Novel syntheses of polysubstituted pyrroles and oxazoles by 1,3-dipolar cycloaddition reactions of benzotriazole-stabilized nitrile ylides

Article abstract of DOI:10.1002/jhet.5570390422

1,3-Dipolar cycloadditions of benzotriazole-stabilized nitrile ylides with benzyl α,β-unsaturated-carboxylates and aldehydes as dipolarophiles proceeded smoothly and efficiently to give polysubstituted pyrroles and oxazoles, respectively, in good yields.

Full text of DOI:10.1002/jhet.5570390422

Jul-Aug 2002
Novel Syntheses of Polysubstituted Pyrroles and Oxazoles by 1,3-Dipolar
Cycloaddition Reactions of Benzotriazole-Stabilized Nitrile Ylides
Alan R. Katritzky,* Suoming Zhang, Mingyi Wang, Hartmuth C. Kolb, Peter J. Steel**
759
§
‡
Department of Chemistry, Center for Heterocyclic Compounds,
University of Florida, Gainesville, FL 32611-7200
Katritzky@chem.ufl.edu
§ Neurogen Corporation, Department of Chemistry, 35 Northeast Industrial Road, Branton CT 06405
‡ Lexicon Pharmaceuticals, Inc., 279 Princeton-Hightstown Road, East Windsor, NJ 08520
** Department of Chemistry, University of Canterbury, Christchurch, New Zealand
Received December 20, 2001
1,3-Dipolar cycloadditions of benzotriazole-stabilized nitrile ylides with benzyl α,β-unsaturated-carboxy-
lates and aldehydes as dipolarophiles proceeded smoothly and efficiently to give polysubstituted pyrroles
and oxazoles, respectively, in good yields.
J. Heterocyclic Chem., 39, 759 (2002).
Introduction.
ease of nitrile ylide generation. Following the literature
[7], N-(benzotriazol-1-ylmethyl)amides 2a-d were pre-
pared in 90–95% yields by refluxing a mixture of the
amide 1a-d and 1-(hydroxymethyl)benzotriazole in ben-
zene in the presence of p-toluenesulfonic acid for an
appropriate time, with azeotropic removal of water by a
Dean-Stark apparatus. Compounds 2a-d are all crystalline;
none required column chromatography purification.
Treatment of 2a-d with phosphorus pentachloride in
toluene at 70−90 °C for 4–6 hours, then evaporation to
dryness, provided the corresponding imidoyl chlorides 3a-
d, which are sensitive to moisture and were used immedi-
ately for the next step.
1,3-Dipolar cycloadditions provide versatile synthetic
routes to five-membered heterocycles [1]. Easy access to
1,3-dipoles and simple reaction conditions are two advan-
tages of such reactions. An important subset involves
nitrile ylides [2], which have traditionally been generated
in three ways: i) treatment of imidoyl halides with base, ii)
thermolysis or photolysis of phosphoric acid esters from
4,5-dihydro-1,3,5-oxazaphospholes and iii) photolysis of
aryl-substituted azirines. Recent work on nitrile ylides has
involved 1,3-dipolar cycloadditions to cyclic dipo-
larophiles, such as substituted azetines [3] and α,β-unsatu-
rated lactones [4]. Considerable attention and effort has
also been devoted to azomethine ylides, which often
behave as nitrile ylide equivalents [5]. In previous work, a
benzotriazole group was employed to generate or stabilize
azomethine and nitrile ylide equivalents or precursors [6].
We now report further on the generation of benzotriazole-
stabilized nitrile ylides and their application in the synthe-
sis of polysubstituted pyrroles, oxazoles, and imidazoles.
Preparation of Pyrroles 5a-c, 5e-g, 6a-g and 7a-f (Table 1).
Nitrile ylides 4a-d are not readily isolated but easily
generated in situ from amides 2a-d. Solutions of the imi-
doyl chlorides 3a-d in THF were cooled to –40 °C, and the
dipolarophiles were added, followed by 4–6 equivalents of
t-BuOK. The reaction mixtures were allowed to warm up
to 20 °C. With a variety of different substituted benzyl
α ,β-unsaturated carboxylates as dipolarophiles, we
obtained benzyl pyrrole esters 5a-c, 5e-g in 76−90%
Results and Discussion.
Preparation of the Nitrile Ylide Precursors.
1
yields. The compounds 5 show a characteristic H nmr sig-
Conventionally, nitrile ylides are generated from amides
via imidoyl halides. The nature of the selected amide
determines both the structure of the final product and the
nal in the 4.95–5.14 ppm range for the benzyl protons, and
6.51–6.61 ppm (doublet, J = 2.3 Hz) for the unsubstituted
pyrrole ring proton. Pyrroles 5 can be alkylated in situ or
Table 1
Preparation of Pyrroles 5, 6 and 7
1
2
Entry
Amide (R)
Dipolarophile (R )
R
5 (%)
6 (%)
7 (%)
a
b
c
d
e
f
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Et
Me
Me
Me
90
81
85
- [a]
76
81
90
93
95
88
85
91
96
96
99
90
96
93
97
_
p-Tolyl
p-Anisyl
p-Anisyl
2-Furyl
p-Tolyl
p-Tolyl
Propyl
2-Thienyl
g
86
2
[a] Compound 5 does not contains R , hence 5d is identical to 5c.

760
A. R. Katritzky, S. Zhang, M. Wang, H. C. Kolb, P. J. Steel
Vol. 39
of a large excess of Pd/C did not result in cleavage of the
benzyl group, but led to desulfurization and formation of
after isolation, to provide N-alkylpyrroles 6a-g in 85−96%
yields. Pyrrole carboxylic acids 7a-f were readily obtained
in 90−99% yield by the hydrogenation of 6 with 5% Pd/C
in dioxane under at least 40 bar pressure (Scheme 1). This
hydrogenolytic removal of the benzyl group provides a
more efficient method for the preparation of pyrrole acids
than the traditional hydrolysis of pyrrolecarboxylic acid
esters, since strongly acidic or basic conditions at elevated
temperatures usually result in incomplete conversion [8] or
decarboxylation [9].
