Carbene reactivity of 4-diazo-4H-imidazoles toward nucleophiles and aromatic compounds

Article abstract of DOI:10.1021/jo902165w

(Chemical Equation Presented) Carbenes derived from diazoimidazolecarboxylates 4 under thermal or photochemical conditions undergo O-H and N-H insertion reactions with alcohols and amines, respectively, in moderate yield, in competition with reduction in good H-donor solvents. Dichloromethane reacts to give the corresponding 4-chloroimidazole. Aromatic hydrocarbons are excellent traps for the imidazolylidene carbene and lead to a range of arylimidazole derivatives 7. Reaction with pyridine leads to the first example of a pyridinium ylide 8 formed from an imidazolylidene carbene, whereas irradiation in hexafluorobenzene gives the imidazoazocine 11, presumably by way of an initial norcaradiene intermediate.

Full text of DOI:10.1021/jo902165w

pubs.acs.org/joc
Carbene Reactivity of 4-Diazo-4H-imidazoles toward Nucleophiles and
Aromatic Compounds
Matthew R. Smith,† Alexander J. Blake,† Christopher J. Hayes,† Malcolm F. G. Stevens,‡
and Christopher J. Moody*,†
†School of Chemistry and ‡School of Pharmacy, University of Nottingham, University Park, Nottingham
NG7 2RD, U.K.
c.j.moody@nottingham.ac.uk
Received October 8, 2009
Carbenes derived from diazoimidazolecarboxylates 4 under thermal or photochemical conditions
undergo O-H and N-H insertion reactions with alcohols and amines, respectively, in moderate
yield, in competition with reduction in good H-donor solvents. Dichloromethane reacts to give the
corresponding 4-chloroimidazole. Aromatic hydrocarbons are excellent traps for the imidazolyli-
dene carbene and lead to a range of arylimidazole derivatives 7. Reaction with pyridine leads to the
first example of a pyridinium ylide 8 formed from an imidazolylidene carbene, whereas irradiation in
hexafluorobenzene gives the imidazoazocine 11, presumably by way of an initial norcaradiene
intermediate.
Introduction
the dominant chemistry of 1 is its facile isomerization with
cyclization into the imidazotriazinone 3 (azahypoxanthine).
Given the importance of the diazoimidazole 1 as a pre-
cursor to temozolomide, surprisingly little work has been
done on this class of compound. The main study was carried
out by Shechter and co-workers and described in two com-
munications published in 1978 and 1986.5,6 In these papers,
the researchers showed that 1, the parent compound
4-diazoimidazole itself, and the 2,5-diphenyl derivative
served as carbene precursors upon heating or irradiation
and that the resulting electrophilic imidazolylidenes under-
went insertion into the C-H bonds of alcohols and addition
to aromatic rings. The absence of kinetic isotope effects in
the addition to C6H6/C6D6 mixtures and the failure to
observe ESR spectra when 4-diazoimidazole was irradiated
at 78 K in a range of solvent matrices suggested that
imidazolylidene carbene had a singlet ground state. This is
notwithstanding the fact that other studies had suggested
Diazo-azoles are heterocyclic analogues of diazocyclopen-
tadiene1 and are potential precursors to azolylidene carbenes,
analogues of cyclopentadienylidene, a much investigated
reactive intermediate.2 Of the diazo-azoles, 4-diazoimidazoles
are the best known, with 4-diazoimidazole-5-carboxamide 1
(Figure 1) the most widely studied. Azole 1 also serves as a
precursor to two antitumor agents: reaction with dimethyla-
mine gives 5-(3,3-dimethyl-1-triazenyl)imidazole-4-carboxa-
mide (DIC, DCTIC),3,4 and reaction with methyl isocyanate
givestheimidazotetrazine2, the marketeddrug temozolomide
(www.temodar.com) used against aggressive brain tumors
and now with sales of over $1 billion/year. Interestingly
temozolomide is a prodrug for 5-(3-methyl-1-triazenyl)-
imidazole-4-carboxamide (MTIC). Aside from the above,
(1) Tisler, M.; Stanovnik, B. Heterocycles 1976, 4, 1115.
(2) Olson, D. R.; Platz, M. S. J. Phys. Org. Chem. 1996, 9, 759.
(3) Audette, R. C. S.; Connors, T. A.; Mandel, H. G.; Merai, K.; Ross,
W. C. J. Biochem. Pharmacol. 1973, 22, 1855.
(5) Kang, U. G.; Shechter, H. J. Am. Chem. Soc. 1978, 100, 651.
(6) Amick, T. J.; Shechter, H. Tetrahedron Lett. 1986, 27, 901.
(4) Falkson, C. I. Anti-Cancer Drugs 1995, 6, 709.
9372 J. Org. Chem. 2009, 74, 9372–9380
Published on Web 11/18/2009
DOI: 10.1021/jo902165w
r
2009 American Chemical Society

Smith et al.
JOCArticle
TABLE 1. X-H Insertion Reactions of Ethyl 4-Diazoimidazole-5-car-
boxylates
diazo
R0XH
R
R0X
MeO
t-BuO
5
yield (%)
6
yield (%)
38
4a
4a
4b
4b
4b
4b
4b
4b
MeOH
t-BuOH
MeOH
i-PrOH
t-BuOH
4-MeOC6H4SH
pyrrolidine
morpholine
H
H
5a
5b
5c
5d
5e
9
6
61
29
65
6a
Ph MeO
Ph i-PrO
Ph t-BuO
6b
6b
49
100
FIGURE 1. Structures of 4-diazoimidazole-5-carboxamide 1,
temozolomide 2, and azahypoxanthine 3.
Ph pyrrolidino 5f
Ph morpholino 5g
50
31
that the carbene derived from 1 behaved as a triplet,7 Much
later, Maier and co-workers, with the benefit of more
sophisticated experimental techniques, concluded that imi-
dazolylidene was in fact a triplet ground state.8
We now report the details of an investigation into the
synthetic utility of diazoimidazoles that sheds further light
on the nature of the carbene intermediate produced upon
heating or irradiation.
5e (65%) was observed. Again, we observed no products of
insertion into the alcohol C-H bonds, as reported for both
4-diazoimidazole-5-carboxamide 1 and 4-diazo-2,5-diphe-
nylimidazole.5 Hydrogen abstraction was the major process
observed under thermal conditions. For example, heating 4b
in cyclohexanol gave a quantitative yield of 6b. Thiols were
also very effective H-donors; irradiation of 4b in the presence
of 4-methoxybenzenethiol gave hydrogen abstraction pro-
duct 6b (100%). On the other hand, use of amines did lead to
carbene N-H insertion products. Thus irradiation of 4b in
the presence of pyrrolidine or morpholine gave the corre-
sponding N-H insertion products 5f and 5g in 50% and
31% yield, respectively (Table 1).
Results and Discussion
To avoid the problems associated with the facile isomer-
ization and cyclization of 4-diazo-5-carboxamides, we used
the corresponding carboxylates 4, readily prepared by dia-
zotization of the corresponding 4-amino heterocycles.9 In
view of our longstanding interest in carbene O-H insertion
reactions,10,11 we first investigated the dirhodium(II) tetra-
acetate catalyzed reaction of diazoimidazole 4b with metha-
nol, but in common with related work on diazoimidazole 1,12
this did not lead to the formation of any O-H insertion
products. However, irradiation of 4a in methanol did give
the O-H insertion product, 5-methoxyimidazole-4-carbox-
ylate 5a, albeit in very poor yield (9%) along with the
hydrogen abstraction product 6a (38%). Irradiation in
tert-butanol gave the O-H insertion product 5b (6%) with
no other identifiable products. These results compare with
those of Kang and Shechter using 4-diazoimidazole-5-car-
boxamide 1 in that O-H insertion and hydrogen abstraction
were observed,5 although we did not isolate products of
insertion into the C-H bonds of the alcohols with the
4-diazoimidazole-5-carboxylate precursor. The poor reac-
tivity of the carbene derived from 4a toward O-H insertion
is further demonstrated by irradiation in methanol/dichlor-
omethane, which results in preferential attack on dichloro-
methane (q.v.).
