Trichloroacetylhydrazones: New highly reactive alkylating agents

Article abstract of DOI:10.1039/a905946f

The behavior of trichloroacylhydrazones as new highly reactive alkylating agents is disclosed; various secondary amines are alkylated within a few minutes at room temperature, and similar alkylating reductions were found with malonates.

Full text of DOI:10.1039/a905946f

Trichloroacetylhydrazones: new highly reactive alkylating agents
V. Atlan, L. El Kaim,* S. Lacroix and R. Morgentin
Laboratoire Re´acteur et Processus, Ecole Nationale Superieure de Techniques Avance´es, 75015 Paris, France.
E-mail: elkaim@ensta.fr
Received (in Cambridge, UK) 22nd July 1999, Accepted 5th August 1999
The behavior of trichloroacylhydrazones as new highly
reactive alkylating agents is disclosed; various secondary
amines are alkylated within a few minutes at room
temperature, and similar alkylating reductions were found
with malonates.
in the Leuckart reaction.5 The reaction seems to be general, with
ketone and aldehyde hydrazones 1 giving in a similar fashion
the new alkylated amines 3 when treated with a large excess of
amine 2 (Table 1). In most instances, the reaction was very clean
and analysis of the crude product revealed that amines 3 and
dichloroamides 4 were the only formed products; the pure
amines 3 were most efficiently recovered through acid-base
extraction and removal of the volatile secondary amine by
evaporation. The poor isolated yield observed for 3f was
probably due to losses during evaporation of the morpholine.
However, with aromatic ketones different behavior was ob-
served when the morpholine was replaced by Et2NH (or
Pri2NH); instead of the expected reduced compounds, formal
oxidation of the ketone to the new a-amino hydrazone 5a (or
5b) occurred (Table 1).
Hydrazones are associated with a wealth of well-known
reactions, such as the Wolf Kishner1 and Shapiro2 reactions and
the Eischenmoser rearrangement.3 In most of these fascinating
reactions, loss of nitrogen is the driving force of the observed
modifications. We recently reported a puzzling reaction of a
class of poorly studied hydrazones, trichloroacetylhydrazones;
when a number aldehyde derivatives were treated with K2CO3,
clean conversion to 1,3,4-oxadiazoles was observed.4 In order
to have a better understanding of the behavior of these
compounds, we decided to treat them in a different basic
medium.
When hydrazone 1a was treated with a large excess of
morpholine in CH2Cl2, fast evolution of nitrogen was observed
at room temperature along with the unexpected formation of the
new alkylated amines 3a and the dichloroacylamide 4a (Scheme
1) as the only isolable compounds. The overall process from the
carbonyl starting material is a reductive alkylation, as observed
Under the same conditions, primary amines also gave a fast
reaction with trichloroacylhydrazones, but no alkylation com-
pounds could be recovered from the complex product mix-
tures.
The use of a large excess of secondary amine could be a
serious drawback for the application of this chemistry to other
nucleophiles. Even if the amount of amine could be lowered, at
least 1 equiv. was always lost as a trap for the dichloroacyl
group. A solution to this problem was eventually given by the
observation that trichloroacylhydrazones were rather unreactive
in ethanolic sodium ethanolate. When hydrazone 1e was left to
react in a EtONa (4 equiv.) solution in EtOH, no change was
observed after 4 h at room temperature; when the same solution
was refluxed for 5 h the new oxadiazole 10a was formed in 48%
yield (Scheme 2). This behavior was similar for various
hydrazones tested. We then added hydrazone 1f to a EtONa (1.2
equiv.) solution in absolute EtOH, observed after a quarter of an
hour the absence of reaction, and then added to this mixture
diethyl malonate (1.2 equiv.); the evolution of nitrogen was
soon observed. The reaction was left at room temperature for
one day, after which the usual workup gave the alkylated
Scheme 1
Table 1 Isolated compounds after aminolysis of hydrazones 1
Hydrazonea
Amine
Product (% yieldb)
1
R1
R2
2
R3
R4
3
4
5
1a
1a
1b
1b
1c
1d
1a
1a
Ph
Ph
Me
Me
2a
2b
2a
2c
2a
2a
2c
2d
–(CH2)2O(CH2)2–
–(CH2)5–
–(CH2)2O(CH2)2–
3a (70)
3b (68)
3c (89)
3d (98)
3e (71)
3f (42)
—
4a (87)
—
—
—
—
—
—
—
—
—
—
—
—
—
5a (57)
5b (67)
–(CH2)2CHNCHCH2–
–(CH2)2CHNCHCH2–
Et
Et
Ph
H
–(CH2)2O(CH2)2–
–(CH2)2O(CH2)2–
–(CH2)4–
Ph
Ph
Me
Me
Et
Pri
Et
Pri
—
a Yields from ketones: 1a (64%), 1b (50%), 1c (75%), 1d (65%). b Isolated yields.
Chem. Commun., 1999, 1893–1894
1893

