Hydro-de-halogenation and consecutive deprotection of chlorinated N-amido-pyrrolidin-2-ones with Raney-Ni: An effective approach to gabapentin

Article abstract of DOI:10.1016/j.tet.2003.10.046

The benzoylamino group was identified as a useful radical cyclization auxiliary that can be smoothly removed on hydro-de-halogenation of chlorinated N-substituted-pyrrolidin-2-ones with Raney-Ni. This methodology was successfully implemented in a new and appealing route to the anti-epileptic drug gabapentin.

Full text of DOI:10.1016/j.tet.2003.10.046

Tetrahedron 59 (2003) 9951–9960
Hydro-de-halogenation and consecutive deprotection of
chlorinated N-amido-pyrrolidin-2-ones with Raney-Ni:
an effective approach to gabapentin
Rita Cagnoli,a Franco Ghelfi,a Ugo M. Pagnoni, Andrew F. Parsons † and Luisa Schenettia
a
b
, ,
,
*
*
a
`
Dipartimento di Chimica, Universita degli Studi di Modena e Reggio Emilia, Via Campi 183, I-41100 Modena, Italy
bDepartment of Chemistry, University of York, Heslington, York YO10 5DD, UK
Received 25 July 2003; revised 9 October 2003; accepted 10 October 2003
Abstract—The benzoylamino group was identified as a useful radical cyclization auxiliary that can be smoothly removed on hydro-de-
halogenation of chlorinated N-substituted-pyrrolidin-2-ones with Raney-Ni. This methodology was successfully implemented in a new and
appealing route to the anti-epileptic drug gabapentin.
q 2003 Published by Elsevier Ltd.
1. Introduction
Gabapentin (1), which is sold under the name neurontinw, is
an anti-epileptic drug marketed by Pfizer that displays an
extremely low toxicity (Fig. 1). Although originally
designed as a lipophilic GABA analogue, it is now known
that gabapentin 1 does not interact with any of the enzymes
on the GABA metabolic pathway. It also does not directly
interact with either the GABAA or GABAB receptors.1
Instead, gabapentin 1 has been shown to bind with high
affinity to a binding site of a calcium channel and it is
thought that it exerts the biological activity through
interaction at this site.2
Scheme 1.
Until relatively recently, all the reported syntheses of 13
aminomethyl moiety in 1 (Scheme 1, path iii).8 Although
all of these approaches utilise cyclohexanone as a starting
material, more recently, alternative routes to 1 have
appeared that start from benzonitrile9a or cyclohexane
carboxaldehyde.9b
followed the route outlined by Sircar in 1928,4 which
involved formation of the intermediate glutaric-anhydride
derivative 3 (in several steps) from cyclohexanone (2)
(Scheme 1, path i). Unfortunately, this route, which entails a
Hofmann, Curtius or Lossen rearrangement to form 1,
requires expensive safety precautions for the handling of
thermally unstable azides and isocyanates. In 1990, Mettler
devised a more economical and technically more attractive
pathway to gabapentin 1, which exploited the addition of
hydrocyanic acid to cyano(cyclohexylidene)acetate (4)
(Scheme 1, path ii).5 However, the problem of using toxic
HCN6 spurred the development of a safer procedure by
Geibel.7 In this approach, nitromethane was reacted with
cyclohexylideneacetate (5) in order to introduce the
The main problem with these approaches is the difficulty in
preparing a wide range of analogues. Hence, although a
variety of different groups have been placed at different sites
within the cyclohexane ring, it is not easy to locate
substituents at the C-2 and C-4 positions of 1.10
Keywords: hydrazides; cyclizations; pyrrolidinones; hydrogenolysis.
*
Corresponding author. Fax: þ39-059-373543;
e-mail: ghelfi.franco@unimore.it; afp2@york.ac.uk
Fax: þ44-1904-432516.
†
Figure 1.
0040–4020/$ - see front matter q 2003 Published by Elsevier Ltd.
doi:10.1016/j.tet.2003.10.046

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R. Cagnoli et al. / Tetrahedron 59 (2003) 9951–9960
A short time ago we were involved in a project to develop
potentially more flexible routes to gabapentin 1.11 Among
the pathways we proposed, the 5-exo halogen atom transfer
radical cyclisation of the cyclohexene derivative 7 to form
8, using copper(I) chloride and TMEDA, emerged as the
most efficient and promising approach (Scheme 2). The
cyclohexyl precursor 7 was prepared by condensation of
1,1-dimethylhydrazine with cyclohex-1-ene carboxalde-
hyde 6, followed by reduction of the hydrazone and N-
acylation of the resulting hydrazine.12 Heating trichloride 8
with Raney nickel resulted in the formation of spirocycle 9
in high yield, thereafter the nitrogen protecting group was
efficiently removed on treatment of 9 with magnesium
monoperoxyphthalate in methanol. This afforded the 2-
azaspiro[4.5]decan-3-one (GBP-L) 10 and since the spiro-
cycle 10 can be easily hydrolyzed to 1, this completed our
formal synthesis of gabapentin 1.6a–c,7,8a,13
preferably cleaved with alkali metals in liquid ammonia.17,18
In fact, the few reported cases for preparing N-unsubstituted
g-lactams from N-(NRR0)-pyrrolidin-2-ones generally
use Li0/NH3.19 Although this method is efficient it is
short of practicality. In contrast the use of Raney-Ni, which
is inexpensive, easily prepared in the laboratory and
commercially available in a number of different forms
with varying activities, offers an attractive alternative
approach to reductive deprotection under non-anhydrous
conditions.20
The first studies on the cleavage of hydrazides with Raney-
Ni were conducted in the late 1950’s by Ainsworth21 and
Hinmam.22 It was observed that monoalkyl substituted
monoacylhydrazines and unsubstituted 1,2-diacylhydra-
zines could be cleaved readily, but when one of the
hydrogen atoms on nitrogen was replaced by another
substituent, the reaction proceeded with difficulty or not at
all.22 Since then, only limited and marginal applications
have been reported.19c,23
Recently, we considered the formation of 5-membered
nitrogen heterocycles by 5-exo-trig atom transfer radical
cyclisation (ATRC) of hydrazide precursors. The ATRC has
captured the attention of synthetic chemists owing to its
attractive features, including the fact that functionalized
cyclic products are formed using catalytic amounts of
inexpensive metal complexes.11,15,24 For ring closure of the
intermediate a-N-allyl-carbamoyl radical, a substituent
bound to the nitrogen atom is critical. Usually, this
cyclization auxiliary is the benzyl group, but its efficient
removal from the cyclic amides has proved problematic.25
Instead, the dimethylamino group proved to be a promising
alternative, since it could be easily and efficiently cleaved
with Raney-Ni in ethanol/water at 100–1108C.15
Scheme 2.
Importantly, this new approach to 1 involves the formation
of trichloride 8, which has chlorine atoms adjacent to the
lactam carbonyl and within the cyclohexane ring. These
chlorine atoms can potentially be used to further functio-
nalise the cyclohexane ring and the C-2 position of 1.
