Use of acylhydrazones as electrophiles in Mannich-type reactions, β-lactam, pyrazolidinone, and pyrazolone synthesis

Article abstract of DOI:10.1055/s-1998-1843

In the presence of a catalytic amount of scandium triflate [Sc(OTf)₃], 4-trifluoromethylbenzoylhydrazones reacted with silyl enolates to afford the corresponding adducts, β-N'-acylhydrazinocarbonyl compounds, in high yields. Reductive cleavage of the nitrogen-nitrogen bond of the hydrazino compounds was performed using Raney Ni under H₂ atmosphere, to give β-aminocarbonyl compounds. The two-step process is regarded as a novel Mannich-type reaction using acylhydrazones as electrophiles. Moreover, the hydrazino compounds were also successfully converted to β-lactam, pyrazolidinone, and pyrazolone derivatives.

Full text of DOI:10.1055/s-1998-1843

September 1998
SYNLETT
1019
Use of Acylhydrazones as Electrophiles in Mannich-Type Reactions, β-Lactam,
Pyrazolidinone, and Pyrazolone Synthesis
a,b*†
b
a,b
a,b
Shu Kobayashi,
Takayuki Furuta, Kasumi Sugita, Hidekazu Oyamada
a
Graduate School of Pharmaceutical Sciences, The University of Tokyo, and CREST, Japan Science and Technology Corporation (JST), Hongo,
Bunkyo-ku, Tokyo 113-0033
b
Department of Applied Chemistry, Faculty of Science, Science University of Tokyo (SUT), Kagurazaka, Shinjuku-ku, Tokyo 162-0825
Received 10 May 1998
Abstract: In the presence of a catalytic amount of scandium triflate
[Sc(OTf) ], 4-trifluoromethylbenzoylhydrazones reacted with silyl
3
enolates
to
afford
the
corresponding
adducts,
β-N'-
acylhydrazinocarbonyl compounds, in high yields. Reductive cleavage
of the nitrogen-nitrogen bond of the hydrazino compounds was
performed using Raney Ni under
H
atmosphere, to give β-
2
aminocarbonyl compounds. The two-step process is regarded as a novel
Mannich-type reaction using acylhydrazones as electrophiles.
Moreover, the hydrazino compounds were also successfully converted
to β-lactam, pyrazolidinone, and pyrazolone derivatives.
Hydrazones are aldehyde and ketone equivalents as well as imines.
Their stability is much higher than imines and actually hydrazones
derived from aliphatic aldehydes are often crystalline and can be
isolated and stored at room temperature. However, their reactivity as
electrophiles is known to be low, and there have been much fewer
reports on the reactions of hydrazones with nucleophiles than those of
1,2
2
imines. We have recently found that benzoylhydrazones reacted with
silyl enolates to afford β-N'-benzoylhydrazinocarbonyl compounds,
3
which were converted to pyrazolone derivatives. Although the
reactions were catalyzed by rare earth triflates, lower yields were
observed in some cases. In the course of our investigations to improve
the yields, we have found that electron-defficient acylhydrazones were
very reactive. In this paper, we report the use of a new acylhydrazone, 4-
trifluoromethylbenzoylhydrazone, as an electrophile in novel Mannich-
type reactions. Facile syntheses of β-lactam, pyrazolone, and
pyrazolidinone derivatives using these reactions are also described.
First we carefully examined the reactions of hydrazones with silyl
enolates. While 3-phenylpropionaldehyde phenylhydrazone did not
2
t
2b
react with ketene silyl acetal
(R = Bu) derived from methyl
isobutyrate at all, 3-phenylpropionaldehyde acylhydrazones reacted
2b
with
in the presence of a catalytic amount of scandium triflate
4
[Sc(OTf) ].
Among
the
acylhydrazones
tested,
4-
3
1
1a
trifluoromethylbenzoylhydrazone ( , R = CF ) gave the best yield
3
(Table 1). It is noteworthy that the electronic effect of the benzoyl
moieties influenced the yields dramatically. While hydrazones with
electron-donating groups gave lower yields, higher yields were obtained
using hydrazones with electron-withdrawing groups. As for Lewis
3,5,6
acids, Sc(OTf) gave an excellent yield,
and much lower yields were
3
obtained by using typical Lewis acids such as TiCl , SnCl , and
4
4
BF ·OEt .
3
2
Several
examples
of
the
reactions
of
4-
trifluoromethylbenzoylhydrazones with silyl enolates are shown in
Table 2. Hydrazones derived from aromatic, aliphatic, and α,β-
unsaturated aldehydes reacted with silyl enolates smoothly to afford the
corresponding β-N'-acylhydrazinocarbonyl compounds in high yields.
3
Lower yields obtained using benzoylhydrazones were much more
improved (entries 6, 9, and 11). It is also noted that several aliphatic
hydrazones, readily prepared from aliphatic aldehydes, reacted with
silyl enolates smoothly to afford the corresponding adducts in high
7
yields. All aliphatic acylhydrazones tested were crystalline and could
be stored at room temperature. As for silyl enolates, the enolates derived

