Structural effects in pyrazolidinone-mediated organocatalytic Diels-Alder reactions

Article abstract of DOI:10.1016/j.tet.2010.09.021

A range of pyrazolidin-3-ones have been prepared and their activity as catalysts for iminium-ion promoted Diels-Alder reactions evaluated. Systematic variation of the C(5)- and N(2)-substituents indicates that the incorporation of an electron withdrawing

Full text of DOI:10.1016/j.tet.2010.09.021

Tetrahedron 66 (2010) 8992e9008
Contents lists available at ScienceDirect
Tetrahedron
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Structural effects in pyrazolidinone-mediated organocatalytic DielseAlder
reactions
,
Eoin Gould a, Tomas Lebl a, Alexandra M.Z. Slawin a, Mark Reid b, Andrew D. Smith a
*
a EaStCHEM, School of Chemistry, University of St Andrews, North Haugh, St Andrews, Fife, KY16 9ST, UK
b MSD, Newhouse, Motherwell, ML1 5SH, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 June 2010
Received in revised form 17 August 2010
Accepted 6 September 2010
Available online 21 September 2010
A range of pyrazolidin-3-ones have been prepared and their activity as catalysts for iminium-ion pro-
moted DielseAlder reactions evaluated. Systematic variation of the C(5)- and N(2)-substituents indicates
that the incorporation of an electron withdrawing substitutent at N(2) and either a Ph or CF3 substitution
at C(5) results in optimal catalytic activity. The diastereoisomeric resolution of a model C(5)-Ph
substituted pyrazolidinone and its ability to impart modest levels of asymmetric induction in the
organocatalytic DielseAlder reaction is also demonstrated.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
centre (as in 9) gave high catalytic activity, while in the cyclic series
piperazines, such as 10, showed better catalytic activity than their
Within the last decade, the use of chiral secondary amines to act
as catalysts for a plethora of iminium-ion catalysed transformations
corresponding pyrazolidines 11 (Fig. 2).13 In related studies, Ogilvie
and co-workers have shown that camphor derived pyrazolidinones,
of a,b
-unsaturated aldehydes has been developed,1 inspired by the
initial pioneering work of MacMillan and co-workers who used
imidazolidinone 1 to promote the asymmetric DielseAlder reaction
of an enal and a diene (Fig. 1).2 Since this landmark publication,
a range of alternative catalyst architectures have been applied in
iminium-ion promoted reactions, with other imidazolidinones,
such as 23 or diarylprolinols, such as 3,4 often used to perform
a variety of asymmetric transformations with high enantiose-
lectivity.5 In the specific area of iminium-ion promoted DielseAlder
reactions, a number of catalysts with markedly different structures
have been applied,6 with pyrrolidines 47 and 58 representative. A
five-membered ring is not a prerequisite for catalytic activity,
however, as exemplified by aziridine 69 and the acyclic catalysts 710
and 8.11
O
Me
O
Me
Ph
N
N
Ph
N
H
N
H
N
H
OTMS
Ph
O
Ph
S
3
1
2
Hayashi &
Jørgensen
MacMillan
Ph
Ph
Ar
N
H
OH
CO2H
Ar
N
H
N
H
Ar = 3,5-Me2C6H3
5
4
6
While extensive progress has been made in the development of
highly stereoselective iminium-ion promoted reactions, relatively
limited studies concerning a detailed mechanistic understanding of
these processes, and the structural effects that lead to high catalytic
efficiency, have been reported. Seminal work by Tomkinson and co-
workers has investigated extensively the effect of structural
changes to simple secondary hydrazides upon their catalytic ac-
tivity in the iminium-ion promoted DielseAlder reaction.12 Nota-
bly, in a series of acyclic hydrazides, the introduction of an electron-
withdrawing N-methyl carbamate adjacent to the reactive nitrogen
Jørgensen
Barbas
Bonini
4-t-BuPh
Me
NH
Me
N
NHMe
NHMe
NH2
4-t-BuPh
Ph
7
8
Ishihara
Maruoka
* Corresponding author. E-mail address: ads10@st-andrews.ac.uk (A.D. Smith).
Fig. 1. Structural diversity in iminium-ion organocatalysts.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.09.021

E. Gould et al. / Tetrahedron 66 (2010) 8992e9008
8993
such as 13 offer high levels of asymmetric induction in the
DielseAlder reaction (up to 94% ee),14 while Lee and co-workers
have introduced the related sulfonyl hydrazide 14 as asymmetric
catalysts of this reaction.15 Notably, recent kinetic studies by
Tomkinson and co-workers have determined that the rate-de-
termining step of the DielseAlder reaction catalysed by pyrrolidine
12, incorporating an electron withdrawing CF3 group at C(2), was
the CeC bond-forming step, rather than iminium-ion formation.16
phenyl ortrifluoromethylsubstituents, respectively, inordertoprobe
the effect of the C(5)-substituent upon catalytic efficiency and dia-
stereoselectivity. The desired pyrazolidinones 31e34 were readily
prepared by addition of hydrazine to the corresponding
a,b-un-
saturated ester,19 regioselective N-Boc protection,20 N-benzylation
and N-Boc deprotection (Scheme 1). The structures of 21, 27 and 34
were unambiguously confirmed by X-ray analysis, consistent with
the expected regioselectivity of these transformations (Figs. 4e6).
O
NH
H
O
NH
NCO2Bn
Me
N
NCO2Bn
CO2Et
F3C
(i)
(ii)
N
H
CO2R
N
H
N
H
N
H
R
R
N
11
12
9
10
N
H
R
Boc
Tomkinson
15, R = Me
16, R = i-Pr
17, R = Ph
18, R = CF3
19, R = Me
23, R = Me
24, R = i-Pr (51 %)
25, R = Ph
20, R = i-Pr (87 %)*
21, R = Ph
NH
Ph
NH
N
22, R = CF3
26, R = CF3 (35 %, 2 steps)
N
O
S
O2
(iii)
O
O
Ogilvie
Lee
14
(iv)
13
N
Bn
N
R
R
Bn
Fig. 2. Catalyst architectures explored by Tomkinson and related catalysts by Ogilvie
and Lee.
N
N
H
Boc
31, R = Me (76 %)
32, R = i-Pr (67 %)
27, R = Me (41 %, 3 steps)
28 R = i-Pr (41 %)
Building upon these studies, and our interest in the development
of catalytically efficient organocatalytic transformations,17 we
wished to prepare a series of structurally related pyrazolidin-3-ones
and systematically evaluate substituent effects upon their catalytic
efficiency in the iminium-ion catalysed DielseAlder reaction.18 In
this manuscript we delineate a simple and flexible route to pyr-
azolidin-3-ones, that allows the incorporation of a range of C(5)-
alkyl or aryl substituents, and N(2)-alkyl, N(2)-acyl or N(2)-carboxyl
substituents. The effect of changing these substituents upon the
catalytic efficiency of iminium-ion catalysed reactions is tested in
the DielseAlder reaction of cyclopentadiene with a range of enals,
before a simple resolution protocol is used to prepare an enantio-
merically pure pyrazolidinone for probing asymmetric induction in
this reaction manifold (Fig. 3).
33, R = Ph (97 %)
34, R = CF3 (50 %, 2 steps)
29, R = Ph (25 %, 3 steps)
30, R = CF3
Scheme 1. Reagents and conditions: (i) hydrazine hydrate, EtOH, reflux; (ii) di-tert
butyl dicarbonate, Na2CO3, dioxane/H2O, rt; (iii) benzyl bromide, DMF, K2CO3, rt; (iv)
TFA, CH2Cl2, rt. *a
,b-Unsaturated ester 16 was prepared directly from iso-butyralde-
hyde and ethyl (triphenylphosphoranylidene)acetate21 and was not isolated due to its
volatility. Yield refers to the two-step procedure.
This work:
Vary C(5)-
O
substituent
R1 = Me, i-Pr,
Ph, CF3
Vary N(2)-substituent
N
R2
R1
N
H
R2 = Me, Bn,
COPh, CO2Bn
O
Vary substituents and
probe catalytic efficiency
of iminium-ion promoted
Diels-Alder reactions
H
+
R
R
CHO
Fig. 3. Proposed pyrazolidin-3-one based iminium-ion catalysts.
2. Results and discussion
2.1. Pyrazolidin-3-one synthesis
Initial studies focused upon the preparation of a range of N-benzyl
substituted pyrazolidin-3-ones bearing C(5)-methyl, iso-propyl,
Fig. 4. Molecular representation of the X-ray crystal structure of 21.

8994
E. Gould et al. / Tetrahedron 66 (2010) 8992e9008
substituted 38 was also prepared in an unoptimised procedure by
bis-alkylation of 27 and N-Boc deprotection (Scheme 2).
O
O
O
(i)
(ii)
NH
N
N
Me
Me
Me
Me
Bn
Me
Me
Me
Bn
N
N
(53 %)
(55 %)
N
H
Boc
23
Boc
35
36
O
O
O
(iii)
(ii)
N
N
N
Me
Bn
N
(26 %)
N
(96 %)
N
H
Boc
27
Boc
37
38
Scheme 2. Reagents and conditions: (i) MeI, DMF, K2CO3, rt; (ii) TFA, CH2Cl2, rt; (iii)
5.0 equiv KHMDS, ꢀ78 ꢁC, THF, then 10 equiv MeI, ꢀ78 ꢁC to rt, then 5.0 equiv KHMDS,
ꢀ78 ꢁC, THF, then 10 equiv MeI, ꢀ78 ꢁC to rt.
To further probe the effect of N(2)-substitution upon catalytic
activity, the incorporation of electron withdrawing substituents,
such as sulfonyl, acyl or carboxyl groups was desired. Following the
method of Corey and co-workers,22 N-triflation of 23 in the presence
of triethylamine was attempted, but exclusive O-, rather than N-
triflation to generate 39 was observed (Scheme 3). N-Tosylation of 23
was also attempted but only O-tosylation to give 40 was observed,
irrespective of the choice of base (triethylamine, sodium hydride,
n-butyllithium or potassium carbonate). The structure of O-tosyl 40
was unambiguously proven by X-ray crystallography (Fig. 7).
Fig. 5. Molecular representation of the X-ray crystal structure of 27.
OTf
O
OTs
(i)
(ii)
N
NH
N
Me
Me
Me
N
N
N
(46 %)
(42 %)
Boc
Boc
Boc
39
23
40
Scheme 3. Reagents and conditions: (i) NEt3, CH2Cl2, then triflic anhydride, ꢀ78 ꢁC to
rt (52%), (ii) NEt3, CH2Cl2, then tosyl chloride, ꢀ78 ꢁC to rt (46%).
Fig. 6. Molecular representation of the X-ray crystal structure of 34. The unit cell
contains two molecules of 34 but for clarity only one is shown.
In order to probe structural effects upon the catalytic activity of
pyrazolidin-3-ones, a series of C(5)methyl-substituted catalysts
were prepared that differed in either skeletal complexity or N(2)
substitution. N(2)-Methyl 36 was readily prepared by N-methyla-
tion and N-Boc deprotection from 23, while gem-dimethyl
Fig. 7. Molecular representation of the X-ray crystal structure of 40.

E. Gould et al. / Tetrahedron 66 (2010) 8992e9008
8995
The incorporation of acyl or carboxyl electron withdrawing
the B3LYP/6-31G
*
level of theory (Table 1). In the case of N func-
groups at N(2) was next investigated. Treatment of 23 with NEt3 or
NaH followed by benzoyl chloride gave selective O-functionalisation
to give 41. However, following the method of Vorozhtsov and co-
workers,23 refluxing O-benzoyl 41 in toluene resulted in rearrange-
ment to give the desired N-benzoyl pyrazolidinone 43 in good yield.
While treatment of 23 with NEt3 and benzyl chloroformate again
gave selective O-functionalisation to give 42, treatment with NaH
and benzyl chloroformate gave N-benzyloxycarbonylpyrazolidinone
44 directly. Compounds 43 and 44 were then readily deprotected to
give the desired pyrazolidinones 45 and 46, respectively (Scheme 4).
The structure of 43 was unambiguously proven by X-ray crystal-
lography (Fig. 8).
tionalised compounds (25, 27, 43 and 44), the N(2) atom has three
substituents and shows sp3 character, while in O-functionalised
compounds (40 and 42), the N(2) atom has two substituents and
shows sp2 character. This change results in O-functionalised com-
pounds showing a significant downfield shift of the corresponding
15N resonance relative to N-substitution by around 140 ppm, allow-
ing the N(2) chemical shift to be used as a simple diagnostic tool. In
contrast, there is no change in the hybridization of N(1) in all com-
pounds and therefore its 15N chemical shift variation is only marginal
(127e156 ppm). The calculated values are slightly overestimated
with an average deviation of 11.7 ppm but, nonetheless, there is good
agreement between the experimental and theoretical data.
Table 1
15N NMR experimental and theoretical data for selected compounds
R
O
O
O
OR'
O
(i)
147-184ppm
2
N
2
NH
N
295-296ppm
155-156ppm
1
1
N
Me
Me
R
R
R'/H
127-137ppm
N
N
N
N
Boc
Boc
Boc
Boc
23
41, R = Ph
N-functionalised
O-functionalised
42, R = OBn
Compound
Experimental (ppm)
B3LYP/6-31G
N(1)
*
(ppm)
(iii)
N(1)
N(2)
N(2)
O
(ii)
127
147
139.9
143.8
170.1
147.7
N
O
Ph
N
O
N
H
25
(iv)
R
Boc
R
N
N
Me
Me
N
H
O
O
O
Boc
136
156
156
295
171.6
311.7
N
Me
Me
Me
Me
Bn
45, R = Ph (86 %)
46, R = OBn (78 %)
43, R = Ph (45 %, 2 steps)
44, R = OBn (41 %, 1 step)
N
27
Boc
Scheme 4. Reagents and conditions: (i) NEt3, CH2Cl2, then benzoyl chloride or benzyl
chloroformate, ꢀ78 ꢁC to rt; (ii) toluene, reflux; (iii) NaH, CH2Cl2, then benzyl
chloroformate, ꢀ78 ꢁC to rt; (iv) TFA, CH2Cl2, rt.
OTs
N
N
40
Boc
OCO2Bn
155
136
296
184
165
145
298
N
N
42
Boc
O
Ph
201.1
N
N
43
O
O
Boc
OBn
137
166
146.5
183.8
N
Me
44
N
O
Boc
2.2. Pyrazolidin-3-one catalyst testing
Fig. 8. Molecular representation of the X-ray crystal structure of 43.
With a range of pyrazolidinones prepared, their efficiency in
catalysis was tested using the DielseAlder reaction of cyclo-
pentadiene and cinnamaldehyde. Using C(5)-Me N-benzyl catalyst
31 and monitoring the reaction by 1H NMR spectroscopy, modest
levels of catalytic activity were observed using triflic acid as the
Given the problems with selective N-functionalisation of N-Boc
pyrazolidinone 23, a simple method for determining if functionali-
sation at either N- or O- had occurred was devised using 15N
NMR.24,25 For selected compounds the values of 15N chemical shifts
were obtained experimentally by 1H,15N HMBC and also calculated at

