Facile structural elucidation of imidazoles and oxazoles based on NMR spectroscopy and quantum mechanical calculations

Article abstract of DOI:10.1016/j.tet.2009.12.019

The reaction of 1,2,3-tricarbonyl derivatives with hexamethylenetetramine and ammonium acetate in acetic acid provides an unambiguous approach to the synthesis of imidazoles, whereas the Bredereck reaction of α-haloketones in formamide, yields both imidazoles and oxazoles. Herein we describe a facile methodology for distinguishing between these heterocyclic compounds based on a combination of NMR spectroscopy and quantum mechanical calculations. In the NMR data the oxazole C-2 has a chemical shift of ca. 150 ppm whereas in the imidazoles it is found at ca. 135 ppm, with a ¹J_C-H of ca. 250 Hz for the oxazoles and ca. 210 Hz for the imidazoles. ¹J_C-H values can be easily obtained from a gated-decoupled ¹³C spectrum, and even more trivially, from the separation of the H-2 ¹³C satellites in the ¹H spectra. Additionally, the computed NMR data, obtained from density functional theory, are found to be in good agreement with the experimental data and serve as valuable tools in identifying the products of the Bredereck reaction.

Full text of DOI:10.1016/j.tet.2009.12.019

Tetrahedron 66 (2010) 1465–1471
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Facile structural elucidation of imidazoles and oxazoles based on NMR
spectroscopy and quantum mechanical calculations
,
,
Michal Weitman a, Lena Lerman a, Shmuel Cohen b z, Abraham Nudelman a
*
,
,
a,
*
Dan T. Major a , Hugo E. Gottlieb
*
a Department of Chemistry, Bar-Ilan University, Ramat-Gan 52900, Israel
b Department of Inorganic Chemistry, The Hebrew University, Jerusalem 91904, Israel
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 August 2009
Received in revised form 4 November 2009
Accepted 4 December 2009
Available online 11 December 2009
The reaction of 1,2,3-tricarbonyl derivatives with hexamethylenetetramine and ammonium acetate in
acetic acid provides an unambiguous approach to the synthesis of imidazoles, whereas the Bredereck
reaction of a-haloketones in formamide, yields both imidazoles and oxazoles. Herein we describe a facile
methodology for distinguishing between these heterocyclic compounds based on a combination of NMR
spectroscopy and quantum mechanical calculations. In the NMR data the oxazole C-2 has a chemical shift
1
of ca. 150 ppm whereas in the imidazoles it is found at ca. 135 ppm, with a JC-H of ca. 250 Hz for the
Keywords:
Oxazoles
Imidazoles
Bredereck reaction
Density functional theory calculations
oxazoles and ca. 210 Hz for the imidazoles. 1JC-H values can be easily obtained from a gated-decoupled 13
C
spectrum, and even more trivially, from the separation of the H-2 13C satellites in the 1H spectra.
Additionally, the computed NMR data, obtained from density functional theory, are found to be in good
agreement with the experimental data and serve as valuable tools in identifying the products of the
Bredereck reaction.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
Ar
In the course of studies dealing with inhibitors of the HIV
reverse transcriptase we reported the synthesis of a family of tri-
cyclic derivatives of Formula I, based on a scaffold of two benzene
rings and a five-membered heterocyclic imidazole or thiazole ring.
The initial structures of this scaffold were derived from molecular
modeling studies, which predicted that the most promising
candidates would be compounds having a carboxamido substituent
on the heterocyclic ring.1 Subsequent studies involved modification
of the scaffold by elongation of the distance between the aromatic
rings leading to compounds of Formula II, which by virtue of the
linking methylene group would have a greater degree of rotational
freedom and possible additional receptor-binding interaction
capabilities than compounds of Formula I (Fig. 1).
Ar
NH2
O
NH2
O
N
N
NH
NH
I
II
Figure 1. Tricyclic carboxamido-substituted imidazoles.
carboxamido or carboxylate ester substituents found in the starting
materials. Further structural analysis, described in this manuscript,
of the compounds, which were earlier assigned as possessing
Formula I, revealed that these were oxazoles and not imidazoles.
Moreover Bredereck and co-workers2c reported that under certain
conditions the products of the reaction were oxazoles and not
imidazoles and that the oxazoles could be converted to the corre-
sponding imidazoles when heated in formamide at high tempera-
tures. Herein we describe a facile and unambiguous method for
distinguishing between the imidazoles and oxazoles based on the
1JCH parameter of their respective NMR spectra. The structural
assignments are further supported by theoretical calculations. To
clarify the mechanism of the transformations involved in the
Bredereck reaction we followed one such example in the NMR tube
and were able to identify intermediates.
