Phosphonic acid catalyzed synthesis of pyrazolidines

Article abstract of DOI:10.1016/j.tetlet.2011.11.083

A phosphonic acid catalyst has been shown to promote the intramolecular cyclization of acylhydrazone 1. The resulting heterocyclic products, pyrazolidines, were isolated in good yield for a variety of acylhydrazones. Studies into the role of the phosphoni

Full text of DOI:10.1016/j.tetlet.2011.11.083

Tetrahedron Letters 53 (2012) 522–525
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Phosphonic acid catalyzed synthesis of pyrazolidines
Lindsey O. Davis a, , William F. M. Daniel a, Suzanne L. Tobey b,
⇑
⇑
a Department of Chemistry, Berry College, PO Box 495016, Mount Berry, GA 30149, United States
b Department of Chemistry, Wake Forest University, Salem 2, Winston-Salem, NC 27106, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 July 2011
Revised 14 November 2011
Accepted 15 November 2011
Available online 22 November 2011
A phosphonic acid catalyst has been shown to promote the intramolecular cyclization of acylhydrazone 1.
The resulting heterocyclic products, pyrazolidines, were isolated in good yield for a variety of acylhydra-
zones. Studies into the role of the phosphonic acid are presented and discussed.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Acylhydrazones
Pyrazolidines
[3+2] Cyclization
Phosphonic acid
The discovery of methods for the synthesis of complex heterocy-
clic rings is a major area of interest for organic chemists.1–4 The
ability to develop methods involving the use of phosphonic acid
catalysts for making heterocyclic compounds is one goal of our re-
search endeavors. In a previous report we described the use of
phosphonic acid as a catalyst for the imino–ene reaction between
a glyoxlate-derived imine and a simple alkene.5 One limitation of
our earlier report was the need to use a very reactive imine. Previ-
ously, phosphonic acids have been shown to be successful catalysts
for a variety of hydrazone-containing substrates.6,7 Therefore, to ex-
pand the scope of our chemistry beyond the reactive imine eno-
philes, acylhydrazones were introduced as a viable substrate for
an imino–ene reaction (Scheme 1). At the outset it was unclear as
to whether the imino–ene reaction would predominate over the po-
tential [3+2]-cycloaddition-type reaction,8,9 for which HCl10 and
chiral zirconium Lewis acid catalysts have been reported.11,12
Initially, a citronellal-derived acylhydrazone was synthesized
and then reacted under reaction conditions (1 equiv of diethyl
phosphate, 2 M in CH2Cl2, 25 °C, 48 h) similar to our previously re-
ported imino–ene chemistry.5 The reaction did not deliver the ex-
pected hydrazine 3a (Scheme 2a), but instead a pyrazolidine
derivative (2a) was isolated (76% yield) as the major product
(Scheme 2b). The pyrazolidine product was the product of the
competing [3+2] cycloaddition.
utility as chiral ligands for asymmetric catalysis,13 as well as bio-
logically important cisplatin derivatives.14 Given our interest in
the reaction and the utility of the products we chose to further
examine this reaction in terms of reaction optimization as well
as mechanistic aspects.
Given the moderate product yield of the trial reaction the full
potential of this reaction was explored by varying several reaction
parameters including the acid catalyst, the number of equivalents
of catalyst, temperature, and concentration (see the Supplemen-
tary data for full details). Using the same reaction conditions (see
Scheme 2) at 4 °C resulted in a decreased product yield (56%).
Additional systematic changes results indicated that using a
0.5 M reaction solution (with respect to the hydrazone) at 4 °C
was optimal for the reaction, thus delivering the product in an
83% yield. The isolated product was a diastereomeric mixture15
that contained only two out of a possible four diastereomers, thus
demonstrating good selectivity.12,16 In part this selectivity arises
from the intramolecular nature of the reaction as it benefits from
favorable entropic factors. Interrogation of the system with regard
to reaction time was expected to shed some light on the distribu-
tion of the product stereoisomers (Table 1).
At 6 h, the reaction yielded over half of what was made at 48 h
and the dr value is at its highest (compare entries 1 and 3 in
The isolation of the pyrazolidine product 2a, though not unex-
pected, warranted additional investigation because such ring sys-
tems can be easily converted into 1,3-diamines after N–N bond
cleavage12 to generate useful synthons. Chiral 1,3-diamines have
H
H
N
N
N
Ar
H
Ar
NH
R1
R1 = alkyl, aryl
R1
⇑
Corresponding authors.
E-mail address: ldavis@berry.edu (L.O. Davis).
Scheme 1. A proposed general ene reaction between a hydrazone and an ene.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.083

