1,4-Disubstituted and 1,4,5-trisubstituted 2-[(benzotriazol-1-yl)methyl]pyrroles as versatile synthetic intermediates

Article abstract of DOI:10.1021/jo951894m

The CH₂Bt substituent, unlike previously used CH₂X substituents, enables (i) the synthetic elaboration of pyrroles with unsubstituted ring positions and (ii) electrophilic as well as nucleophilic substitutions to give pyrroles of typ

Full text of DOI:10.1021/jo951894m

1624
J . Org. Chem. 1996, 61, 1624-1628
1,4-Disu bstitu ted a n d 1,4,5-Tr isu bstitu ted
2-[(Ben zotr ia zol-1-yl)m eth yl]p yr r oles a s Ver sa tile Syn th etic
In ter m ed ia tes
Alan R. Katritzky* and J ianqing Li
Center for Heterocyclic compounds, Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
Received October 24, 1995X
The CH2Bt substituent, unlike previously used CH2X substituents, enables (i) the synthetic
elaboration of pyrroles with unsubstituted ring positions and (ii) electrophilic as well as nucleophilic
substitutions to give pyrroles of type pyrrolyl-2-CHENu. Thus, 1,4-disubstituted (7) and 1,4,5-
trisubstituted 2-[(benzotriazol-1-yl)methyl]pyrroles (15) were easily prepared from the reaction of
5-(benzotriazol-1-yl)-1,2-epoxy-3-pentynes 4 or 14 with primary amines in i-PrOH. The 2-(benzo-
triazol-1-yl)methyl side chains of compounds 7 and 15 were elaborated by nucleophilic substitution
and also by initial alkylation followed by replacement or elimination of the benzotriazolyl moiety
to afford a variety of 1,2,4-trisubstituted (6, 8-9, 11-13) and 1,2,4,5-tetrasubstituted pyrroles (18,
20-22).
Ch a r t 1
In tr od u ction
Novel syntheses of pyrroles are of current interest.1-4
2-(Functionalized-methyl)pyrroles 1 and 2-alkenylpyr-
roles 2 are versatile intermediates in organic synthesis,
especially for natural products.1,4-10 Owing to their great
synthetic importance, a range of pyrrole intermediates
containing 2-CH2X groups have been studied1,2,6-11 in
which X has varied widely: halogen, hydroxy, alkoxy,
alkylthio, amino, cyano, etc., as shown in Chart 1. Among
these, halogenomethyl groups have been most frequently
employed inter alia for the preparation of other CH2X
groups by nucleophilic substitutions.9,11 However, the use
of CH2-halogen groups is limited to the pyrroles in which
all the ring carbons are substituted, otherwise difficulties
arise from their instability and sensitivity to rapid
intermolecular nucleophilic attack to form polymers.9,12-15
Quaternary ammonium groups of type CH2N+R3 can also
be displaced by nucleophiles.7,11 The other functional
groups CH2X mentioned above are less susceptible to
nucleophilic substitution. Base-assisted alkylation has
only been achieved for 2-(cyanomethyl)- and 2-[(alkoxy-
carbonyl)methyl]pyrroles.9 In particular, neither alky-
lation and subsequent nucleophilic substitution of CH2X
to give CHENu nor the elimination to form 2-alkenylpyr-
roles 2 (another class of important compounds) has
previously been reported.
We now report a convenient method for the synthesis
of 1,4-di- and 1,4,5-trisubstituted 2-[(benzotriazol-1-yl)-
methyl]pyrroles 7 and 15 and the transformations of their
side-chain 2-(benzotriazol-1-yl)methyl groups by nucleo-
philic substitution, or by initial alkylation followed by
replacement or elimination of the benzotriazolyl group,
which allows the preparation of elaborated pyrroles
unsubstituted either at the 3- and 5-positions or at the
3-position.
Resu lts a n d Discu ssion
X Abstract published in Advance ACS Abstracts, February 15, 1996.
(1) Kinoshita, H.; Tanaka, S.; Inomata, K. Chem. Lett. 1989, 1107.
(2) Kinoshita, H.; Tanaka, S.; Nishimori, N.; Dejima, H.; Inomata,
K. Bull. Chem. Soc. J pn. 1992, 65, 2660.
(3) Danks, T. N.; Velo-Rego, D. Tetrahedron Lett. 1994, 35, 9443.
(4) Kagabu, S.; Tsuji, H.; Kawai, I.; Ozeki, H. Bull. Chem. Soc. J pn.
1995, 68, 341.
(5) Frydman, B.; Reil, S.; Valasinas, A.; Frydman, R. B.; Rapoport,
H. J . Am. Chem. Soc. 1971, 93, 2738.
(6) Gonsalves, A. M. d’A. R.; Kenner, G. W.; Smith, K. M. Tetrahe-
dron Lett. 1972, 2203.
(7) Magnus, P.; Gallagher, T. J . Chem. Soc., Chem. Commun. 1984,
389.
(8) Wee, A. G. H.; Shu, A. Y. L.; Bunnenberg, E.; Djerassi, C. J .
Org. Chem. 1984, 49, 3327.
(9) J ones, R. A. In Comprehensive Heterocyclic Chemistry; Katritzky,
A. R., Rees, C. W., Eds.; Pergamon Press: Oxford, 1984; Vol. 4, p 270.
(10) J ackson, A. H.; Pandey, R. K.; Rao, K. R. N.; Roberts, E.
Tetrahedron Lett. 1985, 26, 793.
(11) J ones, R. A.; Bean, G. P. In The Chemistry of Pyrroles; Academic
Press: London, 1977; p 355.
