Enhancing Reductive Cleavage of Aromatic Carboxamides

Article abstract of DOI:10.1021/ol010072a

(matrix presented) A set of aromatic and especially heteroaromatic N-benzyl carboxamides, derived from naphthalene, pyridine, pyrazine, and quinoline, and the corresponding tert-butyl acylcarbamates have been synthesized and studied by cyclic voltammetry with respect to facilitated reduction. The latter undergo regiospecific cleavage of their C(O)-N bonds under very mild reductive conditions with formation of Boc-protected (benzyl)-amine in most cases in nearly quantitative yields. Examples of preparative cleavage by controlled potential electrolysis, activated aluminum, and NaBH₄ are given.

Full text of DOI:10.1021/ol010072a

ORGANIC
LETTERS
2001
Vol. 3, No. 13
2021-2023
Enhancing Reductive Cleavage of
Aromatic Carboxamides
Ulf Ragnarsson,* Leif Grehn, Hernani L. S. Maia,† and Luis S. Monteiro†
Department of Biochemistry, UniVersity of Uppsala, Biomedical Center, PO Box 576,
SE-751 23 Uppsala, Sweden, and Departamento de Quimica, UniVersidade do Minho,
Gualtar, P-4700-320 Braga, Portugal
urbki@bmc.uu.se
Received April 16, 2001
ABSTRACT
A set of aromatic and especially heteroaromatic N-benzyl carboxamides, derived from naphthalene, pyridine, pyrazine, and quinoline, and the
corresponding tert-butyl acylcarbamates have been synthesized and studied by cyclic voltammetry with respect to facilitated reduction. The
latter undergo regiospecific cleavage of their C(O)−N bonds under very mild reductive conditions with formation of Boc-protected (benzyl)-
amine in most cases in nearly quantitative yields. Examples of preparative cleavage by controlled potential electrolysis, activated aluminum,
and NaBH are given.
4
Among protected derivatives of amines, simple amides are
exceptionally stable to acidic and basic hydrolysis and they
are therefore often hydrolyzed by brute force by heating with
strongly acidic or basic solutions.1 Aromatic amides such
as benzamides are particularly stable toward these reagents
but can be cleaved by cathodic reduction to give the amines
in respectable yields with concomitant formation of the
corresponding alcohols.2 The potential required for such
cleavages is quite negative, but we have found that it can be
increased moderately by N-Boc substitution.3 Such conver-
sion from amide to tert-butyl acylcarbamate can be easily
accomplished by Boc2O/DMAP.4
corresponding tert-butyl acylcarbamates 2 according to the
following scheme:
With the aim to facilitate mild reductive cleavage of
amides, a number of N-benzyl amides 1 (Ar ) 1- and
2-naphthyl; 2-, 3-, and 4-pyridyl; pyrazyl; and 2-quinolyl)
have been prepared and subsequently converted to the
The common feature of the acyl substituents is that the
corresponding (hetero)arenes are more easily reduced than
benzene.5 Compounds 1 and 2 have initially been studied
by cyclic voltammetry (CV), and their activation potentials
have been determined. These results are summarized in Table
1.
† Universidade do Minho.
(1) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; Wiley-Interscience: New York, 1999; pp 550-564.
(2) Horner, L.; Neumann, H. Chem. Ber. 1965, 98, 3462 and references
therein.
Entries 1 and 3 demonstrate that replacement of phenyl
by 1- or 2-naphthyl has a similar effect on the redox potential
(3) (a) Grehn, L.; Gunnarsson, K.; Maia, H. L. S.; Montenegro, M. I.;
Pedro, L.; Ragnarsson, U. J. Chem. Res. 1988, (S) 399; (M) 3081. (b) Maia,
H. L. S.; Monteiro, L. S.; Degerbeck, F.; Grehn, L.; Ragnarsson, U. J. Chem.
Soc., Perkin Trans. 2 1993, 495.
(4) (a) Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J. Org. Chem. 1983, 48,
2424. (b) Ragnarsson, U.; Grehn, L. Acc. Chem. Res. 1998, 31, 494.
(5) (a) Gerson, F.; Ohya-Nishiguchi, H.; Wydler, C. Angew. Chem. 1976,
88, 617; Angew. Chem., Int. Ed. Engl. 1976, 15, 552. (b) Parker, V. D. J.
Am. Chem. Soc. 1976, 98, 98. (c) Tabner, B. J.; Yandle, J. R. J. Chem.
Soc. A 1968, 381. (d) Wiberg, K. B.; Lewis, T. P. J. Am. Chem. Soc. 1970,
92, 7154.
10.1021/ol010072a CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/02/2001