The early approach to the synthesis of the imidazole moiety was
based on the Bredereck reaction involving treatment of an
a
-haloketone with formamide at elevated temperatures.2a Despite
the fact that imidazoles prepared by this procedure are claimed to
be obtained in 30–70% yields, in our hands the products were
isolated only in 2–7% yields,1 attributed to the presence of the
* Corresponding authors. Tel./fax: þ972 3 5318314.
E-mail address: nudelman@mail.biu.ac.il (A. Nudelman).
z
X-ray crystallographic analysis
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.12.019

1466
M. Weitman et al. / Tetrahedron 66 (2010) 1465–1471
N
O
O
NH
O
Ar
Ar
NH2
VI
Br
H2N
II
O
O
O
CN
CN
or
CN
Ar
Ar
Ar
Br
Br
IV
Figure 2. Retrosynthesis of II.
V
III
2. Results and discussion
Extension of the Bredereck reaction to the synthesis of com-
pounds of Formula II required initial bromination of the corre-
sponding 4-aryl-3-oxobutanenitrile precursors III. An expected
problem in the course of such a bromination was the possibility
that the reaction could take place at either of the methylene groups.
Actually, the bromination proceeded solely at the undesired
benzylic position to give V (Fig. 2), and therefore an alternative
approach for the synthesis of the carboxamido-substituted
imidazoles II was sought.
Table 1
1H and 13C chemical shifts (ppm) and coupling constants (Hz) of carboxamido-
substituted imidazoles
CONH2
5
X
4
1
N
HN
3
2
Compound
X
C-2
C-4
C-5
CONH2
H-2
1JC2-H
The desired products II, were prepared3 from 1,2,3-tricarbonyl
derivatives 4,4,5 hexamethylenetetramine and ammonium acetate
in acetic acid under microwave irradiation conditions6 (Scheme 1).
Although the final cyclization step gave the desired benzyl-
substituted imidazole, the low reaction yields (w10%), preclude this
approach from being of general use for the synthesis of imidazoles.
6a
7a
D
Bn
Ph
133.5
149.9
16
139.6
143.7
4.1
133.7
124.9
9
165.6
159.5
6
7.5
8.3
0.8
210
250
40
a
As shown later, 7 was found to be an oxazole and not an imidazole as assigned
previously.1
OH
NH2
O
HO
O
OH
O
b
c
X
X
CHO
X
X
NH2
O
3a-90%
3b-77%
3c-30%
4a-93%
4c-35%
1a
1b
3a-c
4a-c
B(OH)2
a
d
2
1c
O
O
NH2
X
a H
b Br
c Ph
NH2
X
e
N
HN
OH
5a,c
O
7%
6a, 6c
Scheme 1. Synthesis of carboxamido-substituted imidazoles.
2.1. Structure elucidation based on NMR studies and
theoretical calculations
products, and were confirmed using HMBC spectra (see Supple-
mentary data).
The use of 1JCH values in structure elucidation is well known but,
in our opinion, underutilized, probably because the average
chemist doesn’t bother to extract such parameters from the spectra.
Figure 3 illustrates, for 3-carbomethoxyimidazole (in CD3OD solu-
tion, at 16.4 Tesla), three techniques for the measurement of the
one bond carbon-proton coupling, 1JCH: (a) the observation of 13C
satellites in the 1H spectrum (the unmarked small peaks originate
from impurities, even the low-field ‘B’ peak is superimposed to an
impurity peak); (b) the direct measurement of CH multiplets in
a gated-decoupled 13C spectrum and (c) the measurement of the
Comparison of the products such as compound 7 (a derivative
of Formula I) obtained under the Bredereck reaction conditions, to
those isolated from the 1,2,3-tricarbonyl derivatives, such as
compound 6 (a derivative of Formula II), revealed several dis-
crepancies: (a) The Bredereck products did not form hydrochlo-
ride salts when exposed to aqueous 3 M HCl; (b) they had much
higher Rf elution values on silica gel than the products of the
1,2,3-tricarbonyl derivatives; (c) in the NMR spectra the 13C
chemical shift of the C-2 carbon (found between the heteroatoms)
showed a shift of w15 ppm downfield in the Bredereck products
compared to those of the 1,2,3-tricarbonyl derivatives or other
imidazoles; (d) other changes were also found in the 1H chemical
shift of the proton at position 2 and the 13C chemical shifts of the
carbon at position 5. The major differences are presented in Table
1
doublet splittings in an HMBC (long-range 13Cꢀ H correlation, low
pass J-filter turned off) spectrum. In every case the AA and BB
1
distances correspond to JCH for C-2 and C-4, and their values are
210.7ꢁ0.3 and 193.9ꢁ0.3 Hz, respectively. Of course, each tech-
nique has its advantages: for accuracy of measurement (i.e., digital
resolution), a>b>c; for sensitivity, a>c>b; for robustness (small
amounts of impurities don’t matter) c>b>a.
