An efficient one-pot synthesis of 2-benzylpyrroles and 3-benzylindoles

Article abstract of DOI:10.1002/aoc.1759

One-pot regioselective benzylation of pyrroles and indoles using zirconium tetrachloride is discussed. This has been achieved by in-situ generation of di(1H-pyrrol-1-yl)zirconium(IV) chloride and di(1H-indol-1-yl)zirconium(IV) chloride. It was observed th

Full text of DOI:10.1002/aoc.1759

Full Paper
Received: 25 June 2010
Revised: 29 September 2010
Accepted: 2 November 2010
Published online in Wiley Online Library: 10 January 2011
(wileyonlinelibrary.com) DOI 10.1002/aoc.1759
An efficient one-pot synthesis
of 2-benzylpyrroles and 3-benzylindoles
Ratnesh Sharma, Mangilal Chouhan, Divya Sood and Vipin A. Nair∗
One-pot regioselective benzylation of pyrroles and indoles using zirconium tetrachloride is discussed. This has been achieved
by in-situ generation of di(1H-pyrrol-1-yl)zirconium(IV) chloride and di(1H-indol-1-yl)zirconium(IV) chloride. It was observed
that benzylation reactions of these complexes using n-BuLi occurred at C-2 position for pyrrole and C-3 for indole. Copyright
c
ꢀ 2011 John Wiley & Sons, Ltd.
Keywords: benzylation; zirconium(IV) chloride; pyrrole; indole
Introduction
N
Li
Pyrrole and indole rings are found in many structurally diverse
natural products and pharmaceutical agents, and new meth-
ods for their synthesis and functionalization continue to attract
attention.[1–5] The reactions of pyrrole have always been a chal-
lenge because of its sensitivity to air and acidic condition.[1]
Functional group modification of pharmacophores is one of the
most popular methods employed in drug design and develop-
ment. Often it has been observed that the alkylated molecules
show an altered activity as compared with the lead molecule.[6,7]
The methodologies available for the synthesis of alkylpyrrole
have been dominated by acylation followed by reduction[8–10]
since the direct alkylation using acidic condition leads to side
reactions. Many alternatives have been developed like tandem
alkylation-reduction of 2-acylpyrrole,[11] thermal rearrangement
of N-alkylpyrrole,[12] pyrrolyl magnesium halide[13,14] and using
ionic liquids.[15] These methods have been seriously hampered
by poor regioselectivity. Recent reports indicate that ionic liquids
are marine toxic[16–18] and also flammable.[19]. The synthesis of
alkylindoles is mainly by Friedel Crafts alkylation,[20–22] although
other approaches have also been reported.[23–25] Ionic bases such
as hydroxides, hydrides and alkan-1-ides react at N-1 position[26]
whereas the covalent metallic complexes react at C-3.[27–33] Re-
gioselectivity is still a major concern in many of these reactions.
Theregioselectivealkylationoftheseheterocycleshasthusbeen
an obstinate problem, which defines our interest on C-alkylation of
these heterocycles by zirconium complex. As part of our ongoing
investigations on metal mediated functionalization reactions, we
have recently reported a one-pot synthesis of 2-benzoylpyrroles
using zirconium complex.[34] Based on this, an analogous strategy
was employed for the C-alkylation of pyrrole and indole, which
was found to be successful.
1) ZrCl4
2) n-BuLi
-78 °C to RT, 2 h
3) BnBr 1a, RT, 12 h
N
N
H
2a
H
3a
Scheme 1. Synthesis of 2-benzylpyrrole and 3-benzylindole.
