A convenient synthesis of substituted pyrazolidines and azaproline derivatives through highly regio- and diastereoselective reduction of 2-pyrazolines

Article abstract of DOI:10.1021/jo702050t

(Chemical Equation Presented) The synthesis of substituted N-acetyl- and N-aroyl-2-pyrazolines via intramolecular Michael addition of α,β-unsaturated hydrazones generated through olefination of phosphinyl and phosphonyl hydrazones with carbonyl compounds is reported. The regioselective reduction of the C-N double bond in these 2-pyrazolines using Superhydride (Et₃BHLi) gives pirazolidine derivatives with excellent levels of cis-diastereoselectivity. These 2-pyrazolines can also be obtained in one-pot reaction from allenes, hydrazides, and aldehydes; and pyrazolidines, after reduction, from allenes, hydrazides, and aldehydes. This synthetic route was developed to provide a new approach to substituted azaproline derivatives in a diastereoselective fashion.

Full text of DOI:10.1021/jo702050t

A Convenient Synthesis of Substituted Pyrazolidines and Azaproline
Derivatives through Highly Regio- and Diastereoselective Reduction
of 2-Pyrazolines
Jesu´s M. de los Santos, Yago Lo´pez, Domitila Aparicio, and Francisco Palacios*
Departamento de Qu´ımica Orga´nica I, Facultad de Farmacia, UniVersidad del Pa´ıs Vasco, Apartado 450,
01080 Vitoria, Spain
francisco.palacios@ehu.es
ReceiVed September 18, 2007
The synthesis of substituted N-acetyl- and N-aroyl-2-pyrazolines via intramolecular Michael addition of
R,â-unsaturated hydrazones generated through olefination of phosphinyl and phosphonyl hydrazones with
carbonyl compounds is reported. The regioselective reduction of the C-N double bond in these
2-pyrazolines using Superhydride (Et3BHLi) gives pirazolidine derivatives with excellent levels of cis-
diastereoselectivity. These 2-pyrazolines can also be obtained in one-pot reaction from allenes, hydrazides,
and aldehydes; and pyrazolidines, after reduction, from allenes, hydrazides, and aldehydes. This synthetic
route was developed to provide a new approach to substituted azaproline derivatives in a diastereoselective
fashion.
Introduction
the generation of new heterocycles by means of multistep
reactions is a matter of growing interest.2 Pyrazole, pyrazoline
I, and pyrazolidine II ring systems (Chart 1) are important
heterocycles that are attracting increasing interest of many
researchers,3 not only in medicinal chemistry because of their
antimicrobial,4a antibacterial,4b antipyretic,4c antidepressant,4d,e
and anti-inflammatory4f,g activity, but also in material chemistry
for their role in nanocrystal investigation5a,b or as brightening
agents5c and in the construction of organic electroluminescence
devices.5d,e Among these nitrogen-containing heterocyclic com-
pounds with interesting applications, azaproline (azPro) III
(Chart 1), aza-analogue of the cyclic amino acid proline, is of
especial interest, and azaproline derivatives are important
substrates in biologically important peptide sequences relevant
to metallopeptidase activity6 and in organocatalysis.7 Recently,
the impact of azaproline and its derivatives in stabilizing cis-
amide bonds in selective bioactive peptides has been described.8
For this reason, the development of new strategies for the
The development of new, rapid, and clean synthetic routes
toward focused libraries of nitrogen-containing heterocycles is
of great importance to both medicinal and synthetic chemists.1
Consequently, the design and development of procedures for
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10.1021/jo702050t CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/18/2007
550
J. Org. Chem. 2008, 73, 550-557

Synthesis of Pyrazolidines and Azaproline DeriVatiVes
CHART 1. 2-Pyrazoline and Pyrazolidine Derivatives I-III
CHART 2. Retrosynthetic Pathway for the Preparation of
Pyrazolidine Derivatives IV
preparation of azaproline derivatives could open new alternatives
for the preparation of azapeptides9 and for organocatalysis.7
In this context, we are interested in the preparation of
three-,10 five-,11 and six-membered12 nitrogen-containing het-
erocycles, as well as the synthesis of new amino phosphorus
derivatives13 and their synthetic use for the construction of not
only carbon-carbon double bond (CdC)14 but also carbon-
nitrogen double bond (CdN)15 of functionalized acyclic com-
pounds and heterocycles.16 As part of our ongoing research
programs in the area of nitrogen-containing heterocyclic com-
pounds, we here describe an example of the regio- and
diastereoselective reduction of 2-pyrazolines V to pyrazolidine
derivatives IV including azPro derivatives IV (R2 ) CO2R,
SCHEME 1. Synthetic Approach to r,â-Unsaturated
Hydrazones 5
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2004, 69, 9030-9042. (c) Zhang, W. J.; Berglund, A.; Kao, J. L. F.; Couty,
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M.; Lee, K. B. J. Am. Chem. Soc. 2002, 124, 11881-11893. (e) Gante, J.
Synthesis 1989, 405-413.
(10) (a) Palacios, F.; Ochoa de Retana, A. M.; Alonso, J. M. J. Org.
Chem. 2006, 71, 6141-6148. (b) Palacios, F.; Aparicio, D.; Ochoa de
Retana, A. M.; de los Santos, J. M.; Gil, J. I.; Alonso, J. M. J. Org. Chem.
2002, 67, 7283-7288. (c) Palacios, F.; Ochoa de Retana, A. M.; Mart´ınez
de Marigorta, E.; de los Santos, J. M. Eur. J. Org. Chem. 2001, 2401-
2414.
(11) (a) Palacios, F.; Alonso, C.; Legido, M.; Rubiales, G.; Villegas, M.
Tetrahedron Lett. 2006, 47, 7815-7818. (b) Palacios, F.; Aparicio, D.;
Vicario, J. Eur. J. Org. Chem. 2005, 2843-2850. (c) Palacios, F.; Ochoa
de Retana, A. M.; Gil, J. I.; Alonso, J. M. Tetrahedron 2004, 60, 8937-
8947. (d) Palacios, F.; Ochoa de Retana, A. M.; Pagalday, J. Eur. J. Org.
Chem. 2003, 68, 913-919.
Chart 2) as well as the highly regioselective preparation of new
1,3,5-trisubstituted 2-pyrazolines V via intramolecular Michael
addition of R,â-unsaturated hydrazones VI, generated through
olefination of phosphinyl and phosphonyl hydrazones VII with
carbonyl compounds. The simplest method for preparation of
unsaturated hydrazones involves the condensation of unsaturated
carbonyl compounds with hydrazines (1,2-addition). However,
in the case of ketones a mixture of products is mostly obtained
because of the competitive Michael addition of the hydrazine
to unsaturated ketones (1,4-addition).17
(12) (a) Aparicio, D.; Attanasi, O. A.; Filippone, P.; Ignacio, R.; Lillini,
S.; Mantellini, F.; Palacios, F.; de los Santos, J. M. J. Org. Chem. 2006,
71, 5897-5905. (b) Palacios, F.; Herra´n, E.; Alonso, C.; Rubiales, G.; Lecea,
B.; Ayerbe, M.; Coss´ıo, F. P. J. Org. Chem. 2006, 71, 6020-6030. (c)
Palacios, F.; Alonso, C.; Rubiales, G.; Villegas, M. Tetrahedron 2005, 61,
2779-2794. (d) Palacios, F.; Herra´n, E.; Rubiales, G.; Ezpeleta, J. M. J.