Scheme 2
Scheme 5
to azoalkenes 9 (Scheme 4) whose chemistry has been fully
explored in Michael type additions or cycloadditions with
nucleophiles;7 in our case, their reaction with Et2NH (or
Pri2NH) in excess gives the observed amino hydrazone 5a (or
5b). This elimination is best observed with poorly nucleophilic
amines; indeed highest yields were obtained with Pri2NH
whereas the more nucleophilic morpholine led to tertiary amine
3a.
The acidic requirements of this reaction are stressed by the
experiments conducted in EtOH. The mixture of EtONa in
EtOH is not acidic enough and no reaction is observed at room
temperature, however the reaction starts as soon as the slightly
acidic malonate is added in the mixture.8
The intermediacy of chloride 12 (Scheme 5, path A) was
discarded in view of the sluggish reaction observed between
morpholine and chlorocyclopentane in CH2Cl2. After 4 h at
room temperature, no formation of amine 3f was observed;
hydrazone 1 under the same conditions gives amine 3f within 10
min, revealing the highly electrophilic properties of the
intermediate involved.
Trichloroacylhydrazones certainly deserve further study to
fully understand the mechanism of these reactions and exploit
their full potential, yet these reductive alkylations at room
temperature are most noteworthy. Whatever the structure of the
active alkylating agent generated under weakly basic condi-
tions, it is much more reactive than the related chloride and can
be generated from stable starting materials with weak bases.
Besides their synthetic potential underlined here trichloro-
acylhydrazones could find useful applications in the biological
field as masked alkylating species activated after interaction
with a basic site of an enzyme receptor.
Scheme 3
malonate 11a in 57% yield (Scheme 3). The same reaction with
cinnamaldehyde hydrazone 1g gave the new malonate 11b in a
poor 41% yield.
A reasonable mechanism for all these results is depicted in
Scheme 4. The main assumption lies in a 1,5 chlorine migration
from the anion. Such a migration has never been reported before
but could be relevant in the results described by Yiannios et al.
in 1968.6 In our case the evolution of the resulting anion 6
depends on the nature of the substituted hydrazones (R = alkyl,
aryl, H) and the basic conditions used in the reaction. When
reprotonation of 6 is not possible (K2CO3, dioxane), a
cyclisation to oxadiazole 10 is observed for aldehyde hydra-
zones giving reactive chlorides (R1 = H, R2 = aryl, alkenyl).
When the medium is acidic enough (excess of amine and the
presence of ammonium chloride salts), protonation of 6 to the a-
chloroazo intermediate 7 may lead to the products through
subsequent substitution and elimination reactions. With sub-
strates sensitive to base elimination different behavior is
observed: elimination of HCl from 7 (R1 = Me, R2 = Ph) leads
Notes and references
1 R. O. Hutchins and M. K. Hutchins, Comprehensive Organic Synthesis,
ed. I. Fleming and B. M. Trost, Pergamon, Oxford, 1991, vol. 8, pp.
327–362 and references cited therein.
2 R. M. Adlington and A. G. M. Barrett, Acc. Chem. Res., 1983, 16, 55.
3 A. Eschenmoser, D. Felix and G. Ohloff, Helv. Chim. Acta, 1967, 50,
708.
4 L. El Kaim, I. Le Menestrel and R. Morgentin, Tetrahedron Lett., 1998,
39, 6885.
5 R. M. Kellogg, Comprehensive Organic Synthesis, ed. I. Fleming and
B. M. Trost, Pergamon, Oxford, 1991, vol. 8, pp. 84–86 and references
cited therein.
6 C. N. Yiannios, A. C. Hazy and J. V. Karabinos, J. Org. Chem., 1968, 33,
2076.
7 O. A. Attanasi and P. Filippone, Synlett, 1997, 1128.
8 Alternative intermediates such as oxadiazoles and diazo compounds can
be easily proposed in the alkylation process; several analogues of these
compounds have been isolated during a study on the basic treatment of
the related monochloroacylhydrazones: E. C. Taylor, N. F. Haley and
R. J. Clemens, J. Am. Chem. Soc., 1981, 103, 7743. The experiments
conducted in EtOH are however difficult to explain with these
intermediates.
Scheme 4
Communication 9/05946F
1894
Chem. Commun., 1999, 1893–1894