P r ep a r a tion of 1,4-Di- a n d 1,4,5-Tr isu bstitu ted
2-[(Ben zotr ia zol-1-yl)m eth yl]p yr r oles 7 a n d 15. We
have recently described the synthesis of substituted
furans by base-catalyzed cyclization of alkynyloxiranes
4 and 14 which were easily prepared from the reaction
of 1-propargylbenzotriazole (3) with R-bromo ketones.16
The epoxides of types 4 and 14 have now been further
utilized for the preparation of pyrrole systems: refluxing
4 and 14 with primary amines in i-PrOH gave 1,4-
disubstituted (7, Scheme 1) and 1,4,5-trisubstituted
2-[(benzotriazol-1-yl)methyl]pyrroles (15, Scheme 3) in
good yields. A similar reaction was previously reported
for other alkynyloxiranes without using solvents;17 how-
ever, under these reaction conditions our alkynyloxiranes
4 or 14 reacted with amines to give furans as major
products.16 Presumably 1,4-elimination of 4 and 14
(12) Baltazzi, E.; Krimen, L. I. Chem. Rev. 1963, 63, 511.
(13) Treibs, A.; Grimm, D. Liebigs Ann. Chem. 1978, 2024.
(14) Angelini, G.; Illuminati, G.; Monaci, A.; Sleiter, G.; Speranza,
M. J . Am. Chem. Soc. 1980, 102, 1377.
(15) Angelini, G.; Giancaspro, C.; Illuminati, G.; Sleiter, G. J . Org.
Chem. 1980, 45, 1786.
(16) Katritzky, A. R.; Li, J . J . Org. Chem. 1995, 60, 638.
(17) Perveev, F. Ya.; Kuznetsova, E. M. Zh. Obshch. Khim. 1958,
28, 2360; Chem. Abstr. 1959, 52, 3767g.
0022-3263/96/1961-1624$12.00/0 © 1996 American Chemical Society

2-(Benzotriazol-1-yl)methylpyrroles as Synthetic Intermediates
J . Org. Chem., Vol. 61, No. 5, 1996 1625
Sch em e 1
Ta ble 1. Rea ction s of 1,4-Di- a n d 1,4,5-Tr isu bstitu ted -2-[(ben zotr ia zol-1-yl)a lk yl]p yr r oles 7, 10, 15, 17, a n d 19
found (calcd)
temp time
yield
entry substr
reagent
CH3MgI
NaSPh
NaCN
solvent (°C)
(h) product (%)
mp (°C)
87 oil
mol form
C19H19
C
H
N
1
2
7a
7a
toluene reflux
6
24
6
8
N
87.13 (87.31) 7.38 (7.33) 5.40 (5.36)
84.22 (83.87) 6.57 (6.34) 9.48 (9.79)
DMF
DMF
DMF
THF
THF
150
reflux 12
150 10
reflux 12
reflux 12
65 99-100
52 65-66
79 96-97
73 156-157
90 oil
C
C
C
C
C
C
24H21NS 80.87 (81.09) 5.96 (5.96) 3.89 (3.94)
20H18N2
25H23NS 81.03 (81.27) 6.43 (6.28) 3.78 (3.79)
25H22N2O 82.05 (81.93) 6.05 (6.06) 7.67 (7.65)
20H28N2S 73.35 (73.13) 8.80 (8.60) 8.52 (8.53)
3
4
5
6
7
8
10a
10a
10b
10c
15a
17
9
NaSPh
11
12
13
18
20
21
22
Zn/HOAc
Zn/HOAc
PhMgBr
K2CO3
NaCH(COOEt)2 DMF
NaCN DMF
toluene reflux
3
12
12
91 oil
57 oil
17H23
N
84.93 (84.58) 9.82 (9.61) 5.76 (5.81)
DMF
120
140
C19H25NO 80.68 (80.51) 9.11 (8.90) 4.87 (4.94)
C26H37NO5 70.05 (70.40) 8.51 (8.41) 3.40 (3.16)
C19H22N2
9
17
76 oil
10
19
reflux 12
54a oil
81.65 (81.96) 8.12 (7.97) 10.20 (10.07)
a
Yield was based on compound 15.
predominated instead of nucleophilic attack at the ep-
oxide ring. Therefore, for the present reactions, solvent
is essential and the yields were better with i-PrOH than
with DMF.
were easily converted by lithiation and subsequent
quenching with the appropriate electrophile such as
methyl iodide, phenyl isocyanate, and phenyl isothiocy-
anate to give the corresponding products 10a -c in high
yields. The nucleophilic substitution of the benzotriazolyl
group in the substituted derivatives 10a with sodium
thiophenolate was much faster than that of compound
7a due to the stabilization of the intermediate carbocation
by the directly attached methyl group, and thus the
reaction gave the product 11 in higher yield (Table 1).
Compounds of type 10b and 10c readily underwent
reductive elimination of benzotriazole when they were
treated with zinc in the presence of acetic acid to generate
pyrrol-2-ylacetanilide 12 and -thioacetanilide 13, respec-
tively.
Ela bor a tion of th e 2-(Ben zotr ia zol-1-yl)m eth yl
Sid e Ch a in . Work in our laboratory has demonstrated
that benzotriazole is a good synthetic auxiliary.18 The
good leaving ability and the anion-stabilizing capability
are two of its advantageous features which have been
well recognized. Thus, compound 7a readily underwent
nucleophilic substitution with methylmagnesium iodide
and sodium thiophenolate to give the corresponding
products 6 and 8, respectively, in good yields (Scheme
1). The electron-rich pyrrole nucleus assisted the reac-
tion by stabilizing the transient carbocations.
