Preparation of 1,2-diaryl(heteroaryl)pyrroles and -3-methylpyrroles from N-allylbenzotriazole

Article abstract of DOI:10.1021/jo000885x

Numerous 1,2-diaryl(heteroaryl)pyrroles and -3-methylpyrroles were prepared in a two-step procedure from N-allylbenzotriazoles via intramolecular oxidative cyclization in the presence of Pd(II) catalyst.

Full text of DOI:10.1021/jo000885x

8074
J . Org. Chem. 2000, 65, 8074-8076
P r ep a r a tion of 1,2-Dia r yl(h eter oa r yl)p yr r oles a n d
-3-m eth ylp yr r oles fr om N-Allylben zotr ia zole
Alan R. Katritzky,* Lianhao Zhang, J iangchao Yao, and Olga V. Denisko
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
katritzky@chem.ufl.edu
Received J une 12, 2000
Numerous 1,2-diaryl(heteroaryl)pyrroles and -3-methylpyrroles were prepared in a two-step
procedure from N-allylbenzotriazoles via intramolecular oxidative cyclization in the presence of
Pd(II) catalyst.
Although 1,2-diarylpyrroles have long been known,1
their chemistry remained undeveloped until recently
when their biological properties attracted attention from
medicinal and industrial chemists. 1,2-Diarylpyrroles
have potential application as fungicides and bactericides2
and as active components of nonsteroidal antiinflamma-
tory drugs inhibiting human cyclooxygenase-2.3,4
Sch em e 1
The following procedures are available for the prepara-
tion of 1,2-diarylpyrroles: (i) low-yielding (20-30%) base-
catalyzed condensations of 2-(N-phenylamino)-2-aryl-
acetonitriles with acrolein under mild conditions;1,4,5 (ii)
Paal-Knorr reactions, which provide various 1,2-di-
arylpyrroles (in 45-70% yields),3,6 although preparation
of the starting 3-aroylpropionaldehyde (or its acetal) is
usually a multistep synthesis with overall yields in the
range 35-50%; (iii) a two-step procedure involving S-
methylation of N-allyl-N-phenylthiobenzamide with sub-
sequent treatment of the resulting thioimidate salt with
LiHMDS,7 which was applied to the preparation of 1,2-
diphenylpyrrole; and (iv) cyclization of N-aryl-γ-keto-
amides upon treatment with Lawesson’s reagent, which
affords 1,2-diarylpyrroles in modest yields (30-48%).8
The strong electron-withdrawing ability and nucleo-
fugicity of the benzotriazolyl group have been used
successfully for the preparation of a number of 1,2-
diarylpyrroles.9,10 It was shown that N-allylbenzotriazoles
1 of the general formula BtCH2CHdCHX, where X is a
second leaving group, easily undergo lithiation at the
allylic carbon. The reaction of the anion obtained with a
diarylimine and subsequent acid-catalyzed cyclization
with the elimination of both benzotriazolyl and X groups
affords 1,2-diarylpyrroles 3 in moderate yields (Scheme
1). The nature of the leaving group X (OEt9 or mor-
pholino10) does not affect the yield of the final product
significantly.
In the absence of the leaving group X (4 ≡ 1, X ) H),
the cyclization of the reaction intermediate 5 in the way
shown in Scheme 2 should lead to 2,5-dihydro-1,2-
diarylpyrroles A for which methods for oxidation to the
corresponding pyrroles are known using DDQ11 or
Cu(II) salts.12 Cyclization 5 f 6 does not occur under
acid-catalyzed conditions; but we showed recently that
N-allylbenzotriazoles undergo intermolecular γ-amina-
tion in the presence of Pd(II) or Pd(0) catalysts and a
weak base such as potassium carbonate.13 Applying this
procedure to the similar intramolecular reaction with
simultaneous oxidation of the intermediate ∆3-pyrroline
has now provided a convenient approach to the synthesis
of 1,2-diaryl(heteroaryl)pyrroles 6.
