Benzannulation of 3-substituted pyrroles to indoles

Article abstract of DOI:10.1021/jo026853m

In a new general indole synthesis, the anion derived from benzotriazolyl derivative 5b underwent regioselective 1,4-addition to various α,β-unsaturated ketones; subsequent acid-catalyzed cyclization formed the corresponding indoles 1a-f.

Full text of DOI:10.1021/jo026853m

SCHEME 1. Ben za n n u la tion To Give In d olesa
Ben za n n u la tion of 3-Su bstitu ted P yr r oles
to In d oles
Alan R. Katritzky,* Stephane Ledoux, and
Satheesh K. Nair
Center for Heterocyclic Compounds, Department of
Chemistry, University of Florida, Gainesville, Florida
32611-7200
katritzky@chem.ufl.edu
Received December 16, 2002
Abstr a ct: In a new general indole synthesis, the anion
derived from benzotriazolyl derivative 5b underwent regi-
oselective 1,4-addition to various R,â-unsaturated ketones;
subsequent acid-catalyzed cyclization formed the corre-
sponding indoles 1a -f.
a
For definitions of i-vi, see text.
Despite the elegant and efficient methods accumulated
for indole synthesis over a century, new routes continue
to appear, stimulated by the presence of indole subunits
in numerous biologically active compounds, natural and
artificial.1 Most indole syntheses are based on the
construction of a pyrrole ring onto a functionalized
benzene precursor. Reported syntheses starting from
pyrroles include (Scheme 1) the following: (i) Diels-Alder
cycloadditions of pyrrol-2,3-quinodimethanes, or their
precursors or analogue,2,3 (ii) a similar route from vinyl
pyrroles,4 (iii) cycloadditions of pyrrole-carbene chro-
mium complexes with alkynes,5 (iv) palladium-catalyzed
cyclocarbonylation of 2-pyrrolylallyl acetate6 and our own
synthesis using benzotriazole methodology, and C2-
substitued pyrrole,7 (v) J unjappa’s intramolecular elec-
trophilic cyclization using R-oxoketene dithioacetals of C2
activated pyrroles;8 and (vi) Natsume’s method9 using C2
and C3 substitued pyrroles in intramolecular electrophilic
ring closures. We now report that an approach similar
to (v) can be used from a C3 functionalized pyrrole
(Scheme 1).
SCHEME 2
The benzotriazole-functionalized pyrrole derivative 5
was obtained as a 30:70 mixture of Bt1 and Bt2 isomers,
5a and 5b, respectively, which were separated and
characterized. Heating neat to 200 °C converts 5a into
the thermodynamically more stable 5b. Usually in ben-
zotriazole chemistry, the Bt1 and Bt2 isomers exhibit the
same reactivity.11 However, in the present case, 5a and
5b reacted differently: unexpectedly, the n-BuLi derived
anion from 5a did not react with the chalcone; unreacted
starting materials were recovered after workup. But the
anion generated from 5b reacted smoothly with chal-
cones. Such an unusual difference of reactivity was
previously observed and explained by the formation of
an unstable radical anion intermediate.12
1-(1-Benzenesulfonyl-1H-pyrrol-3-yl)ethanol 4, now uti-
lized as the pyrrole fragment precursor, is readily
available.10a,b Thus, 4 was made in 90% yield starting
from N-phenylsulfonylpyrrole by acetylation followed by
reduction. Compound 5 was obtained by refluxing 4 in
toluene with benzotriazole and a catalytic amount of
p-toluenesulfonic acid (Scheme 2).
(1) Gribble, G. W. J . Chem. Soc., Perkins Trans. 1 2000, 1045.
(2) Chou, T.-S.; Chang, R.-C. J . Chem. Soc., Chem. Commun. 1992,
549.
(3) Andrews, J . F. P.; J ackson, P. M.; Moody, C. J . Tetrahedron 1993,
49, 7353.
(4) Keil, J .-M.; Kampchen, T.; Seitz, G. Tetrahedron Lett. 1990, 31,
4581.
Consequently 5b was deprotonated with n-butyllithi-
um, in THF at -78 °C, and allowed to react with chalcone
9a to afford a mixture of 7 and 8, which without
separation was refluxed in 2-propanol-10% H2SO4 to
give the corresponding indole 1a (Scheme 3). Other
(5) Yamashita, A.; Scahill, T. A.; Toy, A. Tetrahedron Lett. 1985,
26, 2969.
