3,3-Dialkyl- and 3-alkyl-3-benzyl-substituted 2-pyrrolidinones: A new class of anticonvulsant agents

Article abstract of DOI:10.1021/jm9600196

A series of 3,3-dialkyl- and 3-alkyl-3-benzyl-substituted 2- pyrrolidinones (lactams) have been prepared and evaluated for their anticonvulsant activities. In the pentylenetetrazole mouse seizure model, 3,3-diethyl lactam 7c and 3-benzyl-3-ethyl lactam 7j

Full text of DOI:10.1021/jm9600196

1898
J . Med. Chem. 1996, 39, 1898-1906
3,3-Dia lk yl- a n d 3-Alk yl-3-Ben zyl-Su bstitu ted 2-P yr r olid in on es: A New Cla ss of
An ticon vu lsa n t Agen ts
P. Amruta Reddy,† Bonnie C. H. Hsiang,† Tammy N. Latifi,† Matthew W. Hill,‡ Karen E. Woodward,§
Steven M. Rothman,‡,|, J ames A. Ferrendelli,§ and Douglas F. Covey*,†
Departments of Molecular Biology and Pharmacology, Anatomy and Neurobiology, Neurology and Neurosurgery,
Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, and
Division of Pediatric Neurology, St. Louis Children’s Hospital, One Children’s Place, St. Louis, Missouri 63110, and
Department of Neurology, University of Texas Health Science Center, 6431 Fannin Street, Houston, Texas 77030
Received J anuary 9, 1996X
A series of 3,3-dialkyl- and 3-alkyl-3-benzyl-substituted 2-pyrrolidinones (lactams) have been
prepared and evaluated for their anticonvulsant activities. In the pentylenetetrazole mouse
seizure model, 3,3-diethyl lactam 7c and 3-benzyl-3-ethyl lactam 7j are the most effective
anticonvulsants (ED50 ) 46 and 42 mg/kg, respectively) and have protective index (PI ) TD50/
ED50) values of 5.65 and 3.00, respectively. These protective index values compare favorably
to those of the clinically used antiepileptic drugs ethosuximide (ED50 ) 161 mg/kg), phenobar-
bital (ED50 ) 22 mg/kg), and valproic acid (ED50 ) 133 mg/kg), which have PI values of 2.35,
4.00, and 2.12, respectively. The benzyl compounds [3-substituents are Bn, H (7h ); Bn, Me
(7i); and Bn, Et (7j)] are also very effective anticonvulsants against seizures induced by maximal
electroshock (ED50 ) 41, 55, and 74 mg/kg, respectively) and have PI values of 3.51, 3.04, and
1.70, respectively. The corresponding PI values for phenobarbital and valproic acid are 1.37
and 5.18, respectively. As a class of anticonvulsants, the 3,3-disubstituted 2-pyrrolidinones
have a broad spectrum of action and may be useful for the treatment of human epilepsies.
In tr od u ction
picrotoxin on GABAA receptor function.9,10 The dual
modulation of GABA-mediated chloride flux observed
for some compounds has led to the hypothesis that
interactions occur at two different sites on the GABAA
receptor, one being identical to the picrotoxin or TBPS
recognition site and the other an allosterically linked
lactone site.11 Consistent with this hypothesis, prelimi-
nary studies have shown that the potentiating effects
of TBLs on GABA-mediated currents are retained by a
picrotoxin-insensitive form of a rat R1â2γ2 GABAA re-
ceptor.12
The neuroactivities of dialkyl-substituted 2-pyrroli-
dinones, the lactam analogues of the GBLS, have not
been examined extensively. In part, this may be at-
tributable to the lack of potent neuroactivity displayed
by 3,3-dimethyl-2-pyrrolidinone and 4-ethyl-4-methyl-
2-pyrrolidinone in our preliminary evaluations of this
class of compounds.3 The lack of literature reports of
general methods for the preparation of 3,3-disubstituted
2-pyrrolidinones from suitable starting materials also
curtailed our earlier efforts to evaluate these com-
pounds. We now report general methods for the syn-
thesis of these compounds, their anticonvulsant activi-
ties in two different animal seizure models, and
preliminary studies of their pharmacological effects on
GABAA receptor function.
The neuroactive alkyl-substituted γ-butyrolactones
(GBLs) have been reported to possess either convulsant
or anticonvulsant properties depending upon the sub-
stitution pattern.1 While the R-substituted GBLs with
small alkyl groups are anticonvulsants capable of
protecting mice against pentylenetetrazole-induced sei-
zures,1,2 the corresponding â-substituted compounds are
convulsants.3 Structure-activity studies of the effect
of R-alkyl substituent size on neuroactivity have shown
that the GBLs containing three or four carbon atoms
in the R-alkyl group (branched alkyl or alkyl groups with
one or two carbon atoms each or spiroalkyl groups) are
anticonvulsants, whereas the compounds containing
more than five carbon atoms in the R-alkyl group are
convulsants.4 Substitution of sulfur for the ring oxygen
atom yields γ-thiobutyrolactones (TBLs). The TBLs
have enhanced potencies, though their convulsant or
anticonvulsant activity remains dependent on the alkyl
substitution pattern.4b,5 Finally, it was shown that
alkyl-substituted cyclopentanones (i.e., compounds lack-
ing a ring heteroatom) display similar structure-
activity relationships for anticonvulsant and convulsant
activity.6
The pharmacological actions of these compounds are
believed due, at least in part, to complex interactions
involving modulation of the picrotoxin binding site of
the γ-aminobutyric acid type A (GABAA) receptor-
chloride ionophore complex. Thus, these compounds
inhibit the specific binding of [35S]-tert-butylbicyclophos-
phorothionate (TBPS),7,8 a radioligand specific for the
picrotoxin binding site, and modulate the actions of
Ch em istr y
Among the compounds listed in the Table 1, 2-pyrro-
lidinone (1) and 3-methyl-2-pyrrolidinone (2) are com-
mercially available. The published procedure for the
preparation of lactam 2 from N-(trimethylsilyl)-2-pyr-
rolidinone (3)13 was utilized for the preparation of the
known 3-ethyl-2-pyrrolidinone (4).14 Thus, compound
3 was alkylated with ethyl iodide in presence of lithium
diisopropylamide (LDA) in THF to give lactam 4 in 52%
yield.
† Department of Molecular Biology and Pharmacology.
‡ Department of Anatomy and Neurobiology.
§ Department of Neurology.
| Department of Neurology and Neurosurgery.
Division of Pediatric Neurology.
X Abstract published in Advance ACS Abstracts, April 1, 1996.
0022-2623/96/1839-1898$12.00/0 © 1996 American Chemical Society

3,3-Disubstituted 2-Pyrrolidinones
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 9 1899
Ta ble 1. Anticonvulsant activity, Neurotoxicity, and [35S]TBPS Binding Data for 2-Pyrrolidinone Derivativesa
anticonvulsant
b
potency: ED50 (mg/kg)
rotorod toxicity:
TD50c (mg/kg)
[
35S]TBPS displacement:
d
compd
R1
R2
PTZ
MES
IC50 (mM)
1
H
H
>900
>600
>900
435 ( 32
(0/6)e
>900
(2/6)
(0/6)
(0/6)
2
H
Me
Et
>750
(0/6)
>900
(3/6)
260
[219-320]
>600
(0/6)
622
[497-671]
260
215 ( 20
4
H
>750
(2/6)
>600
(2/6)
226
[164-305]
46
[30-63]
118
[69-192]
178
{3,300}
68
[49-90]
238
[119-383]
71
535
48.1 ( 1.8
32.4 ( 4.27
12.1 ( 0.99
5.81 ( 0.12
6.86 ( 0.55
3.26 ( 0.53
2.62 ( 0.17
12.1 ( 0.44
2.44 ( 0.17
0.85 ( 0.05
0.44 ( 0.06
[517-657]f
>600
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
Me
Me
Et
Me
Et
(0/6)
357
{175, 600}g
174
Et
[133-229]
220
{175, 300}
112
{10, 300}
112
[219-320]
307
Me
Me
Et
i-Pr
t-Bu
i-Pr
{175, 450}h
>300
(1/6)
207
[167-255]
307
{100, 450}
144
[125-168]
167
[77-158]
-(CH2)4-
H
Bn
Bn
Bn
41
[20-63]
55
[42-102]
74
[67-93]
[43-101]
63
[50-79]
42
[26-62]
Me
Et
[152-200]
126
[102-155]
a
For the TBPS binding experiments, compounds 7c and 7h -j were dissolved in DMSO. The final DMSO concentration in the incubations
did not exceed 2.5%, a concentration which had no effects on control TBPS binding. Other experimental details, including IC50 values for
TBPS and picrotoxinin, were as described previously.4 Dose at which 50% of the mice were protected from clonic seizures induced by
b
pentylenetetrazole or tonic hindlimb seizures induced by maximal electroshock. At least four groups of six mice each were tested to
obtain ED50 values. Complete experimental details for these evaluations have been described previously.4 c Dose at which 50% of the
d
mice failed the rotorod toxicity test. The methods were as described previously.4 Binding data for compounds 7a -j are presented as the
mean ( SEM of at least three experiments performed in triplicate. Values reported for compounds 1, 2, and 4 are the mean ( range from
duplicate experiments performed in triplicate. e Fractions in parentheses indicate number of mice protected/number of mice in group or
g
number of mice toxic/number of mice in group at the dose reported. f Numbers in brackets are the 95% fiducial limits. Numbers in
braces are the lowest dose tested at which all mice were unprotected and the lowest dose tested at which all mice were protected, respectively.
h
These values are given in place of 95% fiducial limits which could not be calculated from the data available. Italicized numbers in
braces are the lowest dose tested at which all mice were nontoxic and the lowest dose tested at which all mice were toxic, respectively.
