Functional rearrangement of 3-Cl or 3,3-diCl-γ-lactams bearing a secondary 1-chloroalkyl substituent at C-4

Article abstract of DOI:10.1016/j.tet.2009.11.111

The study of the reaction with MeONa/MeOH of chlorinated γ-lactams, prepared from the atom transfer radical cyclization of N-allyl-α-perchloroamides, has been extended to the case of substrates carrying an exo halogen atom on a branched carbon. Only with

Full text of DOI:10.1016/j.tet.2009.11.111

Tetrahedron 66 (2010) 1357–1364
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Functional rearrangement of 3-Cl or 3,3-diCl-g-lactams bearing a secondary
1-chloroalkyl substituent at C-4
,
a
a
b
a,
*
Mariella Pattarozzi a , Fabrizio Roncaglia , Luca Accorsi , Andrew F. Parsons , Franco Ghelfi
*
a
`
Dipartimento di Chimica, Universita degli Studi di Modena e Reggio Emilia, Organic Chemistry, Via Campi 183, I-41100 Modena, Italy
b Department of Chemistry, University of York, Heslington, York, YO10 5DD, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The study of the reaction with MeONa/MeOH of chlorinated g-lactams, prepared from the atom transfer
Received 21 October 2009
Received in revised form
26 November 2009
Accepted 30 November 2009
Available online 4 December 2009
radical cyclization of N-allyl-a-perchloroamides, has been extended to the case of substrates carrying an
exo halogen atom on a branched carbon. Only with secondary exo C–Cl groups, that are not located on
a fused ring, does the functional rearrangement follow the typical transformation route, which with
trichloro-lactams can proceed further to give 4-alkylidene derivatives. From a practical point of view,
the outcome of the reaction with di- or trichloro N-cinnamylamides is synthetically valuable, affording
the 5-methoxy-1H-pyrrol-2(5H)-one or 3-benzylidenepyrrolidine-2,5-dione, respectively, in good to
excellent yield.
Keywords:
Halocompound
Radical reactions
Ó 2009 Elsevier Ltd. All rights reserved.
g-Lactams
Eliminations
Rearrangements
1. Introduction
preparation of polychlorinated 2-pyrrolidinones using TMC-ATRC
has essentially been confined to the development of new catalysts,5
Reducing the number of corrective oxidation or reduction
steps in organic synthesis is one of the endeavours of ‘redox
economy’.1 These steps often undermine the overall efficiency of
a process. Additionally, many redox reactions are difficult to scale
up in industrial settings and frequently are the source of noxious
by-products and environmental problems. One way to reduce the
number of redox steps along a synthetic path is to turn to sys-
tems that may undergo refunctionalization by isomerisation,
which are equivalent to internal redox reactions.1 Examples are
the redox isomerisation of allylic systems to aldehydes developed
by Trost,2 refunctionalization involving N-heterocyclic carbenes,3
and the transition metal catalysed-atom transfer radical cycliza-
tion (TMC-ATRC).
whereas the exploitation of the C-X functionality in the cyclic
products has been somewhat neglected. As far as we are aware, the
few previous applications have regarded: stepwise or sequential
radical processes,6 the preparation of [3,2,0]-hexan-2-ones,7 the
endo-dehydrochlorination of N-tosyl dichloropyrrolidin-2-ones,8
aromatization of bicyclic adducts,6b,c the substitution of the exo-Cl
group with oxygen nucleophiles,9 and, above all, hydro-de-
chlorinations.6c,9b,c,10
TMC-ATRC is a modern and powerful technique for the prepa-
ration of N- or O-heterocycles, generally performed with copper or
ruthenium catalysts.4 Among the various applications of this
technique, the synthesis of polyhalogenated 2-pyrrolidinones from
N-protected-N-allyl-a
-haloamides plays a major role (Scheme 1).5
Despite a key feature of the reaction being the preservation of all
the halo functions in the final product,4 the interest in the
Scheme 1. Atom transfer radical cyclization (in bold are highlighted the functional
groups involved in the transformation and their new appearance and position in the
product).
Some years ago, with the aim of applying the synthetic utility of
* Corresponding authors. Tel.: þ39 059 2055049; fax: þ39 059 373543.
E-mail addresses: mariella.pattarozzi@unimore.it (M. Pattarozzi), franco.ghelfi@
unimore.it (F. Ghelfi).
the TMC-ATRC to the preparation of N-protected-N-allyl-
a-per-
chloroamides, we serendipitously discovered that the
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.111

1358
M. Pattarozzi et al. / Tetrahedron 66 (2010) 1357–1364
polychlorinated 2-pyrrolidinones, when treated with the meth-
oxide ion in methanol, underwent a redox neutral refunctionali-
zation to give 5-methoxy- or 5,5-dimethoxy-3-pyrrolin-2-ones,
depending on the number of halogen atoms at the C-3 and C-6
positions (Scheme 2).11 We named the transformation a functional
rearrangement (FR). The FR is synthetically useful because the
products are precursors of cyclic N-acyliminium ions12 and maleic
anhydrides,13 pivotal structures in organic synthesis14 and in the
realm of natural compounds.15 We have successfully used the se-
quence ATRC/FR for the synthesis of chaetomellic anhydrides A and
C (FPTase inhibitors),13a,16 roccellic acid (metabolite lichenico)16c
and tyromicin A (APase inhibitor).17
Scheme 3. Mechanism of the functional rearrangement (FR).
molecules have differed in the chain bound at position C(3), or in
the group attached at the nitrogen atom.11,13,16,17
With this work we aim to complete an examination of the scope
of the FR, by studying the reaction of a number of substrates where
the C(4) position has secondary or tertiary 1-chloroalkyl sub-
stituents. From a synthetic point of view this is appealing since
monosubstituted maleimides or alkylidensuccinimides could be
prepared. The change, however, is not so innocent as it seems. In-
deed it may have an influence on the regioselectivity of the first
dehydrochlorination of the starting polychlorinated g-lactam, be-
cause the exo-elimination would be favoured by the formation of
a more stable C]C bond.
Scheme 2. FR of polychloro-g-lactams prepared by ATRC (in bold are highlighted the
functional groups involved in the transformation and their new appearance and po-
sition in the product).
2. Results and discussion
Our attention was first directed to the trichloro-
distinguished by the substituent bound at the C-4 position: 1-
chloroethyl (3a), 1-chloro-1-methylethyl (3b) or -chlorobenzyl
(3c) (Scheme 4). A cyclic compound (3d) was also added to the
series and it was of interest to explore these variations because the
nature of the C-4 group was expected to influence the rate of exo-
elimination.
g-lactams 3a–c,
The FR is stereoselective as only cis-3-alkyl-3-chloro-4-chloro-
methyl-pyrrolidin-2-ones undergo the transformation, which by
chance are predominantly produced by the TMC-ATRC; the reaction
proceeds under thermodynamic control to give predominantly the
more stable cis isomer.6b,13,16b The mechanism of the FR starts with
an endo bimolecular hydro-halo-elimination, which is possible only
in the presence of a trans geometry between the C(4)-H and C(3)-Cl
a
bonds of the starting g
-lactam.16b Accordingly, the representative
chloro-pyrrolidin-2-one cis-I is transformed by MeONa/MeOH into
the 3-pyrrolin-2-one II (Scheme 3, A). Owing to the acidity of the
vinylogous C(5)-H hydrogen atom, the conjugated C]C bond mi-
grates from the a,b-position to the b,g-position (III). This shift trig-
gers the subsequent stepwise substitution of the exo chlorine, giving,
through an intermediate N-acyliminium IV, the 5-methoxy lactam V,
which by a C]C exo/D3 base catalyzed transposition leads to the
final 5-methoxy-3-pyrrolin-2-one VI. If chlorine atoms are also
present at the C-3 and C-6 positions of VI, the reaction proceeds
further, following similar steps, to yield the 5,5-dimethoxy adduct.
