An Investigation of Imidazole and Oxazole Syntheses Using Aryl-Substituted TosMIC Reagents

Article abstract of DOI:10.1021/jo991782l

This article describes efficient and mild protocols for preparing polysubstituted imidazoles in a single pot from aryl-substituted tosylmethyl isocyanide (TosMIC) reagents and imines generated in situ. Traditional imine-forming reactions employing virtually any aldehyde and amine followed by addition of the TosMIC reagent delivers 1,4,5-trisubstituted imidazoles with predictable regiochemistry. Employing chiral amines and aldehydes, particularly those derived from α-amino acids, affords imidazoles with asymmetric centers appended to N-1 or C-5 with excellent retention of chiral purity. 1,4-Disubstituted imidazoles are also readily prepared by a simple variant of the above procedure. Selecting glyoxylic acid as the aldehyde component of this procedure leads to intermediates such as 48, which readily undergo decarboxylation and elimination of the tosyl moiety to deliver 1,4-disubstituted imidazoles in high yields. Alternatively, using NH₄OH as the amine component in conjunction with a variety of aldehydes delivers 4,5-disubstituted imidazoles in moderate to good yields in a single pot while avoiding the need for protecting groups. Finally, the facile preparation of mono- and disubstituted oxazoles from these TosMIC reagents and aldehydes is described.

Full text of DOI:10.1021/jo991782l

1516
J . Org. Chem. 2000, 65, 1516-1524
An In vestiga tion of Im id a zole a n d Oxa zole Syn th eses Usin g
Ar yl-Su bstitu ted TosMIC Rea gen ts1
J oseph Sisko,*,† Andrew J . Kassick,‡ Mark Mellinger,† J ohn J . Filan,† Andrew Allen,§ and
Mark A. Olsen§
SmithKline Beecham Pharmaceuticals, Synthetic Chemistry Department and Analytical Sciences
Department, P.O. Box 1539, King of Prussia, Pennsylvania 19406
Received November 16, 1999
This article describes efficient and mild protocols for preparing polysubstituted imidazoles in a
single pot from aryl-substituted tosylmethyl isocyanide (TosMIC) reagents and imines generated
in situ. Traditional imine-forming reactions employing virtually any aldehyde and amine followed
by addition of the TosMIC reagent delivers 1,4,5-trisubstituted imidazoles with predictable
regiochemistry. Employing chiral amines and aldehydes, particularly those derived from R-amino
acids, affords imidazoles with asymmetric centers appended to N-1 or C-5 with excellent retention
of chiral purity. 1,4-Disubstituted imidazoles are also readily prepared by a simple variant of the
above procedure. Selecting glyoxylic acid as the aldehyde component of this procedure leads to
intermediates such as 48, which readily undergo decarboxylation and elimination of the tosyl moiety
to deliver 1,4-disubstituted imidazoles in high yields. Alternatively, using NH4OH as the amine
component in conjunction with a variety of aldehydes delivers 4,5-disubstituted imidazoles in
moderate to good yields in a single pot while avoiding the need for protecting groups. Finally, the
facile preparation of mono- and disubstituted oxazoles from these TosMIC reagents and aldehydes
is described.
Sch em e 1
In tr od u ction
Imidazoles are a common component of a large number
of natural products and pharmacologically active mol-
ecules.2 The prevalence and importance of this component
makes methods which facilitate their preparation highly
valuable. Despite intensive synthetic interest in these
heterocycles during the past century, few methods have
emerged which are general and capable of delivering
highly functionalized imidazoles.3 In addition, many of
the available methods utilize intermediates which are
difficult to prepare, such as R-functionalized carbonyl and
R-diamino compounds.3 One promising and conceptually
different approach to imidazole synthesis was reported
by van Leusen in 1977 involving cycloaddition of tosyl-
methyl isocyanides (TosMICs) to carbon-nitrogen double
bonds.4 However, since the advent of TosMIC chemistry
little work has been done to establish the scope and
limitations of this chemistry when directed toward imi-
dazole synthesis. In particular, most of the examples
published to date use imines which have been devoid of
any additional functionality.
We recently described a one-pot synthesis of imidazole
4, a potent inhibitor of p38 MAP kinase, employing the
route shown in Scheme 1.5 Conversion of pyruvaldehyde
to imidazole 3 by the reaction of tosylisonitrile 26 with
imine 1 in DMF containing significant amounts of water
is the cornerstone of this sequence. The facility with
which 1 and 2 react, even in the presence of water,
† Synthetic Chemistry Department.
‡ Co-op in the Synthetic Chemistry Department.
§ Analytical Sciences Department.
(1) This paper is dedicated to the memory of our colleagues Ken
Tubman and Lendon Pridgen, deceased August 1, 1999.
(2) For examples, see: Greenlee, W. J .; Siegl, P. K. S. Annu. Rep.
Med. Chem. 1992, 27, 59. Hodges, J . C.; Hamby, J . M.; Blankley, C. J .
Drugs Future 1992, 17, 575. Shilcrat, S. C.; Mokhallalati, M. K.;
Fortunak, J . M. D.; Pridgen, L. N. J . Org. Chem. 1997, 62, 8449.
Meanwell, N. A.; Romine, J . L.; Seiler, S. M. Drugs Future 1994, 19,
361. Rizzi, J . P.; Nagel, A. A.; Rosen, T.; McLEan, S.; Seeger, T. J .
Med. Chem. 1990, 33, 2721. Shapiro, G.; Gomez-Lor, B. J . Org. Chem.
1994, 59, 5524. Adams, J . L.; Boehm, J . C.; Kassis, S.; Gorycki, P. D.;
Webb, E. F.; Hall, R.; Sorenson, M.; Lee, J . C.; Ayrton, A.; Griswold,
D. E.; Gallagher, T. F. Bioorg. Med. Chem. Lett. 1998, 8, 3111.
(3) For imidazole syntheses, see: Ebel, K. In Methoden der Orga-
nischen Chemie (Houben-Weyl); Band E8c, Hetarene III/Teil 3; Schau-
mann, E., Ed.; Georg Thieme Verlag: Stuttgart, 1994; pp 1-215.
Grimmett, M. R. In Advances in Heterocyclic Chemistry; Katritzky, A.