Another useful feature of our route to gabapentin 1 is the
preparation of GBP-L 10, which also exhibits significant
pharmacological activity.14
When the same hydro-de-chlorination/deprotection protocol
was explored in the final stage of our new approach to the
gabapentin 1 (Scheme 2) we were, however, disappointed to
observe only reduction of the three C–Cl bonds. This may
be attributed to the steric bulk of the spiro substituent at the
C(4) position of the g-lactam 8, which shields the (CO)N–
N(CH3)2 segment from the metal surface.21b,26 This failure
encouraged us to engineer an alternative nitrogen protecting
group that could be more easily reduced using Raney-Ni. So
we aimed to prepare, and then subject to hydrogenolysis, a
number of N-amino or N-amido 2-pyrrolidinones 13 using
reliable preparative routes that we have recently devised
(Scheme 3).12,24b
The choice of the dimethylamino group as a ‘cyclization
auxiliary’15 offers the opportunity to combine N-deprotec-
tion with C–Cl bond reduction by for example, hydrogen-
ation using Raney-Ni, as has been observed for more simple
2-pyrrolidinones.15 Unfortunately, this expectation was not
realized and the synthesis of GBP-L 10 needed to be
lengthened so as to include a final N-deprotection step
(under oxidizing conditions).
This approach would certainly gain in appeal if a quicker
route to GBP-L 10 from chlorinated pyrrolidin-2-one 8
could be realized. Hence we have been prompted to look for
a more easily removable cyclization auxiliary such as the
benzoylamino group, which we now report to be smoothly
removed by Raney-Ni during the hydro-de-chlorination
step.
The starting a,b-unsaturated hydrazones 11a–g of trans-2-
hexenal were thus easily converted into the corresponding
N-allyl hydrazines by reaction with dimethylamine-borane/
methanesulfonic acid, which were subsequently acylated by
trichloroacetyl chloride/pyridine and, without isolation,
rearranged to the desired polychlorinated pyrrolidin-2-
ones 13 in satisfactory yields (Table 1). The use of
methanesulfonic acid in the reduction step, as a substitute
for p-toluenesulfonic acid (PTS), simplified the procedure
because commercial PTS had to be dried (by azeotropic
distillation) prior to use.12 It should also be noted that in
order to prevent the formation of 4-diethylaminobut-3-en-2-
one, from the parasitic reaction between trichloroacetyl
2. Results and discussion
While Raney-Ni16 has regularly been employed in the
reductive cleavage of the N–N bond of hydrazines, the
situation is much more different for hydrazides, which are

R. Cagnoli et al. / Tetrahedron 59 (2003) 9951–9960
9953
Scheme 3. (a) DMAB/methanesufonic acid, ether, 08C, 3 h, argon. (b) Trichloroacetyl chloride, pyridine, CH2Cl2, 08C, overnight, argon. (c) CuCl/TMEDA,
acetonitrile, 608C, 20 h, argon.
Table 1. Preparation of the polychlorinated g-lactams 13a–ga
Entry
Precursor
Product
Yield (%)b
d.r.b
R
R1
CH3
1
2
3
4
5
6
7
CH3
(CH2)5
(CH2)2O(CH2)2
H
11a 13a
11b 13b
43
44
40
46
48
37
35
92:8
94:6
96:4
100:0
96:4
92:8
100:0
Scheme 5. (a) Wet Raney-Ni, ethanol, 1108C, 21 h.
11c
11d 13d
13c
PhCO
CH3CO 11e
11f
of substrate) was halved compared with the amount
suggested in our previous work (,4 g/0.5 mmol of
substrate).15 This change in the original experimental
procedure was designed to make the effects of the N(1)
substituents on the effectiveness of the N–N cleavage more
evident.
H
13e
13f
COArCO
CH3
PhCO
11g 13g
a
See Scheme 3, reactions performed using 10 mmol of 11.
Determined on isolated material.
b
chloride and triethylamine (observed during the acylation
step),27 pyridine was preferred as the base.
It is clear from the results obtained (Table 2), that the
benzoylamino group is by far the most easily removable
substituent among those investigated (Table 2, entry 4). To
explain this behaviour the ipotetic mechanism, described by
Horner and Jordan for the electoreductive cleavage of
The ATRC of trichloride 12 proceeds with excellent
diastereoselectivity. The higher yield of the (4R p,6S p)-
diastereoisomer of 13 (anti-addition) is consistent with the
intermediate pyrrolidinone radical preferentially adopting
conformation A rather than B (Scheme 4). Assuming the
intermediate radical has an almost planar structure, like that
of a carbocation centre,28a this can be explained on the basis
of steric interactions: for conformer A, the bulky propyl
side-chain is pointing in the opposite direction to the large
hydrazone group. The facial selectivity of the ensuing attack
by CuCl2/TMEDA on A should be very high owing to the
steric hindrance of the chloro groups. An example of a
similar ATRC exhibiting a highly stereoselective anti-
addition has been described by Ikeda.28b The Mn(III)-based
oxidative free-radical cyclization of substituted allyl a-
methyl-b-ketoesters proceeded analogously.28c
Table 2. Reaction of the g-lactams 13 with Raney-Nia
Entry
Precursor
Conv. (%)b
Products
(%)c
1
2
3
4
5
6
7
13a
13b
13c
13d
13e
13f
100
100
100
100
100
100
100
14a (99)
14b (78)
14c (97)
14d (0)b
14e (74)
15 (0)b
15 (8)
15 (1)b
15 (90)
15 (10)
15 (0)b
15 (0)b
d
–
14g (94)
13g
a
Substrate 0.5 mmol, Raney-Ni ,2 g, ethanol 2 mL, T¼1108C.
GC values.
Determined on isolated material.
A complex mixture of products was isolated but there was no trace of
N–N bond cleavage.
b
c
d
The chlorinated and N-substituted pyrrolidin-2-ones 13
were then heated at 1108C with wet Raney-Ni in ethanol for
21 h (Scheme 5). The quantity of the metal (,2 g/0.5 mmol
Scheme 4.

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R. Cagnoli et al. / Tetrahedron 59 (2003) 9951–9960
Scheme 6.
hydrazides,29 could be helpful. These authors suggested that
the N–N bond cleavage is facilitated by electron-transfer to
the carbonyl group (Scheme 6). The highest reactivity
observed with 13d can thus be related to the low energy of
its LUMO as a consequence of the extensive conjugation
between the electron-withdrawing carbonyl group and the
aromatic ring. When the hydrogen atom of the hydrazide
group of 13d is replaced by a methyl substituent, the extent
of conjugation is reduced due to steric effects and the N–N
bond of pyrrolidin-2-one 13g stood up to the reaction
conditions (Table 2, entry 7).
than that reported for the conventional 4-step nitromethane
route (26%) (Scheme 1, step iii).8a
2.1. Structural characterization of substituted
pyrrolidinones 13
The regiochemistry of the two diastereoisomers of
N-(acetylamino)-3,3-dichloro-4-(1-chlorobutyl)-2-pyrroli-
dinone 13e was derived through heteronuclear multiple-
quantum (HMQC)30a and multiple-bond (HMBC)30b
experiments and through 1H Nuclear Overhauser Exchange
Spectroscopy (NOESY).30c The first two experiments allow
us to find the directly bonded H,C pairs and those separated
by two or three bonds. These experiments are very useful for
the determination and assignment of the methylene protons:
the protons at 2.25 and 1.85 ppm correlate with a carbon at
37.4 ppm, are attributed to CH2(7), whereas those at 1.72
and 1.54 ppm which correlate with a carbon at 18.9 ppm, are
assigned to CH2(8) of the butyl chain. The protons at 3.90
and 3.56 ppm correlate with a carbon at 50.6 ppm and are
assigned to the CH2(5) of the pyrrolidinone ring. The
assignment of the methylene groups is necessary in order to
find the relative configuration of the two chiral centers C(4)
and C(6) in 13e. This goal was obtained through a NOESY
experiment performed with a mixing time of 600 ms. The
NOESY spectrum displays a strong cross peak between
H(4) (at 3.19 ppm) and H(5a) (at 3.90 ppm) and a cross peak
of lower intensity with H(5b) (at 3.56 ppm), suggesting a
cis-relationship between H(4) and H(5a). Furthermore, H(4)
displays a NOE of medium intensity with only one proton
(at 1.85 ppm) belonging to the CH2(7) group. A trans-
relationship between H(4) and H(6) (at 4.30 ppm) was
suggested by the lack of a NOE and this allows us to define
the relative configuration of C(4) and C(6) (4R p and 6S p) of
the major diastereoisomer (A). Cross-peaks between H(5b)
(3.56 ppm) and H(7b) (at 1.85 ppm), and cross peaks of
H(6) with H(7a) (2.25 ppm), H(8) (1.54 ppm) and the
methyl protons hint that the butyl chain adopts the
conformation depicted in Figure 2.