'
'
product 6g in 70% yield. The structure of 6g was unam-
biguously established by X-ray crystallography. Figure 1
shows a perspective view of the structure, which has the n-
butyl substituent disordered over two conformations with
approximately equal occupancies. Desulfurization of thio-
phenes is important in the petroleum and natural gas indus-
try [10], where hydrodesulfurization (HDS) is typically
catalyzed by metal sulfides.
Certain heteroatoms, and particularly sulfur, can consid-
erably decrease the activity of the hydrogenation catalyst
Pd/C. In the case of the thienyl derivative 6g, the standard
reaction conditions resulted in the total recovery of the
starting material. The hydrogenation of 6g in the presence
Preparation of Oxazoles 9a-d.
A similar procedure to that applied for pyrroles 5, also
gave satisfactory results for the preparation of oxazoles
9a-d (Scheme 1). While the reaction of imidoyl chloride
3a and isobutyraldehyde with base at low temperatures (0

Jul-Aug 2002
Novel Syntheses of Polysubstituted Pyrroles and Oxazoles
761
air oxidation (Scheme 2). Indeed, direct treatment of imi-
doyl chlorides 13a-d with t-BuOK in THF at a decreased
temperature and shorter reaction time avoided the forma-
tion of pyrazines of type 16 and gave only imidazoles 15a-
d as listed in Table 3. This was thus indicative that the dif-
ference between nitrile ylides 4 and 14 in behavior towards
imines, activated olefins and aldehydes is related to the
ability of benzotriazolyl to act as a leaving group.
Figure 1. Perspective view of the X-ray crystal structure of 6g', showing
the disorder of the n-butyl side chain.
°C to 20 °C) produced a mixture of oxazoline 8a and oxa-
zole 9a, a single product 9a was formed at reflux in THF,
which presumably facilitates aromatization by elimination
of benzotriazole from 8a. This observation led to the
development of one-pot conditions, which avoided the for-
mation and separation of oxazolines 8a-d and allowed the
production of oxazoles 9a-d in good yields (Table 2).
Table 3
Preparation of Imidazoles 15
Table 2
Entry
Amide 12
15
Yield (%)
Preparation of Oxazoles 9
R
Ar
3
Entry
Amide (R)
Aldehyde (R )
Yield (%)
a
b
c
Ph
p-Tolyl
4-Chlorophenyl
4-Chlorophenyl
Ph
53
66
71
62
p-Anisyl
p-Anisyl
Ph
a
b
c
Ph
Ph
p-Tolyl
p-Tolyl
Isopropyl
Ethyl
p-Anisyl
Ph
77
80
73
94
d
d
Conclusions.
In conclusion, we have developed a general methodol-
ogy for the preparation of polysubstituted pyrroles and
oxazoles by the cycloaddition of Bt-stabilized nitrile ylides
with dipolarophiles. In contrast to Bt-stabilized nitrile
ylides 4a-d, the aryl stabilized nitrile ylides 14a-d gave
only the imidazoles 15a-d by self condensation.
Preparation of Imidazoles 15a-d.
Under conditions similar to those used to prepare
pyrroles 5a-c, 5e-g and oxazoles 9a-d, reactions of nitrile
ylides 4a-d with N-benzylideneaniline failed to give the
corresponding imidazoles. The use of imines possessing
strongly electron-withdrawing substituents, e.g. N-[(E)-
phenylmethylidene]benzenesulfonamide, also failed.
EXPERIMENTAL
Concomitantly, we also prepared substituted amides
12a-d that did not carry a benzotriazole group from the
corresponding acid chlorides 10 and benzylamines 11 in
methylene chloride at 0−20 °C in 90−95% yields.
Interestingly, treatment of imidoyl chloride 13a, prepared
from 12a in situ, with i) imines, ii) activated olefins and iii)
aldehydes afforded none of the expected imidazoles,
pyrroles, and oxazoles, but gave, in good yield, imidazole
15a, which is a self [3+2] condensation product of the imi-
doyl chloride 13a. In addition to 15a, a minor amount of
product 16a was also obtained; 16a is presumably formed
by self [3+3] condensation of the imidoyl chloride 13a via
Melting points were determined on a MEL-TEMP capillary
melting point apparatus equipped with a Fluke 51 digital ther-
mometer. NMR spectra were taken in CDCl (unless stated other-
3
1
wise) with tetramethylsilane as the internal standard for H (300
MHz) or a solvent as the internal standard for C (75MHz). THF
13
was distilled from sodium/benzophenone under nitrogen immedi-
ately prior to use. All reactions with air-sensitive compounds
were carried out under an argon or nitrogen atmosphere.
General Procedure for Pyrroles 5a-c, 5e-g.
Amide 2 (2 mmol) was treated with an equimolar amount of
PCl (0.42g, 2 mmol) in toluene at 70−90 °C for 4–6 hours. The
5

762
A. R. Katritzky, S. Zhang, M. Wang, H. C. Kolb, P. J. Steel
Vol. 39
reaction mixture was evaporated in vacuo to dryness. The purple
Benzyl 2-(4-Methylphenyl)-4-(2-thienyl)-1H-pyrrole-3-carbox-
ylate (5g).
residue was dissolved in 20 mL of THF. Under N , the solution
2
was cooled below –40 °C, a benzyl α,β-unsaturated carboxylate
(2 mmol) was added followed by t-BuOK (0.90g, 8 mmol). The
mixture was stirred and allowed to warm up to room temperature
over 12 hours. The reaction mixture was diluted with EtOAc and
washed with saturated aqueous NaCl and water. The organic
White prisms from hexane-ethyl acetate (86%), mp 159−160
°C; H nmr: δ 8.45 (s, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.24−7.10
1
(m, 7H), 6.99−6.97 (m, 3H), 6.81 (d, J = 2.3 Hz, 1H), 5.08 (s,
13
2H), 2.35 (s, 3H); C nmr: δ 165.1, 138.2, 137.8, 136.4, 135.8,
129.3, 128.9, 128.6, 128.1, 128.1, 127.6, 127.0, 126.1, 124.0,
120.0, 117.9, 110.7, 65.8, 21.3.
phase was dried over MgSO . Purification of the crude product
4
by means of column chromatography provided the desired benzyl
pyrrolecarboxylates 5.