8996
E. Gould et al. / Tetrahedron 66 (2010) 8992e9008
O
O
co-catalyst in H2O (e20% conversion in 24 h). Changing the reaction
solvent to methanol and using either triflic acid or HCl as co-catalyst
gave good conversion (>90%) although with disappointing turn-
over, requiring 4e5 days for high conversion. Triflic acid was se-
lected for further studies as it gave a marginally improved rate
relative to HCl.26 Subsequent pyrazolidinone evaluation showed
that the introduction of the C(4)-gem-dimethyl group within the
catalyst architecture gave a significant increase in the rate of
product formation, although with little diastereoselectivity (38,
t1/2¼5 h) (Scheme 5). Within a series of N-benzyl substituted cata-
lysts, the optimal rate was observed with either a C(5)-Ph or C(5)-
CF3 unit (33 and 34, t1/2¼5e6 h), consistent with the observations of
Tomkinson regarding the incorporation of electron withdrawing
substituents within iminium-ion catalysts leading to optimal re-
action rates. Interestingly, a reversal in the diastereoselectivity of
this process was observed using the C(5)-CF3 substituted 34, with
a preference for the endo diastereoisomer observed. Subsequent
studies probed the effect of altering the N(2)-substituent upon
catalyst efficiency, with the incorporation of electron-withdrawing
N-benzoyl or N-carboxybenzyl substituents leading to good cata-
lytic efficiency (45 and 46, t1/2¼2 h).
O
(i), (ii)
(iii)
OBn
OBn
NH
N
N
R
R
R
N
N
N
H
O
O
Boc
Boc
25, R = Ph
26, R = CF3
49, R = Ph (38 %)
50, R = CF3
51, R = Ph (68 %)
52, R = CF3 (42 %, 2 steps)
Scheme 6. Reagents and conditions: (i) NaH, CH2Cl2, then benzyl chloroformate,
ꢀ78 ꢁC to rt; (ii) toluene, reflux; (iii) TFA, CH2Cl2, rt.
pyrazolidinone
O
(20 mol%)
CF3SO3H (0.2 eq)
CHO
+
H
Ph
+
MeOH, rt, time
CHO
Ph
Ph
exo-47
endo-48
O
O
N
OBn
OBn
N
Ph
F3C
N
H
N
H
O
O
52
51
pyrazolidinone
t1/2 = 2 hours
exo:endo = 48:52
t1/2 = 1 hour
exo:endo = 62:38
(20 mol%)
O
CF3SO3H
(0.2 eq)
CHO
+
Scheme 7. Optimised catalyst screening.
H
Ph
+
MeOH, rt,
time
CHO
Ph
Ph
exo-47
These reactions indicate that the incorporation of an electron-
withdrawing N(2)-carboxybenzyl group and either a C(5)-phenyl or
CF3 unit within the pyrazolidinone template led to increased cat-
alytic activity. The generality of the use of pyrazolidinone 51 in the
organocatalytic DielseAlder reaction was next evaluated, giving
good reactivity for a series of enals with cyclopentadiene, fur-
nishing the desired products in good isolated yields (Table 2, entries
1e4). Catalysis using pyrazolidinone 34 was also further evaluated,
giving preferential endo-selectivity in each case (Table 2, entries
5e6). The attempted use of alternative dienes with both 51 and 34
under a range of conditions led to no product conversion.2,14,28
endo-48
O
O
O
N
N
N
Bn
Bn
Bn
Me
Me
i-Pr
N
H
N
N
H
H
31
32
38
t1/2 = 40 hours
exo:endo = 72:28
t1/2 = 30 hours
exo:endo = 44:56
t
1/2 = 5 hours
exo:endo = 46:54
O
O
Table 2
N
N
DielseAlder reactions promoted by pyrazolidinones 51 and 34
Bn
Bn
Ph
F3C
N
H
N
H
O
Pyrazolidinone 34 or 51
33
34
CHO
+
(20 mol%)
H
t1/2 = 5 hours
exo:endo = 73:27
+
t1/2 = 6 hours
exo:endo = 35:65
R
CHO
CF3SO3H (0.2 eq)
R
R
MeOH, rt, time
O
O
O
exo-47, 53, 55, 57
endo-48, 54 56, 58
Ph
Me
O
OBn
N
N
N
Entry
R
Catalyst
Time (h)
Yield (%)
exo:endo
Me
Me
Me
N
H
N
H
N
H
1
2
Ph
51
51
51
51
34
34
7
5
4
24
48
6
89
73
75
80
50
67
62:38
65:35
58:42
50:50
22:78
36:64
O
4-NO2C6H4
n-Pr
CO2Et
Ph
36
46
45
3
t1/2 = 40 hours
exo:endo = 44:56
t1/2 = 2 hours
1/2 = 2 hours
exo:endo = 63:37
exo:endo = 59:41
Scheme 5. Initial catalyst screening.
4a
5
t
6
n-Pr
a
Addition of 5% water.
In an attempt to further optimise catalyst efficiencies for this
model reaction, the incorporation of a C(5)-Ph or C(5)-CF3 group, in
combination with an electron-withdrawing N(2)-carboxybenzyl
substituent, was evaluated. Following the methodology developed
previously, 51 and 52 were prepared using standard methods from
25 and 26 (Scheme 6).27
Pyrazolidinones 51 and 52 were subsequently evaluated as
catalysts for the DielseAlder reaction, with 51 giving the best
catalytic efficiency observed within this series of catalysts (t1/2
w1 h, Scheme 7).
2.3. Proof of concept: pyrazolidinone resolution and testing
in enantioselective catalysis
Having demonstrated that pyrazolidinone 51 shows good cat-
alytic activity as an organocatalyst, its preparation in enantio-
merically pure form was attempted in order to evaluate its ability to
promote an enantioselective DielseAlder reaction. Treatment of
pyrazolidinone 21 with O-methyl mandelic acid under peptide
coupling conditions gave the chromatographically separable

E. Gould et al. / Tetrahedron 66 (2010) 8992e9008
8997
diastereoisomeric N(2)-acyl pyrazolidinone derivatives 59 and 60,
with N(2)-functionalisation of both diastereoisomers confirmed by
15N NMR spectroscopy (Scheme 8).29 Acid hydrolysis of 59 gave (R)-
21 in >95% ee, as shown by derivatisation to 61 and HPLC analy-
sis.30 Enantiomerically pure (R)-21 was subsequently transformed
to (R)-51 in modest yield over four steps.
All dried and purified solvents were obtained from a solvent
purification system (MBraun, SPS-800) except for dry N,N0-dime-
thylformamide (DMF), which was purchased directly from Aldrich.
Petrol refers to the fraction of petroleum ether boiling between
40 ꢁC and 60 ꢁC, dioxane refers to 1,4-dioxane, pH 7 phosphate
buffer refers to a solution of sodium dihydrogen phosphate and di-
sodium hydrogen orthophosphate and brine refers to a saturated
aqueous solution of sodium chloride. Cyclopentadiene was
obtained by cracking of the dimer at 170 ꢁC, after drying over
MgSO4 and stored in the freezer. Catalytic runs for which isolated
yields were obtained were carried out with aldehydes purified
according to the guidelines of Armarego and Chai.32 All other re-
agents were used directly as supplied without further purification.
Flash column chromatography was carried out according to the
method of Still33 with silica gel 60 (0.043e0.060 mm) (Merck) in
the solvent system stated. Analytical thin layer chromatography
was performed on commercially available pre-coated aluminium-
backed plates (Merck silica Kieselgel 60 F254). TLCs were visualised
either by UV fluorescence (254 nm), or by staining with basic
KMnO4 solution.
O
O
O
OMe
OMe
(i)
190
N
192
N
+
Ph
Ph
NH
Ph
Ph
Ph
(53 %)
N
H
104 N
H
104 N
H
O
O
21
59
60
(57 %)
O
(ii)
O
O
(iii)
(iv-vii)
12 %,
NH
OBn
Ph
N
N
NH
Ph
Ph
N
(51 %)
N
H
H
O
4 steps)
Ph
61
(R)-21
(R)-51
Melting points were recorded on an Electrothermal apparatus
and are uncorrected. Microanalyses were carried out on a Carlo
Erba CHNS analyser. Infrared spectra were recorded on a Per-
kineElmer Spectrum GX FT-IR Spectrometer and analysed either as
thin films between NaCl plates (thin film) or KBr discs (KBr disc) as
stated. Absorption maxima (nmax) are quoted in wavenumbers
(cmꢀ1) and only structurally significant peaks are quoted.
>95% ee
Scheme 8. Reagents and conditions: (i) EDCI$HCl, HOBt, (R)-O-methyl mandelic acid,
DMF; (ii) 5 M HCl (aq), reflux; (iii) benzaldehyde, EtOH, rt, then NaBH4. (iv) di-tert butyl
dicarbonate, Na2CO3, dioxane/H2O, rt; (v) NaH, CH2Cl2, then benzyl chloroformate,
ꢀ78 ꢁC to rt; (vi) toluene, reflux; (vii) TFA, CH2Cl2, rt.
Enantiomerically pure pyrazolidinone (R)-51 was then evalu-
ated as an asymmetric catalyst for the DielseAlder reaction of
cinnamaldehyde and cyclopentadiene under standard conditions,
giving a 66:34 ratio of exo:endo diastereoisomers, and with modest
enantioselectivities of 48% and 28%, respectively (Scheme 9).14,31
19F, 1H and 13C nuclear magnetic resonance (NMR) spectra were
acquired on either a Bruker Avance 300 (282 MHz 19F, 300 MHz 1H,
75 MHz 13C), a Bruker Avance 400 (375 MHz 19F, 400 MHz 1H, 100
MHz 13C) or a Bruker Avance 500 (500 MHz 1H, 125 MHz 13C)
spectrometer in the deuterated solvent stated. 13C NMR spectra
were recorded with proton decoupling. 15N NMR spectra were ac-
quired indirectly by 1H, 15N-HMBC experiments on a Bruker Avance
500 equipped by a 5 mm inverse tuneable double resonance probe.
O
OBn
N
Ph
N
O
Chemical shifts (d) are quoted in parts per million (ppm) and ref-
H
O
(R)-51
CHO
erenced to residual solvent peaks. Coupling constants, J, are quoted
in hertz. The abbreviations s, d, dd, dt, td, q, quin, dsept and m
denote singlet, doublet, doublet of doublets, doublet of triplets,
triplet of doublets, quartet, quintet, doublet of septets and multi-
plet, respectively. The abbreviation Ar is used to denote aromatic.
Mass spectrometric (m/z) data was acquired by electrospray ion-
isation (ESI) or chemical ionisation (CI), either at the University of St
Andrews Mass Spectrometry facility or at the EPSRC National Mass
Spectrometry Service Centre, Swansea. At the University of St
Andrews, low and high resolution ESI MS was carried out on
a Micromass LCT spectrometer. At the EPSRC National Mass Spec-
trometry Service Centre, CIMS was carried out on a Micromass
Quattro II spectrometer. High resolution ESI was carried out on
a Finnigan MAT 900 XLT; a Thermofisher LTQ Orbitrap XL spectrom-
eter was used to obtain high resolution ESI MS for accurate mass
determination but also provided fragmentation data for the charac-
terisation of samples. Values are quoted as a ratio of mass to charge in
Daltons.
+
H
(20 mol%)
CF3SO3H (0.2 eq)
CHO
Ph
+
Ph
Ph
exo-47
MeOH, rt, time
endo-48
exo:endo 66:34
exo 48 % ee, endo 28 % ee
Scheme 9. Asymmetric evaluation of pyrazolidinone (R)-51.
3. Conclusion
In conclusion, we have outlined some structural factors that effect
the catalytic activity of pyrazolidinones in the iminium-ionpromoted
organocatalytic DielseAlder reaction, with the incorporation of an
additional electron withdrawing substituent at N(2) and Ph sub-
stitution at C(5) resulting in optimal catalytic activity. The di-
astereoisomericresolutionofamodelpyrazolidinoneand itsabilityto
impart modest levels of asymmetric induction in the organocatalytic
DielseAlder reaction was also evaluated. Current studies are focused
upon developing alternative applications of enantiomerically pure
pyrazolidinones and their derivatives in asymmetric catalysis.
Temperatures of 0 ꢁC were obtained using an ice/water bath and
of ꢀ78 ꢁC were obtained using a dry ice/acetone bath.
4.2. General procedure A: O-functionalisation of (RS)-tert-
butyl 5-methyl-3-oxopyrazolidine-1-carboxylate 23 with
triethylamine
4. Experimental
4.1. General
To a solution of (RS)-tert-butyl 5-methyl-3-oxopyrazolidine-1-
carboxylate 23 (1 equiv) in dichloromethane (0.5 M) was added
triethylamine (1.1 equiv). The resulting suspension was then cooled
to 0 ꢁC and the appropriate chloride or anhydride (1.05 equiv)
added. The mixture was allowed to warm to rt overnight. The
All reactions involving moisture sensitive reagents were per-
formed under an atmosphere of argon or nitrogen using standard
vacuum line techniques and with freshly distilled solvents. All
glassware was flame dried and allowed to cool under vacuum.