The 2-phenyl derivative 4b behaved similarly upon irra-
diation, with the products being isolated in generally higher
yields (Table 1). Thus irradiation of 4b in methanol gave the
5-methoxyimidazole 5c in 61% yield with no evidence for the
formation of the hydrogen abstraction product 6b. However,
hydrogen abstraction did occur when the reaction was
carried out using isopropanol, a better H-donor solvent:
the O-H insertion product, ether 5d, was formed in 29%
yield, along with the hydrogen abstraction product 6b
(49%). With tert-butanol, only the O-H insertion product
The reactions of carbenes with aromatic compounds is a
well-known process and results in the formation of substi-
tuted benzenes by the isomerization of intermediate bicyclo-
[4.1.0]heptadiene and/or direct C-H insertion processes.13
4-Imidazolyidene itself participates in such reactions,
thought to proceed via the singlet carbene.6 Therefore we
investigated the photochemical reactions of diazoimidazole
4b with a range of aromatic, including heteroaromatic,
substrates, with some surprising results. Irradiation of 4b
in toluene gave a mixture of the ortho- and para-substituted
products 7a (41%) and 7b (35%), in p-xylene the 5-(2,5-
dimethylphenyl)imidazole 7c (85%), and in mesitylene the
corresponding 2,4,6-trimethyl derivative 7d, again in good
yield (89%) (Table 2). The reactions involving toluene,
xylene, and mesitylene could also be conducted thermally
in similar yields. In the reactions with methyl substituted
benzenes, there was no evidence for insertion into C-H of
methyl groups.
(7) Ambroz, H. B.; Golding, B. T.; Kemp, T. J.; Shukla, V. S. J. Chem.
Soc., Chem. Commun. 1982, 414.
(8) Maier, G.; Endres, J. Eur. J. Org. Chem. 2000, 2535.
(9) Andersen, K. E.; Pedersen, E. B. Liebigs Ann. 1986, 1012.
(10) Kirmse, W. In Advances in Carbene Chemistry; Brinker, U., Ed.; JAI
Press: Greenwich, CT, 1994; Vol. 1, p 1.
With chlorobenzene and anisole as substrates, the
results mirrored those reported by Amick and Shechter for
(11) Miller, D. J.; Moody, C. J. Tetrahedron 1995, 51, 10811.
(12) Hannah, D. R.; Stevens, M. F. G. J. Chem. Res., Synop. 2003, 398.
(13) Kirmse, W. Carbene Chemistry, 2nd ed.; Academic Press: New York,
1971; Vol. 1.
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TABLE 2. Photochemical Reactions of Ethyl 4-Diazo-2-phenylimidazole-4-carboxylate with Aromatic Substrates
9374 J. Org. Chem. Vol. 74, No. 24, 2009

Smith et al.
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SCHEME 1
SCHEME 2
SCHEME 3a
aThe first quoted yield refers to the reaction under thermal conditions,
the second to photochemical conditions.
4-diazoimidazole.6 Irradiation of 4b in chlorobenzene gave a
mixture of ortho- and para-substituted products 7e (28%)
and 7f (32%), whereas anisole gave three products, the ortho-
and para-compounds 7g and 7h and the 5-phenoxy com-
pound 7i. The latter product presumably results from attack
of the carbene on the anisole oxygen to give an oxonium ylide
that is subsequently demethylated. Interestingly, Amick
and Shechter reported a similar process for chlorobenzene:
attack on chlorine to give a chloronium ylide, which subse-
quently collapsed to give a 4-chloroimidazole, although we
saw no corresponding products from 4b and chlorobenzene.
When diazoimidazole 4b was irradiated in thiophene, the
5-(2-thienyl)imidazole 7j was formed in high yield. Likewise
3-methylthiophene gave the 5-thienyl derivative 7k in modest
yield. The formation of 2-substituted thiophenes presumably
proceeds by attack of the carbene to give a norcaradiene type
of intermediate, ring opening of which would be expected to
lead a 2-substituted thiophene via the more stable cation.
Irradiation in pyridine gave the 3-substituted pyridine 7l in
poor yield (28%). However, the major product (62%) from
the irradiation of 4b in pyridine was the pyridinium ylide 8,
the structure of which was confirmed by X-ray crystallogra-
phy (see Supporting Information). This represents the first
observation of the formation of a pyridinium ylide from an
imidazolylidene carbene, mirrors the behavior of cyclopen-
tadienylidene,2 and is suggestive of the singlet nature of the
carbene intermediate.
compound 11 by X-ray crystallography (see Support-
ing Information). Presumably this compound arises by for-
mation of the norcaradiene 9 that undergoes ring opening to
10 followed by [1,5]-sigmatropic shift to the product 11
(Scheme 1). Although extremely unusual, a similar process
has been observed in the reaction of 2,5-diphenyl-3-diazo-
pyrrole with benzene that gave 1,3-diphenylcycloocta-
[c]pyrrole in 31% yield.14
The poor reactivity of the carbene derived from 4a toward
O-H insertion has already been referred to and was further
demonstrated by irradiation in methanol/dichloromethane,
which results in formation of ethyl 5-chloroimidazole-4-
carboxylate 12a in 44% yield (Scheme 2). Presumably this
results from initial attack of the carbene on the chlorine of
dichloromethane; similar processes have been observed in
dirhodium(II) catalyzed reactions of diazodicarbonyl com-
pounds in dichloromethane.15,16
Finally, in a reaction similar to that reported for 4-di-
azoimidazole and its 2,5-diphenyl derivative,5,6 heating dia-
zoimidazole 4b in cyclohexane or cycloheptane resulted in
C-H insertion reaction to give the cycloalkylimidazoles 13
(Scheme 3). Similar yields were obtained under photochemical
conditions.
Although many of the reactions described above appear
characteristic of the singlet carbene state, the ground state
nature of imidazolylidenes seems a matter of debate (vide
supra). Therefore in order to determine the effect of the ester
substituent, we undertook a brief computational study of the
carbene derived from the diazoimidazole 4a. Calculations at
the B3LYP level of theory using a 6-311þG** basis set
predict a triplet ground state for the ester substituted imida-
zole carbene. The triplet to singlet gap is calculated to be 9.0
kcal mol-1, which is in accord with the value of 10.7 kcal
mol-1 calculated by Maier and Endres for the triplet to
singlet gap of the parent 4H-imidazol-4-ylidene at the same
level of theory.8
Given the apparent ease of additions of the imidazolyli-
dene carbene derived from 4b to aromatic rings, we at-
tempted to effect an intramolecular version of the reaction.
The diazoimidazole 4c bearing a benzyl ester was irradiated
in acetonitrile, but with no success. However, when the
irradiation was repeated in hexafluorobenzene, a new pro-
duct was formed and confirmed as the unusual 8-5 bicyclic
(14) Nagarajan, M.; Shechter, H. J. Org. Chem. 1984, 49, 62.
(15) Pirrung, M. C.; Zhang, J. C.; Lackey, K.; Sternbach, D. D.; Brown,
F. J. Org. Chem. 1995, 60, 2112.
(16) Schulze, B.; Nikolaev, V. V.; Hennig, L.; Rodina, L. L.; Sieler, J.;
Nikolaev, V. A. Russ. J. Org. Chem. 2004, 40, 740.
J. Org. Chem. Vol. 74, No. 24, 2009 9375

Smith et al.
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Conclusions
(1 mL) was added dropwise, and the mixture was stirred for
30 min. The mixture was extracted with dichloromethane (2 ꢀ
5 mL), and the combined organic fractions were dried (Na2SO4),
and evaporated. The residue was purified chromatography
using a solvent gradient of 2% methanol in dichloromethane
to give the title compound as an orange crystalline solid (160 mg,
60%), mp 92-94 °C; νmax (solid)/cm-1 2154, 1731, 1453, 1371,
1247, 1195, 1123, 1092; δH (400 MHz; CDCl3) 8.23 (2H, dd, J =
8.0, 1.6), 7.51-7.37 (8H, m), 5.48 (2H, s); δC (100 MHz; CDCl3)
158.7 (C), 157.4 (C), 150.8 (C), 132.3 (C), 130.1 (C), 127.6 (CH),
126.5 (CH), 126.4 (CH), 126.37 (CH), 126.2 (CH), 125.2 (CH),
101.1 (C), 65.6 (CH2); m/z (ESI) 305 (MHþ, 100%) 247 (12);
(Found M þ H, 305.1036. C17H12N4O2 þ H requires 305.1039).