Resu lts a n d Discu ssion
Several (2-benzotriazolyl-1-arylbut-3-en)anilines 5a -h
and (2-benzotriazolyl-1-heteroarylbut-3-en)anilines 5i-l
were synthesized in moderate to high yields by the known
procedure10 of treating unsubstituted N-allylbenzotriazole
(4) with n-butyllithium followed by a diarylimine or
N-aryl-heteroarylimine, respectively (Scheme 2). Subse-
quently heating the compounds 5a -l in the presence of
a system Pd(OAc)2-PPh3-CuCl2-K2CO3 in THF gave
the targeted 1,2-diaryl(heteroaryl)pyrroles 6a -l (Scheme
2). The yields of the products 6a -h depend dramatically
on the nature of the substituents in the both aromatic
(1) von Treibs, A.; Derra, R. Ann. Chem. 1954, 589, 176.
(2) Tatsuta, K. J pn. Kokai Tokkyo Koho J P 07,206,815; Chem. Abstr.
1996, 124, 8609e.
(3) Khanna, I. K.; Weier, R. M.; Yu, Y.; Collins, P. W.; Miyashiro, J .
M.; Koboldt, C. M.; Veenhuizen, A. W.; Currie, J . L.; Seibert, K.;
Isakson, P. C. J . Med. Chem. 1997, 40, 1619.
(4) Kimura, T.; Noguchi, Y.; Nakao, A.; Suzuki, K.; Ushiyama, S.;
Kawara, A.; Miyamoto, M. Eur. Pat. Appl. EP 799,823; Chem. Abstr.
1997, 127, 331392e.
(5) Grimshaw, J .; Hewitt, S. A. J . Chem. Soc., Perkin Trans. 1 1990,
2995.
(6) Kruse, C. G.; Bouw, J . P.; van Hes, R.; van de Kuilen, A.; den
Hartog, A. J . Heterocycles 1987, 26, 3141.
(7) Magedov, I. V.; Kornienko, A. V.; Zotova, T. O.; Drozd, V. N.
Tetrahedron Lett. 1995, 36, 4619.
(8) Nishio, T. Helv. Chim. Acta 1998, 81, 1207.
(9) Katritzky, A. R.; Wu, H.; Xie, L.; Rachwal, S.; Rachwal, B.; J iang,
J .; Zhang, G.; Lang, H. Synthesis 1995, 1315.
(10) Katritzky, A. R.; Chang, H.-X.; Verin, S. V. Tetrahedron Lett.
1995, 36, 343.
(11) Padwa, A.; Chen, Y.-Y.; Dent, W.; Nimmesgern, H. J . Org.
Chem. 1985, 50, 4006.
(12) Geneˆt, J . P.; Balabane, M.; Ba¨ckvall, J . E.; Nystro¨m, J . E.
Tetrahedron Lett. 1983, 24, 2745.
(13) Katritzky, A. R.; Yao, J .; Qi, M. J . Org. Chem. 1998, 63, 5232.
10.1021/jo000885x CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/21/2000

Preparation of 1,2-Diaryl(heteroaryl)pyrroles
J . Org. Chem., Vol. 65, No. 23, 2000 8075
Sch em e 2
rings. Electron-withdrawing substituents, such as halo-
gen, in the para or meta position facilitate the reaction
significantly; thus, the pyrroles 6b,d were obtained in
79% and 78% yields, respectively [compare to 46% for
1,2-diphenylpyrrole (6a )]. The introduction of a strong
electron-donor substituent shows the opposite effect, and
so, for example, pyrrole 6h with Ar1 ) 4-MeOC6H4 was
obtained in only 21% yield.
