An efficient method for the N-debenzylation of aromatic heterocycles

Article abstract of DOI:10.1081/SCC-200028570

The N-debenzylation of aromatic heterocycles such as substituted pyrroles and indoles, having functional groups like ester, amide, halo, and nitrile, by using sodium in liquid ammonia in the presence of t-BuOH at -78°C cleanly affords N-debenzylated aromatic heterocycles in good yields.

Full text of DOI:10.1081/SCC-200028570

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An Efficient Method for the
N‐Debenzylation of Aromatic
Heterocycles
a
a
T. Srinivasa Rao & Pramod S. Pandey
a
Department of Chemistry, Indian Institute of
Technology, Delhi, Hauz Khas, New Delhi, 110016,
India
Published online: 12 Jan 2011.
To cite this article: T. Srinivasa Rao & Pramod S. Pandey (2004) An Efficient Method
for the N‐Debenzylation of Aromatic Heterocycles, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry,
34:17, 3121-3127, DOI: 10.1081/SCC-200028570
To link to this article: http://dx.doi.org/10.1081/SCC-200028570
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SYNTHETIC COMMUNICATIONS
Vol. 34, No. 17, pp. 3121–3127, 2004
An Efficient Method for the
N-Debenzylation of Aromatic Heterocycles
*
T. Srinivasa Rao and Pramod S. Pandey
Department of Chemistry, Indian Institute of Technology, Delhi, Hauz
Khas, New Delhi, India
ABSTRACT
The N-debenzylation of aromatic heterocycles such as substituted pyrroles
and indoles, having functional groups like ester, amide, halo, and nitrile, by
using sodium in liquid ammonia in the presence of t-BuOH at 2788C
cleanly affords N-debenzylated aromatic heterocycles in good yields.
Key Words: N-debenzylation; Aromatic heterocycles; Sodium in liquid
ammonia; Substituted pyrroles.
The protection of heterocycles such as pyrroles, imidazoles, and indoles is
an important topic due to the importance of nitrogen heterocycles in biological
[1]
systems. Benzyl group is an important protective group for the nitrogen-
*
Correspondence: Pramod S. Pandey, Department of Chemistry, Indian Institute of
Technology, Delhi, Hauz Khas, New Delhi, 110016, India; Fax: 91-11-2658-2037;
E-mail: pramod@netearth.iitd.ac.in.
3
121
DOI: 10.1081/SCC-200028570
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

3
122
Rao and Pandey
containing compounds. The N-alkyl-N-benzyl compounds are easily
[
2]
N-debenzylated by the use of hydrogenolysis (H /Pd-C) or by catalytic
2
[
3]
transfer hydrogenation (CTH) using a variety of hydrogen donors such as
cyclohexene, 1,4-cyclohexadiene, formic acid, ammonium formate, hydrazine
hydrate, and sodium hypophosphite. However, these methods are not found
suitable for N-debenzylation of N-acyl-N-benzyl compounds and N-benzyl
aromatic heterocycles. One of the methods used for the N-debenzylation of
[
4]
aromatic heterocycles includes the utilization of strong Lewis acid AlCl ,
3
[5]
which fails to find its general applicability as in some cases; it was found
that the ester group present in the molecule gets hydrolyzed in this condition.
Also, it is reported that this method is not successful in the N-debenzylation of
[
6]
some of the aromatic heterocycles. The other method is the utilization of
strong base potassium t-butoxide/dimethyl sulfoxide (DMSO) and oxygen,
which is again found to be problematic if sensitive functional groups are
[6]
present in the molecule such as ester and nitro groups.
Although dissolving metals in liquid ammonia has been widely used in
7]
the case of N-acyl-N-benzyl systems, there is only one report on its appli-
[
[8]
cation in the N-debenzylation of aromatic heterocycle, in which NaH was
also used, which afforded poor yield of N-debenzylated product. Hence, appli-
cation of dissolving metals in liquid ammonia as a selective and efficient
method for N-debenzylation of aromatic heterocycles has limitations and
needs to be reexamined in terms of its reaction conditions to find its general
applicability.
During our synthesis of atorvastatin, we have found that of all the above
methods, only the method of dissolving metal in liquid ammonia at low temp-
erature, for example, sodium in liquid ammonia in the presence of t-BuOH at
[9]
2
788C, was successful for the N-debenzylation of N-benzyl pyrrole 1e.
This prompted us to study the general applicability and sensitivity of this
method for the N-debenzylation of various substituted pyrroles and indoles
having ester, amide, halo, and nitrile functional groups 1(a-g) (Sch. 1).
N-Benzyl pyrrole molecules 1(a-d) were synthesized by the reactions of
2
-[benzyl(isobutyryl)amino]-2-phenylacetic acid with ethyl propiolate, ethyl
phenylpropiolate, N1,3-diphenyl-2-propynamide, and N1-(4-methoxy-
phenyl)-3-phenyl-2-propynamide, respectively, following the procedure of
[
10]
Roth et al.
benzoyl)amino]-3-methylbutanoic acid with N1,3-diphenyl-2-propynamide
The 1e was synthesized by the reaction of 2-[benzyl(4-fluoro-
[9]
in the presence of dicyclohexylcarbodiimide (DCC) in toluene. The 1f
and 1g were synthesized by the reaction of their respective N-H indoles
with benzyl bromide in the presence of sodium hydride in tetrahydrofuran
[6]
(
THF).
We have found that the substituted N-benzyl pyrrole 1a gave N-debenzy-
lated pyrrole 2a in 92% yield, using sodium in liquid ammonia in the presence