(6) Iwasaki, M.; Kobayashi, Y.; Li, J .-P.; Matsuzaka, H.; Ishii, Y.;
Hidai, M. J . Org. Chem. 1991, 56, 1922.
(7) Katritzky, A. R.; Levell, J . R.; Li, J . Tetrahedron Lett. 1996, 37,
5641.
(8) Suresh, J . R.; Patra, P. K.; Ila, H.; J unjappa, H. Tetrahedron
1997, 53, 14737.
(9) Muratake, H.; Natsume, M. Heterocycles 1990, 31, 683.
(10) (a) Xiao, D.; Ketcha, D. M. J . Heterocycl. Chem. 1995, 32, 499.
(b) Kakushima, M.; Hamel, P.; Frenette, R.; Rokach, J . J . Org. Chem.
1983, 48, 3214.
(11) Katritzky, A. R.; Lan, X.; Yang, J . Z.; Denisko, O. V. Chem.
Rev. 1998, 98, 4090.
(12) Katritzky, A. R.; Wu, J .; Kuzmierkiewicz, W.; Rachwal, S.;
Balasubramanian, M.; Steel, P. J . Liebigs Ann. Chem. 1994, 7.
10.1021/jo026853m CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/07/2003
5728
J . Org. Chem. 2003, 68, 5728-5730

mol). The mixture was stirred for 2 h, and then 1 M HCl was
added slowly. Ethanol was evaporated; the resulting oil was
taken into dichloromethane and washed with water. The organic
layer was dried over Na2SO4, and then evaporated to give 410a
in quantitative yield (5.02 g). Without further purification, this
was dissolved in toluene (150 mL), and benzotriazole (3.57 g,
0.03 mol) was added followed by a catalytic amount of p-TSA,
(250 mg, 0.0015 mol). The mixture was refluxed under Dean-
Stark apparatus for 10 h. Then the mixture was washed with
10% Na2CO3 solution (100 mL) and water (100 mL) and dried
over Na2SO4. Evaporation of the solvent afforded an oil, which
is a mixture of 5b and 5a (70/30); the two isomers were separated
on silica gel chromatography (hexane/ethyl acetate:3/1), and the
minor isomer 5a was converted to 5b by heating neat at 200 °C
SCHEME 3
1
for 1 h. White microcrystals (70%): mp 95 °C; H NMR δ 2.06
(d, J ) 7 Hz, 3H), 6.04 (q, J ) 7.0 Hz, 1H), 6.37 (br, 1H), 7.15 (t,
J ) 2.7 Hz, 1H), 7.29 (s, 1H), 7.34-7.42 (m, 2H), 7.49-7.55 (m,
2H), 7.60-7.65 (m, 1H), 7.88-7.90 (m, 4H); 13C NMR δ 21.0,
59.7, 112.6, 118.0, 118.1, 121.3, 126.2, 126.9, 128.4, 129.4, 134.0,
138.6, 144.1. Anal. Calcd for C18H16O2N4S: C, 61.35; H, 4.58;
N, 15.90. Found: C, 61.53; H, 4.56; N, 15.79.
Gen er a l P r oced u r e for th e P r ep a r a tion of In d oles 1a -
f. To a solution of 2-1-[1-(phenylsulfonyl)-1H-pyrrol-3-yl]ethyl-
2H-1,2,3-benzotriazole (5b) (2 mmol) in THF (30 mL) at -78
°C was added n-butyllithium (1.58 M in cyclohexane, 1.43 mL,
2.2 mmol). The solution, which turned brown, was stirred for
10 min followed by the addition of appropriate chalcone (2.2
mmol) in one portion. The solution was kept at -78 °C for an
hour, then the temperature was allowed to rise to room tem-
perature and the mixture was stirred overnight. Saturated NH4-
Cl solution (10 mL) was added and the organic layer was
extracted with ethyl acetate. The combined ethyl acetate layer
was washed with water and concentrated. The residue was
refluxed with 50 mL of 10% H2SO4 2-propanol solution. After
24 h, the solution was cooled and neutralized with Na2CO3
solution. The organic phase was extracted with ethyl acetate
and the combined organic layer was washed with water and
brine, dried over Na2SO4, and concentrated under vacuum and
the oil was purified by column chromatography over silica gel
(hexane/ethyl acetate 4/1) to give the pure product.
substituted chalcones 9b-f also reacted similarly and the
respective indoles 1b-f were isolated in yields of 40 to
65%.