Ethyl 5-Methoxyimidazole-4-carboxylate and Ethyl Imida-
zole-4-carboxylate 5a. Ethyl 5-diazoimidazole-4-carboxyate
(100 mg, 0.64 mmol) was dissolved in dry methanol (10 mL)
and irradiated under nitrogen for 1 h. Chromatography with a
solvent gradient of 3% methanol in dichloromethane gave
(i) ethyl 5-methoxyimidazole-4-carboxylate (10 mg, 9%), mp
157-159 °C; νmax(solid)/cm-1 1712, 1335, 1174, 1021, 763; δH
(400 MHz; CDCl3) 10.15 (1H, bs), 7.39 (1H, s), 4.37 (2H, q, J =
7.2), 4.09(3H, s), 1.38(3H, t, J=7.2);δC (100MHz;CDCl3) 160.5
(C), 158.9 (C), 133.0 (CH), 102.3 (C), 62.3 (CH2), 56.5 (Me), 14.5
(Me); m/z (ESI) 193 (MNaþ, 100%), 171 (MHþ, 28); (Found
M þ Na, 193.0589. C7H10N2O3 þ Na requires 193.0589); and
(ii) ethyl imidazole-4-carboxylate 6a (30 mg, 38%), mp 158-
160 °C (lit.,19 mp 156-158 °C); νmax (solid)/cm-1 1713, 1335,
1174, 1021, 859 763; δH (400 MHz; CDCl3) 12.80 (1H, bs) 7.86
(1H, s) 7.82 (1H, s) 4.37 (2H, q, J = 7.2) 1.36 (3H, t, J = 7.2); δC
(100 MHz; CDCl3) 162.5 (C) 137.0 (CH) 131.0 (C) 126.0 (CH)
60.6 (CH2) 14.4 (Me); m/z (ESI) 163 (MNaþ, 100%); (Found
M þ Na, 163.0478. C6H8N2O2 requires 163.0484).
The work described herein both complements and extends
that reported by Shechter and co-workers some 30 years ago.
Carbenes derived from diazoimidazolecarboxylates partici-
pate in a range of processes: hydrogen abstraction, O-H and
N-H insertion, ylide formation with ethers, chloro com-
pounds and pyridine, and addition to aromatic rings. Apart
from the hydrogen abstraction to give 5-unsubstituted imi-
dazole-4-carboxylates, which only occurs in high yield in the
presence of good H-donors, all of these processes are usually
associated with singlet carbene reactivity. Hence singlet
reactivity appears to dominate notwithstanding the fact that
matrix isolation and computational evidence suggests that
imidazolylidenes possess a triplet ground state. However, a
prevalence of singlet carbene reactivity from ground state
triplet carbenes is quite common and occurs with many
carbenes such as cyclopentadienylidene, the all-carbon ring
analogue of imidazolylidenes.2 Irrespective of mechanism,
many of the reactions proceed in synthetically useful yields
and constitute a useful route to substituted imidazoles.
Experimental Section
Ethyl 5-Diazoimidazole-4-carboxylate 4a. To a solution of
ethyl 5-aminoimidazole-4-carboxylate17 (500 mg, 3.2 mmol)
in hydrochloric acid (1 M; 10 mL) was added sodium nitrite
(290 mg, 4.2 mmol) in water (1.5 mL) dropwise at 0 °C. After the
addition was complete, the mixture was extracted with chloro-
form (10 mL), and the aqueous fraction extracted further with
chloroform (3 ꢀ 10 mL). The organic extracts were combined
and dried (Na2SO4), and the solvent was evaporated to give a
dark orange oily residue. On cooling the product crystallized to
crystals of the same color (388 mg, 73%), mp 46-48 °C (lit.,9 mp
47-52 °C); λmax (ethanol)/nm 205.6 (log ε 5.38), 270.4 (5.03),
320.2 (5.11); νmax (solid)/cm-1 2975, 2860, 2178, 1688, 1501,
1285, 1248, 1232; δH (400 MHz; DMSO-d) 7.70 (1H, s), 4.36
(2H, q, J = 7.2), 1.32 (3H, t, J = 7.2); δC (100 MHz; DMSO-d)
159.9 (C), 150.9 (C), 150.2 (CH), 105.3 (C), 62.0 (CH2) 14.3
(Me); m/z (ESI) 167 (MNaþ, 100%); (Found M þ Na,
167.0571. C6H6N4O2 þ Na requires 167.0569).
Ethyl-5-tert-butoxyimidazole-4-carboxylate 5b. Ethyl-5-dia-
zoimidazole-4-carboxylate (100 mg, 0.64 mmol) was dissolved
in tert-butanol (10 mL) and stirred under nitrogen. The mixture
was irradiated with a 300 W Ultra Vitalux lamp for 1 h. The
solvent was removed under reduced pressure, and the residue
was dissolved in chloroform (20 mL) and extracted with water
(10 mL). The aqueous layer was extracted with chloroform (2 ꢀ
20 mL), and organic extracts were combined, dried (Na2SO4),
and evaporated to dryness to give an orange oily residue. The
product was purified by chromatography using a solvent gra-
dient of 3% methanol in dichloromethane to give the title
product as an orange crystalline solid (8 mg 6%), mp 117-
120 °C; νmax (cm-1) 2970, 2940, 1693, 1558, 1500, 1404, 1379,
1350, 1166, 1095; δH (400 MHz; CDCl3) 7.42 (1H, s), 4.34 (2H,
q, J = 7.2), 1.54 (9H, s), 1.39 (3H, t, J = 7.2); δC (100 MHz;
CDCl3) 160.5 (C), 151.8 (C), 132.9 (CH), 107.6 (C), 82.2 (C),
60.5 (CH2), 28.7 (Me) 14.3 (Me); m/z (ESI) 235 (MNaþ, 100%);
(Found M þ Na, 235.1053. C10H16O3N2 þ Na requires
235.1058).
Ethyl 5-Methoxy-2-phenylimidazole-4-carboxylate 5c. Ethyl
5-diazo-2-phenylimidazole-4-carboxylate (80 mg, 0.34 mmol)
was dissolved in dry methanol (10 mL) under nitrogen. The
mixture was irradiated for 1 h. The product was purified by
chromatography using a solvent gradient of 5% methanol in
dichloromethane to give the title compound as an orange
powder (48 mg, 61%), mp 162-164 °C; νmax (solid)/cm-1
2995, 2890, 1660, 1561, 1452, 1278, 1133, 1114, 777; δH (400
MHz; CDCl3) 11.11 (1H, bs), 8.02 (2H, dd, J = 7.8, 1.6),
7.43-7.40 (3H, m), 4.39 (2H, q, J = 7.2), 4.14 (3H, s), 1.38
(3H, t, J = 7.2); δC (100 MHz; CDCl3) 161.4 (C), 159.9 (C),
144.5 (C), 129.2 (CH), 128.8 (C), 128.7 (CH), 126.1 (CH), 103.3
(C), 60.8 (CH2), 56.5 (Me,) 14.6 (Me); m/z (ESI) 247 (MHþ,
100%), 233 (15), 217 (43); (Found M þ H, 247.1088.
C13H14N2O3 þ H requires 247.1082).
Ethyl 5-Diazo-2-phenylimidazole-4-carboxylate 4b. To a solu-
tion of ethyl 5-amino-2-phenylimidazole-4-carboxylate18 (500 mg,
2.16 mmol) in hydrochloric acid (1 M; 15 mL) was added sodium
nitrite (290 mg, 4.2 mmol) in water (2 mL) dropwise at 0 °C. After
addition was complete the mixture was stirred for a further 30 min.
