A convenient synthesis of 1,4-disubstituted imidazoles

Article abstract of DOI:10.1016/j.tetlet.2004.05.011

An efficient method for the regioselective protection of 4-alkyl-, 4-iodo, 4-vinylimidazoles has been developed via an alkylation-isomerization sequence with various imidazole-protecting groups. The initially formed mixture of 4/5-alkyl-, 4/5-iodo, and 4/5-vinylimidazoles are isomerized to the corresponding 4-isomers on treatment of a DMF solution with a small amount of RX and heating at 75°C.

Full text of DOI:10.1016/j.tetlet.2004.05.011

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5529–5532
A convenient synthesis of 1,4-disubstituted imidazoles
Yong He, Yingzhong Chen, Hongwang Du, Lesley A. Schmid and Carl J. Lovely*
Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX 76019, USA
Received 29April 2004; accepted 4 May 2004
Abstract—An efficient method for the regioselective protection of 4-alkyl-, 4-iodo, 4-vinylimidazoles has been developed via an
alkylation–isomerization sequence with various imidazole-protecting groups. The initially formed mixture of 4/5-alkyl-, 4/5-iodo,
and 4/5-vinylimidazoles are isomerized to the corresponding 4-isomers on treatment of a DMF solution with a small amount of RX
and heating at 75 ꢀC.
ꢁ 2004 Elsevier Ltd. All rights reserved.
Some years ago, we began a program to develop syn-
thetic methods for the elaboration of simple imidazoles
into complex natural products.1 A major thrust of these
studies has involved the investigation of the Diels–Alder
chemistry of 4-vinylimidazoles.1b;d;e To obtain many of
these dienes we have employed Stille cross-coupling
reactions of 4-iodoimidazole derivatives with the corre-
sponding vinylstannane.1d;e Alternatively, we have uti-
lized urocanic acid for the preparation of some
substituted derivatives.1b In either case there was an
intrinsic requirement to obtain an N-protected, 4-
substituted imidazole derivative selectively. With a large
protecting group such as the trityl group, this can be
readily achieved from the corresponding 4(5)-iodoimi-
dazole or methyl urocanoate.2–5 On the other hand, with
synthetically more useful N-protecting groups (e.g., Bn,
SEM), mixtures of the 4- and 5-derivatives are
obtained,6 resulting in low yields and difficulties in the
separation of the desired product. A route to circumvent
this issue with iodo substituted systems was developed
through the N-substitution of the ‘symmetrical’ 4,5-di-
iodoimidazole, followed by chemoselective removal of
the 5-iodo substituent through halogen–metal
exchange.1d;e While this approach is feasible with halo-
gen-containing substrates, N-protected urocanic acid
and other derivatives cannot be prepared in this manner.
Therefore the development of an alternative and more
general approach was required. This paper describes a
convenient experimental protocol to access several 4-
protected imidazole derivatives.
The discovery of a potential solution to this problem
was made during the course of the reaction of urocanic
acid methyl ester (1) with several protecting groups.7
When
1
was treated with NaH followed by
dimethylsulfamoyl chloride (DMASCl) and stirred
overnight at room temperature, the desired regioisomer
2a was obtained in excellent yield (entry 1, Table 1).8
However, an attempt to prepare the corresponding
benzyl protected derivative using a similar procedure
with NaH/BnBr, only provided the N-benzylated com-
pound as a variable mixture of regioisomers (4–8:1).
Interestingly, it was found that the ratio of products was
dependent on the work-up conditions. For example,
when the reaction mixture was quenched with water
prior to removal of the DMF the ratio was lower than
when the reaction mixture was quenched after removal
of the DMF by vacuum distillation. Our interpretation
Table 1. Yields and isomer ratios for the protection of methyl uro-
canoate
Entry
RX
Temp, ꢀC
2/3
Yield of 2, %
1
DMASCl
BnBr
BnBr
rt
1:0
1:0.12
1:0
92
80
98
68
78
86
81
87
95
2
rt
3
40
rt
4
MOMCl
MOMCl
MOMCl
SEMCl
SEMCl
SEMCl
1:0.30
1:0.15
1:0
5
6a
70
70
rt
7
1:0.17
1:0.1
1:0
8
9a
70
70
Keywords: Imidazoles; Regioselective; Protection; Isomerization.
* Corresponding author. Tel.: +1-817-272-5446; fax: +1-817-272-3808;
e-mail: lovely@uta.edu
a Yields and ratios are after the isomerization step.