L. O. Davis et al. / Tetrahedron Letters 53 (2012) 522–525
523
O
Ar
O
P
O
N
Ar
NH
OEt
HN
HO
NH
H
OEt
Ar
O
N
3
1 equiv.
3
N
25oC, 48 hrs
2M, CH2Cl2
b
H
a
3a Ar = p-NO2C6H4
1a Ar = p-NO2C6H4
2a Ar = p-NO2C6H4
76%
Scheme 2. (a) Ene reaction of an acylhydrazone to produce hydrazine derivative. (b) Cyclization of an acylhydrazone to form a pyrazolidine derivative.
Table 1
Effect of time on the cyclization reaction
Table 2
Effect of additional Brønsted acids on cyclization reaction
O
P
O
O
N
Ar
NH
O
N
Ar
NH
P
OEt
OEt
HO
HO
OEt
OEt
H
H
Ar
O
Ar
O
N
N
3
3
H
H
N
N
CH2Cl2
48 hrs
CH2Cl2
2a Ar = p-NO2C6H4
2a Ar = p-NO2C6H4
1a Ar = p-NO2C6H4
1a Ar = p-NO2C6H4
Entrya
Equiv of 3
Additive
Equiv of additive
Yield (%)
drd
Entrya
Equiv of 3b
Time (h)
Temp (°C)
Yield (%)
drc
b
b
c
1
2
3
4
5
0
H3PO4
H3PO4
H3PO4
H2SO4
1
0.25
0.25
0.25
0.25
12
74
78
67
60
1:4.8
1:3
1:2.6
1:3.3
1:2.9
1
2
3
4
1
1
1
0.25
6
12
48
48
4
4
4
47
62
83
64
1:4.4
1:3
1:3
0.75
0.75
0.75
0.75
25
1:2.8
CH3COOH
a
All reactions were run at 0.5 M based on 1a.
The phosphonic acid used was synthesized and contained a 25% impurity of
a
b
c
b
All reactions were stirred at 4 °C at a concentration of 0.5 M based on 1a.
Crystalline acid.
85% acid.
crystalline H3PO4 dissolved in it.
Determined by 1H NMR integration.
c
Determined by 1H NMR integration.
d
Table 1). The yield at 12 h increased about 20% more than that
obtained after 6 h of reaction time (Table 1, entry 2). In all cases
the dr value remained the same within error. When the equiva-
lents of acid were lowered to 0.25 equiv, and stirred for 48 h at
25 °C, the product was formed in moderate yield, which was com-
parable to that of the reaction after 12 h using a full equivalent of
acid (Table 1, entry 4). Importantly the dr value does not vary
greatly, thus indicating that there is no equilibration in play
and that the reaction is under thermodynamic control.
An important aspect of this reaction is the phosphonic acid
used. It was clear from early experiments that pure phosphonic
acid was a poor catalyst. The presence of a small amount of
H3PO4 was necessary to deliver the high product yields; therefore
we investigated the role of the acid as well as the potential for
using other acids as additives (Table 2).16
Table 3
Electronic effects on the cyclization
O
P
O
N
Ar
NH
OEt
HO
OEt
3
H
Ar
O
N
N
H
0°C, 48 hrs
CH2Cl2
1a Ar = p-NO2C6H4
1b Ar = C6H5
1c Ar = p-CH3OC6H4
2a Ar = p-NO2C6H4
2b Ar = C6H5
2c Ar = p-CH3OC6H4
Entrya
Hydrazone
[1] (M)
Equiv 3b
Yield (%)
H3PO4 alone is not an effective catalyst (Table 2, entry 1), but
when combined with the phosphonic acid the cyclization product
is isolated in good yield (Table 2, entries 2 and 3), albeit with a low-
er dr value. The yield is similar regardless of whether crystalline or
hydrated H3PO4 is used. Notably, when either H2SO4 or AcOH is
used in combination with the phosphonic acid the reaction pro-
ceeds with moderate yield (Table 2, entries 4 and 5). HCl was also
used as a co-catalyst with 3, but the reaction proceeded in low
yield (44%).17 These results highlight the importance of the phos-
phonic acid, as well as show that the better catalyst system for this
reaction involves a combination of diethyl phosphate and phos-
phoric acid.
1
2
3
1a
1b
1c
0.5
0.5
1.0
1
1
1
82
44c
28
a
All reactions were run at 0 °C for 48 h in dichloromethane.
The commercially available diethyl phosphate was used with 25% phosphoric
acid impurity.
b
c
The major diastereomer was determined to have a trans-ring junction. See the
Supplementary data for full details.18
cyclization to occur in high yield. The reaction with the ring bear-
ing and OMe group is the lowest yielding substrate (Table 3, entry
3). This trend in reactivity is in keeping with the notion that the
electron-withdrawing groups activate the C@N group for nucleo-
philic attack (see below for mechanistic discussion).
To explore the importance of the electronic nature of the acy-
lhydrazone, a series of citronellal-derived acylhydrazones was
tested wherein the substituent of the 4-position of the aryl ring
was varied (Table 3).
Acylhydrazones having substitutions
a to the imine carbon
The results clearly indicate that the electron-withdrawing char-
acter of the group on the 4-position of the aryl ring is crucial for
atom were synthesized to explore the steric tolerance of the cycli-
zation. These acylhydrazones were expected react to form two