The product precipitates from the concentrated solution and
was extracted into chloroform. The organic extracts were com-
bined, dried (Na2SO4), and then evaporated to dryness to give the
product as bright yellow crystals (347 mg, 66%), mp 107-109 °C
(lit.,3 mp not given); λmax (ethanol)/nm 203.7 (log ε 5.10), 254.4
(5.16) 362.9 (4.61); νmax (solid)/cm-1 3050, 2900, 2156, 1739, 1454,
1430, 1234, 1190, 1111, 1089, 1018; δH (400 MHz; DMSO-d) 8.13
(2H, dd, J = 6.8 1.6), 7.51-7.44 (3H, m), 4.39 (2H, q, J = 7.2),
1.35 (3H, t, J = 7.2); δC (100 MHz; DMSO-d) 159.9 (C), 158.9
(C), 151.9 (C), 133.3 (C), 130.0 (CH), 129.3 (CH), 127.0 (CH),
106.0 (C), 62.1 (CH2), 14.4 (Me); m/z (ESI) 243 (MNaþ, 100%);
(Found M þ Na, 243.0783. C12H11N4O2 þ Na requires 243.0783).
Benzyl 5-Diazo-2-phenylimidazole-4-carboxylate 4c. Benzyl
5-amino-2-phenylimidazole-4-carboxylate, prepared in similar
manner as the above ethyl ester,18 (254 mg, 0.87 mmol) was
suspended in hydrochloric acid (2 M; 5 mL), and the mixture
was stirred at 0 °C. Sodium nitrite (119 mg, 1.73 mmol) in water
(17) Brown, T.; Shaw, G.; Durant, G. J. J. Chem. Soc., Perkin Trans. 1
1980, 2310.
(18) Soh, C. H.; Chui, W. K.; Lam, Y. L. J. Comb. Chem. 2006, 8, 464.
(19) Gupta, P.; Hameed, S.; Jain, R. Eur. J. Med. Chem. 2004, 39, 805.
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Ethyl 5-Isopropoxy-2-phenylimidazole-4-carboxylate 5d. Ethyl
5-diazo-2-phenylimidazole-4-carboxylate (100 mg, 0.41 mmol)
was dissolved in isopropyl alcohol (10 mL), and the mixture was
irradiated for 1 h. The excess solvent was removed under reduced
pressure, and the crude residue was purified by chromatography
using a solvent gradient of 2% methanol in dichloromethane
to give (i) ethyl 5-isopropoxy-2-phenylimidazole-4-carboxylate
(31 mg, 29%), mp 115-118 °C; νmax (solid)/cm-1 3278, 2953,
1668, 1554, 1497, 1452, 1294, 1134, 1113, 774; δH (400 MHz;
CDCl3) 8.00 (2H, dd, J = 7.9, 1.6), 7.46-7.41 (3H, m), 5.26 (1H,
hept, J = 6.2), 4.38 (2H, q, J = 7.2), 1.45 (6H, d, J = 6.2), 1.40
(3H, t, J = 7.2); δC (100 MHz; CDCl3) 161.4 (C), 159.2 (C),
144.5 (C), 129.5 (CH), 129.3 (C), 128.7 (CH), 126.0 (CH), 104.4
(C), 72.6 (CH), 60.5 (CH2), 22.3 (Me), 14.4 (Me); m/z (ESI)
273 (M - H, 100%), 215 (10); (Found M - H, 273.1234.
C15H17N2O3 requires 273.1239); and (ii) ethyl 2-phenylimidazole-
4-carboxylate 6b (43 mg, 49%), mp 170-172 °C (lit.,20 mp
174 °C); νmax (solid)/cm-1 1718, 1317, 1179, 1027; δH (400
MHz; CDCl3) 8.03 (2H, dd, J = 7.2, 1.4), 7.93 (1H, s),
7.50-7.41 (3H, m), 4.27 (2H, q, J = 7.1), 1.30 (3H, t, J = 7.1);
δC (100 MHz; CDCl3) 161.4 (C), 148.4 (C), 131.7 (C), 130.4 (CH),
129.5 (C), 128.9 (CH), 127.3 (CH), 126.5 (CH), 61.0 (CH2), 14.2
(Me); m/z (ESI) 217 (MHþ, 100%) 203 (14); (Found M þ H,
217.0974. C12H12N2O2 þ H requires 217.0977).
J = 7.2); δC (100 MHz; CDCl3) 161.4 (C), 147.0 (C), 138.1 (C),
129.3 (CH), 128.9 (CH), 127.6 (C), 126.2 (CH), 112.4 (C), 60.6
(CH2), 51.1 (CH2), 23.9 (CH2), 14.4 (Me); m/z (ESI) 285 (Mþ,
18%) 284 (M - H, 100); (Found M - H, 284.1400. C16H18N3O2
requires 284.1399).
Ethyl 5-(Morpholin-4-yl)-2-phenylimidazole-4-carboxylate 5g.
Ethyl 5-diazo-2-phenylimidazole-4-carboxylate (100 mg, 0.41
mmol) was dissolved in morpholine (10 mL) and stirred. The
mixture was irradiated for 1 h. Excess morpholine was removed
under reduced pressure, and the residue washed with water (3 ꢀ
5 mL). The residue was purified by chromatography using a
solvent gradient of 2% methanol in dichloromethane with 0.2%
triethylaminetogive the title compoundas brown crystals(38mg,
31%), mp 96-99 °C; νmax (solid)/cm-1 2922, 2906, 1691, 1419,
1293, 1262, 1177, 1091, 1015; δH (400 MHz; CDCl3) 8.00 (2H, dd,
J = 7.5, 1.9), 7.43-7.40 (3H, m), 4.40 (2H, q, J = 7.1), 3.91 (4H,
bs), 3.84 (4H, bs), 1.39 (3H, t, J = 7.1); δC (100 MHz; CDCl3)
161.1 (C), 153.4 (C), 147.2 (C), 129.8 (C), 129.0 (CH), 128.7 (CH),
126.3 (CH), 113.9 (C), 66.4 (CH2), 60.9 (CH2), 43.5 (CH2), 14.4
(Me); m/z (ESI) 301 (Mþ, 18%), 300 (M - H, 100); (Found
M - H, 300.1340. C16H18N3O3 requires 300.1348).
Ethyl 2-Phenyl-5-(2-tolyl)imidazole-4-carboylate 7a and Ethyl
2-Phenyl-5-(4-tolyl)imidazole-4-carboxylate 7b. Ethyl 2-phenyl-
5-diazoimidazole-4-carboxylate (100 mg, 0.41 mmol) was dis-
solved in toluene (10 mL) and stirred. The mixture was irra-
diated for 1 h. Excess solvent was removed under reduced
pressure, and the residue was purified by chromatography,
using a solvent gradient of 2% methanol in dichloromethane,
to give (i) ethyl 2-phenyl-5-(4-tolyl)imidazole-4-carboxylate 7b
(44 mg, 35%) as a colorless solid, mp 195-198 °C; νmax (solid)/
cm-1 1709, 1484, 1316, 1235, 1129, 1032; δH (400 MHz; CDCl3)
7.97 (2H, dd, J = 7.9, 1.6), 7.79 (2H, d, J = 7.9), 7.46-7.44 (3H,
m), 7.23 (2H, d, J = 7.9), 4.35 (2H, q, J = 7.1), 2.40 (3H, s), 1.33
(3H, t, J = 7.1); δC (100 MHz; CDCl3) 161.2 (C), 147.3 (C),
138.6 (C), 130.0 (C), 129.8 (CH), 129.3 (CH), 128.9 (CH), 128.6
(CH), 127.7 (C), 126.6 (C), 126.1 (CH), 103.7 (C), 61.0 (CH2),
21.4 (Me), 14.3 (Me); m/z (ESI) 305 (M - H, 100%); (Found M
- H, 305.1290. C19H17N2O2 requires 305.1290); and (ii) ethyl 2-
phenyl-5-(2-tolyl)imidazole-4-carboxylate 7a (51 mg, 41%) as a
colorless solid, mp 85-87 °C; νmax (solid)/cm-1 1712, 1484,
1322, 1225, 1139, 1110, 1025; δH (400 MHz; CDCl3) 7.94 (2H,
dd, J = 7.1, 1.6), 7.36-7.34 (3H, m), 7.19-7.03 (4H, m), 4.10
(2H q, J = 7.1), 2.12 (3H, s), 1.04 (3H, t, J = 7.1); δC (100 MHz;