8998
E. Gould et al. / Tetrahedron 66 (2010) 8992e9008
reaction was quenched with water and extracted three times with
dichloromethane. The combined organic layers were washed with
0.1 M aqueous hydrochloric acid, brine, dried (MgSO4), filtered and
concentrated in vacuo.
To a solution of hydrazine hydrate (9.02 mL, 0.180 mol) in ab-
solute ethanol (200 mL) was added ethyl crotonate 15 (21.0 mL,
0.169 mol) by dropwise addition. The resulting solution was stirred
for 1 h at rt and then at reflux for 4 h before concentration in vacuo
to give crude (RS)-5-methylpyrazolidin-3-one 19 (18.1 g) as a vis-
cous yellow oil with spectroscopic data in accordance with the
literature.19 Product was used without further purification.
dH (400 MHz, CDCl3) 3.78e3.66 (1H, app dquin, J 8.7, 6.7, C(5)H),
2.48 (1H, dd, ABX system, JAB 16.1, JAX 7.1, C(4)HAHB), 2.12 (1H, dd,
ABX system, JBA 16.1, JBX 8.7, C(4)HAHB) and 1.22 (3H, d, J 6.3, C(5)
HCH3).
4.3. General procedure B: N(2)-alkylation of Boc-protected
pyrazolidin-3-one with sodium hydride
A solution of the appropriate Boc-protected pyrazolidin-3-one
(1 equiv) in dichloromethane (0.5 M) was cooled to ꢀ78 ꢁC and
sodium hydride (60% dispersion in mineral oil,1.1 equiv) added. The
resulting suspension was stirred for 10 min before addition of the
appropriate chloride or anhydride (1.05 equiv). The mixture was
allowed to warm to rt overnight. The reaction was quenched with
water and extracted three times with dichloromethane. The com-
bined organic layers were washed with brine, dried (MgSO4), fil-
tered and concentrated in vacuo.
To
a solution of crude (RS)-tert-butyl 5-methyl-3-oxopyr-
azolidine-1-carboxylate 19 (18.1 g, 0.180 mol) in water (100 mL)
were added sodium carbonate (19.1 g 0.180 mol) and dioxane
(50 mL). A solution of di-tert-butyl dicarbonate (39.3 g, 0.240 mol)
in dioxane (50 mL) was then added and the mixture stirred at rt for
1 h. The resulting suspension was filtered and the precipitate
washed with chloroform. The combined organic extracts were then
concentrated in vacuo to approximately 30 mL volume and parti-
tioned between water (100 mL) and dichloromethane (100 mL).
The organic extracts were washed with brine (150 mL), dried
(MgSO4), filtered and concentrated in vacuo to give crude (RS)-tert-
butyl 5-methyl-3-oxopyrazolidine-1-carboxylate 23 (33.9 g) as
a yellow solid with spectroscopic data in accordance with the lit-
erature.20 Product was used without further purification.
4.4. General procedure C: screening of catalysts
To a suspension of catalyst (20 mol %, 0.378 mmol) in methanol
(2 mL) was added either concentrated hydrochloric acid solution
(36% m/v, 3.60 ml, 0.378 mmol) or triflic acid (35.0 ml, 0.378 mmol).
After 2 min of stirring, trans-cinnamaldehyde (0.240 mL,1.89 mmol)
was added, followed by a further 5 min of stirring. Cyclopentadiene
(370 mg, 5.60 mmol) was then added and the resulting mixture left
to stir at rt. The reaction was monitored by taking samples of the
reaction mixture (0.05 mL), which were concentrated in vacuo then
hydrolysed in a chloroform (1 mL), water (0.5 mL), trifluoroacetic
acid (0.5 mL) mixture for 2 h. Saturated sodium hydrogen carbonate
solution (10 mL) was then added and the resulting biphasic mixture
extracted with chloroform (2ꢂ10 mL). The combined organic layer
were washed with brine (20 mL), dried (MgSO4), filtered and con-
centrated in vacuo. 1H NMR of the crude reaction mixture was used
to establish the conversion to the products and exo:endo ratios
through the integration of aldehyde peaks at: dH 9.93 (exo-47), 9.64
(trans-cinnamaldehyde) and 9.60 (endo-48), which were in accor-
dance with previously reported literature values.12
dH (400 MHz, CDCl3) 9.50 (1H, br s, N(2)H), 4.38 (1H, dqd, J 9.6,
6.5, 3.3, C(5)H), 2.92 (1H, dd, ABX system, JAB 17.0, JAX 9.6, C(4)
HAHB), 2.14 (1H, dd, ABX system, JBA 17.0, JBX 3.3, C(4)HAHB), 1.43
(9H, s, C(CH3)3) and 1.29 (3H, d, J 6.5, C(5)HCH3).
A solution of crude (RS)-5-methylpyrazolidin-3-one 46 (33.9 g,
170 mmol) in DMF (125 mL) was treated with benzyl bromide
(20.2 mL, 170 mmol) and potassium carbonate (23.9 g, 173 mmol)
and the suspension stirred at rt for 2.5 h. The reaction mixture was
partitioned between diethyl ether (150 mL) and water (250 mL) and
the resultant aqueous layer washed with further diethyl ether
(2ꢂ150 mL). The combined organic layers were washed with water
(200 mL), brine (200 mL), dried (MgSO4), filtered and concentrated
in vacuo. The crude material was purified by column chromatog-
raphy, eluting with 25% ethyl acetate in petrol to give the title
compound as a colourless solid (19.9 g, 41%).
4.5. General procedure D: screening of aldehyde substrates
nmax (KBr disc) cmꢀ1 3028 (AreH), 2976 (CeH), 2931 (CeH),
2871 (NeCeH), 1706 (C]O), 1690 (C]O), 1557 (Ar C]C) and 1534
(Ar C]C); mp 90e94 ꢁC; dN (CDCl3) 156 (N(2)CH2Ph), 136 (N(1)
Boc); dH (400 MHz, CDCl3) 7.35e7.29 (5H, m, ArH), 5.29 (1H, d, AB
system, JAB 14.2, CHAHBPh), 4.42 (1H, app quin, J 7.2, C(5)H), 4.39
(1H, d, AB system, JBA 14.2, CHAHBPh), 2.95 (1H, dd, J 16.3, 8.2, C(4)
HAHB), 1.96 (1H, d, J 16.3, C(4)HAHB), 1.56 (9H, s, C(CH3)3) and 0.65
(3H, d, J 6.7, C(5)HCH3); dC (100 MHz, CDCl3) 171.5 (C(3)O), 156.1 (C
(O)O), 135.6 (CAripso), 129.7 (CAr), 128.4 (CAr), 128.1 (CAr), 82.6 (C
(CH3)3), 53.7 (C(5)H), 48.6 (CH2Ph), 38.1 (C(4)H2), 28.3 (C(CH3)3)
and 19.7 (C(5)HCH3); m/z (CI) 291.3 (100, MþHþ); HRMS (ESIþ)
C16H23N2O3 requires 291.1703, found 291.1705 (þ0.7 ppm).
To a suspension of catalyst 51 or 34 (20 mol %, 0.189 mmol) in
methanol (1 mL) was added triflic acid (17.0 ml, 0.189 mmol). After
2 min of stirring, the appropriate aldehyde (0.950 mmol) was added,
followed by a further 15 min of stirring. Cyclopentadiene (188 mg,
2.80 mmol) was then added and the resulting mixture left to stir at
rt. Reaction was monitored by TLC. Upon completion, the reaction
mixture was concentrated in vacuo then hydrolysed in a chloroform
(2 mL), water (1 mL), trifluoroacetic acid (1 mL) mixture for 2 h.
Saturated sodium hydrogen carbonate solution (20 mL) was then
added and the resulting biphasic mixture extracted with chloroform
(2ꢂ20 mL). The combined organic layer were washed with brine
(40 mL), dried (MgSO4), filtered and concentrated in vacuo.
4.6.2. (RS)-2-Benzyl-5-methylpyrazolidin-3-one 31.
4.6. Experimental data
O
4.6.1. (RS)-tert-Butyl
boxylate 27.
2-benzyl-5-methyl-3-oxopyrazolidine-1-car-
N
Me
Bn
N
H
O
N
31
(RS)-tert-Butyl
2-benzyl-5-methyl-3-oxopyrazolidine-1-car-
Me
Bn
N
boxylate 27 (2.84 g, 9.78 mmol) was stirred at rt overnight in a 1:1
mixture of trifluoroacetic acid/dichloromethane (8 mL) before be-
ing concentrated in vacuo. The resulting material was redissolved
in dichloromethane (6 mL), cooled to 0 ꢁC before treatment with
Boc
27

E. Gould et al. / Tetrahedron 66 (2010) 8992e9008
8999
triethylamine (2.40 mL, 17.2 mmol). The resulting solution was
stirred at rt for a further 15 min before being partitioned between
water (40 mL) and dichloromethane (40 mL). The resultant aqueous
layer was washed with dichloromethane (40 mL) and the combined
organic layers washed with brine (50 mL), dried (MgSO4), filtered
and concentrated in vacuo. The crude material was then purified by
column chromatography, eluting with 5% methanol in ethyl acetate
to give the title compound as a clear yellow oil (1.42 g, 76%).
nmax (film) cmꢀ1 3202 (NeH), 3063 (AreH), 3031 (AreH), 2970
(CeH), 2925 (CeH), 2868 (NeCeH), 1678 (C]O), 1605 (Ar C]C)
and 1583 (NeH bend); dH (300 MHz, CDCl3) 7.40e7.30 (5H, m, ArH),
4.70 (1H, d, AB system, JAB 14.6, CHAHBPh), 4.55 (1H, d, AB system,
JBA 14.6, CHAHBPh), 4.10 (1H, br s, N(1)H), 3.69 (1H, app dquin, J 8.3,
6.7, C(5)H), 2.71 (1H, dd, ABX system, JAB 16.2, JAX 7.1, C(4)HAHB),
2.29 (1H, dd, ABX system, JBA 16.2, JBX 8.3, C(4)HAHB) and 1.25 (3H, d,
J 6.4, C(5)HCH3); dC (75 MHz, CDCl3) 175.7 (C(3)O), 139.2 (CAripso),
132.1 (CAr), 131.6 (CAr), 131.1 (CAr), 54.8 (C(5)H), 51.4 (CH2Ph), 43.8
(C(4)H2) and 22.1 (C(5)HCH3); m/z (CI) 191.2 (100, MþHþ); HRMS
(ESIþ) C11H15N2O requires 191.1179, found 191.1177 (ꢀ0.8 ppm).
nmax (KBr disc) cmꢀ1 3334 (NeH), 3016 (AreH), 2965 (CeH),
1707 (C]O) and 1681 (C]O); mp 134e137 ꢁC; dN (CDCl3) 147 (N(1)
Boc), 127 (N(2)H); dH (500 MHz, CDCl3) 7.36e7.27 (5H, m, ArH), 5.33
(1H, dd, J 10.4. 3.9, C(5)H), 3.30 (1H, dd, ABX system, JAB 17.3, JAX
10.4, C(4)HAHB), 2.63 (1H, dd, ABX system, JBA 17.3, JBX 3.9, C(4)
HAHB) and 1.36 (9H, s, C(CH3)3); dC (75 MHz, CDCl3) 169.6 (C(3)O),
153.7 (C(O)O), 141.2 (CAripso), 129.3 (CAr), 128.5 (CAr), 126.1 (CAr),
83.2 (C(CH3)3), 59.9 (C(5)H), 40.0 (C(4)H2) and 28.5 (C(CH3)3); m/z
(CI) 224.2 (100, MꢀC(CH3)3þNHþ4 ), 263.3 (20, MþHþ); HRMS (ESIþ)
C14H19N2O3 requires 263.1390, found 263.1392 (þ0.7 ppm).
A solution of crude (RS)-tert-butyl 5-phenyl-3-oxopyrazolidine-
1-carboxylate 25 (4.95 g, 18.9 mmol) in DMF (25 mL) was treated
with benzyl bromide (2.25 mL, 18.9 mmol) and potassium car-
bonate (2.61 g, 18.9 mmol) and the suspension stirred at rt for
90 min. The reaction mixture was partitioned between diethyl
ether (50 mL) and water (50 mL) and the resultant aqueous layer
washed with further diethyl ether (2ꢂ50 mL). The combined or-
ganic layers were washed with brine (60 mL), dried (MgSO4), fil-
tered and concentrated in vacuo. The material was then purified by
column chromatography, eluting with 20% ethyl acetate in petrol.
Chromatography was then repeated, this time eluting with 15e20%
ethyl acetate in petrol to give the title compound as a yellow oil
(2.63 g, 25%).
4.6.3. (RS) tert-Butyl 2-benzyl-3-oxo-5-phenylpyrazolidine-1-car-
boxylate 29.
nmax (film) cmꢀ1 3064 (AreH), 3032 (AreH), 2978 (CeH), 2933
(CeH), 2873 (NeCeH), 1750e1658 (2ꢂC]O), 1604 (Ar C]C) and
1587 (Ar C]C); dH (400 MHz, CDCl3) 7.28e7.24 (1H, m, ArH),
7.21e7.12 (5H, m, ArH), 7.04 (2H, t, J 7.5, ArH), 6.70 (2H, d, J 7.5, ArH),
5.45 (1H, app d, J 9.3, C(5)H), 5.31 (1H, d, AB system, JAB 14.2,
CHAHBPh), 4.59 (1H, d, AB system, JBA 14.2, CHAHBPh), 3.30 (1H, dd, J
16.8, 9.5, C(4)HAHB), 2.66 (1H, d, J 16.8, C(4)HAHB) and 1.56 (9H, s, C
(CH3)3); dC (75 MHz, CDCl3) 170.5 (C(3)O), 156.7 (C(O)O), 139.5
(CAripso), 135.7 (CAripso), 130.1 (CAr), 128.8 (CAr), 128.4 (CAr), 127.8
(CAr), 126.1 (CAr), 83.4 (C(CH3)3), 60.2 (C(5)H), 49.2 (CH2Ph), 37.8 (C
(4)H2) and 28.7 (C(CH3)3); m/z (CI) 353.3 (100, MþHþ); HRMS
(ESIþ) C21H25N2O3 requires 353.1860, found 353.1863 (þ0.8 ppm).
O
N
Ph
Bn
N
Boc
29
Toasolutionofhydrazinehydrate(1.45mL, 29.8mmol)inabsolute
ethanol (25 mL) was added ethyl cinnamate 17 (5.00 mL, 29.8 mmol)
and the resulting solution stirred at reflux overnight. The suspension
was then concentrated in vacuo and redissolved in toluene (25 mL)
andstirred atrefluxfor3 h. Theresultingsolutionwasconcentratedin
vacuo to give crude (RS)-5-phenylpyrazolidin-3-one 21 (3.62 g) as
a brown solid. Product was used without further purification. An
analytical sample was taken and purified by recrystallisation in hot
toluene to give the title compound as an off-white solid.
4.6.4. (RS)-2-Benzyl-5-phenylpyrazolidin-3-one 33.
O
N
nmax (KBr disc) cmꢀ1 3234 (NeH), 3191 (NeH), 3051 (AreH),
3019 (CeH), 1715 (C]O), 1664 (NeH bend) and 1599 (Ar C]C); mp
95e97 ꢁC; dH (400 MHz, CDCl3) 7.44e7.32 (5H, m, ArH), 4.84 (1H,
app t, J 8.5, C(5)H), 2.85 (1H, dd, ABX system, JAB 16.2, JAX 7.6, C(4)
HAHB) and 2.76 (1H, dd, ABX system, JBA 16.2, JBX 9.4, C(4)HAHB); dC
(100 MHz, CDCl3) 176.7 (C(3)O), 138.4 (CAripso), 129.1 (CAr), 128.6
(CAr), 126.7 (CAr), 62.0 (C(5)H) and 38.3 (C(4)H2); m/z (ES) 185.0
(100, MþNaþ), 163.2 (100, MþHþ); HRMS (ESIþ) C9H11N2O requires
163.0866, found 163.0867 (þ0.6 ppm).
Ph
Bn
N
H
33
To a solution of (RS)-tert-butyl 2-benzyl-5-phenyl-3-oxopyr-
azolidine-1-carboxylate 29 (2.28 g, 6.48 mmol) in dichloromethane
(15 mL) was added trifluoroacetic acid (5.00 mL, 64.8 mmol) and
the resulting mixture stirred at rt overnight. The excess acid was
then quenched with saturated sodium hydrogen carbonate solution
(150 mL) and extracted with dichloromethane (2ꢂ100 mL). The
combined organic layers were washed with brine (150 mL), dried
(MgSO4), filtered and concentrated in vacuo to give the title com-
pound as an off-white solid on standing (1.59 g, 97%).
To
a solution of crude (RS)-5-phenylpyrazolidin-3-one 21
(3.62 g, 22.3 mmol) in water (30 mL) were added sodium carbonate
(2.37 g 22.3 mmol) and dioxane (10 mL). A solution of di-tert-butyl
dicarbonate (4.90 g, 22.4 mmol) in dioxane (10 mL) was then added
and the mixture stirred at rt for 3 h. The resulting suspension was
filtered and the precipitate washed with chloroform. The combined
organic extracts were then concentrated in vacuo to approximately
30 mL volume and partitioned between water (100 mL) and
dichloromethane (75 mL). The aqueous layer was extracted with
further dichloromethane (2ꢂ75 mL) and then the combined or-
ganic extracts washed with brine (150 mL), dried (MgSO4), filtered
and concentrated in vacuo to give crude (RS)-tert-butyl 5-phenyl-3-
oxopyrazolidine-1-carboxylate 25 (4.95 g) as a yellow oil. Product
was used without further purification. An analytical sample was
taken and purified by column chromatography, eluting with 50%
dichloromethane in petrol, then 5% methanol in dichloromethane
to give the title compound as a colourless solid.
nmax (film) cmꢀ1 3214 (NeH), 3062 (AreH), 3031 (AreH), 2920
(CeH), 1683 (C]O), 1604 (Ar C]C) and 1560 (NeH bend); mp
60e62 ꢁC; dH (400 MHz, CDCl3) 7.26e7.18 (5H, m, ArH), 4.62 (1H, d,
AB system, JAB 14.6, CHAHBPh), 4.58 (1H, app t, J 8.4, C(5)H), 4.51
(1H, d, AB system, JBA 14.6, CHAHBPh), 2.87 (1H, dd, ABX system, JAB
16.3, JAX 7.8, C(4)HAHB) and 2.71 (1H, dd, ABX system, JBA 16.3, JBX
8.9, C(4)HAHB); dC (100 MHz, CDCl3) 171.4 (C(3)O), 135.8 (CAripso),
135.7 (CAripso), 128.87 (CAr), 128.85 (CAr), 128.5 (CAr), 128.3 (CAr),
128.0 (CAr), 126.5 (CAr), 58.2 (C(5)H), 48.1 (CH2Ph) and 39.3 (C(4)
H2); m/z (CI) 253.2 (100, MþHþ); HRMS (ESIþ) C16H17N2O requires
253.1335, found 253.1333 (ꢀ0.9 ppm).