These shifts are significant as differences in activation
potentials of 0.3-0.6 V for similar compounds could be
exploited for selectiVe cleavage by electrolysis.9
Table 1. Substituted Amides/tert-Butyl Acylcarbamates
Prepared and Studied by Cyclic Voltammetry
The significance of the data in Table 1 with respect to
reductive amide cleavage was first challenged by experiments
with activated Al.10 Compounds 2c, 2d, and 2e thereby
furnished 3 in 89%, 74-85%, and 90% yields, respectively:
entry
amide 1/carbamate 2a
-EP/Vb EP2 - EP1/V
1
2
N-benzyl-1-naphthamide 1a
N-benzyl-N-Boc-1-naphthamide 2a
1-naphthamide
N-benzyl-2-naphthamide 1b
N-benzyl-N-Boc-2-naphthamide 2b
2-naphthamide
2.11
1.81
2.23
2.21
1.89
2.27
2.523b
2.55
2.09
1.74
0.30
3
4
0.32
2 9
Al8 HNBoc-Bn (3)
N-benzylbenzamide
benzamide
5
6
N-benzyl-2-pyridinecarboxamide 1c
N-benzyl-N-Boc-2-pyridine-
carboxamide 2c
2-pyridinecarboxamide
N-benzyl-3-pyridinecarboxamide 1d
N-benzyl-N-Boc-3-pyridine-
carboxamide 2d
3-pyridinecarboxamide
N-benzyl-4-pyridinecarboxamide 1e
N-benzyl-N-Boc-4-pyridine-
carboxamide 2e
4-pyridinecarboxamide
N-benzyl-pyrazinecarboxamide 1f
N-benzyl-N-Boc-pyrazine-
carboxamide 2f
0.35
0.50
0.34
0.40
0.43
This reagent11 is known to reductively cleave sulfon-
amides6 with activation potentials down to -1.7 to -1.8 V,
and it obviously also reacts with carboxamides in a similar
fashion. It also cleaved 2f and 2g (49% and 95%).
2.11
2.29
1.79
7
8
Pyrazine and quinoline are known to undergo dearoma-
tization at even less negative potential than pyridine,5c,d and
this is reflected in the CV data for 1f/2f and 1g/2g. As shown
in entries 11 and 13, the activation potentials of 1f and 1g
are already comparable with the best Boc-derivatives derived
from naphthalene and pyridine above. Interestingly, the shift
induced by introduction of Boc on their amide nitrogens does
not show any indication of decrease, and compounds 2f and
2g exhibit activation potentials of only -1.41 and -1.31 V
vs SCE, respectively, i.e., nearly 0.5 V above the previous
Boc-derivatives. They could also be cleaved by preparative
electrolysis experiments,12 furnishing 3 in 66% and 96%
yields.
Many years ago, Weygand and Frauendorfer demonstrated
that N-trifluoroacetyl and trichloroacetyl groups could be
efficiently cleaved by reduction under exceedingly mild
conditions with NaBH4.13a More recently Ganem et al.
developed a preparatively useful cleavage method for
phthalimides based on partial reduction with this agent.13b
Having established the facile reduction of selected com-
pounds 2 by electrolysis and activated aluminum, a few
experiments with NaBH4 in absolute ethanol at room
temperature were undertaken with isolation of 3 from 2c and
2f in 97-98% and from 2a in 91% yields, in the last case
after column chromatography, which also furnished pure
1-naphthylmethanol (90%). The rate of the reaction with
2.31
2.05
1.71
9
10
2.03
1.81
1.41
11
12
pyrazinecarboxamide
1.75
1.74
1.31
13
14
N-benzyl-2-quinolinecarboxamide 1g
N-benzyl-N-Boc-2-quinoline-
carboxamide 2g
2-quinolinecarboxamide
1.81
a All compounds 1 and 2 were characterized by H and 13C NMR and
FT-IR spectroscopy. All novel substances also gave satisfactory elemental
analyses (C, H, N all within 0.3% of theoretical values). b Versus SCE;
cathode, vitreous carbon; solvent, DMF; supporting electrolyte, Bu4NBF4
0.1 M; substrate concentration, ∼0.005 M.
1
of these carboxamides as was previously noticed in several
cases for sulfonamides.6 Numerically these shifts are about
half the size of the decrease in reduction potential on going
from benzene to naphthalene.5a,b Moreover, by introduction
of N-Boc moieties on these naphthalenecarboxamides, the
peak potentials are further shifted by about 0.3 V to less
negative values.
Previously a few 2- and 3-pyridinecarboxamides have been
prepared and studied with respect to their cleavage.7 4-Py-