CDCl3), 162.2 (C), 147.4 (C), 137.4 (C), 130.0 (CH), 129.6 (CH),
129.4 (CH), 129.2 (C), 128.7 (CH), 128.6 (CH), 128.5 (C), 128.3
(C), 126.1 (CH), 124.9 (CH), 102.5 (C), 60.5 (CH2), 19.8 (Me),
13.9 (Me); m/z (ESI) 305 (M - H, 100%); (Found M - H,
305.1284. C19H17N2O2 requires 305.1290).
Ethyl 5-tert-Butoxy-2-phenylimidazole-4-carboxylate 5e. Ethyl
5-diazo-2-phenylimidazole-4-carboxylate (59 mg, 0.24 mmol)
was dissolved in tert-butanol (10 mL) and stirred under nitrogen.
The mixture was irradiated for 1 h. The product was purified by
chromatography using a solvent gradient of 5% methanol in
dichloromethane to give the title compound as a dark orange
crystalline solid (38 mg, 65%), mp 82-85 °C; νmax (solid)/cm-1
3275, 2953, 1671, 1438, 1296, 1274, 1172, 1129, 1106, 779; δH (400
MHz;CDCl3) 8.00 (2H, dd, J = 7.9, 1.9), 7.42-7.39 (3H, m), 4.36
(2H, q, J = 7.2), 1.61 (9H, s), 1.40 (3H, t, J = 7.2); δC (100 MHz;
CDCl3) 161.6 (C), 157.9 (C), 144.3 (C), 129.5 (C), 128.8 (CH),
128.7 (CH), 125.92 (CH), 107.7 (C), 81.9 (C), 60.9 (CH2), 28.8
(Me), 14.4 (Me); m/z (ESI) 289 (MHþ, 100%), 271 (17), 233 (14);
(Found M þ H, 289.1569. C16H20N2O3 þ H requires 289.1570).
Ethyl 2-Phenylimidazole-4-carboxylate 6b. Ethyl 2-phenyl-5-
diazoimidazole-4-carboxylate (100 mg, 0.41 mmol) was dis-
solved in 4-methoxybenzenethiol (10 mL) and irradiated for
1 h. Excess 4-methoxybenenethiol was then removed under
reduced pressure to give a dark yellow oily residue. The products
were separated by chromatography using a solvent gradient of
2% methanol in dichloromethane to give the title compound as
a colorless crystalline solid (93 mg, 100%), data as above.
Ethyl 2-Phenylimidazole-4-carboxylate 6b. Ethyl 5-diazo-2-
phenylimidazole-4-carboxylate (50 mg, 0.2 mmol) dissolved in
cyclohexanol (5 mL) and heated at reflux for 5 h. Excess
cyclohexanol was then removed under reduced pressure, and
the residue was purified by chromatography using a solvent
gradient of 2% methanol in dichloromethane to give the title
compound as a colorless crystalline solid (43 mg, 100%), data as
above.
Ethyl 2-Phenyl-5-(pyrrolidin-1-yl)imidazole-4-carboxylate 5f.
Ethyl 2-phenyl-5-diazoimidazole-4-carboxylate (100 mg, 0.41
mmol) was dissolved in pyrrolidine (10 mL) and irradiated for
1 h. The excess pyrrolidine was removed under reduced pressure
to give the crude product as a dark brown oily residue. The
product was purified using chromatography with a solvent
gradient of 5% methanol in dichloromethane to give the title
compound as a brown crystalline solid (59 mg, 50%), mp
151-153 °C; νmax (solid)/cm-1 3235, 2985, 1656, 1439, 1403,
1334, 1332, 1296, 1278, 1101, 784; δH (400 MHz; CDCl3) 8.04
(2H, dd, J = 7.3, 1.9), 7.33-7.31 (3H, m), 4.34 (2H, q, J = 7.2),
3.79 (2H, bs), 3.69 (2H, bs), 2.0-1.91 (4H, br m), 1.32 (3H, t,
Ethyl 2-Phenyl-5-(2-tolyl)imidazole-4-carboxylate 7a and Ethyl
2-Phenyl-5-(4-tolyl)imidazole-4-carboxylate 7b. Ethyl 5-diazo-2-
phenylimidazole-4-carboxylate (30 mg, 0.12 mmol) was dissolved
in toluene (3 mL) and heated at reflux overnight. Excess toluene
wasremovedunderreducedpressure, andthe residue was purified
by chromatography using a solvent gradient of 2% methanol in
dichloromethane to give (i) ethyl 2-phenyl-5-p-tolylimidazole-4-
carboxylate 7b (19 mg, 28%), data as above, and (ii) ethyl
2-phenyl-5-o-tolylimidazole-4-carboxylate 7a (21 mg, 31%), data
as above.
Ethyl 5-(2,5-Dimethylphenyl)-2-phenylimidazole-4-carboxy-
late 7c. Ethyl 5-diazo-2-phenylimidazole-4-carboxylate (100
mg, 0.41 mmol) was dissolved in anhydrous p-xylene (10 mL)
and stirred. The mixture was then irradiated for 1 h. Excess
xylene was removed under reduced pressure, and the residue was
purified by chromatography with a solvent gradient of 2%
methanol in dichloromethane to give the title compound as a
pale yellow crystalline solid (112 mg, 85%), mp 202-204 °C;
ν
max (solid)/cm-1 2969, 2844,1703, 1485, 1326, 1231, 1190, 1151,
1120, 1036, 976; δH (400 MHz; CDCl3) 7.94 (2H, dd, J = 7.9,
(20) Lawson, A. J. Chem. Soc. 1957, 4225.
J. Org. Chem. Vol. 74, No. 24, 2009 9377

Smith et al.
JOCArticle
1.6), 7.35-7.30 (3H, m), 6.99 (2H, d, J = 6.6), 6.93 (1H, s), 4.09
(2H, q, J = 7.1), 2.16 (3H, s), 2.05 (3H, s), 1.04 (3H, t, J = 7.1);
δC (100 MHz; CDCl3) 162.2 (C), 147.3 (C), 138.1 (C), 135.8 (C),
134.3 (C), 134.2 (C), 130.6 (CH), 129.6 (CH), 129.5 (CH), 129.4
(CH), 129.1 (C), 128.8 (CH), 126.1 (CH), 110.0 (C), 60.5 (CH2),
20.8 (Me), 19.4 (Me), 13.9 (Me); m/z (ESI) 319 (M - H, 100%),
265 (16), 248 (17), 242 (14); (Found M - H, 319.1455.
C20H19N2O2 requires 319.1447).
Ethyl 5-(2,5-Dimethylphenyl)-2-phenylimidazole-4-carboxylate
7c. Ethyl 5-diazo-2-phenylimidazole-4-carboxylate (50 mg,
0.2 mmol) was dissolved in p-xylene (5 mL) and heated to reflux
for 1.5 h. Excess xylene was removed under reduced pressure, and
the residue was purified by chromatography using a solvent
gradient of 2% methanol in dichloromethane to give the title
compound as a colorless crystalline solid (54 mg, 84%), data as
above.