9000
E. Gould et al. / Tetrahedron 66 (2010) 8992e9008
4.6.5. (RS)-5-iso-Propylpyrazolidin-3-one 20.
C(CH3)3) and 0.88 (6H, d, J 6.8, CH(CH3)2); dC (75 MHz, CDCl3) 170.7
(C(3)O), 154.7 (C(O)O), 82.6 (C(CH3)3), 62.1 (C(5)H), 33.6 (C(4)H2),
32.3 (C(5)HCH), 28.3 (C(CH3)3),17.9 (CH(CH3)A(CH3)B) and 17.7 (C(4)
(CH3)A(CH3)B); m/z (CI) 190.3 (100, MꢀC(CH3)3þNHþ4 ), 229.3 (35,
MþHþ); HRMS (ESIþ) C11H21N2O3 requires 229.1547, found
229.1547.
O
NH
i-Pr
N
H
4.6.7. (RS)-tert-Butyl 2-benzyl-5-iso-propyl-3-oxopyrazolidine-1-car-
20
boxylate 28.
To a solution of iso-butyrlaldehyde (2.17 mL, 24.0 mmol) in
dichloromethane (100 mL), cooled to 0 ꢁC, was added ethyl (tri-
phenylphosphoranylidene)acetate (10.0 g, 29.0 mmol) and the
resulting clear yellow solution stirred at rt overnight before being
concentrated in vacuo. The crude material was then passed through
a plug of silica gel, eluting with 3% ethyl acetate in petrol. The
resulting crude residue was then dissolved in absolute ethanol
(15 mL), hydrazine hydrate (1.17 mL, 24.0 mmol) was added and the
solution stirred for 1 h at rt and then at reflux for 4 h before con-
centration in vacuo. The crude material was purified by column
chromatography, eluting with 5% methanol in dichloromethane,
then flushed with 20% methanol in dichloromethane to give the
product as a clear yellow oil (2.68 g, 87%).
O
N
i-Pr
Bn
N
Boc
28
A
solution of crude (RS)-tert-butyl 5-iso-propyl-3-oxopyr-
azolidine-1-carboxylate 24 (498 mg, 2.18 mmol) in DMF (2 mL) was
treated with benzyl bromide (0.260 mL, 2.18 mmol) and potassium
carbonate (301 mg, 2.18 mmol) and the suspension stirred at rt for
60 min. The reaction mixture was partitioned between diethyl
ether (20 mL) and water (20 mL) and the resultant aqueous layer
washed with further diethyl ether (2ꢂ20 mL). The combined or-
ganic layers were washed with water (30 mL), brine (30 mL), dried
(MgSO4), filtered and concentrated in vacuo. The material was then
purified by column chromatography, eluting with 20% ethyl acetate
in petrol. Chromatography was then repeated, this time eluting
with 15e25% ethyl acetate in petrol to give the title compound as
a crystalline yellow solid (281 mg, 41%).
nmax (film) cmꢀ1 3401 (NeH), 3214 (NeH), 2961 (CeH), 2931
(CeH), 2874 (NeCeH) and 1683 (C]O); dH (300 MHz, CDCl3) 3.33
(1H, app dt, J 9.4, 7.7, C(5)H), 2.43 (1H, dd, ABX system, JAB 16.4, JAX
7.4, C(4)HAHB), 2.23 (1H, dd, ABX system, JBA 16.4, JBX 9.4, C(4)HAHB),
1.67 (1H, dsept,
J 7.9, 6.5C(5)HCH). 0.94 (3H, d, J 6.5 CH
(CH3)A(CH3)B) and 0.89 (3H, d, J 6.5, CH(CH3)A(CH3)B); dC (75 MHz,
CDCl3) 177.6 (C(3)O), 65.6 (C(5)H), 36.6 (C(4)H2), 32.5 (C(5)HCH),
19.7 (CH(CH3)A(CH3)B) and 19.6 (C(4)(CH3)A(CH3)B); m/z (CI) 129.1
(100, MþHþ); HRMS (CI) C6H13N2O requires 129.1028, found
129.1032 (þ3.2 ppm).
nmax (KBr disc) cmꢀ1 3067 (AreH), 3035 (AreH), 2971 (CeH),
2928 (CeH), 2862 (NeCeH), 1744e1661 (2ꢂC]O), 1602 (Ar C]C)
and 1586 (Ar C]C); mp 53e56 ꢁC; dH (300 MHz, CDCl3) 7.23 (5H, br
s, ArH), 5.21 (1H, d, AB system, JAB 14.0, CHAHBPh), 4.39 (1H, d, AB
system, JBA 14.0, CHAHBPh), 3.76 (1H, app t, J 9.3, C(5)H), 2.78 (1H,
dd, JAB 16.6, 8.7, C(4)HAHB), 2.14 (1H, d, J 16.6, C(4)HAHB), 1.45 (9H, s,
C(CH3)3), 0.88 (1H, dsept, J 10.2, 6.6, C(5)HCH), 0.61 (3H, d, J 6.6, CH
(CH3)A(CH3)B) and 0.24 (3H, d, J 6.6, CH(CH3)A(CH3)B); dC (75 MHz,
CDCl3) 170.9 (C(3)O), 156.6 (C(O)O), 135.7 (Aripso), 129.7 (CAr), 128.4
(CAr), 128.2 (CAr), 82.4 (C(CH3)3), 64.1 (C(5)H), 48.6 (CH2Ph), 34.9 (C
(4)H2), 30.8 (C(5)HCH), 28.3 (C(CH3)3), 18.5 (CH(CH3)A(CH3)B) and
18.3 (C(4)(CH3)A(CH3)B); m/z (CI) 219.3 (100, M‑CO2C(CH3)3þNHþ4 ),
319.2 (60, MþHþ); HRMS (ESIþ) C18H27N2O3 requires 319.2016,
found 319.2019 (ꢀ0.8 ppm).
4.6.6. (RS)-tert-Butyl 5-iso-propyl-3-oxopyrazolidine-1-carboxylate
24.
O
NH
i-Pr
N
Boc
24
To a solution of (RS)-5-iso-propylpyrazolidin-3-one 20 (578 mg,
4.51 mmol) in water (6 mL) were added sodium carbonate (503 mg,
4.75 mmol) and dioxane (3 mL). A solution of di-tert-butyl dicar-
bonate (1.02 g, 4.67 mmol) in dioxane (3 mL) was then added and the
mixture stirred at rt overnight. TLC analysis showed incomplete re-
action. Hence, more sodium carbonate (240 mg, 2.26 mmol) and di-
tert-butyl dicarbonate (490 mg, 2.24 mmol) in dioxane (1 mL) were
added and the mixture stirred for a further 3 h. The resulting sus-
pension was then filtered and the precipitate washed with chloro-
form. The combined organic extracts were then concentrated in
vacuo to approximately 5 mL volume and partitioned betweenwater
(40 mL) and dichloromethane (40 mL). The aqueous layer was
washed with further dichloromethane (240 mL) and then the com-
bined organic extracts washed with brine (200 mL), dried (MgSO4),
filtered and concentrated in vacuo. The crude material was purified
by column chromatography, eluting with 2% methanol in dichloro-
methane to give the product as an off-white solid (530 mg, 51%).
nmax (film) cmꢀ1 3171 (NeH), 3072 (NeH), 2970 (CeH), 2933
(CeH), 2877 (NeCeH), 1698 (C]O) and 1676 (C]O); mp 80e81 ꢁC;
dH (300 MHz, CDCl3) 4.13 (1H, ddd, J 9.8, 6.4, 2.5, C(5)H), 2.80 (1H, dd,
ABX system, JAB 17.3, JAX 9.8, C(4)HAHB), 2.23 (1H, dd, ABX system, JBA
17.3, JBX 2.5, C(4)HAHB), 1.84 (1H, app oct, J 6.6, C(5)HCH). 1.43 (9H, s,
4.6.8. (RS)-2-Benzyl-5-iso-propylpyrazolidin-3-one 32.
O
N
i-Pr
Bn
N
H
32
To a solution of (RS)-tert-butyl 2-benzyl-5-iso-propyl-3-oxo-
pyrazolidine-1-carboxylate 28 (390 mg, 1.67 mmol) in dichloro-
methane (2 mL) was added trifluoroacetic acid (0.500 mL,
6.47 mmol) and the resulting solution stirred overnight at rt. TLC
analysis of the crude reaction mixture showed incomplete reaction.
Hence, further trifluoroacetic acid (0.200 mL, 1.62 mmol) was
added and the mixture stirred for 2 h before being concentrated in
vacuo. The resulting material was partitioned between dichloro-
methane (50 mL) and saturated sodium hydrogen carbonate solu-
tion (50 mL). The aqueous layer was washed with dichloromethane
(2ꢂ50 mL) and the combined organic layers washed with brine
(150 mL), dried (MgSO4), filtered and concentrated in vacuo. The