Org. Chem. 2002, 67, 2131-2135. (e) Palacios, F.; Ochoa de Retana, A.
M.; Gil, J. I.; Lo´pez de Munain, R. Org. Lett. 2002, 4, 2405-2408.
(13) For a recent review of â-aminophosphonates, see: Palacios, F.;
Alonso, C.; de los Santos, J. M. Chem. ReV. 2005, 105, 899-931.
(14) (a) Palacios, F.; Aparicio, D.; Lo´pez, Y.; de los Santos, J. M.;
Ezpeleta, J. M. Tetrahedron 2006, 62, 1095-1101. (b) Palacios, F.; Ochoa
de Retana, A. M.; Pascual, S.; Oyarzabal, J. J. Org. Chem. 2004, 69, 8767-
8774. (c) Palacios, F.; Ochoa de Retana, A. M.; Pascual, S. Org. Lett. 2003,
4, 769-772. (d) Palacios, F.; Aparicio, D.; Garc´ıa, J.; Rodr´ıguez, E.;
Ferna´ndez-Acebes, A. Tetrahedron 2001, 57, 3131-3141. (e) Palacios, F.;
Aparicio, D.; de los Santos, J. M.; Rodr´ıguez, E. Tetrahedron 1998, 54,
599-614.
Results and Discussion
As outlined in Scheme 1, the required functionalized phos-
phinyl and phosphonyl hydrazones 4 were easily prepared by
(16) (a) Palacios, F.; Ochoa de Retana, A. M.; Alonso, J. M. J. Org.
Chem. 2005, 70, 8895-8901. (b) Palacios, F.; Aparicio, D.; Lo´pez, Y.; de
los Santos, J. M.; Alonso, C. Eur. J. Org. Chem. 2005, 1142-1147. (c)
Palacios, F.; Ochoa de Retana, A. M.; Pascual, S.; Lo´pez de Munain, R.;
Ezpeleta, J. M. Tetrahedron 2005, 61, 1087-1094. (d) Palacios, F.; Alonso,
C.; Rodr´ıguez, M.; Mart´ınez de Marigorta, E.; Rubiales, G. Eur. J. Org.
Chem. 2005, 1795-1804.
(15) (a) Palacios, F.; Vicario, J.; Maliszewska, A.; Aparicio, D. J. Org.
Chem. 2007, 72, 2682-2685. (b) Palacios, F.; Aparicio, D.; Vicario, J. J.
Org. Chem. 2006, 71, 7690-7696. (c) Coss´ıo, F. P.; Alonso, C.; Lecea,
B.; Ayerbe, M.; Rubiales, G.; Palacios, F. J. Org. Chem. 2006, 71, 2839-
2847. (d) Palacios, F.; Herra´n, E.; Alonso, C.; Rubiales, G. Tetrahedron
2006, 62, 7661-7666. (e) Palacios, F.; Alonso, C.; Amezua, P.; Rubiales,
G. J. Org. Chem. 2002, 67, 1941-1944.
(17) Patai, S. In The Chemistry of the Amino Group; Wiley: London,
1968; p 61.
J. Org. Chem, Vol. 73, No. 2, 2008 551

de los Santos et al.
TABLE 1. Preparation of r-Phosphorylated Hydrazones 3 and 4
TABLE 2. Olefination Reaction of a Series of r-Phosphorylated
Hydrazones 4
entry
product
R
R1
yield (%)a (b)
syn/anti ratioc
entry
product
R1
R2
R3
yield (%)a
1
2
3
4
3a
4a
4b
4c
Ph
Ph
Ph
OEt
71
48/52
Me
Ph
Ph
81 (80)
95 (85)
73
81/19 (77/23)d
0/100 (0/100)d
100/0
1
2
3
4
5
6
7
5a
5b
5c
5d
5e
5f
Ph
Ph
Ph
Ph
Ph
Ph
Me
H
H
H
H
H
Ph
H
Ph
95 (88)b
94 [86]c
91
93
81
p-Me-C6H4
2-furyl
iBu
CO2Et
Ph
a Yield of isolated purified compounds 3 and 4 from phosphorylated
allenes 1. b Yield in parenthesis refers to yield of isolated purified
compounds 4 from primary hydrazones 3. c Syn/anti ratio was calculated
by 31P NMR on the crude reaction mixture. d Syn/anti ratio for 4a,b prepared
from primary hydrazone 3a.
82
5g
p-MeO-C6H4
85 (80)b
a Yield of isolated purified compounds 5 from hydrazones derived from
phosphine oxides 4a,b (R ) Ph). b Yield in parenthesis refers to yield of
isolated purified compounds 5 in a one-pot reaction from allene 1a. c Yield
in brackets refers to yield of isolated purified compounds 5 from hydrazones
derived from phosphonate 4c (R ) OEt).
the reaction of allenic phosphine oxide 1a (R ) Ph) or
phosphonate 1b (R ) OEt) with acethydrazide 2a (R1 ) Me)
or benzhydrazide 2b (R1 ) Ph), in a way similar to that
previously reported for simple hydrazines18 or carbazates.19
Thus, addition of acethydrazide 2a or benzhydrazide 2b to allene
1a in refluxing chloroform led to the formation of â-hydrazono
phosphine oxide 4a and 4b, respectively, in excellent yields
(Scheme 1, Table 1, entries 2 and 3). These compounds were
characterized by their spectroscopic data, which indicated that
they were isolated as a mixture of syn- and anti-hydrazones in
the case of compound 4a, or as the anti-hydrazone, as
determined by NOE experiments, in the case of compound 4b.
The process could be extended to allenes derived from phos-
phonate. In this case, allene 1b (R ) OEt) reacted with
benzhydrazide 2b (R1 ) Ph) in the absence of solvent, giving
â-functionalized phosphonate 4c (Scheme 1, Table 1, entry 4).
A different approach can also be used for the preparation of
these phosphorylated hydrazones 4, which were synthesized in
two steps from allenes 1. Addition of hydrazine monohydro-
chloride 2c, in the presence of triethylamine, to allene 1a in
refuxing chloroform gave primary hydrazone 3a (R ) Ph) as a
mixture of syn- and anti-isomers in good yield (Scheme 1, Table
1, entry 1). Functionalization of this primary hydrazone 3a could
be envisaged by treatment with acyl chlorides in the presence
of a base. In this way, phosphorylated hydrazones 4a and 4b
could be obtained in good yields after treatment of the primary
phosphorylated hydrazone 3a with acetyl or benzoyl chloride,
respectively, in the presence of a base such as Et3N (Scheme 1,
Table 1, entries 2 and 3). The spectroscopic data of hydrazone
4b indicated that, by using this methodology, this compound
was again isolated as the anti-hydrazone 4b. However, a mixture
of syn- and anti-hydrazone 3a was used as starting material for
the preparation of 4b, thus suggesting the presence of an
equilibrium between the hydrazone-enehydrazine tautomeric
forms.