Ethyl 2-Phenyl-5-(2,4,6-trimethylphenyl)imidazole-4-carboxy-
late 7d. Ethyl 5-diazo-2-phenylimidazole-4-carboxylate (100 mg,
0.41 mmol) was dissolved in mesitylene (10 mL) and stirred. The
mixture was then irradiated for 1 h. Excess mesitylene was
removed under reduced pressure, and the residue was purified
by chromatography, using a solvent gradient of 2% methanol in
dichloromethane to give the title compound as a pale yellow
crystalline solid (122 mg, 89%), mp 194-196 °C; νmax (solid)/
cm-1 2969, 2922, 1711, 1482, 1457, 1404, 1323, 1222, 1173, 1121,
1026; δH (400 MHz; CDCl3) 7.96 (2H, dd, J = 7.8, 1.6),
7.33-7.28 (3H, m), 6.73 (2H, s), 3.99 (2H, q, J = 7.1), 2.23
(3H, s), 1.89 (6H, s), 0.97 (3H, t, J = 7.1); δC (100 MHz; CDCl3)
162.6 (C), 147.5 (C), 137.9 (C), 137.2 (C), 129.5 (C), 129.1 (CH),
128.7 (CH), 128.5 (C), 127.7 (CH), 126.5 (C), 126.2 (CH), 60.1
(CH2), 21.2 (Me), 20.0 (Me) 13.9 (Me); m/z (ESI) 333 (M - H,
100%); (Found M - H, 333.1597. C21H21N2O2 requires
333.1603).
Ethyl 2-Phenyl-5-(2,4,6-trimethylphenyl)imidazole-4-carboxy-
late 7d. Ethyl 2-phenyl-5-diazoimidazole-4-carboxylate (50 mg,
0.2 mmol) was dissolved in mesitylene (5 mL) and heated to reflux
for 1.5 h. Excess mesitylene was removed under reduced pressure,
and the residue was purified by chromatography using a solvent
gradient of 2% methanol in dichloromethane to give the title
compound as a colorless crystalline solid (60 mg, 90%), data as
above.
Ethyl 5-(2-Chloro-phenyl)-2-phenylimidazole-4-carboxylate
7e and Ethyl 5-(4-Chlorophenyl)-2-phenylimidazole-4-carboxy-
late 7f. Ethyl 5-diazo-2-phenylimidazole-4-carboxylate (100 mg,
0.41 mmol) was dissolved in chlorobenzene (10 mL) and stirred.
The mixture was then irradiated for 1 h. Excess chlorobenzene
was removed under reduced pressure to give a yellow solid. The
residue was purified by chromatography using a solvent gradi-
ent of 2% methanol in dichloromethane to give (i) ethyl 5-(4-
chlorophenyl)-2-phenylimidazole-4-carboxylate 7f (43 mg,
32%) as a pale yellow crystalline solid, mp 168-170 °C; νmax
(solid)/cm-1 3279, 1666, 1473, 1427, 1295, 1273, 1151, 1111,
1026; δH (400 MHz; CDCl3) 7.99 (2H, dd, J = 6.9, 3.1), 7.82
(2H, d, J = 8.5), 7.44-7.40 (3H, m), 7.36 (2H, d, J = 8.5), 4.32
(2H, q, J = 7.1), 1.29 (3H, t, J = 7.1); δC (100 MHz; CDCl3)
160.1 (C), 147.6 (C), 134.4 (C), 130.8 (CH), 130.3 (C), 129.9
(CH), 128.9 (CH), 128.4 (C), 128.2 (C), 128.0 (CH), 126.2 (CH),
126.1 (C), 61.2 (CH2), 14.2 (Me); m/z (ESI) 327/325 (M - H, 34/
100%), 249 (14); (Found M - H, 325.0748. C18H1335ClN2O2
requires 325.0744); and (ii) ethyl 5-(2-chlorophenyl)-2-phenyl
imidazole-4-carboxylate 7e (38 mg, 28%) as a pale yellow
crystalline solid, mp 88-90 °C; νmax (solid)/cm-1 2970, 1714,
1480, 1321, 1297, 1224, 1142, 1070, 1024; δH (400 MHz; CDCl3)
7.99 (2H, dd, J = 7.1, 3.5), 7.43-7.38 (5H, m), 7.32-7.24 (2H,
m), 4.21 (2H, q, J = 7.1), 1.12 (3H, t, J = 7.1); δC (100 MHz;
CDCl3) 161.4 (C), 148.2 (C), 134.0 (C), 131.8 (CH), 129.7 (CH),
129.5 (C), 129.2 (CH), 129.0 (CH), 128.8 (CH), 128.5 (C), 127.8
(C), 126.3 (CH), 126.2 (CH), 61.0 (CH2), 13.8 (Me); m/z (ESI)
327/325 (M - H, 39/100%), 249 (12); (Found M - H, 325.0755.
C18H1335ClN2O2 requires 325.0744).
Ethyl 5-(2-Methoxyphenyl)-2-phenylimidazole-4-carboxylate
7g, Ethyl 5-(4-Methoxyphenyl)-2-phenylimidazole-4-carboxylate
7h, and Ethyl 5-Phenoxy-2-phenylimidazole-4-carboxylate 7i.
Ethyl 5-diazo-2-phenylimidazole-4-carboxylate (100 mg, 0.41
mmol) was dissolved in anisole (10 mL) and stirred. The mixture
was irradiated with a 300 W Ultra Vitalux lamp for 1 h. Excess
anisole was removed under reduced pressure, and the residue
was purified by chromatography using a solvent gradient of
30% ethyl acetate in light petroleum to give (i) ethyl 5-phenoxy-
2-phenylimidazole-4-carboxylate 7i (15 mg, 12%) as a colorless
solid, mp 180-182 °C; νmax (solid)/cm-1 3204, 2990, 2922, 1648,
1539, 1488, 1446, 1305, 1282, 1238, 1201, 1133, 1111, 1021; δH
(400 MHz; CDCl3) 10.82 (1H, bs), 7.99 (2H, dd, J = 7.0, 2.0),
7.45-7.43 (3H, m), 7.34 (2H, t, J = 7.3), 7.19 (2H, d, J = 7.7),
7.12 (1H, t, J = 7.3), 4.33 (2H, q, J = 7.1), 1.25 (3H, t, J = 7.1);
δC (100 MHz; CDCl3) 160.6 (C), 156.8 (C), 155.6 (C), 145.0 (C),
130.0 (CH), 129.3 (CH), 128.81 (CH), 128.80 (C), 126.0 (CH),
123.2 (CH), 117.7 (CH), 108.1 (C), 61.1 (CH2), 14.2 (Me); m/z
(ESI) 307 (M - H, 100%); (Found M - H, 307.1080.
C18H15N2O3 requires 307.1083); (ii) ethyl 5-(4-methoxyphenyl)-
2-phenylimidazole-4-carboxylate 7h (36 mg, 27%) as a colorless
solid, mp 158-160 °C; νmax (solid)/cm-1 1673, 1496, 1427, 1244,
1191, 1175, 1130, 1026; δH (400 MHz; MeOH-d) 8.10 (2H, d,
J = 6.8), 7.67 (2H, d, J = 8.8), 7.51-7.45 (3H, m), 7.00 (2H, d,
J = 8.8), 4.30 (2H, q, J = 7.1), 3.86 (3H, s), 1.30 (3H, t, J = 7.1);
δC (100 MHz; CDCl3) 160.0 (C), 147.3 (C), 138.1 (C), 130.8
(CH), 129.8 (CH), 129.3 (C), 128.9 (CH), 126.1 (CH), 125.9
(CH), 117.8 (C), 113.3 (CH), 61.0 (CH2), 55.3 (Me), 14.3 (Me);
m/z (ESI) 321 (M - H, 100%); (Found M - H, 321.1247.
C19H17N2O3 requires 321.1239); and (iii) ethyl 5-(2-meth-
oxyphenyl)-2-phenylimidazole-4-carboxylate 7g (49 mg, 37%)
as a colorless solid, mp 122-124 °C; νmax (solid)/cm-1 1704,
1483, 1460, 1252, 1219, 1112, 1025; δH (400 MHz; CDCl3) 7.95
(2H, d, J = 6.1), 7.61 (1H, d, J = 7.2), 7.41-7.34 (4H, m), 7.00
(1H, t, J = 7.5), 6.95 (1H, d, J = 8.2), 4.28 (2H, q, J = 7.1), 3.81
(3H, s), 1.24 (3H, t, J = 7.1); δC (100 MHz; CDCl3) 162.4 (C),
156.7 (C), 146.1 (C), 132.0 (CH), 130.8 (C), 130.4 (CH), 129.5
(CH), 129.0 (C,) 128.8 (CH), 126.1 (CH), 125.9 (CH), 120.5
(CH), 60.6 (CH2) 55.7 (Me), 14.2 (Me); m/z (ESI) 321 (M - H,
100%); (Found M - H, 321.1254. C19H17N2O3 requires
321.1239).