The reactions proceeded through the selective 1,4-
addition of 6 to the enones. We expected that the
interconvertible mixture of 7 and 8 thus formed would
spontaneously cyclize, followed by aromatization to the
indole. However, mild acid treatment was required to
facilitate the cyclization. In the case of 1b, intermediate
7b was isolated. In the case of 1d , 8d was isolated. For
the other indoles prepared, the intermediate addition
products were subjected to acid treatment without isola-
tion. Attempts to generalize this methology with use of
R,â-unsaturated esters failed.
In conclusion we have described a novel route to
substituted indoles proceeding under mild conditions. The
procedure utilizes three characteristics of benzotriazole
chemistry: its easy introduction (4 to 5), its ability to
stabilize an adjacent negative charge (5 to 6), and its
ability to act as a leaving group (7 to 8).
4-Meth yl-5,7-d iph en yl-1-(p h en ylsu lfon yl)-1H-in d ole (1a ).
1
Yellow prisms (60%): mp 153 °C; H NMR δ 2.52 (s, 3H), 6.93
(d, J ) 4.0 Hz, 1H), 7.08 (s, 1H), 7.20-7.70 (m, 15H), 7,87 (d, J
) 4.5 Hz, 1H); 13C NMR δ 16.3, 108.6, 126.4, 126.7, 126.8, 126.8,
127.3, 127.9, 128.0, 128.7, 129.5, 129.7, 130.2, 130.8, 132.1, 133.1,
133.4, 137.0, 138.3, 140.5, 141.0. Anal. Calcd for C27H21NO2S:
C, 76.57; H, 5.00; N, 3.31. Found: C, 76.78; H, 5.12; N, 3.15.
7-(4-Meth oxyph en yl)-4-m eth yl-5-(4-m eth ylph en yl)-1-(ph e-
n ylsu lfon yl)-1H-in d ole (1b). Pale yellow prisms (63%): mp
Exp er im en ta l Section
1
153 °C; H NMR δ 2.43 (s, 3H), 2.49 (s, 3H), 3.90 (s, 3H), 6.77
Melting points were determined on a Bristoline hot-stage
microscope and are uncorrected. 1H (300 MHz) and 13C (75 MHz)
NMR spectra were recorded on a 300-MHz NMR spectrometer
in chloroform-d solution. Column chromatography was per-
formed on silica gel. THF was distilled from sodium-benzophe-
none ketal prior to use. All the reactions were performed under
a nitrogen atmosphere and in flame-dried glasswares.
P r ep a r a tion of 1-(1-(P h en ylsu lfon yl)-1H-p yr r ol-3-yl))-
eth a n on e (3).10b To a suspension of anhydrous AlCl3 (4 g, 0.03
mol) in 40 mL of 1,2-dichloroethane at room temperature was
added slowly acetyl chloride (1.57 g 0.02 mol). The resulting
(d, J ) 8.5 Hz, 2H), 6.89 (d, J ) 3.5 Hz, 1H), 7.00 (s, 1H), 7.13
(d, J ) 8.7 Hz, 2H), 7.21-7.44 (m, 8H), 7.44-7.59 (m, 1H), 7.84
(d, J ) 4.0 Hz, 1H); 13C NMR δ 16.3, 21.1, 55.2, 108.5 112.7,
126.4, 126.6, 127.5, 128.7, 129.5, 130.2, 130.9, 131.0, 132.4, 132.8,
133.0, 133.3, 136.4, 137.0, 138.1, 138.5, 158.6. Anal. Calcd for
C29H25NO3S: C, 74.49; H, 5.39; N, 3.00. Found: C, 74.36; H,
5.43; N, 2.84.
5-(4-Ch lor oph en yl)-7-(4-m eth oxyph en yl)-4-m eth yl-1-(ph e-
n ylsu lfon yl)-1H-in d ole (1c). Gray needles (62%): mp 157 °C
1H NMR δ 2.41 (s, 3H), 3.84 (s, 3H), 6.71 (d, J ) 8.5 Hz, 2H),
6.84 (d, J ) 4.0 Hz, 1H), 6.90 (s, 1H), 7.05 (d, J ) 8.5 Hz, 2H),
7.20-7.39 (m, 8H), 7.43-7.55 (m, 1H), 7.80 (d, J ) 4 Hz, 1H);
13C NMR δ 16.2, 55.2, 108.2, 112.7, 126.4, 126.6, 127.6, 128.2,
128.7, 130.4, 130.7, 130.9, 130.9, 132.6, 132.6, 132.8, 133.1, 133.9,
135.7, 138.6, 139.5, 158.7. Anal. Calcd for C28H22ClNO3S: C,
68.91; H, 4.54; N, 2.87. Found: C, 68.72; H, 4.45; N, 2.71.