In contrast, the trans-I isomer, when treated with methoxide ion
undergoes dehydrohalogenation, affording 4-alkyliden-pyrrolidin-
2-one VII (Scheme 3, B), which can be methoxy-de-halogenated
when the R0 group is small.16b The exo dehydrohalogenated adduct,
however, can undergo the FR, if the trans-I intermediate carries
a hydrogen atom at C(3) (such as for N-benzyl-4-dichloromethyl-2-
pyrrolidinone). In this way the exo C]C bond is allowed to move
into conjugation, and so the rearrangement can start. Inomata
experienced a refunctionalization similar to the one we have
described in the preparation of phycocyanobilin and
phycochromobilin.12b
All the previous FR reactions have considered only halogenated
Scheme 4. (a) Trichloroacetyl chloride, Py, CH2Cl2, 20 h, 25 ꢀC; (b) CuCl/TMEDA
CH3CN, argon, 14–24 h, 25 ꢀC.
g
-lactams bearing
a chloromethyl substituent, or at most
a dichloromethyl group, at the C(4) position. The investigated

M. Pattarozzi et al. / Tetrahedron 66 (2010) 1357–1364
1359
The cycloisomerization proceeded excellently and, with the
substrates carrying a stereoisomeric double bond (2a, 2c and 2d), it
was also highly diastereoselective, as observed by us in the past10a
and, in similar cases, by other researchers.18
We were delighted by the outcome of the FR of 3c where the (E)-
benzylidensuccinimide 9 was formed selectively in good yield
(Scheme 7). The
quence of the extra-stabilization energy gained by conjugation with
the aromatic ring. There are some medicinally important targets
with similar structures to 9.21
D
3/exo shift of the double bond is a clear conse-
The configuration of the major diastereoisomer is consistent
with an anti-addition mechanism and was originally explained by
assuming free rotation around the C(4)–C(6) bond of the in-
termediate pyrrolidinone radical (this is obviously impossible for
the radical arising from 2d) and the preferential adoption of the
conformation X rather than XI (Scheme 5). Assuming the in-
termediate radical has an almost planar structure,19 this can be
explained on the basis of steric interactions: for conformer X, the R0
side-chain takes an outward orientation with respect to the lactam
ring. The facial selectivity of the ensuing attack by CuCl2/TMEDA on
X should be very high, owing to the presence of the two chloro
groups at C(3).
Scheme 7. (a) MeONa/MeOH/toluene, 10 ꢀC, 3 h; (b) HCl/H2O, rt, 48 h.
When the bicyclic lactam 3d was exposed to MeONa, two
products were recovered: the monomethoxy 12 (17%) and the
dimethoxy 13 (42%) bicyclic 3-pyrrolin-2-ones (Scheme 8). Adduct
13 was, moreover, made up of a mixture of two diastereomers,
(4S
*
,7aS
*
)-13 and (4S
*
,7aR )-13 (in a 83:17 ratio). A plausible in-
*
terpretation of the reaction outcome is proposed in Scheme 8. After
the initial dehydrochlorination, the intermediate 10 can proceed
along the FR path to afford 12, or sustain a preferential nucleophilic
substitution of the chloro atom, bound at C(4), made easier by the
axial configuration of the halo function.
Scheme 5. Interpretation of the stereoselective Cl atom transfer in the ATRC to form g-
lactams.
The FR of 3a (Scheme 6) was performed on the individual iso-
mers, (4R ,6S ) and (4R ,6R ). To prevent the isolation of the un-
*
*
*
*
stable acetals 4 and 5, the reaction mixtures underwent an acid
work-up. Both transformations afforded the same results, in-
dicating that the different configuration of lactams 3 has no in-
fluence on the outcome of the FR. Not unexpectedly, from the crude
reaction product, the maleimide 6 (yield 43%) and the thermody-
namically more stable (E)-alkylidensuccinimide 7 (yield 27%) were
isolated.20 Since the 6/7 ratio doesn’t change on doubling the hy-
drolysis time (from 48 h to 96 h) we believe that the prototropic
migration just occurs on the acetal intermediate 4. This hypothesis
is enforced by the failed hydrogen shift on 6 or 7 under the con-
ditions of the FR (opening of the ring was only observed), and by
the observation that at 0 ꢀC the formation of 6 precedes that of 7
(following quenching of the reaction after 3 h).
Scheme 8. (a) MeONa/MeOH/diethyl ether, 25 ꢀC, 3 h.
After these initial results, we explored the reactivity of C(3)-
substituted dichloro
g-lactams prepared by the CuCl/TMEDA cata-
lyzed ATRC of the 2,2-dichlorobutanamides 2e, 2f and 2g (Scheme
9). Owing to the poor result of the FR of 3b, the
from the allylamine 1b was not investigated.
g-lactam attainable
As we expected, the cycloisomerization of 2e–g was effective,
with product yields between 91–97%, and excluding 2g, the prev-
alence of cis adducts was high.
Differently from what we observed with the trichloroamides 2a,
2c and 2d, the stereochemistry of the carbon carrying the Cl ex-
ternal to the lactam ring is not so rigidly controlled. It appears that
replacing a Cl atom with a relatively small alkyl group makes the
abstraction reaction of the intermediate radical less
diastereoselective.5a
Scheme 6. (a) MeONa/MeOH/diethyl ether, 10 ꢀC, 3 h; (b) HCl/H2O, rt, 48 h.
The 1-benzyl-3,4-diethyl-5-methoxy-1H-pyrrol-2(5H)-one 14
(yield 58%) and the (E)-1-benzyl-3-ethyl-4-ethylidene-3-methoxy-
pyrrolidin-2-one 15 (yield 36%) were secured from the FR of 3e
(Scheme 10). This result is astonishing. Indeed, looking at the cis/
The FR of the halo-lactam 3b, was, on the contrary, completely
unselective, yielding a complex mixture of unidentified products.

1360
M. Pattarozzi et al. / Tetrahedron 66 (2010) 1357–1364
trans ratio (87/13) of the starting 2-pyrrolidinone, we had estimated
a similar ratio in the rearrangement product 14 and in the product
derived from exo elimination 15. Evidently a substantial amount of
15 arises from the exo-elimination of cis-3e as well as, in part, from
the elimination of trans-3e.
The FR of 3f was completely selective giving, in excellent yield
(94%), the 1,4-dibenzyl-3-ethyl-5-methoxy-1H-pyrrol-2(5H)-one
(Scheme 11). Differently from 3e, and despite the presence of an
aromatic substituent at C(6), the exo-elimination did not enter into
competitionwith the endo-process. In all likelihood the anti-coplanar
transition state for the exo-dehydrochlorination, owing to the steric
bulkiness of the aromatic substituent, is energetically unfavourable.