These values are given in place of 95% fiducial limits which could not be calculated from the data available.
Sch em e 1
68%. The modest yields of cyano esters, especially in
the case of 6d (30%), are attributed to competing
R-bromination reactions. Thus, the alkylation reaction
of the ester 5d also gave methyl 2-bromo-2,3-dimeth-
ylbutanoate in 35% yield.15 The NaBH4 reduction of
nitriles 6 in THF-water (2:1, v/v) at 0 °C in the presence
of CoCl2‚6H2O,17 after 48 h of stirring at room temper-
ature,18 resulted in concomitant cyclization of the
intermediate amino esters to form lactams 7 in good
yields (56-81%). This method was utilized in the
synthesis of the lactams 7a -d and 7g-j, in which 7a ,19
7g,20 and 7h 13,21 are previously known compounds. The
above reaction sequence was not successful in the
synthesis of 7e and 7f due to the poor results obtained
in the bromoacetonitrile alkylation step.
Alternatively, esters 5e,f were alkylated with allyl
bromide at -78 °C with LDA as base in THF-HMPA
according to the procedure of MacPhee et al.22 to give
the olefinic esters 8e,f in 70 and 82% yield, respectively.
The olefinic esters 8e,f were treated with ozone at -78
°C in CH2Cl2 and the ozonides reduced with PPh3 for 4
h, resulting in the formation of the aldehydic esters 9e,f
(76-88% yield). Treatment of 9e,f with NH2OH‚HCl
in pyridine at 60 °C for 4 h afforded the oximes 10e,f
(86-92% yield) as the syn and anti mixtures. The
NaBH4 reduction of oximes 10e,f in MeOH at -30 °C
in the presence of NiCl2‚6H2O,23 after 1 h of stirring at
room temperature, afforded the amino esters which
The 2-pyrrolidinone derivatives 7a -j listed in Table
1 were synthesized by the routes outlined in Scheme 1.
Alkylation of esters 5 with bromoacetonitrile at -78 °C
with LDA as base in THF or THF-HMPA afforded
â-cyanoalkanoate esters 6 in yields ranging from 30 to

1900 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 9
Reddy et al.
without further purification were treated with t-BuOK
in THF24 for 16 h at room temperature to give the
lactams 7e,f in 57-77% yield.
P h a r m a cology
Compounds were tested for anticonvulsant activity in
mice against seizures induced by pentylenetetrazole
(PTZ) or maximal electroshock (MES), and neurotoxicity
in the animals was assessed by a rotorod test (Table 1).
Unsubstituted lactam 1 did not have anticonvulsant
activity, and it did not cause neurotoxicity at a dose as
high as 900 mg/kg. Monoalkyl-substituted lactams 2
and 4 had very weak anticonvulsant activities, and
lactam 4 was notably more neurotoxic than lactam 2.
For the dialkyl compounds, anticonvulsant potency
against PTZ-induced seizures was found to be depend-
ent on the size and branching of the 3-alkyl groups. For
compounds 7a , 7b, 7d , and 7e, which all contain a
methyl substituent, anticonvulsant potency increases in
the order 7a , 7b < 7e < 7d . For compounds 7b, 7c,
and 7f, which all contain an ethyl substituent, anticon-
vulsant potency increases in the order 7b < 7f < 7c.
Thus, in each series an increase in branching of a second
alkyl substituent initially increases and then decreases
potency. Maximal activity was observed for diethyl
compound 7c. The spiro compound 7g, which is a
constrained analog of 7c, is only as potent as compound
7b.
F igu r e 1. Concentration-response curves for the potentiation
of 3 µM GABA-mediated chloride currents in cultured hippo-
campal neurons by compounds 7c and 7j. Data points are the
mean ( SEM for at least four cells at each concentration
tested.
Ta ble 2. Antagonism of 2-Pyrrolidinone Derivative Induced
Potentiation of 3 µM GABA-Mediated Current by the Picrotoxin
Antagonist R-Isopropyl-R-methyl-γ-butyrolactone (R-IMGBL)
compd potentiation, %
response relative to current
Anticonvulsant potency against MES-induced sei-
zures by the dialkyl compounds also was found to be
dependent on the size and branching of the 3-alkyl
groups. An analysis similar to that used immediately
above indicates that in one series of compounds anti-
convulsant potency increases in the order 7a , 7b <
7d < 7e, and in the other series it increases in the order
7b < 7c < 7f. Hence, in this animal seizure model
anticonvulsant potency continuously increases with
branching of the second alkyl substituent. Maximal
activity was observed for compounds 7e and 7f.
Compounds 7h -j all contain a benzyl group in place
of a 3-alkyl group. Increasing the size of the other C-3
substituent increases the anticonvulsant potency of the
compounds (7h < 7i < 7j) against PTZ-induced seizures,
but decreases the anticonvulsant potency of the com-
pounds (7h > 7i > 7j) against MES-induced seizures.
Compound 7j, which is the most potent of the benzyl-
substituted lactams in the PTZ seizure model, has a
potency equal to that of dialkyl lactam 7c against PTZ-
induced seizures. By contrast, all three compounds in
the benzyl series are more potent than compounds in
the dialkyl series at blocking MES-induced seizures,
with compound 7h being 4 times more potent than
compound 7c.
Results from the rotorod toxicity evaluations demon-
strate that compounds 7h and 7i in the benzyl series
have the best protective index (PI ) TD50/ED50) for
blocking MES-induced seizures (PI ) 3.51 and 3.04,
respectively), whereas compound 7c in the dialkyl series
has the best protective index (PI ) 5.65) for blocking
PTZ-induced seizures.
The interactions of each lactam with the picrotoxin
binding site of the heterogeneous population of GABAA
receptors25 found in membranes prepared from rat brain
was assessed by determining IC50 values for displace-
ment of [35S]TBPS (Table 1). The benzyl compounds are
compd
produced by GABAa
Nb
7c (1 mM)
137 ( 6c
108 ( 2d
136 ( 8
98 ( 2d
8
8
5
5
7c (1 mM) + R-IMGBL (3 mM)
7j (300 µM)
7j (300 µM) + R-IMGBL (3 mM)
a
To calculate the percentage response, the magnitude of the
peak current produced by 3 µM GABA plus compound(s) was
normalized with respect to the peak current produced by 3 µM
GABA alone on the same cell. A percentage response of 100%
reflects no change in the current compared to 3 µM GABA alone.
N ) Number of cells examined. c Values are the mean ( SEM.
b
d
p < 0.01 by Student’s t test. Statistical significance calculated
for test compound alone vs test compound and R-IMGBL.
more potent than the dialkyl compounds as displacers
of [35S]TBPS. Although for the benzyl compounds an
increased ability to displace TBPS correlates with the
rank order of potency for blocking PTZ-induced seizures,
this correlation is not observed for the dialkyl series of
compounds (e.g., compare compounds 7c and 7e). Lac-
tams 1, 2, and 4 had extremely weak, but measurable,
interactions with the picrotoxin site. On the basis of
previous [35S]TBPS binding studies of GBLs, TBLs, and
cyclic ketones,4b,6 no correlation was expected for lactam
displacement of [35S]TBPS and potency for blocking
MES-induced seizures, and no correlation was observed.
The modulatory effects of compounds 7c and 7j, the
best anticonvulsants against PTZ-induced seizures, on
GABAA receptor function were examined in electro-
physiological experiments carried out on cultured rat
hippocampal neurons (Figure 1 and Table 2). A con-
centration-dependent increase in the chloride current
mediated by 3 µM GABA was observed for each com-
pound. Compound 7j, which was a more potent dis-
placer of [35S]TBPS than compound 7c, was more potent
at increasing GABA-mediated current. As summarized
in Table 2, the potentiating effects of each compound
were reversed by the picrotoxin antagonist R-isopropyl-

3,3-Disubstituted 2-Pyrrolidinones
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 9 1901
R-methyl-γ-butyrolactone9c which indicates that these
lactams modulate GABAA receptors in a manner similar
to that found for GBLs.9,10a
potent enhancer of GABA-mediated currents (Figure 1).
Lastly, the benzyl substituent increased, by an unknown
mechanism of action, the anticonvulsant potency of the
lactams against MES-induced seizures.
