8. 2-Ethyl-1-methyl-1H-imidazole (5f). Imidazole 5f
was obtained in 32% yield using either procedure A or
1
B. H NMR (400 MHz, CDCl3) d 1.33 (t, J = 7.6 Hz,
References and notes
3H), 2.69 (q, J = 7.6 Hz, 2H) 3.57 (s, 3H), 6.69 (d,
J = 0.8 Hz, 1H) 6.92 (d, J = 0.8 Hz, 1H); HRMS calcd
for C6H11N2 (MH+) 111.0916, found 111.0922.
1. For recent reviews see: (a) Dembitsky, V. M.; Gloriozova,
T. A.; Poroikov, V. V. Mini-Rev. Med. Chem. 2005, 5, 319;
(b) Jin, Z. Nat. Prod. Reports 2003, 6, 584; (c) Grimmett,
M. R. In Comprehensive Heterocyclic Chemistry II;
Elsevier: Oxford, UK, 1996; Vol. 3, p 77.
2. For recent reviews see: (a) Murry, J. A. Curr. Opin. Drug
Discovery Dev. 2003, 6, 945; (b) Hoffman, H.; Lindel, T.
Synthesis 2003, 12, 1753; (c) Dolensky, B.; Nam, G.;
Deng, W.-P.; Narayanan, J.; Fan, J.; Kirk, K. L. J.
Fluorine Chem. 2004, 125, 501.
2.1.9. 1-Methyl-2-propyl-1H-imidazole (5g). Imidazole
5g was obtained in 32% yield using the procedure A or
1
B. H NMR (400 MHz, CDCl3): d 0.95 (t, J = 7.4 Hz,
3H), 1.73 (sextuplet, J = 7.4 Hz, 2H), 2.59 (t,
J = 7.4 Hz, 2H), 3.52 (s, 3H), 6.73 (s, 1H), 6.87 (s,
1H); 13C NMR (100 MHz, CDCl3): d 13.8, 21.1, 28.5,
32.4, 120.1, 126.7, 148.4. HRMS calcd for C7H13N2
(MH+) 125.1073, found 125.1079.
3. Van Leusen, A. M.; Wildeman, J.; Oldenziel, O. H. J. Org.
Chem. 1977, 42, 1153.
4. Lawson, A. J. Chem. Soc. 1957, 4225.
5. Abbotto, A.; Bradamante, S.; Pagani, G. A. J. Org. Chem.
1996, 61, 1761.
6. (a) Meyers, A. I.; Knaus, G.; Kamata, K.; Ford, M. E. J.
Am. Chem. Soc. 1976, 98, 567; (b) Kolb, H. C.;
Kanamarlapudi, R. C.; Richardson, P. F.; Khan, G.
U.S. Patent 0153728 A1, 2003.;
7. Rousselet, G.; Capdevielle, P.; Maumy, M. Tetrahedron
Lett. 1993, 34, 6395.
8. Jensen, N. P.; Schmitt, S. M.; Windholz, T. B.; Shen, T. Y.
J. Med. Chem. 1972, 15, 341.
9. Prasad, A. S. B.; Stevenson, T. M.; Citineni, J. R.; Nyzam,
V.; Knochel, P. Tetrahedron 1997, 53, 7237.
10. Bowman, R.; Aldabbagh, F. Tetrahedron 1999, 55,
4109.
2.1.10. 2-Benzyl-1H-imidazole (5h). Imidazole 5h was
obtained in 58% yield by following the experimental
procedure A. The spectral data are consistent with the
literature values.13
2.1.11. 1-Benzyl-2-fluoromethyl-1H-imidazole (5i). Imid-
azole 5i was obtained in 53% yield by following the proce-
dure A. 1H NMR (400 MHz, CDCl3) d 5.21 (s, 2H), 5.39
2
(d, JF–H = 48 Hz, 2H), 6.97 (br s, 1H), 7.10 (br s, 1H),
7.13–7.15 (m, 2H), 7.31–7.38 (m, 2H); 13CNMR
(100 MHz, CDCl3) d 49.8, 75.8 (d, J = 164 Hz) 122.2
(br), 126.9, 128.1, 128.4, 128.8, 135.6, 142.9 (br); HRMS
calcd for C11H12N2F 191.0979 (MH+), found 191.0990.
11. Hua, D. H.; Zhang, F.; Chen, J.; Robinson, P. J. Org.
Chem. 1994, 59, 5084.
12. Rokach, J.; Hamel, P.; Hunter, N. R.; Reader, G.;
Rooney, C. S. J. Med. Chem. 1979, 22, 237.
13. Iwasaki, S. Helv. Chim. Acta 1976, 59, 2738.
2.1.12. 5,6,7,8-Tetrahydro-imidazo[1,2-a]pyridine (5j).
Imidazole 5j was obtained in 85% yield by following
the experimental procedure A. The analytical data are
consistent with the literature values.11