1
1; and (e) most surprisingly, the JCH coupling constants for C2-H
were found to be between 35 and 45 Hz greater for the Bredereck

M. Weitman et al. / Tetrahedron 66 (2010) 1465–1471
1467
a)
b)
B
B
CO2Me
N
200 Hz
4
2
N
H
B
C-4
ppm
B
B
c)
127.0
126.5
ppm
B
A
A
A
A
130
× 64
135
H-2
H-4
C-2
A
A
140
8.0
7.9
7.8
139.0
138.5
8.1
8.0
7.9
7.8
ppm
ppm
ppm
1
Figure 3. JCH measurement, for 3-carbomethoxyimidazole, using three different NMR techniques (see text). In every case the AA and BB distances correspond to 1JCH for C-2 and
C-4, respectively.
To elucidate the source of these discrepancies various theoret-
Table 2
ical and experimental approaches were undertaken.
Relative tautomerization potential energy, enthalpy, and free energy (kcal/mol) for
compounds 6a and 7, and their optimized structures
2.2. Structure assignment based on theoretical calculations
a
Compounds
Optimized structures
DEp
DH
DG
(a) Exploration of the possibility of the presence of equilibrating
tautomeric forms7 where in one case the imidazole is the H-bond
donor and in the second case it is the H-bond acceptor to the car-
boxamido moiety. In the spectra of our imidazoles the N–CH–NH
proton appeared as a sharp singlet (both in acetone-d6 and in
CDCl3). This fact could be attributed to: (a) either two rapidly
equilibrating tautomeric forms; or (b) to a situation in which only
one of the possible tautomers is significantly populated. To
determine which of these two possibilities prevailed, theoretical
calculations based on DFT/GIAO methods were conducted, which
revealed that the molecules existed in a single non-equilibrating
form for 6a (Scheme 2). For compound 7 the CH proton also
appeared as a sharp singlet, because this compound was found to
be an oxazole rather than an imidazole, as will be shown in the
conclusion of these studies. In the following discussion, it will be
assumed that 7 is an imidazole, as was initially thought.
6a tautomer A
1.6
1.5
2.8
6a tautomer B
0.0
0.0
0.0
H2N
O
O
H
NH
H
X
N
N
N
HN
7 tautomer A
0.0
0.0
0.0
A
B
Scheme 2. Non-equilibrating tautomeric forms carboxamido-substituted imidazoles.
To explore the possibility that compounds 6a and 7 have differ-
ent non-equilibrating tautomeric forms with different NMR spectra,
density functional theory calculations at the mPW1PW91/6-
311þþG(3df,2p) level, were conducted. Structures A and B were
computed to be close in potential energy. For 6a the potential energy
difference is 1.6 kcal/mol in favor of the B tautomer (Table 2). This is
likely due to a more favorable intramolecular H-bond for tautomer B
than for tautomer A. In the A and B tautomers there are possible
7 tautomer B
0.3
0.3
0.1
favorable intramolecular dipole–p interactions between the amide
group and the aromatic phenyl ring. Such dipole–
p interactions
a
D
Ep corresponds to the potential energy from mPW1PW91/6-311þG(3df,2p)//
have recently been studied.8,9 For 7 the A tautomer is favored by
0.3 kcal/mol (Table 2). In the case of the A tautomer of 7, intra-
mPW1PW91/6-31G(d) electronic structure calculation.
by adding zero-point energy and thermal effects as described in the Computational
Methods.
D
H and G were obtained
D
molecular dipole–p interaction between the amide group and the

1468
M. Weitman et al. / Tetrahedron 66 (2010) 1465–1471
aromatic phenyl ring is possible, while in the B tautomer there is
steric hindrance between the imidazole NH moiety and a phenyl
(b) Influence of the degree of conjugation of the heterocyclic ring on
the chemical shift of C-2 and the corresponding coupling constant 1JCH
.
hydrogen and no possible dipole–
p
interaction, shifting the tauto-
As seen in Table 1 there is a major difference in the chemical shifts
and coupling constants of the CH at position 2 in compounds 6a
and 7. Therefore, it was considered possible that the degree of
conjugation in these compounds would have an effect on these
parameters. For this purpose several model imidazoles (8–15),
unsubstituted or substituted with ester or amido groups were
examined by NMR (Table 4). In all cases the 13C chemical shifts of
the C-2 and the JCH coupling constants corresponded to those of
the compounds obtained from the 1,2,3-tricarbonyls and not to the
Bredereck products.