1020
LETTERS
SYNLETT
17
from both esters and thioesters worked well. 1-Phenyl-1-
trimethylsiloxyethene (a ketone-derived silyl enolate) also reacted with
an aliphatic acylhydrazone to afford the corresponding adduct in a good
yield.
was obtained in the presence of samarium diiodide (SmI ) in THF-
MeOH at rt.
2
We then examined reductive cleavage of nitrogen-nitrogen bonds of the
β-N'-acylhydrazinocarbonyl compounds. If the cleavage is successfully
carried out, the two-step process can be regarded as a novel Mannich-
type reaction. Namely, hydrazones, readily prepared from aldehydes and
acylhydrazines, react with silyl enolates to give β-N'-
acylhydrazinocarbonyl compounds, and reductive cleavage of nitrogen-
nitrogen bonds gives β-aminocarbonyl compounds (Scheme 1).
A typical experimental procedure is described for the reaction of
1
4a
(
isovaleraldehyde 4-trifluoromethylbenzoylhydrazone
,
R
=
2
2a
4a
(CH ) CHCH ) with ketene silyl acetal
(R = Me). To a solution of
(54.2 mg, 0.2 mmol) in
3 2
2
Sc(OTf) (4.9 mg, 0.01 mmol) and
3
2a
acetonitrile (1.2 ml) was added a solution of
(52.6 mg, 0.3 mmol) in
It is known that classical Mannich reactions often induce several side
pathways under rather drastic conditions, and that the yields of the
acetonitrile (0.4 ml) at room temperature. After stirring for 4 h at the
same temperature, the reaction was quenched with saturated aqueous
NaHCO solution, and the aqueous layer was extracted with
dichloromethane. The extract was dried over sodium sulfate and
concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel (hexane/ethyl acetate = 2/1) to
desired adducts are often low. Use of imines as starting materials have
3
8,9
improved the yields,
and among the reactions using imines,
condensation with silyl enolates under the influence of a Lewis acid is
10,11
the most promising.
Although several efficient catalytic processes
11
using imines have been reported, a problem is instability of aliphatic
give
hydrazino]hexanate ( , 65.9 mg, 88%) as white crystals. To a solution
6a
methyl
2,2,5-trimethyl-3-[N'-(p-trifluoromethylbenzoyl)-
6a
(33.0 mg, 0.09 mmol) in ethanol (2.0 ml) was added a catalytic
imines containing α-protons, which are easily isomerized to enamine
12
forms to induce self-condensation, etc.
of
amount of Raney Ni (W-3). After stirring under H at 1 atm for 24 h, a
Reductive cleavage of the nitrogen-nitrogen bond of the hydrazino
2
solution of di-t-butoxydicarbonate (76.9 mg, 0.4 mmol) in ethanol (1.0
ml) was added under argon and the solution was stirred for 15 h at room
temperature. Raney Ni was then filtered off, and the filtrate was
concentrated under reduced pressure. The residue was purified by
compound was successfully carried out using Raney Ni under H
2
13
6a
atmosphere (Scheme 2). Thus, adduct
was treated with a catalytic
amount of Raney Ni (W-3) under H (1 atm) at ambient temperature.
2
After cleavage of the nitrogen-nitrogen bond, the resulting amine was
7
column chromatography on silica gel (dichloromethane) to give (18.0
protected as its t-butoxycarbonyl (Boc) group.
mg, 71 %) as a colorless oil.
In summary, 4-trifluoromethylbenzoylhydrazones reacted with silyl
enolates, in the presence of a catalytic amount of scandium triflate
(Sc(OTf) ), to afford the corresponding adducts, β-N'-
3
acylhydrazinocarbonyl compounds, which were readily converted to β-
aminocarbonyl compounds in high yields. It is noted that aliphatic
hydrazones, which are mostly crystalline and can be stored at room
temperature, reacted smoothly, and that these reactions may supersede
Mannich-type reactions using imines. Moreover, the hydrazino
compounds were also successfully converted to β-lactam, pyrazolone,
and pyrazolidinone derivatives. Further studies to use acylhydrazones as
electrophiles in synthetic reactions as well as to develop catalytic
asymmetric Mannich-type reactions are now in progress in our
laboratories.
Finally, cyclization of β-N'-acylhydrazinocarbonyl compound 6a to
Acknowledgment.
14
The authors are grateful to Prof. Yukihiko
heterocycles was examined (Scheme 3). It was found that β-lactam 8
15
Hashimoto (University of Tokyo) for the X-ray analysis. This work was
partially supported by a Grant-in-Aid for Scientific Research from the
Ministry of Education, Science, Sports, and Culture, Japan, and a SUT
Special Grant for Research Promotion.
was obtained by treatment of 6a with n-BuLi at -78 °C, while
3
pyrazolone 9 was produced in the presence of NaOMe at room
temperature (rt). Since isomerization from 8 to 9 was observed under
these conditions (NaOMe), 8 and 9 were expected to be kinetic and
16
thermodynamic products, respectively. Moreover, pyrazolidinone 10

September 1998
SYNLETT
1021
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–1
1
14. 8: IR (neat) 1765, 1685, 1325 cm ; H NMR (CDCl ) δ 0.93 (dd,
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–1
1
16. 10: Mp 114-115 °C. IR (neat) 1717 cm
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3
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13
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