Encouraged by these promising results, our attention turned
to the use of this method to prepare GBP-L 10 from
halogenated pyrrolidin-2-one 8 (Scheme 2). The hydrazone
precursor 16 was prepared, in 94% yield, from condensation
of benzoylhydrazine with cyclohex-1-ene carboxaldehyde 6
(Scheme 7). The ensuing reduction of the CvN bond with
dimethylamine-borane/methanesulfonic acid and N-acyl-
ation of the resulting hydrazine gave the amide 17 with high
efficiency (81%). On treatment of 17 with CuCl/TMEDA3a
the desired spirocycle 18 was formed in 77% yield, as a
single diastereoisomer, which was tentatively assigned as
having (5R p,6S p) stereochemistry in accord with a selective
anti-addition of the chlorine atom (see earlier). Finally, we
were pleased to see that heating the intermediate trichloride
g-lactam 18 with Raney-Ni at 1108C smoothly resulted in
the formation of GBP-L 10 (90%), and this step completed
our formal synthesis of gabapentin 1. The overall yield of 1
prepared via this 5-step approach is 37%, which is higher
The proton spectrum of the second diastereoisomer (B)
shows similar peaks for the pyrrolidinone ring protons,
whereas marked differences are found for the butyl chain
protons, that are clearly diastereotopic in A but not in B.
Scheme 7. (a) Benzoylhydrazine, CH2Cl2, rt, overnight. (b): i) DMAB/-
methanesulfonic acid, ether, 08C, 3 h, argon; ii) trichloroacetyl chloride,
pyridine, CH2Cl2, 08C, overnight, argon. (c) CuCl/TMEDA, acetonitrile,
608C, 20 h, argon. (d) Wet Raney-Ni, ethanol, 1108C, 21 h. (e) HCl, heat.8a
Applying the same experiments, we were able to obtain the
complete characterisation of diastereoisomer B and to

R. Cagnoli et al. / Tetrahedron 59 (2003) 9951–9960
9955
squared sine function (SSB¼2) in f2 and Gaussian
multiplication (LB¼21, GB¼0.01) in f1 were applied
before Fourier transformation. IR spectra were obtained
with a Perkin–Elmer 1600 Series FTIR. Mass spectra were
acquired with a combined HP 5890 GC/HP 5989A MS
Engine. Reagents and solvents were standard grade
commercial products, purchased from Aldrich or Fluka,
and used without further purification. The acyl hydrazones
11e and 11g were secured following the protocol of Feid–
Allah.32
Figure 2.
establish, through a NOESY experiment, the relative
configuration of the two chiral centers: a high intensity
cross-peak between H(4) (at 3.19 ppm) and H(6) (at
4.29 ppm), besides the expected NOEs allows us to attribute
a (4R p-6R p) relative configuration to B.
4.1.1. Typical procedure for the preparation of hydra-
zones: trans-2-hexenal N,N-dimethylhydrazone (11a). In
a single-necked round-bottom flask (100 mL) trans-2-
hexenal (5.8 mL, 50.0 mmol) and N,N-dimethylhydrazine
(4.1 mL, 52.5 mmol) were successively dissolved, at room
temperature, in CH2Cl2 (50 mL), and the solution was
stirred until complete conversion (16–24 h). Afterward the
reaction mixture was diluted with water (50 mL) and
extracted. The organic phases were collected and dried by
azeotropic distillation with toluene, and concentrated. The
crude product 11a, was recovered (6.59 g, 94%) as a reddish
oil, which did not require further purification. [Found: C,
68.4; H, 11.4; N, 20.2. C8H16N2 requires C, 68.52; H, 11.50;
N, 19.98]; dH (200 MHz, CDCl3) 7.05 (1H, d, J¼8.8 Hz,
CHvN), 6.22 (1H, ddt, J¼15.5, 8.8, 1.3 Hz,
CHvCHCHvN), 5.83 (1H, dt, J¼15.5, 7.5 Hz,
CHvCHCHvN), 2.84 (6H, s, NMe2), 2.14 (2H, dq,
J¼7.5, 1.3 Hz, CH2-allylic), 1.47 (2H, sex, J¼7.5 Hz,
CH2Me), 0.94 (3H, t, J¼7.5 Hz, CH2Me); m/z (EI): 140
(100, Mþ), 125 (16), 111 (77), 96 (51), 82 (38), 68 (36).
On the same basis, a confident attribution of the configur-
ation can be made for lactams 13a–d,f,g.
3. Conclusion
Our endeavour to increase the appeal of a new route to
gabapentin 1 from cyclohexane carboxaldehyde 6 was
fulfilled by the discovery that the benzoylamino group is an
effective radical cyclization auxiliary, which can be
smoothly removed during the hydro-de-halogenation of
the chlorinated spirocycle intermediate 18 with Raney-Ni.
Importantly, the formation of the polychlorinated adduct 18,
which has chlorine atoms adjacent to the lactam carbonyl
and within the cyclohexane ring, has the potential to be used
to further functionalise the cyclohexane ring and the C-2
position of 1. Moreover with the replacement of trichloro-
acetyl chloride with other a-perchloroacyl chlorides the
procedure is also potentially adaptable to the preparation of
a vast array of modified gabapentins. Another useful feature
of our route to 1 is the intermediate formation of GBP-L 10,
a substance with an interesting pharmacological activity.
4.1.2. 1-(1-Aza-1,3-eptadienyl)-piperidine (11b). Accord-
ing to the general procedure trans-2-hexenal (5.8 mL,
50.0 mmol) gave 11b (8.38 g, 93%) as a dark orange oil;
[Found: C, 73.4; H, 11.3; N, 15.6. C11H20N2 requires C,
73.28; H, 11.18; N, 15.54]; dH (200 MHz, CDCl3) 7.30 (1H,
d, J¼8.7 Hz, CHvN), 6.23 (1H, ddt, J¼15.6, 8.7, 1.3 Hz,
CHvCHCHvN), 5.86 (1H, dt, J¼15.6, 6.8 Hz,
CHvCHCHvN), 3.02 (4H, m, 2£CH2(a)-pip), 2.14 (2H,
dq, J¼7.5, 1.3 Hz, CH2-allylic), 1.70 (4H, m, 2£CH2(b)
-pip) 1.52 (2H, m, CH2(g) -pip), 1.47 (2H, sex,
J¼7.50 Hz, CH2Me), 0.93 (3H, t, J¼7.5 Hz, CH2Me);
m/z (EI): 180 (95 Mþ), 164 (8), 151 (100), 137 (18), 122
(18), 96 (27), 84 (72).
Studies on the application of this approach to the synthesis
of the GABA analogue pregabalin31 will be reported in due
course.
4. Experimental
4.1. General
4.1.3.
4-(1-Aza-1,3-eptadienyl)-morpholine
(11c).