0040-4039/$ - see front matter ꢁ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.011

5530
Y. He et al. / Tetrahedron Letters 45 (2004) 5529–5532
of these observations suggested that the initially formed
‘kinetic’ distribution of products equilibrated to the
‘thermodynamic’ distribution on heating during re-
moval of the DMF. Presumably, the addition of water
hydrolyzed any remaining BnBr, thereby preventing
further equilibration. Subsequently it was found that
simply heating the reaction mixture after introduction of
the BnBr led to the exclusive formation of desired 4-
isomer (entry 3, Table 1).9
Table 2. Yields and isomer ratios for the protection and isomerization
of 4(5)-iodoimidazole
Entry
RX
Yield, % (5/6)a
Yield, % (5/6)b
1
2
3
4
BnBr
93 (1:0.3)
96 (1:0.3)
86 (1:0.5)
93 (1:0.7)
93 (1:0)
95 (1:0)
80 (1:0)
86 (1:0.3)
SEMCl
MOMCl
MeI
a Yields and ratios are based on the crude products from the alkylation
step.
b Yields and ratios are after the isomerization step.
The extension of this approach to introduction of other
N-protecting groups, for example, SEM and MOM was
investigated (Scheme 1). In these cases, it was found that
at room temperature, a mixture of two regioisomers was
obtained for both derivatives (entries 4 and 7, Table 1).
If the reaction was elevated to 70 ꢀC immediately after
introduction of the reagent, under similar conditions to
those employed for the preparation of 2a, the ratio of
two regioisomers increased (entries 5 and 8, Table 1),
but still did not give one regioisomer exclusively. How-
ever a minor modification of the procedure permitted
the preparation of a single isomer. Specifically when the
mixture of two regioisomers, for example, 2d/3d, formed
at room temperature, was treated with 5–10 mol %
MOMCl and then heated in DMF at 75–80 ꢀC, the
minor isomer 3d was completely isomerized to the major
isomer 2d (entry 6, Table 1). Similarly, the complete
isomerization was also observed when the mixture of
two SEM protected regioisomers (2c/3c) was heated in
the presence of a small amount of SEMCl in DMF
(Scheme 1).10–13
Scheme 2.
interpreted in terms of the steric interactions between
the iodo moiety and protecting group, R. After treating
the mixture of two isomers with 5–10 mol % RX in
DMF and heating at 75 ꢀC overnight, the minor isomers
are completely isomerized to the major 4-isomer.13 The
only exception is the Me protected substrate. In this
case, it appears that the isomerization reaches equilib-
rium of the two isomers.15
Given that access to a single regioisomer of the uro-
canoate derivatives could be obtained, we began to
investigate whether this isomerization protocol was
applicable to the selective protection of other 4(5)-
substituted imidazoles. As alluded to earlier, a number
of 4-iodoimidazole derivatives had been prepared
through the selective reductive dehalogenation of the
corresponding 4,5-diiodoimidazole,1d;e therefore, the
regioselective protection of 4(5)-iodoimidazole14 was
investigated as means to obtain these derivatives di-
rectly. The alkylation and isomerization of various
protected iodoimidazoles have been carried out and are
summarized in Table 2 (Scheme 2). Following standard
protection procedures (NaH, RX), two isomers were
obtained, the ratio of which depends on the size of the
protecting groups. As indicated in Table 2, as the pro-
tective group decreases in size (from Bn to Me), more of
the 5-isomer is formed (from 1:0.3 to 1:0.7). This can be
In addition to the urocanoate derivatives and the iodo-
imidazoles, a similar approach has been employed in the
preparation of various protected 4-cyanomethylimidaz-
oles. The cyanomethylimidazole derivative was prepared
Scheme 3.
Table 3. Yields and isomer ratios for the protection and isomerization
of 4(5)-cyanomethylimidazole
Entry
RX
Yield, % (8/9)a
Yield, % (8/9)b
1
2
3
BnBr
SEMCl
MOMCl
85 (1:0.6)
91 (1:0.5)
83 (1:0.8)
85 (1:0.08)
85 (1:0)
78 (1:0)
a Yields and ratios are based on the crude products from the alkylation
step.
Scheme 1.
b Yields and ratios are after the isomerization step.