Discu ssion
Overall, the results reported indicate that 3,3-disub-
stituted 2-pyrrolidinones have anticonvulsant activities
against PTZ-induced seizures which are superior to
those reported for the previously studied anticonvulsant
GBLs, TBLs, and cyclopentanones, wherein the most
potent of these compounds was R,R-diethyl-γ-thiobuty-
rolactone (ED50 ) 104 mg/kg and PI ) 2.74).4b In the
PTZ animal seizure model, lactams 7c (ED50 ) 46 mg/
kg) and 7j (ED50 ) 42 mg/kg) have protective index
values of 5.65 and 3.00, respectively. These protective
index values compare favorably to those of the clinically
used antiepileptic drugs ethosuximide (ED50 ) 161 mg/
kg), phenobarbital (ED50 ) 22 mg/kg), and valproic acid
(ED50 ) 133 mg/kg) which, when evaluated by the same
methods, have protective index values of 2.35, 4.00, and
2.12 respectively.27
The benzyl compounds are also very effective against
seizures induced by MES and the protective index
values for 7h , 7i, and 7j are 3.51, 3.04, and 1.70,
respectively. The corresponding protective index values
for phenobarbital and valproic acid are 1.37 and 5.18,
respectively.27 Whereas ethosuximide is not effective
against seizures induced by MES, the phenyl-containing
succinimide analogues phensuximide and methsuximide
are effective anticonvulsants in this animal seizure
model.28 Thus, the introduction of aromatic substitu-
ents adjacent to a carbonyl group in either the succin-
imide or 2-pyrrolidinone ring systems produces com-
pounds having anticonvulsant activity against MES-
induced seizures. Direct comparisons of potency and
PI values for lactams 7h -j, phensuximide, and meth-
suximide are not possible since the succinimides have
not been evaluated using the exact methods reported
in this study.
Although anticonvulsant activity was not observed for
2-pyrrolidinone in this study, other investigators using
an oral route of 2-pyrrolidinone administration and
waiting 2 h before subcutaneously injecting PTZ (100
mg/kg) reported that 2-pyrrolidinone at a dose of 400
mg/kg protected 80% of the mice from PTZ-induced
seizures.26 The different results obtained for 2-pyrro-
lidinone in the two studies indicate the important role
played by pharmacokinetic parameters in the screening
of compounds for anticonvulsant activity and suggest
that under a different set of test conditions the lactams
studied herein may display even greater anticonvulsant
activity. Nevertheless, even in the absence of compre-
hensive pharmacokinetic data, it is already clear from
the results summarized in Table 1 that the anti-PTZ
activity of 2-pyrrolidinone is markedly altered by sub-
stitution at C-3. Very weak anticonvulsant activity
became evident with the introduction of a methyl or an
ethyl substituent or dimethyl substituents at C-3 (com-
pounds 2, 4, and 7a , respectively), and further increases
in anticonvulsant activity accompanied the introduction
of larger substituents at this position. The previously
reported failure to observe anticonvulsant activity for
compound 7a 2 appears to be attributable to the small
size of the methyl substituents and not, as originally
suggested, to protonation of the nitrogen at physiological
pH.
Previous structure-activity studies of R,R-dialkyl-
substituted TBLs have shown a good correlation (r )
0.898, p ) 0.01, n ) 7) between anticonvulsant potency
in the PTZ test and the IC50 value for displacement of
[35S]TBPS.4b As the results summarized in Table 1
demonstrate, no correlation between these experimental
parameters was observed for the 3,3-dialkyl-substituted
2-pyrrolidinones. Moreover, while lactam 7c is 2.8-fold
more potent against PTZ-induced seizures than R-ethyl-
R-methyl-γ-thiobutyrolactone (ED50 ) 128 mg/kg4b,27),
the best of the earlier prepared GBL, TBL, and cyclo-
pentanone congeners, lactam 7c is < 17-fold as potent
a displacer of [35S]TBPS than the thiobutyrolactone
(IC50 ) 0.33 mM4b). Additionally, lactam 7c is ∼10-fold
less potent at enhancing currents mediated by 3 µM
GABA in cultured rat hippocampal neurons than R-ethyl-
R-methyl-γ-thiobutyrolactone.10a These results suggest
that mechanisms of anticonvulsant action which do not
involve GABAA receptor modulation also contribute to
the enhanced potency of lactam 7c against PTZ-induced
seizures.
Among the seizure models used here, the PTZ test is
thought to be predictive of anticonvulsant drug efficacy
against generalized absence and/or myoclonic seizures,
while the MES test is thought to represent a valid model
for generalized tonic-clonic seizures in humans.29 As
a class of anticonvulsants, the 3,3-disubstituted 2-pyr-
rolidinones have a broad spectrum of action and may
be useful for the treatment of human epilepsies.
Exp er im en ta l Section
Gen er a l Meth od s. Unless otherwise noted, the starting
materials were obtained from commercial suppliers and used
without further purification. Dichloromethane (CH2Cl2) was
distilled over calcium hydride. Hexamethylphosphoramide
(HMPA) was dried over activated 13X molecular sieves.
Tetrahydrofuran (THF) was distilled over sodium-benzophe-
none. Ozonolysis was performed using a Model T-408 Wels-
bach Ozonator. A Varian model 3700 or 3400 CX gas chro-
matograph equipped with a glass column (0.25 in. i.d., 6 ft
length) packed with 1% SP2401 on 80/100 mesh Supelcoport
(Supelco, Inc.) was utilized to monitor the progress of the
reactions and to assess the purity of the intermediate products.
Thin-layer chromatography was performed on 250 µm Anal-
tech silica gel plates containing a fluorescent indicator. Flash
chromatography was carried out by using Scientific Adsor-
bents, Inc. 40 µm silica gel. Bulb-to-bulb distillations were
performed using an Aldrich Kugelrohr apparatus. Melting
points were determined with either Thomas-Hoover capillary
or Kofler-type micro hot stage apparatus and are uncorrected.
IR spectra were obtained with Perkin-Elmer 1710 FT-IR
Since structure-activity studies involving benzyl
substituents were not carried out for the earlier studied
GBLs, TBLs, and cyclopentanones, it is not possible to
compare results for compounds having benzyl substit-
uents in the different ring systems. However, because
it was found previously that R-ethyl-R-tert-butyl-γ-
butyrolactone was a convulsant,4a we expected that a
substituent as large as benzyl would produce a lactam
with convulsant properties. This was not found to be
the case. Moreover, a benzyl substituent on the lactam
ring enhanced a compound's ability to displace [35S]-
TBPS and in the one case examined, it gave a more

1902 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 9
Reddy et al.
instrument as thin films on NaCl plate, and NMR spectra (1H
and 13C) were recorded in CDCl3 solutions on a Varian Gemini-
300 spectrometer. Chemical shifts are expressed in parts per
million (δ) relative to tetramethylsilane as an internal stan-
dard. Elemental analyses were performed at M-H-W Labo-
ratories in Phoenix, AZ.
(225 mL), as described above in the preparation of 6a , gave
27.8 g of a dark-colored liquid. After two vacuum distillations,
the nitrile 6c (12.4 g, 45%) was obtained as a colorless liquid
(about 96% pure by GC): bp 84-85 °C (1.3 mmHg). An
analytical sample was prepared by column chromatography
over silica gel (hexanes-EtOAc, 19:1) followed by bulb-to-bulb
distillation [pot temperature 80 °C (1 mmHg)]: Rf ) 0.36
3-Eth yl-2-p yr r olid in on e (4). A solution of N-(trimethyl-
silyl)-2-pyrrolidinone (3, 11.0 g, 70.0 mmol)13 in THF (10 mL)
was added dropwise to a solution of LDA (prepared from
diisopropylamine (7.07 g, 70.0 mmol) and n-butyllithium in
hexanes (2.5 M, 28 mL, 70 mmol)) in THF (190 mL) at -78 °C
in a nitrogen atmosphere. After 1 h, iodoethane (10.9 g, 70.0
mmol) was added, and the resulting solution was allowed to
warm to room temperature (ca. 3 h) and stirred overnight.
Water (75 mL) was added, the layers were separated, the
aqueous phase was extracted with ether (3 × 50 mL), and the
combined organic extract was dried over MgSO4. The solvent
was removed in vacuo to give 8.09 g of colorless oil, which upon
flash chromatography over silica gel (1% MeOH in CHCl3-
EtOAc, 1:1) afforded the pure lactam 4 (4.14 g, 52%; 66% based
on the 79% purity of the starting material) as a colorless
solid: Rf ) 0.31 (2% MeOH in CHCl3-EtOAc, 1:1); mp 43-44
°C (hexanes at -5 °C) (lit.14a mp 38-39 °C; lit.14b mp 47-48.5
(hexanes-EtOAc, 9:1); IR 2249 (CN), 1729 (CdO) cm-1 1H
;
NMR δ 4.20 (q, 2, J ) 7.1 Hz, OCH2CH3), 2.68 (s, 2, CH2CN),
1.91-1.79 (m, 2, diastereotopic H of each CH2CH3), 1.76-1.64
(m, 2, diastereotopic H of each CH2CH3), 1.28 (t, 3, J ) 7.1
Hz, OCH2CH3), 0.87 (t, 6, J ) 7.4 Hz, 2 × CH2CH3); 13C NMR
δ 173.74 (CdO), 117.48 (CN), 61.08 (OCH2), 48.84 (CCdO),
29.26 (2 × CH2CH3), 20.82 (CH2CN), 14.11 (OCH2CH3), 8.59
(2 × CH2CH3). Anal. (C10H17NO2) C, H, N.
Meth yl 2-(Cya n om eth yl)-2,3-d im eth ylbu ta n oa te (6d ).
The reaction of methyl 2-methylisovalerate (5d , 19.5 g, 150
mmol)30
with bromoacetonitrile (21.6 g, 180 mmol) in the
presence of LDA (prepared from diisopropylamine (16.7 g, 165
mmol) and n-butyllithium in hexanes (2.5 M, 66 mL, 165
mmol)) in THF (225 mL), as described above in the preparation
of 6a , gave 20.6 g of the crude product as a dark-colored liquid.
