Divergent and regioselective synthesis of 1,2,4- and 1,2,5-trisubstituted imidazoles

Article abstract of DOI:10.1021/jo801256b

(Chemical Equation Presented) A divergent and regioselective synthesis of 1,2,4- and 1,2,5-trisubstituted imidazoles from a readily available (two steps) common intermediate has been developed. This methodology is based on the regiocontrolled N-alkylation of 1-(N,N-dimethylsulfamoyl)-5-iodo-2-phenylthio- 1H-imidazole (10). When this intermediate is engaged in reaction with methyl triflate, selective formation of the corresponding 1,2,5-trisubsituted 1H-imidazole is observed. NMR studies have revealed that this regioselectivity can be accounted for by in situ rapid isomerization of 10 into its 1,2,4-isomer (13) followed by regiospecific N-alkylation of the latter. Conversely, when key intermediate 10 is slowly added to Meerwein's salt, isomerization can be constrained and regiospecific N-alkylation of 10 leads to 1,2,4-trisubstituted 1H-imidazole with a high selectivity. The general character of this methodology has been illustrated by showing that iodine in position 4 or 5 could be easily substituted by an aryl group by Suzuki coupling, whereas the phenylthio group at position 2 could, after oxidation into sulfone, be displaced by nucleophilic substitution.

Full text of DOI:10.1021/jo801256b

Divergent and Regioselective Synthesis of 1,2,4- and
1,2,5-Trisubstituted Imidazoles
Bruno Delest,†,‡ Prosper Nshimyumukiza,†,‡ Olivier Fasbender,† Bernard Tinant,†
Jacqueline Marchand-Brynaert,† Francis Darro,*,‡ and Raphae¨l Robiette*,†
Chemistry Department, UniVersite´ catholique de LouVain, Place Louis Pasteur 1, B-1348
LouVain-la-NeuVe, Belgium, and Unibioscreen SA, 40 aVenue Joseph Wibran, B-1070 Brussels, Belgium
francis.darro@unibioscreen.com; raphael.robiette@uclouVain.be
ReceiVed June 13, 2008
A divergent and regioselective synthesis of 1,2,4- and 1,2,5-trisubstituted imidazoles from a readily
available (two steps) common intermediate has been developed. This methodology is based on the
regiocontrolled N-alkylation of 1-(N,N-dimethylsulfamoyl)-5-iodo-2-phenylthio-1H-imidazole (10). When
this intermediate is engaged in reaction with methyl triflate, selective formation of the corresponding
1,2,5-trisubsituted 1H-imidazole is observed. NMR studies have revealed that this regioselectivity can
be accounted for by in situ rapid isomerization of 10 into its 1,2,4-isomer (13) followed by regiospecific
N-alkylation of the latter. Conversely, when key intermediate 10 is slowly added to Meerwein’s salt,
isomerization can be constrained and regiospecific N-alkylation of 10 leads to 1,2,4-trisubstituted 1H-
imidazole with a high selectivity. The general character of this methodology has been illustrated by
showing that iodine in position 4 or 5 could be easily substituted by an aryl group by Suzuki coupling,
whereas the phenylthio group at position 2 could, after oxidation into sulfone, be displaced by nucleophilic
substitution.
Introduction
preparation of these motifs. One such route consists of the
introduction of substituents prior to imidazole ring formation.
Suitable precursors may, however, be difficult, or impossible,
to synthesize. Many substituents are also sensitive and do not
tolerate the reaction conditions for the cyclization. A more
general strategy is to introduce substituents to the preformed
ring. However, the limitation of such an approach is often a
lack of regioselectivity.
We are interested in developing a short and divergent
synthesis of 1,2,4- and 1,2,5-trisubstituted imidazoles. So, our
goal is to find a key intermediate which would be readily
available (in a few steps), storable, and could lead selectiVely
to both families of compounds, with a large range of substituents.
Substituted imidazoles are key substructures present in many
compounds possessing interesting pharmacological properties.1,2
As a result, a number of strategies have been explored for the
† Universite´ catholique de Louvain
‡ Unibioscreen SA.
(1) For some reviews on imidazole synthesis, see: (a) Grimmett, M. R.
Imidazole and Benzimidazole Synthesis; Academic Press, Inc.: San Diego, CA,
1997. (b) Grimmett, M. R. In ComprehensiVe Heterocyclic Chemistry III;
Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V., Taylor, R. J. K., Eds.;
Pergamon Press: Oxford, 2008; Vol. 4, pp 143-364. (c) Kamijo, S.; Yamamoto,
Y. Chem. Asian J. 2007, 2, 568–578. (d) Du, H.; He, Y.; Rasapalli, S.; Lovely,
C. J. Synlett 2006, 7, 965–992. (e) Bellina, F.; Cauteruccio, S.; Rossi, R.
Tetrahedron 2007, 63, 4571–4624. (f) Begtrup, M. Bull. Soc. Chim. Belg. 1988,
97, 573–597.
The main challenge faced by the regioselective substitution
of imidazoles is the differentiation of positions 4 and 5.1 An
elegant way to solve this issue is the introduction of a protecting
(2) For reviews on biological activities of imidazoles, see: (a) Bolani, M.;
Gonzalez, M. Mini-ReV. Med. Chem. 2005, 5, 409–424. (b) Jin, Z. Nat. Prod.
Rep. 2006, 23, 464–496.