E. Gould et al. / Tetrahedron 66 (2010) 8992e9008
9001
crude material was then purified by column chromatography,
4.6.10. (RS)-2-Benzyl-5-(trifluoromethyl)pyrazolidin-3-one 34.
eluting with 50% ethyl acetate in petrol to give the title compound
as a clear yellow oil, which solidified on standing (179 mg, 67%).
nmax (KBr disc) cmꢀ1 3178 (NeH), 3061 (AreH), 3035 (AreH),
2961 (CeH), 2954 (CeH), 2880 (N‑CeH), 1661 (C]O), 1602 (Ar C]
C) and 1560 (NeH bend); mp 53e54 ꢁC; dH (400 MHz, CDCl3)
7.37e7.27 (5H, m, ArH), 4.64 (1H, d, AB system, JAB 14.5, CHAHBPh),
4.52 (1H, d, AB system, JBA 14.5, CHAHBPh), 4.07 (1H, br s, N(1)H),
3.22 (1H, app q, J 8.1, C(5)H), 2.61 (1H, dd, ABX system, JAB 16.4, JAX
7.7, C(4)HAHB), 2.34 (1H, d, ABX system, JBA 16.4, JBX 8.7, C(4)HAHB),
1.61 (1H, dsept, J 7.8, 6.7, C(5)HCH), 0.91 (3H, d, J 6.7, CH
(CH3)A(CH3)B) and 0.89 (3H, d, J 6.7, CH(CH3)A(CH3)B); dC (75 MHz,
CDCl3) 172.1 (C(3)O), 136.1 (Aripso), 128.9 (CAr), 128.4 (CAr), 127.9
(CAr), 61.3 (C(5)H), 48.1 (CH2Ph), 37.0 (C(4)H2), 32.2 (C(5)HCH) and
19.2 (CH(CH3)2); m/z (CI) 219.3 (100, MþHþ); HRMS (EI) C13H18N2O
requires 218.1414, found 218.1413 (ꢀ0.3 ppm).
O
N
F3C
Bn
N
H
34
A
solution of (RS)-tert-butyl 3-oxo-5-(trifluoromethyl)pyr-
azolidine-1-carboxylate 26 (1.00 g, 3.94 mmol) in DMF (8 mL) was
treated with benzyl bromide (0.50 mL, 3.95 mmol) and potassium
carbonate (544 mg, 3.95 mmol) and the suspension stirred at rt for 2
days. The reaction mixture was partitioned between diethyl ether
(100 mL) and water (100 mL) andthe resultantaqueous layer washed
with further diethyl ether (2ꢂ100 mL). The combined organic layers
were washed with brine (150 mL), dried (MgSO4), filtered and con-
centrated in vacuo to give crude (RS)-tert-butyl 2-benzyl-5-(tri-
fluoromethyl)-3-oxopyrazolidine-1-carboxylate 30 (1.27 g) as a clear
yellow oil. Product was used without further purification. An ana-
lytical sample was taken and purified by column chromatography,
eluting with 15% ethyl acetate in petrol, to give the title compound as
a clear oil, which became a colourless solid on standing.
4.6.9. (RS)-tert-Butyl 3-oxo-5-(trifluoromethyl)pyrazolidine-1-car-
boxylate 26.
O
nmax (KBr disc) cmꢀ1 3064 (AreH), 3014 (AreH), 2985 (CeH),
1730 (C]O) and 1700 (C]O); mp 58e59 ꢁC; dF (282 MHz, CDCl3)
ꢀ79.0 (3F, d, J 7.3, CF3); dH (300 MHz, CDCl3) 7.32e7.27 (5H, m, ArH),
5.19 (1H, d, AB system, JAB 14.3, CHAHBPh), 4.77 (1H, dqd, J 10.1, 7.3,
1.6, C(5)H), 4.58 (1H, d, AB system, JBA 14.3, CHAHBPh), 3.06 (1H, dd, J
17.5, 10.1, C(4)HAHB), 2.50 (1H, d, J 17.5, 1.6, C(4)HAHB) and 1.53 (9H,
s, C(CH3)3); dC (75 MHz, CDCl3) 168.5 (C(3)O), 155.5 (C(O)O), 134.4
(CAripso), 129.8 (CAr), 128.4 (CAr), 128.3 (CAr), 123.3 (q, J 281, CF3),
84.6 (C(CH3)3), 56.9 (q, J 33.8, C(5)H), 50.0 (CH2Ph), 30.8 (C(4)H2)
and 28.2 (C(CH3)3); m/z HRMS (ESIþ) C16H20F3N2O3 requires
345.1421, found 345.1425 (þ1.3 ppm).
NH
F3C
N
Boc
26
To a solution of hydrazine hydrate (1.60 mL, 32.7 mmol) in ab-
solute ethanol (50 mL) was added ethyl 4,4,4-trifluorocrotonate 18
(4.40 mL, 29.3 mmol) and the resulting solution stirred at reflux for
3 h before concentration in vacuo to give crude (RS)-5-(tri-
fluoromethyl)pyrazolidin-3-one 22 (3.35 g) as a yellow solid.
Product was used without further purification. An analytical sam-
ple was taken and purified by recrystallisation in hot toluene to give
the title compound as colourless plates.
Crude (RS)-tert-butyl 2-benzyl-5-(trifluoromethyl)-3-oxopyr-
azolidine-1-carboxylate 30 (1.04 g, 3.02 mmol) was stirred at rt
overnight in a 1:2 mixture of trifluoroacetic acid/dichloromethane
(15 mL) before being concentrated in vacuo. The resulting material
was partitioned between dichloromethane (100 mL) and saturated
sodium hydrogen carbonate solution (100 mL). The aqueous layer
was washed with dichloromethane (2ꢂ100 mL) and the combined
organic layers washed with brine (250 mL), dried (MgSO4), filtered
and concentrated in vacuo. The crude material was then purified by
recrystallisation from diethyl ether and the minimum quantity of
dichloromethane to give the title compound as a colourless solid
(484 mg, 50%).
nmax (KBr disc) cmꢀ1 3248 (NeH), 3190 (NeH), 1694 (C]O) and
1648 (NeH bend); mp 130e132 ꢁC; dF (375 MHz, CD3OD) ꢀ81.0 (3F,
d, J 8.2, CF3); dH (300 MHz, CD3OD) 4.18 (1H, dqd, J 10.3, 8.2, 2.6, C(5)
H), 3.02 (1H, dd, ABX system, JAB 17.4, JAX 10.3, C(4)HAHB) and 2.42
(1H, dd, ABX system, JBA 17.4, JBX 2.6, C(4)HAHB); dC (75 MHz,
CD3OD) 174.2 (C(3)O), 125.2 (q, J 279, CF3), 56.2 (q, J 31.4, C(5)H) and
31.0 (q, J 1.5, C(4)H2); m/z HRMS (ESIþ) C4H9F3N3O requires
172.0692, found 172.0688 (ꢀ2.6 ppm).
C11H11F3N2O requires C, 54.1; H 4.5; N, 11.5%; found C 53.9; H,
4.3; N, 11.6%; nmax (KBr disc) cmꢀ1 3219 (NeH), 3068 (AreH), 3029
(AreH), 2951 (CeH), 2916 (CeH), 1700 (C]O) and 1667 (C]O); mp
85e86 ꢁC; dF (282 MHz, CDCl3) ꢀ79.1 (3F, d, J 7.2, CF3); dH (300 MHz,
CDCl3) 7.38e7.28 (5H, m, ArH), 4.92 (1H, d, AB system, JAB 14.6,
CHAHBPh), 4.69 (1H, s, N(1)H), 4.25 (1H, d, AB system, JBA 14.6,
CHAHBPh), 3.93 (1H, dqd, J 10.0, 7.2, 3.3, C(5)H), 2.96 (1H, dd, J 17.4,
10.0, C(4)HAHB) and 2.66 (1H, d, J 17.4, 3.3, C(4)HAHB); dC (75 MHz,
CDCl3) 168.3 (C(3)O), 135.1 (CAripso), 129.0 (CAr), 128.6 (CAr), 128.3
(CAr), 124.7 (q, J 279, CF3), 54.0 (q, J 32.3, C(5)H), 48.5 (CH2Ph) and
31.9 (C(4)H2); m/z HRMS (ESIþ) C11H12F3N2O requires 245.0896,
found 245.0890 (þ0.7 ppm).
To a solution of crude (RS)-5-(trifluoromethyl)pyrazolidin-3-one
22(2.62 g,17.0 mmol)inwater(20 mL) were addedsodium carbonate
(1.80 g, 17.0 mmol) and dioxane (10 mL). A solution of di-tert-butyl
dicarbonate (3.70 g, 17.0 mmol) in dioxane (10 mL) was then added
and the mixture stirred at rt overnight. The resulting suspension was
filtered and the precipitate washed with ethyl acetate. The combined
organicextractswere thenconcentratedinvacuotoasmallvolumeat
which point the title compound began to precipitate. This solid was
collected by filtration and washed with water. The combined filtrate
was cooled to 0 ꢁC overnight to yield a second crop of the title
compound, which was collected by filtration and washed with fur-
ther cold water. The combined solids were dried in a desiccator to
give the title compound as a colourless solid (2.64 g, 35%).
nmax (film) cmꢀ1 3343 (NeH), 3010 (NeH), 2986 (CeH), 1717
(C]O) and 1697 (C]O); mp 141e144 ꢁC; dF (375 MHz, CDCl3) ꢀ79.3
(3F, d, J 6.7, CF3); dH (300 MHz, CDCl3) 4.89 (1H, dqd, J 10.6, 6.7, 2.3, C
(5)H), 3.08 (1H, dd, ABX system, JAB 17.8, JAX 10.6, C(4)HAHB), 2.64
(1H, dd, ABX system, JBA 17.8, JBX 2.3, C(4)HAHB) and 1.52 (9H, s, C
(CH3)3); dC (100 MHz, CDCl3) 168.7 (C(3)O), 154.0 (C(O)O), 124.0 (q, J
281, CF3), 84.7 C(CH3)3, 56.7 (q, J 34.0, C(5)H), 30.8 (C(4)H2) and 28.1
(C(CH3)3); m/z HRMS (ESIþ) C9H14F3N2O3 requires 255.0951, found
255.0954 (þ1.2 ppm).
4.6.11. (RS)-tert-Butyl 2,5-dimethyl-3-oxopyrazolidine-1-carboxylate
35.
O
N
Me
Me
N
Boc
35

9002
E. Gould et al. / Tetrahedron 66 (2010) 8992e9008
A solution of crude (RS)-tert-butyl 5-methyl-3-oxopyrazolidine-
To a solution of (RS)-tert-butyl 2-benzyl-5-methyl-3-oxopyr-
azolidine-1-carboxylate 27 (268 mg, 0.923 mmol) in THF (5 mL),
cooled to ꢀ78 ꢁC, was added KHMDS (0.46 M in toluene, 10.0 mL,
4.60 mmol) and the red solution stirred for 70 min before
treatment with methyl iodide (0.570 mL, 9.23 mmol). The mix-
ture was stirred at ꢀ78 ꢁC for 90 min, then at rt for 60 min. The
reaction was then quenched with pH 7 phosphate buffer solution
(20 mL), the resulting biphasic solution extracted with diethyl
ether (3ꢂ15 mL) and the combined organic extracts washed with
brine (30 mL) and dried (MgSO4) before being filtered through
a plug of silica gel and concentrated in vacuo. 1H NMR showed
a mixture of starting material 27, monomethylated material and
product 37 in the ratio 27:44:29 and so the crude material was
redissolved in THF (5 mL), cooled to ꢀ78 ꢁC and treated, as before,
with identical amounts of KHMDS and methyl iodide. The mix-
ture was stirred at ꢀ78 ꢁC for 60 min before being quenched and
following of the work-up procedure previously described. The
crude material was purified by column chromatography, eluting
with 10% ethyl acetate in petrol to give the product as a colourless
oil (75 mg, 26%).
1-carboxylate 23 (2.92 g, 13.6 mmol) in DMF (30 mL) was treated
with methyl iodide (2.80 mL, 45.0 mmol) and potassium carbonate
(2.49 g, 18.0 mmol) and the suspension stirred at rt overnight. The
reaction mixture was partitioned between diethyl ether (60 mL)
and water (60 mL) and the resultant aqueous layer washed with
further diethyl ether (60 mL). The combined organic layers were
washed with brine (120 mL), dried (MgSO4), filtered and concen-
trated in vacuo. The material was then purified by column chro-
matography, eluting with 25% ethyl acetate in petrol to give the title
compound as a colourless oil with spectroscopic data in accordance
with the literature (1.60 g, 53%).20
dH (300 MHz, CDCl3) 4.53 (1H, app quin, J 7.0, C(5)H), 3.20 (3H, s,
N(2)CH3), 2.91 (1H, dd, J 16.3, 8.3, C(4)HAHB), 2.00 (1H, d, J 16.3, C(4)
HAHB), 1.48 (9H, s, C(CH3)3) and 1.22 (3H, d, J 6.8, C(5)HCH3).
4.6.12. (RS)-2,5-Dimethylpyrazolidin-3-one 36.
O
N
nmax (film) cmꢀ1 3065 (AreH), 3032 (AreH), 2978 (CeH), 2934
(CeH), 2871 (NeCeH), 1747e1674 (2ꢂC]O) and 1605 (Ar C]C);
dH (300 MHz, CDCl3) 7.24e7.20 (5H, m, ArH), 5.15 (1H, d, AB
system, JAB 14.2, CHAHBPh), 4.31 (1H, d, AB system, JBA 14.2,
CHAHBPh), 3.99 (1H, q, J 6.9, C(5)H), 1.48 (9H, s, C(CH3)3), 1.09 (3H,
s, C(4)(CH3)A(CH3)B), 0.92 (3H, s, C(4)(CH3)A(CH3)B) and 0.42 (3H,
d, J 6.9, C(5)HCH3); dC (75 MHz, CDCl3) 176.6 (C(3)O), 157.3 (C(O)
O), 136.2 (CAripso), 130.2 (CAr), 128.8 (CAr), 128.5 (CAr), 82.7 (C
(CH3)3), 65.3 (C(5)H), 49.1 (CH2Ph), 44.6 (C(4)(CH3)2), 28.7 (C
(CH3)3), 24.8 (C(5)HCH3), 18.2 (C(4)(CH3)A(CH3)B) and 15.8 (C(4)
(CH3)A(CH3)B); m/z (CI) 219.2 (100, MꢀBocþ2Hþ), 319.3 (60,
MþHþ); HRMS (ESIþ) C18H27N2O3 requires 319.2016, found
319.2015 (þ0.2 ppm).
Me
Me
N
H
36
To a solution of (RS)-tert-butyl 2,5-dimethyl-3-oxopyrazolidine-
1-carboxylate 35 (1.59 g, 7.42 mmol) in dichloromethane (5 mL)
was added trifluoroacetic acid (1.80 mL, 23.3 mmol) and the
resulting solution stirred overnight at rt. TLC analysis of the crude
reaction mixture showed incomplete reaction. Hence, further tri-
fluoroacetic acid (0.580 mL, 7.51 mmol) was added and the mixture
stirred overnight before concentration in vacuo. The resulting
material was partitioned between dichloromethane (100 mL) and
saturated sodium hydrogen carbonate solution (100 mL). The
aqueous layer was washed with dichloromethane (100 mL) and the
combined organic layers washed with brine (150 mL), dried
(MgSO4), filtered and concentrated in vacuo to give the title com-
pound as a colourless oil (145 mg). The aqueous layer was treated
with triethylamine then extracted with further dichloromethane
(100 mL). The organic layer was dried (MgSO4), filtered and con-
centrated in vacuo to give further material (177 mg). The aqueous
layer was then concentrated in vacuo and partitioned between 1 M
sodium hydroxide solution (50 mL) and dichloromethane (80 mL).
The organic layer was dried (MgSO4), filtered and concentrated in
vacuo to give further material (151 mg) (473 mg in total, 55%).
nmax (film) cmꢀ1 3196 (NeH), 2969 (CeH), 2927 (CeH), 1667
(C]O), 1605 and 1597 (NeH bend); dH (300 MHz, CDCl3) 4.12 (1H,
br s, N(1)H), 3.66 (1H, app dquin, J 8.3, 6.7, C(5)H), 3.01 (3H, s, N(2)
CH3), 2.59 (1H, dd, ABX system, JAB 16.1, JAX 7.2, C(4)HAHB), 2.20
(1H, dd, ABX system, JBA 16.1, JBX 8.3, C(4)HAHB) and 1.24 (3H, d, J
6.4, C(5)HCH3); dC (75 MHz, CDCl3) 172.6 (C(3)O), 51.4 (C(5)H),
40.4 (C(4)H2), 31.4 (N(2)CH3) and 19.1 (C(5)HCH3); m/z (CI) 115.2
(100, MþHþ); HRMS (ESIþ) C5H11N2O requires 115.0866, found
115.0865 (ꢀ0.4 ppm).
4.6.14. (RS)-2-Benzyl-4,4,5-trimethylpyrazolidin-3-one 38.
O
N
Me
Bn
N
H
38
To a solution of (RS)-tert-butyl 2-benzyl-4,4,5-trimethyl-3-oxo-
pyrazolidine-1-carboxylate 37 (142 mg, 0.446 mmol) in dichloro-
methane (2 mL) was added trifluoroacetic acid (0.2 mL, 2.69 mmol)
and the resulting solution stirred overnight at rt. TLC analysis of the
crude reaction mixture showed incomplete reaction. Hence, further
trifluoroacetic acid (0.2 mL, 2.69 mmol) was added and the mixture
stirred for 2 h before being concentrated in vacuo. The resulting
material was partitioned between dichloromethane (20 mL) and
saturated sodium hydrogen carbonate solution (20 mL). The
aqueous layer was washed with dichloromethane (2ꢂ20 mL) and
the combined organic layers washed with brine (50 mL), dried
(MgSO4), filtered and concentrated in vacuo to give the title com-
pound as a colourless oil (94 mg, 96%).
4.6.13. (RS)-tert-Butyl 2-benzyl-4,4,5-trimethyl-3-oxopyrazolidine-
1-carboxylate 37.
nmax (film) cmꢀ1 3202 (NeH), 3064 (AreH), 3032 (AreH), 2969
(CeH), 2930 (CeH), 2873 (NeCeH), 1678 (C]O), 1606 (Ar C]C)
and 1587 (NeH bend); dH (400 MHz, CDCl3) 7.37e7.24 (5H, m,
ArH), 4.82 (1H, d, AB system, JAB 14.7, CHAHBPh), 4.34 (1H, d, AB
system, JBA 14.7, CHAHBPh), 3.76 (1H, br s, N(1)H), 3.24 (1H, q, J
6.6, C(4)HCH3), 1.15 (3H, s, C(4)(CH3)A(CH3)B), 1.06 (3H, d, J 6.6, C
(5)HCH3) and 0.95 (3H, s, C(4)(CH3)A(CH3)B); dC (100 MHz, CDCl3)
177.7 (C(3)O), 136.2 (CAripso), 128.9 (CAr), 128.2 (CAr), 127.9
(CAr), 61.4 (C(5)H), 48.1 (CH2Ph), 43.5 (C(4)(CH3)2), 21.7 (C(4)
O
N
Me
Bn
N
Boc
37