Anal. Calcd for C
H NO S: C, 73.97; H, 5.13; N, 3.75.
23 19 2
Found: C, 73.57; H, 5.18; N, 3.76
Benzyl 2,4-Diphenyl-1H-pyrrole-3-carboxylate (5a).
General Procedure for Benzyl N-Alkylpyrrole Carboxylates 6a-g.
Yellow needles from hexane-ethyl acetate (90%), mp 94−95
To a solution of 5 (2 mmol) in 20 mL of THF, sodium hydride
was added, followed by a solution of alkyl halide (2.2 mmol) in 5
mL of THF at 0 °C. After the addition, the reaction mixture was
stirred at 0 °C to room temperature overnight. The reaction mix-
ture was diluted with EtOAc and washed with saturated aqueous
1
°C; H nmr: δ 8.58 (s, 1H), 7.41−7.12 (m, 13H), 6.87 (d, J = 7.4
13
Hz, 2H), 6.61 (s, 1H), 5.00 (s, 2H); C nmr: δ 165.6, 137.2,
135.7, 135.3, 132.2, 129.0, 128.7, 128.2, 128.1, 128.0 (2C),
127.8, 127.7, 127.6, 126.4, 117.4, 110.5, 65.7.
Anal. Calcd for C
H NO : C, 81.56; H, 5.42; N, 3.96.
24 19 2
NaCl and water. The organic phase was dried over MgSO .
4
Found: C, 81.20; H, 5.42; N, 3.96.
Purification of the crude product by means of column chromatog-
raphy gave pure products 6.
Benzyl 2-(4-Methylphenyl)-4-phenyl-1H-pyrrole-3-carboxylate
(5b).
Benzyl 1-Methyl-2,4-diphenyl-1H-pyrrole-3-carboxylate (6a).
Yellow needles from hexane-ethyl acetate (81%), mp 153−154
°C; H nmr: δ 8.61 (s, 1H), 7.36−7.22 (m, 7H), 7.18−7.10 (m,
1
Compound 6a was obtained as a yellow oil (90%); H nmr: δ 7.40
1
(d, J = 6.7 Hz, 2H), 7.36−7.21 (m, 8H), 7.14−7.07 (m, 3H), 6.76 (d,
J = 6.1 Hz, 2H), 6.60 (s, 1H), 4.96 (s, 2H), 3.31 (s, 3H); C nmr: δ
164.6, 138.9, 135.9, 135.2, 131.9, 130.4, 129.0, 128.1, 127.9 (2C),
127.6 (2C), 127.2, 126.3, 126.1, 121.6, 111.4, 65.1, 34.4.
3H), 7.05 (d, J = 7.8 Hz, 2H), 6.84 (d, J = 6.5 Hz, 2H), 6.55 (d,
13
13
J = 2.6 Hz, 1H), 4.97 (s, 2H), 2.29 (s, 3H); C nmr: δ 165.7,
137.9, 137.6, 135.7, 135.5, 129.4, 129.0, 128.8, 128.7, 128.0
(2C), 127.8, 127.5 (2C), 126.3, 117.2, 110.1, 65.7, 21.2.
+
HRMS (FAB) Calcd for C H NO [M] : 367.1572. Found:
25 21
2
Anal. Calcd for C
H NO : C, 81.72; H, 5.76; N, 3.81.
25 21 2
367.1578.
Found: C, 81.26; H, 5.88; N, 3.82.
Benzyl 1-Methyl-2-(4-methylphenyl)-4-phenyl-1H-pyrrole-3-
carboxylate (6b).
Benzyl 2-(4-Methoxyphenyl)-4-phenyl-1H-pyrrole-3-carbox-
ylate (5c).
1
Compound 6b was obtained as a yellow oil (93%); H nmr: δ
7.40 (d, J = 6.9 Hz, 2H), 7.30−7.11 (m, 10H), 6.78 (d, J = 6.7
Hz, 2H), 6.61 (s, 1H), 4.97 (s, 2H), 3.35 (s, 3H), 2.37 (s, 3H);
nmr: δ 164.7, 139.2, 137.9, 135.9, 135.3, 130.3, 129.1, 128.9,
White prisms from hexane-ethyl acetate (85%), mp 126−127
1
°C; H nmr: δ 8.59 (s, 1H), 7.36−7.12 (m, 10H), 6.87 (d, 2H, J =
13
C
6.2 Hz), 6.77 (d, 2H, J = 3.1 Hz), 6.53 (d, 1H, J = 2.3 Hz), 4.98
13
(s, 2H), 3.71 (s, 3H); C nmr: δ 165.8, 159.3, 137.4, 135.6,
128.7, 127.8, 127.7, 127.6, 127.2, 126.3, 126.1, 121.4, 111.3,
135.5, 130.0, 129.0, 128.0 (2C), 127.7, 127.5, 127.3, 126.2,
124.6, 117.2, 113.4, 109.6, 65.6, 55.0.
65.1, 34.4, 21.1.
+
HRMS (FAB) Calcd for C H NO [M] : 381.1729. Found:
26 23
2
Anal. Calcd for C
H NO : C, 78.31; H, 5.52; N, 3.65.
25 21 3
381.1719.