Y. He et al. / Tetrahedron Letters 45 (2004) 5529–5532
5531
4. The use of a trityl group for the selective preparation 1,5-
disubstituted imidazoles via the 4-substituted N-trityl
derivative is well known (formally the reverse of Scheme
4, in which 12 R ¼ Tr), for example, see: (a) Shih, N. Y.;
Lupo, A. T., Jr.; Aslanian, R.; Orlando, S.; Piwinski, J. J.;
Green, M. J.; Ganguly, A. K.; Clark, M. A.; Tozzi, S.;
Kreutner, W.; Hey, J. A. J. Med. Chem. 1995, 38, 1593; (b)
Kim, B. M.; Park, J. S.; Cho, J. H. Tetrahedron Lett. 2000,
41, 10031; (c) Panosyan, F. B.; Still, I. W. J. Can. J. Chem.
2001, 79, 1110; (d) Jones, J. H.; Rathbone, D. L.; Wyatt,
P. B. Synthesis 1987, 1110. For an alternative approach to
the selective protection of 1,5-disubstituted derivatives see:
Horvath, A. Synthesis 1995, 1183.
5. It has been reported in the literature that under compa-
rable conditions that the direct selective synthesis of N-
alkyl urocanoate derivatives can be achieved, see: Lauth-
de Viguerie, N.; Sergueeva, N.; Damiot, M.; Mawlawi, H.;
Riviere, M.; Lattes, A. Heterocycles 1994, 37, 1561.
6. (a) Harusawa, S.; Araki, L.; Terashima, H.; Kawamura,
M.; Takashima, S.; Sakamoto, Y.; Hashimoto, T.; Ya-
mamoto, Y.; Yamatodani, A.; Kurihara, T. Chem. Pharm.
Bull. 2003, 51, 832; (b) Bhagavatula, L.; Premchandran, R.
H.; Plata, D. J.; King, S. A.; Morton, H. E. Heterocycles
2000, 53, 729; (c) Cliff, M. D.; Pyne, S. G. J. Org. Chem.
1995, 60, 2378; (d) Kim, J.-W.; Abdelaal, S. M.; Bauer, L.
J. Heterocycl. Chem. 1995, 32, 611; (e) Benjes, P.;
Grimmett, R. Heterocycles 1994, 37, 735; (f) Iddon, B.;
Lim, B. L. J. Chem. Soc., Perkin Trans. 1 1983, 4, 735,
Also see Ref. 1d,e.
Scheme 4.
according to a literature method, by the oxidation of
histidine with bleach.16 Subsequent treatment with
BnBr, MOMCl, or SEMCl provided the corresponding
mixture of 4- and 5-isomers (Scheme 3 and Table 3).
Isomerization to the more stable 4-isomer was then
achieved by heating a DMF solution of the protected
imidazole, and in the case of the MOM and SEM
derivatives, an additional portion of MOMCl and
SEMCl, respectively, were added. It should be noted
that complete isomerization of the Bn-derivative was not
achieved.17–19
Presumably, a mechanism similar to that proposed by
Premchandran and co-workers6b for the isomerization
of DMAS-protected 5-iodoimidazole to 4-iodoimidazole
is involved (Scheme 4). The alkyl halide alkylates 10 at
N3, to generate an imidazolium ion 11,20 which then
undergoes a nucleophilic displacement at the N1-sub-
stituent, to provide the 4-substituted isomer 12.
7. Pirrung, M. C.; Pei, T. J. Org. Chem. 2000, 65, 2229.
8. It has previously been noted that the 5-isomers with this
N-protecting group can isomerize to the 4-isomer, and so
it is conceivable that initially a mixture forms and then
isomerizes. See Refs. 6b,d.
In conclusion, an efficient protocol for the regioselective
synthesis of N1-protected 4-vinyl, 4-cyanomethyl, and 4-
iodoimidazole has been developed through a protec-
tion–isomerization sequence with a variety of protecting
groups. Critical for the regioselective alkylation is the
isomerization of N1-substituted-5-imidazoles to 4-imi-
dazoles. This isomerization method may have potential
applications for the regioselective protection of other 4-
substituted imidazoles.