Method for N-Debenzylation of Aromatic Heterocycles
3123
Scheme 1.
of t-BuOH as proton donor at 2788C, without affecting the ester functional
group. N-Debenzylation of other substituted pyrrole and indole molecules
1
(b–g) having ester, amide, halo, and nitrile functional groups using the same
condition afforded N-debenzylated aromatic heterocyclic compounds 2(b–g)
in excellent yields in 10min, without affecting the other functional groups.
We have also successfully N-debenzylated the methyl 2-[benzyl(isobu-
[
10]
tyryl)amino]-2-phenylacetate 1h in 75% yield to afford methyl 2-(isobutyr-
ylamino)-2-phenylacetate 2h, where the ester and other groups are unaffected
(Sch. 2). This suggests that in this condition, the functional groups, which are
not attached to aromatic heterocyclic ring, are also unaffected.
In conclusion, we have developed a mild and efficient methodology for
the deprotection of benzyl group of N-benzyl aromatic heterocycles using
sodium in liquid NH and t-BuOH as a proton donor at 2788C, which may
3
find its general applications in the synthesis of nitrogen-containing
heterocycles.

3
124
Rao and Pandey
Scheme 2.
EXPERIMENTAL
Melting points were determined using a SONAR melting point apparatus and
are uncorrected. Infrared (IR) absorption spectra were recorded on a Nicolet 5DX
FTIR instrument (Thermo Electron Corporation, USA) and values are reported in
21
1
13
cm . H and C NMR spectra were recorded on a DPX-300 Brucker spec-
trometer (Switzerland). Data are reported as follows: integration, chemical shift
in parts per million (ppm) from tetramethylsilane (TMS) on the d scale, multi-
plicity (s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, bs ¼ broad singlet,
and m ¼ multiplet), coupling constant in hertz (Hz), and assignment. The fast
atom bombardment (FAB) mass spectra were recorded on a JEOL SX 102/
DA-6000 mass spectrometer using argon/xenon (6 kV, 10 mA) as the FAB
gas; m-nitrobenzyl alcohol (NBA) was used as the matrix. Microanalyses were
obtained using a Perking-Elmer elemental analyzer PE 2400 Series II instrument.
Monitoring of the reactions was performed using silica gel TLC plates (silica
gel G with binder). Column chromatography was performed using silica gel
(60–120 mesh). Organic solvents were purified by standard procedures.
Typical Procedure for N-Debenzylation of Aromatic
Heterocycles
To a 50-mL two-necked flask cooled to 2788C was added freshly cut
sodium metal (52 mg, 1.6 mmole) and liquid ammonia (20 mL). When the
solution became blue in color (5 min), t-BuOH (84 mg, 0.8 mmole) in THF
(
2 mL) was added followed by 1a (200 mg, 0.4 mmole) in THF (8 mL). The
reaction mixture was stirred at 2788C for 10 min; by then all blue color had
disappeared. Ammonia was evaporated by replacing the cooling bath with a
water bath (308C–408C). The reaction mixture was then quenched with
1
layer was dried over Na SO , concentrated, and purified by column chromato-
mL of aqueous NH Cl and extracted with EtOAc (25 mL). The organic
4
2
4
graphy (silica gel) to afford 156 mg of 2a as a white solid in 92% yield.