Scheme 11. (a) MeONa/MeOH/diethyl ether, 37 ꢀC, 22 h.
Finally, the FR of 3g was considered (Scheme 12). Unfortunately,
the TMC-ATRC of 2g was only moderately stereoselective (cis/trans
ratio¼60/40). The (4R
*
,7aR )-1-benzyl-3-ethyl-4-methoxy-5,6,7,7a-
*
tetrahydro-1H-indol-2(4H)-one 17 (46%) and the 1-benzyl-3-ethyl-
5,6-dihydro-1H-indol-2(4H)-one 18 (14%) were the products
recovered from the reaction mixture (Scheme 12). Both arise from
cis-3g, andtheirformationcanberationalisedbyamechanismsimilar
to the one depicted for 3d (Scheme 8). The intermediate adduct 19,
afforded from cis-3g by the endo-elimination of HCl, can undergo
a premature, but favoured, methoxy-de-chlorination to give 17. Al-
ternatively, it can follow the FR path, which now proceeds further,12
providing the doubly eliminated adduct 18.
Scheme 9. (a) 2,2-Dichlorobutanoyl chloride, Py, CH2Cl2, 20 h, 25 ꢀC; (b) CuCl/TMEDA,
CH3CN, argon, 24 h, 50 ꢀC.
Scheme 12. (a) MeONa/MeOH/diethyl ether, 50 ꢀC, 4 h.
As predicted, the crude reaction mixture also included the re-
covered diastereomer (3R
*
,3aR
*
,4R
*
,7aR )-3g, which, due to the
*
relative cis configuration of the two C–Cl functions and the proton
C(3a)-H, cannot undergo elimination. However, this diastereomer
was isolated in a slightly higher yield (19%) than that present in the
original 3g mixture (13%). This is a clear sign of partial epimeriza-
tion of the stereogenic centre C(3)–Cl of diastereomer
Scheme 10. (a) MeONa/MeOH/diethyl ether, 25 ꢀC, 22 h.
This statement was unequivocally proved, by subjecting the
major cis-isomer of 3e to FR, which yielded both the adduct 14
(tR¼8.79 min; GCarea%¼66%) and 15 (tR¼10.17 min; GCarea%¼31%).y
From the E-geometry of the C]C bond in 15, it is possible to trace
back the configuration of the C(6) site for all the diastereomers 3e.
Since the exo-elimination is stereoselective, it should reasonably
follow an E2 mechanism. As a consequence, the E-geometry of the
(3R
*
,3aR
*
,4S
*
,7aR
)-3g under the reaction conditions of the FR.13b
*
3. Conclusions
With this work we have extended the study of the reaction of
chlorinated -lactams, derived from the TMC-ATRC of N-allyl-a-
alkylidene lactam 15 requires a relative configuration of 4R
*
,6S
*
g
between the stereogenic centres at C(4) and C(6) in cismajor-3e and
trans-3e, therefore the same atoms in the cisminor-3e must have the
perchloroamides, with MeONa/MeOH to the case of substrates
carrying an exo halogen atom on a branched carbon. Only with
secondary exo C–Cl groups, that are not located on a fused ring, did
the FR proceed via the desired transformation route. With tri-
chloro-lactams the FR can proceed further and give 4-alkylidene
configuration 4R
*
,6R . Since the stereoisomer Z-15 is virtually ab-
*
sent from the reaction mixture, it is clear that the transition state
for the endo-elimination of cisminor-3e is much more stable than the
one for the exo-elimination, and thus fully followed.
derivatives. For cis-(4R
*
,6R )-3-chloro-4-(1-chloroalkyl)lactam 3e,
*
in the initial elimination step, an unfavourable exo/endo competi-
tion was observed. From a practical point of view, the outcome of
the reaction with di- or trichloro N-cinnamylamides, 3c and 3f, is
y
Column HP-5, 30 m, i.d.¼0.25 mm; GC conditions: Tinjector¼250 ꢀC,
Tdetector¼280 ꢀC, Tinitial¼150 ꢀC (5 min), rate¼10 ꢀC/min.

M. Pattarozzi et al. / Tetrahedron 66 (2010) 1357–1364
1361
synthetically valuable, affording the 5-methoxy-1H-pyrrol-2(5H)-
one or 3-benzylidenepyrrolidine-2,5-dione nuclei, 16 and 9, re-
4.3. 1-Benzyl-3,3-dichloro-4-(1-chloro-1-methylethyl)-2-
pyrrolidinone (3b)
spectively, in good to excellent yields.
Following the procedure for the preparation of 3a, 2b (12.83 g,
40 mmol) gave, after flash-chromatography of the crude product on
silica gel, using a petroleum ether (bp 40–60 ꢀC)/diethyl ether
gradient (from 100/0 to 70/30), 11.62 g of 3b (91%), as a white solid
[Found: C, 52.2; H, 5.1; N, 4.3. C14H16Cl3NO requires C, 52.44; H, 5.03;
N, 4.37]; mp 73–74 ꢀC. nmax (KBr) 1716 cmꢂ1; dH (200 MHz, CDCl3)
7.24–7.44 (m, 5H, 5 Ph), 4.66 (d, J¼14.7, 1H, CHHPh), 4.50 (1H, d,
J¼14.7 Hz, CHHPh), 3.35–5.55(m,2H, C(4)HandC(5)HH),3.19(1H, dd,
J¼9.4, 7.1 Hz, C(5)HH),1.90 (3H, s, CH3),1.88 (3H, s, CH3); dC (50 MHz,
CDCl3) 166.1,134.6,129.0,128.2,128.1, 82.8, 68.7, 59.3, 47.8, 45.5, 33.4,
29.9; m/z (EI, 70 eV) 284 (25, MþꢂCl), 248 (2), 206 (3), 91 (100).
4. Experimental part
4.1. General
Reagents and solvents were standard grade commercial prod-
ucts, purchased from Aldrich, Acros, Fluka or RdH, and used with-
out further purification, except acetonitrile and CH2Cl2 that were
dried over three batches of 3 Å sieves (5% w/v, 12 h). The silica gel
used for flash-chromatography was Silica Gel 60 Merck (0.040–
0.063 mm). All of the amines 1a–d were obtained by N-alkylation
of benzylamine with the appropriate allyl chloride, adapting the
procedure of Shipman.22 The 2,2-dichlorobutanoyl chloride was
prepared from 2,2-dichlorobutanoic acid23 by halo-de-hydroxyl-
ation with (COCl)2, following a reported method.10e NMR spectra
were recorded on a Bruker DPX 200, a Bruker Avance 400 and a Jeol
GSX 400 spectrometer. NMR peaks attributions were based on
gradient-enhanced 1H,1H-DQF-COSY and 1H,13C-Edited-HSQC
spectroscopy, using standard pulse programs. The double bond
configurations in compounds 7, 9 and 15 and the relative configu-
rations of 3e–g, 13 and 17 were determined by NOESY experiments.
IR, MS and HRMS spectra were recorded, respectively, on a Perkin
Elmer 1600 Series FTIR, a HP 5890 GC-HP 5989A MS and a Bruker
microTOF instrument.