524
L. O. Davis et al. / Tetrahedron Letters 53 (2012) 522–525
O
N
Ar
NH
Ar
O
N
HN
NO2
H
H
Ar
O
N
3 (1 equiv.)
NH
N
N
a
O
N
Ar
NH
CH2Cl2, 0.5M
48 hrs, 25oC
a
H
O
4
2
2d
1d Ar = p-NO2C6H4
73%, d.r. = 1:0
HO
Ar
H
b
O
N
Ar
NH
N
H
N
H
1
Ar
N
NO2
N
H
3 (1 equiv.)
O
NH
N
b
CH2Cl2, 0.5M
48 hrs, 25oC
5
2
H
O
Scheme 4. (a) A step-wise cyclization and (b) a concerted [3+2] cyclization of an
acylhydrazone to form a pyrazolidine derivative.
2e
67%, d.r. = 5.3:1
1e Ar = p-NO2C6H4
Scheme 3. Scope of the reaction with (a) alpha-methyl acylhydrazone and (b)
alpha-dimethyl acylhydrazone. 1H NMR was used to determine dr ratio, however
the major diastereomer has not been fully characterized.
Ar
O
O
N
Ar
3 (1 equiv.)
N
N
H
NH
CH2Cl2 (1.0M)
4oC, 28 hours
fused five-membered rings instead of the fused ring system ob-
served with the citronellal acylhydrazone. The reaction of
recovered starting
a
-methyl acylhydrazone 1d proceeded with good yield and excel-
lent diastereoselectivity when using 1 equiv the catalyst (Scheme
3a). A similar result was found with the -dimethyl acylhydrazone
material
6 Ar = p-NO2C6H4
1f Ar = p-NO2C6H4
a
1e (Scheme 3b). Notably, the reaction proceeds well when using
other acylhydrazones to generate heterocycles containing fused
five-membered rings. Additionally, the substitution at the carbon
Scheme 5. Proposed ene product when a methylated acylhydrazone was subjected
to phosphonic acid conditions.
atom
a to the hydrazone carbon center has little effect on the reac-
indicated that the signal corresponding to the –OH proton of the
phosphonic acid shifted as the concentration changed.20,21 For this
reason, the concentration of diethyl phosphate was kept constant
while the hydrazone 1a was added incrementally (concentrations
of 0.002 M–0.5 M; see the Supplementary data). A change in the
shift of the NH proton on the hydrazone confirmed an interaction
between 3 and 1a. Consequently, Job plot analyses (see the Supple-
mentary data) were employed to identify the stoichiometry of the
catalyst–substrate interaction. The Job analysis was run using 31P
NMR spectroscopy data and indicated that the interaction between
the acylhydrazone and phosphonic acid is not a clean 1:1 interac-
tion as there is potentially aggregation or ternary-type complexes
arising from the presence of the phosphoric acid. The data confi-
dently supports the proposal that the phosphonic acid interacts
with the acylhydrazone substrate to effect cyclization and our pro-
posed substrate–catalyst interaction is shown in Figure 1.
In summary we have described a detailed study of the phos-
phonic acid catalyzed reaction of acylhydrazones to generate het-
erocyclic rings. The chemistry reported herein adds yet another
example of phosphonic acid catalysts promoting reactions of acyl-
hydrazones to the organocatalysis literature. Currently, our studies
have been restricted to hydrazones containing alkyl substituents
on the olefin, and we plan to study hydrazones having various sub-
stitutions on the olefin, such as those containing aryl groups. The
tion yield, but does affect the selectivity of the reaction. The intro-
duction of one methyl group is sufficient to selectively deliver one
stereoisomer, and although the introduction of a second methyl
group results in a 5.3:1 dr value, it suggests that the additional
methyl group is enough to diminish the selectivity.
Collectively the data confirmed the role of the phosphonic acid
as a catalyst for the cyclization reaction and indicated that a ste-
reoelectronic effect was present. A closer look at mechanism for
the reaction revealed two possible mechanistic pathways that
the cyclization could undergo: (1) a stepwise cyclization (Scheme
4a), or (2) a concerted [3+2] cycloaddition (Scheme 4b).11,19 In
the stepwise reaction, a nucleophilic addition generates carbocat-
ion 4 and then successive cyclization leads to the pyrazolidine
product 2. In the [3+2] cycloaddition, a 1,3-dipole, possibly in the
tautomer form 5, reacts in a concerted manner with the olefin. Re-
ported mechanistic studies11 with the analogous Lewis acid cata-
lyzed cyclization of acylhydrazones suggest that the mechanism
proceeds in a concerted manner, but an additional investigation
is necessary to see if this applies to the Brønsted acid cyclization
reaction.
A preliminary experiment was conducted to test the methyl-
ated acylhydrazone 1f. The presence of the methylated nitrogen
atom was expected to preclude the tautomerization to the more
reactive 1,3-dipole substrate, therefore reducing the nucleophilic-
ity of this nitrogen atom. It was expected that if this reaction
was stepwise, the first addition would occur and perhaps the for-
mal ene product 6 would be observed (Scheme 5). However, nei-
ther this product, nor any cyclization product was observed
under Brønsted acid conditions, suggesting that perhaps the NMe
group prevented the interaction of the substrate with the phos-
phonic acid, thereby completely shutting down its reactivity.
In an attempt to learn more about the interaction between the
catalyst and the acylhydrazone substrate 1H NMR spectroscopy
was used to identify and quantify this interaction. Previous work
Ar
N
O
H
O
O
N
OEt
P
H
OEt
Figure 1. Proposed interaction between acylhydrazone and phosphonic acid 3.