6816 J. Org. Chem. 2008, 73, 6816–6823
10.1021/jo801256b CCC: $40.75 2008 American Chemical Society
Published on Web 08/06/2008

Synthesis of 1,2,4- and 1,2,5-Trisubstituted Imidazoles
SCHEME 1. Common Strategy for the Synthesis of
Substituted Imidazoles
SCHEME 2. Alkylation/Deprotection of
N-Sulfamoylimidazoles
imidazoles at position 5 (1 f 2; Scheme 3). Subsequent selective
alkylation of the nonsubstituted nitrogen atom (2 f 3) and
deprotection should then lead to 1,2,4-trisubstituted imidazoles
(4).
group on the nitrogen atom (position 1) which will direct the
substitution at position 5 (or 4). However, when this assistant
group has served its purpose and one needs to change it for
another, the deprotection/substitution process leads to mixtures
of 1,4- and 1,5-isomers (Scheme 1). Indeed, the 5-substituted
1H-imidazole obtained after N-deprotection undergoes a rapid
tautomeric equilibrium, and alkylation leads to mixtures in which
the 1,4-isomer is usually the major product (due to steric
factors).3,4
We reasoned that one way to overcome this problem would
be to find a protecting group which could direct both the C(5)-
substitution and the subsequent N-alkylation. To serve these
purposes, we envisaged the use of the N,N-dimethylsulfamoyl
group.
Finally, it has been shown that 5-substituted N-sulfamoyl-
1H-imidazoles (2) isomerize under equilibrating conditions to
give the corresponding, more stable, 4-substituted N-sulfa-
moylimidazoles (5).9 Application of the alkylation/deprotection
procedure (vide supra) to this isomer should allow now obtaining
1,2,5-trisubstituted imidazoles (7) (Scheme 3).
Therefore, if R1 and R3 are functional groups which can be
easily transformed into a wide variety of substituents, 2,5-
substituted 1-(N,N-dimethylsulfamoyl)-1H-imidazoles 2 could
constitute a general, selective, and divergent route to 1,2,4- and
1,2,5-substituted imidazoles.
We selected phenylsulfonyl (R1) and iodine (R3) as trans-
formable functional groups so that our designed key intermediate
is 12 (Scheme 4). Indeed, the phenylsulfonyl group at position
2 should be easily displaced by nucleophilic substitution,10 and
the iodine atom at position 4 or 5 will enable metal-catalyzed
coupling.11
When positioned on an aromatic ring, the N,N-dimethylsul-
famoyl group is known to direct lithiation in the ortho position.5
If position 2 of the 1H-imidazole is already substituted, the
presence of this sulfamoyl group on N(1) of the imidazole
enables thus highly selective deprotonation and substitution in
position 5 (see Scheme 1; PG ) SO2NMe2).1a,6
Moreover, N-sulfamoylimidazoles are known to react with
alkylating reagents exclusively via their nonsubstituted nitrogen
atom (position 3).7 Alkylation on N(1) is indeed blocked by
the N,N-dimethylsulfamoyl group. Formation of a salt by N(3)-
alkylation increases the lability of the dimethylsulfamoyl group
which is then easily removed upon addition of a nucleophile
(Scheme 2).7 The outcome of this procedure is thus the
N-alkylation of the imidazole ring selectively at the previously
nonsubstituted nitrogen atom (numbered 3 in Scheme 2).8
The use of the N,N-dimethylsulfamoyl group then should
allow regioselective lithiation/substitution of 2-substituted 1H-
Results and Discussion
Synthesis of the Key Intermediate. The synthesis of the
intermediate (12) leading to 1,2,4- and 1,2,5-trisubstituted
imidazoles was envisaged in three steps.
It has been shown that 1-(N,N-dimethylsulfamoyl)-1H-
imidazole (8) can be monolithiated selectively in position 2.6
Thus, selective deprotonation of 1-(N,N-dimethylsulfamoyl)-
1H-imidazole (8) followed by addition of phenyl disulfide gives
2-substituted N-sulfamoyl-1H-imidazole 9 in excellent yield
(Scheme 4).6a Subsequent oxidation of the sulfide leads to the
corresponding 2-phenylsulfonyl-substituted 1H-imidazole 11.12
This latter showed, however, to be poorly stable, leading to
(3) For some recent examples, see: (a) Lovely, C. J.; Du, H.; Sivappa, R.;
Bhandari, M. R.; He, Y.; Dias, H. V. R. J. Org. Chem. 2007, 72, 3741–3749.
(b) He, Y.; Chen, Y.; Du, H.; Schmid, L. A.; Lovely, C. J. Tetrahedron Lett.
2004, 45, 5529–5532.
(4) For a personal example, see Supporting Information.
(9) Bhagavatula, L.; Premchandran, R. H.; Plata, D. J.; King, S. A.; Morton,
H. E. Heterocycles 2000, 53, 729–732.
(10) (a) Jones, T. K.; Mani, N. US 2005250948, 2005; Chem. Abstr. 2005,
143, 460319. (b) Bogenstaetter, M.; Carruthers, N. I.; Lovenberg, T. W.; Ly,
K. S.; Jablonowski, J. A. WO 2002079168, 2002; Chem. Abstr. 2002, 137,
279192.
(11) For some examples of metal-catalyzed coupling involving 4- or
5-iodoimidazoles, see: ref 1c. (a) Yang, X.; Knochel, P. Chem. Commun. 2006,
2170–2172. (b) Langhammer, I.; Erker, T. Heterocycles 2005, 65, 1975–1984.
(c) Yoshida, T.; Nishiyachi, M.; Nakashima, N.; Murase, M.; Kotani, E. Chem.
Pharm. Bull. 2003, 51, 209–214. (d) Lovely, C. J.; Du, H.; Dias, H. V. R. Org.
Lett. 2001, 3, 1319–1322. (e) Kawasaki, I.; Katsuma, H.; Nakayama, Y.;
Yamashita, M.; Ohta, S. Heterocycles 1998, 48, 1887–1901. (f) Carver, D. S.;
Lindell, S. D.; Saville-Stones, E. A. Tetrahedron 1997, 53, 14481–14496. (g)
Cliff, M. D.; Pyne, S. G. J. Org. Chem. 1995, 60, 2378–2383.