R., Boulton, A. J ., Eds.; Academic: New York, 1980; Vol. 27, p 241.
Grimmett, M. R. In Advances in Heterocyclic Chemistry; Katritzky, A.
R., Boulton, A. J ., Eds.; Academic: New York, 1970; Vol. 12, p 103.
See also, Reiter, L. A. J . Org. Chem. 1987, 52, 2714. Lantos, I.; Zhang,
W. Y.; Shui, X.; Eggleston, D. S. J . Org. Chem. 1993, 58, 7092. Nunami,
K.; Yamada, M.; Fukui, T.; Matsumoto, K. J . Org. Chem. 1994, 59,
7635. Hunt, J . T.; Bartlett, P. A. Synthesis 1978, 741.
(4) van Leusen, A. M.; Wildeman, J .; Oldenziel, O. H. J . Org. Chem.
1977, 42, 1153. van Leusen, A. M. Lect. Heterocycl. Chem. 1980, 5,
S-111.
(5) Sisko, J . J . Org. Chem. 1998, 63, 4529.
(6) Sisko, J .; Mellinger, M., Sheldrake, P. W.; Baine, N. H. Tetra-
hedron Lett. 1996, 37, 8113. Sisko, J .; Mellinger, M., Sheldrake, P.
W.; Baine, N. H. Org. Synth., in press.
10.1021/jo991782l CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/15/2000

Imidazole and Oxazole Syntheses
J . Org. Chem., Vol. 65, No. 5, 2000 1517
Ta ble 1. Syn th esis of 1,4,5-Tr isu bstitu ted Im id a zoles
fr om Tosylison itr iles a n d Im in es Gen er a ted in Situ
presents new opportunities for expanding TosMIC chem-
istry for the synthesis of imidazoles from small molecule
building blocks with multiple functionalities. Although
published procedures employing substituted TosMIC
reagents imply the need for strictly anhydrous condi-
tions,4,7 the results shown in Scheme 1 belie that notion.
Described herein are the results of an investigation which
has culminated in the development of processes for the
efficient synthesis of functionally rich 1,4- and 4,5-
disubstituted imidazoles, as well as 1,4,5-trisubstituted
imidazoles, under partially aqueous conditions. Notable
features of these methods are the mild reaction condi-
tions, experimental simplicity, and extensive functional
group compatibility. A brief investigation of the reaction
of these TosMIC reagents with aldehydes to form ox-
azoles is also presented.
Resu lts a n d Discu ssion
P r ep a r a tion of 1,4,5-Tr isu bstitu ted Im id a zoles.
Several years ago we described an improved procedure
for the preparation of aryl-substituted tosylmethyl isoni-
triles.6 Prior to this report, few examples of such reagents
existed and little was known about their chemistry.4,7 The
examples shown in Table 1 illustrate the stuctural
diversity which can be achieved using these reagents in
this one-pot, three-component reaction. In each case, the
imines are prepared in situ prior to the addition of the
TosMIC reagent. In addition to providing the desired
imidazoles in good yields, the reactions are also experi-
mentally simple. The reactions work well in most com-
mon organic solvents (EtOAc, THF, MeCN, DMF, CH2-
Cl2, MeOH) and require only very mild bases to promote
the cycloaddition (piperazine, morpholine, K2CO3). The
choice of reaction conditions is typically governed by the
solubility of the aldehyde and amine as well as ease of
product isolation. For instance, the combination of DMF/
K2CO3 is typically the best choice for ensuring successful
TosMIC/imine cycloadditions. However, other solvent/
base combinations can be equally effective and avoid
difficulties associated with removing DMF from the
product.
Table 1 shows a number of examples of this chemistry.
Entries 1-4 show imidazoles with C-5 substituents at
various oxidation states which are poised for further
manipulations. Aldehyde 6 (entry 2) ensues from the
reaction of the di-tert-butylimine of glyoxal8 with 1 equiv
of isonitrile 2. The initially formed imidazole imine is
hydrolyzed with aqueous HCl to deliver the aldehyde 6.
Alkyl, aryl, and heteroaryl aldehydes work equally well,
as shown in entries 5-7, and highlight the ease with
which unprotected functionalities can be accommodated
in this mildly basic process.
a
b
(4-Fluorophenyl) tosylmethyl isonitrile (2) was used. (3,4-
Dichlorophenyl) tosylmethyl isonitrile (2b) was used. c (2-Meth-
oxyphenyl) tosylmethyl isonitrile (2c) was used. (4-Methoxyphe-
nyl) tosylmethyl isonitrile (2c) was used.
d
increased congestion surrounding the benzylic carbon
since TosMIC reagents similar to 2 with electron-
deficient aryl rings are, in general, very reactive. The only
other ortho aromatic-substituted TosMIC reagent which
was investigated, o-methoxyphenyl derivative 2c, under-
goes clean cycloaddition to form imidazole 9 (Table 1).
Unfortunately, alkyl-substituted TosMIC reagents and
TosMIC itself have so far been unreactive partners under
all conditions tried.9
A variety of TosMIC reagents containing electron-poor
and electron-rich aryl rings have been prepared by our
standard method6 and show comparable reactivity. One
exception is the o-bromophenyl derivative of 2 which
failed to react with several imines under all conditions
tried. This lack of reactivity can be attributed to the
Dialdehydes and diamines have also been used suc-
cessfully in this multicomponent reaction to generate
dimeric bis-imidazoles. Glutaric dialdehyde, available as
a 50% aqueous solution, readily reacts with 2 equivalents
of allylamine to form the corresponding diimine 14 in situ
(7) (a) DiSanto, R.; Costi, R.; Massa, S.; Artico, M. Synth. Commun.
1995, 25, 795. (b) Sasaki, H.; Nakagawa, H.; Khuhara, M.; Kitagawa,
T. Chem. Lett. 1988, 1531.
(8) Haaf, M.; Schmiedl, A.; Schmedake, T. A.; Powell, D. R.;
Millevolte, A. J .; Denk, M.; West, R. J . Am. Chem. Soc. 1998, 120,
12714.

1518 J . Org. Chem., Vol. 65, No. 5, 2000
Sisko et al.
Sch em e 2
Sch em e 4
Sch em e 5
Sch em e 3
of antiviral and antibiotic agents. The syntheses devel-
oped for these substrates, however, are lengthy and low-
yielding.10 We considered the reaction of a cyclic imine
with an aryl-substituted TosMIC reagent as a viable
alternative to this potentially useful class of molecules.