A heterocyclic moiety, such as pyrid-3-yl, thiophen-3-
yl, or even acid-sensitive furan-2-yl fragment, could be
successfully used in place of the Ar1 substituent, which
enabled the synthesis of previously unknown bis-hetero-
cyclic systems 6i-l. Interestingly, in contrast to the case
of 1,2-diarylpyrroles discussed above, the electron-donat-
ing (or electron-withdrawing) properties of a heterocyclic
moiety do not have a significant effect on the yield of the
resulting pyrrole derivative. Thus, the cyclization reac-
tions of thiophen-3-yl-substituted allylbenzotriazole 5j
and pyrid-3-yl-substituted allylbenzotriazole 5l gave the
2-heteroarylpyrroles 6j and 6l, respectively, in similar
yields.
Introduction of a methyl group into the R-position to
the benzotriazolyl group in the starting N-allylbenzo-
triazole caused some complications, probably for steric
reasons. Thus, compounds 8a ,b, obtained by lithiation
of 2-(buten-3-yl)benzotriazole (7) and subsequent reaction
with an imine, were difficult to purify, but could be used
crude in the subsequent cyclization reaction (analogous
to that used for the preparation of 1,2-disubstituted
pyrroles), thus affording 1,2,3-trisubstituted pyrroles
9a ,b in low yields [calculated on the starting 2-(buten-
3-yl)benzotriazole (7)]. Products 9a ,b possess Rf values
close to that of triphenylphosphine, which hinders their
separation. Modification of the cyclization procedure by
applying polymer-supported triphenylphosphine instead
of the monomeric reagent improved the quality of 9a ,b
after chromatographic purification without affecting the
yields.
X ) H) as a starting material is more convenient than
the earlier utilization of 1 (X ) OEt) or 1 (X ) mor-
pholino) which requires multistep preparation.
Exp er im en ta l Section
Gen er a l Com m en ts. Melting points were measured on a
hot-stage apparatus and are uncorrected. 1H and 13C NMR
data were recorded on 300 MHz NMR spectrometer (300 and
75 MHz, respectively) in CDCl3 as a solvent and with TMS as
an internal standard. Column chromatography was carried out
on silica gel (activated, neutral, 50-200 micron). Tetrahydro-
furan was purified by distillation from Na/benzophenone under
nitrogen. Diarylimines and N-aryl-heteroarylimines were pre-
pared according to procedure described.14 N-Allylbenzotriazole
(4) and 2-(buten-3-yl)benzotriazole (7) were prepared by the
known procedures.15
Gen er a l P r oced u r e for th e Syn th esis of N-Ar yl-2-
(ben zotr iazol-1-yl)-1-ar yl(h eter oar yl)bu ten -3-ylam in es (5).
A solution of N-allylbenzotriazole (4) (1.59 g, 0.01 mol) in dry
THF (60 mL) was cooled under nitrogen to -78 °C, and a 1.5
M solution of n-butyllithium in hexanes (6.6 mL, 0.01 mol)
was added dropwise at this temperature during 20 min. The
reaction mixture was stirred at -78 °C for another 30 min,
and then a solution of a corresponding diarylimine (or N-aryl-
heteroarylimine) (0.01 mol) in dry THF (20 mL) was added
dropwise. The resulting solution was stirred at -78 °C for an
additional 1 h and then quenched with water. The product was
extracted with chloroform, and the chloroform extracts were
filtered and washed with water. Removal of the solvent gave
a crude product, which was additionally purified by recrys-
tallization from methanol.
N -P h e n yl-2-(b e n zot r ia zol-1-yl)-1-p h e n ylb u t e n -3-yl-
a m in e (5a ): white plates; mp 164-165 °C; yield 85%; 1H NMR
δ 8.00-7.95 (m, 1H), 7.31-7.22 (m, 2H), 7.14-7.03 (m, 8H),
6.71-6.54 (m, 4H), 5.49-5.33 (m, 3H), 5.01 (d, J ) 7.6 Hz,
1H), 4.72 (br s, 1H); 13C NMR δ 146.4, 145.3, 139.0, 132.8,
132.4, 129.0, 128.5, 127.8, 127.1, 126.7, 123.8, 121.5, 119.8,
118.3, 114.0, 109.2, 67.4, 61.6. Anal. Calcd for C22H20N4: C,
77.61; H, 5.93; N, 16.47. Found: C, 77.36; H, 6.23; N, 16.69.