1H NMR spectra were recorded in CDCl3 solutions with a
Bruker 400AMX WB and a Jeol EX 270 spectrometer, and
the chemical shifts are reported in ppm relative to
tetramethylsilane as external standard. Conditions for
HMQC30a spectra were: evolution delay¼3.57 ms, spectral
width¼10 ppm with 2048 complex points in f2; 256 t1
values and 32 scans for t1 value. A squared sine function
(SSB¼2) in f2 and f1 was applied before Fourier
transformation. Similar conditions were used for
HMBC30b experiments except: delay for low-pass
filter¼3.57 ms, evolution delay¼50 ms (optimization of
nJ(H,C)¼10 Hz responses) and 64 scans for t1 value.
Conditions for NOESY30c phase-sensitive spectra by time-
proportional phase incrementation (TPPI) were: mixing
time of 600 ms, spectral width 8.16 ppm with 2048 complex
points in f2; 128 t1 values and 64 scans for t1 value. A
According to the general procedure trans-2-hexenal
(5.8 mL, 50.0 mmol) gave 11c (8.57 g, 94%) as an orange
oil; [Found: C, 66.1; H, 9.9; N, 15.6. C10H18N2O requires C,
65.90; H, 9.95; N, 15.37]; dH (200 MHz, CDCl3) 7.31 (1H,
d, J¼8.7 Hz, CHvN), 6.20 (1H, ddt, J¼15.5, 8.7, 1.3 Hz,
CHvCHCHvN), 5.90 (1H, dt, J¼15.5, 7.5 Hz,
CHvCHCHvN), 3.82 (4H, m, CH2OCH2), 3.02 (4H, m,
CH2NCH2), 2.13 (2H, dq, J¼7.5, 1.3 Hz, CH2-allylic), 1.45
(2H, sex, J¼7.5 Hz, CH2Me), 0.91 (3H, t, J¼7.5 Hz,
CH2Me); m/z (EI): 182 (100 Mþ), 153 (58), 125 (12), 110
(13), 96 (62), 86 (32), 82 (30), 56 (47).
4.1.4.
N-(1-Aza-1,3-eptadienyl)-phthalimide
(11f).
According to the general procedure trans-2-hexenal
(1,2 mL, 10.0 mmol) gave 11f (2.23 g, 92%) as a slightly
orange solid, mp 73–758C; [Found: C, 69.6; H, 5.9; N, 11.5.

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R. Cagnoli et al. / Tetrahedron 59 (2003) 9951–9960
C14H14N2O2 requires C, 69.41; H, 5.82; N, 11.56]; dH
(200 MHz, CDCl3) 8.98 (1H, m, CHvN), 7.92–7.73 (4H,
m, Ph), 6.58–6.28 (2H, m, CHvCHCHvN), 2.27 (2H, m,
CH2-allylic), 1.52 (2H, sex, J¼7.5 Hz, CH2Me), 0.97 (3H, t,
J¼7.5, CH2Me); m/z (EI): 242 (67 Mþ), 199 (88), 148 (52),
130 (55), 105 (100), 104 (82), 96 (55), 80 (50), 76 (65).
6 mL) and left under stirring for a further 0.5 h to cleave any
residual boron-nitrogen bond, always keeping an inert
atmosphere. The organic phase (ether) was cannulated into
another Schlenk tube, evaporated and CH2Cl2 (20 mL)
added. After cooling at 08C, pyridine (0.97 mL, 12 mmol)
and trichloroacetyl chloride (1.23 mL, 11 mmol) were
introduced. After overnight stirring, the mixture was diluted
with NaOH (5% w/v, 60 mL), and extracted with CH2Cl2
(2£10 mL). The combined organic layers were dried over
MgSO4 and concentrated into a Schlenk tube. Then CuCl
(0.1 g, 1 mmol) was introduced, followed by dry acetonitrile
(20 mL) and TMEDA (0.30 mL, 2 mmol) under argon. The
mixture was stirred at 608C for 20 h, then diluted with H2O
(10 mL) and extracted with CH2Cl2 (2£10 mL). The
organic phases were collected, dried by azeotropic distilla-
tion with toluene, and concentrated. Flash chromatography
of the crude product on silica gel, using a petroleum ether
(bp 40–608C)/diethyl ether gradient, gave the major
diastereoisomer (4R p,6S p)-13a (1.14 g, 40%) as an orange
solid; mp 73–758C; [Found: C, 41.8; H, 5.8; N, 9.8.
C10H17Cl3N2O requires C, 41.76; H, 5.96; N, 9.74]; nmax
(KBr) 1734 cm21; dH (200 MHz, CDCl3) 4.29 (1H, dt,
J¼2.7, 9.5, 9.5 Hz, H6), 3.70 (1H, dd, J¼7.2, 10.0 Hz,
H5b), 3.25 (1H, dd, J¼8.7, 10.0 Hz, H5a), 2.97 (1H, m, H4),
2.72 (6H, s, NMe2), 2.40–1.39 (4H, m, CH2CH2Me), 0.99
(3H, t, J¼7.3 Hz, CH2CH2Me); m/z (EI): 286 (15 Mþ), 244
(100), 118 (38), 93 (8), 72 (55), 43 (48). From flash
chromatography, the minor diastereoisomer (4R p,6S p)-13a
(98 mg, 3%) was also recovered as a dark red oil; [Found: C,
41.8; H, 5.8; N, 9.8. C10H17Cl3N2O requires C, 41.76; H,
5.96; N, 9.74]; nmax (liquid film) 1734 cm21; dH (200 MHz,
CDCl3) 4.31 (1H, m, H6), 3.52 (1H, dd, J¼7.2, 9.6 Hz,
H5b), 3.24 (1H, dd, J¼7.4, 9.6 Hz, H5a), 3.07 (1H, m, H4),
2.75 (6H, s, N(CH3)2), 1.84–1.39 (4H, m, CH2CH2CH3),
0.97 (3H, t, J¼7.3 Hz, CH2CH2CH3); m/z (EI): 286 (15
Mþ), 244 (100), 118 (38), 93 (8), 72 (54), 43 (48).
4.1.5. trans-2-Hexenal benzoylhydrazone (11d). Accord-
ing to the procedure of Feid–Allah,32 trans-2-hexenal
(5.8 mL, 50.0 mmol) gave 11d (10.27 g, 95%) as a white
powder mp 105–1078C; [Found: C, 72.1; H, 7.3; N, 12.8.
C13H16N2O requires C, 72.19; H, 7.46; N, 12.95]; dH
(200 MHz, CDCl3) 9.08 (1H, bs, NH), 7.87–7.43 (6H, m,
Ph–CHvN), 6.42–6.11 (2H, m, CHvCHCHvN), 2.24
(2H, q, J¼7.5 Hz, CH2-allylic), 1.47 (2H, sex, J¼7.5 Hz,
CH2Me), 0.97 (3H, t, J¼7.5 Hz, CH2Me); m/z (EI): 216 (7
Mþ), 173 (4), 147 (7), 105 (100), 77 (63), 51 (27).
4.1.6. trans-2-Hexenal acetylhydrazone (11e). According
to the procedure of Feid–Allah,32 trans-2-hexenal (5.8 mL,
50.0 mmol) gave 11e (7.02, 91%) as a reddish oil; [Found:
C, 62.2; H, 9.3; N, 18.3. C8H14N2O requires C, 62.31; H,
9.15; N, 18.17]; dH (200 MHz, CDCl3) 10.5 (1H, s, NH),
7.53 (1H, m, CHvN), 6.24–6.10 (2H, m,
CHvCHCHvN), 2.27 (3H, s, COMe), 2.17 (2H, m, CH2-
allylic), 1.50 (2H, sex, J¼7.5 Hz, CH2Me), 0.95 (3H, t,
J¼7.4, CH2Me); m/z (EI): 154 (96 Mþ), 111 (15), 96 (84),
83 (77), 69 (99), 60 (65), 43 (100).