ridinemethyl esters8a and carbamates8b,c are stable to a variety
of experimental conditions and can be cleaved electro-
chemically8a,c and by zinc dust reduction.8c The quoted work
induced us to include pyridinecarboxamides and the corre-
sponding N-Boc derivatives in this study. Entries 5, 7, and
9 show that the activation potentials for the three isomeric
pyridinecarboxamides 1c-e are of about the same size as
for 1a and 1b with positions 2 and 4 in the pyridine rings
favorously activated for reductive attack. Introduction of Boc
on the nitrogens (entries 6, 8 and 10) gives rise to a further
shift in the same direction and of about the same size as
observed for the corresponding naphthalene derivatives.
(9) Grehn, L.; Maia, H. L. S.; Monteiro, L. S.; Montenegro, M. I.;
Ragnarsson, U. J. Chem. Res. 1991, (S) 144; (M) 1501.
(10) The cleavage experiments with activated Al were performed with
1 mmol of 2 and 10 mmol of reducing agent, essentially as described in
the example given in ref 6. Occasionally 2d required additional Al to go to
completion. As an example, 2c (312 mg, 1.00 mmol) was treated in moist
Et2O under stirring with 10 mmol reagent overnight, whereupon TLC
indicated that all 2c had been consumed. After filtration of the solid material
and evaporation of the combined filtrate and washings, a brown oil was
1
obtained. TLC and H NMR indicated that it consisted of essentially pure
3. Only trace signals beyond 7.5 ppm, indicating pyridine derivates
originating from the picolyl residue, could be detected. The yield of crude
3 was 184 mg (89%).
(11) Hudlicky´, M. Reductions in Organic Chemistry, 2nd ed.; ACS
Monograph 188; American Chemical Society: Washington, DC, 1996; p
35.
(6) Nyasse, B.; Grehn, L.; Maia, H. L. S.; Monteiro, L. S.; Ragnarsson,
U. J. Org. Chem. 1999, 64, 7135.
(7) (a) Auzeil, N.; Dutruc-Rosset, G.; Largeron, M. Tetrahedron Lett.
1997, 38, 2283. (b) Ushida, S. Chem. Lett. 1989, 59.
(8) (a) Camble, R.; Garner, R.; Young, G. T. J. Chem. Soc. C 1969,
1911. (b) Macrae, R.; Young, G. T. J. Chem. Soc., Chem. Commun. 1974,
446. (c) Veber, D. F.; Paleveda, W. J. Jr.; Lee, Y. C.; Hirschmann, R. J.
Org. Chem. 1977, 42, 3286.
(12) The preparative electrolysis experiments with 2f and 2g were
performed as described in the example under Controlled Potential Elec-
trolysis in ref 6 (at a scale of ca. 0.7 mmol and the potentials -1.46 and
-1.36 V, respectively), and 3 was identified by mp and spectroscopic
comparison with an authentic sample.
(13) (a) Weygand, F.; Frauendorfer, E. Chem. Ber. 1970, 103, 2437. (b)
Osby, J. O.; Martin, M. G.; Ganem, B. Tetrahedron Lett. 1984, 25, 2093
and references therein.
2022
Org. Lett., Vol. 3, No. 13, 2001

NaBH4 varies from substrate to substrate and is very high
for 2f, for which the starting material is consumed in 10-
15 min, whereas for 2c and even 2g reaction times of 2-4
h are required, using 2-2.5 mol of reagent. Compound 2a
reacts even more slowly.
In summary, as a consequence of extended conjugation a
few heteroaromatic acylcarbamates derived from easily
reduced heterocycles have been shown to undergo regio-
selective acyl-nitrogen cleavage under exceedingly mild
reductive conditions. Selected derivatives have been cleaved
by activated aluminum, controlled potential electrolysis, and
NaBH4. A deeper understanding of the factors promoting
enhanced reductive cleavage is expected to lead to robust
protecting groups with high versatility.
Acknowledgment. U.R. thanks NFR and Magnus
Bergvalls Stiftelse for generous support and RSC for a
journals grant for international authors. L.G. acknowledges
a grant from TFR, and H.L.S.M. and L.S.M. thank the
Foundation for Science and Technology (Portugal) for
financial support to the Institute of Biotechnology and Fine
Chemistry (University of Minho).
OL010072A
Org. Lett., Vol. 3, No. 13, 2001
2023