N-P h en yl-2-(ben zotr iazol-1-yl)-1-(4-flu or oph en yl)bu ten -
3-yla m in e (5b): white needles; mp 165-166 °C; yield 71%;
1H NMR δ 7.99 (dd, J ) 6.8, 1.7 Hz, 1H), 7.33-7.25 (m, 2H),
The presence of an oxidizing agent, CuCl2, is crucial
for the reaction. Thus, we showed that no cyclization
occurs when Pd(II) catalyst is used alone. The use in the
present work of readily available N-allylbenzotriazole (1,
(14) Bigelow, L. A.; Eatough, H. Organic Syntheses; Wiley: New
York, 1941; Collect. Vol. I, p 80.
(15) Katritzky, A. R.; Li, J .; Malhotra, N. Liebigs Ann. Chem. 1992,
843.

8076 J . Org. Chem., Vol. 65, No. 23, 2000
Katritzky et al.
Ta ble 1. N-Ar yl-2-(ben zotr ia zolyl)-1-
a r yl(h eter oa r yl)bu ten -3-yla m in es (5)
Calcd for C16H12FN: C, 80.98; H, 5.10; N, 5.91. Found: C,
80.87; H, 4.88; N, 5.83.
1-P h en yl-2-(fu r a n -2-yl)p yr r ole (6i): white needles; mp
71-73 °C; yield 56%; 1H NMR δ 7.35-7.18 (m, 6H), 6.76 (t, J
) 2.0 Hz, 1H), 6.51 (dd, J ) 3.6, 1.9 Hz, 1H), 6.24 (t, J ) 3.0
Hz, 1H), 6.15 (dd, J ) 2.2, 1.7 Hz, 1H), 5.56 (d, J ) 3.4 Hz,
1H); 13C NMR δ 147.3, 140.9, 140.3, 129.0, 127.5, 126.2, 125.2,
124.3, 110.7, 109.7, 109.2, 105.5. Anal. Calcd for C14H11NO:
C, 80.36; H, 5.30; N, 6.69. Found: C, 80.07; H, 5.39; N, 6.88.
1-P h en yl-2-(th iop h en -3-yl)p yr r ole (6j): white plates; mp
86-88 °C; yield 70%; 1H NMR δ 7.28-7.20 (m, 3H), 7.14-
7.11 (m, 2H), 7.03 (dd, J ) 5.1, 2.9 Hz, 1H), 6.80-6.74 (m,
2H), 6.64 (dd, J ) 2.9, 1.2 Hz, 1H), 6.35 (dd, J ) 3.4, 1.7 Hz,
1H), 6.23 (t, J ) 3.2 Hz, 1H); 13C NMR δ 140.4, 133.4, 129.4,
129.0, 127.7, 127.0, 126.1, 124.7, 123.7, 120.3, 109.8, 108.9.
Anal. Calcd for C14H11NS: C, 74.63; H, 4.92; N, 6.22. Found:
C, 74.38; H, 4.75; N, 6.24.
Gen er a l P r oced u r e for th e Syn th esis of 1,2-Dia r yl-
(h et er oa r yl)-3-m et h ylp yr r oles (9). 2-(Buten-3-yl)benzo-
triazole (7) (1.74 g, 0.01 mol) in dry THF (60 mL) was cooled
under nitrogen to -78 °C, and 1.5 M solution of n-butyllithium
in hexanes (6.6 mL, 0.01 mol) was added dropwise at this
temperature during 20 min. The reaction mixture was stirred
at -78 °C for another 30 min, and then the corresponding
diarylimine (or N-aryl-heteroarylimine) (0.01 mol) in dry THF
(20 mL) was added dropwise. The resulting solution was
stirred at -78 °C for an additional 1 h and then quenched with
water. The product was extracted with chloroform, and the
chloroform extracts were filtered and washed with water.
