Semicarbazones from N-hydroxyureas and amines: A novel entry in the reactivity of the acyl nitroso group

Article abstract of DOI:10.1021/ol2003226

The condensation of carbamoyl nitroso compounds, obtained by oxidation of N-hydroxyureas, with amines unexpectedly afforded semicarbazones (aka carbamoyl hydrazones). Although the substitution of the nitrosyl moiety might compete to afford the correspondi

Full text of DOI:10.1021/ol2003226

ORGANIC
LETTERS
2011
Vol. 13, No. 7
1800–1803
Semicarbazones from N-Hydroxyureas
and Amines: A Novel Entry in the
Reactivity of the Acyl Nitroso Group
ꢀ
Jairo Paz, Carlos Perez-Balado, Beatriz Iglesias, and Luis Munoz*
~
´
Departamento de Quımica Organica, Facultade de Quımica, Universidade de Vigo,
Campus Universitario, 36310 Vigo, Spain
ꢀ
´
lmunoz@uvigo.es
Received February 2, 2011
ABSTRACT
The condensation of carbamoyl nitroso compounds, obtained by oxidation of N-hydroxyureas, with amines unexpectedly afforded
semicarbazones (aka carbamoyl hydrazones). Although the substitution of the nitrosyl moiety might compete to afford the corresponding
urea, an excess of amine led to the semicarbazone as the major product, which is presumably formed via isomerization of an initially generated
acyl azo compound.
The discovery of important roles in a number of biolo-
gical metabolic processes has focused attention on
C-nitroso compounds in recent decades.1 These compounds
are particularly used as reactive dienophiles in Diels-
Alder-type reactions, and the unique properties of this
versatile, although elusive, functional group continue to
drive the synthesis of nitrogen-containing molecules.2 Acyl
nitroso compounds, which can be considered equivalents
of a 1,2-dicarbonyl function, are known to react at the
carbonyl site to give amides.3 However, addition reactions
on the labile nitroso moiety have not been described to
date.
We report here an unprecedented type of reactivity of
carbamoyl nitroso compounds in the presence of amines to
give semicarbazones.4,5 We investigated a possible me-
chanism that involves an initial condensation between
the nitroso group and the amine and we explored the
structural features of the key azo-semicarbazone isomer-
ization using computational methods.
In the course of our investigations on the reactivity of
carbamoyl nitroso compounds,6 the formation of two
main products was observed when the N-hydroxyurea7 1
was treated with tetrabutylammonium periodate in the
presence of 400 mol % of cyclohexenylethylamine. One of
these products was the expected urea 3, formally obtained
by the nitroso group substitution of the carbamoyl nitroso
(1) (a) Miller, T. W.; Isenberg, J. S.; Roberts, D. D. Chem. Rev. 2009,
109, 3099. (b) Fukuto, J. M.; Ignarro, L. J. Acc. Chem. Res. 1997, 30, 149.
(c) Averill, B. A. Chem. Rev. 1996, 96, 2951. (d) Butler, A. R.; Williams,
D. L. H. Chem. Soc. Rev. 1993, 22, 233.
(2) (a) Yamamoto, H.; Momiyama, N. Chem. Commun. 2005, 3514.
(b) Zuman, P.; Shah, B. Chem. Rev. 1994, 94, 1621.
(3) Atkinson, R. N.; Storey, B. M.; King, S. B. Tetrahedron Lett.
1996, 37, 9287.
(4) Semicarbazones and their thio derivatives are often found in
biologically relevant molecules. See: (a) Yu, Y.; Kalinowski, D. S.;
Kovacevic, Z.; Siafakas, A. R.; Jansson, P. J.; Stefani, C.; Lovejoy,
D. B.; Sharpe, P. C.; Bernhardt, P. V.; Richardson, D. R. J. Med. Chem.
2009, 52, 5271. (b) Christlieb, M.; Dilworth, J. R. Chem.;Eur. J. 2006,
12, 6194. (c) Lobana, T. S.; Sharma, R.; Bawa, G.; Khanna, S. Coord.
Chem. Rev. 2009, 253, 977. (d) Klayman, D. L.; Bartosevich, J. F.;
Griffin, T. S.; Mason, C. J.; Scovill, J. P. J. Med. Chem. 1979, 22, 855.
(5) Semicarbazones are commonly synthesized by condensation of
carbonyl compounds with the corresponding semicarbazide. See: de
Oliveira, R. B.; de Souza-Fagundes, E. M.; Soares, R. P. P.; Andrade,
A. A.; Krettli, A. U.; Zani, C. L. Eur. J. Med. Chem. 2008, 43, 1983.
(6) Unpublished results.
(7) For preparation of N-hydroxyureas see: Paz, J.; Perez-Balado, C.;
ꢀ
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Iglesias, B.; Munoz, L. J. Org. Chem. 2010, 75, 8039.
r
10.1021/ol2003226
Published on Web 03/08/2011
2011 American Chemical Society