Since approaches (a) and (b) did not provide a convincing ex-
planation for the indicated discrepancies, an X-ray crystallogram
(Fig. 4) of one of the Bredereck products, obtained upon treatment
of methyl 2-bromo-3-(3-iodophenyl)-3-oxopropanoate with
formamide, to which an imidazole (15) had been assigned, was
obtained revealing that the structure of this compound corre-
sponded to that of oxazole 16; moreover, the computed NMR data
of oxazole is similar to that of compound 16. The computed
chemical shifts for oxazole are: H-2 (7.86 ppm), C-2 (154.50 ppm),
C-4 (141.38 ppm), C-5 (131.97 ppm), and the 1JCH coupling constant
is 209.93 Hz.
meric equilibrium in favor of the A tautomer. These potential energy
differences are near the expected error-bar for the theoretical
method employed.10 Inclusion of zero-point energy and thermal
enthalpy effects gives nearly identical results, while adding entropy
effects changes these values only slightly. The free energy difference
between the two tautomers of 6a is slightlygreaterat 2.8 kcal/mol in
favor of tautomer B, while for 7 the difference is a negligible 0.1 kcal/
mol in favor of tautomer A.11 Thus, the computations suggest that for
6a only a single tautomer exists in accord with experimental data,
while for 7 two co-existing tautomers are predicted.
In an attempt to elucidate the differences in chemical shifts
and coupling constants between 6a and 7, the GIAO method was
employed in conjunction with DFT electronic structure calcula-
tions at the mPW1PW91/6-311þG(2d,p) level. The use of com-
puted shielding constants has become an increasingly useful tool
in elucidating NMR spectra.12,13 The chemical shifts of imidazole
were initially computed to serve as benchmarks for the
substituted imidazoles. Inspection of the data in Table 3 suggests
that the computed chemical shifts are in good accord with the
experimental values shown in Table 1. Turning to the computed
NMR data for compounds 6a and 7, it is interesting that the
chemical shifts of the tautomer B of 6a are in better overall
agreement with experiment than those for the tautomer A. This is
clear from the chemical shifts at positions C-2, C-4, C-5, and
CONH2 that support the above predicted tautomerization equi-
librium. In the case of 7, the computed NMR data are similar to
those of 6a, but differ considerably from the experimentally de-
termined values (Table 1). In summary, the computed properties
of compound 6a are in accord with the experimental data.
However, the computations cannot rationalize the existence of
only a single tautomer for 7 or its NMR spectra.
1
Figure 4. ORTEP drawing of 16. The thermal ellipsoids are scaled to enclose 50%
probability.
Table 3
1
Computed 1H and 13C chemical shifts (ppm) and JCH coupling (Hz) for 6a and 7a
Compound
C-2
C-4
C-5
CONH2
H-2
1JC2-H
Bredereck reported that under similar reaction conditions
imidazoles as well as oxazoles could be prepared.2c For instance
when Theilig reacted a-haloketones in the presence of equimolar
amounts of formamide at 130 ꢂC, oxazoles were isolated, whereas
in the presence of an excess formamide at 180 ꢂC the obtained
products were imidazoles. Furthermore, upon heating the oxazoles
in formamide at reflux they underwent conversion into imidazoles.
6a tautomer A
6a tautomer B
6a experimental values
7 tautomer A
7 tautomer B
135.9
133.2
133.5
137.3
133.1
149.9
147.8
138.2
139.6
147.5
137.6
143.7
126.4
134.7
133.7
124.2
136.2
124.9
163.5
166.2
165.6
162.5
165.8
159.5
7.57
7.21
7.50
7.64
7.46
8.3
188.8
190.4
210
189.1
190.4
250
7 experimental values
a
Chemical shifts and coupling constants were obtained by the GIAO method at
the mPW1PW91/6-311þG(2d, p)//mPW1PW91/6-31G(d) level.