L. O. Davis et al. / Tetrahedron Letters 53 (2012) 522–525
525
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Acknowledgments
We would like to thank Dr. Marcus Wright (Wake Forest Uni-
versity) for his help with NMR analyses and Dr. Cynthia Day (Wake
Forest University) for her help with crystal structure analysis. We
are grateful to Professor Paul Jones at Wake Forest University for
his helpful discussions. Tabitha Callaway and Professor Kenneth
Martin at Berry College are acknowledged for their assistance with
crystal structure analysis. Financial support for this work was pro-
vided by the Frasch Foundation, Wake Forest University, and Berry
College.
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15. The major product was determined to have
a cis ring junction (see
Supplementary data for crystal structure). The minor product has not been
fully characterized.
16. Preliminary attempts have been made to test other phosphonic acids with
varying ester moieties. The cyclization of hydrazone 1a under conditions
similar to those in Table 1, entry 3 with dibutyl phosphate (without H3PO4)
yielded 54% of 2a with a dr value of 1:1.6. The cyclization of 1a under
conditions similar to those in Table 1, entry 3 using diphenyl phosphate
(without H3PO4) resulted in a 26% yield with only the major diastereomer
observed. The study of this interesting observation will be a topic for future
work.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.11.083.
17. 0.75 equiv of 3 and 0.25 equiv of HCl were used at 0.5 M in CH2Cl2 at 0 °C for
48 h.
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