1H NMR spectra of compounds 5 (R2 ) H) showed a vicinal
3JHH coupling constant in the range of 15.5 and 16.5 Hz between
the vinylic protons of 5, which is consistent with the E-
configuration of the carbon-carbon double bond.14d,e The
geometry of C-N double bond in compounds 5 was unambigu-
ously determined by NOE experiments. Thus, an NOE (2.5%)
was observed between the NH group of the hydrazone 5g and
the methyl group linked to the hydrazono moiety, suggesting
an anti-configuration for the carbon-nitrogen double bond. The
scope of the olefination reaction was not limited to aromatic
(Table 2, entries 1, 2, and 7) and aliphatic aldehydes (Table 2,
entry 4), since heteroaromatic aldehydes (Table 2, entry 3), ethyl
glyoxalate (Table 2, entry 5), and ketones (Table 2, entry 6)
could also be used. A Wadsworth-Emmons reaction of hydra-
zone 4c derived from phosphonate was also achieved in almost
the same yield as that obtained when hydrazone 4b derived from
phosphine oxide was used as starting material. It is noteworthy
that the synthesis of R,â-unsaturated hydrazones 5 did not
require the isolation and purification of phosphorylated hydra-
zones 4. Similar overall yields were obtained in a one-pot
reaction from allenes 1a derived from phosphine oxide, when
hydrazones 4, obtained either by addition of acylhydrazides 2a,b
or by addition of hydrazine 2c and subsequent reaction with
acyl chlorides, after evaporation of the solvent, were directly
treated with MeLi and subsequent addition of the carbonyl
compound (Scheme 1).
Next, we studied the intramolecular Michael addition of
conjugate hydrazones 5 for the preparation of 2-pyrazoline
derivatives 6. Formation of N-benzoyl-2-pyrazolines 6 (R1 )
Ph) took place by thermal treatment of R,â-unsaturated hydra-
zones 5 (R1 ) Ph) in refluxing toluene (method A, Table 3,
entries 1, 2, and 6). It is importat to point out that the presence
of a base (sodium methoxide, NaOMe) favored the intramo-
lecular cyclization to give the 2-pyrazolines 6 with a consider-
able reduction in the reaction time (Table 3, entry 3). However,
N-acetyl-R,â-unsaturated hydrazones 5 (R1 ) Me) did not react
under thermal heating, and a base such as sodium methoxide
and higher temperatures (refluxing DMF) were necessary
(method B, Table 3, entry 8). The cyclizations of these R,â-
unsaturated hydrazones 5 may take place through an intramo-
lecular Michael addition of the hydrazone nitrogen to the
carbon-carbon double bond. Unfortunately, R,â-unsaturated
hydrazone 5e (R1 ) Ph, R2 ) H, R3 ) CO2Et), with a
carboxylate group at the terminal carbon of the azadiene system,
did not cyclize when using thermal conditions (method A), nor
when a base and higher temperatures (method B) were used,
and instead only either the starting material or decomposition
products were obtained. However, similar overall yields were
R-Phosphorylated hydrazones 4a-c could be suitable to
efficiently achieve the homologation of hydrazones into their
vinylogous compounds. Thus, treatment of hydrazones 4 with
a base such as methyllithium (MeLi) at -78 °C, followed by
addition of the corresponding carbonyl compound (Table 2),
led to the formation of 1-azadienes 5 with high E-stereoselec-
tivity of the carbon-carbon double bond formed and in excellent
yields (Scheme 1). The structure of 5a-g was inferred from
spectroscopic as well as elemental analytical data. Thus, the
(18) Palacios, F.; Aparicio, D.; de los Santos, J. M. Tetrahedron 1994,
50, 12727-12742.
(19) (a) Palacios, F.; Aparicio, D.; Lo´pez, Y.; de los Santos, J. M.
Tetrahedron 2005, 61, 2815-2830. (b) Palacios, F.; Aparicio, D.; Lo´pez,
Y.; de los Santos, J. M. Tetrahedron Lett. 2004, 45, 4345-4348.
(20) Auwers, K.; Cauer, E. J. Prakt. Chem. 1930, 136, 146-176.
(21) Postovskii, I. Y.; Vereshchagina, N. N. Dokl. Akad. Nauk SSSR 1956,
110, 802-804; Chem. Abstr. 1957, 51, 43369.
552 J. Org. Chem., Vol. 73, No. 2, 2008

Synthesis of Pyrazolidines and Azaproline DeriVatiVes
TABLE 3. Preparation of Substituted 2-Pyrazolines 6
SCHEME 2. Preparation of Optically Active 2-Pyrazoline 10
cyclization yield
time (days) (%)b
entry product methoda R1 R2
R3
1
2
3
4
5
6
7
8
6a20
6b
6c
A
A
B
C
D
A
B
B
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
Ph
9
9
5
5
5
10
6
4
68
81
60
64
61
38
70
62
p-Me-C6H4
2-furyl
2-furyl
2-furyl
iBu
6c
6c21
6d
6e
Ph Ph Ph
Me p-MeO-C6H4
6f
H
a Method A: Toluene, reflux. Method B: MeONa, DMF, reflux. Method
C: One-pot reaction from hydrazone 4b using NaH in refluxing DMF.
Method D: Same conditions as method C in a one-pot reaction from allene
1a. b Yield of isolated purified compounds 6 from R,â-unsaturated hydra-
zones 5.
prepared in almost quantitative yields by treatment of starting
chiral hydrazone 8 with 2.5 equiv of NaH at 0 °C, followed by
addition of benzaldehyde (Scheme 2). The 1H NMR spectra of
3
compound 9 showed a vicinal JHH coupling constant of 16.9
obtained for the preparation of the 2-pyrazoline 6c in a one-pot
reaction from hydrazone 4b (method C, Table 3, entry 4), or
from allene 1a (method D, Table 3, entry 5) when hydrazone
4b was first obtained (vide supra), which was then treated with
2.2 equiv of sodium hydride (NaH) in DMF followed by the
addition of 2-furaldehyde and thermal treatment.
Hz between the vinylic protons, establishing the E-stereochem-
istry of the carbon-carbon double bond, while the anti-
configuration of the C-N double bond was confirmed by NOE
experiments, since an NOE (2.2%) was observed between the
hydrazonic proton and the methyl group of hydrazone 9.
Thermal treatment of the R,â-unsaturated hydrazone 9 led to
the formation of 2-pyrazoline 10 in moderate yield, as a 1:1
mixture of nonseparable diastereoisomers (Scheme 2). These
results suggest that the chiral group of the R,â-unsaturated
hydrazone 9 is too distant from the reaction center with a
negligible influence on it. 2-Pyrazoline 10 could be also directly
prepared in a one-pot reaction from â-ketophosphonate 7 when
hydrazone 8 was initially synthesized by condensation reaction
with hydrazide 2b and then this compound 8 was treated with
2.2 equiv of sodium hydride (NaH) in DMF followed by the
addition of benzaldehyde and thermal treatment.