pyrrole-1-ide. The solution of lithium pyrrole-1-ide on addition to
zirconium(IV) chloride in dry tetrahydrofuran maintained at the
same temperature would afford di(1H-pyrrol-1-yl)zirconium(IV)
chloride. Addition of n-butyllithium to this suspension generates
carbanion at C-2 position. The reaction mixture was subsequently
allowed to attain room temperature and reacted with benzyl
bromide to afford 2-benzyl pyrrole. Various substituted benzyl
bromides were tried to generalize the scope of the reaction and
the yields obtained were good in all the cases (Table 1). The
reaction rates were faster with electron-deficient aromatic rings
as compared with electron-rich rings. Longer reaction time in
the case of electron-rich substrates led to dibenzylation. The
success of the strategy prompted us to extrapolate the reaction
condition to indole as well. After the NH proton, the hydrogen
at C-2 is the next most acidic proton on indole. Reactions
of N-protected indoles with lithium bases results in lithiation
exclusively at the C-2 position. Quite interestingly, the di(1H-indol-
1-yl)zirconium(IV) chloride prepared from N-lithiated indole and
zirconium(IV)chloridewhentreatedwithn-butyllithiumgenerated
carbanion at C-3 position, which on treatment with substituted
Results and Discussion
∗
The paper discusses a new methodology for the benzylation of
pyrrole using benzyl bromide (Scheme 1) in a one-pot reaction
by in-situ generation of di(1H-pyrrol-1-yl)zirconium(IV) chloride. A
solution of pyrrole in dry tetrahydrofuran when treated with n-
butyllithium at −78 ◦C under nitrogen atmosphere yields lithium
Correspondenceto:Vipin A. Nair,DepartmentofMedicinalChemistry,National
Institute of PharmaceuticalEducation and Research, Sector 67, Mohali, Punjab
160 062, India. E-mail: vn74nr@yahoo.com
Department of Medicinal Chemistry, National Institute of Pharmaceutical
Education and Research, Sector 67, Mohali, Punjab 160 062, India
c
Appl. Organometal. Chem. 2011, 25, 305–309
Copyright ꢀ 2011 John Wiley & Sons, Ltd.

R. Sharma et al.
Table 1. Synthesis of 2-benzylpyrroles
Table 1. (Continued)
Sample no.
1
Starting material
Product
Yield (%)
798
Sample no.
10
Starting material
Product
Yield (%)
7232
2
878
benzyl bromides afforded 3-benzylindoles (Table 2). A kinetic
study of the reaction suggests that reaction follows a first-order
rate equation. The initial phase of the reaction demonstrated an
exponential increase in product formation, followed by a gradual
increase in yield with time. Since concentration of benzyl bromide
did not affect the rate of reaction, the rate-determining step would
be the generation of carbanion.
3
4
82
Conclusion
The above strategy afforded 2-benzylpyrroles and 3-benzylindoles
with reasonably good yields in a one-pot reaction which had
previously been synthesized in 2–3 steps or by using expensive
and toxic chemicals.
6414
Experimental
5
6
868
General Procedure for 2-Benzylpyrroles
To a solution of pyrrole (0.5 g, 7.5 mmol) in dry tetrahydrofuran
(10 ml), n-butyllithium (1.6 M in hexane, 4.7 ml, 7.5 mmol) was
addedat−78 ◦Candstirredfor20 minundernitrogenatmosphere.
The solution of lithium pyrrole-1-ide was then added to a solution
ofzirconium(IV)chloride(0.87 g,3.75 mmol)indrytetrahydrofuran
(10 ml) at −78 ◦C. It was stirred for additional 20 min and to this
suspensionn-butyllithium(4.7 ml, 7.5 mmol)wasaddeddrop-wise
and stirred for 10 min. It was allowed to reach RT and stirred for 2 h,
followedbytheadditionofbenzylbromide(3.75 mmol)andstirred
for another 12 h at RT. Progress of the reaction was monitored
by GCMS. Reaction mixture was quenched with aqueous NH4Cl
solution, filtered through celite, extracted with ethyl acetate and
washed with brine. The organic layer was dried over anhydrous
sodium sulfate and concentrated under reduced pressure to get
the crude mixture. The product was isolated from the crude
mixture by column chromatography on silica gel (100–200 mesh)
using ethyl acetate–hexane mixture as eluent. The product was
characterized by spectroscopic methods. The spectral data of
compounds 2a, 2b, 2d, 2e and 2j have been compared with
literature reports.[8,14,32]
95
7
8
9
90
67
90
2-(2-Fluorobenzyl)-1H-pyrrole, 2c
Liquid. 1H NMR (400 MHz, CDCl3): δ 7.96 (bs, 1H, Pyrrole–NH),
7.21–7.13 (m, 2H, Ar–H), 7.06–6.97 (m, 2H, Ar–H), 6.65 (d,
J = 1.3 Hz, 1H, Pyrrole–H), 6.11 (q, J = 2.8 Hz, 1H, Pyrrole–H),
6.00–5.97 (m, 1H, Pyrrole–H), 3.96 (s, 2H, Ar–CH2). 13C NMR
(100 MHz, CDCl3): δ 159.6 (Ar–C), 130.8 (Ar–C), 129.4 (pyrrole–C),
128.2 (Ar–C), 126.9 (Ar–C), 124.3 (Ar–C), 117.1 (pyrrole–C), 115.4
(Ar–C), 108.4 (pyrrole–C), 106.5 (pyrrole–C), 27.3 (Ar–CH2). MS
(EI): m/z calcd for C11H10FN: 175.08; found: 175.04 [M+]. HRMS
(ESI): m/z [M + H]+ calcd for C11H10FN: 176.0876; found: 176.0870.