Table 1. Semicarbazones from Alkylamines
Scheme 1. Reactivity of Carbamoyl Nitroso Compounds
intermediate 2.3 The other product was identified as an E/
Z mixture of the semicarbazone 4 (Scheme 1). In an
attempt to improve the selectivity in favor of the semicar-
bazone, an excess of amine (400-1500 mol %) was used.
Although under these conditions the urea was still ob-
served, the semicarbazone became the major product with
yields ranging from 90 to60% when alkylamines were used
(Table 1). Interestingly, the excess of amine helped to
prevent the formation of other byproducts like symmetri-
cal ureas and N-carbamoyloxyureas, which are generated
by degradation of the acyl nitroso intermediates.8 This
observation highlights the short half-life of the acyl nitroso
species and the requirement for the rapid trapping of the
nitroso group.
As shown in Table 1, the substitution of the starting
N-hydroxyurea does not seem to be crucial for the feasi-
bility of the reaction, although the steric hindrance and/or
the electron effect ofthe amine appear tohave a deleterious
effect on the formation of the semicarbazone. Amines
derived from alanine and valine led to the formation of
the corresponding semicarbazones 15 and 16 in low yields
(entries 11 and 12), while the ethyl ester of glycine afforded
semicarbazone 14in 62% yield (entry 10).9 Inseveral cases,
the semicarbazones were obtained as a mixture of E and Z
isomers. Indeed, a strong tendency for the ETZ isomer-
ization was found. When a single isomer could be isolated
from the mixture, in most cases this evolved toward a new
E/Z mixture, making characterization of these compounds
difficult. Nevertheless, some amines, particularly benzyla-
mines, afforded the corresponding semicarbazones as a
single isomer (Table 2). In this regard, the observation of a
sole isomer in the case of benzylamines might be an
indication of a geometrical bias for the phenyl group.
The E/Z geometry was determined when possible on the
basisofthe observedNOE effectsandbycomparison of1H
and 13C NMR chemical shifts. Analogous reactivity was
found with N-hydroxythioureas, which afforded the
(8) The oxidation of N-hydroxyureas in the absence of amine
afforded a 1:1 mixture of the corresponding symmetrical urea and
N-carbamoyloxyurea (80% yield). See Supporting Information for
details (compounds 38 and 39).
(9) Various hindered amines give rise to the urea as the only product
under the same reaction conditions. See Supporting Information for
details (compounds 18 and 19).
corresponding thiosemicarbazones in good yields
(Table 1, entry 13 and Table 2, entry 8).
To propose a mechanistic rationale for these results, it
seemed to us that the reaction of an amine with a carba-
moyl nitroso function could follow two different
Org. Lett., Vol. 13, No. 7, 2011
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Table 2. Semicarbazones from Benzylamines
Scheme 2. Mechanistic Proposal
explain the final formation of the semicarbazone. The
condensation of aryl nitroso derivatives with arylamines
to give azo compounds is known,10 and this process
proceeds in either acidic or basic media.11 Likewise, tri-
fluoronitrosomethane is known to react with alkylamines
to yield trifluoromethylazoalkanes.12 According to our
hypothesis, the initial addition of the amine to the nitroso
group would generate an azo intermediate that would
evolve to give the final semicarbazone (Scheme 2). The
presence of a product that disappears to afford the semi-
carbazone was detected in some cases by TLC. In the case
of (R)-1-hydroxy-3-(1-phenylethyl)urea treated with iso-
propylamine, this product was isolated after flash chro-
matography (8% yield). In an attempt to characterize this
compound, we observed that the transformation of this
intermediate into the corresponding semicarbazone can be
monitored by 1H NMR (Figure 1). After 120 h at 25 °C in
deuterated chloroform, the semicarbazone was the major
1
product in a 99:1 ratio. The H NMR spectrum of this
short-lived compound was consistent with the structure of
the postulated azo intermediate, which presumably iso-
merizes to give the final semicarbazone. This isomerization
could take place since a proton exchange is possible in the
R-position to the nitrogen of the amine. The use of an
amine bearing a tertiary substituent would lead exclusively
to the azo compound since the tautomerization is not
feasible. With this purpose, N-hydroxyurea 35 was treated
with tBuNH2 in the presence of nBu4NIO4. Besides urea 37
(55% yield), the expected acyl azo compound 36 was
isolated in 20% yield (Scheme 2).
(10) (a) Boyer, J. H. In The Chemistry of the Nitro and Nitroso Groups,
Part 1; Feuer, H., Ed.; Interscience: New York, 1969; pp 278-283. (b)
Davey, M. H.; Lee, V. Y.; Miller, R. D.; Marks, T. J. J. Org. Chem. 1999,
64, 4976.
(11) (a) Mills, C. J. Chem. Soc. 1895, 67, 925. (b) Campbell, N.;
Henderson, A. W.; Taylor, D. J. Chem. Soc. 1953, 1281.
(12) Abe, T.; Joo, Y.-H.; Tao, G.-H.; Teamley, B.; Shreeve, J. M.
Chem.;Eur. J. 2009, 15, 4102.
pathways. The addition of the amine to the carbonyl group
would lead to the formation of the urea, asexpected,3 while
the addition of the amine to the nitroso group could
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Org. Lett., Vol. 13, No. 7, 2011