Vacuum distillation afforded 9.00 g of the nitrile as a colorless
oil (about 90% pure): bp 89-92 °C (2.2 mmHg). Column
chromatography over silica gel (hexanes-EtOAc, 19:1) fol-
lowed by bulb-to-bulb distillation [pot temperature 85 °C (1
mmHg)] gave the pure nitrile 6d (7.55 g, 30%) as a colorless
oil: Rf
1
°C); IR 3257 (br, NH), 1693 (CdO) cm-1; H NMR δ 6.95 (br,
1, NH), 3.38-3.27 (m, 2, NHCH2), 2.36-2.22 (m, 2, NHCH2CH2)
1.93-1.73 (m, 2, diastereotopic H of CH2CH3, CHCdO), 1.50-
1.35 (m, 1, diastereotopic H of CH2CH3), 0.98 (t, 6, J ) 7.5
Hz, CH2CH3); 13C NMR δ 180.06 (CdO), 42.34 (CHCdO), 40.40
(NHCH2), 26.63 (NHCH2CH2), 23.67 (CH2CH3), 11.35 (CH2CH3).
Meth yl 3-Cya n o-2,2-d im eth ylp r op a n oa te (6a ). A solu-
tion of methyl isobutyrate (5a , 10.2 g, 100 mmol) in THF (10
mL) was added dropwise to a solution of LDA (prepared from
diisopropylamine (11.1 g, 110 mmol) and n-butyllithium in
hexanes (2.5 M, 44 mL, 110 mmol)) in THF (125 mL) at -78
°C in a nitrogen atmosphere. The resulting mixture was
stirred at -78 °C for 1 h, and then a solution of bromoaceto-
nitrile (14.4 g, 120 mmol) in THF (15 mL) was introduced
slowly over a period of 30 min. (The reaction mixture starts
getting darker as the addition progresses.) The resulting dark
mixture was allowed to warm to room temperature (ca. 3 h)
and stirred overnight. The reaction was quenched by addition
of HCl (1 N, 150 mL) at 0 °C. The layers were separated, and
the aqueous phase was further extracted with ether (3 × 75
mL). The combined organic extract was washed sequentially
with 75 mL portions of saturated NaHCO3, water (several
times), and brine and dried over MgSO4. The solvent was
removed in vacuo to give 15.0 g of dark-colored liquid. Flash
chromatography over silica gel (hexanes-EtOAc, 19:1) fol-
lowed by short-path distillation afforded the nitrile 6a (6.66
g, 47%) as a colorless liquid: bp 95-97 °C (20 mmHg); Rf )
) 0.33 (hexanes-EtOAc, 9:1); IR 2247 (CN), 1733
(CdO) cm-1; 1H NMR δ 3.74 (s, 3, OCH3), 2.71 (d, 1, J ) 16.7
Hz, diastereotopic H of CH2), 2.45 (d, 1, J ) 16.7 Hz,
diastereotopic H of CH2), 2.04 (septet, 1, CH(CH3)2), 1.33 (s,
3, CH3), 0.91 (d, 6, J ) 7.1 Hz, CH(CH3)2); 13C NMR δ 174.73
(CdO), 118.10 (CN), 52.30 (OCH3), 48.15 (CCdO), 34.81 (CH-
(CH3)2), 24.23 (CH2), 19.41 (CH3), 17.55 (CH(CH3)2). Anal.
(C9H15NO2) C, H, N.
Meth yl 1-(Cyan om eth yl)cyclopen tan ecar boxylate (6g).
A solution of methyl cyclopentanecarboxylate (5g, 5.12 g, 40.0
mmol) in dry THF (10 mL) was added dropwise to a solution
of LDA (prepared from diisopropylamine (4.44 g, 44.0 mmol)
and n-butyllithium in hexanes (2.5 M, 17.6 mL, 44 mmol)) in
THF (60 mL) at -78 °C in a nitrogen atmosphere. The
mixture was stirred at -78 °C for 45 min, and then a solution
of bromoacetonitrile (5.76 g, 48.0 mmol) in THF (10 mL) and
HMPA (3.5 mL, 20 mmol) was introduced slowly over a period
of 15 min. The resulting dark mixture was allowed to warm
to room temperature (ca. 3 h) and stirred overnight. The
reaction was quenched by addition of HCl (1 N, 75 mL) at 0
°C. The layers were separated, and the aqueous phase was
further extracted with ether (3 × 50 mL). The combined
organic extract was washed with 75 mL portions of saturated
NaHCO3, water (several times), and brine and dried over
MgSO4. The solvent was removed in vacuo to give 6.50 g of
dark-colored liquid, which after column chromatography over
silica gel (hexanes-acetone, 19:1) followed by short-path
distillation afforded the pure nitrile 6g (3.87 g, 58%) as a
colorless liquid: bp 97-99 °C (0.8 mmHg); Rf ) 0.28 (hexanes-
acetone, 9:1); IR 2250 (CN), 1733 (CdO) cm-1; 1H NMR δ 3.75
0.32 (hexanes-EtOAc, 17:3); IR 2248 (CN), 1735 (CdO) cm-1
;
1H NMR δ 3.74 (s, 3, OCH3), 2.62 (s, 2, CH2), 1.37 (s, 6, 2 ×
CH3); 13C NMR δ 175.26 (CdO), 117.42 (CN), 52.46 (OCH3),
40.84 (CCdO), 27.89 (CH2), 24.67 (2 × CH3). Anal. (C7H11
-
NO2) C, H, N.
Meth yl 2-(Cya n om eth yl)-2-m eth ylbu ta n oa te (6b). The
reaction of methyl 2-methylbutyrate (5b, 13.34 g, 115.0 mmol)
with bromoacetonitrile (16.56 g, 138.0 mmol) in the presence
of LDA (prepared from diisopropylamine (12.78 g, 126.5 mmol)
and n-butyllithium in hexanes (2.5 M, 50.6 mL, 126.5 mmol))
in THF (175 mL), as described above in the preparation of 6a ,
gave 16.57 g of a dark-colored liquid. The crude product was
vacuum distilled to give the nitrile 6b (10.85 g, 61%) as a
colorless liquid: bp 83-85 °C (10 mmHg); IR 2248 (CN), 1734
(CdO) cm-1; 1H NMR δ 3.74 (s, 3, OCH3), 2.68 (d, 1, J ) 16.8
Hz, diastereotopic H of CH2CN), 2.58 (d, 1, J ) 16.8, Hz
diastereotopic H of CH2CN), 1.82-1.66 (m, 2, CH2CH3), 1.36
(s, 3, CH3), 0.87 (t, 3, J ) 7.5 Hz, CH2CH3); 13C NMR δ 174.86
(CdO), 117.64 (CN), 52.45 (OCH3), 44.95 (CCdO), 31.26 (CH2-
CH3), 25.45 (CH2CN), 22.63 (CH3), 8.95 (CH2CH3). Anal.
(C8H13NO2) C, H, N.
(s, 3, OCH3
), 2.66 (s, 2, CH2CN), 2.24-2.11 (m, 2, CH2), 1.85-
1.68 (m, 6, 3 × CH2); 13C δ NMR 175.81 (CdO), 118.15 (CN),
52.61 (OCH3), 50.66 (CCdO), 36.62 (2 × CH2), 26.04 (CH2CN),
25.61 (2 × CH2). Anal. (C9H13NO2) C, H, N.
Meth yl 2-(Cyan om eth yl)-3-ph en ylpr opan oate (6h ). The
reaction of methyl 3-phenylpropionate (5h , 4.10 g, 25.0 mmol)
with bromoacetonitrile (3.60 g, 30.0 mmol) in the presence of
LDA (prepared from diisopropylamine (2.78 g, 27.5 mmol) and
n-butyllithium in hexanes (2.5 M, 11 mL, 27.5 mmol)) in THF
(50 mL) and HMPA (2.2 mL, 12.5 mmol), as described above
in the preparation of 6g, gave 5.70 g of the crude product as
a dark-colored liquid. Column chromatography over silica gel
(hexanes-EtOAc, 17:3) followed by short-path distillation
afforded the pure nitrile 6h (1.70 g, 34%) as a colorless oil:
bp 129-131 °C (0.3 mmHg); Rf ) 0.22; IR 2249 (CN), 1739
Eth yl 2-(Cya n om eth yl)-2-eth ylbu ta n oa te (6c). The re-
action of ethyl 2-ethylbutyrate (5c, 21.6 g, 150 mmol) with
bromoacetonitrile (21.6 g, 180 mmol) in the presence of LDA
(prepared from diisopropylamine (16.7 g, 165 mmol) and
n-butyllithium in hexanes (2.5 M, 66 mL, 165 mmol)) in THF
1
(CdO), 1604 (CdC) cm-1; H NMR δ 7.36-7.16 (m, 5, ArH),
3.74 (s, 3, OCH3), 3.17 (dd, 1, J ) 12.6, 5.0 Hz, diastereotopic
H of CH2Ph), 3.06-2.90 (m, 2, CHCdO and diastereotopic H
of CH2Ph), 2.52 (d, 2, J ) 6.2 Hz, CH2CN); 13C δ NMR (CDCl3)

3,3-Disubstituted 2-Pyrrolidinones
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 9 1903
172.26 (CdO), 136.60 (ArC), 128.85 (2 × ArC), 128.79 (2 ×
ArC), 127.17 (ArC), 117.66 (CN), 52.37 (OCH3), 43.11 (CHCdO),
36.74 (CH2Ph), 18.31 (CH2CN). Anal. (C12H13NO2) C, H, N.