Moriarty has shown that secondary, cyclic amines are
readily oxidized by the action of (PhIO)n to the corre-
sponding imine.11 Although these imines can be difficult
to isolate due to their propensity to trimerize, they are
well-suited for our one-pot approach. In the event,
treatment of pyrrolidine with (PhIO)n in CH2Cl2 for 15
min at room temperature produces 1-pyrroline (25)
(Scheme 5). Addition of TosMIC reagent 2e and pipera-
zine yields the fused, bicyclic imidazole 26 in a single
operation in 69% isolated yield.
We have also investigated a process wherein the
aldehyde and imine are generated in situ prior to
cycloaddition with a TosMIC reagent. Floyd and co-
workers have reported the conversion of phenacyl halides
to the corresponding R-keto aldehydes under mild condi-
tions.12 Thus, stirring bromide 27 in a DMSO/H2O
mixture for 24 h at room temperature produces aldehyde
28 (Scheme 6). Addition of the primary amine 29 leads
to formation of the imine 30 which reacts with 2f to form
the ketoimidazole 31 in 50% overall yield. This efficient,
one-pot method allows rapid entry to a class of molecules
that have been difficult to attain by literature methods.13
P r ep a r a tion of Ch ir a l 1,4,5-Tr isu bstitu ted Im i-
d a zoles. Another family of attractive target molecules
for this methodology are 2-imidazol-1-yl alkanoic acids.
Despite their promise as pharmaceutical agents, few
methods exist for the preparation of such compounds in
optically pure form.14 The extensive functional group
(Scheme 2). Cycloaddition of 14 with isonitrile 2 proceeds
smoothly to deliver the bis-imidazole 15 in 50% isolated
yield.
Likewise, bis-imidazoles connected via N-1, such as 19,
are accessible using a similar process from the corre-
sponding diamines (Scheme 3). Diimine 18 is easily
prepared from the di-HCl salt of cysteamine (17) and
5-methylfurfural (16) in aqueous methanol containing
NaHCO3. Subsequent [3 + 2] cycloaddition of 18 with 2
proceeds smoothly to deliver bis-imidazole 19 in 86%
isolated yield.
In addition to those prepared in the classical method,
imines generated by less direct routes can also undergo
cycloaddition with these TosMIC reagents with equal
success to form interesting products. For example, reduc-
tion of γ-valerolactone (20) with DIBAL at -78 °C leads
to lactol 21 (Scheme 4). Without isolation, this intermedi-
ate was condensed with aminoacetaldehyde dimethyl
acetal (22) to generate imine 23 which undergoes the
desired cycloaddition with TosMIC 2. From this one-pot
sequence, adduct 24 can be isolated in 68% yield.
Several groups have reported an interest in using
fused, bicyclic imidazoles as the nucleus for new classes
(9) This observation is rather surprising in light of the original
results reported by van Leusen et al.4 In that seminal paper, the
reaction of TosMIC with simple, isolated imines is reported to work
well under mild conditions in protic solvents (e.g., t-BuNH2 or K2CO3
in MeOH). However, fairly subtle stereoelectronic effects seem to
govern the outcome of these reactions. For example, C,N-diaryl- and
C,N-dialykylimines react with TosMIC to give the corresponding
imidazoles in good to excellent yields while C-aryl,N-alkylimines react
poorly with TosMIC to give low yields of imidazole product (0-37%).
In the only example of its kind reported, the methyl-substituted
TosMIC reagent combines with a C,N-diarylimine to give the imidazole
in 75% yield, but required the action of NaH in an aprotic solvent
(DME).
(10) Frannowski, A.; Seliga, C.; Bur, D.; Streith, J . Helv. Chim. Acta
1991, 74, 934. Nishi, T.; Higashi, K.; Soga, T.; Takemura, M.; Sato,
M. J . Antibiot. 1994, 47, 357. Browne, L. J .; Gude, C.; Rodriguez, H.;
Steele, R. E. J . Med. Chem. 1991, 34, 725. See also: Aldabbagh, F.;
Bowman, W. R.; Mann, E. Tetrahedron Lett. 1997, 38, 7937.
(11) Ochiai, M.; Inenaga, M.; Nagao, Y.; Moriarty, R. M.; Vaid, R.
K.; Duncan, M. P. Tetrahedron Lett. 1988, 29, 6917.
(12) Floyd, M. B.; Du, M. T.; Fabio, D. F.; J acob, L. A.; J ohnson, B.
D. J . Org. Chem. 1985, 50, 5022.
(13) See ref 5 and references therein.

Imidazole and Oxazole Syntheses
J . Org. Chem., Vol. 65, No. 5, 2000 1519
Ta ble 2. Syn th esis of 1,4,5-Tr isu bstitu ted Im id a zoles
fr om Tosylison itr iles a n d Im in es Der ived fr om r- a n d
â-Am in o Acid s
Sch em e 6
compatibility that has been demonstrated in these cy-
cloadditions led us to pursue this class of compounds
using imines derived from optically pure amino acids. The
results are shown in Table 2. Following the procedure of
Narita,15 the desired imines are readily prepared in situ
by allowing an aldehyde and an amino acid in MeOH:
H2O (10:1) to react in the presence of 1 equiv of NaOH.
Upon addition of the TosMIC reagent and piperazine, the
desired compounds are obtained in high yield with >99%
ee. In addition to R-amino acids, we have also demon-
strated the utility of â-alanine (entry 4) in this sequence
for the preparation the homologated carboxylic acids.
We also recognized the potential for incorporating a
chiral center at C-5 of the imidazole ring by using, among
other things, a chiral R-amino aldehyde. These aldehydes
are readily available by several methods,16 and in certain
instances are commercially available. Aldehyde 36 and
the primary amine 22 produce the desired imine which
undergoes cycloaddition with 2 to deliver imidazole 37
in high yields with 96.4% ee (Scheme 7).
a
b
(4-Fluorophenyl) tosylmethyl isonitrile (2) was used. (3,4-
Thienyl) tosylmethyl isonitrile (2g) was used.