(12) (a) Moreno, P.; Heras, M.; Maestro, M.; Villagordo, J. M. Synthesis
2002, 18, 2691–2700. (b) Schickaneder, H.; Engler, H.; Szelenyi, I. J. Med.
Chem. 1987, 30, 547–551.
(5) (a) MacNeil, S. L.; Familoni, O. B.; Snieckus, V. J. Org. Chem. 2001,
66, 3662–3670. (b) Watanabe, H.; Schwarz, R. A.; Hauser, C. R.; Lewis, J.;
Slocum, D. W. Can. J. Chem. 1969, 47, 1543–1546.
(6) (a) Feldman, K. S.; Skoumbourdis, A. P. Org. Lett. 2005, 7, 929–931.
(b) Winter, J.; Re´tey, J. Synthesis 1994, 245–246. (c) Kudzma, L. V.; Turnbull,
S. P. Synthesis 1991, 1021–1022. (d) Ngochindo, R. I. J. Chem. Soc., Perkin
Trans. 1 1990, 1645–1648. (e) Katritzky, A. R.; Slawinski, J. J.; Brunner, F.
J. Chem. Soc., Perkin Trans. 1 1989, 1139–1145. (f) Carpenter, A. J.; Chadwick,
D. J. Tetrahedron 1986, 42, 2351–2358.
(7) (a) Lee, H. K.; Bang, M.; Pak, C. S. Tetrahedron Lett. 2005, 46, 7139–
7142. (b) Beaudoin, S.; Kinsey, K. E.; Burns, J. F. J. Org. Chem. 2003, 68,
115–119.
(8) For punctual examples of 1,5-substituted imidazole synthesis using a
similar strategy with other protecting groups, see: (a) Chandana, P.; Nayyar, A.;
Jain, R. Synth. Commun. 2003, 33, 2925–2933. (b) Panosyan, F. B.; Still, I. W. J.
Can. J. Chem. 2001, 79, 1110–1114. (c) Chivikas, C. J.; Hodges, J. C. J. Org.
Chem. 1987, 52, 3591–3594.
J. Org. Chem. Vol. 73, No. 17, 2008 6817

Delest et al.
SCHEME 3. Designed Strategy to 1,2,4- and 1,2,5-Trisubstituted Imidazoles
SCHEME 4. Synthesis of the Key Intermediate
SCHEME 5. Isomerization of 10
SCHEME 6. Alkylation/Deprotection of 13
N-deprotected 2-phenylsulfonylimidazole upon workup condi-
tions. This observation can be attributed to the electron-
withdrawing character of the phenylsulfonyl substituent which
increases the lability of the sulfamoyl group.
intermediate 10 necessitates the isomerization of the latter into
its 1,2,4-regioisomer 13 (Scheme 5). As previously described
on similar substrates, this can be done at 70 °C in the presence
of a catalytic amount of N,N-dimethylsulfamoyl chloride.9 Upon
these conditions, the more stable 1,2,4-isomer 13 was obtained
in excellent yield (96%). Isomerization could be observed by
the low field shift of HC(imidazole) signal from 7.03 to 7.49
ppm in 1H NMR (see Experimental Section for the full
characterization data).
We have thus shown that both 1,2,4- and 1,2,5-isomers of
our key intermediates, respectively, 13 and 10, are readily
available in high yields. We investigated then their respective
regioselective N-alkylation.
In order to keep a high stability of our key intermediate, we
decided therefore to redesign our strategy and leave the group
at position 2 as a sulfide. The oxidation could indeed be
performed later in the synthesis (right before the nucleophilic
substitution), giving a new key intermediate 10. This new
intermediate is obtained in excellent yield by regioselective
deprotonation of 9 in position 51a,6 and iodination. Intermediate
10 is a nice solid obtained in crystalline form which can be
stored in the refrigerator for months13 and of which structure
could be confirmed by X-ray analysis (see Supporting Informa-
tion).14
Having our key intermediate in hand (two steps, 83% overall
yield), we investigated its potential as a platform for the selective
synthesis of 1,2,4- and 1,2,5-trisubstituted imidazoles.
Isomerization of 10 into 13. According to our strategy, the
access to 1,2,5-trisubstituted 1H-imidazoles from our key
Alkylation/Deprotection of 13: Synthesis of 1,2,5-
Trisubstituted Imidazoles. Previous studies have shown that
N-sulfamoyl-1H-imidazoles react with alkylating reagent ex-
clusively via N(3), alkylation on N(1) being blocked by the
N-protecting group.7 Accordingly, addition of methyltriflate to
13 gives selectively the salt 14 (Scheme 6). Slow formation of
1
this salt could be detected in H NMR when carrying out the
reaction in CD2Cl2: H(4) is low field shifted in 14 (7.71 ppm),
as compared to 13 (7.50 ppm), and a new CH3 signal appears
at 3.83 ppm.
Alkylation of 13 increases the lability of the dimethylsul-
famoyl group which can then be removed upon addition of
methylbutylamine to yield 1,2,5-trisubstituted imidazole 15 in
(13) Neither isomerization nor degradation was observed after 4 months at-
18 °C.
(14) For both structures determined by X-ray diffraction analysis in this paper,
10 and 18, two independent molecules are observed in the asymmetric parts of
the unit cell; they differ only by a slight different orientation of the phenyl group.
The bond lengths indicate clearly a greater conjugation in the imidazole ring of
10 as compared to 18.