E t h yl 2-(Cya n om et h yl)-2-(p h en ylm et h yl)p r op a n oa t e
(6i). The reaction of ethyl 2-methyl-3-phenylpropionate (5i,
9.60 g, 50.0 mmol)31 with bromoacetonitrile (9.00 g, 75.0 mmol)
in the presence of LDA (prepared from diisopropylamine (6.06
g, 60.0 mmol) and n-butyllithium in hexanes (2.5 M, 24 mL,
60 mmol) in THF (150 mL) and HMPA (4.3 mL, 25 mmol), as
described above in the preparation of 6g, gave 12.0 g of the
crude product as a pale yellow colored liquid. Flash chroma-
tography over silica gel (hexanes-CH2Cl2, 3:2) afforded the
pure nitrile 6i (7.86 g, 68%) as a colorless viscous liquid. An
analytical sample was prepared by bulb-to-bulb distillation
[pot temperature 110-115 °C (0.9 mmHg)]: Rf ) 0.28 (hex-
anes-CH2Cl2, 1:1); IR 2247 (CN), 1729 (CdO), 1605 (CdC)
cm-1; 1H NMR δ 7.32-7.24 (m, 3, ArH), 7.15-7.12 (m, 2, ArH),
4.18 (q, 2, J ) 7.1 Hz, OCH2CH3), 3.12 (d, 1, J ) 13.7 Hz,
diastereotopic H of CH2Ph), 2.90 (d, 1, J ) 13.7 Hz, diaste-
reotopic H of CH2Ph), 2.56 (d, 1, J ) 16.8 Hz, diastereotopic
H of CH2CN), 2.45 (d, 1, J ) 16.8 Hz, diastereotopic H of CH2-
CN), 1.42 (s, 3, CH3), 1.26 (t, 3, J ) 7.1 Hz, OCH2CH3); 13C
NMR δ 173.64 (CdO), 135.49 (ArC), 129.57 (2 × ArC), 128.32
(2 × ArC), 127.08 (ArC), 117.66 (CN), 61.29 (OCH2CH3), 45.54
(CCdO), 43.43 (CH2Ph), 24.93 (CH2CN), 23.09 (OCH2CH3),
13.84 (CH3). Anal. (C14H17NO2) C, H, N.
Flash chromatography over silica gel (1% MeOH in CHCl3-
EtOAc, 1:1) afforded the pure lactam 7b (4.30 g, 71%) as a
colorless solid: Rf ) 0.31 (2% MeOH in CHCl3-EtOAc, 1:1);
mp 39-40 °C (pentane at -5 °C); IR 3214 (br, NH), 1693
(CdO) cm-1 1H NMR δ 6.45 (br, 1, NH), 3.33-3.26 (m, 2,
;
NHCH2), 2.12-2.03 (m, 1, diastereotopic H of NHCH2CH2),
1.89-1.80 (m, 1, diastereotopic H of NHCH2CH2), 1.63-1.46
(m, 2, CH2CH3), 1.14 (s, 3, CH3), 0.92 (t, 6, J ) 7.5 Hz,
CH2CH3); 13C NMR δ 183.11 (CdO), 43.26 (CCdO), 38.85
(NHCH2), 32.88 (NHCH2CH2), 30.06 (CH2CH3), 22.46 (CH3),
8.77 (CH2CH3). Anal. (C7H13NO) C, H, N.
3,3-Dieth yl-2-p yr r olid in on e (7c). The reaction of nitrile
6c (8.24 g, 45.0 mmol) with NaBH4 (8.55 g, 225 mmol) and
CoCl2‚6H2O (5.36 g, 22.5 mmol) in THF (158 mL) and H2O
(79 mL) was carried out as described above in the preparation
of 7a . After the addition of NaBH4, the reaction mixture was
stirred and refluxed for 72 h and subjected to the usual workup
to give 6.20 g of a colorless viscous residue. Flash chroma-
tography over silica gel (1% MeOH in CHCl3-EtOAc, 1:1)
afforded the pure lactam 7c (4.42 g, 70%) as a colorless solid:
Rf ) 0.34 (2% MeOH in CHCl3-EtOAc, 1:1); mp 52-53 °C
1
(hexanes at -5 °C); IR 3199 (br, NH), 1679 (CdO) cm-1; H
NMR δ 6.59 (br, 1, NH), 3.28 (t, 2, J ) 7.4 Hz, NHCH2), 1.89
(t, 2, J ) 7.4 Hz, NHCH2CH2), 1.63-1.46 (m, 4, 2 × CH2CH3),
0.91 (t, 6, J ) 7.4 Hz, 2 × CH2CH3); 13C NMR δ 182.51 (CdO),
47.44 (CCdO), 39.29 (NHCH2), 29.37 (NHCH2CH2), 28.98 (2
× CH2CH3), 8.60 (2 × CH2CH3). Anal. (C8H15NO) C, H, N.
3-Meth yl-3-(1-m eth yleth yl)-2-p yr r olid in on e (7d ). The
reaction of nitrile 6d (6.42 g, 38.0 mmol) with NaBH4 (7.22 g,
190 mmol) and CoCl2‚6H2O (4.52 g, 19.0 mmol) in THF (132
mL) and H2O (66 mL), as described above in the preparation
of 7a , gave 4.35 g of the crude product as a colorless solid.
Flash chromatography over silica gel (1% MeOH in CHCl3-
EtOAc, 1:1) afforded the pure lactam 7d (3.77 g, 70%) as a
colorless solid: Rf ) 0.33 (2% MeOH in CHCl3-EtOAc, 1:1);
mp 88-90 °C (hexanes at -5 °C); IR 3207 (br, NH), 1689
Meth yl 2-(Cya n om eth yl)-2-(p h en ylm eth yl)bu ta n oa te
(6j). The reaction of methyl 2-ethyl-3-phenylpropionate (5j,
9.60 g, 50.0 mmol)32 with bromoacetonitrile (7.20 g, 60.0 mmol)
in the presence of LDA (prepared from diisopropylamine (5.56
g, 55.0 mmol) and n-butyllithium in hexanes (2.5 M, 22 mL,
55 mmol)) in THF (150 mL) and HMPA (4.3 mL, 25 mmol), as
described above in the preparation of 6g, gave 12.1 g of the
crude product as a dark-colored liquid. Column chromatog-
raphy over silica gel (hexanes-CH2Cl2, 3:2) afforded the pure
nitrile 6j (5.98 g, 52%) as a colorless viscous liquid. An
analytical sample was prepared by bulb-to-bulb distillation
[pot temperature 105 °C (0.5 mmHg)]: Rf ) 0.22; IR 2247 (CN),
(CdO) cm-1 1H NMR δ 6.53 (br, 1, NH), 3.36-3.21 (m, 2,
;
NHCH2), 2.18-2.05 (m, 1, diastereotopic H of NHCH2CH2),
1.92 (septet, 1, CH(CH3)2), 1.72-1.61 (m, 1, diastereotopic H
of NHCH2CH2), 1.15 (s, 3, CH3), 0.92 (d, 3, J ) 6.6 Hz, CH-
(CH3)2), 0.89 (d, 3, J ) 6.6 Hz, CH(CH3)2); 13C NMR δ 183.61-
(CdO), 46.86 (CCdO), 39.22 (NHCH2), 32.87 (CH(CH3)2), 28.83
(NHCH2CH2), 22.26 (CH3), 18.30 (CH(CH3)2), 17.01 (CH-
(CH3)2). Anal. (C8H15NO) C, H, N.
1732 (CdO), 1605 (CdC) cm-1 1H NMR δ 7.33-7.25 (m, 3,
;
ArH), 7.16-7.12 (m, 2, ArH), 3.73 (s, 3, OCH3), 3.22 (d, 1, J )
14.1 Hz, diastereotopic H of CH2Ph), 2.90 (d, 1, J ) 14.1 Hz,
diastereotopic H of CH2Ph), 2.60 (d, 1, J ) 16.5 Hz, diaste-
reotopic H of CH2CN), 2.46 (d, 1, J ) 16.5 Hz, diastereotopic
H of CH2CN), 2.07-1.94 (m, 1, diastereotopic H of CH2CH3),
1.86-1.75 (m, 1, diastereotopic H of CH2CH3), 0.91 (t, 3, J )
7.5 Hz, CH2CH3; 13C NMR δ 173.62 (CdO), 135.70 (ArC),
129.54 (2 × ArC), 128.65 (2 × ArC), 127.29 (ArC), 117.77 (CN),
52.21 (OCH3), 50.44 (CCdO), 42.47 (CH2Ph), 30.03 (CH2CH3),
20.77 (CH2CN), 8.90 (CH2CH3). Anal. (C14H17NO2) C, H, N.
3,3-Dim eth yl-2-p yr r olid in on e (7a ). A pink solution of
CoCl2‚6H2O (4.52 g, 19.0 mmol) and nitrile 6a (5.36 g, 38.0
mmol) in THF (132 mL) and H2O (66 mL) was stirred
vigorously and cooled to 0 °C while NaBH4 (7.22 g, 190 mmol)
was added in portions over 30 min in an atmosphere of N2.