Sch em e 7
P r ep a r a tion of 1,4-Disu bstitu ted Im id a zoles. Dur-
ing the course of these investigations, we had cause to
examine the reaction shown in Scheme 8. Cycloaddition
of imine 39, prepared in situ from a 40% aqueous solution
of pyruvaldehyde and amine 38, with isonitrile 2 and K2-
CO3 in DMF leads to ketone 40 in 75% isolated yield.
Surprisingly, when the reaction is run at 0 °C the product
40 is contaminated with 15-20% of the 1,4-disubstituted
imidazole 41.
likely, it was the easier scenario to investigate. Imidazole
41 represents the formal cycloadduct derived from form-
aldimine 42 reacting with isonitrile 2 (Scheme 9). We
speculated that contamination of pyruvaldehyde with
formaldehyde17 could account for the presence of imine
42 in the reaction mixture. This hypothesis was easily
tested by mixing 37% aqueous formaldehyde, amine 38,
and 2 under conditions identical to those used in Scheme
8. This reaction, however, yields a new cycloadduct as
the major product with only 5-10% of the expected
product 41 observed in the reaction mixture. The major
product, isolated in 70% yield, was ultimately determined
to be the 2-aminooxazoline 44 which results from the
We considered two possible pathways to account for
the formation of imidazole 41. While the first seemed less
(14) Palkowitz, A. D.; Steinberg, M. I.; Thrasher, K. J .; Reel, J . K.;
Hauser, K. L.; Zimmerman, K. M.; Wiest, S. A.; Whitesitt, C. A.; Simon,
R. L.; Pfeifer, W.; Lifer, S. L.; Boyd, D. B.; Barnett, C. J .; Wilson, T.
M.; Deeter, J . B.; Takeuchi, K.; Riley, R. E.; Miller, W. D.; Marshall,
W. S. J . Med. Chem. 1994, 37, 4508. Zaderenko, P.; Lopez, P.;
Ballesteros, P.; Takumi, H.; Toda, F. Tetrahedron: Asymmetry 1995,
6, 381. Zaderenko, P.; Lopez, M. C.; Ballesteros, P. J . Org. Chem. 1996,
61, 6825. Birkett, P. R.; King, H.; Chapleo, C. B.; Ewing, D. F.;
Mackenzie, G. Tetrahedron 1993, 49, 11029. Messina, F.; Botta, M.;
Corelli, F.; Schneider, M. P.; Fazio, F. J . Org. Chem. 1999, 64, 3767.
(15) Narita, M.; Akiyama, M.; Bull. Chem. Soc. J pn. 1974, 47, 197.
(16) For the preparation of chiral amino aldehydes, see: J urczak,
J .; Golebiowski, A. Chem. Rev. 1989, 89, 149. McNulty, J .; Still, I. W.
Synth. Commun. 1992, 22, 979. Fehrentz, J .-A.; Castro, B. Synthesis
1983, 676.
(17) Pyruvaldehyde is known to decompose under certain conditions
to give formaldehyde, see: Tyndall, G. S.; Staffelbach, T. A.; Orlando,
J . J .; Calvert, J . G. Int. J . Chem. Kinet. 1995, 27, 1009. An alternative
explanation would involve deacylation of imine 39 to give formaldimine
42 directly.

1520 J . Org. Chem., Vol. 65, No. 5, 2000
Sisko et al.
Sch em e 8
Sch em e 10
Sch em e 11
Sch em e 9
CO3 in DMF delivers the expected imine 47 (Scheme 11).
Upon addition of reagent 2 and additional base, the
putative intermediate 48 thus formed suffers decarboxy-
lation and subsequent elimination of TolSO2K to generate
the observed product (41) in high yields.
This reaction was found to be quite general and
accommodates a broad range of functional groups, deliv-
ering 1,4-disubstituted imidazoles of varying complexity
in good to excellent yields (see Table 3). In addition to
the conditions mentioned, aqueous methanol containing
NaOH is also an effective combination for forming imine
carboxylates similar to 47. Addition of the TosMIC
reagent and a mild base, such as piperazine or morpho-
line, is sufficient to complete the imidazole synthesis in
these cases. Despite the results in Table 2, the use of
amino acids in this sequence fail to provide any of the
expected 1,4-disubstituted imidazole. NMR studies seem
to indicate the formation of the expected imines in
DMSO-d6 with K2CO3, but upon addition of 2 they fail
to undergo any productive reaction. This shortcoming is
circumvented by using an amino acid ester, as shown in
entry 6. Combining valine methyl ester hydrochloride
with glyoxylic acid in DMF with NaHCO3 and trapping
the resultant imine with isonitrile 2b delivers ester 54
in 83% isolated yield with 98% ee.
P r ep a r a tion of 4,5-Disu bstitu ted Im id a zoles. Hav-
ing established that aryl-substituted TosMIC cycloaddi-
tions with imines are quite general, we considered the
possibility of extending this methodology to prepare 4,5-
disubstituted imidazoles. Several strategies have been
reported for the synthesis of N-unsubstituted imidazoles
using TosMIC derivatives. Shih has reported the use of
N-trimethylsilyl imines as reaction partners with TosMIC
derivatives.19 However, these imines are generally pre-
sequence shown in Scheme 9. The slow and incomplete
conversion of formaldehyde to imine 42, made evidence
by the low yield of imidazole 41, allows for the competi-
tive cycloaddition of formaldehyde with reagent 2 to
produce the tosyloxazoline 43. Subsequent addition of the
primary amine at C2 and elimination of the toluenesulfi-
nate moiety completes the formation of the observed
product 44.18 Control experiments confirm this sequence.
Cycloaddition of 37% aqueous formaldehdye with 2
proceeds smoothly to give oxazoline 43 in 73% yield.
Combining amine 38 with oxazoline 43 in DMF at room
temperature leads to clean formation of 44 in high yields.
An alternative sequence which could account for 41 is
shown in Scheme 10. Addition of a nucleophile (HO-) to
the ketone of putative intermediate 454 gives rise to the
tetrahedral intermediate 46. Ejection of acetic acid
followed by elimination of the p-toluenesulfinate anion
from 46 leads to 41.
Before proceeding with experiments designed to sup-
port this mechanism, we opted instead to seek methods
to facilitate the expulsion of the C-5 substituent to
develop a general method for preparing 1,4-disubstituted
imidazoles. Replacing the acetyl moiety of 45 with a
carboxylate group was seen as the optimal substitution.