Method for N-Debenzylation of Aromatic Heterocycles
3125
Physical and Spectroscopic Data for Ethyl 2-isopropyl-5-phenyl-1H-3-
pyrrolecarboxylate 2a
Yield 92%; m.p.: 1008C; IR (KBr) 3295, 3039–2727, 1668, 1608, 1591,
525, 1466, 1391, 1232, 1089, 785, 761, 693 cm . H NMR (300 MHz,
2
1 1
1
CDCl ) d 8.38 (bs, 1H), 7.71–7.13 (m, 5H), 6.84 (s, 1H), 4.29 (q, J ¼ 7 Hz,
3
2
6
1
2
H), 3.86 (septet, J ¼ 6.9 Hz, 1H), 1.36 (t, J ¼ 7 Hz, 3H), 1.33 (d, J ¼ 6.9,
1
H); C NMR (75 MHz, CDCl ) d 165.56, 145.96, 131.91, 129.66, 128.89,
3
3
26.56, 123.76, 107.58, 59.43, 29.67, 26.07, 21.93, 14.46; FAB MS (m/z)
þ
58 (Mþ1, 70), 257 (M , 100%), 242 (20), 228 (6), 212 (20); Anal. Calcd.
for C H NO : C 74.68, H 7.44, N 5.44%; Found: C 74.60, H 7.48, N 5.50%.
1
6
19
2
Ethyl 2-isopropyl-4,5-diphenyl-1H-3-pyrrolecarboxylate 2b
Yield 84%; m.p.:1058C–1078C; IR (KBr) 3297, 3039–2853, 1672, 1454,
1
260, 1189, 1088, 800, 697; H NMR (300 MHz, CDCl ) d 8.2 (bs, 1H), 7.19–
1
3
7
.03 (m, 10H), 3.99 (q, J ¼ 7.0 Hz, 2H), 3.79 (septet, J ¼ 6.9 Hz, 1H), 1.30
(d, J ¼ 6.9 Hz, 6H), 0.93 (t, J ¼ 7.0, 3H); Anal. Calcd. for C H NO : C
2
2
23
2
7
9.25, H 6.95, N 4.20%; Found: C 79.28, H 7.29, N 4.19%.
N3,4,5-Triphenyl-2-isopropyl-1H-3-pyrrolecarboxamide 2c
Yield 85%; m.p.: 2108C–2118C; IR (KBr) 3404, 3292, 3058–2853,
2
1
1
. H NMR
1
642, 1595, 1523, 1436, 1312, 1251, 1191, 757, 694 cm
300 MHz, CDCl ) d 8.34 (bs, 1H), 7.44–6.98 (m, 16H), 4.09 (septet,
(
3
1
3
J ¼ 6.9 Hz, 1H), 1.38 (d, J ¼ 6.9, 6H); C NMR (75 MHz, CDCl ) d
3
1
1
63.56, 144.64, 138.42, 135.18, 131.27, 129.16, 128.86, 128.61, 127.81,
26.69, 126.12, 124.96, 124.53, 123.19, 119.44, 119.14, 25.94, 22.23; FAB
þ
MS (m/z) 381 (M þ 1, 80%), 380 (M , 60), 307 (20), 288 (100), 279 (10);
Anal. Calcd. for C H N O: C 82.08, H 6.36, N 7.36%; Found: C 82.07, H
2
6 24 2
6
.29, N 7.07%.
N3-(4-Methoxyphenyl)-2-isopropyl-4,5-diphenyl-1H-3-
pyrrolecarboxamide 2d
Yield 81%; m.p.: 1988C–2008C; IR (KBr) 3395, 3274, 3026–2865,
635, 1598, 1528, 1509, 1460, 1348, 1230, 1190, 1095, 824, 702 cm ; H
21 1
1
NMR (300 MHz, CDCl ) d 8.33 (bs, 1H), 7.42–6.71 (m, 15H), 4.07 (septet,
3
J ¼ 6.9 Hz, 1H), 3.73 (s, 3H), 1.40 (d, J ¼ 6.9, 6H); Anal. Calcd. for
C H N O : C 79.00, H 6.38, N 6.82%; Found: C 79.19, H 6.27, N 6.66%.
27 26 2 2

3
126
Rao and Pandey
N3,4-Diphenyl-5-(4-fluorophenyl)-2-isopropyl-1H-3-
pyrrolecarboxamide 2e
Yield 83%; m.p.: 2088C–2108C; IR (KBr) 3404, 3291, 3059-2870, 1642,
21 1
528, 1438, 1313, 1253, 1192, 752, 692 cm . H NMR (300 MHz, CDCl ) d
1
8
3
.34 (bs, 1H), 7.43–6.96 (m, 15H), 4.11 (septet, J ¼ 6.9 Hz, 1H), 1.41
1
3
(
d, J ¼ 6.9, 6H); C NMR (75 MHz, CDCl ) d 168.67, 165.73, 163.52,
3
1
1
45.3, 144.6, 137.9, 132.19, 131.29, 129.20, 128.64, 127.87, 126.70,
24.65, 123.20, 121.29, 119.13, 118.52, 116.50, 25.95, 22.27; FAB MS (m/
z) 397 (M-H , 5%), 382 (30), 381 (100), 380 (70), 288 (90), 289 (10), 262
þ
(5), 220 (5); Anal. Calcd. for C H FN O: C 78.37, H 5.82, N 7.03%;
26 23 2
Found: C 78.67, H 6.11, N 7.12%.
Methyl 2-(isobutyrylamino)-2-phenylacetate 2h
Yield 75%; m.p.: 1158C; IR (KBr) 3275, 3036–2873, 1752, 1640, 1533,
509, 1456, 1347, 1264, 1210, 1163, 1095, 979, 780, 753, 696 cm ; H
21 1
1
NMR (300 MHz, CDCl ) d 7.42–7.26 (m, 5H), 6.43 (bs, 1H), 5.57
3
(
d, J ¼ 7.1 Hz, 1H), 3.73 (s, 3H), 2.44 (septet, J ¼ 6.9 Hz, 1H), 1.16 (dd,
J ¼ 6.9, 6H); Anal. Calcd. for C H NO : C 66.36, H 7.28, N 5.95%;
1
3
17
3
Found: C 66.97, H 7.39, N 5.90%.
ACKNOWLEDGMENT
T.S.R. thanks the Council of Scientific and Industrial Research, New
Delhi, for the award of Senior Research Fellowship.
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Received in India May 17, 2004