Table 4
1
Substituent effects on the 1H and 13C chemical shifts (ppm) and JCH coupling constants (Hz) of imidazoles
Y
C-2
C-4
C-5
CO
H-2
1JC2-H
X
Y
X
N
HN
8
9
H
Ph
H
H
H
135.0
135.9
134.4
122.0
133.9
118.4
d
d
7.6
7.7
7.6
205
f
115.9
118.6
126.4b
121.2c
140.6b
126.0d
139.2e
d
10
11
12
13
14
15a
Me
Me
H
Me
H
d
208
208
210
209
210
234
CONH2
CONH2
COOEt
COOMe
COOMe
135.0b
135.8c
136.5b
137.0d
153.8e
138.2b
134.5c
124.9b
129.6d
144.5e
165.9b
162.8c
163.9b
162.8d
159.4e
7.8b
7.7c
7.6b
7.7d
8.45e
m-I-Ph
a
As shown later, 15 was found to be an oxazole and not an imidazole as assigned here.
b
c
d
e
f
CDCl3–CD3OD.
DMSO-d6.
CD3OD.
Acetone-d6.
Not reported.

M. Weitman et al. / Tetrahedron 66 (2010) 1465–1471
1469
1
Two alternative mechanisms for the conversion were proposed,2b
and using virtually analogous conditions, other reports14–17
describe the synthesis of either oxazoles or imidazoles and one
article16 illustrates the isolation of mixtures of both heterocyclic
compounds.
imidazoles it is found at ca. 135 ppm, with a JC-H of ca. 250 Hz for
the oxazoles and ca. 210 Hz for the imidazoles (1JC-H values can be
easily obtained from a gated-decoupled 13C spectrum, but, even
more trivially, from the separation of the H-2 13C satellites in the 1H
spectra).
In an attempt to clarify the sequence of events in the reaction of
a
-haloketones with formamide, we followed the NMR spectra (1H
and 13C) of a solution of
a-bromoacetophenone in formamide, as
4. Experimental
4.1. General
a function of time and temperature. (a) At room temperature (ca.
30 ꢂC) the peaks of the starting materials could be seen. As soon as
the probe equilibrated at ca. 45 ꢂC the appearance of a new
1H and 13C NMR spectra were obtained on 200, 300 or 600 MHz
spectrometers. Chemical shifts are expressed in parts per million
downfield from Me4Si used as internal standard. For some com-
pounds the NMR data assignment was aided by several two-
dimensional spectra including COSY, HMQC and HMBC analyses.
Mass spectra and HRMS were obtained on CI¼chemical ionization/
CH4 mode. Progress of the reactions was monitored by TLC on silica
gel or alumina plates. Flash chromatography was carried out on
silica gel. The microwave experiments were carried out at a maxi-
mum power of 300 W/frequency 2450 MHz. Commercially avail-
able compounds were used without further purification.
methylene peak at d 6.17 was detected, which was attributed to the
methylene protons of compound 18 (Scheme 3); the presence of
a carbonyl at 194.9 and the CH2O moiety at 67.0 ppm supports the
proposed structure. Within 30 min all the starting material had
disappeared. (b) Since the mixture at ca. 45 ꢂC seemed to have
reached equilibrium, the NMR tube was further heated to ca. 110 ꢂC.
Immediately the formation of oxazole 1918 was noticed, but the
reaction proceeded relatively slowly, and after 30 min, roughly
equal amounts of 18 and 19 were present. (c) Some 15 min later
when the temperature was raised to ca. 140 ꢂC, 18 had completely
disappeared and 19 dominated, but some 25% of a new species-9-
β
β
O
O
NH
O
γ
γ
~140 °C
γ
O
H
~80 °C
~110 °C
Br
α
α
α
α
N
N
β
β
HCONH2
HCONH2
NH2
Br
18
17
19
9
Scheme 3. Synthesis of imidazole 9 via oxazole 19.
was present; and 2 h later, the latter compound had completely
replaced 19. The mechanism for the thermal conversion of an
oxazole to an imidazole in the presence of formamide has been
discussed by Theilig.2b
Although the signals of the ortho hydrogens of the phenyl ring
were primarily monitored, the 13C signals of the heterocycle were
diagnostic in defining each product. (d) The reaction was repeated
in the laboratory under roughly the same conditions as those
described in a–c, and the intermediates were isolated. Their NMR
chemical shifts are presented in Table 5. The assignments for 18 and
19 were confirmed by 2D spectra (COSY, and HMBC).
4.1.1. 5-Amino-4-hydroxy-2-phenylfuran-3(2H)-one, (3a)4,5
(300 MHz, DMSO-d6):
¼5.37 (1H, s, HC–CO), 7.34 (5H, m, H-aro-
matic), 7.8 (2H, br s, NH2). 13C NMR (50.3 MHz, DMSO-d6):
(CH–O), 111.5 (C–OH), 126.35 (C-o), 128.1 (C-p), 128.2 (C-m), 138.2
(C-ipso), 172.5 (CONH2), 182.5 (CO ketone).
.