Found: C, 78.19; H, 5.91; N, 3.63.
Benzyl 2-(4-Methoxyphenyl)-1-methyl-4-phenyl-1H-pyrrole-3-
carboxylate (6c).
Benzyl 2-(2-Furyl)-4-phenyl-1H-pyrrole-3-carboxylate (5e).
1
Dark oil (76%); H nmr: δ 9.11 (s, 1H), 7.27−7.11 (m, 10H),
White prisms from hexane-ethyl acetate (95%), mp 87−88 °C;
H nmr: δ 7.40 (d, J = 6.8 Hz, 2H), 7.29−7.21 (m, 5H), 7.15−
1
6.96−6.93 (m, 2H), 6.51 (d, J = 2.3 Hz, 1H), 6.36−6.34 (m, 1H),
5.12 (s, 2H); C nmr: δ 164.9, 145.8, 141.4, 135.8, 135.4, 129.2,
128.2, 128.1, 128.0, 127.9, 127.7, 127.6, 126.4, 117.4, 112.1,
110.0, 109.3, 65.7.
HRMS (FAB) Calcd for C H NO [M] : 343.1208. Found:
13
7.10 (m, 3H), 6.86 (d, J = 8.5 Hz, 2H), 6.81−6.78 (m, 2H), 6.58
13
(s, 1H), 4.96 (s, 2H), 3.76 (s, 3H), 3.31 (s, 3H); C nmr: δ 164.7,
159.4, 138.9, 135.9, 135.3, 131.6, 129.0, 127.8, 127.6, 127.6,
127.2, 126.2, 126.0, 123,9, 121.3, 113.3, 111.2, 65.1, 54.9, 34.3.
+
22 17
3
343.1208.
Anal. Calcd for C
H NO : C, 78.57; H, 5.83; N, 3.52.
26 23 3
Found: C, 78.37; H, 6.31; N, 3.50.
Benzyl 2-(4-Methylphenyl)-4-propyl-1H-pyrrole-3-carboxylate
(5f).
Benzyl 1-Ethyl-2-(4-methoxyphenyl)-4-phenyl-1H-pyrrole-3-
carboxylate (6d).
White needles from hexane-ethyl acetate (81%), mp 125−126
1
°C; H nmr: δ 8.14 (s, 1H), 7.33−7.25 (m, 5H), 7.18−7.10 (m,
White prisms from hexane-ethyl acetate (88%), mp 70−72 °C;
H nmr: δ 7.44−7.42 (m, 2H), 7.33−7.25 (m, 5H), 7.19−7.12 (m,
1
4H), 6.53 (s, 1H), 5.14 (s, 2H), 2.68 (t, J = 7.7 Hz, 2H), 2.35 (s,
13
3H), 1.63−1.55 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H); C nmr: δ
3H), 6.91 (d, J = 8.8 Hz, 2H), 6.83−80 (m, 2H), 6.72 (s, 1H),
4.98 (s, 2H), 3.84 (s, 3H), 3.74 (q, J = 7.3 Hz, 2H), 1.26 (t, J =
165.4, 138.1, 137.8, 136.4, 130.2, 129.0, 128.7, 128.2 (2C),
127.7, 127.6, 115.7, 110.3, 65.3, 29.0, 23.6, 21.2, 14.1.
13
7.3 Hz, 3H); C nmr: δ 164.5, 159.2, 138.1, 135.7, 135.2, 131.4,
Anal. Calcd for C
Found: C, 79.17; H, 7.04; N, 4.22.
H NO : C, 79.25; H, 6.95; N, 4.20.
128.8, 127.6, 127.4 (2C), 127.0, 126.2, 125.8, 123.9, 119.2,
113.1, 111.0, 64.8, 54.7, 41.4, 16.1.
22 23 2

Jul-Aug 2002
Novel Syntheses of Polysubstituted Pyrroles and Oxazoles
763
Anal. Calcd for C
H
NO : C, 78.81; H, 6.12; N, 3.40.
Anal. Calcd for C H NO : C, 78.33; H, 5.88; N, 4.81.
19 17 2
27 25
3
Found: C, 78.55; H, 6.25; N, 3.40.
Found: C, 78.07; H, 6.39; N, 4.80.
2-(4-Methoxyphenyl)-1-methyl-4-phenyl-1H-pyrrole-3-car-
boxylic Acid (7c).
Benzyl 2-(2-Furyl)-1-methyl-4-phenyl-1H-pyrrole-3-carboxylate
(6e).
1
1
White prisms from ethanol (90%), mp 223−224 °C; H nmr
Compound 6e was obtained as a dark oil (85%); H nmr: δ
(DMSO-d ); δ 11.47 (s, 1H), 7.40−7.26 (m, 6H), 7.22 (t, J = 7.1
7.45 (d, J = 1.1 Hz, 1H), 7.37−7.34 (m, 2H), 7.29−7.18 (m, 6H),
6.99−6.97 (m, 2H), 6.65 (s, 1H), 6.61 (d, J = 3.3 Hz, 1H), 6.44
(dd, J = 3.3, 1.8 Hz, 1H), 5.07 (s, 2H), 3.55 (s, 3H); C nmr: δ
6
Hz, 1H), 6.98 (d, J = 8.5 Hz, 2H), 6.95 (s, 1H), 3.80 (s, 3H), 3.40
13
13
(s, 3H); C nmr (DMSO-d ): δ 166.7, 159.4, 137.8, 136.0, 132.2,
6
128.8, 128.2, 126.1, 124.9, 124.4, 122.4, 113.8, 112.4, 55.5. 34.9.
164.5, 144.1, 142.8, 135.9, 134.9, 128.9, 128.0, 128.0, 127.8,
127.7, 127.5, 126.4, 126.3, 122.9, 113.7, 112.3, 110.8, 65.6, 35.3.
Anal. Calcd for C
H NO : C, 74.25; H, 5.58; N, 4.56.