6818 J. Org. Chem. Vol. 73, No. 17, 2008

Synthesis of 1,2,4- and 1,2,5-Trisubstituted Imidazoles
SCHEME 7. Alkylation/Deprotection of 10
SCHEME 8. Potential Causes of the In Situ Isomerization
of 10
good overall yield (80%) and total regioselectivity (no 1,2,4-
isomer could be detected in the crude mixture).15
Oxidation of 15 by m-CPBA gives quantitatively sulfone 16,
which is now on hand for further functionalization in positions
2 and 5.
Alkylation/Deprotection of 10: Synthesis of 1,2,4-
Trisubstituted Imidazoles. According to our strategy, 1,2,4-
trisubstitued imidazole derivatives could be accessible by
regioselective alkylation/deprotection of 10 (see Scheme 3). Key
imidazole (10) was reacted with methyl triflate followed by
addition of methylbutylamine under the same reaction conditions
as for 13 but to our surprise this led to 15 (71% isolated yield),
with only traces of 18 (4%) observed in the crude mixture
(Scheme 7).15
In order to investigate formation of 15, we performed the
reaction in CD2Cl2 and followed it by 1H NMR. No signal which
could be attributed to salt 17 was detected. Instead, formation
of salt 14 was observed. This suggests a rapid isomerization
(faster than alkylation) of 10 into 13 under the reaction
conditions, subsequent alkylation/deprotection of 13 yielding
1,2,5-isomer 15 as observed above (see Scheme 6).
it is possible that isomerization is mediated by the salt 17 (and
14) (Scheme 9; hypothesis 4).
In order to test hypothesis 2 and 3, we carried out the reaction
in the presence of, respectively, molecular sieves and a non-
nucleophilic base, 2,6-di-tert-butyl-4-methylpyridine (DTB-
MP)16 (Table 1, entries 5 and 6). Molecular sieves provided
exclusive formation of isomer 15, whereas the presence of 10%
of DTBMP in the medium did not lead to any significant change
in regioselectivity. Isomerization is thereby not due to traces
of water or acid.17
Hypothesis 4 was then investigated. In this scenario, at the
initial stage of the reaction (<5% conversion), the salt 17 is
formed. Then, this very small amount of 17 in the medium
catalyzes the rapid isomerization of 10 into 13 which eventually
leads to isomer 15 (Scheme 9).18 In order to prevent this
pathway, one needs thereby to avoid, or strongly reduce, the
coexistence of 10 and 17. Accordingly, imidazole 10 was slowly
added to a solution of Meerwein’s salt in dichloromethane over
15 h (Table 1, entry 9). We were pleased to find that this
procedure leads quantitatively to alkylated imidazole 18 with a
good regioselectivity (18/15 ) 83/17), the two regioisomers
being easily separable by standard flash chromatography.15,19
The structure of 18 has been unambiguously confirmed by
X-ray diffraction analysis (see Supporting Information).14 The
two regioisomers, 15 and 18, have very similar analytical
properties, but we found that they could be clearly differentiated
In fact, it is interesting to note that access to 15 does not
actually necessitate a prior isolation of 13 but that 15 can be
directly obtained in good yield (71%) by addition of methyl
triflate to 10, the isomerization step taking place in situ.
However, to access 1,2,4-imidazoles from 10, one needs to
be capable of preventing this in situ rapid isomerization. We
tried therefore to identify the causes of this isomerization. First,
we demonstrated the importance of alkylating reagent in
isomerization by showing that imidazole 10 was stable in
CH2Cl2 for 5 days. We thus reasoned that the origin of the
isomerization could lie in the low nucleophilicity of triflate
counterion (Scheme 8; hypothesis 1). Accordingly, we per-
formed the reaction with alkylating reagents producing non-
nucleophilic counterions (Table 1, entries 2-4). As anticipated,
the use of dimethyl sulfate and Meerwein’s salt enabled
formation of the desired isomer 18. The latter is, however, the
minor product with the selectivity still being in favor of
imidazole 15. The nucleophilicity of the counterion cannot
thereby account for all the observed isomerization of 10.
We thought then that three other reasons could explain the
isomerization (Schemes 8 and 9). First, it is likely that traces
of water are present in the medium and act as nucleophile
(Scheme 8; hypothesis 2). Second, isomerization may be
catalyzed by traces of acid (Scheme 8; hypothesis 3). Finally,
(16) Deutsch, E.; Cheung, N. K. V. J. Org. Chem. 1973, 38, 1123–1126.
(17) Test experiment showed that DTBMB does not isomerize 10 after
strirring in CH2Cl2 for 3 days in the presence of 0.3 equiv of the base. Conversely,
formation of 13 is observed when stirring 10 in the presence of molecular sieve.
(18) Once formed, the salt 14 may as well catalyze isomerization of 10.
(19) It has been noted that purity of reactants and solvent is crucial for
reproducibility of this experiment (see Supporting Information).
(15) As a comparison, methylation of corresponding N-deprotected imidazole
leads to a 57/43 mixture of 1,2,4- and 1,2,5-isomers (see Supporting Information).
J. Org. Chem. Vol. 73, No. 17, 2008 6819

Delest et al.
TABLE 1. Alkylation of 10
entry
conditions
yield (%)
18/15a
1
2
MeOTf (2 equiv), CH2Cl2, RT, 24 h
Me2SO4 (2.6 equiv), CH2Cl2, RT, 5 days
73
91
0/100
13/87
3
4
5
6
7
8
9
10
Me3S·BF4 (2.6 equiv), CH3CN, 80 °C, 2 days
0
74
100
96
91
100
100
100
Me3O·BF4 (1.2 equiv), CH2Cl2, RT, 15 h
43/57
0/100
50/50
67/33
26/74
83/17
6/94
Me3O·BF4 (3 equiv), CH2Cl2, RT, 3 days, ms 4 Å
Me3O·BF4 (2 equiv), CH2Cl2, RT, 3 days, DTBMP (0.1 equiv)
Me3O·BF4 (5 equiv), CH2Cl2, RT, 4 days
Me2SO4 (2.6 equiv), toluene, RT, 5 days
slow addition (15 h) to Me3O·BF4 (5 equiv), CH2Cl2, RT, 4 days
slow addition (15 h) to MeOTf (4 equiv), CH2Cl2, RT, 3 days
a
1
Determined by H NMR and/or GC analysis.