4.4. (R
*
)-1-Benzyl-3,3-dichloro-4-((R )-
*
chloro(phenyl)methyl)-2-pyrrolidinone (3c)
Following the procedure for the preparation of 3a, but lowering
the reaction time to 14 h, 2c (14.75 g, 40 mmol) gave, after flash-
chromatography of the crude product on silica gel, using a petro-
leum ether (bp 40–60 ꢀC)/diethyl ether gradient (from 100/0 to 70/
30), 13.13 g of 3b (89%), as a white solid [Found: C, 58.6; H, 4.4; N,
3.8. C18H16Cl3NO requires C, 58.64; H, 4.37; N, 3.80]; mp 138–
139 ꢀC; nmax (KBr) 1721 cmꢂ1; dH (200 MHz, CDCl3) 7.28–7.57 (m,
10H, 2 Ph), 5.27 (1H, d, J¼9.9 Hz, C(4)HCHPh), 4.69 (1H, d,
J¼14.7 Hz, CHHPh), 4.48 (1H, d, J¼14.7H, CHHPh), 3.67 (1H, dd,
J¼9.7, 6.6 Hz, C(5)HH), 3.45 (1H, ddd, J¼9.9, 8.9, 6.6 Hz, C(4)HCCl),
3.29 (1H, dd, J¼9.7, 8.9 Hz, C(5)HH); dC (50 MHz, CDCl3) 166.3,137.7,
134.7, 129.5, 129.1, 128.6, 128.4, 128.3, 83.6, 61.7, 55.7, 48.1, 47.8; m/z
(EI, 70 eV) 367 (1, Mþ), 332 (58), 296 (2), 206 (7), 125 (21), 91 (100).
4.2. 1-Benzyl-3,3-dichloro-4-(1-chloroethyl)-2-pyrrolidinone
(3a)-typical procedure
4.5. (3aR
*
,4R
*
,7aR )-1-Benzyl-3,3,4-trichlorohexahydro-1H-
*
CuCl (0.40 g, 4 mmol) and the 2,2-dichloroamide 2a (12.27 g,
40 mmol) were weighed in a Schlenk tube fitted with a pierceable
septum (blocked by a screw cap) and a magnetic stirring bar. Dry
CH3CN (30 mL) and TMEDA (1.2 mL, 8 mmol) were then added
under argon. The mixture was stirred at 25 ꢀC and after 24 h diluted
with H2O (30 mL), acidified with HCl 10% w/v, and extracted with
CH2Cl2 (3ꢁ20 ml). The combined organic layers were concentrated
and the crude product was purified by flash-chromatography on
silica gel, eluting with a petroleum ether (bp 40–60 ꢀC)/diethyl
ether gradient (from 100/0 to 80/20). This gave the pyrrolidinones
indol-2(3H)-one (3d)
Following the procedure for the preparation of 3a, 2d (6.65 g,
20 mmol) gave, after flash-chromatography of the crude product on
silica gel, using a petroleum ether (bp 40–60 ꢀC)/diethyl ether
(from 100/0 to 70/30) gradient, 5.51 g of 3d (83%), as a white solid;
mp 84–86 ꢀC.10f
4.6. 1-Benzyl-3-chloro-4-(1-chloroethyl)-3-ethyl-2-
pyrrolidinone (3e)
(4R
*
,6S
*
)-3a (9.00 g, 73%) [Found: C, 50.9; H, 4.6; N, 4.6.
,6R )-3a
C13H14Cl3NO requires C, 50.92; H, 4.60; N, 4.57] and (4R
*
*
Following the procedure for the preparation of 3a, but in-
creasing the reaction temperature to 50 ꢀC, 2e (7.21 g, 24 mmol)
gave, after flash-chromatography of the crude product on silica gel,
using a petroleum ether (bp 40–60 ꢀC)/diethyl ether (from 100/0 to
70/30) gradient, 6.71 g of 3e (93%), as a pale yellow oil [Found: C,
60.2; H, 6.3; N, 4.7. C15H19Cl2NO requires C, 60.01; H, 6.38; N, 4.67];
cismajor/cisminor/trans¼60:27:13 (1H NMR); nmax (liquid film)
1711 cmꢂ1; dH (400 MHz, CDCl3) (cismajor) 7.15–7.45 (m, 5H, Ph),
4.60 (1H, d, J¼14.8, CHHPh), 4.45 (1H, d, J¼14.8 Hz, CHHPh), 4.28
(1H, dq, J¼10.1, 6.5 Hz, C(4)CHCl), 3.44 (1H, dd, J¼10.3, 7.4 Hz,
C(5)HH), 3.12 (1H, dd, J¼10.3, 10.1 Hz, C(5)HH), 2.62 (1H, td, J¼10.1,
7.4 Hz, C(4)H), 2.54 (1H, dq, J¼14.5, 7.3 Hz, C(3)CHH), 2.06 (1H, dq,
J¼14.5, 7.3 Hz, C(3)CHH), 1.69 (3H, d, J¼6.5 Hz, C(4)CHClCH3), 0.99
(3H, t, J¼7.3 Hz, CH2CH3); dH (cisminor) 7.15–7.45 (m, 5H, Ph), 4.59
(1H, d, J¼14.8 Hz, CHHPh), 4.44 (1H, d, J¼14.8 Hz, CHHPh), 4.37 (1H,
dq, J¼9.3, 6.6 Hz, C(4)CHCl), 3.16 (1H, dd, J¼9.3, 7.4 Hz, C(5)HH),
2.95 (1H, t, J¼9.3 Hz, C(5)HH), 2.69 (1H, td, J¼9.3, 7.4 Hz, C(4)H),
2.48 (1H, q, J¼7.5 Hz, C(3)CHH), 1.47 (3H, d, J¼6.6 Hz, C(4)CHClCH3),
0.99 (3H, t, J¼7.5 Hz, CH2CH3); dH (trans) 7.15–7.45 (5H, m, Ph), 4.60
(1H, d, J¼14.6 Hz, CHHPh), 4.44 (1H, d, J¼14.6 Hz, CHHPh), 4.23 (1H,
qn, J¼7.0 Hz, C(4)CHCl), 3.49 (1H, dd, J¼10.4, 7.0 Hz, 3.08 (1H, dd,
J¼10.4, 7.0 Hz, C(5)HH), 2.81 (1H, q, J¼7.1 Hz, C(4)H), C(5)HH), 2.06
(1.58 g, 13%) [Found: C, 51.0; H, 4.6; N, 4.5. C13H14Cl3NO requires C,
50.92; H, 4.60; N, 4.57], both as a white crystalline solid.
4.2.1. (R
*
)-1-Benzyl-3,3-dichloro-4-[(S
*
)-1-chloroethyl]-pyrrolidin-
2-one [(4R
*
,6S
*
)-3a]. Mp 68–69 ꢀC; nmax (KBr) 1733 cmꢂ1; dH
(200 MHz, CDCl3) 7.22–7.43 (m, 5H, 5 Ph), 4.65 (1H, d, J¼16.7 Hz,
CHHPh), 4.44 (1H, d, J¼16.7 Hz, CHHPh), 4.31 (1H, dq, J¼9.6, 6.5 Hz,
C(4)CHCl), 3.50 (1H, dd, J¼10.2, 7.3 Hz, C(5)HH), 3.10 (1H, dd,
J¼10.2, 8.9 Hz, C(5)HH), 2.91 (1H, ddd, J¼9.6, 8.9, 7.3 Hz, C(4)H),1.83
(3H, d, J¼6.5 Hz, CH3); dC (50 MHz, CDCl3) 166.2, 134.6, 129.0, 128.3,
128.2, 83.5, 56.6, 56.2, 48.1, 47.8, 23.7; m/z (EI, 70 eV) 305 (0.5, Mþ),
270 (45), 236 (7), 91 (100).