19 17 3
Found: C, 74.26; H, 5.76; N, 4.54.
Anal. Calcd for C
H NO : C, 77.29; H, 5.36; N, 3.92.
23 19 3
Found: C, 76.85; H, 5.41; N, 4.22.
1-Ethyl-2-(4-methoxyphenyl)-4-phenyl-1H-pyrrole-3-carboxylic
Acid (7d).
Benzyl 1-Methyl-2-(4-methylphenyl)-4-propyl-1H-pyrrole-3-
carboxylate (6f).
1
White prisms from ethanol (96%), mp 178−179 °C; H nmr
(DMSO-d ): δ 11.45 (s, 1H), 7.39 (d, J = 7.3 Hz, 2H), 7.33−7.26
White needles from hexane-ethyl acetate (91%), mp 46−47 °C;
H nmr: δ 7.17−7.11 (m, 7H), 6.97−6.95 (m, 2H), 6.38 (s, 1H),
6
1
(m, 4H), 7.24−7.17 (m, 1H), 7.04−6.96 (m, 3H), 3.80 (s, 3H),
13
3.71 (q, J = 7.3 Hz, 2H), 1.16 (t, J = 7.3 Hz, 3H); C nmr
5.04 (s, 2H), 3.24 (s, 3H), 2.70 (t, J = 7.6 Hz, 2H), 2.34 (s, 3H),
13
(DMSO-d ): δ 167.0, 159.8, 137.9, 136.5, 132.6, 129.3, 128.5,
1.68−1.54 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H); C nmr: δ 164.8,
6
126.5, 125.6, 124.9, 120.9, 114.3, 112.8, 55.9, 42.2, 17.2.
138.9, 137.4, 136.2, 130.1, 129.5, 128.4, 127.8, 127.5, 127.1,
126.1, 120.1, 111.0, 64.7, 34.0, 28.6, 23.5, 21.1, 14.0.
Anal. Calcd for C
H NO : C, 74.75; H, 5.96; N, 4.36.
20 19 3
Found: C, 74.48; H, 6.09; N, 4.33.
Anal. Calcd for C
H NO : C, 79.51; H, 7.25; N, 4.03.
23 25 2
Found: C, 79.45; H, 7.70; N, 4.04.
2-(2-Furyl)-1-methyl-4-phenyl-1H-pyrrole-3-carboxylic Acid
(7e).
Benzyl 1-Methyl-2-(4-methylphenyl)-4-(2-thienyl)-1H-pyrrole-
3-carboxylate (6g).
Compound 7e was obtained as a white solid (93%), mp 157−
1
158 °C; H nmr (DMSO-d ): δ 11.95 (s, 1H), 7.80−7.78 (m, 1H),
White prisms from hexane-ethyl acetate (96%), mp 96−98 °C;
H nmr: δ 7.24−7.13 (m 9H), 7.01−6.98 (dd, J = 5.1, 3.6 Hz,
6
1
7.40−7.29 (m, 4H)), 7.25−7.19 (m, 1H), 7.08 (s, 1H), 6.70 (d, J =
13
3.3 Hz, 1H), 6.61 (dd, J = 3.3, 1.9 Hz, 1H), 3.58 (s, 3H); C nmr
1H), 6.87−6.82 (m, 2H), 6.79 (s, 1H), 5.01 (s, 2H), 3.39 (s, 3H),
13
(DMSO-d ): δ 166.1, 144.2, 143.3, 134.9, 128.1, 127.9, 126.0,
2.39 (s, 3H); C nmr: δ 164.5, 139.5, 138.1, 136.4, 136.0, 130.3,
6
125.9, 124.3, 123.4, 114.5, 111.2, 111.1, 35.0.
128.9, 128.8, 127.9, 127.8, 127.4, 127.0, 126.1, 123.8, 122.2,
118.6, 111.6, 65.4, 34.6, 21.3.
Anal. Calcd for C
H NO : C, 71.90; H, 4.90; N, 5.24.
16 13 3
Found: C, 71.64; H, 5.07; N, 5.22.
Anal. Calcd for C
H NO S: C, 74.39; H, 5.46; N, 3.61.
24 21 2
Found: C, 74.22; H, 5.53; N, 3.59.
1-Methyl-2-(4-methylphenyl)-4-propyl-1H-pyrrole-3-carboxylic
Acid (7f).
General Procedure for N-Alkylpyrrole Acids 7a-f.
1
White prisms from ethanol (97%), mp 189−191 °C; H nmr
To a pressure-resistant hydrogenation bottle charged with a mix-
ture of 6 (1 mmol) and equal amount of 5% Pd/C (in weight) in 30
mL of dioxane was introduced hydrogen. After air was replaced
with hydrogen 3-4 times, the bottle was sealed and the reaction was
(DMSO-d ): δ 11.24 (s, 1H), 7.24−7.15 (m, 4H), 6.62 (s, 1H),
3.29 (s, 3H), 2.60 (t, J = 7.6 Hz, 2H), 2.34 (s, 3H), 1.62−1.48 (m,
2H), 0.93 (t, J = 7.3 Hz, 3H); C nmr (DMSO-d ): δ 166.2,
6
13
6
138.1, 137.1, 130.6, 129.7, 128.4, 124.9, 121.0, 111.5, 34.3, 28.6,
23.3, 21.0, 14.3.
carried out under at least 40 bar pressure of H overnight. Filtration
to remove catalyst, concentration in vacuo to remove dioxane and
purification by recrystallization gave pure products 7.
2
Anal. Calcd for C
H NO : C, 74.68; H, 7.44; N, 5.44.
16 19 2
Found: C, 74.54; H, 7.71; N, 5.42.
1-Methyl-2,4-diphenyl-1H-pyrrole-3-carboxylic Acid (7a).