SCHEME 9. Isomerization of 10 Catalyzed by 17
SCHEME 11. Functionalization of 16 and 19a
a Reagents and conditions: (a) naphthalen-2-ylboronic acid, Pd(PPh3)4
(cat.), Cs2CO3, DMF, 80 °C; (b) 3-butene-1-oxide, THF, microwave, 80
°C.
positions makes possible functionalization by metal-catalyzed
coupling reactions.11 Accordingly, as illustrated, we performed
the palladium-catalyzed coupling of 16 and 19 with 2-naph-
thaleneboronic acid (Scheme 11). In both cases, the correspond-
ing substituted imidazoles were obtained in good yield.
As planned, sulfone group at position 2 can also be
substituted. Indeed, addition of sodium butenolate to 16 and 19
followed by microwave heating gives the corresponding 2-alkoxy
imidazoles in moderate to good yield (Scheme 11).20
The interest of 16 has also been demonstrated by Blass et
al.21 In their study, these authors describe the synthesis of some
potentially positive inotropes by successive Suzuki coupling and
amination of 16.
SCHEME 10. Oxidation of 18
1
by H NMR when using benzene-d6 as solvent; chemical shift
of CH3 is 2.85 and 2.54 ppm, and chemical shift of HC(imi-
dazole) is 7.31 and 6.21 ppm, for 15 and 18, respectively (see
Supporting Information for a full comparison).
Our experiments confirm that isomerization of 10 into 13 can
be catalyzed both by triflate anion (hypothesis 1) and by the
salt 17 (hypothesis 4). In order to investigate the relative
importance of these factors, we performed the slow addition of
10 to an excess of methyl triflate (Table 1, entry 10). The
observed 4/96 selectivity in that case suggests that triflate anion
is the main factor accounting for isomerization of 10 into 13
when using MeOTf as alkylating reagent.
Conclusion
We have developed a divergent and regioselective synthesis
of 1,2,4- and 1,2,5-trisubstituted imidazoles from a stable and
readily available (two steps) common intermediate, 10 (Scheme
12).
Oxidation of 18 by m-CPBA gives sulfone 19 in excellent
yield (Scheme 10). Overall thus, 19 could be obtained in four
steps from commercially available products. This intermediate
is now ready to undergo further functionalization at C2 and C4
positions.
Our strategy is based on regiocontrolled N-alkylation of
N-sulfamoyl-1H-imidazole 10. When this intermediate is en-
gaged in reaction with methyl triflate selective formation of
1,2,5-trisubstituted 1H-imidazole 15 is observed. NMR studies
Functionalization of 16 and 19. In order to demonstrate the
synthetic potential of compounds 16 and 19, the possibility of
substitution at positions 5 and 4, respectively, was first explored.
It has been reported that the presence of iodine atom in these
(20) The reaction was also tried under classical thermal conditions (heating
bath), but it was found to be much slower and leading to more side products.
(21) Blass, B. E.; Huang, C. T.; Kawamoto, R. M.; Li, M.; Liu, S.; Portlock,
D. E.; Rennels, W. M.; Simmons, M. Bioorg. Med. Chem. Lett. 2000, 10, 1543–
1545.
6820 J. Org. Chem. Vol. 73, No. 17, 2008

Synthesis of 1,2,4- and 1,2,5-Trisubstituted Imidazoles
SCHEME 12. Divergent and Regioselective Synthesis of 1,2,4- and 1,2,5-Trisubstituted Imidazoles
was purified by flash chromatography over silica with cyclohexane/
have shown that this regioselectivity can be accounted for by
in situ rapid isomerization of 10 into 13 followed by regiospe-
cific N-alkylation of this latter. Experiments have also revealed
that observed isomerization is catalyzed both by the triflate anion
and the salt 17.
This identification of factors controlling isomerization enabled
us then to control it. Indeed, when key intermediate 10 is slowly
added to an excess of Meerwein’s salt, isomerization can be
constrained and regiospecific N-alkylation of 10 leads to 1,2,4-
isomer 18 with a high selectivity.
We have thus demonstrated that 10 can lead regioselectively
to either 1,2,4- or 1,2,5-trisubstituted 1H-imidazoles according
to alkylating reagent and reaction conditions.
Furthermore, in order to make this strategy general, the key
intermediate 10 was designed so as to allow, after N-alkylation,
further selective functionalizations. Indeed, we have shown that
iodine in position 4 or 5 could be easily substituted by an aryl
group by Suzuki coupling, whereas a phenylthio group at
position 2 can, after oxidation into sulfone, be displaced by
nucleophilic substitution.
ethyl acetate 70/30 as eluent to yield 52 mg of white solid. This
solid could be recrystallized in diisopropyl ether. Overall yield:
1
84%; mp 98 °C; H NMR (300 MHz, acetone-d6) δ 7.54-7.57
(m, 2H), 7.40-7.42 (m, 3H), 7.03 (s, 1H), 3.10 (s, 6H); 13C NMR
(75 MHz, acetone-d6) δ 148.1, 140.9, 135.1, 131.7, 130.0, 129.9,
67.2, 39.2; IR (cm-1) ν 1477, 1419, 1218, 1180, 1145, 972, 825,
783, 725; MS (APCI) m/z 410, 303, 302, 301, 225, 219; HRMS
calcd for C11H12IN3O2S2Na 431.9313, found 431.9317.
