A chemoselective method for the reductive N-formylation of aryl azides under catalytic transfer hydrogenation conditions

Article abstract of DOI:10.1016/S0040-4039(02)00143-0

A highly facile and chemoselective method for the reductive N-formylation of aryl azides under catalytic transfer hydrogenation conditions is described.

Full text of DOI:10.1016/S0040-4039(02)00143-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1919–1922
A chemoselective method for the reductive N-formylation of aryl
azides under catalytic transfer hydrogenation conditions
P. Ganapati Reddy and S. Baskaran*
Department of Chemistry, Indian Institute of Technology Madras, Chennai 600 036, India
Received 16 October 2001; revised 8 January 2002; accepted 18 January 2002
Abstract—A highly facile and chemoselective method for the reductive N-formylation of aryl azides under catalytic transfer
hydrogenation conditions is described. © 2002 Elsevier Science Ltd. All rights reserved.
Catalytic transfer hydrogenation (CTH) is an important
synthetic methodology by which compounds such as
cyclohexadiene,1 formic acid,2 hydrazine3 and phos-
phinic acid4 act as in situ hydrogen donors. With the
advent of ammonium formate as a source of hydrogen,5
catalytic transfer hydrogenation has become a versatile
synthetic tool to achieve the hydrogenation/
hydrogenolysis of several functional groups.6 Unlike
conventional hydrogenation techniques, CTH reactions
do not require any elaborate experimental set up or
high-pressure reactors. The ammonium formate–Pd/C
reagent system has been used for the facile reduction of
azides to amines,7a dehalogenation of mono- and poly-
chlorinated aryl compounds,7b the conversion of aryl
cyano to arylmethyl derivatives,7c the reduction of aryl
ketones to aryl alcohols,7d the reduction of aryl oximes
to amines,7e the stereoselective reduction of nitro alco-
hols to 1,2-amino alcohols,7f the reductive cyclization of
b-nitro styrenes to indoles,7g the deoxygenation of het-
eroaromatic N-oxides,7h the regioselective hydrogenoly-
sis of benzyl glycosides,7i the hydrogenolysis of dibenzyl
uracils7j and the selective reduction of a,b-unsaturated
ketones.7k
tions. During the course of our study to moderate the
reactivity of CTH, we made the interesting observation
that ammonium formate in aprotic solvents such as
acetonitrile can function as a formylating agent as well
as being a source of hydrogen.8 Herein we report a
novel and chemoselective method which makes it possi-
ble to convert aryl azides directly into the correspond-
ing N-formanilides in the presence of several reducible
functional groups under CTH conditions (Scheme 1).
To the best of our knowledge, this is the first example
of a one-step, reductive, N-formylation of aryl azides
under mild conditions.
Given the synthetic utility of N-formanilides as key
intermediates for the synthesis of biologically active
compounds9 such as N,N-diaryl ureas,10 cancer
chemotherapeutic agents11 and quinolone antibacteri-
als,12 we feel that this one-pot transformation will be of
great use to synthetic chemists.
The aryl azide 1 on treatment with Pd/C and ammo-
nium formate at reflux temperature was smoothly con-
verted to the corresponding N-formanilide 2 in good
yields. In a typical experiment, the aryl azide 1 in
acetonitrile was stirred under reflux with a suspension
of 10% Pd/C and ammonium formate for several hours
until the completion of reaction as indicated by TLC.
The usual work up and evaporation of the solvent
Catalytic transfer hydrogenation reactions are usually
carried out in protic solvents such as methanol.6
Although CTH reactions are very facile in methanol,
they are non-selective and almost all labile functional
groups undergo reduction under these conditions.
Chemoselective reduction of a functional group in the
presence of other sensitive functional groups is much
sought after, but difficult to achieve under CTH condi-
Pd / C, HCO2NH4
NH-CHO
N3
CH3CN, Reflux
R
R
2
1
R = Functional groups
Keywords: chemoselective; aryl azide; formanilide; CTH.
* Corresponding author. Fax: 0091-44-235 2545; e-mail: sbhaskar@
iitm.ac.in
Scheme 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00143-0

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P. G. Reddy, S. Baskaran / Tetrahedron Letters 43 (2002) 1919–1922
however, under our reaction conditions, 4-bromophenyl
azide (entry 3) afforded 4-bromoformanilide 2c in good
yield as the only product. Although aryl ketones are
known to undergo Leuckart-reductive amination in the
presence of ammonium formate,14 4-acetylphenyl azide
1d (entry 4) was smoothly converted to 4-acetyl for-
manilide 2d with the keto group intact. Similarly, car-
boxylic esters (entries 5 and 7) and aryl alkyl ethers
(entries 2 and 7) were also found to be stable under the
reaction conditions. Interestingly, hydroxy phenyl
azides (entries 10 and 11) were chemoselectively con-
verted to the corresponding formanilides in excellent
yields. It is worth mentioning that aryl azides having
oxime and cyano functional groups (entries 6 and 9)
were also found to be compatible with the reaction
conditions and provided the corresponding N-formyl
derivatives, respectively, in excellent yields. Aliphatic
azides, however, gave the corresponding alkyl ammo-
nium salts with benzyl azide (entry 12) being an excep-
followed by purification by column chromatography
furnished the pure N-formanilide 2 as a mixture of
rotamers.13 In general, 10% by weight of Pd/C and 5
equiv. of ammonium formate were found to give the
best results. A wide range of chemically sensitive aryl
azides has been subjected to these CTH conditions to
provide the corresponding N-formylated anilines,
chemoselectively, in good yields. Selected examples of
this one-step transformation are shown in Table 1,
which summarizes some important findings.
The unique ability of the ammonium formate mediated
CTH reaction in acetonitrile is apparent from the
chemoselective reductive N-formylation of aryl azides
in the presence of other reducible functional groups
such as aryl halides, oximes, aryl ketones, nitriles and
ethers. The dehalogenation of aryl halides under CTH
conditions is a facile and well studied transformation,7b
Table 1. Reductive N-formylation of aryl azides under CTH conditions