4.2.2. (R
*
)-1-Benzyl-3,3-dichloro-4-[(S
*
)-1-chloroethyl]-pyrrolidin-
2-one [(4R
*
,6R
*
)-3a]. Mp 100–101 ꢀC; nmax (KBr) 1718 cmꢂ1; dH
(200 MHz, CDCl3) 7.19–7.42 (m, 5H, 5 Ph), 4.61 (d, J¼14.7 Hz, 1H,
CHHPh), 4.45 (1H, d, J¼14.7 Hz, CHHPh), 4.27–4.45 (1H, m,
C(4)CHCl), 3.25–3.40 (m, 1H, C(5)HH), 2.94–3.10 (2H, m, C(4)H and
C(5)HH), 1.43 (3H, d, J¼6.6 Hz, CH3); dC (CDCl3, 50 MHz) 166.4,
134.4, 129.1, 128.4, 128.2, 84.2, 55.5, 53.9, 47.7, 45.9, 22.1; m/z (EI,
70 eV) 305 (0.5, Mþ), 270 (45), 236 (7), 91 (100).

1362
M. Pattarozzi et al. / Tetrahedron 66 (2010) 1357–1364
(1H, dq, J¼14.7, 7.3 Hz, C(3)CHH), 1.97 (1H, dq, J¼14.7, 7.3 Hz,
C(3)CHH), 1.66 (3H, d, J¼7.0 Hz, C(4)CHClCH3), 1.16 (3H, t, J¼7.3 Hz,
CH2CH3); dC (100 MHz, CDCl3) (cismajor) 170.3, 135.4, 128.8, 128.2,
J¼15.2 Hz, CHHPh), 4.39 (q, J¼3.6 Hz, C(4)H), 4.03 (1H, d,
J¼15.2 Hz, CHHPh), 3.89–3.97 (1H, m, C(7a)H), 2.56–2.62 (1H, m,
C(3a)H), 2.53 (1H, dq, J¼15.2, 7.3 Hz, CHHCH3), 2.30–2.40 (1H, m,
CHHCH3), 2.00–2.12 (2H, m, C(5)HH and C(7)HH), 1.72–1.85 (2H,
m, C(5)HH and C(6)HH), 1.50–1.65 (1H, m, C(7)HH), 1.33–1.43 (1H,
m, C(6)HH), 1.22 (t, J¼7.3 Hz, CH2CH3); dH (transminor) 7.10–7.30
(5H, m, Ph), 5.08 (1H, d, J¼15.2 Hz, CHHPh), 3.93 (1H, q, J¼4.7 Hz,
C(7a)Heq), 3.86 (1H, d, J¼15.2 Hz, CHHPh), 3.73 (1H, ddd, J¼10.9,
8.9, 4.7 Hz, C(4)Hax), 2.66 (1H, dd, J¼8.9, 4.7 Hz, C(3a)Hax), 2.36
(1H, dq, J¼14.9, 7.1 Hz, CHHCH3), 2.11–2.20 (1H, m, C(5)Heq), 2.07
(1H, dq, J¼14.9, 7.1 Hz, CHHCH3), 1.92–2.02 (1H, m, C(7)Heq), 1.62–
1.73 (1H, m, C(5)Hax), 1.56–1.66 (1H, m, C(6)Heq), 1.45–1.56 (1H, m,
C(7)Hax), 1.30 (3H, t, J¼7.1 Hz, CH2CH3), 1.14–1.28 (1H, m, C(6)Hax);
dC (100 MHz, CDCl3) (cismajor) 170.0, 135.9, 128.8, 127.9, 127.8, 70.7,
127.9, 127.8, 72.5, 58.2, 48.5, 47.0, 46.4, 31.02, 23.7, 10.1; dC (cisminor
)
170.7, 135.4, 128.8, 128.2, 127.9, 127.8, 74.0, 55.1, 46.9, 46.6, 46.3,
30.5, 23.0, 10.0; dC (trans) 170.6, 135.4, 128.8, 128.2, 127.9, 127.8,
72.8, 55.7, 53.0, 47.1, 46.9, 26.9, 24.4, 9.0; m/z (EI, 70 eV) 299 (3, Mþ),
264 (63), 208 (13), 200 (35), 91 (100).
4.7. 1-Benzyl-3-chloro-4-[chloro(phenyl)methyl]-3-ethyl-2-
pyrrolidinone (3f)
Following the procedure for the preparation of 3a, but in-
creasing the reaction temperature to 50 ꢀC, 2f (8.69 g, 24 mmol)
gave, after flash-chromatography of the crude product on silica gel,
using a petroleum ether (bp 40–60 ꢀC)/diethyl ether (from 100/0 to
70/30) gradient, 8.58 g of 3f (99%), as a white solid [Found: C, 66.4;
H, 5.9; N, 3.9. C20H21Cl2NO requires C, C, 66.30; H, 5.84; N, 3.87];
57.0, 52.4, 46.9, 44.9, 32.7, 31.8, 26.7, 16.9, 9.5;
d (cisminor) 170.4,
135.9, 128.8, 127.9, 127.8, 71.8, 57.8, 55.7, 45.0, 41.0, 32.7, 32.2, 26.3,
22.2, 10.6; dC (transmaior) 172.4, 135.8, 128.5, 127.8, 127.4, 75.7, 55.6,
51.6, 48.1, 43.8, 32.5, 25.7, 23.7, 15.3, 9.1; dC (transminor) 172.3,
135.3, 128.4, 127.8, 127.7, 75.7, 56.3, 53.9, 53.7, 44.0, 35.8, 26.5, 24.8,
19.2, 10.0; HRMS-FAB (CI, NH3): m/z MHþ, found 326.1073,
C17H22Cl2NO requires 326.1073.
cismajor/cisminor/trans¼77:20:3 (1H NMR); nmax (KBr) 1699 cmꢂ1
;
dH (400 MHz, CDCl3) (cismajor
)
0.66 (3H, t, J¼6.6 Hz, CH3),
7.45–7.55 (2H, m, CHAr), 7.20–7.45 (8H, m, CHAr), 5.22 (1H, d,
J¼9.8 Hz, C(4)CHCl), 4.68 (1H, d, J¼14.8 Hz, CHHPh), 4.47 (1H, d,
J¼14.8 Hz, CHHPh), 3.59 (dd, J¼9.8, 7.1 Hz, 1H, C(5)HH), 3.30 (1H, t,
J¼9.8 Hz, C(5)HH), 3.12 (1H, td, J¼9.8, 7.1 Hz, C(4)H), 1.99 (1H, dq,
4.9. 1-Benzyl-3-ethyl-1H-pyrrole-2,5-dione (6)
J¼13.2, 6.6 Hz, C(3)CHH), 0.66–0.80 (1H, m, C(3)CHH); dH (cisminor
)
In a Schlenk tube, fitted with a pierceable septum blocked by
a screw cap, diethyl ether/CH3OH 1/3 (4 mL) and 3a (1.23 g,
4 mmol) were added. The solution was thermostated at 10 ꢀC.