Benzyl 4-Butyl-1-methyl-2-(4-methylphenyl)-1H-pyrrole-3-car-
boxylate (6g ).
1
White needles from ethanol (96%), mp 184−185 °C; H nmr
'
(DMSO-d ): δ 11.5 (s, 1H), 7.48−7.36 (m, 6H), 7.31 (t, J = 7.3
6
13
The procedure is similar to that of 7a-f except for the use of 15
Hz, 2H), 7.24−7.16 (m, 1H), 6.99 (s, 1H), 3.41 (s, 3H); C nmr
times the amount of 5% Pd/C. Recrystallization from hexane-ethyl
acetate furnished white needles (70%), mp 82−83 °C; H nmr: δ
(DMSO-d ): δ 166.5, 137.7, 135.6, 132.0, 130.7, 128.6, 128.2
(2C), 128.0, 126.1, 124.7, 122.5, 112.4, 34.7.
6
1
7.23−7.12 (m, 7H), 7.10−6.96 (m, 2H), 6.41 (s, 1H), 5.05 (s, 2H),
3.31(s, 3H), 2.72 (t, J = 7.8 Hz, 2H), 2.37 (s, 3H), 1.63−1.51 (m,
2H), 1.42−1.30 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H); C nmr: δ 165.0,
139.2, 137.6, 136.4, 130.3, 129.7, 128.6, 127.9, 127.7, 127.3,
126.5, 120.1, 111.1, 64.9, 34.2, 32.7, 26.4, 22.7, 21.3, 14.0.
Anal. Calcd for C
Found: C, 77.62, H, 5.85; N, 5.01.
H NO : C, 77.96; H, 5.45; N, 5.05.
18 15 2
13
1-Methyl-2-(4-methylphenyl)-4-phenyl-1H-pyrrole-3-carboxylic
Acid (7b).
1
Anal. Calcd for C
H NO : C, 79.74; H, 7.53; N, 3.87.
White needles from ethanol (99%), mp 218−219 °C; H nmr
24 27 2
(DMSO-d ): δ 11.5 (s, 1H), 7.38 (d, J = 7.1 Hz, 2H), 7.33−7.20
(m, 7H), 6.97 (s, 1H), 3.41 (s, 3H), 2.36 (s, 3H); C nmr
Found: C, 79.70; H, 7.78; N, 3.88.
Crystal data for 6g': C H NO , MW 361.47, monoclinic,
6
13
24 27
2
(DMSO-d ): δ 166.2, 137.4, 137.2, 135.5, 130.3, 128.9, 128.5,
128.3, 127.7, 125.7, 124.4, 122.1, 112.0, 34.4, 20.9.
space group P2 /c, a = 13.770(6), b 14.080(6), c = 10.676(4) Å,
β = 96.425(5) , V = 2057(1) Å , F(000) = 776, Z = 4, T =
6
1
o
3

764
A. R. Katritzky, S. Zhang, M. Wang, H. C. Kolb, P. J. Steel
Vol. 39
-1
-3
1-Benzyl-2,4,5-triphenylimidazole (15a) [14].
-105 °C, µ (MoKα) = 0.073 mm , D
= 1.167 g.cm , 2θ
max
calcd
o
46 (CCD area detector, MoKα radiation, 99.9% completeness),
GOF = 1.029, wR(F ) = 0.1779 (all 2859 data), R = 0.0514
White prisms from hexane (53%), mp 163−164 °C; lit. mp
2
1
163−164 °C; H nmr: δ 7.77 −7.60 (m, 4H), 7.32− 7.07 (m, 14H),
(2038 data with I > 2σI).
13
6.77−6.74 (m, 2H), 5.04 (s, 2H); C nmr: δ 147.8, 137.8, 137.3
(2C), 134.3, 130.8, 130.7, 129.8, 128.7, 128.6, 128.5, 128.4,
128.34, 128.3, 127.9, 127.1, 126.5, 126.1, 125.7, 48.0.
General Procedure for Oxazoles 9a-d.
Oxazoles 9a-d were prepared using the same procedure as
pyrroles 5 with aldehydes as dipolarophiles.
1-(4-Methoxybenzyl)-2,5-di(4-methylphenyl)-4-(4-methoxy-
phenyl)-1H-imidazole (15b).
5-Isopropyl-2-phenyl-1,3-oxazole (9a).
White needles from hexane-ethyl acetate (66%), mp 97−98 °C;
H nmr: δ 7.55 (d, J = 8.7 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H),
1
Compound 9a was obtained as a yellow oil (77%); H nmr: δ
1
7.78 (s, 1H), 7.63 (d, J = 7.4 Hz, 2H), 7.40 (t, J = 7.7 Hz, 2H),
7.31−7.26 (m, 1H), 3.45−3.30 (m, 1H), 1.31 (d, J = 7.0 Hz, 6H);
7.12−7.07 (m, 4H), 7.01 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 8.7 Hz,
2H), 6.73 (s, 4H), 3.81 (s, 3H), 3.75 (s, 3H), 2.27 (s, 3H), 2.04 (s,
13
C nmr: δ 152.2, 148.7, 132.3, 132.1, 128.4, 127.2, 126.9, 25.6,
13
3H); C nmr: δ 159.9, 158.7, 147.6, 138.2, 137.7, 135.6, 131.9,
21.0.
130.9, 130.3, 129.9, 129.4, 129.3, 128.7, 128.2, 127.2, 126.6,
123.7, 113.9, 113.8, 55.3. 55.2, 47.5, 21.3, 21.1.
+
HRMS (FAB) Calcd for C H NO [M+1] : 188.1075. Found:
12 14
188.1074.
Anal. Calcd for C
H N O : C, 80.98; H, 6.37; N, 5.90.
32 30 2 2
Found: C, 80.55; H, 6.83; N, 5.67.
5-Ethyl-2-phenyl-1,3-oxazole (9b) [11].