The reaction was exothermic, producing a black precipitate
and copious quantities of hydrogen. After the reaction mixture
was stirred for 48 h at room temperature, 28% NH4OH (5 mL)
was added, centrifuged, and the supernatant biphasic liquid
was decanted. The sediment was washed with 15 mL of the
same solvent mixture, and the combined supernatants were
concentrated in vacuo to remove the bulk of THF. The
aqueous residue was extracted with CHCl3 (3 × 50 mL), and
the combined CHCl3 layers were washed with brine (100 mL)
and dried over MgSO4. The solvent was removed in vacuo to
give 3.73 g of a colorless viscous residue, which upon flash
chromatography over silica gel (1% MeOH in CHCl3-EtOAc,
1:1) afforded the pure lactam 7a (2.80 g, 65%) as a colorless
solid: Rf ) 0.29 (2% MeOH in CHCl3-EtOAc, 1:1); mp 69-70
°C (pentane at -5 °C) (lit.19 mp 65-67 °C); 13C NMR δ 183.94
(CdO), 39.59 (CCdO), 38.71 (NHCH2), 36.29 (NHCH2CH2),
24.14 (2 × CH3).
2-Aza sp ir o[4.4]n on a n -1-on e (7g). The reaction of nitrile
6g (3.34 g, 20.0 mmol) with NaBH4 (3.78 g, 100 mmol) and
CoCl2‚6H2O (2.38 g, 10.0 mmol) in THF (70 mL) and H2O (35
mL), as described above in the preparation of 7a , gave 3.10 g
of the crude product as a colorless solid. Column chromatog-
raphy over silica gel (1% MeOH in CHCl3-EtOAc, 1:1) afforded
the pure lactam 7g (2.25 g, 81%) as a colorless solid: Rf )
0.33 (2% MeOH in CHCl3-EtOAc, 1:1); mp 110-111 °C (CH2-
Cl2-hexanes) (lit.20 mp 110 °C); IR 3200 (br, NH), 1678 (CdO)
cm-1 1H NMR δ 6.70 (br, 1, NH), 3.31 (t, 2, J ) 6.8 Hz,
;
NHCH2), 1.99 (t, 2, J ) 6.8 Hz, NHCH2CH2), 1.94-1.52
(overlapping m, 8, (CH2)4); 13C NMR δ 184.08 (CdO), 50.17
(CCdO), 39.53 (NHCH2), 36.41 (NHCH2CH2), 36.10 (2 × CH2),
25.52 (2 × CH2).
3-(P h en ylm eth yl)-2-p yr r olid in on e (7h ). The reaction of
nitrile 6h (3.05 g, 15.0 mmol) with NaBH4 (2.85 g, 75.0 mmol)
and CoCl2‚6H2O (1.79 g, 7.50 mmol) in THF (54 mL) and H2O
(27 mL), as described above in the preparation of 7a , gave 2.37
g of the crude product as a colorless solid. Flash chromatog-
raphy over silica gel (1% MeOH in CHCl3-EtOAc, 1:1) afforded
the pure lactam 7h (1.48 g, 56%) as a colorless solid: Rf )
0.30 (2% MeOH in CHCl3-EtOAc, 1:1); mp 112-113 °C (CH2-
Cl2-hexanes) (lit.13 mp 109-110 °C); 13C NMR δ 180.17 (CdO),
139.53 (ArC), 128.90 (2 × ArC), 128.45 (2 × ArC), 126.26 (ArC),
42.96 (CHCdO), 40.43 (NHCH2), 36.63 (CH2Ph), 26.88
(NHCH2CH2).
3-Meth yl-3-(p h en ylm eth yl)-2-p yr r olid in on e (7i). The
reaction of nitrile 6i (8.32 g, 36.0 mmol) with NaBH4 (6.80 g,
180 mmol) and CoCl2‚6H2O (4.28 g, 18.0 mmol) in THF (126
mL) and H2O (63 mL), as described above in the preparation
7c, gave 6.78 g of the crude product as a pale brown colored
solid. Flash chromatography over silica gel (1% MeOH in
3-Eth yl-3-m eth yl-2-p yr r olid in on e (7b). The reaction of
nitrile 6b (7.36 g, 47.5 mmol) with NaBH4 (9.030 g, 23.75
mmol) and CoCl2‚6H2O (5.650 g, 23.75 mmol) in THF (166 mL)
and H2O (83 mL), as described above in the preparation of
7a , gave 5.79 g of the crude product as a colorless oily residue.

1904 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 9
Reddy et al.
CHCl3-EtOAc, 1:1) afforded the pure lactam 7i (5.34 g, 78%)
as a colorless solid: Rf ) 0.36 (2% MeOH in CHCl3-EtOAc,
1:1); mp 89-90 °C (CH2Cl2-hexanes); IR 3225 (br, NH), 1680
CH2CH3); 13C NMR δ 176.33 (CdO), 135.19 (CHd), 117.24
(dCH2), 52.49 (CCdO), 51.13 (OCH3), 35.92 (CH2CHd), 33.01
(CH(CH3)2), 25.60 (CH2CH3), 18.20 (CH(CH3)2), 18.00 (CH-
(CH3)2), 8.93 (CH2CH3). Anal. (C11H20O2) C, H.
1
(CdO), 1604 (CdC) cm-1; H NMR δ 7.31-7.21 (m, 5, ArH),
6.08 (br, 1, NH), 3.18-3.11 (m, 1, diastereotopic H of NHCH2),
2.98 (d, 1, J ) 13.3 Hz, diastereotopic H of CH2Ph), 2.82-
2.74 (m, 1, diastereotopic H of NHCH2), 2.65 (d, 1, J ) 13.3
Hz, diastereotopic H of CH2Ph), 2.21-2.12 (m, 1, diastereotopic
Meth yl 2-(1,1-Dim eth yleth yl)-2-m eth yl-4-oxobu ta n oa te
(9e). A solution of olefinic ester 8e (2.76 g, 15.0 mmol) in CH2-
Cl2 (60 mL) was reacted with ozone at -78 °C. When excess
ozone was observed (blue coloration), N2 was bubbled through
the solution, and Ph3P (5.90 g, 22.5 mmol) was added in one
portion while stirring. The system was allowed to warm to
room temperature (ca. 2 h) and stirred for an additional 2 h.
The solvent was removed in vacuo and the residue triturated
with hexanes (150 mL). The precipitated Ph3PO (ca. 5.78g)
was filtered off and the filtrate concentrated in vacuo to give
2.80 g of the crude product as a colorless viscous residue.
Flash chromatography over silica gel (hexanes-EtOAc, 19:1)
afforded 2.12 g (76%) of the aldehyde 9e as a colorless oil:35 Rf
H
of NHCH2CH2), 1.84-1.75 (m, 1, diastereotopic H of
NHCH2CH2), 1.21 (s, 3, CH3); 13C NMR δ 182.67 (CdO), 137.81
(ArC), 130.09 (2 × ArC), 128.13 (2 × ArC), 126.49 (ArC), 44.60
(CCdO), 43.37 (CH2Ph), 38.87 (NHCH2), 32.54 (NHCH2CH2),
23.65 (CH3). Anal. (C12H15NO) C, H, N.
3-Eth yl-3-(p h en ylm eth yl)-2-p yr r olid in on e (7j). The re-
action of nitrile 6j (5.54 g, 24.0 mmol) with NaBH4 (4.54 g,
120 mmol) and CoCl2‚6H2O (2.86 g, 12.0 mmol) in THF (84
mL) and H2O (42 mL), as described above in the preparation
of 7a , gave 4.95 g of the crude product as a slightly brown
colored oily residue. Flash chromatography over silica gel (1%
MeOH in CHCl3-EtOAc, 1:1) afforded the pure lactam 7j (3.69
g, 76%) as a colorless solid: Rf ) 0.44 (2% MeOH in CHCl3-
EtOAc, 1:1); mp 89-90 °C (ether-hexanes at -5 °C); IR 3220
(br, NH), 1688 (CdO) cm-1; 1H NMR δ 7.31-7.17 (m, 5, ArH),
6.01 (br, 1, NH), 3.09-3.03 (m, 1, diastereotopic H of NHCH2),
2.99 (d, 1, J ) 13.3 Hz, diastereotopic H of CH2Ph), 2.64 (d, 1,
J ) 13.3 Hz, diastereotopic H of CH2Ph), 2.60-2.51 (m, 1,
diastereotopic H of NHCH2), 2.12-1.91 (m, 2, NHCH2CH2),
1.78-1.66 (m, 1, diastereotopic H of CH2CH3), 1.62-1.50 (m,
1, diastereotopic H of CH2CH3), 0.97 (t, 3, J ) 7.5 Hz, CH2CH3);
13C NMR δ 181.76 (CdO), 137.83 (ArC), 130.08 (2 × ArC),
128.08 (2 × ArC), 126.46 (ArC), 48.87 (CCdO), 42.60 (CH2-
Ph), 39.17 (NHCH2), 30.26 (NHCH2CH2), 28.56 (CH2CH3), 8.80
(CH2CH3). Anal. (C13H17NO) C, H, N.