was found between the two tautomers. However, analysis
of atomic energies E(Ω) showed small differences between
tautomers in the atoms involved in tautomerization. Thus,
the sum of the atomic energies of the atoms involved in the
tautomerization is ca. 0.13 hartree lower in the semicarba-
zone.14 This can be related to the differences in electron
distribution associated with different electronegativity values
for nitrogen and carbon. The ability of hydrogens to experi-
ence significant variations of electron population depending on
their environment plays an important role in diverse chemical
processes.15 For example, electron density transference from
hydrogens to more electronegative atoms is a general stabiliza-
tion mechanism that can be found on the grounds of diverse
tautomeric and conformational equilibria.16
In summary, we have described an unprecedented mode
of reactivity of acyl nitroso compounds. The condensation
of carbamoyl nitroso compounds, obtained by oxida-
tion of N-hydroxyureas, with amines afforded semi-
carbazones. Although the substitution of the nitrosyl
moiety might compete to afford the corresponding
urea, an excess of amine led to semicarbazone as the
major product, which is presumably formed through
isomerization of an initially generated acyl azo com-
pound. DFT calculations show that semicarbazones
are more stable than the corresponding azo com-
pounds because of electronegativity effects on chan-
ging a C-H bond to an N-H bond. Contrary to the
expected situation, delocalization is not substantially
affected on changing from one tautomer to the other.
Figure 1. Azo-semicarbazone isomerization: (a) 0 h, (b) 24 h, (c)
36 h, (d) 48 h, and (e) 120 h.
All of these results seem to support a mechanism in
which an azo compound 33 is initially formed by conden-
sation of the amine with the nitroso group, presumably
with the elimination of water. Further tautomerization
leads to the final semicarbazone 34.13 This significant
preference for the semicarbazone form prompted us to
carry out calculations at the DFT level to gain some
insights into the structural features that favor the semi-
carbazone over the initial acyl azo compound.
Acknowledgment. We are grateful to the Xunta de
Galicia and the Spanish Ministerio de Ciencia e In-
ꢀ
novacion. Helpful discussions with Prof. Ricardo A. Mos-
quera are gratefully acknowledged.
A conformational search for azo compound 33a and
semicarbazone 34a (Scheme 2) showed that whereas the
azo compound has two meaningful conformers, the semi-
carbazone only has a single conformer. In addition, the
semicarbazone is at least 10 kcal mol-1 more stable than
the azo compound. This finding is in full agreement with
the aforementioned experimental results. Quantum theory
of atoms in molecules (QTAIM) calculations were per-
formed to ascertain the reason for this energy difference.
Initially, delocalization indexes were calculated since it
seemed that the semicarbazone might have higher electron
delocalization than the azo compound. Although deloca-
lization indexes correlate well with bond distances, no
appreciable variation of delocalized electron population
Supporting Information Available. Experimental in-
formation and data for all new compounds. Detailed
calculations results and discussion, SCF and free en-
ergies, Cartesian coordinates, and delocalization in-
dexes for compounds 33a and 34a. This material is
available free of charge via the Internet at http://pubs.
acs.org.
(14) See Supporting Information for a detailed discussion of the
calculation results.
(15) Stutchbury, N. C. J.; Cooper, D. L. J. Chem. Phys. 1983, 79,
4967.
(13) (a) For a precedent on the isomerization of a carbamoyl azo
compound to the corresponding semicarbazone see: Horner, L.; Ferne-
kess, H. Chem. Ber. 1961, 94, 712. (b) See also ref 12 for the isomerization
of trifluoromethylazoalkanes to hydrazones.
ꢀ
(16) (a) Gonzalez Moa, M. J.; Mandado, M.; Mosquera, R. A. Chem.
Phys. Lett. 2006, 428, 255. (b) Vila, A.; Mosquera, R. A. J. Comput.
Chem. 2007, 28, 1516.
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