Interestingly, the reaction of 10a with sodium cyanide
in DMF gave the SN′ type of “abnormal” product 9 in 52%
yield; this result supports the SN1 pathway described by
Maryanoff and co-workers.19 The proposed mechanism
is illustrated in Scheme 2. We were unable to isolate
the other possible isomers by column chromatography.
It is well-known that pyrroles smoothly undergo 2-lithi-
ation; however, in the case of compounds 7, lithiation
occurred regiospecifically at the carbon attached to the
benzotriazolyl group due to the electron-withdrawing
ability of the benzotriazolyl moiety. Accordingly, the 3,5-
unsubstituted 2-[(benzotriazol-1-yl)methyl]pyrroles 7a ,b
(18) Katritzky, A. R.; Wu, H.; Xie, L.; Rachwal, S.; Rachwal, B.;
J iang, J .; Zhang, G.; Lang, H. Synthesis 1995, 1315.
(19) Carson, J . R.; Hortenstine, J . T.; Maryanoff, B. E.; Molinari,
A. J . J . Org. Chem. 1977, 42, 1096.

1626 J . Org. Chem., Vol. 61, No. 5, 1996
Katritzky and Li
Sch em e 2
ing of the reaction with benzaldehyde generated the
alkylated anion which was trapped by addition of methyl
iodide and HMPA to give the intermediate 19. 19 was
treated with sodium cyanide without purification to
undergo initially nucleophilic substitution of the benzo-
triazolyl group by cyanide and then elimination of
methanol to afford vinylpyrrole 22.
In conclusion, 1,4-di- and 1,4,5-trisubstituted 2-[(ben-
zotriazol-1-yl)methyl]pyrroles 7 and 15, derived from the
reaction of alkynyloxiranes 4 and 14 with R-bromo
ketones, readily underwent nucleophilic replacement of
the benzotriazolyl group with Grignard reagents and
sodium thiophenolate. Compounds 7 and 15 were alky-
lated via lithiation and subsequent quenching with the
appropriate electrophile to give intermediates 10, 17 and
19 in which the benzotriazolyl group could either be
replaced by a variety of nucleophiles or eliminated in the
presence of a base. Compounds 10b,c were reduced by
zinc in acetic acid to afford the corresponding products
12 and 13. The above benzotriazole-mediated transfor-
mations should find general use in synthesis; the trans-
formation should be applicable to any alkyl or aryl
substituents at C-4 and C-5.
Sch em e 3
Exp er im en ta l Section
Gen er a l. Melting points were determined on a hot-stage
microscope and are uncorrected. 1H NMR spectra were
recorded on a 300 MHz spectrometer using TMS as the
internal standard and CDCl3 as the solvent. 13C NMR spectra
were recorded at 75 MHz on the same instrument with the
solvent peak (CDCl3) as the reference. Elemental analyses (C,
H, N) were carried out within the department.
1-Propargylbenzotriazole (3) was prepared according to the
procedure described in the literature.20 All R-bromo ketones
were purchased neat and used without further purification.
The preparation of compound 14a was reported in a previous
paper.16
Gen er a l P r oced u r e for th e P r ep a r a tion of Ep oxid es
4a ,b a n d 14b. To a stirred solution of 1-propargylbenzotria-
zole (3) (1.57 g, 10 mmol) in THF (50 mL) was added at -78
°C a solution of n-BuLi (5.5 mL, 11 mmol, 2.0 M in cyclohex-
ane). The mixture was stirred at this temperature for 1 h,
and R-bromo ketone (indicated in Schemes 1 and 3) (10 mmol)
in THF (5 mL) was added slowly. After stirring at -78 °C for
5 to 8 h, diethyl ether (100 mL) and water (100 mL) were added
and the organic phase was separated, washed with a saturated
NH4Cl solution (3 × 100 mL), and dried (MgSO4). Evaporation
of the solvent gave the crude product which was purified by
column chromatography using EtOAc/hexane (1:4) as the
eluent to afford the pure product.
5-(Be n zot r ia zol-1-yl)-1,2-e p oxy-2-p h e n yl-3-p e n t yn e
1
(4a ): yellow oil, yield 76%; H NMR δ 8.05 (d, J ) 8.4 Hz, 1
H), 7.69 (d, J ) 8.3 Hz, 1 H), 7.46-7.52 (m, 1 H), 7.28-7.41
(m, 6 H), 5.55 (s, 2 H), 3.35 (d, J ) 6.0 Hz, 1 H), 2.97 (d, J )
6.0 Hz, 1 H); 13C NMR δ 145.9, 135.9, 132.2, 128.3, 128.2 (2C),
127.5, 125.1 (2C), 124.0, 119.8, 109.5, 84.1, 75.9, 58.6, 50.5,
38.0. Anal. Calcd for C17H13N3O: C, 74.15; H, 4.76; N, 15.27.
Found: C, 74.03; H, 4.77; N, 15.37.