Synthesis of 1-(N,N-Dimethylsulfamoyl)-4-iodo-2-phenylthio-
1H-imidazole (13). Dimethylsulfamoyl chloride (26 µL, 0.24 mmol,
0.05 equiv) was added to a solution of 1-(N,N-dimethylsulfamoyl)-
2-phenylthio-5-iodo-1H-imidazole (10, 2 g, 4.89 mmol, 1 equiv)
in dry heptane (30 mL), in the dark under Ar atmosphere. The
suspension was heated at 70 °C for 2.5 h and then filtered. The
white crystals were washed with heptane and dried under reduced
pressure. Yield: 96%; mp 116-117 °C; 1H NMR (300 MHz,
CDCl3) δ 7.49 (s, 1H), 7.42-7.48 (m, 2H), 7.31-7.39 (m, 3H),
2.99 (s, 3H); 13C NMR (75 MHz, acetone-d6) δ 143.5, 133.5, 131.5,
130.1, 129.6, 128.2, 83.3, 38.9; IR (cm-1) ν 1388, 1276, 1176,
1149, 1049, 968, 725, 686; MS (APCI) m/z 410, 303, 302, 301,
283, 219; HRMS calcd for C11H12IN3O2S2Na 431.9313, found
431.9317.
Thus, we have shown that N-sulfamoyl-1H-imidazole 10
constitutes a platform enabling the access to 1,2,4- and 1,2,5-
trisubstituted imidazoles in a regioselective manner. The ap-
plication of this methodology to the synthesis of biologically
active compounds will be reported shortly.
Synthesis of 5-Iodo-1-methyl-2-phenylthio-1H-imidazole
(15) from N,N-Dimethyl-5-iodo-2-phenylthio-1H-imidazole-
1-sulfonamide (10). Methyltrifluoromethanesulfonate (633 µL, 5.59
mmol, 1.3 equiv) was added dropwise to a solution of 1-(N,N-
dimethylsulfamoyl)-2-phenylthio-5-iodo-1H-imidazole (10, 1.76 g,
4.3 mmol, 1 equiv) in dichloromethane (8 mL), at 0 °C under Ar.
The mixture was then allowed to warm to room temperature and
stirred overnight in the dark. The solvent was evaporated under
reduced pressure. The crude solid was dissolved in acetonitrile (15
mL), and butylmethylamine (1.07 mL, 9.03 mmol, 2.1 equiv) was
added at room temperature. The solution was stirred for 15 h. The
suspension was then filtered and washed with acetonitrile to yield
971 mg of white crystals of 1-methyl-2-phenylthio-5-iodo-1H-
imidazole. Yield: 71%; mp 178-179 °C; Rf ) 0.40 (dichlo-
romethane/acetone 99/1), 0.53 (cyclohexane/ethyl acetate 70/30);
1H NMR (300 MHz, CDCl3) δ 7.26 (s, 1H), 7.09-7.14 (m, 2H),
6.76-6.89 (m, 3H), 3.63 (s, 3H); 1H NMR (300 MHz, acetone-d6)
δ 7.26 (s, 1H), 7.09-7.14 (m, 2H), 6.76-6.89 (m, 3H), 3.69 (s,
Experimental Section
Synthesis of 1-(N,N-Dimethylsulfamoyl)-5-iodo-2-phenylthio-
1H-imidazole (10). A 1.6 M solution of n-butyllithium in hexane
(1.45 mL, 2.29 mmol, 1.3 equiv) was added dropwise to a solution
of 1-(N,N-dimethylsulfamoyl)-2-phenylthio-1H-imidazole (9, 0.5 g,
1.77 mmol, 1 equiv) in dry THF (13 mL), at -78 °C under Ar.
The reaction mixture was stirred for 3.25 h at -78 °C, and a solution
of iodine (0.58 g, 2.29 mmol, 1.3 equiv) in THF (3 mL) was added
slowly. The reaction mixture was then allowed to warm to room
temperature and stirred overnight. Ethyl acetate (60 mL), a saturated
solution of ammonium chloride (20 mL), and sodium bisulfite (75
mg) were added. The phases were separated, and the organic phase
was washed twice with a saturated aqueous solution of ammonium
chloride. The combined aqueous phases were extracted twice with
ethyl acetate. The organic phases were collected and washed with
brine, dried (MgSO4), and concentrated in vacuo. The crude product
crystallized spontaneously and was rinsed with a minimum of
cyclohexane/ethyl acetate 70/30 to yield 514 mg of colorless
crystals. Mother liquors were concentrated. A second crop of
product crystallized to yield 45 mg of product. The oily residue
1
3H); H NMR (300 MHz, CD2Cl2) δ 7.28 (s, 1H), 7.09-7.14 (m,
2H), 6.76-6.89 (m, 3H), 3.66 (s, 3H); 1H NMR (300 MHz, C6D6)
δ 7.31 (s, 1H), 7.09-7.14 (m, 2H), 6.76-6.89 (m, 3H), 2.85 (s,
3H); 13C NMR (75 MHz, acetone-d6) δ 140.1, 138.3, 135.7, 130.3,
128.7, 127.6, 75.9, 35.5; IR (cm-1) ν 1434, 1396, 1373, 1249, 929,
779, 732, 686; GC (140 °C for 5 min and then f 290 at 10 °C/
min) 19.6 min; MS (APCI) m/z 317, 239, 190, 189, 157, 112.
J. Org. Chem. Vol. 73, No. 17, 2008 6821

Delest et al.