4.1.7. Preparation of N-methyl-benzoylhydrazone (11g).
In a double-necked round-bottom flask (100 mL) fitted
with a Liebig condenser and a rubber septum adapter,
N-methylhydrazine (2.7 mL, 50 mmol) was dissolved, at
08C, in CH2Cl2 (50 mL), then a solution of trans-2-hexenal
(5.8 mL, 50.0 mmol) solubilized in CH2Cl2 (20 mL) was
added. After 1 h, under vigorous stirring, pyridine (6.1 mL
75, mmol) and, slowly, benzoyl chloride (8.7 mL, 75 mmol)
were added by syringe. The reaction mixture was left at
room temperature for 2 h, then diluted with water (50 mL)
and extracted. The aqueous phase was further washed with
CH2Cl2 (2£10 mL). The organic phases were then col-
lected, dried by azeotropic distillation with toluene, and
concentrated. Flash chromatography of the crude product on
silica gel, using a petroleum ether (bp 40–608C)/diethyl
ether gradient, gave 11g (9.67 g, 84%) as an orange solid;
mp 63–648C; [Found: C, 72.8; H, 7.8; N, 12.2. C14H18N2O
requires C, 73.01; H, 7.88; N, 12.16]; dH (200 MHz, CDCl3)
7.71–7.37 (6H, m, PhþCHvN), 6.25–6.11 (2H, m,
CHvCHCHvN), 3.48 (3H, s, NMe), 2.19 (2H, dq,
J¼1.3, 7.5 Hz, CH2-allylic), 1.48 (2H, sex, J¼7.5 Hz
CH2Me), 0.95 (3H, t, J¼7.5, CH2Me); m/z (EI): 230 (5
Mþ), 134 (15), 105 (77), 77 (42), 51 (13).
4.1.9. N-(1-Piperazinyl)-3,3-dichloro-4-(1-chlorobutyl)-
2-pyrrolidinone (13b). According to the general procedure,
the hydrazone 11b (10.0 mmol, 1.80 g) gave the major
diastereoisomer (4R p,6S p)-13b (1.36 g, 41%) as an orange
oil; [Found: C, 47.8; H, 6.5; N, 8.7. C13H21Cl3N2O requires
C, 47.65; H, 6.46; N, 8.55]; nmax (liquid film) 1732 cm21
;
dH (200 MHz, CDCl3) 4.29 (1H, dt, J¼2.8, 9.6, Hz, H6),
3.72 (1H, dd, J¼7.3, 10.1 Hz, H5b), 3.28 (1H, dd, J¼8.7,
10.1 Hz, H5a), 3.16–2.89 (5H, m, H4þCH2(a)-pip), 2.50–
1.10 (10H, m, 2£CH2(b)þ2£CH2(g)-pipþCH2CH2Me),
0.99 (3H, t, J¼7.3 Hz, CH2CH2Me); m/z (EI): 326 (2
Mþ), 244 (8), 199 (12), 139 (5), 111 (8), 83 (100), 55 (23).
From flash chromatography, the minor diastereoisomer
(4R p,6R p)-13b (85 mg, 3%) was also recovered as a pallid
orange oil; [Found: C, 47.8; H, 6.5; N, 8.7. C13H21Cl3N2O
requires C, 47.65; H, 6.46; N, 8.55]; nmax (liquid film)
1732 cm21; dH (200 MHz, CDCl3) 4.30 (1H, m, H6), 3.52
(1H, dd, J¼7.3, 9.8 Hz, H5b), 3.24 (1H, dd, J¼7.3, 9.8 Hz,
H5a), 3.16–2.89 (5H, m, H4þ2£CH2(a)-pip), 2.50–1.10
(10H, m, 2£CH2(b)þ2£CH2(g)-pipþCH2CH2Me), 0.96
(3H, t, J¼7.3 Hz, CH2CH2Me); m/z (EI): 326 (2 Mþ), 244
(8), 199 (12), 139 (5), 111 (8), 83 (100), 55 (23).
4.1.8. Typical procedure for the preparation of chlori-
nated lactams 13: N-(dimethylamino)-3,3-dichloro-4-(1-
chlorobutyl)-2-pyrrolidinone (13a). DMAB (0.94 g,
16 mmol) and trans 2-hexenal N,N-dimethylhydrazone
11a (1.40 g, 10 mmol) were weighted in a screw capped
Schlenk tube equipped with a perforable septum; then,
under argon and at 08C, diethyl ether (20 mL) and a solution
of methanesulfonic acid (3.89 mL, 60 mmol) in diethyl
ether (20 mL), both cooled to 08C, were added. After 3 h,
the reaction mixture was quenched with Na2CO3 (10% w/v,
4.1.10. N-(4-Morpholinyl)-3,3-dichloro-4-(1-chlorobu-
tyl)-2-pyrrolidinone (13c). According to the general
procedure, the hydrazone 11c (10.0 mmol, 1.82 g) gave

R. Cagnoli et al. / Tetrahedron 59 (2003) 9951–9960
9957
the major diastereoisomer (4R p,6S p)-13c (1.27 g, 38%) as a
pale orange solid; mp 121–1248C; [Found: C, 43.8; H, 5.9;
N, 8.3. C12H19Cl3N2O2 requires C, 43.72; H, 5.81; N, 8.50];
4.1.13. N-(Phthalimido)-3,3-dichloro-4-(1-chlorobutyl)-
2-pyrrolidinone (13f). According to the general procedure,
the hydrazone 11f (10.0 mmol, 2.42 g) gave the major
diastereoisomer (4R p,6S p)-13f (1.32 g, 34%) as a white
solid; mp 110–1148C; [Found: C, 49.4; H, 4.1; N, 7.4.
C16H15Cl3N2O3 requires C, 49.32; H, 3.88; N, 7.19]; nmax
(KBr) 1766, 1739 cm21; dH (200 MHz, CDCl3) 7.98–7.81
(4H, m, Ph), 4.40 (1H, dt, J¼2.8, 9.7 Hz, H6), 3.96 (1H, dd,
J¼7.4, 9.7 Hz, H5a), 3.74 (1H, t, J¼9.7 Hz, H5b), 3.49 (1H,
m, H4), 2.50–1.50 (4H, m, CH2CH2Me), 1.04 (3H, t,
J¼7.4 Hz, CH2CH2Me); m/z (EI): 388 (2 Mþ), 353 (41), 317
(9), 254 (13), 206 (16), 150 (59), 148 (41), 130 (32), 105
(49), 104 (100), 99 (50), 76 (73). From flash chromato-
graphy, the minor diastereoisomer (4R p,6R p)-13f (0.12 g,
3%) was also recovered as a white solid; mp 181–1858C;
[Found: C, 49.4; H, 4.1; N, 7.4. C16H15Cl3N2O3 requires C,
49.32; H, 3.88; N, 7.19]; nmax (KBr) 1766, 1739 cm21; dH
(200 MHz, CDCl3) 7.97–7.82 (4H, m, Ph), 4.42 (1H, m,
H6), 3.85 (1H, dd, J¼7.4, 8.7 Hz, H5a), 3.68 (1H, dd,
J¼7.5, 8.7 Hz, H5b), 3.46 (1H, m, H4), 1.78–1.50 (4H, m,
CH2CH2Me), 0.98 (3H, t, J¼7.4 Hz, CH2CH2Me); m/z
(EI): 388 (2 Mþ), 353 (41), 317 (9), 254 (13), 206 (16),
150 (59), 148 (41), 130 (32), 105 (49), 104 (100), 99
(50), 76 (73).