Removal of the solvent gave a viscous oil which was subjected
to flash column chromatography (SiO2, hexane/ethyl acetate
) 7:3). The crude product 8 so obtained was used in the next
step.
compd
Ar1(Het)
Ar2
mp, °C
yield, %
5a
5b
5c
5d
5e
5f
5g
5h
5i
Ph
4-FC6H4
Ph
Ph
Ph
4-ClC6H4
4-MeC6H4
4-MeOC6H4
2-furyl
3-thiophenyl
3-pyridyl
3-pyridyl
Ph
Ph
164-165
165-166
194-195
159-160
60-62
171-172
167-168
176-178
118-120
143-144
173-174
189-190
85
71
81
52
65
80
76
75
46
66
71
48
2-ClC6H4
3-ClC6H4
4-ClC6H4
Ph
Ph
Ph
Ph
Ph
5j
5k
5l
Ph
4-ClC6H4
Ta ble 2. 1-Ar yl-2-a r yl(h eter oa r yl)p yr r oles (6) a n d
1-Ar yl-2-a r yl(h eter oa r yl)-3-m eth ylp yr r oles (9)
reaction
time, h
compd
Ar1(Het)
Ph
Ar2
mp, °C
yield, %
46
6a
Ph
Ph
24
68-70
(82-83)
73-74
72-74
liquid
74-75
110-112
liquid
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
9a
9b
4-FC6H4
Ph
12
12
16
6
79
52
78
72
76
76
21
56
70
56
68
26a
24a
2-ClC6H4
3-ClC6H4
4-ClC6H4
Ph
Ph
Ph
4-ClC6H4
4-MeC6H4
4-MeOC6H4 Ph
2-furyl Ph
3-thiophenyl Ph
3-pyridyl
3-pyridyl
Ph
8
Ph
24
12
16
15
16
24
16
24
liquid
71-73
86-88
liquid
78-80
liquid
Ph
4-ClC6H4
Ph
A mixture of crude 8 (18.8 mmol), prepared as described
above, anhydrous CuCl2 (0.51 g, 37.6 mmol), potassium
carbonate (0.52 g, 37.6 mmol), and catalytic amounts of
palladium(II) acetate (30 mg) and polymer-supported tri-
phenylphosphine (178 mg) in dry THF (50 mL) was heated
under reflux under nitrogen (for the reaction time required,
see Table 2). The residue obtained after solvent removal was
subjected to column chromatography (SiO2, hexane/chloroform
) 7:3) to give the corresponding 1,2-diaryl(heteroaryl)-3-
methylpyrrole.
3-thiophenyl Ph
liquid
a
Total yield, based on 2-(buten-3-yl)benzotriazole (7).
7.12-7.06 (m, 5H), 6.78-6.52 (m, 6H), 5.52-5.39 (m, 3H), 5.00
(dd, J ) 7.8, 3.3 Hz, 1H), 4.66 (d, J ) 2.4 Hz, 1H); 13C NMR δ
162.1 (d, J ) 246.8 Hz), 146.2, 145.3, 134.8, 132.7, 132.4, 129.0,
128.3 (d, J ) 8.1 Hz), 127.3, 123.9, 121.7, 119.8, 118.5, 115.4
(d, J ) 21.2 Hz), 114.0, 109.1, 67.4, 60.8. Anal. Calcd for
C
22H19FN4: C, 73.72; H, 5.34; N, 15.63. Found: C, 73.78; H,
1,2-Dip h en yl-3-m eth ylp yr r ole (9a ): colorless liquid, yield
26% (total yield, based on 2-(buten-3-yl)benzotriazole); 1H
NMR δ 7.56-7.06 (m, 8H), 6.94 (dd, J ) 2.9, 1.2 Hz, 1H), 6.84
(d, J ) 2.7 Hz, 1H), 6.70 (dd, J ) 4.9, 1.2 Hz, 1H), 6.22 (d, J
) 2.9 Hz, 1H), 2.20 (s, 3H); 13C NMR δ 140.7, 132.6, 131.0,
129.1, 128.9, 128.8, 128.5, 126.2, 125.3, 124.3, 122.9, 122.8,
121.9, 110.9, 12.3; HRMS (FAB) calcd for C17H16N (M + 1)
234.1283, found 234.1263. Anal. Calcd for C17H15N: N, 6.00.