Similarly, the benzotriazolyl group of the 3-unsubsti-
tuted 2-[(benzotriazol-1-yl)methyl]pyrrole 15a was readily
replaced by phenylmagnesium bromide to give compound
18 (Scheme 3). Compound 15b was treated with 1.1
equiv of n-BuLi at -78 °C for 1 h followed by reaction
with n-butyl iodide to yield product 17. Upon treatment
with potassium carbonate in DMF under reflux, com-
pound 17 underwent base-catalyzed elimination of ben-
zotriazole to form alkenylpyrrole 20 which is stable and
can be isolated by column chromatography as a 3:1 E:Z
mixture. When compound 17 was refluxed with sodium
malonate in DMF for 12 h, the substituted product of type
21 was obtained in 76% yield. Treatment of compound
15a with 1.1 equiv of n-butyllithium followed by quench-
5-(Be n zot r ia zol-1-yl)-1,2-e p oxy-2-t er t -b u t yl-3-p e n -
1
tyn e (4b): white solid, yield 76%; mp 49-50 °C; H NMR δ
8.09 (d, J ) 8.4 Hz, 1 H), 7.71 (d, J ) 8.3 Hz, 1 H), 7.51-7.57
(m, 1 H), 7.30-7.44 (m, 1 H), 5.51 (s, 2 H), 2.93 (d, J ) 5.2 Hz,
1 H), 2.86 (d, J ) 5.2 Hz, 1 H), 0.97 (s, 9 H); 13C NMR δ 146.2,
132.4, 127.6, 124.1, 120.1, 109.6, 85.4, 74.5, 57.1, 51.5, 38.2,
33.2, 25.4. Anal. Calcd for C15H17N3O: C, 70.55; H, 6.72; N,
16.47. Found: C, 70.22; H, 6.69; N, 16.77.
5-(Ben zot r ia zol-1-yl)-1,2-ep oxy-1-m et h yl-2-p h en yl-3-
p en tyn e (14b): yellow oil, yield 67%; 1H NMR δ 8.05 (d, J )
(20) Katritzky, A. R.; Li, J .; Malhotra, N. Liebigs Ann. Chem. 1992,
843.

2-(Benzotriazol-1-yl)methylpyrroles as Synthetic Intermediates
J . Org. Chem., Vol. 61, No. 5, 1996 1627
8.3 Hz, 1 H), 7.66 (d, J ) 8.3 Hz, 1 H), 7.46-7.51 (m, 1 H),
7.30-7.42 (m, 6 H), 5.51 (s, 2 H), 3.53 (q, J ) 5.4 Hz, 1 H),
1.01 (d, J ) 5.5 Hz, 3 H); 13C NMR δ 146.0, 134.3, 132.3, 128.1,
128.0 (2C), 127.5, 126.7 (2C), 124.0, 119.9, 109.6, 86.2, 74.5,
62.7, 55.2, 38.1, 12.9. Anal. Calcd for C18H15N3O: C, 74.71;
H, 5.23; N, 14.53. Found: C, 74.37; H, 5.24; N, 14.73.
21.2. Anal. Calcd for C25H22N4: C, 79.34; H, 5.86; N, 14.80.
Found: C, 79.34; H, 5.94; N, 14.43.
r-(N-Ben zyl-4-p h en ylp yr r ol-2-yl)-r-(ben zotr ia zol-1-yl)-
a ceta n ilid e (10b): recrystallized from EtOAc/hexane (1:3),
1
white solid, yield 87%; mp 104-105 °C; H NMR δ 9.70 (s, 1
H), 7.56 (d, J ) 8.4 Hz, 1 H), 7.34-7.44 (m, 5 H), 6.92-7.24
(m, 10 H), 6.58-6.74 (m, 4 H), 6.33 (d, J ) 7.2 Hz, 2 H), 4.68
(d, J ) 16.2 Hz, 1 H), 4.54 (d, J ) 16.2 Hz, 1 H); 13C NMR δ
164.5, 145.8, 137.4, 135.8, 134.5, 133.2, 128.9 (2C), 128.6 (2C),
128.1 (2C), 127.8, 127.1, 125.9, 125.7 (2C), 124.8 (2C), 124.7,
124.2, 121.5, 119.9 (2C), 119.0, 112.2, 109.9, 60.6, 50.4. Anal.
Calcd for C31H25N5O: C, 77.00; H, 5.21; N, 14.49. Found: C,
77.29; H, 5.24; N, 14.43.
Gen er a l P r oced u r e for th e P r ep a r a tion of 1,4-Di- a n d
1,4,5-Tr isu b st it u t ed 2-[(Ben zot r ia zol-1-yl)m et h yl]p yr -
r oles 7 a n d 15. A solution of epoxide 4 or 14 (20 mmol) and
the appropriate primary amine (40 mmol) (see Schemes 1 and
3) in i-PrOH (100 mL) was refluxed for 24-48 h. After cooling,
the solvent was removed under reduced pressure to give an
oil was purified by short column chromatography using EtOAc/
hexane as the eluent to afford the corresponding product.
N-Ben zyl-2-[(b en zot r ia zol-1-yl)m et h yl]-4-p h en ylp yr -
r ole (7a ): white needles, yield 82%; mp 157-158 °C; 1H NMR
δ 7.97 (d, J ) 8.0 Hz, 1 H), 7.51 (d, J ) 7.2 Hz, 2 H), 7.16-
7.44 (m, 9 H), 7.02 (d, J ) 1.9 Hz, 1 H), 6.90-6.93 (m, 2 H),
6.76 (d, J ) 1.9 Hz, 1 H), 5.74 (s, 2 H), 5.08 (s, 2 H); 13C NMR
δ 146.3, 136.8, 135.0, 132.7, 128.7 (2C), 128.6 (2C), 127.6,
127.3, 126.3 (2C), 125.8, 125.6, 124.9 (2C), 124.0, 123.9, 120.9,
119.9, 110.1, 109.8, 50.9, 44.9. Anal. Calcd for C24H20N4: C,
79.08; H, 5.53; N, 15.38. Found: C, 78.81; H, 5.46; N, 15.35.