Taking into account the importance of the pyrazolidine ring
system in medicinal and synthetic organic chemistry, we then
explored the regioselective carbon-nitrogen double bond reduc-
tion of the N-acyl-2-pyrazolines V to access the corresponding
pyrazolidines IV (vide supra, Chart 2). To this end, several
attempts using different reducing systems such as NaBH4/MeOH
or NaBH4/TFA for the reduction of the C-N double bond in
2-pyrazolines 6 were unsuccessful. The best results in the C-N
double bond reduction of 6 were achieved by using Superhydride
(Et3BHLi) in THF at 0 °C, which furnished the pyrazolidines
12 in good yields, exclusively as a sole diastereoisomer cis-12,
which could be isolated by chromatographic separation (Scheme
3, Table 4).
Since the pioneering work on the synthesis of 2-pyrazolines
by Fischer and Kno¨venagel in the late nineteenth century,22
a
large number of methods of preparation of 2-pyrazolines have
been developed,3 mainly involving carbonyl derivatives and
hydrazines. However, using this approach a mixture of regioi-
somers is usually formed. Series of specially substituted
representatives have rarely been prepared using other synthetic
approaches such as the 1,3-dipolar cycloaddition of diazoalkanes
or nitrile imines with alkynes or alkenes.23 As far as we know,
the strategy reported here describes, for the first time, the
selective preparation of 2-pyrazolines by means of a one-pot
reaction from allenes, hydrazides, and carbonyl compounds
without obtaining mixtures of regioisomers.
We also explored the effect of the presence of an optically
active group at C-3 of the R,â-unsaturated hydrazone VI (vide
supra, Chart 2) in the intramolecular Michael addition. The
preparation of 1-azadienes 9 derived from lactate (Scheme 2)
was performed in several steps. Initially, we synthesized
optically pure â-ketophosphine oxide 7 by addition of (2S)-
ethyl lactate benzyl ester to lithium salts derived from meth-
ylphosphine oxide by means of a modified procedure of the
Shapiro method.24 Condensation reaction of â-ketophosphine
oxide 7 with benzhydrazide in refluxing methanol led to the
formation of syn-hydrazone 8 in good yield (Scheme 2). The
syn-configuration of the C-N double bond in the hydrazone 8
was confirmed by NOE experiments. When the hydrazonic
proton was irradiated, there was no NOE effect with the methyl
group or the benzoxy group, and a NOE effect (3.1%) was
observed between the hydrazonic proton and the methylene
group of hydrazone 8. R,â-Unsaturated hydrazone 9 was
The structures of 12a-e were characterized from their
spectroscopic as well as elemental analytical data. Thus, the
1H NMR spectra of compounds 12c showed an absorption at
δH 1.26 ppm as a well-resolved doublet with coupling constant
3JHH ) 6.1 Hz for the methyl group bonded to the pyrazolidine
ring. Two different protons corresponding to the methylene
proton of the ring system appear at δH 1.94 ppm (2JHH ) 12.7
Hz, 3JHH ) 7.9 and 10.1 Hz) for H-4trans (relative stereochemistry
3
with H-3 and H-5) and δH 2.66 ppm (2JHH ) 12.7 Hz, JHH
)
(22) Fischer, E.; Kno¨venagel, O. Ann. Chem. 1887, 239, 194-206.
(23) Conti, P.; Pinto, A.; Tamborini, L.; Rizzo, V.; De Micheli, C.
Tetrahedron 2007, 63, 5554-5560.
(24) Shapiro, G.; Buechler, D.; Hennet, S. Tetrahedron Lett. 1990, 31,
5733-5736.
6.3 and 8.5 Hz) for H-4cis (relative stereochemistry with H-3
and H-5). The stereochemistry of 12 was assigned on the basis
of conventional 1H and 13C NMR data as well as NOE
J. Org. Chem, Vol. 73, No. 2, 2008 553

de los Santos et al.
The scope of the selective reduction was not limited to
aromatic aldehydes (Table 4, entries 1, 2, and 5) since
heteroaromatic aldehydes (Table 4, entry 3) and aliphatic
aldehydes (Table 4, entry 4) could also be used. It is noteworthy
that similar overall yields were obtained for the preparation of
the pyrazolidine 12c (Table 4, entry 3) in a one-pot reaction
from allene 1a when 2-pyrazoline 6c was first obtained (vide
supra) and subsequent reduction with Superhydride (Et3BHLi)
in THF at 0 °C. As far as we know, the strategy reported here
is the first description of the synthesis of pyrazolidines contain-
ing cis-substituents at the 3-position (methyl group) and
5-position (aryl or heteroaryl groups) from 2-pyrazolines by
means of a one-pot reaction from allenes, hydrazides, and
carbonyl compounds and subsequent reduction.
FIGURE 1. NOE observed for pyrazolidine 12c.
SCHEME 3. Stereoselective Preparation of Pyrazolidine
Derivatives 12
The incorporation of azPro, the nitrogen analogue of the
amino acid proline where the R-carbon is replaced with a
nitrogen atom, into biologically active peptides has, in some
cases, led to peptidomimetics with enhanced activity or meta-
bolic stability.27 Peptides containing azPro were shown to
stabilize the cis-amide conformer8 for the acyl-azPro bond and
prefer type VI â-turns both in crystals28 and in organic
solvents.29 A series of azPro dipeptides with various N-
substituents were also prepared as potent inhibitors of two
proline-specific serine proteases: dipeptidyl peptidase IV and
prolyl oligopeptidase,30 while several FKBP12 ligands contain-
ing azPro derivatives were synthesized, and their neuroprotective
effects were evaluated in vitro and in vivo.31 The synthetic
potential of this methodology (vide supra) can be applied to
the preparation of azPro derivatives IV (R2 ) CO2R) (vide
supra, Chart 2) if pyrazolidine 12e (R ) CO2Et) by 12 (R2 )
CO2Et) was available. However, as reported before, the 2-pyra-
zoline 6 (R2 ) H, R3 ) CO2R) containing a carboxylate group
at C-5 is not accessible through intramolecular Michael addition
of the starting R,â-unsaturated hydrazone 5e (vide supra).
Nevertheless, a straightforward alternative synthetic route to
azaproline derivatives can be designed by using 2-pyrazoline
6c with a furyl ring at C-5, keeping in mind that the furan ring
is a synthetic equivalent of the carboxylate group.32-34
TABLE 4. Pyrazolidines 12 Prepared through Regioselective
Reduction of 2-Pyrazolines 6
entry
product
R1
R2
yield (%)a
1
2
3
4
5
12a26
12b
12c
12d
12e
Ph
Ph
Ph
Ph
Me
Ph
80
83
p-Me-C6H4
2-furyl
73 (67)b
67
iBu
p-MeO-C6H4
60
a Yield of isolated purified pyrazolidines 12 from pyrazolines 6. b Yield
of isolated purified pyrazolidines 12 in a one-pot reaction from allene 1a.
experiments. The 3,5-cis-relationship of H-3 and H-5 in the ring
of pyrazolidine 12c was evident since an NOE was observed
between H-3 and H-4cis (1.7%) (cis-relative stereochemistry)
and between H-4cis and H-5 (1.4%) (Figure 1). Conversely, a
very small NOE was observed between H-3 and H-4trans
(0.28%). Likewise, an NOE was observed between H-4trans and
the methyl group at C-3 (1.2%), while this proton (H-4trans) did
not show an NOE with the hydrogen at C-5 (trans-relationship
between these protons). These results suggest a cis relative
stereochemistry between H-3 and H-5. The coupling constants
are also consistent with those reported for other pyrazolidine
derivatives.25 A pentagonal intermediate 11 where the Super-
hydride may coordinate with the oxygen atom of the N-acyl
moiety and the nitrogen atom (N-2) of the pyrazoline could
explain the selective attack of the hydride by the underside of
the carbon-nitrogen double bond. Thus, the formation of the
cis-pyrazolidine 12 can be fully understood considering that the
hydride attacks from the opposite side of the R2 substituent,
taking into account that the N-acyl group at N-1 and R2 should
adopt a trans-configuration because of a steric hindrance.