) 0.32 (hexanes-EtOAc, 9:1); IR 2734 (aldehyde CH), 1725
1
(CdO) cm-1
; H NMR δ 9.70 (d, 1, J ) 2.1 Hz, CHO), 3.69 (s,
3, OCH3), 3.11 (d, 1, J ) 17.0 Hz, diastereotopic H of CH2),
2.37 (dd, 1, J ) 17.0, 2.1 Hz, diastereotopic H of CH2), 1.26 (s,
3, CH3), 0.95 (s, 9, C(CH3)3); 13C NMR δ 201.35 (CHO), 178.68
(CdO), 51.52 (OCH3), 48.90 (CCdO), 48.23 (CH2), 35.60
(C(CH3)3), 25.97 (C(CH3)3), 18.09 (CH3).
Meth yl 2-Eth yl-2-(1-m eth yleth yl)-4-oxobu ta n oa te (9f).
The reaction of olefinic ester 8f (9.20 g, 50.0 mmol) with ozone
in CH2Cl2 (200 mL) at -78 °C, followed by the treatment of
the resulting ozonide with Ph3P (19.7 g, 75.0 mmol) as
described above in the preparation of 9e, gave 14.4 g of an
oily residue. Flash chromatography over silica gel (hexanes-
EtOAc, 9:1) afforded the aldehyde 9f (8.20 g, 88%) as a
colorless oil:35 Rf ) 0.40; IR 2742 (aldehyde CH), 1725 (CdO)
1
cm-1; H NMR δ 9.86 (t, 1, J ) 2.6, 2.3 Hz, CHO), 3.73 (s, 3,
OCH3), 2.68 (dd, 1, J ) 16.3, 2.3 Hz, diastereotopic H of CH2-
CHO), 2.48 (dd, 1, J ) 16.3, 2.6 Hz, diastereotopic H of CH2-
CHO), 2.08 (septet, 1, CH(CH3)2), 1.88-1.67 (m, 2, CH2CH3),
0.89 (d, 6, J ) 6.7 Hz, CH(CH3)2), 0.87 (t, 3, J ) 7.5 Hz,
CH2CH3); 13C NMR δ 202.51 (CHO), 175.81 (CdO), 51.93
(CCdO), 51.74 (OCH3), 45.50 (CH2CHO), 33.64 (CH(CH3)2),
27.47 (CH2CH3), 18.49 (CH(CH3)2), 17.29 (CH(CH3)2), 9.21
(CH2CH3).
Meth yl 2-(1,1-Dim eth yleth yl)-2-m eth yl-4-p en ten oa te
(8e). A solution of methyl 2,3,3-trimethylbutyrate (5e, 38.9
g, 270 mmol)34 in THF (30 mL) was added slowly to a solution
of lithium diisopropylamide (prepared from diisopropylamine
(40.9 g, 405 mmol) and n-butyllithium in hexanes (2.5 M, 154.4
mL, 386 mmol)) in THF (350 mL) at 0 °C in a nitrogen
atmosphere, and the mixture was stirred for 45 min. The
temperature was then reduced to -78 °C, and a solution of
allyl bromide (51.3 g, 424 mmol) in THF (20 mL) and HMPA
(40.3 mL, 232 mmol) was added over a period of 15 min.
Stirring was continued for 2 h at -78 °C, and the system was
allowed to warm to room temperature (ca. 6 h). The reaction
was quenched by addition of HCl (3 N, 300 mL) at 0 °C. The
layers were separated, and the aqueous phase was further
extracted with ether (3 × 150 mL). The combined organic
extract was washed with 100 mL portions of water, 5%
Na2S2O3, saturated NaHCO3, water, and brine and dried over
MgSO4. The solvent was removed in vacuo to give 48.9 g of
brown-colored liquid, which upon two vacuum distillations
afforded pure olefinic ester 8e (34.9 g, 70%) as a colorless
liquid: bp 87-89 °C (20 mmHg); IR 1730 (CdO), 1641 (CdC)
Meth yl 2-(1,1-Dim eth yleth yl)-2-m eth yl-4-oxobu ta n oa te
Oxim e (10e). A solution of aldehyde 9e (2.05 g, 11.0 mmol)
and H2NOH‚HCl (1.15 g, 16.5 mmol) in dry pyridine (10 mL)
was stirred at 60 °C for 4 h in an atmosphere of N2. After
cooling it was poured into ice cold HCl (3 N, 50 mL) and
extracted with ether (3 × 40 mL). The combined ether extract
was washed successively with 40 mL portions of saturated
NaHCO3, water, and brine and dried over MgSO4. The solvent
was removed in vacuo to give 2.30 g of pale brown colored
viscous liquid. Flash chromatography over silica gel (hex-
anes-EtOAc, 4:1) followed by bulb-to-bulb distillation [pot
temperature 100-105 °C (0.4 mmHg)] afforded the anti and
syn oxime mixture 10e (2.03 g, 92%) in the ratio of 58/42 as a
colorless viscous liquid: Rf ) 0.27, 0.19; IR 3529 (br, OH), 1725
cm-1 1H NMR δ 5.72-5.58 (m, 1, CHd), 5.06-5.00 (m, 2,
;
1
dCH2), 3.65 (s, 3, OCH3), 2.76 (dd, 1, J ) 13.2, 6.0 Hz,
diastereotopic H of CH2), 1.96 (dd, 1, J ) 13.2, 8.2 Hz,
diastereotopic H of CH2), 1.08 (s, 3, CH3), 0.95 (s, 9, C(CH3)3);
13C NMR δ 176.41 (CdO), 135.61 (CHd), 117.55 (dCH2), 51.87-
(CCdO), 51.02 (OCH3), 38.39 (CH2), 35.68 (C(CH3)3), 26.26
(C(CH3)3), 17.58 (CH3). Anal. (C11H20O2) C, H.
(CdO), 1660 (CdN) cm-1; H NMR major isomer, δ 8.50 (br,
1, OH), 7.32 (dd, 1, J ) 8.4, 4.4 Hz, CHd), 3.68 (s, 3, OCH3),
2.85 (dd, 1, J ) 13.8, 4.4 Hz, diastereotopic H of CH2), 2.17
(dd, 1, J ) 13.8, 8.4 Hz, diastereotopic H of CH2), 1.12 (s, 3,
CH3), 0.95 (s, 9, C(CH3)3); Minor isomer, δ 8.50 (br, 1, OH),
6.62 (t, 1, J ) 5.4 Hz, CHd), 3.69 (s, 3, OCH3), 2.72 (d, 2, J )
5.4 Hz, CH2), 1.16 (s, 3, CH3), 0.97 (s, 9, C(CH3)3); 13C NMR δ
175.78 (CdO), 150.62 (CHd), 150.54 (CHd), 51.47 (OCH3),
50.93 (CCdO), 50.53 (CCdO), 35.87 (CH2), 29.53 (CH2), 34.04
(C(CH3)3), 26.19 (C(CH3)3), 26.13 (C(CH3)3), 17.97 (CH3), 17.92
(CH3). Anal. (C10H19NO3) C, H, N.
Meth yl 2-Eth yl-2-(1-m eth yleth yl)-4-pen ten oate (8f). The
reaction of methyl 2-ethyl-3-methylbutyrate (5f, 23.8 g, 165
mmol)30 with allyl bromide (31.3 g, 259 mmol) in the presence
of lithium diisopropylamide (prepared from diisopropylamine
(25.0 g, 248 mmol) and n-butyllithium in hexanes (2.5 M, 94.4
mL, 236 mmol)) in THF (330 mL) and HMPA (24.7 mL, 142
mmol), as described above in the preparation of 8e, followed
by the vacuum distillation of crude product afforded the pure
olefinic ester 8f (24.9 g, 82%) as a colorless liquid: bp 92-94
Met h yl
2-E t h yl-2-(1-m et h ylet h yl)-4-oxob u t a n oa t e
Oxim e (10f). The reaction of aldehyde 9f (8.00 g, 43.0 mmol)
and H2NOH‚HCl (4.78 g, 68.8 mmol) in dry pyridine (40 mL),
as described above in the preparation of 10e, gave 8.20 g of
slightly yellowish viscous liquid. Column chromatography
over silica gel (hexanes-EtOAc, 4:1) followed by bulb-to-bulb
distillation [pot temperature 110 °C (0.6 mmHg)] afforded the
anti and syn oxime mixture 10f (7.47 g, 86%) in the ratio of
60/40 as a colorless viscous liquid: Rf ) 0.45, 0.39 (hexanes-
1
°C (20 mmHg); IR 1728 (CdO), 1639 (CdC) cm-1; H NMR δ
5.85-5.71 (m, 1, CHd), 5.11-5.02 (m, 2, dCH2), 3.67 (s, 3,
OCH3), 2.49 (dd, 1, J ) 14.5, 6.7 Hz, diastereotopic H of CH2-
CHd), 2.33 (dd, 1, J ) 14.5, 7.9 Hz, diastereotopic H of CH2-
CHd), 1.90 (septet, 1, CH(CH3)2), 1.82-1.50 (m, 2, CH2CH3),
0.91 (d, 6, J ) 7.1 Hz, CH(CH3)2), 0.83 (t, 3, J ) 7.5 Hz,
EtOAc, 7:3); IR 3400 (br, OH), 1728 (CdO), 1660 (CdN) cm-1
;

3,3-Disubstituted 2-Pyrrolidinones
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 9 1905
1H NMR characteristic signals in major isomer, δ 7.52 (dd, 1,
J ) 7.3, 6.0 Hz, CHd), 3.70 (s, 3, OCH3), 2.56 (dd, 1, J ) 14.8,
6.0 Hz, diastereotopic H of CH2CHd), 2.45 (dd, 1, J ) 14.8,
7.3 Hz, diastereotopic H of CH2CHd); minor isomer, δ 6.89
(dd, 1, J ) 5.0, 6.0 Hz, CHd), 3.71 (s, 3, OCH3), 2.76 (dd, 1, J
) 14.8, 6.0 Hz, diastereotopic H of CH2CHd), 2.64 (dd, 1, J )
14.8, 5.0 Hz, diastereotopic H of CH2CHd); other signals
belonging to both isomers, δ 2.06-1.92 (m, 2, 2 × CH(CH3)2),
1.84-1.52 (m, 4, 2 × CH2CH3), 0.93-0.83 (m, 18, 2 × CH-
(CH3)2) and 2 × CH2CH3); 13C NMR δ 176.07 (CdO), 175.89
(CdO), 150.84 (CHd), 150.44 (CHd), 52.29 (CCdO), 51.72
(CCdO), 51.55 (OCH3), 33.80 (CH(CH3)2), 33.64 (CH(CH3)2),
31.29 (CH2CHd), 27.17 (CH2CH3), 26.73 (CH2CH3), 18.38 (2
× CH(CH3)2), 17.53 (CH(CH3)2), 17.43 (CH(CH3)2), 9.08
(CH2CH3), 8.99 (CH2CH3). Anal. (C10H19NO3) C, H, N.