E. Gould et al. / Tetrahedron 66 (2010) 8992e9008
9003
(CH3)A(CH3)B), 16.4 (C(4)(CH3)A(CH3)B) and 12.0 (C(5)HCH3); m/z
4.6.17. (RS)-tert-Butyl
pyrazole-1-carboxylate 41.
3-(benzoyloxy)-5-methyl-4,5-dihydro-1H-
(ESIþ) 241.1 (100, MþNaþ); HRMS (ESIþ) C13H18N2ONa requires
241.1317, found 241.1317.
Ph
O
4.6.15. (RS)-tert-Butyl 3-(trifluoromethylsulfonyloxy)-5-methyl-4,5-
dihydro-1H-pyrazole-1-carboxylate 39.
O
N
Me
N
OTf
Boc
41
N
Me
N
(RS)-tert-Butyl 5-methyl-3-oxopyrazolidine-1-carboxylate 23
(250 mg, 1.25 mmol) triethylamine (0.200 mL, 1.38 mmol) and
benzoyl chloride (0.200 mL, 1.73 mmol) were combined according
to general procedure A to give crude product (568 mg). Attempted
purification of this material by column chromatography led to de-
composition to unidentified side-products. Hence, characterisation
was carried out on the crude mixture.
Boc
39
To a solution of (RS)-tert-butyl 5-methyl-3-oxopyrazolidine-1-
carboxylate 23 (250 mg, 1.25 mmol) in dichloromethane (5 mL) was
added triethylamine (0.700 mL, 5.00 mmol). The resulting sus-
pension was then cooled to ꢀ78 ꢁC and triflic anhydride (0.410 mL,
2.50 mmol) added dropwise. The reaction mixture was stirred at
ꢀ78 ꢁC for 2 h and 1:1 water/methanol added (4 mL). The reaction
mixture was warmed to rt, maintained for 30 min, then diluted
with diethyl ether (30 mL). The organic layer was washed with
0.1 M hydrochloric acid (50 mL), brine (50 mL), dried (MgSO4),
filtered and concentrated in vacuo. The crude material was then
purified by column chromatography, eluting with 10% ethyl acetate
in petrol to give the title compound as a colourless oil, which so-
lidified on standing (176 mg, 42%).
nmax (film) cmꢀ1 3065 (AreH), 2979 (CeH), 2932 (CeH), 2862
(NeCeH), 1750 (C]O), 1642 (C]O) and 1601 (C]N); dH (300 MHz,
CDCl3) 8.11e8.07 (2H, m, ArH), 7.56e7.45 (3H, m, ArH), 4.59 (1H, app
dquin, J 11.0. 6.0, C(5)H), 3.50 (1H, dd, ABX system, JAB 17.6, JAX 11.0, C
(4)HAHB), 2.83 (1H, dd, ABX system, JBA 17.6, JBX 4.9, C(4)HAHB), 1.54
(9H, s, C(CH3)3) and 1.45 (3H, d, J 6.3, C(5)HCH3); dC (100 MHz, CDCl3)
163.2 (C(O)Ph),157.3 (C(4)N),134.6 (CAripso),130.6 (CAr),130.5 (CAr),
128.8 (CAr), 81.5 (C(CH3)3), 55.8 (C(5)H), 38.7 (C(4)H2), 28.4 (C
(CH3)3) and 20.6 (C(5)HCH3); m/z (ESIþ) 327.1 (100, MþNaþ); HRMS
(ESIþ) C16H20N2NaO4 requires 327.1321, found 327.1323 (þ0.6 ppm).
nmax (KBr disc) cmꢀ1 2990 (CeH), 2932 (CeH), 2873 (NeCeH),
1713 (C]O), 1635 (C]N) and 1572 (Ar C]C); mp 41e43 ꢁC; dH
(400 MHz, CDCl3) 4.61 (1H, app dquin, J 11.3. 6.3, C(5)H), 3.38 (1H,
dd, ABX system, JAB 17.8, JAX 11.3, C(4)HAHB), 2.70 (1H, dd, ABX
system, JBA 17.8, JBX 5.3, C(4)HAHB), 1.52 (9H, s, C(CH3)3) and 1.42
(3H, d, J 6.3, C(5)HCH3); dC (100 MHz, CDCl3) 153.2 (C(O)O), 151.6 (C
(4)N), 118.5 (q, J¼321, CF3), 82.4 (C(CH3)3), 56.9 (C(5)H), 38.7 (C(4)
H2), 28.4 (C(CH3)3) and 20.8 (C(5)HCH3); m/z (CI) 132.3 (100,
SO2CFþ3 ), 350.3 (20, MþNH4þ); HRMS (ESIþ) C10H19F3N3O5S requires
350.0992, found 350.0991 (ꢀ0.3 ppm).
4.6.18. (RS)-tert-Butyl 3-(benzyloxycarbonyloxy)-5-methyl-4,5-dihy-
dro-1H-pyrazole-1-carboxylate 42.
OBn
O
O
N
Me
N
Boc
42
(RS)-tert-Butyl 5-methyl-3-oxopyrazolidine-1-carboxylate 23
(1.00 g, 5.00 mmol) triethylamine (0.800 mL, 5.74 mmol) and
benzyl chloroformate (0.75 mL, 5.25 mmol) were combined
according to general procedure A to give crude product (1.77 g).
Attempted purification of this material by column chromatography
led to decomposition and return of starting compound 23. Hence,
characterisation was carried out on the crude mixture.
4.6.16. (RS)-tert-Butyl 5-methyl-3-(tosyloxy)-4,5-dihydro-1H-pyr-
azole-1-carboxylate 40.
OTs
N
Me
N
Boc
nmax (film) cmꢀ1 3066 (AreH), 3035 (AreH), 2978 (CeH), 2932
(CeH), 2863 (NeCeH), 1751 (C]O), 1725 (C]O), 1648 (C]N) and
1587 (Ar C]C); dN (CDCl3) 296 (N(2)COC(O)), 155 (N(1)Boc); dH
(300 MHz, CDCl3) 7.40e7.33 (5H, m, ArH), 5.23 (2H, s, CH2Ph), 4.54
(1H, app dquin, J 11.1. 6.1, C(5)H), 3.37 (1H, dd, ABX system, JAB 17.7,
JAX 11.1, C(4)HAHB), 2.68 (1H, dd, ABX system, JBA 17.7, JBX 5.0, C(4)
HAHB), 1.52 (9H, s, C(CH3)3) and 1.39 (3H, d, J 6.3, C(5)HCH3); dC
(100 MHz, CDCl3) 156.3 (C(4)N), 151.2 (OC(O)O), 134.1 (CAripso),
129.2 (CAr), 128.9 (CAr), 128.7 (CAr), 81.6 (C(CH3)3), 71.2 (CH2Ph),
56.0 (C(5)H), 38.1 (C(4)H2), 28.5 (C(CH3)3) and 20.7 (C(5)HCH3); m/z
(ESIþ) 357.0 (100, MþNaþ); HRMS (ESIþ) C17H22N2NaO5 requires
357.1426, found 357.1419 (ꢀ2.1 ppm).
40
(RS)-tert-Butyl 5-methyl-3-oxopyrazolidine-1-carboxylate 23
(0.991 g, 4.95 mmol) triethylamine (0.800 mL, 5.74 mmol) and tosyl
chloride (1.00 g, 5.25 mmol) were combined according to general
procedure A. The crude material was then purified by column
chromatography, eluting with 15% ethyl acetate in petrol to give the
title compound as a colourless oil, which solidified on standing
(810 mg, 46%).
nmax (KBr disc) cmꢀ1 2987 (CeH), 2934 (CeH), 1698 (C]O), 1645
(C]N), 1596 (Ar C]C) and 1586 (Ar C]C); mp 84e86 ꢁC; dN
(CDCl3) 295 (N(2)COS(O)2), 156 (N(1)Boc); dH (300 MHz, CDCl3) 7.94
(2H, d, J 8.4, ArH), 7.36 (2H, d, J 8.4, ArH), 4.46 (1H, app dquin, J 11.0.
6.1, C(5)H), 3.26 (1H, dd, ABX system, JAB 17.8, JAX 11.0, C(4)HAHB),
2.61 (1H, dd, ABX system, JBA 17.8, JBX 5.3, C(4)HAHB), 1.49 (9H, s, C
(CH3)3) and 1.34 (3H, d, J 6.3, C(5)HCH3); dC (75 MHz, CDCl3) 155.0 (C
(O)O), 151.9 (C(4)N), 146.3 (CAripso), 132.3(CArpara), 129.9 (CAr),
129.3 (CAr), 81.3 (C(CH3)3), 55.5 (C(5)H), 39.0 (C(4)H2), 28.4 (C
(CH3)3), 21.9 (CArparaCH3) and 20.7 (C(5)HCH3); m/z (ESIþ) 372.2
(100, MþNHþ4 ); HRMS (ESIþ) C10H19F3N3O5S requires 372.1588,
found 372.1593 (þ1.4 ppm).
4.6.19. (RS)-tert-Butyl 2-benzoyl-5-methyl-3-oxopyrazolidine-1-car-
boxylate 43.
O
Ph
N
Me
N
O
Boc
43

9004
E. Gould et al. / Tetrahedron 66 (2010) 8992e9008
(RS)-tert-Butyl 5-methyl-3-oxopyrazolidine-1-carboxylate 23
purified by column chromatography, eluting with 25% ethyl acetate
in petrol to give the title compound as a colourless oil (684 mg,
41%).
(988 mg, 4.93 mmol), sodium hydride (225 mg, 5.63 mmol) and
benzoyl chloride (0.60 mL, 5.24 mmol) were combined according to
general procedure B. The resulting material was dissolved in toluene
(15 mL) and refluxed for 5 h. The crude material was then purified by
column chromatography, eluting with 25% ethyl acetate in petrol to
give the title compound as a colourless solid (685 mg, 45%).
nmax (film) cmꢀ1 3066 (AreH), 3034 (AreH), 2979 (CeH), 2933
(CeH), 2874 (NeCeH), 1799 (C]O), 1751 (C]O), 1728 (C]O) and
1587 (Ar C]C); dN (CDCl3) 166 (N(2)CO2Bn), 137 (N(1)Boc); dH
(300 MHz, CDCl3) 7.45e7.28 (5H, m, ArH), 5.36 (1H, d, AB system,
JAB 12.3, CHAHBPh), 5.26 (1H, d, AB system, JBA 12.3, CHAHBPh), 4.42
(1H, app quin, J 7.0, C(5)H), 2.97 (1H, dd, J 17.1, 8.0, C(4)HAHB), 1.96
(1H, d, J 17.1, C(4)HAHB), 1.38 (9H, s, C(CH3)3) and 1.31 (3H, d, J 6.8, C
(5)HCH3); dC (75 MHz, CDCl3) 169.9 (C(3)O), 155.8 (N(1)C(O)O),
149.7 (N(2)C(O)O), 135.0 (CAripso), 128.7 (CAr), 128.6 (CAr), 128.4
(CAr), 83.6 (C(CH3)3), 68.9 (CH2Ph), 53.6 (C(5)H), 39.6 (C(4)H2), 28.0
(C(CH3)3) and 19.9 (C(5)HCH3); m/z (CI) 235.1 (100, MꢀBocþ2Hþ),
352.2 (96, MþNH4þ); HRMS (ESIþ) C17H26N3O5 requires 352.1867,
found 352.1872 (þ1.4 ppm).
nmax (KBr disc) cmꢀ1 2984 (CeH), 2932 (CeH), 2863 (NeCeH),
1759 (C]O), 1727 (C]O), 1699 (C]O) and 1596 (Ar C]C); mp
129e132 ꢁC; dN (CDCl3) 184 (N(2)C(O)),136 (N(1)Boc); dH (300 MHz,
CDCl3) 7.81 (2H, dd, J 8.4, 1.3, ArHortho), 7.57 (1H, app tt, J 7.9, 1.3,
ArHpara), 7.48e7.40 (2H, m, ArHmeta), 4.78 (1H, app quin, J 7.1, C(5)H),
3.14 (1H, dd, J 16.9, 8.3, C(4)HAHB), 2.28 (1H, d, J 16.9, C(4)HAHB),1.40
(9H, s, C(CH3)3) and 1.39 (3H, d, J 6.4, C(5)HCH3); dC (100 MHz,
CDCl3) 170.8 (C(3)O), 166.6 (C(O)Ph), 154.5 (C(O)O), 133.2 (CAripso),
133.1 (CAr), 130.0 (CAr), 128.2 (CAr), 83.5 (C(CH3)3), 52.7 (C(5)H),
39.9 (C(4)H2), 28.2 (C(CH3)3) and 20.4 (C(5)HCH3); m/z (ESIþ) 139.2
(100, H2NC(O)PhþNHþ4 ), 305.2 (15, MþHþ), 322.3 (20, MþNHþ4 );
HRMS (ESIþ) C16H24N3O4 requires 322.1761, found 322.1761.
4.6.22. (RS)-Benzyl 3-methyl-5-oxopyrazolidine-1-carboxylate 46.
O
4.6.20. (RS)-2-Benzoyl-5-methylpyrazolidin-3-one 45.
OBn
N
Me
N
O
H
O
46
Ph
N
Me
N
H
O
To a solution of (RS)-1-benzyl 2-tert-butyl 3-methyl-5-oxopyr-
azolidine-1,2-dicarboxylate 44 (560 mg, 1.67 mmol) in dichloro-
methane (3 mL) was added trifluoroacetic acid (0.600 mL,
8.09 mmol) and the resulting solution stirred overnight at rt. TLC
analysis of the crude reaction mixture showed incomplete reaction.
Hence, further trifluoroacetic acid (0.120 mL,1.62 mmol) was added
and the mixture stirred for 4 h before being concentrated in vacuo.
The resulting material was partitioned between dichloromethane
(30 mL) and saturated sodium hydrogen carbonate solution (30 mL).
The aqueous layer was washed with dichloromethane (2ꢂ30 mL)
and the combined organic layers washed with brine (90 mL), dried
(MgSO4), filtered and concentrated in vacuo. The crude material was
then purified by column chromatography, eluting with ethyl acetate
to give the title compound as a colourless oil (304 mg, 78%).
nmax (film) cmꢀ1 3234 (NeH), 2972 (CeH), 2927 (CeH), 1783
(C]O), 1729 (C]O), 1638 (NeH bend) and 1583 (Ar C]C); dH
(300 MHz, CDCl3) 7.47e7.42 (2H, m, ArH), 7.40e7.31 (3H, m, ArH),
5.34 (1H, d, AB system, JAB 12.3, CHAHBPh), 5.27 (1H, d, AB system,
JBA 12.3, CHAHBPh), 4.56 (1H, d, J 9.9, N(1)H), 3.71 (1H, app tquin, J
9.7, 6.5, C(5)H), 2.75 (1H, dd, ABX system, JAB 16.9, JAX 6.7, C(4)HAHB),
2.37 (1H, dd, ABX system, JBA 16.9, JBX 9.7, C(4)HAHB) and 1.31 (3H, d,
J 6.4, C(5)HCH3); dC (100 MHz, CDCl3) 172.1 (C(3)O), 150.0 (N(2)C(O)
O), 135.1 (CAripso), 128.7 (CAr), 128.6 (CAr), 128.5 (CAr), 68.6
(CH2Ph), 50.9 (C(5)H), 41.9 (C(4)H2) and 18.4 (C(5)HCH3); m/z (CI)
257.0 (100, MþHþ); HRMS (ESIþ) C12H14N2NaO3 requires 257.0902,
found 257.0910 (þ3.2 ppm).
45
To a solution of (RS)-tert-butyl 2-benzoyl-5-methyl-3-oxopyr-
azolidine-1-carboxylate 43 (457 mg, 1.50 mmol) in dichloro-
methane (5 mL) was added trifluoroacetic acid (0.600 mL,
8.10 mmol) and the resulting solution stirred overnight at rt before
being concentrated in vacuo. The resulting material was partitioned
between dichloromethane (40 mL) and saturated sodium hydrogen
carbonate solution (40 mL). The aqueous layer was washed with
dichloromethane (2ꢂ40 mL) and the combined organic layers
washed with brine (100 mL), dried (MgSO4), filtered and concen-
trated in vacuo to give the title compound as a clear yellow oil
(263 mg, 86%).
nmax (film) cmꢀ1 3224 (NeH), 3061 (AreH), 3029 (AreH), 2974
(CeH), 2931 (CeH), 2873 (NeCeH), 1757 (C]O), 1672 (C]O), 1631
(NeH bend), 1600 (Ar C]C) and 1579 (Ar C]C); dH (400 MHz,
CDCl3) 7.65 (2H, dd, J 8.3, 1.3, ArHortho), 7.54 (1H, app tt, J 7.5, 1.3,
ArHpara), 7.45e7.39 (2H, m, ArHmeta), 5.19 (1H, d, J 8.3, N(1)H), 3.84
(1H, app tquin, J 9.1, 6.4C(5)H), 2.85 (1H, dd, ABX system, JAB 17.1, JAX
6.8, C(4)HAHB), 2.50 (1H, dd, ABX system, JBA 17.1, JBX 9.5, C(4)HAHB)
and 1.40 (3H, d, J 6.3, C(5)HCH3); dC (100 MHz, CDCl3) 171.9 (C(3)O),
166.7 (C(O)Ph), 133.1 (CAripso), 132.4 (CAr), 129.4 (CAr), 128.0 (CAr),
50.2 (C(5)H), 42.1 (C(4)H2) and 18.8 (C(5)HCH3); m/z (CI) 205.1 (100,
MþHþ); HRMS (CI) C11H13N2O2 requires 205.0977, found 205.0978
(þ0.5 ppm).
4.6.21. (RS)-1-Benzyl 2-tert-butyl 3-methyl-5-oxopyrazolidine-1,2-
dicarboxylate 44.
4.6.23. (RS)-1-Benzyl 2-tert-butyl 5-oxo-3-phenylpyrazolidine-1,2-
dicarboxylate 49.
O
O
OBn
N
Me
N
OBn
N
Ph
N
O
Boc
O
Boc
44
49
(RS)-tert-Butyl 5-methyl-3-oxopyrazolidine-1-carboxylate 23
(1.01 g, 5.04 mmol), sodium hydride (220 mg, 5.50 mmol) and
benzyl chloroformate (0.75 mL, 5.25 mmol) were combined
according to general procedure B. The crude material was then
(RS)-1-Benzyl 2-tert-butyl 5-oxo-3-phenylpyrazolidine-1,2-
dicarboxylate 25 (3.15 g, 12.1 mmol), sodium hydride (530 mg,