In the event, mixing glyoxylic acid, amine 38, and K2-
(18) A similar sequence has been proposed by Buchi et al., to account
for the formation of imidazoles from the reaction of amines with
tosyloxazolines similar to 43. However, they apparantly were unable
to isolate intermediates similar to 44. See: Horne, D. A.; Yakushijin,
K.; Bu¨chi, G. Heterocycles 1994, 39, 139.
(19) Shih, N.-Y. Tetrahedron Lett. 1993, 34, 595.

Imidazole and Oxazole Syntheses
J . Org. Chem., Vol. 65, No. 5, 2000 1521
Ta ble 3. Syn th esis of 1,4-Disu bstitu ted Im id a zoles fr om
Tosylison itr iles a n d Im in es Gen er a ted in Situ
Sch em e 12
12). We suspected that either species, 56 or 57, might be
a suitable partner in this cycloaddition reaction for the
preparation of 4,5-disubstituted imidazoles (58). Accord-
ingly, hydrobenzamide 57 was prepared and isolated by
the procedure of Bhawal,22 and then reacted in a separate
step with isonitrile 2 in THF to provide imidazole 58 in
60% isolated yield. Subsequent experiments revealed that
the isolation of 57 in a separate step was unnecessary.
Simply treating p-anisaldehyde with excess NH4OH (30%
aqueous) in THF followed by addition of isonitrile 2
generates imidazole 58 in 65% overall yield in a single
operation (Scheme 12). Table 4 shows additional ex-
amples of this one-pot transformation. In addition to aryl
aldehydes, several alkyl aldehydes have been used with
equal success to give the corresponding imidazole prod-
ucts. The low yield reported in entry 2 was in part due
to difficulties in isolating the product. From other ex-
amples it is apparent that various functional groups are
tolerated in the process, including phenols, alcohols, and
olefins. Surprisingly, no pyrrole byproducts were obtained
from the reaction in entry 7.23
Although the results in Table 4 are encouraging, the
reaction of NH4OH with most aldehydes is a poorly
understood process which is complicated by a large
number of possible intermediates and products.24 Elec-
tronic factors have been found to play a large role in
determining the rate and extent to which the hydroben-
zamides are formed.25 These considerations, in addition
to the difficulty in monitoring the progress of the alde-
hyde to hydrobenzamide conversion, have profound ef-
fects on the yield of imidazole products obtained from this
process. For aldehydes which suffer poor conversion to
the hydrobenzamide, the most common side products are
4,5-disubstituted oxazoles which result from cycloaddi-
a
b
(4-Fluorophenyl) tosylmethyl isonitrile (2) was used. (3-
Thienyl) tosylmethyl isonitrile (2g) was used. c Phenyl tosylmethyl
isonitrile (2h ) was used. (3,4-Dichlorophenyl tosylmethyl isoni-
trile (2b) was used.
d
pared under strongly basic conditions which are incom-
patible with certain substrates. More recently, van
Leusen described the cycloaddition of TosMIC with
N-(dimethylsulfamoyl)aldimines and N-tosylimines to
obtain 4(5)-monosubstituted imidazoles.20 While it’s likely
this method could also prepare 4,5-disubstituted imida-
zoles, no examples to support this were reported. Regard-
less, this method requires a separate step (or steps) to
prepare the imines and, in the case of the N-(dimethyl-
sulfamoyl)aldimines, an additional step to liberate the
N-unsubstituted imidazole. Hence, we explored a method
to prepare 4,5-disubstituted imidazoles under mild condi-
tions that also avoids a protection/deprotection sequence.
For this, the logical choice of reagents was also the
cheapest and easiest: NH4OH.
The reaction of certain aromatic aldehydes with NH4-
OH is known to give “hydrobenzamides” 57 in high
yields,21 presumably via the parent arylimines 56 (Scheme
(22) Karupaiyan, K.; Srirajan, V.; Deshmuck, A. R. A. S.; Bhawal,
B. M. Tetrahedron 1998, 54, 4375.
(23) van Leusen, A. M.; Siderius, H.; Hoogenboom, B. E.; van
Leusen, D. Tetrahedron Lett. 1972, 5337.
(24) Larter, M. L.; Phillips, M.; Ortega, F.; Aguirre, G.; Somanathan,
R.; Walsh, P. J . Tetrahedron Lett. 1998, 39, 4785. Hunter, D. H.; Kim,
S. K. Can. J . Chem. 1972, 50, 669.
(20) ten Have, R.; Huisman, M.; Meetsma, A.; van Leusen, A. M.
Tetrahederon 1997, 53, 11355. For another possible alternative method,
see: van Leusen, A. M.; Schaart, F. J .; van Leusen, D. Rec. Trav. Chim.
Pays-Bas 1979, 98, 258.
(21) See Corey, E. J .; Ku¨hnle, F. N. M. Tetrahedron Lett. 1997, 38,
8631 and references therein.
(25) Ogata, Y.; Kawasaki, A.; Okumura, N. J . Org. Chem. 1964, 29,
1985.

1522 J . Org. Chem., Vol. 65, No. 5, 2000
Sisko et al.
Ta ble 4. Syn th esis of 4,5-Disu bstitu ted Im id a zoles fr om
Tosylison itr iles a n d Im in es Gen er a ted in Situ fr om
Ald eh yd es a n d NH4OH
Sch em e 13
to give an arylimine similar to 56 which undergoes
cycloaddition with 2 to give 66. A reexamination of the
crude product mixtures from the reactions in Table 4
showed that 66 is present in most of these reactions,
although usually as a minor component (5-10%).
4,5-Disu bstitu ted Oxa zoles. Reactions of TosMIC
and its alkyl-substituted derivatives with aldehydes are
known to give the corresponding oxazoles.27 Conversely,
reactions of aryl-substituted TosMIC reagents with al-
dehydes have been relatively unexplored.7b From the
results discussed above, it was clear that these reactions
should be particularly facile, require mild reaction condi-
tions, and be tolerant of a broad array of functional
groups. Table 5 shows the results of a few reactions that
exemplify the ease with which these aldehyde/TosMIC
cycloadditions occur. Methyl ketone 67 can be prepared
in good yield from pyruvaldehyde and isonitrile 2 (entry
1). To our surprise, small amounts of oxazoline 43 were
also found by NMR in the crude reaction mixture (<5%).