N-n -Bu tyl-2-[(ben zotr iazol-1-yl)m eth yl]-4-ter t-bu tylpyr -
r-(N-n -Bu tyl-4-ter t-bu tylp yr r ol-2-yl)-r-(ben zotr ia zol-1-
yl)th ioa ceta n ilid e (10c): recrystallized from Et2O, white
1
solid, yield 94%; mp 147-148 °C; H NMR δ 10.00 (s, 1 H),
8.01 (d, J ) 8.3 Hz, 1 H), 7.72 (d, J ) 7.7 Hz, 2 H), 7.33-7.48
(m, 5 H), 7.22-7.27 (m, 2 H), 6.54 (d, J ) 2.0 Hz, 1 H), 6.48
(d, J ) 2.0 Hz, 1 H), 3.59-3.73 (m, 2 H), 1.42-1.54 (m, 1 H),
1.03-1.36 (m, 12 H), 0.72 (t, J ) 7.3 Hz, 3 H); 13C NMR δ
192.8, 145.7, 138.2, 135.3, 133.4, 128.9 (2C), 128.0, 127.0,
124.3, 123.4, 122.9 (2C), 119.9, 119.0, 110.5, 108.5, 68.4, 46.8,
33.1, 31.7, 30.5, 19.8, 13.5. Anal. Calcd for C26H31N5S: C,
70.08; H, 7.01; N, 15.72. Found: C, 70.21; H, 7.08; N, 15.83.
1
r ole (7b): white solid, yield 63%; mp 69-70 °C; H NMR δ
N-(2-Met h oxyet h yl)-2-[r-(b en zot r ia zol-1-yl)p en t yl]-4-
p h en yl-5-m eth ylp yr r ole (17): purified by column chroma-
8.01 (d, J ) 8.2 Hz, 1 H), 7.26-7.37 (m, 3 H), 6.44 (d, J ) 2.0
Hz, 1 H), 6.31 (d, J ) 2.0 Hz, 1 H), 5.79 (s, 2 H), 3.73 (t, J )
7.4 Hz, 2 H), 1.02-1.40 (m, 4 H), 1.25 (s, 9 H), 0.79 (t, J ) 7.3
Hz, 3 H); 13C NMR δ 146.2, 134.5, 132.7, 127.0, 123.6, 123.2,
119.6, 117.7, 110.2, 108.8, 46.3, 45.1, 33.2, 31.6, 30.3, 19.7, 13.5.
Anal. Calcd for C19H26N4: C, 73.50; H, 8.45; N, 18.06.
Found: C, 73.86; H, 8.57; N, 18.16.
1
tography using EtOAc/hexane (1:4), yellow oil, yield 77%; H
NMR δ 8.00-8.04 (m, 1 H), 7.50-7.55 (m, 1 H), 7.19-7.44 (m,
7 H), 6.67 (s, 1 H), 6.41 (t, J ) 7.6 Hz, 1 H), 3.94-4.04 (m, 1
H), 3.80-3.89 (m, 1 H), 3.15-3.20 (m, 2 H), 3.17 (s, 3 H), 2.45-
2.53 (m, 2 H), 2.26 (s, 3 H), 1.26-1.47 (m, 3 H), 1.08-1.18 (m,
1 H), 0.86 (t, J ) 7.1 Hz, 3 H); 13C NMR δ 146.7, 136.9, 131.6,
128.2 (2C), 128.0 (2C), 127.4, 126.9, 126.7, 125.3, 123.7, 121.4,
119.8, 111.1, 108.4, 71.7, 58.9, 56.9, 43.5, 32.6, 28.4, 22.0, 13.7,
11.0. Anal. Calcd for C25H30N4O: C, 74.58; H, 7.52; N, 13.93.
Found: C, 74.93; H, 7.55; N, 13.67.
N-n -Bu t yl-2-[(b en zot r ia zol-1-yl)m et h yl]-4,5-d im et h -
ylp yr r ole (15a ): white solid, yield 62%; mp 86-87 °C; 1H
NMR δ 7.99 (d, J ) 8.2 Hz, 1 H), 7.47 (d, J ) 8.2 Hz, 1 H),
7.24-7.37 (m, 2 H), 6.17 (s, 1 H), 5.76 (s, 2 H), 3.74 (t, J ) 7.8
Hz, 2 H), 2.04 (s, 3 H), 2.01 (s, 3 H), 1.10-1.28 (m, 4 H), 0.81
(t, J ) 7.1 Hz, 3 H); 13C NMR δ 146.1, 132.5, 126.9, 126.6,
123.5, 121.3, 119.4, 113.8, 111.5, 110.3, 45.1, 43.7, 32.9, 19.7,
13.5, 10.9, 9.5. Anal. Calcd for C17H22N4: C, 72.29; H, 7.86;
N, 19.85. Found: C, 72.60; H, 7.88; N, 19.92.
N-(2-Met h oxyet h yl)-2-[(b en zot r ia zol-1-yl)m et h yl]-4-
p h en yl-5-m eth ylp yr r ole (15b): brown oil, yield 57%; 1H
NMR δ 8.02 (d, J ) 8.3 Hz, 1 H), 7.53 (d, J ) 8.2 Hz, 1 H),
7.26-7.38 (m, 6 H), 7.17-7.21 (m, 1 H), 6.46 (s, 1 H), 5.91 (s,
2 H), 4.09 (t, J ) 5.4 Hz, 2 H), 3.33 (t, J ) 5.4 Hz, 2 H), 3.21
(s, 3 H), 2.27 (s, 3 H); 13C NMR δ 146.2, 136.6, 132.7, 128.2
(2C), 127.9 (2C), 127.1, 127.0, 125.2, 123.9, 123.7, 121.4, 119.6,
110.5, 110.2, 71.8, 58.9, 45.0, 43.8, 10.9. Anal. Calcd for
C21H22N4O: C, 72.79; H, 6.40; N, 16.18. Found: C, 73.12; H,
6.57; N, 16.11.