n
max (KBr) 1736 cm21; dH (200 MHz, CDCl3) 4.29 (1H, dt,
J¼2.7, 9.5 Hz, H6), 3.78 (4H, t, J¼5.4 Hz, 2£CH2(O)-mor),
3.73 (1H, dd, J¼7.3, 10.0 Hz, H5b), 3.30 (1H, dd, J¼8.7,
10.0 Hz, H5a), 3.21–2.92 (5H, m, H4þ2£CH2(N)-mor),
2.32–1.41 (4H, m, CH2CH2Me), 0.99 (3H, t, J¼7.3 Hz,
CH2CH2Me); m/z (EI): 328 (3 Mþ), 244 (15), 201 (3), 118
(5), 85 (100), 55 (73). From flash chromatography, the
minor diastereoisomer (4R p,6R p)-13c (53 mg, 2%) was
also recovered as an orange solid; mp 110–1128C; [Found:
C, 43.8; H, 5.9; N, 8.3. C12H19Cl3N2O2 requires C, 43.72; H,
5.81; N, 8.50]; nmax (KBr) 1736 cm21; dH (200 MHz,
CDCl3) 4.31 (1H, m, H6), 3.78 (4H, t, J¼5.4 Hz,
2£CH2(O)-mor), 3.57 (1H, dd, J¼7.3, 9.7 Hz, H5b), 3.29
(1H, dd, J¼7.4, 9.7 Hz, H5a), 3.21–3.04 (5H, m,
H4þ2£CH2(N)-mor), 1.78–1.41 (4H, m, CH2CH2Me),
0.99 (3H, t, J¼7.3 Hz, CH2CH2Me); m/z (EI): 328 (3
Mþ), 244 (15), 201 (3), 118 (5), 85 (100), 55 (73).
4.1.11. N-(Benzoylamino)-3,3-dichloro-4-(1-chlorobu-
tyl)-2-pyrrolidinone (13d). According to the general
procedure, the hydrazone 11d (10.0 mmol, 2.16 g) gave
the single diastereoisomer (4R p,6S p)-13d (1.67 g, 46%) as
a white solid; mp 171–1728C; [Found: C, 49.5; H, 4.8; N,
7.8. C15H17Cl3N2O2 requires C, 49.54; H, 4.71; N, 7.70];
nmax (KBr) 1757, 1656 cm21; dH (200 MHz, CDCl3) 8.59
(1H, s, NH), 7.85–7.22 (5H, m, Ph), 4.35 (1H, dt, J¼2.8,
9.6 Hz, H6), 4.02 (1H, dd, J¼7.4, 9.6 Hz, H5a), 3.68 (1H, t,
J¼9.6 Hz, H5b), 3.30 (1H, m, H4), 2.41–1.50 (4H, m,
CH2CH2Me), 1.03 (3H, t, J¼7.4 Hz, CH2CH2Me); m/z (EI):
362 (4 Mþ), 135 (13), 105 (100), 77 (35), 51 (5).
4.1.14. N-(Benzoylmethylamino)-3,3-dichloro-4-(1-
chlorobutyl)-2-pyrrolidinone (13g). According to the
general procedure, the hydrazone 11g (10.0 mmol, 2.30 g)
gave the single diastereoisomer (4R p,6S p)-13g (1.32 g,
35%) as a brownish solid; mp 75–778C; [Found: C, 50.9; H,
5.2; N, 7.5. C16H19Cl3N2O2 requires C, 50.88; H, 5.07; N,
7.42]; nmax (KBr) 1752, 1676 cm21; dH (200 MHz, CDCl3)
7.47–7.43 (5H, m, Ph), 4.20 (1H, m, H6), 3.70 (1H, m,
H5a), 3.45 (1H, m, H5b), 3.30 (3H, s, MeN), 3.10 (1H, m,
H4), 2.40–1.40 (4H, m, CH2CH2Me), 0.97 (3H, t,
J¼7.2 Hz, CH2CH2Me); m/z (EI): 376 (5 Mþ), 135 (14),
105 (100), 77 (35), 51 (5).
4.1.12. N-(Acetylamino)-3,3-dichloro-4-(1-chlorobutyl)-
2-pyrrolidinone (13e). According to the general procedure,
the hydrazone 11e (10.0 mmol, 1.54 g) gave the major
diastereoisomer (4R p,6S p)-13e (1.39 g, 46%) as a pale
yellow solid; mp 115–1188C; [Found: C, 39.8; H, 5.2; N,
9.4. C10H15Cl3N2O2 requires C, 39.82; H, 5.01; N, 9.29];
nmax (KBr) 1748, 1681 cm21; dH (400 MHz, CDCl3) 8.53
(1H, s, NH), 4.30 (1H, dt, J¼2.7, 9.8 Hz, H6), 3.90 (1H, dd,
J¼7.5, 9.8 Hz, H5a), 3.56 (1H, t, J¼9.8 Hz, H5b), 3.19 (1H,
dt, J¼9.8, 7.6 Hz, H4), 2.25 (1H, m, H7a), 2.07 (3H, s,
COMe), 1.85 (1H, m, H7b), 1.72 (1H, m, H8a), 1.54 (1H, m,
H8b), 0.99 (3H, t, J¼7.4 Hz, CH2CH2CH2Me); dc
(100.6 MHz, CDCl3) 168.8 (COMe), 165.6 (C2), 81.7
(C3), 61.1 (C6), 53.6 (C4), 50.6 (C5), 37.4 (C7), 20.8
(C11), 18.9 (C8), 13.2 (C9); m/z (EI): 300 (1 Mþ), 258
(100), 223 (85), 187 (8), 133 (17), 43 (73). From flash
chromatography, the minor diastereoisomer (4R p,6R p)-13e
(57 mg, 2%) was also recovered as a white solid; mp
168–1728C; [Found: C, 39.8; H, 5.2; N, 9.4.
C10H15Cl3N2O2 requires C, 39.82; H, 5.01; N, 9.29]; nmax
(KBr) 1748, 1681 cm21; dH (400 MHz, CDCl3) 8.75 (1H, s,
NH), 4.29 (1H, dt, J¼2.7, 9.4 Hz, H6), 3.73 (1H, dd, J¼7.8,
9.4 Hz, H5a), 3.49 (1H, t, J¼9.4 Hz, H5b), 3.19 (1H, dt,
J¼9.4, 7.8 Hz, H4), 2.07 (3H, s, COMe), 1.72–1.68 (2H, m,
H7), 1.52–1.48 (2H, m, H8), 0.95 (3H, t, J¼7.0 Hz,
CH2CH2CH2Me); dc (100.6 MHz, CDCl3) 169.0 (COMe),
165.8 (C2), 82.4 (C3), 58.5 (C6), 53.8 (C4), 48.8 (C5), 36.6
(C7), 20.8 (C11), 18.8 (C8), 13.3 (C9); m/z (EI): 300 (1
Mþ), 258 (100), 223 (85), 187 (8), 133 (17), 43 (73).