1-(4-Methoxybenzyl)-2,5-di(4-chlorophenyl)-4-(4-methoxy-
phenyl)-1H-imidazole (15c).
1
Compound 9b was obtained as a yellow oil (80%); H nmr: δ
7.79 (s, 1H), 7.67−7.62 (m, 2H), 7.44−7.37 (m, 2H), 7.32−7.26
(m, 1H), 2.90 (q, J = 7.6 Hz, 2H), 1.29 (t, J = 7.6 Hz, 3H);
nmr: δ 148.9, 148.9, 133.3, 132.0, 128.5, 127.2, 126.7, 19.2, 12.3.
5-(4-Methoxyphenyl)-2-(4-methylphenyl)-1,3-oxazole (9c) [12].
White prisms from hexane (73%), mp 126−128 °C; lit. mp 127
°C; H nmr: δ 7.96 (d, J = 8.1 Hz, 2H), 7.61 (d, J = 8.8 Hz, 2H),
7.28 (s, 1H), 7.25 (d, J = 8.1 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H),
3.81 (s, 3H), 2.38 (s, 3H); C nmr: δ 160.7, 159.6, 150.9, 140.2,
129.4, 126.0, 125.5, 124.8, 121.7, 120.8, 114.3, 55.2, 21.4.
13
C
White needles from hexane-ethyl acetate (71%), mp 171−172
1
°C; H nmr: δ 7.56 (d, J = 8.7 Hz, 2H), 7.46 (d, J = 8.5 Hz, 2H),
7.30 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 7.10 (d, J =
8.4 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H), 6.76−6.68 (m, 4H), 4.99 (s,
13
2H), 3.82 (s, 3H), 3.76 (s, 3H); C nmr: δ 160.2, 158.9, 148.4,
1
137.2, 134.8, 132.8, 132.2, 132.1, 130.3, 129.4, 129.2, 129.1,
128.5, 128.3, 128.0, 127.1, 123.0, 114.1, 114.0, 55.3, 55.2, 47.8.
13
Anal. Calcd for C H Cl N O : C, 69.91; H, 4.69; N, 5.43.
30 24
2 2 2
Found: C, 70.00; H, 4.84; N, 5.42.
2-(4-Methylphenyl)-5-phenyl-1,3-oxazole (9d) [13].
1-Benzyl-2,5-di(4-chlorophenyl)-4-phenyl-1H-imidazole (15d).
1
1
White prisms from hexane (90%), mp 75 °C; lit. mp 75 °C; H
White prisms from hexane-ethyl acetate (62%), mp 150 °C; H
nmr: δ 7.97 (d, J = 8.1 Hz, 2H); 7.67 (d, J = 7.6 Hz, 2H); 7.43−
7.37 (m, 3H); 7.30 (d, J = 7.3 Hz, 1H), 7.25 (d, J = 8.1 Hz, 2H),
2.37 (s, 3H); C nmr: δ 161.2, 150.8, 140.5, 129.4, 128.8, 128.2,
nmr: δ 7.63 (brs, 2H), 7.47 (d, J = 7.9 Hz, 2H), 7.39−7.37 (m,
3H), 7.26 (d, J = 8.4 Hz, 2H), 7.23−7.16 (m, 5H), 7.10 (d, J =
8.4 Hz, 2H), 6.80−6.78 (m, 2H), 5.07 (s, 2H); C nmr: δ 148.5,
137.5, 137.1 (2C), 134.9 (2C), 132.7, 132.2, 130.5, 129.2, 129.1,
128.9, 128.8, 128.7, 128.6, 128.3, 128.0, 127.5, 125.9, 48.4.
13
13
128.0, 126.1, 124.6, 124.0, 123.2, 21.4.
1-(5-Isopropyl-2-phenyl-4,5-dihydro-1,3-oxazol-4-yl)-1H-1,2,3-
benzotriazole (8a).
Anal. Calcd for C H Cl N : C, 73.85; H, 4.43; N, 6.15.
28 20
2 2
Found: C, 73.75; H, 4.38; N, 6.14.
1
Compound 8a was obtained as a yellow oil (10%); H nmr: δ
2,3,5,6-Tetraphenylpyrazine (16a) [15].
8.11-8.07 (m, 3H), 7.61−7.56 (m, 1H), 7.51−7.33 (m, 5H), 6.90
(d, J = 5.5 Hz, 1H), 4.90−4.85 (m, 1H), 2.23−2.15 (m, 1H), 1.13
White needles from hexane (20%), mp 250 °C; lit. mp 253−
13
(d, J = 6.7 Hz, 3H), 1.10 (d, J = 6.9 Hz, 3H); C nmr: δ 167.9,
1
13
254 °C; H nmr: δ 7.66−7.62 (m, 8H), 7.34−7.32 (m, 12H).;
C
146.8, 132.6, 131.5, 128.9, 128.6, 127.7, 126.2, 124.2, 120.2,
nmr: δ 148.4, 138.5, 129.9, 128.6, 128.2.
109.9, 88.3, 83.5, 31.9, 17.3, 17.1.
General Procedure for Amides 12b-d.
+
HRMS (FAB) Calcd for C
Found: 307.1557.
H
N O [M+1] : 307.1559.
18 18
4
To a solution of the acid chloride (10 mmol) and pyridine (0.9
mL, 11 mmol) in 50 mL of methylene chloride was added drop-
wise a solution of the amine (10 mmol) in 10 mL of methylene
chloride at 0 °C. After the addition, the mixture was stirred at 0
°C to room temperature overnight. After quenching the reaction
General Procedure for Imidazoles 15a-d.