Apart, in a second Schlenk tube, Na0 (0.37 g, 16 mmol) was carefully
dissolved in CH3OH (8 mL) and, when the effervescence ceased, the
alkaline solution was thermostated at 10 ꢀC, after which it was
poured into the first Schlenk tube. The reaction mixture was stirred
for 3 h. Then it was diluted with water (15 mL), acidified with HCl
10% w/v (red litmus) and left under vigorous stirring for 48 h at
room temperature. Afterwards the mixture was extracted with
CH2Cl2 (3ꢁ10 mL). The combined organic layers were collected and
concentrated. Flash-chromatography of the crude product on silica
gel, using a petroleum ether (bp 40–60 ꢀC)/diethyl ether gradient
(from 100/0 to 60/40), afforded 0.37 g of 6 (43%), as a white solid
[Found: C, 72.4; H, 6.1; N, 6.5. C13H13NO2 requires C, 72.54; H, 6.09;
N, 6.51]; mp 52–53 ꢀC; nmax (KBr): 1707 cmꢂ1; dH (200 MHz, CDCl3)
7.24–7.42 (5H, m, Ph), 6.30 (1H, dt, J¼2.0, 0.5 Hz, C(3)H), 4.66 (2H, s,
CH2Ph), 2.46 (2H, dq, J¼7.5, 2.0 Hz, C(4)HCH2CH3), 1.21 (3H, t,
J¼7.5 Hz, CH2CH3); dC (50 MHz, CDCl3) 171.2, 170.6, 151.7, 136.5,
128.6, 128.4, 127.7, 125.7, 41.4, 18.9, 11.1; m/z (EI, 70 eV) 215 (100,
Mþ), 172 (90), 104 (28), 91 (30).
7.20–7.45 (8H, m, CHAr), 7.15–7.20 (2H, m, CHAr), 5.20 (1H, d,
J¼9.8 Hz, C(4)CHCl), 4.63 (1H, d, J¼14.8 Hz, CHHPh), 4.23 (1H, d,
J¼14.8 Hz, CHHPh), 3.19 (1H, td, J¼9.8, 7.4 Hz, C(4)H), 2.75 (1H, t,
J¼9.8H, C(5)HH), 2.65 (2H, q, J¼7.4 Hz, C(3)CH2), 2.56 (1H, dd, J¼9.8,
7.4 Hz, C(5)HH), 1.12 (3H, t, J¼7.4 Hz, CH3); dH (trans) 7.00–7.70
(10H, m, 2 Ph), 5.14 (1H, d, J¼7.2 Hz, C(4)CHCl), CH2Ph not detect-
able, 3.50–3.60 (1H, m, C(5)HH), 3.30–3.40 (1H, m, C(5)HH),
3.13–3.25 (1H, m, C(4)H), 2.15 (1H, dq, J¼7.4 Hz, C(3)CHH), 2.00–
2.10 (1H, m, C(3)CHH), 1.18 (3H, t, J¼7.4 Hz, CH3); dC (100 MHz,
CDCl3) (cismajor) 170.3, 138.8, 135.5, 129.3, 128.8, 128.6, 128.0, 127.8,
73.4, 62.8, 48.3, 46.9, 46.2, 28.9, 9.7; dC (cisminor)¼170.6,138.7,135.4,
129.1, 129.0, 128.7, 127.7,127.6, 127.3, 74.0, 61.0, 47.0, 46.8, 45.9, 30.5,
10.2; dC (trans)¼unobservable due to the too low intensity; m/z
(EI, 70 eV) 361 (3, Mþ), 326 (53), 290 (3), 208 (37), 200 (68), 125
(30), 91 (100).
4.8. 1-Benzyl-3,4-dichloro-3-ethylhexahydro-1H-indol-2(3H)-
one (3g)
Following the procedure for the preparation of 3a, but in-
creasing the reaction temperature to 50 ꢀC, 2g (6.53 g, 20 mmol)
gave, after flash-chromatography of the crude product on silica gel,
using a petroleum ether (bp 40–60 ꢀC)/diethyl ether gradient (from
0.18 g (21%) of (E)-1-Benzyl-3-ethylidenepyrrolidine-2,5-dione
(7), as a yellowish oil [Found: C, 72.5; H, 6.1; N, 6.6. C13H13NO2 re-
quires C, 72.54; H, 6.09; N, 6.51], was also recovered; nmax (liquid film)
1709,1679 cmꢂ1; dH (200 MHz, CDCl3) 7.20–7.43 (5H, m, Ph), 6.86 (tq,
J¼7.0, 2.4 Hz, 1H, C(4)¼CHCH3), 4.70 (2H, s, CH2Ph), 3.18 (2H, m,
C(3)H2), 1.83 (3H, dt, J¼7.0, 1.5 Hz,¼CHCH3); dC (100 MHz, CDCl3)
173.4,169.0, 135.7, 133.5,128.4, 128.2, 127.5, 126.5, 41.8, 31.5, 15.0; m/z
(EI, 70 eV) 215 (100, Mþ) 186 (32), 172 (39), 104 (36), 91 (58).
100/0 to 60/40), 5.94 g of 3g (91%), as
a
pale yellow oil;
(3S
4R
*
,3aR
*
,4R
*
,7aR
*
)/(3S
*
,3aR
*
,4S
*
,7aR
*
)/(3R
*
,3aR
*
,4S ,7aR )/(3R ,3aR
*
*
*
*
,
*
,7aR
*
)¼cismajor/cisminor/transmajor/transminor¼56:4:26:14 (1H NMR);
nmax (liquid film) 1705 cmꢂ1; dH (400 MHz, CDCl3) (cismajor) 7.20–
7.38 (5H, m, Ph), 4.98, (1H, d, J¼15.0 Hz, CHHPh), 4.61 (1H, dt,
J¼3.6, 1.6 Hz, C(4)Heq), 4.12 (1H, d, J¼15.0 Hz, CHHPh), 3.56 (1H,
ddd, J¼11.6, 7.6, 5.6 Hz, C(7a)Hax), 2.82 (1H, dd, J¼7.6, 1.6 Hz,
C(3a)Heq), 2.27–2.38 (1H, m, C(5)Hax), 2.20 (dq, J¼14.8, 7.4 Hz, 1H,
CHHCH3), 2.16 (1H, dq, J¼14.8, 7.4 Hz, CHHCH3), 1.97–2.05 (1H, m,
C(7)Heq), 1.92 (1H, dq, J¼14.7, 3.6 Hz, C(5)Heq), 1.60–1.70 (2H, m,
C(6)H2), 1.43–1.56 (1H, m, C(7)Hax), 1.06 (3H, t, J¼7.4 Hz, CH2CH3);
dH (cisminor) 7.19–7.37 (5H, m, Ph), 5.08 (1H, d, J¼15.0 Hz, CHHPh),
4.19 (1H, ddd, J¼12.7, 7.0, 5.3 Hz, C(4)Hax), 4.04 (1H, d, J¼15.0 Hz,
CHHPh), 3.31 (1H, ddd, J¼11.6, 7.0, 5.7 Hz, C(7a)Hax), 2.90 (1H, t,
J¼7.0 Hz, C(3a)Heq), 2.42–2.63 (3H, m, CH2CH3 and C(5)HH), 1.85–
2.02 (3H, m, C(5)HH, C(6)Heq and C(7)Heq), 1.64–1.76 (1H, m,
C(7)Hax), 1.20 (1H, qt, J¼13.9, 3.5 Hz, C(6)Hax), 0.94 (3H, t, J¼7.4 Hz,
CH2CH3); dH (transmaior) 7.10–7.30 (5H, m, Ph), 5.03 (1H, d,
4.10. (E)-1-Benzyl-3-benzylidenepyrrolidine-2,5-dione (9)
Following the procedure for the preparation of 6 and 7, but
replacing diethyl ether with toluene, 3c (1.48 g, 4 mmol) gave, after
crystallization of the crude product in petroleum ether/diethyl
ether, 0.70 g of 9 (63%), as a white solid [Found: C, C, 77.9; H, 5.4; N,
5.1. C18H15NO2 requires C, 77.96; H, 5.45; N, 5.05]; mp 198–199 ꢀC;
nmax (KBr) 1697 cmꢂ1; dH (400 MHz, CDCl3) 7.63 (1H, m,]CHPh),
7.20–7.50 (10H, m, Ph), 4.79 (2H, s, CH2Ph), 3.57 (2H, d, J¼2.4 Hz,
C(3)H2); dC (100 MHz, CDCl3) 173.6, 170.6, 135.8, 134.5, 134.0,
130.13, 130.10, 129.1, 128.9, 128.6, 127.9, 123.4, 42.5, 34.1; m/z (EI,
70 eV) 277 (91, Mþ), 248 (14), 144 (18), 115 (100), 91 (27).