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Appl. Organometal. Chem. 2011, 25, 305–309

One-pot synthesis of 2-benzylpyrroles and 3-benzylindoles
(pyrrole–C), 120.2 (pyrrole–C), 117.2 (Ar–C), 108.5 (pyrrole–C),
106.7 (pyrrole–C), 33.5 (Ar–CH2). MS (EI): m/z calcd for C11H10BrN:
235.00; found: 235.36 [M+], 237.36 [M+2]. HRMS (ESI): m/z [M +
H]+ calcd for C11H10BrN: 236.0075; found: 236.0077.
Table 2. Synthesis of 3-benzylindoles
Sample no. Starting material
1
Product
Yield (%)
8523
2-(4-Iodobenzyl)-1H-pyrrole, 2g
Liquid. 1H NMR (400 MHz, CDCl3): δ 7.80 (bs, 1H, Pyrrole–NH),
7.63 (d, J = 8.4 Hz, 2H, Ar–H), 6.97 (d, J = 8.4 Hz, 2H, Ar–H),
6.67–6.66 (m, 1H, Pyrrole–H), 6.15–6.12 (q, J = 2.9 Hz, 1H,
Pyrrole–H), 5.97–5.96 (m, 1H, Pyrrole–H), 3.92 (s, 2H, Ar–CH2).
13C NMR (100 MHz, CDCl3): δ 139.2 (Ar–C), 137.6 (Ar–C), 130.7
(Ar–C), 129.8 (pyrrole–C), 117.2 (pyrrole–C), 108.5 (pyrrole–C),
106.8 (pyrrole–C), 91.5 (Ar–C) 33.6 (Ar–CH2). MS (EI): m/z calcd for
C11H10IN: 282.99; found: 282.94 [M+]. HRMS (ESI): m/z [M + H]+
calcd for C11H10IN: 283.9936; found: 283.9928.
2
3
74
76
2-(4-Nitrobenzyl)-1H-pyrrole, 2h
Liquid. 1H NMR (400 MHz, CDCl3): δ 8.14 (d, J = 8.7 Hz, 2H, Ar–H),
8.00 (bs, 1H, Pyrrole–NH), 7.36 (d, J = 8.7 Hz, 2H, Ar–H), 6.75–6.73
(m, 1H, Pyrrole–H), 6.19 (q, J = 2.8 Hz, 1H, Pyrrole–H), 6.02–6.01
(m, 1H, Pyrrole–H), 4.08 (s, 2H, Ar–CH2). 13C NMR (100 MHz, CDCl3):
δ 147.5 (Ar–C), 146.6 (Ar–C), 129.3 (Ar–C), 128.5 (pyrrole–C), 123.7
(Ar–C), 117.7 (pyrrole–C), 108.7 (pyrrole–C), 107.4 (pyrrole–C),
33.9 (Ar–CH2). MS (EI): m/z calcd for C11H10N2O2: 202.07; found
202.00 [M+]. HRMS (ESI): m/z [M + Na]+ calcd for C11H10N2O2:
225.0640; found: 225.0631.