P. G. Reddy, S. Baskaran / Tetrahedron Letters 43 (2002) 1919–1922
1921
tion as it gave the expected N-benzyl formamide 2l in
good yield.
Acknowledgements
Although a detailed investigation of the mechanism of
this novel transformation is yet to be carried out, a
plausible mechanism is given in Eqs. (1–4). In the
presence of Pd/C, ammonium formate can undergo
decomposition to generate hydrogen along with carbon
dioxide and ammonia (Eq. (1)).6 Reduction of the aryl
azide to the aniline takes place in the presence of Pd/C
and hydrogen (Eq. (2)).7a It is known that under ther-
mal conditions, ammonium formate can decompose to
generate formamide14 (Eq. (3)) which in turn can react
with aniline to furnish N-formanilide (Eq. (4)).15
Pd/C
We thank Dr. B. Parthasarathi Reddy C. M. D. Het-
ero Drugs Ltd, Hyderabad and Professor K. K. Bala-
subramanian for providing spectral data. We thank
DST, New Delhi for financial support and P.G.R.
(SRF) thanks CSIR, New Delhi for a research fellow-
ship.
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HCO2NH4ꢀꢀꢀꢀꢀꢁH2+CO2+NH3
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ArꢀN3ꢀꢀꢀꢀꢀꢀꢁArꢀNH2
D
HCO2NH4 X NH2ꢀCHO+H2O
ArꢀNH2+NH2ꢀCHO“ArꢀNHꢀCHO+NH3
In conclusion, we have developed an unusually novel
and chemoselective method for the direct conversion of
aryl azides to N-formanilides under catalytic transfer
hydrogenation reaction conditions. We are confident
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1. Experimental
1.1. Representative procedure16
Synthesis of ethyl 3-(N-formylamino)phenoxy acetate
(2 g): To a stirred solution of ethyl 3-azidophenoxy
acetate 1g (130 mg, 0.59 mmol) in dry acetonitrile (5
mL) was added 10% palladium on carbon (26 mg) and
anhydrous ammonium formate (185 mg, 2.94 mmol).
The resulting mixture was stirred for 20 h at reflux
temperature under a nitrogen atmosphere. The reaction
mixture was filtered through a pad of Celite and the
filtrate was concentrated under reduced pressure. The
residue obtained was diluted with ethyl acetate (20 mL),
washed with water (2×10 mL) and dried over anhy-
drous sodium sulfate. The organic layer was concen-
trated under reduced pressure to afford the pure title
compound 2g as a mixture of rotamers (98 mg, 75%
yield): mp=62–64°C; 1H NMR (400 MHz) l=8.68 and
8.34 (two d, J=11.3 Hz and 2.0 Hz, 1H), 8.05 (bd) and
7.50 (bs, 1H), 7.31–7.21 (m, 2H), 7.09–7.07 and 6.73–
6.67 (two m, 2H), 4.63 (s, 2H), 4.28 and 4.27 (two q,
J=7.3 Hz, 2H), 1.31 and 1.30 (two t, J=7.3 Hz, 3H);
13C NMR (100 MHz) l=14.1, 61.4, 61.5, 65.3, 105.8,
106.6, 110.4, 110.7, 111.8, 113.1, 129.8, 130.6, 138.1,
138.3, 158.1, 158.7, 159.3, 162.5, 168.6, 168.9; IR
(KBr): 3335, 1745, 1704 cm−1; MS (EI, 70 eV) m/z (rel.
intensity) 223 (M+, 49), 65 (100). Anal. calcd for
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58.97; H, 5.65; N, 6.15.
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1
as seen by H NMR spectroscopy. Please see: Manea, V.
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1922
P. G. Reddy, S. Baskaran / Tetrahedron Letters 43 (2002) 1919–1922
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(a) formanilide and 2-methylformanilide are commer-
cially available from Aldrich; (b) (4-methoxyformanilide
and 4-bromoformanilide) Carter, R. E. Acta Chem.
Scand. 1968, 22, 2643; (c) (4-acetyl formanilide)
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(c) (N-benzylformanilide) Buehler, C. A.; Mackenzie, C.
A. J. Am. Chem. Soc. 1937, 59, 421; (d) (4-(N-formyl-
amino) benzyl cyanide) Maron, D.; Kontorowitsch, M.;
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