Alk yla tion of 1,4-Di- a n d 1,4,5-Tr isu bstitu ted -2-[(ben -
zotr ia zol-1-yl)m eth yl]p yr r oles 7 a n d 15. To a solution of
compound 7 or 15 (5 mmol) in THF (80 mL) at -78 °C was
added a solution of n-BuLi (5.5 mmol, 2.75 mL, 2.0 M in
cyclohexane). The reaction mixture was stirred at -78 °C for
1 h, and then a solution of an appropriate electrophile (5 mmol)
in THF (5 mL) such as methyl iodide, phenyl isocyanate,
phenyl isothiocyanate, and butyl iodide was added. After the
reaction solution was stirred for another hour, water (100 mL)
was poured into the solution and the mixture was extracted
with ethyl acetate (100 mL), washed with water (3 × 100 mL),
and dried (MgSO4). The solvent was removed under reduced
pressure to give the crude product which was purified either
by recrystallization or column chromatography to afford the
corresponding product in pure state.
Nu cleop h ilic Su bstitu tion of 7a a n d 15a w ith Gr ig-
n a r d Rea gen ts. To a solution of compound 7a or 15a (2
mmol) in toluene (30 mL) was added a freshly prepared
solution of CH3MgI (5 mmol) in Et2O (5 mL) at room temper-
ature, and the solution was then refluxed for the time indicated
in Table 1. After cooling, the solvent was removed under
reduced pressure and the residue was extracted with Et2O (50
mL), washed with water (3 × 50 mL), and dried (MgSO4). After
removal of the solvent, the crude product was purified by
column chromatography using CH2Cl2/hexane (1:4) as eluent
to afford product 6 or 18.
1
N-Ben zyl-2-eth yl-4-p h en ylp yr r ole (6): see Table 1; H
NMR δ 7.47-7.50 (m, 2 H), 7.19-7.29 (m, 5 H), 7.06-7.11 (m,
1 H), 6.98 (d, J ) 7.0 Hz, 2 H), 6.87 (d, J ) 2.0 Hz, 1 H), 6.28
(d, J ) 2.0 Hz, 1 H), 4.93 (s, 2 H), 2.43 (q, J ) 7.5 Hz, 2 H),
1.19 (t, J ) 7.5 Hz, 3 H); 13C NMR δ 138.1, 136.1, 135.9, 128.6
(2C), 128.5 (2C), 127.3, 126.3 (2C), 125.0, 124.7 (2C), 123.5,
117.5, 103.4, 50.2, 19.3, 12.8.
N-n -Bu tyl-2-ben zyl-4,5-d im eth ylp yr r ole (18): see Table
1
1; H NMR δ 7.11-7.28 (m, 5 H), 5.61 (s, 1 H), 3.87 (s, 2 H),
3.59 (t, J ) 7.9 Hz, 2 H), 2.09 (s, 3 H), 1.98 (s, 3 H), 1.34-1.44
(m, 2 H), 1.21-1.30 (m, 2 H), 0.85 (t, J ) 7.4 Hz, 3 H); 13C
NMR δ 140.0, 128.9, 128.6 (2C), 128.3 (2C), 126.0, 123.9, 113.2,
108.3, 43.7, 33.2, 33.1, 20.1, 13.7, 11.2, 9.7.
Nu cleop h ilic Su bstitu tion of 7a a n d 10a w ith Sod iu m
Th iop h en ola te. A solution of compound 7a or 10a (1 mmol)
and sodium thiophenolate (0.66 g, 5 mmol) in DMF (50 mL)
under nitrogen was heated at 150 °C for the time indicated in
Table 1. After cooling, water (100 mL) and Et2O (100 mL)
were added. The organic phase was separated, washed with
a saturated NaCl solution (3 × 100 mL), and dried (MgSO4).
After removal of the solvent, the residue was subjected to
column chromatography using CH2Cl2/hexane (1:4) as eluent
to afford product 8 or 11.
N-Ben zyl-2-[1-(b en zot r ia zol-1-yl)et h yl]-4-p h en ylp yr -
r ole (10a ): recrystallized from EtOAc/hexane (1:3), white
1
plates, yield 98%; mp 142-143 °C; H NMR δ 7.91-7.95 (m,
1 H), 7.58 (d, J ) 8.0 Hz, 2 H), 7.37 (t, J ) 7.6 Hz, 2 H), 7.18-
7.27 (m, 4 H), 7.08-7.13 (m, 3 H), 7.02 (d, J ) 1.6 Hz, 1 H),
6.93 (d, J ) 1.6 Hz, 1 H), 6.76-6.80 (m, 2 H), 6.24 (q, J ) 7.1
Hz, 1 H), 4.83 (d, J ) 16.2 Hz, 1 H), 4.69 (d, J ) 16.2 Hz, 1 H),
2.01 (d, J ) 7.1 Hz, 3 H); 13C NMR δ 148.2, 138.1, 136.7, 133.1,
131.4, 130.4 (2C), 130.1 (2C), 129.1, 128.8, 127.8 (2C), 127.4,
126.5 (2C), 125.4, 125.3, 122.5, 121.5, 112.4, 109.1, 54.1, 52.3,
N -Be n zyl-2-[(p h e n ylt h io)m e t h yl]-4-p h e n ylp yr r ole
1
(8): see Table 1; H NMR δ 7.50 (d, J ) 7.2 Hz, 2 H), 7.06-
7.34 (m, 13 H), 6.95 (d, J ) 1.6 Hz, 1 H), 6.36 (d, J ) 1.6 Hz,
1 H), 5.17 (s, 2 H), 4.00 (s, 2 H); 13C NMR δ 137.7, 135.8, 135.5,

1628 J . Org. Chem., Vol. 61, No. 5, 1996
Katritzky and Li
130.6 (2C), 128.8 (2C), 128.7 (2C), 128.5 (2C), 128.3, 127.6,
126.7, 126.6 (2C), 125.3, 124.8 (2C), 123.7, 119.5, 108.0, 50.7,
31.1.