4
79
9223
93
5
4-[(1H-Pyrrol-2-yl)methyl]benzonitrile, 2i
6
Liquid. 1H NMR (400 MHz, CDCl3): δ 7.95 (bs, 1H, Pyrrole–NH),
7.56 (d, J = 8.0 Hz, 2H, Ar–H), 7.29 (d, J = 8.1 Hz, 2H, Ar–H),
6.72–6.70 (m, 1H, Pyrrole–H), 6.16 (q, J = 2.8 Hz, 1H, Pyrrole–H),
5.99–5.96 (m, 1H, Pyrrole–H), 4.04 (s, 2H, Ar–CH2). 13C NMR
(100 MHz, CDCl3): δ 145.4 (Ar–C), 132.3 (Ar–C), 129.3 (Ar–C), 128.7
(pyrrole–C), 118.9 (Ar–C N), 117.6 (pyrrole–C), 110.2 (Ar–C),
108.6 (pyrrole–C), 107.3 (pyrrole–C), 34.1 (Ar–CH2). MS (EI): m/z
calcd for C12H10N2: 182.08; found 182.03 [M+]. HRMS (ESI): m/z [M
+ Na]+ calcd for C12H10N2: 205.0742; found: 205.0738.
7
85
8
89
General Procedure for 3-Benzylindoles
To a solution of indole (0.38 g, 3.2 mmol) in dry tetrahydrofuran
(5 ml), n-butyllithium (1.6 M in hexane, 2 ml, 3.2 mmol) was added
at −78 ◦C and stirred for 20 min under nitrogen atmosphere. The
solution of lithium indole-1-ide was then added to a solution of
zirconium(IV) chloride (0.37 g, 1.6 mmol) in dry tetrahydrofuran
(5 ml) at −78 ◦C. It was stirred for additional 20 min and to this
suspension n-butyllithium (2 ml, 3.2 mmol) was added drop-wise
and stirred for 10 min. It was allowed to reach RT and stirred
for 2 h followed by the addition of benzyl bromide (1.6 mmol). It
was allowed to stir for 12 h at RT. Progress of the reaction was
monitored by GCMS. The reaction mixture was quenched with
aqueous NH4Cl solution, filtered through celite, extracted with
ethyl acetate and washed with brine. The organic layer was dried
over anhydrous sodium sulfate and concentrated under reduced
pressure to get the crude mixture. The product was isolated
from the crude mixture by column chromatography on silica gel
(100–200 mesh) using ethyl acetate–hexane mixture as eluent.
The product was characterized by spectroscopic methods. The
spectral data of compounds 3a, 3e and 3j have been compared
with literature reports.[23,32]
9
90
10
8632
2-(4-Bromobenzyl)-1H-pyrrole, 2f
Liquid. 1H NMR (400 MHz, CDCl3): δ 7.82 (bs, 1H, Pyrrole–NH),
7.44 (d, J = 8.4 Hz, 2H, Ar–H), 7.09 (d, J = 8.5 Hz, 2H, Ar–H),
6.71–6.69 (m, 1H, Pyrrole–H), 6.17 (q, J = 2.92 Hz, 1H, Pyrrole–H),
6.00–5.99 (m, 1H, Pyrrole–H), 3.94 (s, 2H, Ar–CH2). 13C NMR
(100 MHz, CDCl3): δ 138.5 (Ar–C), 131.6 (Ar–C), 131.2 (Ar–C), 130.4
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R. Sharma et al.
3-(4-Methylbenzyl)-1H-indole, 3b
(Indole–C), 122.1 (Indole–C), 119.4 (Indole–C), 119.0 (Indole–C),
115.0 (Indole–C), 111.1 (Indole–C), 90.9 (Ar–C), 31.1 (Ar–CH2). MS
(EI): m/z calcd for C15H12IN: 333.00; found: 333.05 [M+]. HRMS (ESI):
m/z [M + H]+ calcd for C15H12IN: 334.0092; found: 334.0083.