4,7-Dim eth yl-5-ph en yl-1-(ph en ylsu lfon yl)-1H-in dole (1d).
solution was stirred for 20 min, then
a solution of 1-H-
phenylsulfonyl-pyrrole (2 g, 0.01 mol) in 15 mL of 1,2-dichloro-
ethane was added slowly and the mixture was stirred at room
temperature for 3 h. The reaction mixture was poured into ice
and water, and the product was extracted with dichloromethane.
After concentration the solid obtained was recrystallized from
diethyl ether. White needles (92%): mp 97 °C (lit.10b mp 97-99
°C); 1H NMR δ 2.41 (s, 3H), 6.67 (dd, J ) 1.5, 3.5 Hz, 1H), 7.19
(dd, J ) 2.5, 3.5 Hz, 1H), 7.42-7.72 (m, 3H), 7.76 (dd, J ) 2.5,
3.5 Hz, 1H), 7.95-7.99 (m, 2H); 13C NMR δ 27.3, 112.5,
121.7;124.6, 127.2, 129.8, 134,6, 139.2, 196.2.
1
Yellow prisms (43%): mp 102 °C; H NMR δ 2.46 (s, 3H), 2.57
(s, 3H), 6.87 (d, J ) 4 Hz, 1H), 7.02 (s, 1H), 7.36-7.65 (m, 9H),
7,79 (d, J ) 8.0 Hz, 2H), 7.93 (d, J ) 4 Hz, 1H); 13C NMR δ
16.1, 21.5, 107.5, 121.6, 125.4, 126.4, 126.7, 128.1, 129.4, 129.6,
129.6, 130.4, 133.1, 133.6, 133.6, 137.1, 140.2, 141.4. Anal. Calcd
for C22H19NO2S: C, 73.10; H, 5.30; N, 3.87. Found: C, 73.32; H,
5.21; N, 3.64.
P r ep a r a t ion of 1-[1-(P h en ylsu lfon yl)-1H-p yr r ol-3-yl]-
eth yl-2H-1,2,3-ben zotr ia zole (5b). To a solution of 5 g (0.020
mol) of 3 in 200 mL of ethanol was added NaBH4 (0.76 g 0.02
J . Org. Chem, Vol. 68, No. 14, 2003 5729

5-(4-Ch lor op h en yl)-7-(3,4-d im eth oxyp h en yl)-4-m eth yl-1-
(p h en ylsu lfon yl)-1H-in d ole (1e). White microcrystals (65%):
mp 170 °C; 1H NMR δ 2.43 (s, 3H), 3.68 (s, 3H), 3.92 (s, 3H),
6.58 (br s, 1H), 6.68 (br s, 2H), 6.85 (d, J ) 4 Hz, 1H), 6.92 (s,
1H), 7.20-7.52 (m, 10H), 7.85 (d, J ) 4 Hz, 1H); 13C NMR δ
16.2, 55.5, 55.8, 107.7, 109.9, 113.5, 122.4, 126.3, 126.7, 127.4,
128.2, 128.7, 130.3, 130.5, 130.9, 132.3, 132.5, 132.8, 133.0, 133.3,
7-(3-Br om op h en yl)-4-m eth yl-5-(4-m eth ylp h en yl)-1-(p h e-
n ylsu lfon yl)-1H-in d ole (1f). White prisms (68%): mp 161 °C;
1H NMR δ 2.36 (s, 3H), 2.44 (s, 3H), 6.84 (d, J ) 3.5 Hz, 1H),
6.91 (s, 1H), 7.12-7.58 (m, 13H), 7.79 (s, 1H); 13C NMR δ 16.3,
21.1, 108.2, 121.2, 126.0, 126.3, 127.5, 128.7, 128.7, 129.0, 129.0,
129.4, 130.0, 130.2, 130.6, 131.6, 132.6, 133.3, 133.4, 136.5, 136.9,
137.8, 138.2, 142.4. Anal. Calcd for C28H22BrNO2S: C, 65.12;
H, 4.29; N, 2.71. Found: C, 64.80; H, 4.33; N, 2.56.
135.5, 138.7, 139.4, 147.4, 148.1. Anal. Calcd for C29H24
-
ClNO4S: C, 67.24; H, 4.67; N, 2.70. Found: C, 67.53; H, 4.57;
N, 2.54.
J O026853M
5730 J . Org. Chem., Vol. 68, No. 14, 2003