purified by column chromatography using EtOAc/hexane (1:
4) as eluent to give product 20 as a 3:1 E:Z mixture: see Table
1; 1H NMR δ 7.31-7.39 (m, 4 H), 7.16-7.22 (m, 1 H), 6.37 (s,
1 H), 6.28 (d, J ) 16.1 Hz, 1 H), 5.99-6.06 (m, 1 H), 4.05 (t, J
) 6.5 Hz, 2 H), 3.57 (t, J ) 6.5 Hz, 2 H), 3.33 (s, 3 H), 2.34 (s,
3 H), 2.13-2.20 (m, 2 H), 1.44-1.54 (m, 2 H), 0.94 (t, J ) 7.3
Hz, 3 H); 13C NMR δ 137.4, 131.0, 129.4, 128.2 (2C), 128.1 (2C),
125.4, 125.2, 125.1, 122.0, 118.8, 104.8, 72.0, 59.1, 43.3, 35.3,
22.7, 13.6, 11.1. (Peaks quoted refer to trans isomer; minor
product for cis isomer was also detected.)
P r ep a r a tion of 1-(2-Meth oxyeth yl)-2-m eth yl-3-p h en yl-
5-[1-[bis(eth oxyca r bon yl)m eth yl]p en tyl]p yr r ole (21). To
a solution of diethyl malonate (0.34 g, 2 mmol) in DMF (30
mL) was added sodium hydride (0.08 g, 2 mmol, 60% disper-
sion in mineral oil) at room temperature. After the mixture
was stirred for 30 min, compound 17 (0.40 g, 1 mmol) in DMF
(5 mL) was added and the reaction solution was heated at 120
°C for 12 h. After cooling, diethyl ether (50 mL) and water
(50 mL) were added and the organic phase was separated,
washed with water (3 × 50 mL), and dried (MgSO4). The
solvent was removed under reduced pressure to give an oil
which was separated by column chromatography using CH2-
Cl2/hexane (1:4) as eluent to afford product 21: see Table 1;
1H NMR δ 7.33-7.34 (m, 4 H), 7.15-7.19 (m, 1 H), 6.02 (s, 1
H), 4.16-4.27 (m, 3 H), 3.94-4.04 (m, 3 H), 3.52-3.67 (m, 4
H), 3.35 (s, 3 H), 2.34 (s, 3 H), 1.63-1.66 (m, 2 H), 1.22-1.31
(m, 7 H), 1.03 (t, J ) 7.1 Hz, 3 H), 0.82-0.87 (m, 3 H); 13C
NMR δ 168.6, 168.3, 137.7, 131.8, 128.2 (2C), 127.9 (2C), 124.8,
124.2, 121.2, 105.6, 72.0, 61.4, 61.2, 59.0, 58.4, 43.0, 36.2, 34.5,
28.9, 22.8, 14.1, 13.9, 13.8, 11.3.
P r ep a r a t ion of N-n -Bu t yl-2-(1-cya n o-2-p h en ylvin yl)-
4,5-d im eth ylp yr r ole (22). To a solution of compound 15
(1.41 g, 5 mmol) in THF (80 mL) was added a solution of
n-BuLi (2.75 mL, 5.5 mmol, 2.0 M in cyclohexane) at -78 °C,
and the resulting solution was stirred for 1 h. Benzaldehyde
(0.53 g, 5 mmol) in THF (5 mL) was added, and the reaction
mixture was stirred at -78 °C for another hour. Methyl iodide
(2.84 g, 20 mmol) in HMPA (10 mL) was added, and the
mixture was allowed to warm to room temperature overnight.
Water (100 mL) and diethyl ether (100 mL) were poured into
the reaction mixture, and the organic layer was separated,
washed with water (3 × 100 mL), and dried (MgSO4). The
solvent was removed under reduced pressure to give oil 19
which was not further purified.
N -Be n zyl-2-[1-(p h e n ylt h io)e t h yl]-4-p h e n ylp yr r ole
1
(11): see Table 1; H NMR δ 7.38 (dd, J ) 8.3 and 1.3 Hz, 2
H), 7.10-7.26 (m, 10 H), 6.97-7.07 (m, 3 H), 6.86 (d, J ) 1.7
Hz, 1 H), 6.31 (d, J ) 1.7 Hz, 1 H), 5.27 (d, J ) 16.2 Hz, 1 H),
5.03 (d, J ) 16.2 Hz, 1 H), 4.06 (q, J ) 6.9 Hz, 1 H), 1.49 (d,
J ) 6.9 Hz, 3 H); 13C NMR δ 138.0, 135.6, 133.8, 133.5 (2C),
133.4, 128.8 (2C), 128.7 (2C), 128.5 (2C), 127.6, 127.5, 126.5
(2C), 125.2, 124.7 (2C), 123.5, 119.1, 105.8, 50.5, 39.6, 20.9.