Amide 12 (2 mmol) was treated with 1.0 equivalent of PCl
5
(0.42g, 2 mmol) in toluene at 70–90 °C for 2–4 hours. The
reaction mixture was evaporated in vacuo to dryness. The pur-
ple residue was dissolved in 20 mL of THF. After the solution
was cooled below –40 °C, t-BuOK (0.45g, 4 mmol) was
added. The mixture was stirred and allowed to warm up to
room temperature over 4−6 hours. The reaction mixture was
diluted with EtOAc and washed with saturated aqueous NaCl
and H O. The organic phase was dried over MgSO .
with water, the organic layer was washed with 5% NaHCO ,
3
water, and dried over MgSO . Evaporation to remove CH Cl
4
2
2
gave a white solid, which was recrystallized from hexane-ethyl
acetate to give colorless needles in excellent yield.
N-(4-Methoxybenzyl)-4-methylbenzamide (12b).
White needles from hexane-ethyl acetate (85%), mp 115−117
2
4
1
Purification of the crude product by means of column chro-
°C; H nmr: δ 7.67 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 7.0 Hz, 2H),
matography provided imidazoles 15.
7.20 (d, J = 7.7 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 6.42 (brs, 1H),

Jul-Aug 2002
Novel Syntheses of Polysubstituted Pyrroles and Oxazoles
765
13
Comprehensive Heterocyclic Chemistry II, Pergamon, Exeter, 1996.
[2] A. Padwa, In Comprehensive Organic Synthesis; B. M.
Trost, I. Fleming and M. F. Semmelhack, ed, Pergamon, Oxford,
1991, pp1069.
[3] A.-B. N. Luheshi, R. K. Smalley, P. D. Kennewell and R.
Westwood, Tetrahedron Lett., 31, 123 (1990).
4.54 (d, J = 5.2 Hz, 2H), 3.79 (s, 3H), 2.38 (s, 3H); C nmr; δ
167.2, 159.0, 141.8, 131.5, 130.4, 129.2, 129.1, 126.9, 114.1,
55.2, 43.5, 21.4.
Anal. Calcd for C
H NO : C, 75.27; H, 6.71; N, 5.49.
16 17 2
Found: C, 75.01; H, 6.92; N, 5.45.
4-Chloro-N-(4-methoxybenzyl)benzamide (12c).
White needles from hexane-ethyl acetate (90%), mp 138−139
[4] P. de March, M. Arrad, M. Figueredo and J. Font,
Tetrahedron, 54, 11613 (1998).
[5a] M. Ohno, M. Komatsu, H. Miyata and Y. Ohshiro,
Tetrahedron Lett., 32, 5813 (1991); [b] K. I. Washizuka, S.
Minakata, I. Ryu and M. Komatsu, Tetrahedron, 55, 2969 (1999).
[6a] A. R. Katritzky, G. J. Hitchings and X. Zhao, Synthesis,
863 (1991); [b] A. R. Katritzky, J. Koditz and H. Lang, Tetrahedron,
50, 12571 (1994); [c] A. R. Katritzky, T.-B. Huang, M. V. Voronkov,
M. Wang and H. Kolb, J. Org. Chem., 65, 8819 (2000).
[7] A. R. Katritzky, G. Yao, X. Lan and X. Zhao, J. Org.
Chem., 58, 2086 (1993).
[8] T. P. Toube, In Pyrrole; R. A. Jones, ed, John Wiley and
Sons, New York, 1990, pp86 and references cited therein.
[9a] N. P. Pavri and M. L. Trudell, J. Org. Chem., 62, 2649
(1997); [b] Z. Xu and X. Lu, J. Org. Chem., 63, 5031 (1998).
[10a] C. Bianchini and A. Meli, Acc. Chem. Res., 31, 109
(1998); [b] R. J. Angelici, Polyhedron, 16, 3073 (1997).
[11] C. Kashima and H. Arao, Synthesis, 873 (1989).
[12] L. P. Goshcheno, Chem. Heterocycl. Compd. (Engl.
Transl.), 21, 157 (1985).
1
°C; H nmr: δ 7.70 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 7.4 Hz, 2H),
7.24 (d, J = 9.1 Hz, 2H), 6.85 (d, J = 7.8 Hz, 2H), 6.58 (brs, 1H),
13
4.52 (d, J = 5.1 Hz, 2H), 3.78 (s, 3H); C nmr: δ 166.2, 159.1,
137.6, 132.7, 129.9, 129.2, 128.7, 128.4, 114.1, 55.2, 43.6.
Anal. Calcd for C H ClNO : C, 65.34; H, 5.12; N, 5.08.
15 14
2
Found: C, 65.21; H, 5.16; N, 5.05.
N-Benzyl-4-chlorobenzamide (12d) [16].
White needles from hexane-ethyl acetate (92%), mp 162−163
1
°C; lit. mp 164−165 °C; H nmr (DMSO-d ): δ 9.15 (brs, 1H),
6
7.93 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.5 Hz, 2H), 7.33 (d, J =
13
4.4 Hz, 4H), 7.27−7.24 (m, 1H), 4.49 (d, J = 5.9 Hz, 2H);
C
nmr (DMSO-d ): δ 165.3, 139.6, 136.2, 133.2, 129.4, 128.6,
6
128.5, 127.4, 126.9, 42.8.
Anal. Calcd for C
H ClNO: C, 68.44; H, 4.92; N, 5.70.
14 12
Found: C, 68.19; H, 4.97; N, 5.62.
[13] A. T. Balaban, L. Birladeanu, I. Bally, P. T. Frangopol, M.
Mocanu and Z. Simon, Tetrahedron, 19, 2199 (1963).
[14] M. Weiss, J. Am. Chem. Soc., 74, 5193 (1952).
[15] R. H. Fischer and H. M. Weitz, Synthesis, 53 (1976).
[16] C. J. O'Connor and R. E. Ramage, Aust. J. Chem., 30, 527
(1977).
REFERENCES AND NOTES
Email: suoming_zhang@nrgn.com
** Email: p.steel@chem.canterbury.ac.nz
[1] A. R. Katritzky, C. W. Rees and E. F. V. Scriven, ed,
§