Ethyl 2-Phenyl-5-(thien-2-yl)imidazole-4-carboxylate 7j. Ethyl
5-diazo-2-phenylimiazole-4-carboxylate (100 mg, 0.41 mmol)
was dissolved in thiophene (10 mL) and stirred. The mixture
was then irradiated for 1 h. Excess thiophene was then removed
under reduced pressure, and the residue was purified by chroma-
tography using a solvent gradient of 2% methanol in dichlor-
omethane to give the title compound as a off white solid (120 mg,
98%), mp 132-134 °C; νmax (solid)/cm-1 3296, 1669, 1274, 1447,
1270, 1108, 1025; δH (400 MHz; CDCl3) 10.07 (1H, bs), 8.13 (1H,
d, J = 3.2), 7.98 (2H, d, J = 7.0), 7.51-7.45 (3H, m), 7.42 (1H, d,
J = 5.0), 7.14 (1H, t, J = 4.8), 4.45 (2H, q, J = 7.1), 1.46 (3H, t,
J = 7.1); δC (100 MHz; CDCl3) 160.2 (C), 147.8 (C), 142.3 (C),
136.4 (C), 130.1 (CH), 128.9 (CH), 128.6 (C), 128.3 (CH), 127.5
(CH), 127.0 (CH), 126.2 (CH), 117.1 (C), 61.3 (CH2), 14.5 (Me);
m/z (ESI) 297 (M - H, 100%); (Found M - H, 297.0697.
C16H13N2O2S requires 297.0698).
Ethyl 5-(3-Methylthien-5-yl)-2-phenylimidazole-4-carboxy-
late 7k. Ethyl 5-diazo-2-phenylimidazole-4-carboxylate (100
mg, 0.41 mmol) was dissolved in 3-methylthiophene (10 mL)
and stirred. The mixture was then irradiated with a 300 W Ultra
Vitalux lamp for 1 h. Excess 3-methylthiophene was removed
under reduced pressure to give a dark orange solid. The product
was purified by chromatography using a solvent gradient of 2%
methanol in dichloromethane to give the title compound as a
pale orange solid (61 mg, 48%), mp 152-154 °C; νmax (solid)/cm-1
9378 J. Org. Chem. Vol. 74, No. 24, 2009

Smith et al.
JOCArticle
3311, 1666, 1447, 1270, 1108, 1025; δH (400 MHz; CDCl3) 10.25
(1H, bs), 7.98 (2H, d, J = 5.8), 7.95 (1H, s), 7.47-7.45 (3H, m),
6.99 (1H, s), 4.45 (2H, q, J = 7.0), 1.45 (3H, t, J = 7.0); δC (100
MHz; CDCl3) 160.2 (C), 147.8 (C), 142.6 (C), 138.0 (C), 135.9
(C), 130.6 (CH), 130.0 (CH), 128.9 (CH), 128.6 (C) 126.2 (CH),
122.6 (CH), 116.9 (C), 61.3 (CH2), 15.6 (Me), 14.4 (Me); m/z
(ESI) 312 (Mþ, 20%) 311 (M - H, 100); (Found M - H,
311.0858. C17H15N2O2S requires 311.0854).
(400 MHz; CDCl3) 7.75 (1H, s), 4.41 (2H, q, J = 7.2), 1.42
(3H, t, J = 7.2); δC (100 MHz; CDCl3) 159.4 (C), 136.0 (CH),
134.8 (C), 117.0 (C), 61.5 (CH2), 14.3 (Me); m/z (ESI) 175
(MHþ, 34%), 173 (M - H, 100); (Found M - H, 173.0125.
C6H635ClN2O2 requires 173.0118).
Ethyl 5-Chloro-2-phenylimidazole-4-carboxylate 12b. Ethyl
5-diazo-2-phenylimidazole-4-carboxylate (100 mg, 0.41 mmol)
was dissolved in dry dichloromethane (10 mL) and stirred.
Methanol (25 μL) was added, and the mixture was irradiated
for 1 h. The solvent was removed under reduced pressure to give
dark yellow residue. The crude residue was purified by chroma-
tography using as solvent gradient of 2% methanol in dichlor-
omethane to give the title compound (45 mg, 44%), mp 162-
165 °C; νmax (solid)/cm-1 3275, 1671, 1516, 1466, 1413, 1389,
1296, 1267, 1210, 1038; δH (360 MHz; CDCl3) 8.00 (2H, dd, J =
6.6, 2.9), 7.49-7.47 (3H, m), 4.43 (2H, q, J = 7.2), 1.44 (3H, t,
J = 7.2); δC (90 MHz; CDCl3) 160.1 (C), 147.6 (C), 130.4 (CH),
129.1 (C), 129.0 (CH), 128.1 (C), 126.1 (CH), 118.2 (C), 61.7
(CH2), 14.3 (Me); m/z (ESI) 251 (MHþ, 31%) 249 (M - H, 100);
(Found M - H, 249.0422. C12H1035ClN2O2 requires 249.0431).
Ethyl 5-Cyclohexyl-2-phenylimidazole-4-carboxylate 13a. (a)
Ethyl 5-diazo 2-phenylimidazole-4-carboxylate (50 mg,
0.2 mmol) was dissolved in cyclohexane (5 mL) and heated at
reflux overnight. Excess cyclohexane was removed under reduced
pressure, and the residue was purified by chromatography using a
solvent gradient of 2% methanol in dichloromethane to give the
residual starting material (28 mg, 56%) and the title compound as
a colorless crystalline solid (22 mg, 37%), mp 188-190 °C; νmax
(solid)/cm-1 2925, 1706, 1485, 1327, 1201, 1087; δH (400 MHz;
CDCl3) 7.93 (2H, dd, J = 7.7, 1.6), 7.42-7.39 (3H, m), 4.37 (2H,
q, J = 7.1), 3.40 (1H, br m), 1.94-1.85 (4H, m), 1.77-1.68 (3H,
m), 1.48-1.31 (3H, m), 1.38 (3H, t, J = 7.1); δC (100 MHz;
CDCl3) 161.7 (C), 146.4 (C), 138.1 (C), 129.8 (CH), 128.8 (CH),
128.5 (C), 128.1 (C), 126.2 (CH), 60.7 (CH2), 36.2 (CH), 32.1
(CH2), 26.5 (CH2), 25.9 (CH2), 14.3 (Me); m/z (ESI) 297 (M - H,
100%); (Found M - H, 297.1603. C18H21N2O2 requires
297.1603).
(b) Ethyl 5-diazo-2-phenylimidazole-4-carboxylate (50 mg,
0.21 mmol) was dissolved in cyclohexane (5 mL) and stirred. The
mixture was irradiated with a 300 W Ultra Vitalux lamp for 1 h.
Excess cyclohexane was removed under reduced pressure, and
the residue was purified by chromatography using a solvent
gradient of 2% methanol in dichloromethane to give the title
compound (26 mg, 41%); data as above.