Found: N, 5.92.
5.52; N, 15.79.
N-P h en yl-2-(ben zotr ia zol-1-yl)-1-(th iop h en -3-yl)bu ten -
3-yla m in e (5j): white needles; mp 143-144 °C; yield 66%; 1H
NMR δ 8.01 (d, J ) 6.8 Hz, 1H), 7.35-7.24 (m, 2H), 7.15-
7.02 (m, 4H), 6.88 (d, J ) 2.4 Hz, 1H), 6.71 (t, J ) 6.9 Hz,
2H), 6.64-6.52 (m, 3H), 5.54-5.37 (m, 3H), 5.18 (d, J ) 7.3
Hz, 1H), 4.55 (br s, 1H); 13C NMR δ 146.4, 145.4, 140.3, 132.9,
132.6, 129.1, 127.2, 126.3, 125.6, 123.8, 122.5, 121.4, 119.8,
118.5, 113.9, 109.4, 67.0, 57.6. Anal. Calcd for C20H18N4S: C,
69.34; H, 5.24; N, 16.17. Found: C, 68.98; H, 5.26; N, 16.31.
Gen er a l P r oced u r e for th e Syn th esis of 1,2-Dia r yl-
(h eter oa r yl)p yr r oles (6). A mixture of an amino-substituted
allylbenzotriazole (5) (26.4 mmol), anhydrous CuCl2 (0.71 g,
52.8 mmol), potassium carbonate (0.73 g, 52.8 mmol), tri-
phenylphosphine (0.14 g, 0.5 mmol), and catalytic amount (30
mg) of palladium(II) acetate in dry THF (50 mL) was heated
under reflux under nitrogen (for the reaction time required,
see Table 2). The residue obtained after the solvent removal
was subjected to column chromatography (SiO2, hexane/
chloroform ) 7:3) to give the corresponding 1,2-diaryl(het-
eroaryl)pyrrole.
1-P h en yl-2-(th iop h en -3-yl)-3-m eth ylp yr r ole (9b): color-
less liquid; yield 24% (total yield, based on 2-(buten-3-yl)-
1
benzotriazole); H NMR δ 7.58-7.46 (m, 1H), 7.32-7.20 (m,
2H), 7.18-7.08 (m, 3H), 6.93 (d, J ) 2.9 Hz, 1H), 6.84 (d, J )
2.8 Hz, 1H), 6.69 (d, J ) 5.0 Hz, 1H), 6.22 (d, J ) 2.8 Hz, 1H);
13C NMR δ 140.7, 132.8, 131.0, 128.9, 128.8, 126.2, 125.3,
124.3, 122.9, 121.9, 119.0, 110.9, 12.3; HRMS (FAB) calcd for
C
C
15H14NS (M + 1) 240.0847, found 240.0853. Anal. Calcd for
15H13NS: N, 5.85. Found: N, 5.97.
Ack n ow led gm en t. We thank the National Science
Foundation (CHE-9629854) for partial support.
1-P h en yl-2-(4-flu or op h en yl)p yr r ole (6b): white micro-
crystals; mp 73-74 °C; yield 79%; H NMR δ 7.20-7.08 (m,
3H), 7.04-6.92 (m, 4H), 6.82-6.72 (m, 3H), 6.27 (dd, J ) 3.7,
1.8 Hz, 1 H), 6.23 (t, J ) 3.1 Hz, 1H); 13C NMR δ 161.5 (d, J
) 245.8 Hz), 140.2, 132.7, 129.8 (d, J ) 8.1 Hz), 129.1, 129.0,
126.6, 125.6, 124.2, 115.0 (d, J ) 21.7 Hz), 110.5, 109.2. Anal.
1
Su p p or tin g In for m a tion Ava ila ble: Experimental data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O000885X