E. Gould et al. / Tetrahedron 66 (2010) 8992e9008
9005
13.3 mmol) and benzyl chloroformate (1.81 mL, 12.7 mmol) were
combined according to general procedure B. The resulting material
was taken up in toluene (40 mL) and refluxed for 4 h before con-
centration in vacuo. The crude material was then purified by col-
umn chromatography, eluting with 15 then 25% ethyl acetate in
petrol to give the title compound as a clear yellow oil, which be-
came a colourless solid on trituration with petrol (1.83 g, 38%).
nmax (KBr disc) cmꢀ1 3064 (AreH), 3025 (AreH), 2982 (CeH),
1795 (C]O), 1733 (2ꢂC]O) and 1560 (Ar C]C); mp 112e114 ꢁC; dN
(CDCl3) 169 (N(2)CO2Bn), 133 (N(1)Boc); dH (500 MHz, CDCl3)
7.44e7.28 (10H, m, ArH), 5.70 (1H, d, J 8.6, C(5)H), 5.36 (1H, d, AB
system, JAB 12.3, CHAHBPh), 5.30 (1H, d, AB system, JBA 12.3,
CHAHBPh), 3.35 (1H, dd, J 17.2, 8.6, C(4)HAHB), 2.79 (1H, d, J 17.2, C(4)
HAHB) and 1.43 (9H, s, C(CH3)3); dC (100 MHz, CDCl3) 169.2 (C(3)O),
155.8 (N(1)C(O)O),149.2 (N(2)C(O)O),138.4 (CAripso), 134.9 (CAripso),
129.1 (CAr), 128.7 (CAr), 128.6 (CAr), 128.4 (CAr), 128.2 (CAr), 125.6
(CAr), 84.1 (C(CH3)3), 69.0 (CH2Ph), 59.7 (C(5)H), 40.1 (C(4)H2) and
28.0 (C(CH3)3); m/z HRMS (ESIþ) C22H24N2NaO5 requires 419.1577,
found 419.1585 (þ1.8 ppm).
hydride (107 mg, 2.68 mmol) and benzyl chloroformate (0.400 mL,
2.55 mmol) were combined according to general procedure B with
a modified work-up. In this case, the reaction was quenched with
water (2 mL) and concentrated in vacuo. The resulting material was
taken up in toluene (20 mL) and refluxed for 3 h before being
cooled, filtered and concentrated in vacuo to give crude product
(930 mg) as a yellow oil. Product was used without further purifi-
cation. An analytical sample was taken and purified by column
chromatography, eluting with 10% ethyl acetate in petrol to give the
title compound as a colourless solid.
nmax (KBr disc) cmꢀ1 3028 (CeH), 2984 (CeH), 1790 (C]O)
and 1748 (C]O); mp 65e67 ꢁC; dF (282 MHz, CDCl3) ꢀ78.8 (3F,
d, J 7.2, CF3); dH (300 MHz, CDCl3) 7.43e7.32 (5H, m, ArH), 5.35
(1H, d, AB system, JAB 12.3, CHAHBPh), 5.30 (1H, d, AB system, JBA
12.3, CHAHBPh), 4.42 (1H, dqd, J 9.5, 7.2, 1.3, C(5)H), 3.14 (1H, dd,
J 18.2, 9.5, C(4)HAHB), 2.77 (1H, d, J 18.2, 1.3, C(4)HAHB) and 1.38
(9H, s, C(CH3)3); dC (100 MHz, CDCl3) 167.1 (C(3)O), 154.3 (N(1)C
(O)O), 149.9 (N(2)C(O)O), 134.7 (CAripso), 128.8 (CAr), 128.7 (CAr),
128.5 (CAr), 123.8 (q, J 281, CF3), 85.4 (C(CH3)3), 69.4 (CH2Ph),
56.2 (q, J 33.9, C(5)H), 32.2 (C(4)H2) and 27.9 (C(CH3)3); m/z
HRMS (ESIþ) C17H23F3N3O5 requires 406.1584, found 406.1588
(þ0.9 ppm).
4.6.24. (RS)-Benzyl 5-oxo-3-phenylpyrazolidine-1-carboxylate 51.
O
A solution of crude (RS)-1-benzyl-2-tert-butyl 5-oxo-3-(tri-
fluoromethyl)pyrazolidine-1,2-dicarboxylate
50
(890
mg,
OBn
N
2.29 mmol) was stirred in a 1:2 mixture of trifluoroacetic acid/
dichloromethane (15 mL) overnight at rt before being concen-
trated in vacuo. The resulting material was partitioned between
dichloromethane (100 mL) and saturated sodium hydrogen car-
bonate solution (100 mL). The aqueous layer was washed with
dichloromethane (2ꢂ100 mL) and the combined organic layers
washed with brine (150 mL), dried (MgSO4), filtered and con-
centrated in vacuo. The crude material was purified by recrys-
tallisation from diethyl ether and the minimum quantity of
dichloromethane to give the title compound as colourless nee-
dles (281 mg, 42%).
Ph
N
H
O
51
To a solution of (RS)-1-benzyl-2-tert-butyl 5-oxo-3-phenyl-
pyrazolidine-1,2-dicarboxylate 49 (1.60 g, 4.04 mmol) in dichloro-
methane (10 mL) was added trifluoroacetic acid (1.50 mL,
19.7 mmol) and the resulting solution stirred overnight at rt before
being concentrated in vacuo. The resulting material was partitioned
between dichloromethane (60 mL) and saturated sodium hydrogen
carbonate solution (60 mL). The aqueous layer was washed with
dichloromethane (2ꢂ60 mL) and the combined organic layers
washed with brine (100 mL), dried (MgSO4), filtered and concen-
trated in vacuo. The crude material was purified by recrystallisation
from petrol and the minimum quantity of dichloromethane to give
the title compound as colourless needles (816 mg, 68%).
C17H16N2O3 requires C, 68.9; H 5.4; N, 9.5%; found C 68.6; H, 5.2;
N, 9.5%; nmax (KBr disc) cmꢀ1 3226 (NeH), 3058 (CeH), 3030 (CeH),
1739 (C]O), 1653 (NeH bend); mp 101e102 ꢁC; dN (CDCl3) 167 (N
(2)CO2Bn), 103 (N(1)H); dH (300 MHz, CDCl3) 7.49e7.43 (2H, m,
ArH), 7.41e7.31 (8H, m, ArH), 5.37 (1H, d, AB system, JAB 12.2,
CHAHBPh), 5.31 (1H, d, AB system, JBA 12.2, CHAHBPh), 4.94 (1H, br s,
N(1)H), 4.75 (1H, app t, J 8.2C(5)H), 3.05 (1H, dd, ABX system, JAB
17.0, JAX 7.3, C(4)HAHB) and 2.93 (1H, dd, ABX system, JBA 17.0, JBX
9.8, C(4)HAHB); dC (75 MHz, CDCl3) 170.7 (C(3)O), 149.8 (N(2)C(O)O),
137.3 (CAripso), 135.1 (CAripso), 129.2 (CAr), 128.9 (CAr), 128.8 (CAr),
128.7 (CAr), 128.6 (CAr), 126.7 (CAr), 68.7 (CH2Ph), 57.9 (C(5)H) and
41.0 (C(4)H2); m/z HRMS (ESIþ) C17H17N2O3 requires 297.1234,
found 297.1237 (þ1.1 ppm).
nmax (film) cmꢀ1 3261 (NeH), 3014 (AreH), 2935 (CeH), 1760
(C]O) and 1714 (C]O); mp 90e92 ꢁC; dF (282 MHz, CDCl3) ꢀ78.5
(3F, d, J 7.6, CF3); dH (300 MHz, CDCl3) 7.44e7.33 (5H, m, ArH), 5.34
(1H, d, AB system, JAB 12.3, CHAHBPh), 5.32 (1H, d, J 7.9, N(1)H), 5.30
(1H, d, AB system, JBA 12.3, CHAHBPh), 4.13e3.98 (1H, m, C(5)H),
3.07 (1H, dd, ABX system, JAB 18.1, JAX 9.6, C(4)HAHB) and 2.84 (1H,
dd, ABX system, JBA 18.1, JBX 4.1, C(4)HAHB); dC (75 MHz, CDCl3) 168.3
(C(3)O), 149.5 (N(2)C(O)O), 135.9 (CAripso), 128.8 (CAr), 128.4 (CAr),
124.1 (q, J 280, CF3), 68.9 (CH2Ph), 53.4 (q, J 32.6, C(5)H) and 33.1 (C
(4)H2); m/z HRMS (ESIþ) C12H15F3N3O3 requires 306.1090, found
306.1066 (þ2.0 ppm).
4.6.26. exo-3-Phenylbicyclo[2.2.1]hept-5-ene-2-carboxaldehyde 47
and endo-3-phenylbicyclo[2.2.1]hept-5-ene-2-carboxaldehyde 48.
CHO
+
Ph
CHO
Ph
exo-47
endo-48
4.6.25. (RS)-Benzyl 5-oxo-3-(trifluoromethyl)pyrazolidine-1-carbox-
ylate 52.
trans-Cinnamaldehyde (0.120 mL, 0.950 mmol) and catalyst 51
(56 mg, 0.190 mmol) were combined according to general pro-
cedure D. The crude material was then purified by column chro-
matography, eluting with 5% diethyl ether in petrol to yield the title
compounds as a 62:38 mixture of diastereomers, with spectro-
scopic data in accordance with the literature (168 mg, 89%).12
Compound exo-47: dH (300 MHz, CDCl3) 9.93 (1H, d, J 2.1, CHO),
7.34e7.13 (5H, m, ArH), 6.34 (1H, dd, J 5.8, 3.6, CHA]CHB), 6.08 (1H,
dd, J 5.8, 3.3, CHA]CHB), 3.73 (1H, dd, J 5.2, 3.4, CHPh), 3.24e3.21
O
OBn
N
F3C
N
H
O
52
(RS)-1-Benzyl
2-tert-butyl
5-oxo-3-(trifluoromethyl)pyr-
azolidine-1,2-dicarboxylate 26 (619 mg, 2.43 mmol), sodium