1
9. Data for 2b: mp 119–120.0 ꢀC, H NMR (500 MHz): 7.54
(s, 1H), 7.52 (d, J ¼ 15:8 Hz, 1H), 7.36–7.34 (m, 3H),
7.16–7.15 (m, 2H), 7.06 (s, 1H), 6.54 (d, J ¼ 15:8 Hz, 1H),
5.09(s, 2H), 3.75 (s, 3H); 13C NMR (125 MHz): 168.1,
138.81, 138.79, 136.3, 135.5, 129.2, 128.7, 127.5, 121.8,
115.9, 51.6, 51.2; IR (KBr, cmꢀ1): 3132, 3098, 3024, 2950,
1702, 1633, 1494, 1438, 1299, 1276, 1196, 1163, 1009, 859,
793, 716, 625, 520. Anal. Calcd for C14H14N2O2: C, 69.41;
H, 5.82; N, 11.56. Found: C, 69.57; H, 6.59; N, 11.40.
10. General N-alkylation procedure: Methyl 3-(1H-imidazol-
4-yl)propenoate 1 (390 mg, 2.57 mmol) was dissolved in
THF or DMF (6.4 mL) under Ar protection. The mixture
was cooled to 0 ꢀC and NaH (60% in mineral oil, 113 mg,
2.83 mmol) was added portionwise. The mixture was
allowed to warm up to rt and stirred for 1.5 h, then
cooled to 0 ꢀC again and RX (1.20 mmol) was added
dropwise. The mixture was allowed to warm up to rt and
stirred overnight. After quenching with a small amount of
water, the solvent was completely removed in vacuo. The
residue was dissolved in CH2Cl2 and washed with H2O
(2·), brine, dried (Na2SO4) and concentrated. For 3d, 5d,
5e, 8c: the residue was partitioned in small amount of
water and CH2Cl2 (3·). The combined organics were dried
(Na2SO4) and concentrated. The crude sample obtained
was dried under vacuum and used directly in the next
isomerization step without further purification. The ratio
of two regioisomers was determined by 1H NMR spec-
troscopy by integration of appropriate signals.
Acknowledgements
This work was supported by the Robert A. Welch
Foundation (Y-1362), the Texas Higher Education
Coordinating Board-Advanced Research Program
(003626-0004-1999), and the National Institutes of
Health (GM065503).
References and notes
1. (a) Lovely, C. J.; Du, H.; He, Y.; Dias, H. V. R. Org. Lett.
2004, 6, 735; (b) He, Y.; Chen, Y.; Wu, H.; Lovely, C. J.
Org. Lett. 2003, 5, 3623; (c) Chen, Y.; Dias, H. V. R.;
Lovely, C. J. Tetrahedron Lett. 2003, 44, 1379; (d) Lovely,
C. J.; Du, H.; Dias, H. V. R. Heterocycles 2003, 60, 1; (e)
Lovely, C. J.; Du, H.; Dias, H. V. R. Org. Lett. 2001, 3,
1319.
2. Kirk, K. L. J. Heterocycl. Chem. 1985, 22, 57.
3. Kosaka, K.; Maruyama, K.; Nakamura, H.; Ikeda, M.
J. Heterocycl. Chem. 1991, 28, 1941.
1
11. Data for 2d: mp 85–86 ꢀC, H NMR (500 MHz): 7.56 (s,
1H), 7.48 (d, J ¼ 15:8 Hz, 1H), 7.17 (s, 1H), 6.51 (d,
J ¼ 15:8 Hz, 1H), 5.16 (s, 2H), 3.70 (s, 3H), 3.22 (s, 3H);
13C NMR (125 MHz): 168.0, 139.0, 138.7, 136.0, 121.3,
116.4, 77.9, 56.4, 51.5; IR (KBr, cmꢀ1): 3140, 3117, 2992,
2949, 1702, 1640, 1500, 1432, 1369, 1300, 1275, 1181, 1163,
1139, 1105, 1038, 977, 916, 854, 788, 746, 619. Anal. Calcd

5532
Y. He et al. / Tetrahedron Letters 45 (2004) 5529–5532
for C9H12N2O3: C, 55.09; H, 6.16; N, 14.28. Found: C,
1983, 735; (b) Bensusan, H. B.; Naidu, M. S. R.
Biochemistry 1967, 6, 12.
15. The isomerization was allowed to proceed more than 72 h,
but did not result in any further change on the ratio of two
methyl isomers.