Finally, the oxidation process of the furyl ring in 12c was
explored for the preparation of azPro derivatives. However, to
(27) Hartley, O.; Gaertner, H.; Wilken, J.; Thompson, D.; Fish, R.;
Ramos, A.; Pastore, C.; Dufour, B.; Cerini, F.; Melotti, A.; Heveker, N.;
Picard, L.; Alizon, M.; Mosier, D.; Kent, S.; Offord, R. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 16460-16465.
(28) (a) Didierjean, C.; Del Duca, V.; Benedetti, E.; Aubry, A.; Zouikri,
M.; Marraud, M.; Boussard, G. J. Pept. Res. 1997, 50, 451-457. (b)
Didierjean, C.; Aubry, A.; Zouikri, M.; Boussard, G.; Marraud, M. Acta
Crystallogr., Sect. C 1995, 51, 688-690. (c) Lecoq, A.; Boussard, G.;
Marroud, M.; Aubry, A. Biopolymers 1993, 33, 1051-1059.
(29) Zouikri, M.; Vicherat, A.; Aubry, A.; Marraud, M.; Boussard, G.
J. Pept. Res. 1998, 52, 19-26.
(30) Borloo, M.; Augustyns, K.; Belyaev, A.; de Meester, I.; Lambeir,
A.-M.; Goossens, F.; Bollaert, W.; Rajan, P.; Scharpe, S.; Haemers, A. Lett.
Pept. Sci. 1995, 2, 198-202.
(31) Wilkinson, D. E.; Thomas, B. E., IV; Limburg, D. C.; Holmes, A.;
Sauer, H.; Ross, D. T.; Soni, R.; Chen, Y.; Guo, H.; Howorth, P.; Valentine,
H.; Spicer, D.; Fuller, M.; Steiner, J. P.; Hamilton, G. S.; Wu, Y.-Q. Bioorg.
Med. Chem. 2003, 11, 4815-4825.
(32) The synthetic equivalence of a furan ring system and a carboxylate
group has been reported since the furan can be oxidized by ozonolysis33 or
through the use of ruthenium reagents34 and converted into a carboxylate
group.
(33) (a) Koriyama, Y.; Nozawa, A.; Hayakawa, R.; Shimizu, M.
Tetrahedron 2002, 58, 9621-9628. (b) Zhang, H.; Xia, P.; Zhou, W.
Tetrahedron: Asymmetry 2000, 11, 3439-3447.
(34) (a) Sun, X.-L.; Kai, T.; Takayanagi, H.; Furuhata, K. Synlett 1999,
1399-1400. (b) Dondoni, A.; Junquera, F.; Merchan, F. L.; Merino, P.;
Tejero, T. J. Chem. Soc., Chem. Commun. 1995, 2127-2128.
(25) Ban˜uelos, L. A.; Cuadrado, P.; Gonza´lez-Nogal, A. M.; Lo´pez-
Solera, I.; Pulido, F. J.; Raithby, P. R. Tetrahedron 1996, 52, 9193-9206.
(26) Described with undefined relative stereochemistry: Hesse, K. D.
Justus Liebigs Ann. Chem. 1971, 743, 50-56.
554 J. Org. Chem., Vol. 73, No. 2, 2008

Synthesis of Pyrazolidines and Azaproline DeriVatiVes
SCHEME 4. Synthesis of Azaproline Derivative 15
Experimental Section
General Methods. Reagent and solvent purification, workup
procedures, and analyses were performed in general as described
in the Supporting Information.
General Procedure for the Preparation of anti- and syn-[2-
(Diphenylphosphinoyl)-1-methylethylidene] Hydrazine (3a). To
a stirred solution of phosphorylated allene 1a (2.40 g, 10 mmol) in
dry chloroform (60 mL) were added hydrazine monohydrochloride
(0.82 g, 12 mmol) and triethylamine (2.11 mL, 15 mmol) under a
nitrogen atmosphere. Then, the mixture was stirred and refluxed
for 48 h. The crude reaction mixture was washed with water (3 ×
15 mL), and the aqueous phase was extracted with CH2Cl2 (2 ×
10 mL). The organic phase was dried over MgSO4, the solvent
was evaporated under vacuum, and the crude product was precipi-
tated with diethyl ether and recrystallized from a mixture of hexanes/
CH2Cl2 to afford 3a (1.93 g, 71%) as a white solid: mp 164-
166 °C; 1H NMR (300 MHz, CDCl3) δ 7.75-7.21 (m, 10H), 5.89
2
(bs, 2H), 4.87 (bs, 2H), 3.38 (d, 2H, JPH ) 14.5, anti), 3.27 (d,
2
2H, JPH )14.0 Hz, syn), 1.78 and 1.46 (s, 3H, anti and syn); 13C
NMR (75 MHz, CDCl3) δ 143.4 (syn), 143.2 (anti), 133.2, 132.3,
132.3, 131.9, 131.8, 131.7, 131.0, 130.9, 130.8, 130.7, 130.6, 128.9,
128.7, 128.6, 128.6, 128.5, 128.4, 128.3, 40.9 (d, 1JPC ) 67.3 Hz,
avoid either secondary products or the reversal to the starting
2-pyrazolines in the oxidation process, it was previously
necessary to protect the N-2 of the pyrazolidine ring. Thus, N-H
protection of pyrazolidine 12c as N-trifluoroacetyl-protected
derivatives35 was performed by treatment with trifluoroacetic
anhydride leading to N,N′-diacylated pyrazolidine 13 in excellent
yields. azPro derivative 15 could be obtained in 33% yield from
pyrazolidine 13 when this compound was treated with the
oxidizing agent (NaIO4/RuCl3) and subsequent esterification by
using thionyl chloride in methanol. In this process, the formation
of the amino acid azPro 14 with a concomitant deprotection of
the N-trifluoroacetyl group at N-2 (Scheme 4) could explain
the formation of compound 15. Azaprolines without an alkyl
group at the 3-position have been prepared.36 However, as far
as we know, this strategy affords the synthesis of 5-methyl
azaproline derivatives for the first time and with the cis-
configuration between the methyl group (5-position) and the
carboxylate ester moiety (3-position).
1
anti), 33.8 (d, JPC ) 65.1 Hz, syn), 25.2 (syn), 15.3 (anti); 31P
NMR (120 MHz, CDCl3) δ 30.9 (anti), 29.5 (syn); IR (KBr) 3381,
3342, 3058, 2942, 1630, 1437, 1186, 1124; MS (EI) m/z 272 (M+,
13). Anal. Calcd for C15H17N2OP: C, 66.17; H, 6.29; N, 10.29.
Found C, 65.94; H, 6.32; N, 10.25.