M. Pattarozzi et al. / Tetrahedron 66 (2010) 1357–1364
1363
4.11. 1-Benzyl-4,7a-dimethoxy-5,6,7,7a-tetrahydro-1H-indol-
2(4H)-one (13)
5H, 5 Ph), 4.68 (d, J¼14.9 Hz, 1H, CHPh), 4.63 (d, J¼14.9 Hz, 1H,
CHPh), 4.38 (q, J¼6.6 Hz, 1H, H-6), 3.74 (s, 2H, 2 H-5), 3.24 (s, 3H,
OCH3), 2.34–2.46 (m, 2H, C(3)CH2), 1.32 (3H, d, J¼6.6 Hz,]CHCH3),
1.16 (3H, t, J¼7.5 Hz, CH2CH3); dC (100 MHz, CDCl3) 171.4, 149.7,
137.3, 135.9, 128.6, 128.0, 127.4, 72.2, 56.5, 48.3, 46.2, 20.6, 17.2, 13.5;
m/z (EI, 70 eV) 259 (90, Mþ), 244 (26), 228 (18), 212 (26), 200 (18),
91 (100).
Following the procedure for the preparation of 6 and 7, but
thermostating at 25 ꢀC and increasing the reaction time to 3 h, 3d
(1.33 g, 4 mmol) gave, after flash-chromatography of the crude
product on silica gel, using a petroleum ether (bp 40–60 ꢀC)/diethyl
ether (from 100/0 to 50/50) gradient, 0.41 g of (4S
*
,7aS
*
)-13 (35%),
as a pale brown solid [Found: C, 85.1; H, 9.2; N, 5.9. C17H22NO3
4.13. 1,4-Dibenzyl-3-ethyl-5-methoxy-1H-pyrrol-2(5H)-
one (16)
requires C, 84.95; H, 9.22; N, 5.83], and 0.08 g of (4R
*
,7aS )-13 (7%),
*
as a brownish oil.
Following the procedure for the preparation of 14, but ther-
mostating at 37 ꢀC for 22 h, 3f (1.45 g, 4 mmol) gave, after
flash-chromatography of the crude product on silica gel, using
a petroleum ether (bp 40–60 ꢀC)/diethyl ether (from 100/0 to 70/
30) gradient, 1.21 g of 16 (94%), as a yellow oil [Found: 74.2; H, 8.1;
N, 5.3. C21H23NO2 requires C, 78.6; H, 7.3; N, 4.4]; nmax (liquid film)
1699 cmꢂ1; dH (200 MHz, CDCl3) 7.15–7.55 (10H, m, 2 Ph); 5.01 (1H,
s, C(5)H), 4.84 (1H, d, J¼14.9 Hz, NCHHPh), 4.20 (1H, d, J¼14.9 Hz,
NCHHPh), 3.82 (1H, d, J¼14.8 Hz, C(4)CHHPh), 3.46 (1H, d,
J¼14.8 Hz, C(4)CHHPh), 2.93 (3H, s, OCH3), 2.46 (2H, q, J¼7.5 Hz,
C(3)CH2), 1.20 (3H, t, J¼7.5 Hz, CH2CH3); dC (50 MHz, CDCl3) 170.5,
147.4, 137.9, 137.4, 129.4, 128.9, 128.6, 128.0, 127.4, 126.7, 86.7, 49.4,
43.6, 32.1, 17.3, 13.5; m/z (EI, 70 eV) 321 (27, Mþ), 306 (4), 290 (19),
230 (15), 91 (100).
4.11.1. (4S
*
,7aS
*
)-1-Benzyl-4,7a-dimethoxy-5,6,7,7a-tetrahydro-1H-
,7aS
)-13]. Mp 78–79 ꢀC; nmax (KBr)
indol-2(4H)-one [(4S
*
*
1693 cmꢂ1; dH (400 MHz, CDCl3) 7.10–7.29 (5H, m, Ph), 6.01 (1H, s,
C(3)H), 4.63 (1H, d, J¼15.2 Hz, CHHPh), 4.09 (1H, d, J¼15.2 Hz,
CHHPh), 3.77 (1H, dd, J¼11.2, 5.7 Hz, C(4)H), 3.39 (3H, s, C(4)OCH3),
2.76 (3H, s, C(7a)OCH3), 2.17–2.23 (1H, m, C(5)Heq), 1.95–2.01 (1H,
m, C(7)Heq), 1.50–1.58 (2H, m, C(6)H2), 1.11 (1H, dq, J¼11.7, 5.4 Hz,
C(5)Hax), 0.96 (1H, dt, J¼12.6, 5.4 Hz, C(7)Hax); dC (100 MHz, CDCl3)
170.9, 162.0, 139.8, 129.8, 128.6, 128.5, 120.5, 95.6, 77.2, 58.7, 51.1,
43.1, 39.3, 35.2, 20.9; HRMS-FAB (CI, NH3): m/z MHþ, found
288.1593, C17H22NO3 requires 288.1594.
4.11.2. (4S
*
,7aR
*
)-1-Benzyl-4,7a-dimethoxy-5,6,7,7a-tetrahydro-1H-
,7aS
)-13]. nmax (liquid film) 1701 cmꢂ1; dH
indol-2(4H)-one [(4R
*
*
(400 MHz, CDCl3) 7.14–7.29 (5H, m, Ph), 6.10 (1H, s, C(3)H), 4.71 (d,
J¼15.2 Hz. 1H, CHHPh), 4.09–4.12 (1H, m, C(4)H), 4.02 (1H, d,
J¼15.2 Hz, CHHPh), 3.27 (3H, s, C(4)OCH3), 2.83 (3H, s, C(7a)OCH3),
2.00–2.11 (2H, m, C(5)HH and C(7)Heq), 1.79–1.90 (1H, m, C(6)HH),
1.24–1.35 (2H, m, C(5)HH and C(6)HH), 0.99 (1H, dt, J¼13.4, 3.7 Hz,
C(7)Hax); dC (100 MHz, CDCl3) 170.3, 157.3, 139.8, 129.7,128.6, 126.6,
94.8, 75.7, 58.7, 52.2, 42.8, 40.3, 34.0, 18.0; HRMS-FAB (CI, NH3): m/z
MHþ, found 288.1591, C17H22NO3 requires 288.1594.