1H NMR
d
d¼82.6
4.1.2. 5-Amino-2-(3-bromophenyl)-4-hydroxyfuran-3(2H)-one
(3b). Compound 3b was obtained as a white solid in 77% yield from
compound 1b as described:4,5 mp 176–178 ꢂC. The NMR data as-
signment was aided by several two-dimensional spectra including
COSY, HMQC, and HMBC analysis. 1H NMR (600 MHz, DMSO-d6):
While this reaction sequence had been postulated in the
literature2 we believe that we have been the first to directly observe
the intermediates. Based on the NMR data of the compounds syn-
thesized earlier1 by the Bredereck procedure, it is obvious that the
reported products were oxazoles and not imidazoles.
d
¼5.44 (1H, s, HC–CO), 7.27 (1H, s, OH), 7.28 (1H, d, J¼7.8 Hz, H-6),
7.36 (1H, t, J¼7.8 Hz, H-5), 7.43 (1H, s, H-2), 7.54 (1H, d, J¼7.8 Hz,
H-4), 7.82 (2H, br s, NH2). 13C NMR (150.9 MHz, DMSO-d6):
d¼81.9
(CH–O), 111.2 (C-OH), 121.5 (CBr), 125.2 (C-6), 128.6 (C-2), 130.7
(C-5), 130.9 (C-4), 138.9 (C–CH–O), 172.7 (CNH2) 182.0 (CO ketone).
Table 5
13C NMR data for products and intermediates of the reaction shown in Scheme 3
Compd.
1H NMR,
d
(ppm) chemical shifts
13C NMR,
d (ppm) chemical shifts
ortho
meta
para
H-
b
H-
g
ipso
ortho
meta
para
C-
a
C-
b
C-
g
17a
18b
19c
9a
7.95
7.87
7.73
7.72
7.46
7.43
7.38
7.37
7.58
7.56
7.29
7.24
4.45
5.39
7.92
7.35
d
134.1
128.8
128.8
133.8
191.0
31.3
65.30
133.72
114.89
d
8.21
7.91
7.71
139.14
130.62
133.89
127.70
125.51
124.14
128.83
128.72
128.37
134.00
128.12
125.97
191.13
140.25
138.06
160.06
151.32
135.88
a
CDCl3, 300 MHz, data from the Aldrich library of 13C and 1H FT NMR spectra (1993).
Reaction was conducted in formamide. NMR was carried out in CDCl3 600 MHz, 80 ꢂC.
Formamide, 600 MHz, 110 ꢂC.
b
c
3. Conclusions
MS (CIþ) m/z (%) 270.97 (Mþ, 31.6), 268.97 (Mþ, 32.5), 197.96
(MþꢃCO, 66.9), 195.08 (MþꢃCO, 66.8), 170.97 (BrBnþ, 37.2), 168.97
(BrBnþ, 39.6). HRMS calcd for C10H8NO3Br 270.963; found 270.967.
From the above discussion it can be concluded that it is difficult
to predict whether the products of the Bredereck reaction will be
oxazoles or imidazoles. Experimental NMR data provide a facile
method for identification of the products where the C-2 in the
oxazoles has a chemical shift of ca. 150 ppm whereas in the
4.1.3. 5-Amino-2-(biphenyl-3-yl)-4-hydroxyfuran-3(2H)-one
(3c). Compound 3c was obtained in 30% yield from 1c, as de-
scribed:4,5 mp 164–166 ꢂC. 1H NMR (300 MHz, DMSO-d6):
d¼5.47

1470
M. Weitman et al. / Tetrahedron 66 (2010) 1465–1471
(1H, s, HC–CO), 7.40 (1H, m, H-p), 7.48 (3H, m, H-m, H-5), 7.54 (1-H,
s, H-2), 7.64 (3H, m, H-o, H-4), 7.86 (2H, br s NH2). 13C NMR
6.2 (1H, br s, NH), 7.11 (1H, br s, NH), 7.34 (3H, m, H-aromatic), 7.42
(3H, m, H-aromatic), 7.51 (1H, s, CH-imidazole), 7.62 (3H, m, H-
(75.5 MHz, CDCl3):
d
¼82.5 (CH–O), 111.5 (C–OH), 124.8, 125.3, 126.5,
aromatic). 13C NMR (75.5 MHz, acetone-d6):
d¼31.3 (CH2), 125.6,
126.7, 127.6, 129.05, 129.09, (CH-aromatic), 138.0 (C-ipso CH), 139.9,
140.3 (C-ipso biphenyl, C-ipso biphenyl) 172.7 (CONH2), 182.5 (CO
ketone). MS (CIþ) m/z (%) 267.09 (MHþ, 0.63), 250.08 (MHþꢃH2O,
0.42). HRMS calcd for C16H13NO3 267.0900; found 267.092.