N-Ben zyl-2-cya n o-3-p h en yl-5-eth ylp yr r ole (9). A solu-
tion of compound 10a (0.76 g, 2 mmol) and NaCN (0.49, 10
mmol) in DMF (25 mL) was refluxed for 12 h. After cooling,
water (100 mL) and diethyl ether (100 mL) were added and
the organic phase was separated, washed with a saturated
NaCl solution (3 × 100 mL), and dried (MgSO4). The solvent
was removed to give an oil which was separated by column
chromatography using CH2Cl2/hexane (1:4) as eluent to afford
1
product 9: see Table 1; H NMR δ 7.73 (d, J ) 8.0 Hz, 2 H),
7.24-7.44 (m, 6 H), 7.07 (d, J ) 7.2 Hz, 2 H), 6.31 (s, 1 H),
5.23 (s, 2 H), 2.51 (q, J ) 7.4 Hz, 2 H), 1.23 (t, J ) 7.4 Hz, 3
H); 13C NMR δ 142.0, 136.2, 134.6, 132.9, 128.9 (2C), 128.8
(2C), 127.8, 127.5, 126.5 (2C), 126.2 (2C), 115.2, 106.3, 100.4,
49.0, 19.8, 12.3.
Gen er a l P r oced u r e for th e P r ep a r a tion P yr r ol-2-
yla ceta n ilid e 12 a n d -th ioa ceta n ilid e 13 via Red u ctive
Elim in a tion of Ben zotr ia zole. A mixture of compound 10b
or 10c (2 mmol), acetic acid (10 mL), THF (20 mL), and zinc
dust (2.60 g, 40 mmol) was refluxed for 12 h. After cooling,
the reaction solution was filtered and extracted with diethyl
ether (100 mL). The organic phase was separated, washed
with water (3 × 50 mL), and dried (MgSO4). The solvent was
removed under reduced pressure to give the crude product
which was purified either by recrystallization or by column
chromatography to afford the corresponding product 12 or 13.
r-(N-Ben zyl-4-p h en ylp yr r ol-2-yl)a ceta n ilid e (12): re-
crystallized from EtOAc/hexane (1:4), see Table 1; 1H NMR δ
7.53 (d, J ) 7.2 Hz, 2 H), 7.17-7.38 (m, 11 H), 7.05-7.10 (m,
4 H), 6.54 (d, J ) 1.9 Hz, 1 H), 5.07 (s, 2 H), 3.63 (s, 2 H); 13
C
NMR δ 167.7, 137.3, 136.9, 135.1, 128.9 (2C), 128.8 (2C), 128.7
(2C), 128.6, 127.8, 126.6 (2C), 125.7, 124.8 (2C), 124.5, 124.4,
120.0, 119.8 (2C), 108.2, 51.0, 36.0.
r-(N-n -Bu t yl-4-ter t-b u t ylp yr r ol-2-yl)t h ioa cet a n ilid e
(13): purified by column chromatography using EtOAc/hexane
(1:4) as the eluent, see Table 1; 1H NMR δ 8.94 (s, 1 H), 7.62-
7.65 (m, 2 H), 7.35-7.40 (m, 2 H), 7.23-7.26 (m, 1 H), 6.52 (d,
J ) 2.1 Hz, 1 H), 6.12 (d, J ) 2.1 Hz, 1 H), 4.20 (s, 2 H), 3.75
(t, J ) 7.4 Hz, 2 H), 1.60-1.70 (m, 2 H), 1.28 (s, 9H), 1.18-
1.34 (m, 2 H), 0.89 (t, J ) 7.3 Hz, 3 H); 13C NMR δ 199.1,
138.4, 135.1, 128.8 (2C), 126.6, 124.2, 122.6 (2C), 118.0, 108.1,
46.6, 46.5, 33.4, 31.8, 31.7, 30.5, 19.9, 13.6.
N-(2-Meth oxyeth yl)-2-tr a n s-1-p en ten yl-4-p h en yl-5-m e-
th ylp yr r ole (20). A solution of compound 17 (0.80 g, 2 mmol)
and K2CO3 (0.84 g, 4 mmol) in DMF (30 mL) was heated at
120 °C for 12 h. After cooling, diethyl ether (100 mL) and
water (100 mL) were added and the organic layer was
separated, washed with water (3 × 100 mL), and dried
(MgSO4). After removal of the solvent, the residue was
The above oil was dissolved in DMF (50 mL) and treated
with NaCN (0.98 g, 20 mmol). The mixture was refluxed for
12 h. Water (100 mL) and diethyl ether (100 mL) were poured
into the solution, and the organic layer was separated, washed
with NaOH (2 N, 2 × 50 mL) and water (3 × 100 mL), and
dried (MgSO4). After removal of the solvent, the residue was
subjected to column chromatography using EtOAc/hexane as
1
the eluent to afford the product 22: see Table 1; H NMR δ
7.52-7.56 (m, 2 H), 7.22-7.40 (m, 5 H), 3.89 (t, J ) 7.5 Hz, 2
H), 2.18 (s, 3 H), 2.05 (s, 3 H), 1.56-1.64 (m, 2 H), 1.32-1.39
(m, 2 H), 0.95 (t, J ) 7.4 Hz, 3 H); 13C NMR δ 135.6, 131.9,
128.8 (2C), 128.2, 127.3, 125.8, 124.8 (2C), 119.7, 118.4, 114.7,
100.1, 43.2, 33.6, 20.0, 13.7, 11.2, 10.3.
J O951894M