Neu r ologica l Eva lu a tion s a n d [35S]TBP S Bin d in g. The
methods used have been described previously.4
Electr op h ysiology. Neurons were voltage-clamped at -60
mV using a Dagan Model 8900 amplifier and exposed to
GABA, or GABA and the compound were dissolved in extra-
cellular fluid by a gravity-driven application system for 400
ms. Application pipets were positioned 10-30 µm away from
cells. GABA was applied 30 s before and 30 s after GABA
and compound application. Data were discarded if GABA
response after drug application was <90% of GABA response
prior to compound application. The maximum current is
expressed as a percentage of the response to GABA alone.
Extracellular fluid contained 140 mM NaCl, 3 mM KCl, 10
mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES,
pH 7.3), 5 mM MgCl2, and 5.5 mM glucose. Intracellular fluid
contained 130 mM CsCl, 10 mM tetraethyl ammonium chlo-
ride, 10 mM HEPES pH 7.3, 2 mM QX-314 (lidocaine N-ethyl
bromide), 5.5 mM glucose, and 2 mM MgATP. Additional
details for cell culture and electrophysiological methods can
be found in ref 11.
3-(1,1-Dim et h ylet h yl)-3-m et h yl-2-p yr r olid in on e (7e).
A green solution of NiCl2‚6H2O (4.76 g, 20.0 mmol) and oximes
10e (2.01 g, 10.0 mmol) in MeOH (100 mL) was stirred
vigorously and cooled to -30 °C while NaBH4 (3.80 g, 100
mmol) was added in portions over 30 min in an atmosphere of
N2. The reaction was exothermic, producing a black precipi-
tate and copious quantities of hydrogen. The cooling bath was
removed and the mixture stirred for 1 h at room temperature.
After removal of the solvent in vacuo, the black precipitate
was dissolved in HCl (6 N, 100 mL), and then the acidic
solution was made alkaline (pH 8-9) by the addition of 28%
NH4OH (ca. 35 mL) at 0 °C. Then it was extracted with CH2-
Cl2 (3 × 40 mL), and the combined CH2Cl2 layers were washed
with brine (50 mL) and dried over MgSO4. The solvent was
removed in vacuo to give the crude methyl 4-amino-2-(1,1-
dimethylethyl)-2-methylbutyrate (1.62 g , 87%) as a colorless
Ack n ow led gm en t. We thank Ms. Nancy Lancaster
for all of the preparation and maintenance of the
primary hippocampal cultures and Mr. Gregory Mat-
thews and Mr. Korwyn Williams for preliminary elec-
trophysiological studies. The work was supported by
NIH Grant NS14834 and by Training Grant 5 T32
GM07805. Assistance was also provided by the Wash-
ington University High Resolution NMR Facility sup-
ported in part by NIH 1 S10 RR00204 and a gift from
Monsanto Company.
semisolid: IR 3359 (br, NH), 1722 (CdO) cm-1
.
To a stirred solution of the above amino ester (1.62 g, 8.66
mmol) in THF (18 mL) was added t-BuOK (7.57 g, 67.6 mmol)
at 0 °C in an atmosphere of N2. The cooling bath was removed,
and the mixture was stirred for 16 h at room temperature.
The reaction was quenched with saturated aqueous NH4Cl (50
mL) and extracted with EtOAc (3 × 30 mL). The combined
organic extract was washed with brine (30 mL) and dried over
MgSO4. The solvent was removed in vacuo to give 1.37 g of a
colorless solid. Column chromatography over silica gel (1%
MeOH in CHCl3-EtOAc, 1:1) afforded the pure lactam 7e
(1.19 g, 77%) as a colorless solid: Rf ) 0.35 (2% MeOH in
CHCl3-EtOAc, 1:1); mp 179-181 °C (ether-hexanes); IR 3194
(br, NH), 1673 (CdO) cm-1; 1H NMR δ 6.39 (br, 1, NH), 3.31-
3.18 (m, 2, NHCH2), 2.32-2.22 (m, 1, diastereotopic H of
NHCH2CH2), 1.75-1.67 (m, 1, diastereotopic H of NHCH2CH2),
1.16 (s, 3, CH3), 1.02 (s, 9, C(CH3)3); 13C NMR δ 182.76 (CdO),
48.08 (CCdO), 38.69 (NHCH2), 34.80 (C(CH3)3), 31.73
(NHCH2CH2), 25.65(C(CH3)3), 19.26 (CH3). Anal. (C9H17NO)
C, H, N.
Refer en ces
(1) Klunk, W. E.; McKeon, A. C.; Covey, D. F.; Ferrendelli, J . A.
Alpha-Substituted γ-Butyrolactones: New Class of Anticonvul-
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(2) Klunk, W. E.; Covey, D. F.; Ferrendelli, J . A. Anticonvulsant
Properties of R-, γ-, and R,γ-Substituted γ-Butyrolactones. Mol.
Pharmacol. 1982, 22, 438-443.
(3) Klunk, W. E.; Covey, D. F.; Ferrendelli, J . A. Comparison of
Epileptogenic Properties of Unsubstituted and â-Alkyl-Substi-
tuted γ-Butyrolactones. Mol. Pharmacol. 1982, 22, 431-437.
(4) (a) Peterson, E. M.; Xu, K.; Holland, K. D.; McKeon, A. C.;
Rothman, S. M.; Ferrendelli, J . A.; Covey, D. F. R-Spirocyclo-
pentyl- and R-Spirocyclopropyl-γ-Butyrolactones: Conforma-
tionally Constrained Derivatives of Anticonvulsant and Convul-
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37, 275-286. (b) Canney, D. J .; Holland, K. D.; Levine, J . A.;
McKeon, A. C.; Ferrendelli, J . A.; Covey, D. F. Synthesis and
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and γ-Thiobutyrolactones: Ligands for the Picrotoxin Receptor.
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3-Eth yl-3-(1-m eth yleth yl)-2-p yr r olid in on e (7f). The re-
action of the oximes 10f (7.04 g, 35.0 mmol) with NaBH4 (13.3
g, 350 mmol) and NiCl2‚6H2O (16.7 g, 70.0 mmol) in MeOH
(250 mL), as described above in the preparation of 7e, gave
the crude methyl 4-amino-2-ethyl-2-(1-methylethyl)butyrate
(7.59 g) as a dark-colored liquid: IR 3350 (br, NH), 1725 (CdO)
cm-1
.
The reaction of above amino ester with t-BuOK (15.29 g,
136.5 mmol) in THF (70 mL), as described above in the
preparation of 7e, gave 7.14 g of a dark-colored semisolid.
Flash chromatography over silica gel (1% MeOH in CHCl3-
EtOAc, 1:1) afforded the pure lactam 7f (3.11 g, 57% based on
the oximes) as a colorless solid: Rf ) 0.41 (2% MeOH in
CHCl3-EtOAc, 1:1); mp 63-64 °C (hexanes at -5 °C); IR 3188
(br, NH), 1682 (CdO) cm-1; 1H NMR δ 6.01 (br, 1, NH), 3.32-
3.20 (m, 2, NHCH2), 2.13-2.03 (m, 1, diastereotopic H of
NHCH2CH2), 1.95 (septet, 1, CH(CH3)2), 1.84-1.75 (m, 1,
diastereotopic H of NHCH2CH2), 1.57 (q, 2, J ) 7.4 Hz, CH2-
CH3), 0.92 (t, 3, J ) 7.4 Hz, CH2CH3), 0.90 (d, 3, J ) 6.9 Hz,
CH(CH3)2), 0.88 (d, 3, J ) 6.9 Hz, CH(CH3)2); 13C NMR δ
182.07 (CdO), 50.89 (CCdO), 39.60 (NHCH2), 32.48 (CH-
(CH3)2), 29.12 (NHCH2CH2), 25.60 (CH2CH3), 18.27 (CH-
(CH3)2), 16.80 (CH(CH3)2), 8.80 (CH2CH3). Anal. (C9H17NO)
C, H, N.
(8) Holland, K. D.; Bouley, M. G.; Covey, D. F.; Ferrendelli, J . A.
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