127.7, 128.10, 128.16, 128.56, 129.63, 129.77 (CH-aromatic) 134.33,
134.55 (CCONH2, CH-imidazole). At the concentration of the
sample, the quaternary (CCONH2 and CCH2) were not observed.
4.1.10. Methyl 4-(3-iodophenyl)oxazole-5-carboxylate (16). A solu-
tion of methyl 2-bromo-3-(3-iodophenyl)-3-oxopropanoate
(2.61 mmol)informamide(1 mL)towhich0.1 mL of waterwasadded
was heated at 140 ꢂC for 5 h. Na2CO3 1 M and CHCl3 were then added
and the organic phase was separated, dried over MgSO4 and evapo-
rated. The residue was purified by chromatography (hexane/EtOAc
20:1) to provide 16 as a white solid in 2.3% yield. 1H NMR (300 MHz,
4.1.4. 2,2-Dihydroxy-3-oxo-4-phenylbutanamide (4a)4,5
(75.5 MHz, CDCl3):
(C-m), 130.7 (C-o), 135.3 (C-ipso), 172.1 (CONH2), 204.3 (CO ketone).
MS (CIþ) (%) 192.067 (MHþ, 15), 174.06 (MþꢃNH3, 7.5) 147.048 (Mþ-
CONHþ2 , 100), 119.06 (BnCOþ, 16.3). HRMS calcd for C10H10NO3
192.066; found 192.067.
.
13C NMR
d
¼42.7 (CH2), 95.4 (C(OH)2), 127.4 (C-p), 128.9
CDCl3):
8 (1H s,), 7.76 (1H, ddd, J¼8.14; 1.73; 1 Hz), 7.19 (1H, t, J¼8.2 Hz), 3.94
(3H s,). 13C NMR (150.9 MHz, CDCl3/acetone-d6):
d
¼8.46 (1H, t, J¼1.73 Hz), 8.08 (1H, ddd, J¼8.14; 1.73; 1 Hz, H),
4.1.5. 4-(3-Bromophenyl)-2,2-dihydroxy-3-oxobutanamide
(4b)4,5. Compound 4b was obtained as a pale white solid yield from
compound 3b as described and was found to be mixed with
residual unreacted 3b. The diagnostic 1H NMR peak for 3b is the
HC–CO found at 5.72 ppm, whereas that of the product 4b is the
CH2 found at 4.08 ppm.
d¼159.3, 153.8,
144.56, 139.26, 138.65, 138, 133.16, 130.9, 129.32, 94.03, 52.67.
4.2. Computational methods
The structures of compounds 6a (tautomers A and B), 7 (tau-
tomers A and B), 12, and oxazole were optimized with the
mPW1PW91 density functional19 in conjunction with the 6-31G(d)
basis set.20–22 Frequency calculations were performed to analyze
the nature of the stationary points, and local minima were verified.
Thermal corrections were added employing standard statistical
mechanics equations.23 The frequencies were scaled by 0.9547.24
Single-point energies were calculated at the mPW1PW91/6-
311þþG(3df,2p) level.25,26 To obtain tautomerization free energies,
the mPW1PW91/6-311þþG(3df,2p) level energies were combined
with the mPW1PW91/6-31G(d) level zero-point energy and ther-
mal corrections. To verify the reliability of the mPW1PW91 func-
tional, test calculations on compound 12 (tautomers A and B) with
the above functional as well as the B1B9527 and BB1K28 functionals
and second-order perturbation theory calculations (MP2) were
conducted with the 6-31þG(d,p) basis set. All four methods favored
tautomer B by a 1.4–1.6 kcal/mol potential energy difference (see
Supplementary data).
To obtain the computational shielding data, the GIAO method
was employed. In this method, the nuclear shielding is computed as
the second derivative of the energy with respect to the applied
magnetic field and the nuclear moment using field dependent
atomic orbitals.29,30 The mPW1PW91 density functional was
employed as it has been shown to give good accord with experi-
mental spectra.31 The 6-311þG(2d,p) basis set was chosen as it was
found suitable for nuclear shielding calculations.32
4.1.6. 4-(Biphenyl-3-yl)-2,2-dihydroxy-3-oxobutanamide
(4c)4,5. Compound 4c was obtained as a pale yellow solid in 35%
yield from compound 3c as described:4,5 mp 90–92 ꢂC. 1H NMR
(300 MHz, acetone-d6):
(1H, br s, NH), 7.34 (9H, m, H-aromatic, NH). 13C NMR (75.5 MHz,
CD3OD):
d
¼4.11 (2H, s, CH2), 6.15 (1H, br s, OH) 7.2
d
¼41.4 (CH2), 97.3 (C(OH)2), 123.8, 125.4, 125.7, 127.0,
127.12, 127.15, 127.27 (CH-aromatic),133.3 (C-ipso to the methylene),
139.7, 137.9 (C-ipso to the biphenyl), 169.8 (CONH2), 202.1 (CO
ketone). MS (CIþ) m/z (%) 267.09 (MꢃH2O, 7.4), 212.06 (Ph–Bn–
COOH, 40.6). HRMS calcd for C16H13NO3 267.090; found 267.093.