◦
1
Pink solid. M.p. 78–79 C. H NMR (400 MHz, CDCl3): δ 7.89 (bs,
1H, Indole–NH), 7.52 (d, J = 7.8 Hz, 1H, Indole–H), 7.33 (d,
J = 8.1 Hz, 1H, Indole–H), 7.19–7.16 (m, 3H, Ar–H, Indole–H),
7.09–7.05 (m, 3H, Ar–H, Indole–H), 6.89 (m, 1H, Indole–H), 4.07
(s, 2H, Ar–CH2), 2.30 (s, 3H, Ar–CH3). 13C NMR (100 MHz, CDCl3): δ
138.1 (Indole–C), 136.4 (Ar–C), 135.2 (Ar–C), 129.0 (Ar–C), 128.5
(Ar–C), 127.4 (Indole–C), 122.2 (Indole–C), 122.0 (Indole–C), 119.3
(Indole–C), 119.1 (Indole–C), 116.1 (Indole–C), 111.0 (Indole–C),
31.1 (Ar–CH2), 21.0 (Ar–CH3). MS (EI): m/z calcd for C16H15N:
221.12; found: 221.15 [M+]. HRMS (ESI): m/z [M + Na]+ calcd for
C16H15N: 244.1102; found: 244.1089.
3-(4-Nitrobenzyl)-1H-indole, 3h
Dark-brown solid. M.p. 129–130 ◦C. 1H NMR (400 MHz, CDCl3):
δ 8.11 (d, J = 11.0 Hz, 2H, Ar–H), 8.05 (bs, 1H, Indole–NH),
7.42–7.36 (m, 4H, Indole–H, Ar–H), 7.22–7.18 (m, 1H, Indole–H),
7.10–7.06 (m, 1H, Indole–H), 6.98–6.97 (m, 1H, Indole–H), 4.20
(s, 2H, Ar–CH2). 13C NMR (100 MHz, CDCl3): δ 149.1 (Ar–C), 146.4
(Ar–C), 136.4 (Indole–C), 129.3 (Ar–C), 127.0 (Indole–C), 123.6
(Ar–C), 122.6 (Indole–C), 122.4 (Indole–C), 119.7 (Indole–C), 118.8
(Indole–C), 113.8 (Indole–C), 111.3 (Indole–C), 31.5 (Ar–CH2). MS
(EI): m/z calcd for C15H12N2O2: 252.09; found: 252.08 [M+]. HRMS
(ESI): m/z [M + Na]+ calcd for C15H12N2O2: 275.0797; found:
275.0791.
3-(2-Fluorobenzyl)-1H-indole, 3c
◦
1
Pink solid. M.p. 95–96 C. H NMR (400 MHz, CDCl3): δ 7.93 (bs,
1H, Indole–NH), 7.56 (d, J = 7.9 Hz, 1H, Indole–H), 7.34 (d,
J = 8.1 Hz, 1H, Indole–H), 7.20–6.94 (m, 7H, Ar–H, Indole–H), 4.13
(s, 2H, Ar–CH2). 13C NMR (100 MHz, CDCl3): δ 159.7 (Ar–C), 136.3
(Indole–C), 130.8 (Ar–C), 130.7 (Ar–C), 128.2 (Ar–C), 128.0 (Ar–C),
127.6 (Indole–C), 127.3 (Ar–C), 123.9 (Ar–C), 122.4 (Indole–C),
122.1 (Indole–C), 119.4 (Indole–C), 119.1 (Indole–C), 115.0 (Ar–C),
114.2 (Indole–C), 111.1 (Indole–C), 24.3 (Ar–CH2). MS (EI): m/z
calcd for C15H12FN: 225.10; found: 225.14 [M+]. HRMS (ESI): m/z [M
+ Na]+ calcd for C15H12FN: 248.0852; found: 248.0880.
4-[(1H-indol-3-yl)methyl]benzonitrile, 3i
Off-white solid. M.p. 139–140 ◦C. 1H NMR (400 MHz, CDCl3): δ 8.04
(bs, 1H, Indole–NH), 7.54 (d, J = 8.3 Hz, 2H, Ar–H), 7.42–7.35 (m,
4H, Ar–H, Indole–H), 7.22–7.18 (m, 1H, Indole–H), 7.10–7.06 (m,
1H, Indole–H), 6.97–6.96 (m, 1H Indole–H), 4.17 (s, 2H, Ar–CH2).
13C NMR (100 MHz, CDCl3): δ 146.9 (Ar–C), 136.4 (Indole–C), 132.1
(Ar–C), 129.3 (Ar–C), 127.0 (Indole–C), 122.5 (Indole–C), 122.3
(Indole–C), 119.6 (Indole–C), 119.1 (Indole–C), 118.8 (Ar–C N),
113.9 (Indole–C), 111.2 (Indole–C), 109.7 (Ar–C), 31.7 (Ar–CH2).