General Procedure for the Preparation of Functionalized
Hydrazones Derived from Phosphine Oxides and Phosphonate
(4). Method A: To a stirred solution of phosphorylated allene 1a
or 1b (10 mmol) in dry chloroform (50 mL) was added the
corresponding hydrazide (12 mmol) under a nitrogen atmosphere.
Then, the mixture was stirred and heated at reflux for 16-24 h.
The solvent was evaporated under vacuum, and the crude product
was precipitated with diethyl ether and recrystallized from a mixture
of hexanes/CH2Cl2 (for â-hydrazones 4a,b derived from phosphine
oxides); while â-hydrazone 4c derived from phosphonate was
purified by flash chromatography (silica gel). Method B: A mixture
of allene derived from phosphonate 1b (1.76 g,10 mmol) and the
corresponding hydrazide (12 mmol) under a nitrogen atmosphere
was stirred and heated at 65 °C, without solvent for 16-24 h. The
crude product was purified by flash chromatography (silica gel).
Method C: To a 0 °C stirred solution of hydrazone 3a (0.27 g, 1
mmol) in dry chloroform (8 mL) triethylamine (0.28 mL, 2 mmol)
was added under a nitrogen atmosphere. After 30 min at 0 °C, a
solution of the corresponding acyl chloride (1.2 mmol) in dry
chloroform (2 mL) was added dropwise, and the mixture was stirred
at room temperature for 6 h. The crude reaction mixture was washed
with water (3 × 3 mL), and the aqueous phase was extracted with
CH2Cl2 (2 × 3 mL). The organic phase was dried over MgSO4,
the solvent was evaporated under vacuum, and the crude product
was precipitated with diethyl ether and recrystallized from a mixture
of hexanes/CH2Cl2.
Conclusion
In conclusion, an efficient procedure for the synthesis of
2-pyrazolines 6 from unsaturated hydrazones was reported. The
selective reduction of the carbon-nitrogen double bond of these
heterocycles afforded only 3,5-cis-disubstituted pyrazolidines
12 in a stereoselective fashion. 2-Pyrazolines 6 can also be
prepared in a one-pot reaction from very simple reagents such
as allenes 1, hydrazides 2, and carbonyl compounds, and
similarly pyrazolidines 12 were obtained from allenes 1,
hydrazides 2, and carbonyl compounds followed by reduction
with Superhydride. This strategy has been applied for the
preparation of a new 3,5-cis- disubstituted azPro derivative 15.
2-Pyrazolines, pyrazolidines, and azaproline derivatives are
important synthons in organic synthesis for the preparation of
biologically active compounds of interest to medicinal chem-
istry.3-5,8,9
anti-Benzoic Acid [2-Diphenylphosphinoyl-1-methylethylidene]
Hydrazide (4b). The title compound (3.57 g, 95%) obtained as a
white solid from allene 1a (2.40 g, 10 mmol) and benzhydrazide
(1.67 g, 12 mmol) as described in the general procedure (method
A). The title compound (0.32 g, 85%) was also obtained from
hydrazone 3a (0.27 g, 1 mmol) and benzoyl chloride (140 µL, 1.2
mmol) as described in the general procedure (method C). The crude
product was purified by precipitation with diethyl ether and
recrystallization from a mixture of hexanes/CH2Cl2: mp 238-
239 °C; 1H NMR (300 MHz, CDCl3) δ 12.15 (bs, 1H), 8.11-7.37
(35) This protecting group can be easily removed by a weak basic
treatment.
2
(m, 15H), 3.43 (d, JPH ) 14.8 Hz, 2H), 1.68 (s, 3H); 13C NMR
(36) (a) Guerra, F. M.; Mish, M. R.; Carreira, E. M. Org. Lett. 2000, 2,
4265-4267. (b) Barluenga, J.; Ferna´ndez-Mari, F.; Viado, A. L.; Aguilar,
E.; Olano, B.; Garc´ıa-Granda, S.; Moya-Rubiera, C. Chem. Eur. J. 1999,
5, 883-896. (c) Mish, M. R.; Guerra, F. M.; Carreira, E. M. J. Am. Chem.
Soc. 1997, 119, 8379-8380.
(75 MHz, CDCl3) δ 165.2, 151.0, 133.2, 133.0, 132.1, 131.6, 131.0,
130.8, 129.5, 129.2, 129.0, 128.5, 127.9, 36.9 (d, 1JPC ) 66.4 Hz),
26.3; 31P NMR (120 MHz, CDCl3) δ 33.0; IR (KBr) 3198, 2939,
1686, 1537, 1284, 1165; MS (CI) m/z 377 (M+ + 1, 100). Anal.
J. Org. Chem, Vol. 73, No. 2, 2008 555

de los Santos et al.
Calcd for C22H21N2O2P: C, 70.20; H, 5.62; N, 7.44. Found C, 70.42;
H, 5.60; N, 7.46.
Et2O (10 mL) and washed with a saturated solution of ammonium
chloride (3 × 4 mL). The organic phase was dried over MgSO4
and evaporated under vacuum. The crude pyrazolines 6 were
purified by flash chromatography (silica gel, AcOEt/hexanes, 1:9).
Method D (one-pot reaction from allene 1a): To a stirred solution
of phosphorylated allene 1a (1 mmol) in dry chloroform (5 mL)
was added the corresponding hydrazide (1.2 mmol) under a nitrogen
atmosphere. Then, the mixture was stirred and heated at reflux for
16 h. The solvent was evaporated under vacuum, and a solution of
crude product 4b in DMF (2 mL) was added dropwise and under
a nitrogen atmosphere to a 0 °C stirred suspension of sodium
hydride (0.053 g, 2.2 mmol) in DMF (4 mL). The mixture was
stirred at the same temperature for 1 h, and the corresponding
aldehyde (1.1 mmol) in DMF (1 mL) was then added dropwise.
The reaction mixture was allowed to stand from 0 °C to room
temperature for 16 h and refluxed for 5 days. Then, the crude
mixture was extracted with Et2O (10 mL) and washed with a
saturated solution of ammonium chloride (3 × 4 mL). The organic
phase was dried over MgSO4 and evaporated under vacuum. The
crude pyrazolines 6 were purified by flash chromatography (silica
gel, AcOEt/hexanes, 1:9).
General Procedure for the Preparation of r,â-Unsaturated
Hydrazones (5). Method A: To a -78 °C stirred solution of
R-phosphorylated hydrazone 4 (5 mmol) in THF (80 mL) was added
a solution of MeLi (6.6 mL, 10.5 mmol) under a nitrogen
atmosphere. The mixture was stirred at the same temperature for 1
h, and the corresponding carbonyl compound (5.5 mmol) in THF
(5 mL) was then added dropwise. The reaction mixture was stirred
for 16 h and allowed to stand from -78 °C to room temperature.