4.1.15. Typical procedure for the reaction of 12 with
Raney-Ni: N-(dimethylamino)-4-butyl-2-pyrrolidinone
(14a). In a Schlenk tube fitted with a stirring bar was
added 20 mL of a Fluka suspension of Raney-Ni in
H2O. After sedimentation of the nickel, supernatant water
was carefully removed. To the wet Raney-Ni (,2 g), the
lactam 13a (144 mg, 0.5 mmol) and ethanol (2 mL) were
added in succession. The mixture was stirred at 1108C, and
after 21 h it was filtered and concentrated. Chromatography
of the crude product on silica gel, eluting with a diethyl
ether/methanol gradient, gave 14a (91 mg, 99%), as a
colourless oil; [Found: C, 65.3; H, 10.8; N, 15.1.
C10H20N2O requires C, 65.18; H, 10.90; N, 15.20]; nmax
(liquid film) 1699 cm21; dH (200 MHz, CDCl3) 3.50 (1H,
t, J¼9.4 Hz, H5a), 2.98 (1H, dd, J¼7.5, 9.4 Hz, H5b),
2.62 (6H, s, NMe2), 2.56–188 (3H, m, H3a,bþH4), 1.52–
1.20 (6H, m, CH2CH2CH2Me), 0.90 (3H, t, J¼6.1 Hz,
CH2CH2CH2Me); m/z (EI): 184 (17 Mþ), 169 (5), 155 (5),
142 (100), 84 (8), 72 (20), 55 (15), 44 (48).
4.1.16. N-(1-Piperazinyl)-4-butyl-2-pyrrolidinone (14b).
According to the general procedure lactam 13b (164 mg,
0.5 mmol) gave 14b (87 mg, 78%) as a colourless oil;
[Found: C, 69.5; H, 10.9; N, 12.5. C13H24N2O requires C,
69.60; H, 10.78; N, 12.49]; nmax (liquid film) 1698 cm21; dH

9958
R. Cagnoli et al. / Tetrahedron 59 (2003) 9951–9960
(200 MHz, CDCl3) 3.53 (1H, dd, J¼8.4, 9.1 Hz, H5a), 3.02
(1H, dd, J¼7.3, 9.1 Hz, H5b), 2.86 (4H, m, 2£CH2N-pip),
2.44 (1H, dd, J¼4.0, 8.7 Hz, H3a), 2.20 (1H, m, H4), 1.96
(1H, dd, J¼4.0, 8.7 Hz, H3b), 1.78–1.15 (12H, m,
J¼6.4 Hz, CH2CH2CH2Me); m/z (EI): 224 (10 Mþ), 142
(100), 84 (100), 83 (77), 68 (7), 55 (35). The hydro-de-
halogenated and deprotected lactam 15 (6 mg, 8%) was also
recovered on column chromatography.
dissolved, at room temperature, in CH2Cl2 (10 mL), and the
solution was stirred until complete conversion (16–24 h).
Afterward, the reaction mixture was diluted with water
(10 mL) and extracted. The aqueous phase was further
washed with CH2Cl2 (2£10 mL). The organic phases were
then collected, dried by azeotropic distillation with toluene,
and concentrated. The crude product 16, which did not
require additional purification, was recovered (2.04 g, 94%)
as a white solid; mp 188–1898C; [Found: C, 73.5; H, 7.1; N,
12.0. C14H16N2O requires C, 73.66; H, 7.06; N, 12.27]; nmax
(KBr) 1638 cm21; dH (200 MHz, CDCl3) 8.9 (1H, bs, NH),
8.0–7.35 (6H, m, PhþCHvN), 6.10 (1H, s,
CHvCCHvN), 2.0–1.44 (8H, m, (CH2)4); m/z (EI): 228
(5 Mþ), 122 (30), 105 (100), 77 (35), 51 (5).
CH2CH2CH2MeþCH2CH2CH2-pip),
0.87
(3H,
t,
4.1.17. N-(4-Morpholinyl)-4-butyl-2-pyrrolidinone (14c).
According to the general procedure, lactam 13c (165 mg,
0.5 mmol) gave 14c (110 mg, 97%) as a colourless oil;
[Found: C, 63.7; H, 9.8; N, 12.3. C12H22N2O2 requires C,
63.69; H, 9.80; N, 12.38]; nmax (liquid film) 1697 cm21; dH
(200 MHz, CDCl3) 3.78 (4H, m, 2£CH2(O)-mor), 3.54 (1H,
t, J¼8.4 Hz, H5a), 3.04 (1H, t, J¼8.4 Hz, H5b), 2.95 (4H,
m, 2£CH2(N)-mor), 2.52–1.80 (3H, m H3a,bþH4), 1.50–
1.18 (6H, m, CH2CH2CH2Me), 0.88 (3H, t, J¼6.7 Hz,
CH2CH2CH2Me); m/z (EI): 226 (8 Mþ), 169 (2), 142 (100),
86 (67), 85 (45), 55 (45).
4.1.22. N0-(1-Cyclohexenyl-methyl)-N-trichloroacetyl-
benzohydrazide (17). DMAB (0.94 g, 16 mmol) and
hydrazone 16 (2.28 g, 10 mmol) were weighted in a screw
capped Schlenk tube equipped with a perforable septum;
then, under argon and at 08C, diethyl ether (20 mL) and a
solution of methanesulfonic acid (3.89 mL, 60 mmol) in
diethyl ether (20 mL), both cooled to 08C, were added. After
3 h, the reaction mixture was quenched with Na2CO3 (10%
w/v, 6 mL) and left to stir for a further 0.5 h to cleave any
residual boron–nitrogen bond, always keeping an inert
atmosphere. The organic phase (ether) was cannulated into
another Schlenk tube, evaporated and CH2Cl2 (20 mL)
added. After cooling to 08C, pyridine (0.97 mL, 12 mmol)
and trichloroacetyl chloride (1.23 mL, 11 mmol) were
introduced. After stirring overnight, the mixture was diluted
with NaOH (5% w/v, 60 mL) and extracted with CH2Cl2
(2£10 mL). The organic phases were collected, dried by
azeotropic distillation with toluene, and concentrated. Flash
chromatography of the crude product on silica gel, using a
petroleum ether (bp 40–608C)/diethyl ether gradient, gave
17 (3.04 g, 81%) as a yellowish solid; mp 141–1448C;
[Found: C, 51.3; H, 4.3; N, 7.7. C16H17Cl3N2O2 requires C,
51.15; H, 4.56; N, 7.46]; nmax (KBr) 1703, 1677 cm21; dH
(200 MHz, CDCl3) 8.8 (1H, bs, NH), 7.9–7.4 (5H, m, Ph),
5.65 (1H, s, CHvC), 4.35 (2H, bs, CH2N), 2.1–1.5 (8H, m,
(CH2)4); m/z (EI): 256 (27), 254 (9), 163 (25), 122 (20), 105
(100), 94 (56), 77 (57).
4.1.18. N-(Acetylamino)-4-butyl-2-pyrrolidinone (14e).
According to the general procedure, lactam 13e (151 mg,
0.5 mmol) gave 14e (73 mg, 74%) as a colourless oil;
[Found: C, 60.6; H, 9.3; N, 14.3. C10H18N2O2 requires C,
60.58; H, 9.15; N, 14.13]; nmax (liquid film) 1717,
1679 cm21; dH (200 MHz, CDCl3) 9.18 (1H, s, NH), 3.69
(1H, t, J¼8.3 Hz, H5a), 3.31 (1H, t, J¼8.3 Hz, H5b),
2.70–2.16 (3H, m H3a,b þ H4), 1.99 (3H, s, COMe), 1.55–
1.17 (6H, m, CH2CH2CH2Me), 0.88 (3H, t, J¼6.7 Hz,
CH2CH2CH2Me); m/z (EI): 198 (2 Mþ), 156 (67), 140 (63),
99 (18), 55 (23), 45 (100), 43 (25). The hydro-de-
halogenated and deprotected lactam 15 (7 mg, 10%) was
also recovered on column chromatography.