MS (EI): m/z calcd for C16H12N2: 232.10; found: 232.06 [M+]. HRMS
(ESI): m/z [M+ Na]+ calcdforC16H12N2:255.0898;found:255.0890.
3-(4-Fluorobenzyl)-1H-indole, 3d
Pink solid. M.p. 103–104 ◦C. 1H NMR (400 MHz, CDCl3): δ 7.93 (bs,
1H, Indole–NH), 7.47 (dd, J = 0.6 Hz, J = 8.1 Hz, 1H, Indole–H),
7.36 (dd, J = 0.7 Hz, J = 8.1 Hz, 1H, Indole–H), 7.24–7.16 (m,
3H, Ar–H, Indole–H), 7.07 (m, 1H, Indole–H), 6.97–6.90 (m, 3H,
Ar–H, Indole–H), 4.08 (s, 2H, Ar–CH2). 13C NMR (100 MHz, CDCl3):
δ 160.1 (Ar–C), 136.7 (Indole–C), 136.4 (Ar–C), 130.0 (Ar–C), 129.9
(Ar–C), 127.2 (Indole–C), 122.2 (Indole–C), 122.1 (Indole–C), 119.4
(Indole–C), 119.0 (Indole–C), 115.7 (Indole–C), 115.1 (Ar–C), 114.9
(Ar–C), 111.1 (Indole–C), 30.8 (Ar–CH2). MS (EI): m/z calcd for
C15H12FN: 225.10; found: 225.08 [M+], 130.13. HRMS (ESI): m/z [M
+ H]+ calcd for C15H12FN: 226.1032; found: 226.1028.
Acknowledgment
The authors acknowledge the research funding from the Council
of Scientific and Industrial Research, India.
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3-(4-Bromobenzyl)-1H-indole, 3f
Pink solid. M.p. 119–120 ◦C. 1H NMR (400 MHz, CDCl3): δ 7.99
(bs, 1H, Indole–NH), 7.47–7.44 (m, 1H, Indole–H) 7.39–7.34 (m,
3H, Ar–H), 7.21–7.05 (m, 4H, Indole–H, Ar–H), 6.92–6.91 (m, 1H,
Indole–H), 4.08 (s, 2H, Ar–CH2). 13C NMR (100 MHz, CDCl3): δ
140.1 (Indole–C), 136.4 (Ar–C), 131.3 (Ar–C), 130.4 (Ar–C), 127.2
(Indole–C), 122.3 (Indole–C), 122.1 (Indole–C), 119.6 (Ar–C), 119.4
(Indole–C), 119.0 (Indole–C), 115.1 (Indole–C), 111.1 (Indole–C),
31.0 (Ar–CH2). MS (EI): m/z calcd for C15H12BrN: 285.02; found:
285.06 [M+]. HRMS (ESI): m/z [M + H]+ calcd for C15H12BrN:
286.0231; found: 286.0225.
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3-(4-Iodobenzyl)-1H-indole, 3g
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Off-white solid. M.p. 125–126 ◦C. 1H NMR (400 MHz, CDCl3): δ
7.97 (bs, 1H, Indole–NH), 7.57 (d, J = 8.3 Hz, 2H, Ar–H), 7.46 (d,
J = 7.8 Hz, 1H, Indole–H), 7.36 (d, J = 8.1 Hz, 1H, Indole–H),
7.21–7.17 (m, 1H, Indole–H), 7.09–7.05 (m, 1H, Indole–H), 7.02
(d, J = 8.3 Hz, 2H, Ar–H) 6.92–6.91 (m, 1H, Indole–H), 4.05
(s, 2H, Ar–CH2). 13C NMR (100 MHz, CDCl3): δ 140.8 (Indole–C),
137.3 (Ar–C), 136.4 (Ar–C), 130.7 (Ar–C), 127.2 (Indole–C), 122.3
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One-pot synthesis of 2-benzylpyrroles and 3-benzylindoles
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Appl. Organometal. Chem. 2011, 25, 305–309
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