Ethyl 5-Cycloheptyl-2-phenylimidazole-4-carboxylate 13b. (a)
Ethyl 5-diazo-2-phenylimiazole-4-carboxylate (50 mg, 0.2
mmol) was dissolved in cycloheptane (5 mL) and heated at
reflux for 3 h. Excess cycloheptane was then removed under
reduced pressure, and the crude residue was purified by chro-
matography using a solvent gradient of 2% methanol in di-
chloromethane to give the title compound as a colorless
crystalline solid (35 mg, 56%), mp 180-182 °C; νmax (solid)/
cm-1 2923, 1704, 1458, 1326, 1197, 1086; δH (400 MHz; CDCl3)
7.93 (2H, dd, J = 7.9, 1.6), 7.40-7.37 (3H, m), 4.35 (2H, q, J =
7.1), 3.56 (1H, br m), 1.97-1.92 (2H, m), 1.81-1.77 (4H, m),
1.70-1.67 (2H, m), 1.61-1.54 (4H, m), 1.35 (3H, t, J = 7.1); δC
(100 MHz; CDCl3) 162.3 (C), 146.6 (C), 138.1 (C), 129.4 (CH),
129.0 (C), 128.8 (CH), 126.0 (CH), 125.9 (C), 60.5 (CH2), 38.1
(CH), 34.2 (CH2), 27.8 (CH2), 27.2 (CH2), 14.4 (Me); m/z (ESI)
311 (M - H, 100%); (Found M - H, 311.1759. C19H23N2O2
requires 311.1760).
Ethyl 2-Phenyl-5-(pyridin-3-yl)imidazole-4-carboxylate 7l and
1-(4-Ethoxycarbonyl-2-phenylimidazolidin-4-yl)pyridinium inner
Salt 8. Ethyl 5-diazo-2-phenylimidazole-4-carboxylate (100 mg,
0.41 mmol) was dissolved in anhydrous pyridine (10 mL) and
stirred. The mixture was then irradiated 300W Ultra Vitalux
lamp for 1 h. Excess pyridine was removed under reduced
pressure, and the residue was purified by chromatography using
a solvent gradient of 2% methanol in dichloromethane, increas-
ing to 5% methanol to give (i) ethyl 2-phenyl-5-(pyridin-3-
yl)imidazole-4-carboxylate 7l (35 mg, 29%) as a brown crystal-
line solid, mp 130-132 °C; νmax (solid)/cm-1 1710, 1473, 1419,
1302, 1280, 1141, 1110, 1024; δH (400 MHz; CDCl3) 9.13 (1H, s),
8.57 (1H, d, J = 4.8), 8.28 (1H, d, J = 7.8), 8.04 (2H, d, J = 7.6),
7.44-7.40 (3H, m), 7.38-7.34 (1H, m), 4.30 (2H, q, J = 7.1),
1.25 (3H, t, J = 7.1); δC (100 MHz; CDCl3) 160.8 (C), 149.9
(CH), 148.8 (C), 148.7 (C), 137.2 (CH), 129.9 (CH), 129.3 (C),
128.9 (CH), 128.4 (C), 127.8 (C), 126.3 (CH), 122.9 (CH), 61.2
(CH2), 14.1 (Me); m/z (ESI) 293 (Mþ, 23%), 292 (M - H, 100);
(Found M - H, 292.1079. C17H14N3O2 requires 292.1080); and
(ii) 1-(4-ethoxycarbonyl-2-phenylimidazolidin-4-yl)pyridinium
inner salt 8 (73 mg, 62%) as yellow crystalline solid, mp
224-226 °C; νmax (solid)/cm-1 1689, 1659, 1627, 1494, 1470,
1421, 1243, 1230, 1033; δH (400 MHz; CDCl3) 9.44 (2H, d, J =
6.5), 8.26 (1H, dd, J = 6.5, 1.2), 8.21 (2H, d, J = 7.9), 7.89 (2H, t,
J = 6.5), 7.41-7.37 (2H, m), 7.30-7.26 (1H, m), 4.37 (2H, q,
J = 7.1), 1.41 (3H, t, J = 7.1); δC (100 MHz; CDCl3) 164.3 (C),
154.7 (C), 143.6 (CH), 142.9 (CH), 135.0 (C), 128.2 (CH), 127.3
(CH), 126.2 (CH), 125.9 (CH), 122.1 (C), 100.6 (C), 60.6 (CH2),
14.5 (Me); m/z (ESI) 294 (MHþ, 100%); (Found M þ Hþ,
294.1241. C17H15N3O2 þ H requires 294.1243).
Benzyl 5,6,7,8,9,10-Hexafluoro-2-phenylimidazo[1,5-a]azocine-
4-carboxylate 11. Benzyl 5-diazo-2-phenylimidazole-4-carboxy-
late (100 mg, 0.33 mmol) was dissolved in hexafluorobenzene
(10 mL) and stirred. The mixture was irradiated for 1 h. Excess
hexafluorobenzene was removed under reduced pressure, and the
residue was purified by chromatography using a solvent gradient
of 2% methanol in dichloromethane to give the title compound as
a colorless crystalline solid (61 mg, 51%), mp 94-96 °C; νmax
(solid)/cm-1 2927, 1740, 1406, 1340, 1313, 1214, 1179, 1109, 1018,
971, 911; δH (400 MHz; CDCl3) 7.81 (2H, d, J = 7.7), 7.58-7.52
(3H, m), 7.48 (2H, d, J = 6.8), 7.42-7.36 (3H, m), 5.46 (2H, s); δC
(125 MHz; CDCl3) 160.2 (C), 149.6 (C), 139.8 (dt, J = 270.3,
23.6, CF), 138.9 (dt, J = 250.9, 24.0, CF), 137.7 (C), 136.8 (dt,
J = 248.1, 25.4, CF), 135.6 (C), 135.1 (C), 132.0 (dt, J = 260.2,
27.8, CF), 131.5 (CH) 129.3 (CH), 128.6 (CH), 128.5 (CH), 127.7
(CH), 126.9 (C), 67.6 (CH2); δF (376 MHz; CDCl3) -94.11 (s),
-108.97 (d, J = 20.3), -122.97 (dd, J = 38.0, 17.8), -127.17 (dd,
J = 37.4, 17.8), -129.95 (dd, J = 38.0, 20.3), -134.41 (d, J =
37.4); m/z (ESI) 463 (MHþ, 100%); (Found M þ H, 463.0906.
C23H12F6N2O2 requires 463.0881).
Ethyl 5-Chloroimidazole-4-carboxylate 12a. Ethyl 5-diazoi-
midazole-4-carboxylate (73.4 mg, 0.47 mmol) was dissolved in
dichloromethane (10 mL) and stirred. Dry methanol (22.5 mg,
28.5 μL) was added, and the mixture was irradiated for 2 h.
Solvent was removed under reduced pressure to give a pale
brown residue. The residue was purified with chromatography
using a solvent gradient of 3% methanol in dichloromethane to
give the title compound as a pale yellow crystalline solid (32 mg,
44%), mp 183-185 °C (lit.,17 mp 178 °C); νmax(solid)/cm-1
3280, 1710, 1553, 1344, 1222, 1197, 1160, 1050, 836; δH
(b) Ethyl 5-diazo-2-phenylimidazole-4-carboxylate (50 mg,
0.21 mmol) was dissolved in cycloheptane (5 mL) and stirred.
The mixture was irradiated with a 300 W Ultra Vitalux lamp for
1 h. Excess cycloheptane was removed under reduced pressure,
and the residue was purified by chromatography using a solvent
gradient of 2% methanol in dichloromethane to give th etitle
compound (40 mg, 61%); data as above.
J. Org. Chem. Vol. 74, No. 24, 2009 9379

Smith et al.
JOCArticle
Computational Methods. Calculations were performed on the
singlet and triplet carbenes derived from diazoimidazole 4a.
Geometry optimizations were performed at the B3LYP/6-
311þG** level of theory for the singlet carbene and UB3LYP/
6-311þG** for the triplet carbene using Q-Chem. Zero point
vibrational energies were calculated for all structures, and the
absence of imaginary frequencies was used to characterize the
structures as minima on their potential energy surfaces.
Acknowledgment. We thank Marloes Technologies Ltd.
for support of this work.
Supporting Information Available: General experimental
details, calculated coordinates for singlet and triplet carbenes
derived from diazoimidazole 4a, copies of 1Hand13CNMRspectra,
and files in CIF format for compounds 8 and 11. This material is
available free of charge via the Internet at http://pubs.acs.org.
9380 J. Org. Chem. Vol. 74, No. 24, 2009