0.20 g (17%) of 1-Benzyl-3-chloro-7a-methoxy-5,6,7,7a-tetra-
hydro-1H-indol-2(4H)-one (12), as a brownish oil, was also re-
covered. nmax (liquid film) 1702 cmꢂ1; dH (400 MHz, CDCl3) 7.13–
7.30 (5H, m, Ph), 4.65 (1H, d, J¼15.1 Hz, CHHPh), 4.15 (1H, d,
J¼15.1 Hz, CHHPh), 2.73–2.78 (1H, m, C(4)HH), 2.69 (3H, s, OCH3),
2.03–2.08 (1H, m, C(7)HH), 1.93 (1H, dt, J¼13.1, 5.5 Hz, C(4)HH),
1.83–1.89 (1H, m, C(5)HH), 1.46–1.60 (2H, m, C(6)H2), 1.14 (1H, tq,
J¼13.1, 4.4 Hz, C(5)HH), 0.99 (1H, dt, J¼13.1, 5.2 Hz, C(7)HH); dC
(100 MHz, CDCl3) 164.9, 151.3, 137.9, 128.4, 128.3, 127.3, 122.5, 91.5,
49.6, 42.2, 38.2, 26.4, 24.5, 21.3; HRMS-FAB (CI, NH3): m/z MHþ,
found 292.1096, C16H19ClNO2 requires 292.1099.
4.14. (4R
*
,7aR )-1-Benzyl-3-ethyl-4-methoxy-5,6,7,7a-
*
tetrahydro-1H-indol-2(4H)-one (17)
Following the procedure for the preparation of 14, but ther-
mostating at 50 ꢀC for 4 h, 3g (1.31 g, 4 mmol) gave, after
flash-chromatography of the crude product on silica gel, using
a petroleum ether (bp 40–60 ꢀC)/diethyl ether (from 90/10 to 50/
50) gradient, 0.53 g of 17 (46%), as a colourless liquid; nmax (liquid
film) 1682 cmꢂ1; dH (400 MHz, CDCl3) 7.22–7.36 (5H, m, Ph), 4.97
(1H, d, J¼15.2 Hz, CHHPh), 4.40 (1H, t, J¼2.6 Hz, C(4)H), 4.29 (1H, d,
J¼15.2 Hz, CHHPh), 3.78 (1H, dd, J¼11.4, 5.8 Hz, C(7a)H), 3.20 (3H, s,
OCH3), 2.34–2.47 (2H, m, CH2CH3), 2.25–2.33 (1H, m, C(7)Heq), 2.13
(1H, dqn, J¼14.1, 2.9 Hz, C(5)Heq), 1.69 (1H, tq, J¼13.7, 3.2 Hz,
C(6)Hax), 1.57 (1H, dqn, J¼13.7, 3.2 Hz, C(6)Heq), 1.36 (1H, tdd,
J¼13.7, 4.3, 3.2 Hz, C(5)Hax), 1.16 (3H, t, J¼7.5 Hz, CH2CH3), 0.90 (1H,
dq, J¼12.4, 3.8 Hz, C(7)Hax); dC (100 MHz, CDCl3) 170.8, 150.3, 137.8,
134.5, 128.5, 127.8, 127.2, 72.0, 57.3, 55.9, 44.0, 33.5, 33.0, 17.7, 16.9,
13.9; HRMS-FAB (CI, NH3): m/z MHþ, found 286.1803, C18H24NO2
requires 286.1802.
0.16 g (16%) of 1-Benzyl-3-ethyl-5,6-dihydro-1H-indol-2(4H)-
4.12. 1-Benzyl-3,4-diethyl-5-methoxy-1H-pyrrol-2(5H)-
one (14)
one (18), as a brownish oil, and 0.25 g (19%) of (3R
*
,3aR
*
,4R
*
,7aR )-
*
3g, as a pale yellow oil, were also recovered; nmax (liquid film)
1686 cmꢂ1; dH (400 MHz, CDCl3) 7.12–7.25 (5H, m, Ph), 5.35 (1H, t,
J¼4.7 Hz, C(7)H), 4.68 (2H, s, CH2Ph), 2.49 (2H, t, J¼6.0 Hz, C(4)H2),
2.30 (2H, q, J¼7.6 Hz, CH2CH3), 2.16 (2H, dt, J¼6.0, 4.7 Hz, C(6)H2),
1.71 (2H, qn, J¼6.0 Hz, C(5)H2), 1.06 (3H, t, J¼7.6 Hz, CH2CH3); dC
(100 MHz, CDCl3) 170.6, 139.5, 138.9, 137.9, 128.9, 128.5, 127.1, 127.0,
108.5, 42.7, 24.2, 23.3, 22.4, 16.9, 13.2; HRMS-FAB (CI, NH3): m/z
MHþ, found 254.1530, C17H20NO requires 254.1539.
Following the procedure for the preparation of 6 and 7, but using
3 equiv of Na0 (0.28 g, 12 mmol) and thermostating at 25 ꢀC for
22 h, 3e (1.20 g, 4 mmol) gave, after flash-chromatography of the
crude product on silica gel, using a petroleum ether (bp 40–60 ꢀC)/
diethyl ether (from 100/0 to 60/40) gradient, 0.61 g of 14 (58%), as
a pale yellow oil [Found: 74.1; H, 8.1; N, 5.4. C16H21NO2 requires C,
74.10; H, 8.16; N, 5.40]; nmax (liquid film) 1701 cmꢂ1; dH (200 MHz,
CDCl3) 7.19–7.37 (5H, m, Ph), 5.09 (1H, s, C(5)H), 4.93 (1H, d,
J¼14.8 Hz, CHHPh), 4.09 (1H, d, J¼14.8 Hz, CHHPh), 2.92 (3H, s,
OCH3), 2.09–2.51 (4H, m, 2CH2CH3), 1.11 (3H, t, J¼7.5 Hz, CH2CH3),
1.08 (3H, t, J¼7.5 Hz, CH2CH3); dC (50 MHz, CDCl3) 170.6, 150.4,
137.5, 136.8, 128.6, 128.3, 127.4, 86.0, 49.1, 43.3, 19.1, 16.9, 13.6, 12.8;
m/z (EI, 70 eV) 259 (49, Mþ), 244 (7), 228 (40), 91 (100).
Acknowledgements
`
We thank the Ministero dell’Istruzione, dell’Universita e della
Ricerca (MIUR) and the EU (under the ERASMUS scheme) for
financial assistance.
0.37 g (36%) of (E)-1-Benzyl-3-ethyl-4-ethylidene-3-methoxy-
2-pyrrolidinone (15), as a colourless oil [Found: 74.2; H, 8.1; N, 5.3.
C16H21NO2 requires C, 74.10; H, 8.16; N, 5.40], was also recovered;
nmax (liquid film) 1683 cmꢂ1; dH (400 MHz, CDCl3) 7.25–7.38 (m,
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