4.1.7. 3-Hydroxy-2-oxo-4-phenylbut-3-enamide (5a)4,5. Compound
5a was obtained as a pale yellow solid, mp 165–167 ꢂC, in 93% yield
upon evaporation of a solution of 4a in acetone. 1H NMR (300 MHz,
acetone-d6):
d
¼7.06 (1H, s, enol), 7.36 (3H, m, H-m, H-p), 7.93 (2H,
m, o). 13C NMR (75.5 MHz, CDCl3):
d
¼118.8 (CH enolic), 128.5 (C-m),
128.8 (C-p), 130.7 (C-o), 134.6 (C-ipso), 146.9 (COH enolic), 165.3
(CONH2), 184.6 (CO ketone).
4.1.8. 4-Benzyl-1H-imidazole-5-carboxamide (6a). A solution of 4a
(0.1 g, 0.34 mmol) hexamethylenetetramine (0.1 g, 0.69 mmol),
NH4OAc (26 mg, 0.34 mmol) in acetic acid (1.5 mL) was heated with
stirring at 165 ꢂC for 5 min under microwave irradiation conditions.
The mixture was poured into a saturated aqueous NH4OH solution
cooled to 0 ꢂC. The brown precipitate formed was filtered and the
filtrate was extracted with EtOAc. The organic phase was dried
(MgSO4), filtered and evaporated to give a brown residual oil, which
was purified by flash chromatography (EtOAc). Compound 6a was
isolated as white needles (crystallized from acetone) in 4% yield
(microwave irradiation) or 7% yield (thermal conditions, 1 h at
165 ꢂC, using the same workup). 1H NMR (600 MHz, acetone-d6):
The quantity computed by the DFT-GIAO calculations is the
shielding of the nuclei by the electrons. The experimentally
observed chemical shift for carbon atoms, dC, is related to the
computed shielding sC by sC¼186.4ꢃdC where the experimentally
determined shielding of tetramethylsilane (TMS) has been
employed.33 The experimentally observed chemical shift for
d
¼4.48 (2H, s, CH2), 6.28 (1H, br s, NH), 7.15 (1H, br s, NH), 7.16 (1H,
hydrogens, dH, is related to the computed shielding sH by
t, J¼7.2 Hz, H-p), 7.25 (2H, t, J¼7.2 Hz, H-m), 7.3 (2H, d, J¼7.2 Hz, H-
sH¼196.1ꢃdH where the computed shielding of TMS has been
o), 7.50 (1H, s, CH-imidazole). 13C NMR (150.9 MHz, acetone-d6):
employed. All calculations employed the Gaussian 03 program.34
d
¼30.3 (CH2), 126.0 (C-p), 128.2 (C-m), 128.5 (C-o), 130.4 (C-m),
Acknowledgements
138.2 (C-ipso), 133.5 (CH-imidazole), 133.7 (CCONH2) 139.6 (Bn-C),
165.2 (CONH2). MS (CIþ) m/z (%) 202.10 (MHþ, 4), 185.068
(MHþꢃNH3, 2), 159.10 (MHþꢃCONH3, 0.81). HRMS (MHþ) calcd for
C11H12N3O 202.098; found 202.097.
We thank the ‘Marcus Center for Pharmaceutical and Medicinal
Chemistry’ at Bar Ilan University.
4.1.9. 4-(Biphenyl-3-ylmethyl)-1H-imidazole-5-carboxamide
(6c). Compound 6c prepared from 4c was isolated as described for
6a, as a yellow oil in 7% yield (microwave irradiation or thermal
Supplementary data
Tables of geometries and potential energies for molecules 6, 7,
12, and oxazole. Table of tautomerization energies for compound 12
conditions). 1H NMR (300 MHz, acetone-d6):
d¼4.50 (2H, s, CH2),

M. Weitman et al. / Tetrahedron 66 (2010) 1465–1471
1471
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