The presence of this impurity confounds our interpreta-
tion of the results in Schemes 8-10 since nucleophilic
deacylation of the expected intermediate 73, as in Scheme
10, should lead to the monosubstituted oxazole 74
(Scheme 14). The presence of 43 instead of 74 implies
that decomposition of pyruvaldehyde to formaldehyde
under the reaction conditions may occur, at least to a
small extent, prior to cycloaddition with 2.
a
b
As expected, glyoxylic acid undergoes cycloaddition
with TosMIC reagents to produce the monosubstituted
oxazole 68 in good yield (entry 2). Reaction of isonitrile
2 with chloroacetaldehyde gives a somewhat unexpected
result (entry 3). Combining the reagents in DMF with
K2CO3 at room temperature for 18 h leads to oxazoline
75 as the major product (mixture of cis and trans isomers,
Scheme 15). Heating the solution to 95 °C to induce
elimination of TolSO2H and form the oxazole ring instead
produces the tosylmethyl oxazole 69 exclusively, presum-
ably via chloride 76. Finally, bisulfite adduct 71 is also
capable of smooth cycloaddition with 2 to give oxazole
72 in good yield (entry 5), presumably via the interme-
diacy of the corresponding aldehyde.
(4-Fluorophenyl) tosylmethyl isonitrile (2) was used. Phenyl
tosylmethyl isonitrile (2h ) was used. c (3-Thienyl) tosylmethyl
isonitrile (2g) was used. (3-Trifluoromethyl)phenyl tosylmethyl
isonitrile (2i) was used.
d
tion of the TosMIC reagent with the aldehyde.26 Several
low molecular weight aldehydes, such as glyoxal, pyru-
valdehyde, and glyoxylic acid, fail to form the expected
imidazole products after reaction with NH4OH (Scheme
13). In these reactions, the only product isolated is
imidazole 66. The structure of this unexpected product
was verified by independent synthesis involving the
reaction of 4-fluorobenzaldehyde with NH4OH and re-
agent 2. At present, the exact mechanism for the forma-
tion of 66 is uncertain. However, it appears that 2 has a
limited lifetime under these reaction conditions, and that
lacking a suitable cycloaddition partner, it decomposes
(27) Possel, O.; van Leusen, A. M. Heterocycles 1977, 7, 77. Saikachi,
H.; Kitagawa, T.; Sasaki, H.; van Leusen, A. M. Chem. Pharm. Bull.
1979, 27, 793. Hiemstra, H.; Houwing, H. A.; Possel, O., van Leusen,
A. M. Can. J . Chem. 1979, 57, 3168.
(26) van Leusen, A. M.; Hoogenboom, B. E.; Siderius, H. Tetrahedron
Lett. 1972, 2369.

Imidazole and Oxazole Syntheses
J . Org. Chem., Vol. 65, No. 5, 2000 1523
Ta ble 5. Syn th esis of 1,4,5-Tr isu bstitu ted Im id a zoles
fr om Tosylison itr iles a n d Im in es Gen er a ted in Situ
has been conducted on the reactivity of substituted
TosMIC derviatives, due in large part to the lack of a
robust method for their preparation. We have reported
here that aryl-substituted TosMIC reagents readily
undergo cycloaddition with a variety of simple and
polyfunctional imines, under anhydrous or partially
aqueous conditions, to give rise to 1,4,5-trisubstituted,
as well as 1,4- and 4,5-disubstituted, imidazoles in a
single operation. The sequence is conducted under mild
conditions and tolerates a host of functional groups. The
method can easily accommodate chiral amines and al-
dehydes, such as those derived from amino acids, to
generate products in high enantiomeric excess. Similar
cycloadditions with simple and multifunctional aldehydes
proceed smoothly to generate a host of interesting ox-
azoles.
Exp er im en ta l Section
Gen er a l Exp er im en ta l. The 13C spectra of the 4,5-disub-
stituted imidazoles in Table 4 were collected at 25 °C. Due to
annular tautomerism, the width of some signals in the 13C
spectrum (10-20 Hz) under these conditions makes them
undetectable and accounts for less than the expected number
of resonances for these compounds.28 WARNING: Isonitrile
2 is thermally unstable at temperatures above 80 °C. To obtain
a margin of safety, care should be taken to avoid heating 2
and similar TosMIC derivatives at temperatures above 35-
40 °C.
1-[1-(2,2-Dim eth oxyeth yl)-4-(4-flu or op h en yl)im id a zol-
5-yl]eth a n -1-on e (5). A solution of pyruvaldehyde (40%
aqueous, 3.97 mL mL, 25.9 mmol) and aminoacetaldehyde
dimethyl acetal (3.77 mL, 34.6 mmol) in THF (75 mL) was
stirred at ambient temperature for 15 min, at which point the
isonitrile 2 (5 g, 17.3 mmol) and piperazine (1.94 g, 22.3 mmol)
were added. The solution was stirred an additional 18 h and
diluted with EtOAc and water, and the layers were separated.
The organic layer was stirred with 3 N HCl for 10 min (to
hydrolyze any ketimine product) and then made basic with
solid K2CO3. The aqueous layer was removed, the organics
were concentrated in vacuo to dryness, and the residue was
eluted through a short plug of silica gel with EtOAc. The eluent
was concentrated to give the product (3.6 g, 71%) as a yellow
a
b
(4-Fluorophenyl) tosylmethyl isonitrile (2) was used. (3-
Thienyl) tosylmethyl isonitrile (2g) was used. c 2-Naphthyl tosyl-
methyl isonitrile (2f) was used.
Sch em e 14
1
oil: IR (neat) 1670 cm-1; H NMR (300 MHz, CDCl3) δ 7.61
(1H, s), 7.45 (2H, m), 7.11 (2H, t, J ) 8.6 Hz), 4.54 (1H, t, J )
5.0 Hz), 4.32 (2H, d, J ) 5.0 Hz), 3.41 (6H, s), 2.11 (3H, s); 13
C
NMR (75 MHz, CDCl3) δ 190.6, 162.9 (d, J ) 248 Hz), 149.0,
142.3, 131.4 (d, J ) 8.3 Hz), 131.2, 127.2, 115.3 (d, J ) 21.7
Hz), 103.3, 55.2, 49.2, 29.8. Anal. Calcd for C15H17N2O3F: C,
61.6; H, 5.9; N, 9.6. Found C, 61.5; H, 5.9; N, 9.4.