9006
E. Gould et al. / Tetrahedron 66 (2010) 8992e9008
(2H, m, CHCH2), 2.60 (1H, app dt, J 5.2, 2.1, CHCHO) and 1.62e1.53
(2H, m, CH2).
4.6.29. exo-Ethyl 3-formylbicyclo[2.2.1]hept-5-ene-2-carboxaldehyde
57 and endo-ethyl 3-formylbicyclo[2.2.1]hept-5-ene-2-carboxalde-
hyde 58.
Compound endo-48: dH (300 MHz, CDCl3) 9.60 (1H, d, J 2.2, CHO),
7.34e7.13 (5H, m, ArH), 6.42 (1H, dd, J 5.7, 3.2, CHA]CHB), 6.18 (1H,
dd, J 5.7, 2.8, CHA]CHB), 3.36e3.32 (1H, m, CHCH2), 3.14e3.12 (1H,
m, CHCH2), 3.09 (1H, dd, J 4.8, 1.5, CHPh), 2.98 (1H, ddd, J 4.8, 3.4,
2.2, CHCHO), 1.84e1.79 (1H, m, CHAHB) and 1.65e1.63 (1H, m,
CHAHB).
CHO
+
CO2Et
CHO
CO2Et
exo-57
endo-58
4.6.27. exo-3-(4-Nitrophenyl)bicyclo[2.2.1]hept-5-ene-2-carbox-
aldehyde 53 and endo-3-(4-nitrophenyl)bicyclo[2.2.1]hept-5-ene-2-
carboxaldehyde 54.
Ethyl trans-4-oxo-2-butenoate (0.120 mL, 0.950 mmol) and
catalyst 51 (56 mg, 0.190 mmol) were combined according to
general procedure D. The crude material was then purified by col-
umn chromatography, eluting with 15% diethyl ether in petrol to
yield the product as a 50:50 mixture of diastereomers with spec-
troscopic data in accordance with the literature (147 mg, 80%).10,35
Compound exo-57: dH (300 MHz, CDCl3) 9.84 (1H, d, J 0.9, CHO),
6.30 (1H, dd, J 5.6, 3.2, CHA]CHB), 6.13 (1H, dd, J 5.6, 2.8, CHA]CHB),
4.11 (2H, d, J 7.1, OCH2), 3.42 (1H, dd, J 4.4, 3.7, CHCO2), 3.29 (1H, br s,
CHCH2), 3.20 (1H, br s CHCH2), 2.83e2.81 (1H, m, CHCHO),
1.47e1.42 (1H, m, CHACHB), 1.36e1.11 (1H, m, CHACHB) and 1.24 (3H,
t, J 7.1, CH3).
CHO
NO2
+
CHO
NO2
exo-53
endo-54
Compound endo-58: dH 9.55 (1H, d, J 1.2, CHO), 6.26 (1H, dd, J 5.7,
3.3, CHA]CHB), 6.09 (1H, dd, J 5.7, 2.6, CHA]CHB), 4.16 (2H, q, J 7.1,
OCH2), 3.39e3.33 (2H, m, CHCO2 and CHCH2), 3.20 (1H, br s CHCH2),
2.70 (1H, ddd, J 4.3, 1.2, 0.5, CHCHO), 1.69e1.65 (1H, m, CHACHB),
1.53e1.48 (1H, m, CHACHB) and 1.27 (3H, t, J 7.1, CH3).
4-Nitrocinnamaldehyde (168 mg, predominantly trans-,
0.950 mmol) and catalyst 51 (56 mg, 0.190 mmol) were combined
according to general procedure D. The crude material was then
purified by column chromatography, eluting with 10% diethyl
ether in petrol to yield the product as a 65:35 mixture of di-
astereomers with spectroscopic data in accordance with the lit-
erature (169 mg, 73%).14
Compound exo-53: dH (300 MHz, CDCl3) 9.92 (1H, d, J 1.7, CHO),
8.13e8.08 (2H, m, ArH), 7.32e7.27 (2H, m, ArH), 6.41 (1H, dd, J 5.7,
3.2, CHA]CHB), 6.05 (1H, dd, J 5.7, 2.8, CHA]CHB), 3.88 (1H, dd, J
5.0, 3.5, CHAr), 3.33 (1H, br s, CHCH2), 3.25 (1H, br s, CHCH2), 2.62
(1H, br d, J 5.0, CHCHO) and 1.62e1.60 (2H, m, CH2).
Compound endo-54: dH (300 MHz, CDCl3) 9.64 (1H, d, J 1.7, CHO),
8.19e8.14 (2H, m, ArH), 7.45e7.40 (2H, m, ArH), 6.44 (1H, dd, J 5.9,
3.6, CHA]CHB), 6.20 (1H, dd, J 5.7, 2.8, CHA]CHB), 3.43 (1H, br s,
CHCH2), 3.22e3.18 (2H, m, CHAr and CHCH2), 2.95 (1H, ddd, J 5.0,
3.5, 1.7, CHCHO) and 1.78e1.68 (2H, m, CH2).
4.6.30. (R)-2-((R)-2-Methoxy-2-phenylacetyl)-5-phenylpyrazolidin-
3-one 59 and (S)-2-((R)-2-Methoxy-2-phenylacetyl)-5-phenylpyra-
zolidin-3-one 60.
O
O
OMe
OMe
Ph
+
Ph
N
N
Ph
Ph
N
H
N
H
O
O
59
60
N-(3-Dimethylaminopropyl)-N0-ethylcarbodiimide hydrochlo-
ride (14.4 g, 75.3 mmol), 1-hydroxybenzotriazole (10.2 g,
75.3 mmol) and (R)-O-methyl mandelic acid (12.5 g, 75.3 mmol)
were combined in DMF (300 mL) and stirred at room temperature
for 15 min. (RS)-5-Phenylpyrazolidin-3-one 21 (12.2 g, 75.3 mmol)
was then added and the resultant solution stirred at rt overnight.
The reaction mixture was then concentrated in vacuo and the re-
sultant residue taken up in dichloromethane (500 mL) and washed
4.6.28. exo-3-Propylbicyclo[2.2.1]hept-5-ene-2-carboxaldehyde 55
and endo-3-propylbicyclo[2.2.1]hept-5-ene-2-carboxaldehyde 56.
CHO
+
n-Pr
CHO
n-Pr
with 0.1
M
hydrochloric acid solution (2ꢂ500 mL), water
exo-55
endo-56
(2ꢂ500 mL), dried (MgSO4), filtered and concentrated in vacuo. The
crude material was purified by column chromatography, eluting
with 35% ethyl acetate in petrol to give first the title compound 60
as an amorphous yellow solid (1.17 g, 5%) and then title compound
59 as a cream solid (1.60 g, 7%). Mixed fractions (10.9 g) were also
collected and subjected again to column chromatography, eluting
with 25% ethyl acetate in petrol to give more compound 60
(830 mg, 4%), compound 59 (3.76 g, 16%) and 5.01 g of mixed
fractions (12.4 g of compounds 59 and 60 over all fractions, 53%
combined yield).
trans-2-Hexen-1-al (0.110 mL, 0.950 mmol) and catalyst 51
(56 mg, 0.190 mmol) were combined according to general pro-
cedure D. The crude material was then purified by column chro-
matography, eluting with 2.5% ethyl acetate in petrol to yield the
product as a 58:42 mixture of diastereomers with spectroscopic
data in accordance with the literature (117 mg, 75%).2,34
Compound exo-55: dH (300 MHz, CDCl3) 9.78 (1H, d, J 2.8, CHO),
6.21 (1H, dd, J 5.7, 3.1, CHA]CHB), 6.13 (1H, dd, J 5.7, 2.9, CHA]CHB),
3.01 (1H, br s, CHCH2), 2.87 (1H, br s CHCH2), 2.28 (1H, tdd, J 7.6, 4.7,
3.1, CHCH2CH2), 1.76 (1H, ddd, J 4.7, 2.8, 1.7, CHCHO), 1.77e1.06 (6H,
m, CHCH2CH, CH2CH2) and 0.88 (3H, t, J 7.2, CH3).
Compound endo-56: dH 9.37 (1H, d, J 3.4, CHO), 6.27 (1H, dd, J 5.7,
3.2, CHA]CHB), 6.06 (1H, dd, J 5.7, 2.8, CHA]CHB), 3.12 (1H, br s,
CHCH2), 2.66 (1H, br s, CHCH2), 2.38 (1H, dt, J 4.4, 3.4, CHCHO), 1.72
(1H, m, CHCH2CH2), 1.77e1.06 (6H, m, CHCH2CH, CH2CH2) and 0.88
(3H, t, J 7.2, CH3).
Compound 59 (lower spot): [
a
]
20 ꢀ1.5 (c 1.0, dichloromethane);
D
nmax (KBr disc) cmꢀ1 3231 (NeH), 3025 (AreH), 2985 (CeH), 2934
(CeH), 1744 (C]O) and 1701 (C]O); mp 140e144 ꢁC; dN (CDCl3)
190 (N(2)C(O)), 104 (N(1)H); dH (400 MHz, CDCl3) 7.52 (2H, dd, J 6.6,
3.2, ArH), 7.38e7.34 (3H, m, ArH), 7.31e7.27 (3H, m, ArH), 7.23e7.21
(2H, m, ArH), 5.89 (1H, s, CHOCH3), 4.71 (1H, dd, J 9.3, 7.5, C(5)H),
3.40 (3H, s, OCH3), 3.07 (1H, dd, ABX system, JAB 17.1, JAX 7.5, C(4)

E. Gould et al. / Tetrahedron 66 (2010) 8992e9008
9007
HAHB) and 2.82 (1H, dd, ABX system, JBA 17.1, JBX 9.3, C(4)HAHB); dC
(75 MHz, CDCl3) 169.9 (N(2)C(O)), 167.0 (N(1)C(O)), 138.0 (CAripso),
135.4 (CAripso), 129.2 (CAr), 129.1 (CAr), 128.8 (CAr), 128.7 (CAr),
126.5 (CAr), 81.6 (CHOCH3), 58.1 (C(5)H), 57.4 (CHOCH3) and 41.9 (C
(4)H2); m/z HRMS (ESIþ) C18H19N2O3 requires 311.1390, found
0.46 cmꢂ25 cm), hexane/iso-propanol¼93:7, 1.0 mL/min, 220 nm,
18.8 min (minor). Absolute configuration determined by compari-
son of the optical rotation to literature value.36
20
20
[
a
]
þ168 (c 0.9, dichloromethane), lit. [
a
]
ꢀ163 ((S)-enan-
D
D
tiomer, c 0.90, dichloromethane);36 mp 106e109 ꢁC; dH (400 MHz,
CDC13) 7.48 (1H, br s, N(2)H), 7.40e7.37 (2H, m, ArH), 7.35e7.20
(8H, m, ArH), 4.15 (1H, app t, J 8.6, C(5)H), 3.95 (1H, d, AB system, JAB
12.9, CHAHBPh), 3.56 (1H, d, AB system, JBA 12.9, CHAHBPh), 2.90 (1H,
dd, ABX system, JAB 16.8, JAX 8.3, C(4)HAHB) and 2.47 (1H, dd, ABX
system, JBA 16.8, JBX 8.9, C(4)HAHB).
311.1393 (þ0.9 ppm).
20
Compound 60 (upper spot): [
a]
ꢀ62.6 (c 0.5, dichloro-
D
methane); nmax (KBr disc) cmꢀ1 3246 (NeH), 3064 (AreH), 3025
(AreH), 2927 (CeH), 1750 (C]O) and 1701 (C]O); mp 43e46 ꢁC;
dN (CDCl3) 192 (N(2)C(O)), 104 (N(1)H); dH (300 MHz, CDCl3)
7.55e7.53 (2H, m, ArH), 7.41e7.33 (8H, m, ArH), 5.87 (1H, s,
CHOCH3), 4.61 (1H, app dt, J 10.0, 7.4, C(5)H), 3.40 (3H, s, OCH3),
3.00 (1H, dd, ABX system, JAB 17.1, JAX 7.6, C(4)HAHB) and 2.93 (1H,
dd, ABX system, JBA 17.1, JBX 10.0, C(4)HAHB); dC (75 MHz, CDCl3)
170.0 (N(2)C(O)), 167.2 (N(1)C(O)), 137.5 (CAripso), 135.7 (CAripso),
129.2 (CAr), 128.9 (CAr), 128.8 (CAr), 126.7 (CAr), 81.7 (CHOCH3),
57.7 (C(5)H), 57.4 (CHOCH3) and 41.7 (C(4)H2); m/z HRMS (ESIþ)
C18H19N2O3 requires 311.1390, found 311.1396 (þ1.9 ppm).
4.6.33. (R)-Benzyl 5-oxo-3-phenylpyrazolidine-1-carboxylate (R)-51.
O
OBn
N
Ph
N
H
O
(R)-51
4.6.31. (R)-5-Phenylpyrazolidin-3-one (R)-21.
Synthesised from (R)-21 by identical means to those described
above. [
a
]
20 þ22.4 (c 0.25, dichloromethane); mp 123e125 ꢁC.
D
O
Acknowledgements
NH
Ph
N
H
The authors would like to thank the Royal Society for a Univer-
sity Research Fellowship (A.D.S.) and MSD (Case award to E.G.). The
EPSRC mass spectrometry facility is also acknowledged.
(R)-21
(S)-1-((R)-2-Hydroxy-2-phenylacetyl)-5-phenylpyrazolidin-3-
one 59 (4.62 g, 14.9 mmol) was suspended in 6 M aqueous hydro-
chloric acid solution (40 mL) and heated to reflux for 30 min. The
reaction mixture was basified with 2 M sodium hydroxide solution
(150 mL) and extracted with dichloromethane (3ꢂ150 mL). The
combined organic layers were washed with brine (300 mL), dried
(MgSO4), filtered and concentrated in vacuo to give a small quantity
of the title compound (191 mg). Hence, the aqueous phase was
neutralised to pH 7 with 37% hydrochloric acid solution and again
extracted with dichloromethane (3ꢂ150 mL). The combined or-
ganic layers were washed with brine (300 mL), dried (MgSO4), fil-
tered and concentrated in vacuo to give a further 1.20 g of the title
Supplementary data
Spectroscopic and HPLC data is available for all products. Crys-
tallographic data (excluding structure factors) for compounds 21,
27, 34, 40 and 43 have been deposited with the Cambridge Crys-
tallographic Data Centre and allocated the deposition numbers
CCDC 772907, 772908, 772909, 772910 and 772911, respectively.
Copies of the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: þ44 (0)1223
336033 or e-mail: deposit@ccdc.cam.ac.uk). Supplementary data
associated with this article can be found in online version at
doi:10.1016/j.tet.2010.09.021. These data include MOL files and
InChiKeys of the most important compounds described in this
article.
compound as a colourless solid, with spectroscopic data identical to
20
(RS)-21 (1.39 g, 57%). [
a
]
ꢀ13.0 (c 1.0, methanol); mp 94e96 ꢁC.
D
4.6.32. (S)-1-Benzyl-5-phenylpyrazolidin-3-one (S)-61.
References and notes
O
€
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(S)-61
To a solution of (S)-5-phenylpyrazolidin-3-one (R)-21 (42 mg,
0.259 mmol) in ethanol (1 mL) was added benzaldehyde (0.1 mL,
1.03 mmol) and the resulting mixture left to stir at room temper-
ature overnight. Sodium borohydride (49 mg, 1.30 mmol) was then
added and the mixture stirred for a further hour. The reaction
mixture was partitioned between water (5 mL), saturated sodium
hydrogen carbonate solution (5 mL) and dichloromethane (10 mL).
The resulting aqueous layer was extracted with further dichloro-
methane (3ꢂ10 mL). The combined organic layers were washed
with brine (30 mL), dried (MgSO4), filtered and concentrated in
vacuo. The crude material was purified by column chromatography,
eluting with 40% ethyl acetate in petrol to give the title compound
as a colourless solid with 1H NMR in accordance with the litera-
ture30,36 (33 mg, 51%). The compound was determined to have an
enantiomeric excess of 95% by HPLC (Daicel Chiralpak AD-H
10. Nakano, K.; Ishihara, K. J. Am. Chem. Soc. 2005, 127, 10504e10505.
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ꢀ
€
ꢀ
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albeit with modest activity in MeOH (t1/2 w8 h) and preferential endo selec-
tivity (exo:endo ratio 14:86).
27. The functionalisation of 49 and 51 was confirmed by 15N NMR, see
Supplementary data.
28. Catalyst 51 was found to return only starting material in the reaction of cin-
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no change in reactivity. Catalyst 34 also returned only starting material using
both cyclohexadiene and isoprene.
29. For theoretically determined 15N NMR chemical shifts, see Supplementary data.
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