The solvent was evaporated under vacuum, and the crude mixture
was diluted with CH2Cl2 (30 mL) and washed with water (2 × 10
mL), and the aqueous phase was extracted with CH2Cl2. The organic
phase was dried over MgSO4 and evaporated under vacuum. The
crude product was purified by flash chromatography (silica gel,
AcOEt/hexanes, 1:9). Method B (one-pot reaction from allene
1a): To a stirred solution of phosphorylated allene 1a (1.2 g, 5
mmol) in dry chloroform (25 mL) was added the corresponding
hydrazide (6 mmol) under a nitrogen atmosphere. Then, the mixture
was stirred and heated at reflux for 16 to 24 h, and the solvent was
evaporated under vacuum. To a -78 °C stirred solution of the crude
R-phosphorylated hydrazone 4 in THF (80 mL) was added a
solution of MeLi (6.6 mL, 10.5 mmol) under a nitrogen atmosphere.
The mixture was stirred at the same temperature for 1 h, and the
corresponding carbonyl compound (5.5 mmol) in THF (5 mL) was
then added dropwise. The reaction mixture was stirred for 16 h
and allowed to stand from -78 °C to room temperature. The solvent
was evaporated under vacuum, and the crude mixture was diluted
with CH2Cl2 (30 mL) and washed with water (2 × 10 mL), and
the aqueous phase was extracted with CH2Cl2. The organic phase
was dried over MgSO4 and evaporated under vacuum. The crude
product was purified by flash chromatography (silica gel, AcOEt/
hexanes, 1:9).
1-Benzoyl-3-methyl-5-furan-2-yl-4,5-dihydro-1H-pyrazole (6c).
The title compound (0.15 g, 60%) was obtained from R,â-
unsaturated hydrazone 5c (0.25 g, 1 mmol) as described in the
general procedure (method B). The title compound (0.16 g, 64%)
was also obtained from R-phosphorylated hydrazone 4b (0.38 g, 1
mmol) and 2-furaldehyde (91 µL, 1.1 mmol) as described in the
general procedure (method C). The title compound (0.15 g, 61%)
was also obtained from allene 1a (0.24 g, 1 mmol), hydrazide (0.17
g, 1.2 mmol), and 2-furaldehyde (91 µL, 1.1 mmol) as described
in the general procedure (method D). Mp 76-77 °C; 1H NMR (300
MHz, CDCl3) δ 7.73 (d, 3JHH ) 6.6 Hz, 2H), 7.32-7.18 (m, 4H),
6.22-6.17 (m, 2H), 5.61 (dd, 3JHH ) 5.4 Hz, 3JHH ) 11.4 Hz, 1H),
Furan-2-ylbuten-3-one-N-benzoylhydrazone (5c). The title
compound (1.16 g, 91%) was obtained from R-phosphorylated
hydrazone 4b (1.88 g, 5 mmol) and 2-furaldehyde (0.46 mL, 5.5
mmol) as described in the general procedure. Mp 132-133 °C; 1H
NMR (300 MHz, CDCl3) δ 8.88 (bs, 1H), 7.81-7.37 (m, 7H), 6.71
2
3
2
3.10 (dd, JHH ) 18.0 Hz, JHH ) 11.4 Hz, 1H), 2.89 (dd, JHH
)
3
18.0 Hz, JHH ) 5.4 Hz, 1H), 1.93 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 166.4, 156.3, 152.1, 141.9, 134.4, 130.8, 129.8, 127.6,
110.5, 107.6, 54.1, 41.4, 16.1; IR (KBr) 2926, 1739, 1633, 1454,
1215; MS (EI) m/z 254 (M+, 3). Anal. Calcd for C15H14N2O2: C,
70.85; H, 5.55; N, 11.02. Found C, 71.04; H, 5.52; N, 10.99.
3
(d, JHH ) 16.6 Hz, 1H), 6.52-6.32 (m, 2H), 2.06 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 163.8, 152.2, 144.1, 143.1, 133.3, 131.7,
128.5, 127.1, 121.8, 112.3, 111.8, 110.4, 10.9; IR (KBr) 3310, 3118,
1646, 1513, 1480; MS (EI) m/z 254 (M+, 7). Anal. Calcd for
C15H14N2O2: C, 70.85; H, 5.55; N, 11.02. Found C, 70.66; H, 5.57;
N, 11.06.
General Procedure for the Reduction of Pyrazolines (6).
Synthesis of Pyrazolidines (12). Method A: To a 0 °C stirred
solution of pyrazolines 6 (0.5 mmol) in THF (15 mL) was added
dropwise a 1 M solution in THF of lithium triethylborohydride (1.25
mL, 1.25 mmol) in THF (2.5 mL) under a nitrogen atmosphere.
The reaction mixture was stirred at 0 °C for 1 h and quenched
with a 2 M solution of NaOH (5 mL). The solvent was evaporated
under vacuum and diluted with CH2Cl2 (15 mL), and the organic
phase was washed with 2 M NaOH (3 × 5 mL). The organic phase
was dried over MgSO4 and evaporated under vacuum. The crude
pyrazolidines 12 were purified by flash chromatography (silica gel,
AcOEt/hexanes, 10:90). Method B (one-pot reaction from allene
1a): To a stirred solution of phosphorylated allene 1a (0.12 g, 0.5
mmol) in dry chloroform (2.5 mL) was added the corresponding
hydrazide (0.6 mmol) under a nitrogen atmosphere. Then, the
mixture was stirred and heated at reflux for 16 h, and the solvent
was evaporated under vacuum. A solution of crude product 4b in
DMF (2 mL) was added dropwise and under a nitrogen atmosphere
to a 0 °C stirred suspension of sodium hydride (0.027 g, 1.1 mmol)
in DMF (2 mL). The mixture was stirred at the same temperature
for 1 h, and the corresponding aldehyde (0.5 mmol) in DMF (1
mL) was then added dropwise. To a 0 °C stirred solution of crude
pyrazolines 6 in THF (15 mL) was added dropwise a 1 M solution
in THF of lithium triethylborohydride (1.25 mL, 1.25 mmol) in
THF (2.5 mL) under a nitrogen atmosphere. The reaction mixture
was stirred at 0 °C for 1 h and quenched with a 2 M solution of
NaOH (5 mL). The solvent was evaporated under vacuum and
diluted with CH2Cl2 (15 mL), and the organic phase was washed
with 2 M NaOH (3 × 5 mL). The organic phase was dried over
Intramolecular Cyclization Reaction of r,â-Unsaturated
Hydrazones (5). Synthesis of Substituted 2-Pyrazolines (6).
Method A: A stirred solution of R,â-unsaturated hydrazone 5 (1
mmol) in dry toluene (5 mL) was refluxed under a nitrogen
atmosphere for 9 to 10 days. The solvent was evaporated under
vacuum, and the crude product was purified by flash chromatog-
raphy (silica gel, AcOEt/hexanes, 1:9) to give pyrazolines 6. Method
B: To a 0 °C stirred suspension of sodium methoxide (0.065 g,
1.2 mmol) in DMF (5 mL) was added dropwise and under a
nitrogen atmosphere a solution of R,â-unsaturated hydrazone 5 (1
mmol) in DMF (3 mL). The reaction mixture was allowed to stand
from 0 °C to room temperature and refluxed for 4-6 days. Then,
the crude mixture was extracted with Et2O (10 mL) and washed
with a saturated solution of ammonium chloride (3 × 4 mL). The
organic phase was dried over MgSO4 and evaporated under vacuum.