Sch em e 15
3-[1-(2,2-Dim eth oxyeth yl)-4-(4-flu or op h en yl)im id a zol-
5-yl]p r op a n -1-ol (24). A solution of γ-butyrolactone (1.78 g,
20.7 mmol) in THF (80 mL) was cooled to -78 °C, and
DIBAL-H (1.5 M in toluene, 15.2 mL, 22.8 mmol) was added
dropwise. After 45 min, aminoacetaldehyde dimethyl acetal
(3.27 g, 30.1 mmol) was added, and the solution was allowed
to warm to room temperature. After 1 h at this temperature,
isonitrile 2 (3.0 g, 10.4 mmol) and piperazine (1.34 g, 15.6
mmol) were added, and the solution was stirred for 18 h. After
adding 3 N HCl (6 mL) and EtOAc, the slurry was filtered
through a bed of Celite and rinsed with EtOAc. The filtrate
was washed with water and concentrated in vacuo. The
product which was isolated by silica gel chromatography using
EtOAc:MeOH (19:1) crystallized on standing (2.16 g, 68%) as
a white solid: IR (neat) 3270 cm-1; 1H NMR (300 MHz, CDCl3)
Con clu sion
(28) See Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles;
Thieme: Stuttgart, 1995; p. 167. Papadopoulos, E. P.; Hollstein, U.
Org. Magn. Reson. 1982, 19, 188.
(29) Boehm, J . C.; Smietana, J . M.; Sorenson, M. E.; Garigipati, R.
S.; Gallagher, T. F.; Sheldrake, P. L.; Bradbeer, J .; Badger, A. M.;
Laydon, J . T.; Lee, J . C.; Hillegass, L. M.; Griswold, D. E.; Breton, J .
J .; Chabot-Fletcher, M. C.; Adams, J . L. J . Med. Chem. 1996, 39, 3929.
The reaction of imines with TosMIC has been known
for over 20 years as a trusted method for preparing 1,5-
disubstituted imidazoles with predictable regiochemistry.
However, in the intervening years, no systematic study

1524 J . Org. Chem., Vol. 65, No. 5, 2000
Sisko et al.
δ 7.58 (2H, m), 7.50, (1H, s), 7.02 (2H, t, J ) 8.7 Hz), 4.43
(1H, t, J ) 5.1 Hz), 3.97 (2H, d, J ) 5.1 Hz), 3.57 (2H, t, J )
6.0 Hz), 3.36 (6H, s), 3.06 (1H, br s), 2.84 (2H, t, J ) 7.8 Hz),
1.74 (2H, m); 13C NMR (75 MHz, CDCl3) δ 161.7 (d, J ) 246
Hz), 136.9, 136.7, 131.3, 128.6 (d, J ) 7.8 Hz), 127.3, 115.2 (d,
J ) 21.4 Hz), 103.7, 61.2, 55.1, 47.1, 32.3, 19.8. Anal. Calcd
for C16H21N2O3F: C, 62.3; H, 6.9; N, 9.1. Found C, 62.5; H,
6.9; N, 9.0.
3-Na p h th ylp yr r olid in o[1,2-d ]im id a zole (26). To a solu-
tion of pyrrolidine (0.42 g, 5.84 mmol) in CH2Cl2 (50 mL) was
added freshly prepared (PhIO)n (1.38 g, 5.84 mmol). After 15
min, the isonitrile 2e (1.25 g, 3.89 mmol) and piperazine (0.5
g, 5.84 mmol) were added, and the solution was stirred an
additional 18 h at room temperature. Water and CH2Cl2 were
added, and the layers were separated. The organics were
washed with water and brine and were concentrated in vacuo.
After silica gel chromatography using EtOAc, the product was
obtained as a viscous yellow oil (0.63 g, 69%): 1H NMR (300
MHz, CDCl3) δ 8.56 (1H, d, J ) 8.2 Hz), 7.75 (1H, d, J ) 7.9
Hz), 7.66 (1H, d, J ) 7.9 Hz), 7.49 (1H, d, J ) 7.0 Hz), 7.40
(4H, m), 3.65 (2H, t, J ) 7.1 Hz), 2.61 (2H, t, J ) 7.1 Hz), 2.26
(2H, m); 13C NMR (75 MHz, CDCl3) δ 135.3, 134.1, 132.7, 131.3,
130.2, 128.1, 127.0, 126.7, 126.1, 125.7, 125.6, 125.4, 44.2, 29.2,
22.9. Anal. Calcd for C16H14N2: C, 82.0; H, 6.0; N, 12.0. Found
C, 81.8; H, 6.2; N, 11.6.
d, J ) 2.8 Hz), 6.25 (1H, d, J ) 2.8 Hz), 4.74 (1H, q, J ) 7.2
Hz), 2.28 (3H, s), 1.64 (3H, d, J ) 7.2 Hz); 13C NMR (75 MHz,
DMSO-d6) δ 171.7, 161.1 (d, J ) 244 Hz), 153.2, 140.2,
138.8, 137.2, 130.6, 127.8 (d, J ) 7.9 Hz), 118.2, 114.9 (d, J )
21.3 Hz), 113.9, 107.5, 53.3, 17.3, 13.1. Anal. Calcd for
C
17H15N2O3F: C, 65.0; H, 4.8; N, 8.9. Found C, 65.0; H, 4.8;
N, 8.8. The enantiomeric excess was determined by HPLC
using a Chiralcel OD column, with EtOH:hexane:TFA (10:90:
0.1) as mobile phase, flow rate of 0.5 mL/min and UV detection
at 254 nm. Retention times: S-isomer at 12.6 min, R-isomer
at 15.4 min.
Gen er a l P r oced u r e for th e P r ep a r a tion of 1,4-Disu b-
stitu ted Im id a zoles. A solution of gyoxylic acid (monohydrate
or 50% aqueous solution, 21.6 mmol), K2CO3 (43.2 mmol), and
amine (25.9 mmol) in DMF (50 mL) was stirred at ambient
temperature for 3 h, at which point the isonitrile (17.3 mmol)
was added. The solution was stirred an additional 18 h and
diluted with TBME and water, and the layers were separated.