Synthesis of 4-Iodo-1-methyl-2-phenylthio-1H-imidazole
(18). To a solution of trimethyloxonium tetrafluoroborate22 (54 mg,
0.3664 mmol, 5 equiv) in 1.5 mL of extra dry dichloromethane
was slowly added a solution of 1-(N,N-dimethylsulfamoyl)-2-
phenylthio-5-iodo-1H-imidazole 10 (30 mg, 0.0733 mmole) in 1
mL of extra dry dichloromethane. The addition was performed over
a period of 15 h by means of a syringe pump. The resulting mixture
was then stirred for 4 days at room temperature. Butylmethylamine
(87.5 µL, 0.7327 mmol, 10 equiv) was added at once, and the
solution was stirred for 15 h. Dichloromethane (20 mL) was added,
and the solution was washed three times with water. The organic
phase was dried (MgSO4) and concentrated in vacuo. The crude
product was obtained as a mixture of regioisomers 18/15 in a 83/
17 ratio. The two regioisomers can be separated by flash chroma-
tography over silica with dichloromethane/acetone 99/1 as eluent,
1-methyl-4-iodo-2-phenylsulfonylimidazole (18, 50 mg, 0.14 mmol,
1 equiv), naphthalen-2-yl-boronic acid (27 mg, 0.16 mmol, 1.1
equiv), and Cs2CO3 (70 mg, 0.22 mmol, 1.5 equiv) were dissolved
in dry DMF (6 mL). A flow of Ar was passed through the solution
for 20 min. The solution was transferred into a sealed tube and
heated under microwave for 4 h at 80 °C. The reaction mixture
was poured into water, and ethyl acetate was added. The solution
was filtered on Celite. The layers were separated, and the aqueous
phase was extracted with ethyl acetate. The combined organic
phases were washed with brine, dried (MgSO4), and concentrated
under reduced pressure. Flash chromatography over silica with ethyl
acetate/cyclohexane 30/70 as eluent affords the desired product.
Yield: 47%; mp 168-169 °C; 1H NMR (300 MHz, CDCl3) δ 8.28
(s, 1H), 8.14-8.10 (m, 2H), 7.88-7.79 (m, 4H), 7.68-7.55 (m,
3H), 7.35 (s, 1H), 4.02 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
142.4, 140.2, 133.9, 133.5, 133.0, 129.7, 129.4, 128.3, 128.2, 128.1,
127.7, 126.3, 125.9, 123.9, 123.5, 121.9, 77.2, 35.6; HRMS calcd
for C20H16N2O2NaS 371.0830, found 371.0824.
1
which gave pure 18: mp 63-64 °C; H NMR (300 MHz, CDCl3)
δ 7.30-7.24 (m, 2H), 7.22-7.15 (m, 3H), 7.16 (s, 1H), 3.62 (s,
1
3H); H NMR (300 MHz, acetone-d6) δ 7.52 (s, 1H), 7.36-7.30
1
(m, 2H), 7.28-7.17 (m, 3H), 3.71 (s, 3H); H NMR (300 MHz,
Synthesis
of
2-(But-3-enyloxy)-5-iodo-1-methyl-1H-
CD2Cl2) δ 7.35-7.19 (m, 5H), 7.22 (s, 1H), 3.64 (s, 3H); 1H NMR
(300 MHz, C6D6) δ 7.11-7.08 (m, 2H), 6.86-6.78 (m, 3H), 6.21
(s, 1H), 2.54 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 140.1, 134.2,
129.7, 129.5, 128.4, 127.1, 82.0, 34.1; GC (140 °C for 5 min and
then f 290 at 10 °C/min) 18.6 min; HRMS calcd for C10H10IN2S
316.9609, found 316.9599.
imidazole (22). 3-Buten-1-ol (900 µL, 750 mg, 10.40 mmol, 5
equiv) was added to a solution of sodium hydride (383 mg of a
60% suspension in mineral oil, 9.58 mmol, 4.6 equiv) in dry THF
(7 mL), under argon. The solution was stirred until no more gas
evolution was observed and then added to a solution of 1-methyl-
5-iodo-2-phenylsulfonylimidazole (16, 725 mg, 2.08 mmol, 1 equiv)
in dry THF (35 mL). The reaction mixture was transferred into a
sealed tube and heated under microwave for 6.5 h at 80 °C. Ethyl
acetate (50 mL) and 10% sodium hydroxide solution (30 mL) were
successively added. The organic phase was further washed twice
with a 10% solution of sodium hydroxide (30 mL). Combined
aqueous phases were extracted with ethyl acetate (20 mL). The
combined organic phases were washed with brine, dried (MgSO4),
and evaporated under reduced pressure. Flash chromatography over
silica with dichloromethane/methanol 99/1 as eluent affords a
colorless oil (Rf ) 0.3). Yield: 78%; 1H NMR (300 MHz, CDCl3)
δ 6.73 (s, 1H), 5.84 (tdd, 1H, J ) 6.7, 10.2, 17.0 Hz), 5.06-5.19
(m, 2H), 4.37 (t, 3H, J ) 6.6 Hz), 3.32 (s, 3H), 2.52 (tq, 2H, J )
1.3, 6.7 Hz); 13C NMR (75 MHz, CDCl3) 153.7, 134.0, 130.3, 117.4,
68.8, 63.6, 33.5, 31.2; IR (cm-1) ν 3115, 2982, 2947, 1639, 1539,
1496, 1473, 1407, 1369, 1254; MS-APCI m/z ) 279, 225; HRMS
calcd for C8H11N2ONaI 300.9814, found 300.9811.