The crude pyrazolines 6 were purified by flash chromatography
(silica gel, AcOEt/hexanes, 1:9). Method C (one-pot reaction from
hydrazone 4b): To a 0 °C stirred suspension of sodium hydride
(0.053 g, 2.2 mmol) in DMF (4 mL) was added dropwise and under
a nitrogen atmosphere a solution of R-phosphorylated hydrazone
4b (1 mmol) in DMF (2 mL). The mixture was stirred at the same
temperature for 1 h, and the corresponding aldehyde (1.1 mmol)
in DMF (1 mL) was then added dropwise. The reaction mixture
was allowed to stand from 0 °C to room temperature for 16 h and
refluxed for 5 days. Then, the crude mixture was extracted with
556 J. Org. Chem., Vol. 73, No. 2, 2008

Synthesis of Pyrazolidines and Azaproline DeriVatiVes
MgSO4 and evaporated under vacuum. The crude pyrazolidines 12
were purified by flash chromatography (silica gel, AcOEt/hexanes,
10:90).
General Procedure and Spectral Data of Methyl 2-Benzoyl-
5-methylpyrazolidine-3-carboxylate (15). To a 0 °C stirred
solution of pyrazolidine 13 (88 mg, 0.25 mmol) in a mixture of
acetonitrile (0.5 mL) and CCl4 (0.5 mL) were added dropwise NaIO4
(0.81 g, 3.75 mmol) and RuCl3‚H2O (1 mg) under a nitrogen
atmosphere. After 2 h at room temperature, the crude mixture was
washed with H2O (2 × 2 mL) and extracted with CH2Cl2 (2 × 2
mL). The organic phase was dried over MgSO4 and evaporated
under vacuum. The crude compound was dissolved in MeOH (1
mL), and thionyl chloride (37 µL, 0.5 mmol) was added. The
reaction mixture was refluxed for 20 min, and the solvent was
evaporated under vacuum. The crude product was purified by flash
chromatography (silica gel, AcOEt/hexanes, 50:50) to obtain (21
mg, 33%) 15. Mp 87-88 °C; 1H NMR (300 MHz, CDCl3) δ 7.81-
cis-1-Benzoyl-5-furan-2-yl-3-methylpyrazolidine (12c). The
title compound (93 mg, 73%) was obtained from pyrazoline 6c (127
mg, 0.5 mmol) as described in the general procedure (method A).
The title compound (85 mg, 67%) was also obtained from allene
1a (0.12 g, 0.5 mmol), hydrazide (85 mg, 0.6 mmol), and
2-furaldehyde (45 µL, 0.6 mmol) as described in the general
procedure (method B). Mp 123-124 °C; 1H NMR (300 MHz,
CDCl3) δ 7.72-7.32 (m, 6H), 6.32-6.31 (m, 2H), 5.66 (bs, 1H),
2
3
4.01 (bs, 1H), 3.18 (bs, 1H), 2.66 (ddd, JHH ) 12.7 Hz, JHH
)
)
3
2
3
6.3 Hz, JHH ) 8.5 Hz, 1H), 1.94 (ddd, JHH ) 12.7 Hz, JHH
3
3
7.9 Hz, JHH ) 10.1 Hz, 1H), 1.26 (d, JHH ) 6.1 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 170.0, 153.9, 141.98, 135.0, 130.3, 129.0,
127.4, 110.4, 107.1, 56.5, 55.3, 40.9, 16.7; IR (KBr) 3211, 2965,
1619, 1507, 1387; MS (EI) m/z 256 (M+, 51). Anal. Calcd for
C15H16N2O2: C, 70.29; H, 6.29; N, 10.93. Found C, 70.52; H, 6.31;
N, 10.97.
3
7.35 (m, 5H), 4.95 (t, JHH ) 8.2 Hz, 1H), 4.10 (bs, 1H), 3.78 (s,
2
3
3H), 3.23 (bs, 1H), 2.70 (ddd, JHH ) 12.6 Hz, JHH ) 6.1 Hz,
2
3
3JHH ) 8.9 Hz, 1H), 1.65 (ddd, JHH ) 12.6 Hz, JHH ) 8.2 Hz,
3JHH ) 10.1 Hz, 1H), 1.23 (d, JHH ) 6.3 Hz, 3H); 13C NMR (75
3
General Procedure and Spectral Data of cis-1-Benzoyl-2-
trifluoroacetyl-5-furan-2-yl-3-methylpyrazolidine (13). To a
stirred solution of pyrazolidine 12c (128 mg, 0.5 mmol) in CH2Cl2
(2 mL) were added dropwise and under a nitrogen atmosphere Et3N
(84 µL, 0.6 mmol), trifluoroacetic anhydride (83 µL, 0.6 mmol),
and 18-crown-6 (159 mg, 0.6 mmol). The reaction mixture was
stirred at room temperature for 2 h. Then, the reaction mixture was
washed with H2O (2 × 1 mL) and extracted with CH2Cl2 (2 × 1
mL). The organic phase was dried over MgSO4 and evaporated
under vacuum. The crude pyrazolidine were purified by flash
chromatography (silica gel, AcOEt/hexanes, 10:90) to afford
compound 13 (171 mg, 97%). Mp 79-81 °C; 1H NMR (300 MHz,
MHz, CDCl3) δ 172.6, 168.7, 134.2, 130.5, 129.0, 127.5, 59.6, 56.3,
52.3, 40.3, 16.4; IR (KBr) 3217, 2932, 1752, 1454, 1208; MS (EI)
m/z 248 (M+, 100). Anal. Calcd for C13H16N2O3: C, 62.89; H, 6.50;
N, 11.28. Found C, 62.75; H, 6.52; N, 11.25.
Acknowledgment. This article is dedicated to Prof. Miguel
Yus on the occasion of his 60th birthday. This work was
financially supported by the University of the Basque Country
(UPV, GIU 06/51) and Direccio´n General de Investigacio´n del
Ministerio de Ciencia y Tecnolog´ıa (MCYT, Madrid DGI,
CTQ2006-09323). A Ramo´n y Cajal contract to J.M.S. from
MCYT is acknowledged.
3
CDCl3) δ 7.89-7.45 (m, 6H), 6.41 (d, JHH ) 7.1 Hz, 2H), 5.15
(d, 3JHH ) 8.2 Hz, 1H), 4.43 (bs, 1H), 2.56-2.49 (m, 1H), 2.26-
3
2.20 (m, 1H), 1.45 (d, JHH ) 6.4 Hz, 3H); 13C NMR (75 MHz,
2
CDCl3) δ 175.8, 154.7 (q, JCF ) 38.2 Hz), 150.6, 142.6, 133.0,
Supporting Information Available: Full characterization data,
1
1
132.8, 131.5, 131.1, 128.8, 128.6, 128.5, 127.2, 115.7 (q, JCF
)
procedures for the synthesis of all new compounds, and H and
288.1 Hz), 110.3, 107.7, 58.8, 54.4, 36.5, 18.0; IR (KBr) 3409,
3151, 2979, 1719, 1460, 1202; MS (EI) m/z 352 (M+, 2). Anal.
Calcd for C17H15F3N2O3: C, 57.96; H, 4.29; N, 7.95. Found C,
58.07; H, 4.30; N, 7.91.
13C spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO702050T
J. Org. Chem, Vol. 73, No. 2, 2008 557