4.1.19. N-(Benzoylmethylamino)-4-butyl-2-pyrrolidi-
none (14g). According to the general procedure, lactam
13g (189 mg, 0.5 mmol) gave 14g (129 mg, 94%) as a
colourless oil; [Found: C, 70.2; H, 8.0; N, 10.1. C16H22N2O2
requires C, 70.04; H, 8.08; N, 10.21]; nmax (liquid film)
1729, 1671 cm21; dH (200 MHz, CDCl3) 7.49–7.27 (5H, m,
Ph), 3.64 (1H, t, J¼9.2 Hz, H5a), 3.22 (3H, s, MeN), 3.18
(1H, t, J¼9.2 Hz, H5b), 2.70–1.00 (9H, m, H3a,bþH4þ
CH2CH2CH2Me), 0.84 (3H, t, J¼6.2 Hz, CH2CH2CH2Me);
m/z (EI): 274 (1 Mþ), 169 (7), 140 (43), 105 (100), 77 (22),
55 (12).
4.1.23. 2-(Benzoylamino)-4,4,6-trichloro-3-oxo-2-aza-
spiro[4,5]decane (18). In a screw capped Schlenk tube
equipped with a perforable septum were added trichloro-
amide 17 (3.76 g, 10 mmol) and CuCl (0.1 g, 1 mmol),
followed by acetonitrile (20 mL) and TMEDA (0.30 mL,
2 mmol) under argon. The mixture was stirred at 608C for
20 h, then diluted with H2O (10 mL) and extracted with
CH2Cl2 (2£10 mL). The organic phases were collected,
dried by azeotropic distillation with toluene, and concen-
trated. Flash chromatography of the crude product on silica
gel, using a petroleum ether (bp 40–608C)/diethyl ether
gradient, gave the lactam diastereoisomer (5R p,6S p)-18
(2.89 g, 77%) as a white solid; mp 120–1228C; [Found: C,
51.3; H, 4.3; N, 7.7. C16H17Cl3N2O2 requires C, 51.15; H,
4.56; N, 7.46]; nmax (KBr) 1755, 1663 cm21; dH (200 MHz,
CDCl3) 9.45 (1H, bs, NH), 7.8–7.2 (5H, m, Ph), 4.35 (1H,
dd, J¼4.1, 10.8 Hz, CHCl), 4.00 (1H, d, J¼10.1 Hz, H5a),
3.70 (1H, d, J¼10.1 Hz, H5b), 2.6–1.5 (8H, m, (CH2)4); m/z
(EI): 374 (1 Mþ), 339 (1), 253 (2), 218 (2), 121 (13), 105
(100), 77 (35).
4.1.20. 4-Butyl-2-pyrrolidinone (15). According to the
general procedure, lactam 13d (182 mg, 0.5 mmol) gave 15
(64 mg, 90%) as a white solid; mp 70–728C; [Found: C,
67.9; H, 10.8; N, 9.8. C8H15NO requires C, 68.04; H, 10.71;
N, 9.92]; nmax (liquid film) 1684 cm21; dH (200 MHz,
CDCl3) 3.45 (1H, dd, J¼8.7, 9.4 Hz, H5a), 2.98 (1H, dd,
J¼6.2, 9.4 Hz, H5b), 2.57–1.80 (3H, m, H3a,bþH4), 1.43–
1.26 (6H, m, CH2CH2CH2Me), 0.87 (3H, t, J¼6.8 Hz,
CH2CH2CH2Me); m/z (EI): 141 (18 Mþ), 124 (82), 111
(33), 84 (38), 69 (32), 56 (100), 54 (97), 41 (78).
4.1.21. 1-Cyclohexen-1-carboxaldehyde benzoylhydra-
zone (16). In a single-necked round-bottom flask (25 mL)
benzoylhydrazine (1.36 g, 10 mmol) and 1-cyclohexen-1-
carboxyaldehyde (1.05 g, 9.5 mmol) were in succession

R. Cagnoli et al. / Tetrahedron 59 (2003) 9951–9960
9959
K.; Ratcliffe, G. S.; Horwell, D. C.; Kneen, C. O.; Morrell,
A. I.; Oles, R. J.; O’Toole, J. C.; Perkins, G. M.; Singh, L.;
Suman-Chauhan, N.; O’Neill, J. A. J. Med. Chem. 1998, 41,
1838. (b) Receveur, J.-M.; Bryans, J. S.; Field, M. J.; Singh,
L.; Horwell, D. C. Bioorg. Med. Chem. Lett. 1999, 9, 2329. (c)
Bryans, J. S.; Horwell, D. C.; Ratcliffe, G. S.; Receveur, J.-M.;
Rubin, J. R. Bioorg. Med. Chem. 1999, 7, 715. (d) Griffiths, G.;
Mettler, H.; Mills, L. S.; Previdoli, F. Helv. Chim. Acta 1991,
74, 309.
4.1.24. 3-Oxo-2-aza-spiro[4,5]decane (10). In a Schlenk
tube fitted with a stirring bar was added 20 mL of a Fluka
suspension of Raney-Ni in H2O. After sedimentation of the
nickel, supernatant water was carefully removed. To the wet
Raney-Ni (,2 g) were added lactam 18 (188 mg, 0.5 mmol)
and ethanol (2 mL) in succession. The mixture was stirred at
1108C, and after 21 h it was filtered and concentrated.
Chromatography of the crude product on silica gel, eluting
with a diethyl ether/methanol gradient, gave 10 (69 mg,
90%), as a white solid; mp 84–898C; [Found: C, 70.4; H,
9.7; N, 9.0. C9H15NO requires C, 70.55; H, 9.87; N, 9.14];
nmax (liquid film) 1679 cm21; dH (200 MHz, CDCl3) 6.3
(1H, bs, NH), 3.15 (2H, s, CH2NH), 2.15 (2H, s, CH2CO),
1.64–1.25 (10H, m, (CH2)5); m/z (EI): 153 (100 Mþ), 152
(45), 110 (33), 96 (28), 81 (74), 67 (43).
11. Bryans, J. S.; Chessum, N. E.; Huther, N.; Parsons, A. F.;
Ghelfi, F. Tetrahedron 2003, 59, 6221.
12. Casarini, M. E.; Ghelfi, F.; Libertini, E.; Pagnoni, U. M.;
Parsons, A. F. Tetrahedron 2002, 58, 7925.
13. (a) Peverali, D.; Fornaroli, M.; Velardi, F. US US 2003-
6518456 (Chem. Abstr. 2003, 138, 153247). (b) Augart, H.;
Gebhardt, U.; Herrmann, W. Eur. Pat. Appl. EP, 91-414263
(Chem. Abstr. 1991, 115, 29916).
14. (a) Feuerstein, T. J.; Knoerle, R. US Pat. Appl. Publ. US,
2002173537 (Chem. Abstr. 2002, 137, 363097). (b) Jehle, T.;
Feuerstein, T. J.; Lagreze, W. A. Ophthalmologe 2001, 98,
237.
Acknowledgements
`
We thank the Ministero della Universita e della Ricerca
Scientifica e Tecnologica (MURST) for financial assistance.
15. Ghelfi, F.; Parsons, A. F. J. Org. Chem. 2000, 65, 6249.
16. Burke, S. D.; Danheiser, R. L. Handbook of Reagents for
Organic Synthesis: Oxidizing and Reducing Agents. Wiley:
New York, 1999; pp 335.
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