Synthesis
of
4-Iodo-1-methyl-2-phenylsulfonyl-1H-
imidazole (19). m-CPBA 70% (307 mg, 1.25 mmol, 2.2 equiv)
was added to a solution of 1-methyl-2-phenylthio-4-iodo-1H-
imidazole (18, 179 mg, 0.57 mmol, 1 equiv) in 10 mL of
dichloromethane, in a flask surrounded by aluminum foil to protect
the solution from light. After 8 h at room temperature, sodium
bisulfite (131 mg, 1.25 mmol, 2.2 equiv), water (4 mL), and a
saturated sodium bicarbonate solution (6 mL) were successively
added. Phases were separated, and the organic phase was washed
with saturated sodium bicarbonate. The aqueous phases were
extracted three times with dichloromethane. The combined organic
phases were washed with brine, dried (MgSO4), and concentrated
in vacuo to give 191 mg of pure product as a white solid. Yield:
1
97%; mp 91-92 °C; H NMR (300 MHz, CDCl3) δ 8.03 (d, 2H,
J ) 9.4 Hz), 7.5-7.7 (m, 3H), 7.04 (s, 1H), 3.95 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 144.7, 139.6, 134.4, 131.4, 129.6, 128.3, 82.5,
35.6; MS (APCI) m/z 349; HRMS calcd for C10H9IN2O2SNa
370.9327, found 370.9317.
Synthesis
of
2-(But-3-enyloxy)-4-iodo-1-methyl-1H-
imidazole (23). 3-Buten-1-ol (185 µL, 156 mg, 2.15 mmol, 5 equiv)
was added to a solution of sodium hydride (47.5 mg of a 60%
suspension in mineral oil, 1.98 mmol, 4.6 equiv) in dry THF (2
mL), under argon. The solution was stirred until no more gas
evolution was observed and then added to a solution of 1-methyl-
4-iodo-2-phenylsulfonylimidazole (19, 150 mg, 0.43 mmol, 1 equiv)
in dry THF (7 mL). The reaction mixture was transferred into a
sealed tubes and heated under microwave for 6.5 h at 80 °C. Ethyl
acetate (30 mL) and 10% sodium hydroxide solution (10 mL) were
successively added. The organic phase was further washed twice
with a 10% solution of sodium hydroxide (10 mL). Combined
aqueous phases were extracted with ethyl acetate (10 mL). The
combined organic phases were washed with brine, dried (MgSO4),
and evaporated under reduced pressure. Flash chromatography over
silica with dichloromethane/methanol 99/1 as eluent affords 62 mg
Synthesis of 1-Methyl-5-(naphthalene-3-yl)-2-phenylsulfonyl-
1H-imidazole (20). Pd(PPh3)4 (5 mg, 0.04 mmol, 0.03 equiv),
1-methyl-5-iodo-2-phenylsulfonylimidazole (16, 50 mg, 0.14 mmol,
1 equiv), naphthalen-2-ylboronic acid (27 mg, 0.16 mmol, 1.1
equiv), and Cs2CO3 (70 mg, 0.22 mmol, 1.5 equiv) were dissolved
in dry DMF (6 mL). A flow of Ar was passed through the solution
for 20 min. The solution was transferred into a sealed tube and
heated under microwave for 4 h at 80 °C. The reaction mixture
was poured into water, and ethyl acetate was added. The solution
was filtered on Celite. The layers were separated, and the aqueous
phase was extracted with ethyl acetate. The combined organic
phases were washed with brine, dried (MgSO4), and concentrated
under reduced pressure. Flash chromatography over silica with ethyl
acetate/cyclohexane 30/70 as eluent affords the desired product.
Yield: 70%; 1H NMR (300 MHz, acetone-d6) δ 8.10-7.95 (m, 6H),
7.80-7.57 (m, 6H), 7.28 (s, 1H), 4.04 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 144.2, 140.1, 138.5, 134.4, 133.5, 133.4, 129.7, 129.4,
129.1, 128.7, 128.5, 128.2, 127.6, 127.4, 126.7, 125.6, 77.6, 33.7;
MS-APCI: m/z ) 350; HRMS calcd for C20H16N2O2NaS 371.0830,
found 371.0832.
1
of a colorless oil (Rf ) 0.3). Yield: 52%; H NMR (300 MHz,
CDCl3) δ 6.60 (s, 1H), 5.81 (m, 1H), 5.10-5.18 (m, 2H), 4.39 (t,
3H, J ) 6.6 Hz), 3.36 (s, 3H), 2.51 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 153.2, 134.2, 122.0, 117.6, 74.3, 69.4, 33.7, 30.8; MS-
APCI m/z ) 279, 225; HRMS calcd for C8H11N2ONaI 300.9814,
found 300.9816.
Synthesis of 1-Methyl-4-(naphthalene-3-yl)-2-phenylsulfonyl-
1H-imidazole (21). Pd(PPh3)4 (5 mg, 0.04 mmol, 0.03 equiv),
Acknowledgment. This work was supported by the Fonds
de la Recherche Scientifique - FNRS (F.R.S.-FNRS) and the
Region Bruxelles-Capitale. Authors thank Drs. E. Van Quaque-
beke and L. Ingrassia for fruitful comments on this manuscript.
(22) Me3O · BF4 was purchased from Acros and purified prior to use
(following the procedure described by: Curphey, T. J. Org. Synth. 1971, 51,
142–147.
6822 J. Org. Chem. Vol. 73, No. 17, 2008

Synthesis of 1,2,4- and 1,2,5-Trisubstituted Imidazoles
R.R. is a Charge´ de recherches F.R.S.-FNRS and J.M.-B. is a
senior research associate of the F.R.S.-FNRS.
of 1H and 13C NMR spectra of new compounds. Crystal structure
data (CIF) for 10 and 18. This material is available free of charge
via the Internet at http://pubs.acs.org.
Supporting Information Available: Detailed experimental
JO801256B
procedures and characterization data for all compounds. Copies
J. Org. Chem. Vol. 73, No. 17, 2008 6823