The aqueous layer was extracted again with TBME, and the
organic layers were combined and washed with water. The
organic layer was concentrated in vacuo to dryness, and the
residue was either recrystallized or purified by flash chroma-
tography.
Gen er a l P r oced u r e for th e P r ep a r a tion of 4,5-Disu b-
stitu ted Im id a zoles. A solution of the aldehyde (25.9 mmol)
and NH4OH (30% aqueous, 69.2 mmol) in THF (75 mL) was
stirred at ambient temperature for 3-8 h, at which point the
TosMIC reagent (17.3 mmol) and piperazine (25.9 mmol) were
added. The solution was stirred an additional 18 h and diluted
with EtOAc and water, and the layers were separated. The
organic layer was washed with water and saturated NaHCO3
solution and concentrated in vacuo to dryness. The products
were isolated by crystallization or chromatography.
4-Br om op h en yl 1-(3-im id a zolylp r op yl)-4-(2-n a p h th yl)-
im id a zol-5-yl k eton e (31). A solution of 1,4′-dibromoac-
etophenone (3.84 g, 13.8 mmol) dissolved in DMSO (23 mL)
and water (0.25 mL) was stirred at room temperature for 24
h. Triethylamine (9 mL) was added to adjust the pH of the
solution to 8 prior to the addition of 1-(3-aminopropyl)-
imidazole (1.65 mL, 13.8 mmol). After 1 h, isonitrile 2f (2.21
g, 6.91 mmol) and piperazine (0.89 g, 10.4 mmol) were added,
and the solution was stirred at room temperature for an
additional 24 h. Water was added, and the solution was stirred
for 20 min. EtOAc was added, and the layers were separated.
The organics were washed with water and brine. The organics
were concentrated in vacuo, and the residue was purified by
silica gel chromatography using EtOAc:MeOH (9:1). The
product (1.68 g, 50%) solidified on standing as a yellow solid:
1-[4-(4-F lu or op h en yl)-1,3-oxa zol-5-yl]eth a n -1-on e (67).
Pyruvaldehyde (40% solution, 3.17 mL, 20.7 mmol), isonitrile
2 (5 g, 17.3 mmol), and K2CO3 (2.75 g, 19.9 mmol) were
combined in 35 mL of DMF. After 5 h, the solution was diluted
with water and extracted with TBME (three times). The
combined organic layers were washed with water (three times)
and concentrated in vacuo. The residue was crystallized from
EtOAc/hexane as a beige crystal (2.48 g, 70%): mp 59-61 °C;
1
mp ) 118-122 °C; IR (KBr) 3072, 1627, 1585, 1506 cm-1; H
1
IR (KBr) 1680 cm-1; H NMR (300 MHz, CDCl3) δ 8.28 (2H,
NMR (300 MHz, CDCl3) δ 7.76 (1H, s), 7.70-7.25 (10H, m),
7.15 (2H, d, J ) 8.5 Hz), 7.08 (1H, s), 6.91 (1H, s), 4.20 (2H, t,
J ) 7.2 Hz), 4.01 (2H, t, J ) 6.9 Hz), 2.34 (2H, m); 13C NMR
(75 MHz, CDCl3) δ 187.0, 149.5, 141.1, 137.0, 136.4, 132.8,
132.7, 131.4, 131.0, 130.6, 129.8, 128.9, 127.9, 127.6, 126.6,
126.4, 126.2, 125.76, 118.6, 44.2, 44.1, 32.4; HRMS calcd for
m), 7.95 (1H, s), 7.13 (2H, t, J ) 8.8 Hz), 2.58 (3H, s); 13C NMR
(75 MHz, CDCl3) δ 187.2, 163.8 (d, J ) 208 Hz), 150.8, 143.7,
143.5, 131.4 (d, J ) 9.3 Hz), 126.1, 115.3 (d, J ) 21.4 Hz),
28.3. Anal. Calcd for C11H8NO2F: C, 64.4; H, 3.9; N, 6.8. Found
C, 64.2; H, 3.9; N, 6.5.
C
26H21N4OBr 484.0899, found 484.0901.
(2S)-2-[4-(4-F lu or op h en yl)-5-(5-m eth yl(2-fu r yl))im id a -
Ack n ow led gm en t. The authors would like to thank
the Analytical Sciences and Physical and Structural
Chemistry Departments at SmithKline Beecham, in-
cluding Ms. Priscilla Offen and Mr. Gary Zuber for
obtaining IR spectra, Mr. Lewis Kilmer for obtaining
mass spectra, and Dr. Alan Freyer for obtaining and
interpreting NMR spectra. In addition, we thank Smith-
Kline Beecham for financial support for A.J .K.
zolyl]p r op a n oic Acid (32). A solution of 5-methylfurfural
(1.71 g, 15.6 mmol), L-alanine (1.39 g, 15.6 mmol), and NaOH
(0.62 g, 15.6 mmol) in MeOH (15 mL) and water (2 mL) was
stirred at ambient temperature for 1.5 h prior to the addition
of isonitrile 2 (3 g, 10.4 mmol) and piperazine (1.34 g, 15.6
mmol). The solution was stirred an additional 18 h and
concentrated under vacuum. The brown syrup was dissolved
in water and EtOAc. The solution was adjusted to pH 3.0-
3.5 with 3 N HCl and transferred to a separatory funnel, and
the organic layer was separated. The aqueous layer was
extracted a second time with EtOAc, and the organic layers
were combined and concentrated to 25-30 mL. After standing
for 1 h, the crystallized product was filtered and rinsed with
EtOAc. The product was dried under vacuum to give 2.2 g
(67%) of an off-white solid: mp ) 171-172 °C; IR (KBr) 3432,
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of compounds 2b-g,i, 8, 9, 15, 31, 33, 34, 37, 62, 65,
and 68, and experimental details and characterization of the
isolated products which were not described in the Experimen-
tal Section. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
1728 cm-1; H NMR (300 MHz, DMSO-d6) δ 12.1 (1H, br s),
8.02 (1H, s), 7.50 (2H, m), 7.13 (2H, t, J ) 8.8 Hz), 6.48 (1H,
J O991782L