55.17; H, 5.97; N, 14.03. Data for 3d: mp 74–75 ꢀC, 1H
NMR (500 MHz): 7.63 (s, 1H), 7.57 (d, J ¼ 15:8 Hz, 1H),
7.46 (s, 1H), 6.33 (d, J ¼ 15:8 Hz, 1H), 5.30 (s, 2H), 3.77
(s, 3H), 3.27 (s, 3H); 13C NMR (125 MHz): 167.3, 141.1,
133.5, 129.7, 128.6, 117.1, 76.2, 56.1, 51.8; IR (KBr, cmꢀ1):
3094, 2990, 2947, 2837, 1705, 1633, 1543, 1485, 1465, 1434,
1387, 1360, 1308, 1295, 1273, 1234, 1198, 1174, 1125, 1101,
1053, 982, 916, 860, 826, 736, 650. Anal. Calcd for
C9H12N2O3: C, 55.09; H, 6.16; N, 14.28. Found: C, 55.12;
H, 5.88; N, 14.04.
16. (a) Bauer, H.; Tabor, H. Biochem. Prep. 1957, 5, 97; (b)
Hirsch, A.; Richardson, K. S. C. J. Appl. Chem. 1969, 19,
83.
1
17. Data for 8a: H NMR (500 MHz): 7.46 (s, 1H), 7.33–7.30
(m, 3H), 7.14–7.13 (m, 2H), 6.87 (s, 1H), 5.03 (s, 2H), 3.62
(s, 2H); 13C NMR (125 MHz): 137.7, 135.7, 132.2, 129.2,
128.6, 127.5, 117.7, 117.1, 51.1, 17.9; IR (neat, cmꢀ1):
3144, 3117, 3090, 3067, 3035, 2953, 2252, 1559, 1504, 1456,
1414, 1239, 1153, 1045, 989, 745, 711, 663, 636.
12. General isomerization procedure: The mixture of the two
regioisomers (2.5 mmol) was dissolved in DMF (6 mL) and
RX (5–10 mol %) was added and the resulting solution
heated at 75 ꢀC for 24 h. After cooling to room temper-
ature, a small amount of water was added and then the
solvent was completely removed under vacuum. The
residue was purified by passing through a short pad of
silica gel if necessary.
13. The spectroscopic data of all the known compounds are
consistent with literature reports. 2a: De Esch, I. J. P.;
Vollinga, R. C.; Goubitz, K.; Schenk, H.; Appelberg, U.;
Hacksell, U.; Lemstra, S.; Zuiderveld, O. P.; Hoffmann,
M.; Leurs, R.; Menge, W. M. P. B.; Timmerman, H.
J. Med. Chem. 1999, 42, 1115, and Ref. 1b; 2c: Ref.
4a; 5a: Ref. 1d; 5b, 6b: Ref. 6a; 5c, 5d: see Ref. 1e; 6d: Ref.
4c; 8b, 9b: Iwaoka, K.; Koshio, H.; Ito, H.; Miyata,
K.; Ohta, M. PCT Int. Appl. WO 9406791 A1 19940331,
1994.
18. Data for 8b: 1H NMR (500 MHz): 7.52 (s, 1H), 7.04 (s,
1H), 5.20 (s, 2H), 3.68 (s, 2H) 3.45 (t, J ¼ 8:3 Hz, 2H), 0.87
(t, J ¼ 8:3 Hz, 2H), )0.05 (s, 9H); 13C NMR (125 MHz):
137.7, 132.5, 117.5, 116.7, 76.2, 66.7, 17.8, 17.7, )1.4; IR
(neat, cmꢀ1): 2954, 2926, 2896, 2251, 1501, 1416, 1360,
1249, 1149, 1096, 860, 837.
19. Data for 8c: 1H NMR (500 MHz): 7.52 (s, 1H) 7.02 (s,
1H), 5.15 (s, 2H), 3.65 (s, 2H), 3.23 (s, 3H); 13C NMR
(125 MHz): 137.8, 132.6, 117.4, 116.8, 78.0, 56.5, 17.8; IR
(neat, cmꢀ1): 3117, 2652, 2256, 1695, 1493, 1404, 1224,
1
1190, 1113, 919, 787. Data for 9c: H NMR (500 MHz):
7.58 (s, 1H) 7.09(s, 1H), 5.28 (s, 2H), 3.77 (s, 2H), 3.27 (s,
3H).
20. In the case of the preparation of N-benzyl 4-urocanoate
(2a) and N-methyl-4-iodoimidazole (5d), the correspond-
ing imidazolium salts were obtained in ca. <5% yield,
which provides circumstantial support for the proposed
mechanism.
14. 4(5)-Iodoimidazole was prepared via the polyiodination of
imidazole and partial reductive deiodination with Na2SO3:
(a) Iddon, B.; Lim, B. L. J. Chem. Soc., Perkin Trans. 1