Spiro cyclisations of N-acyliminium ions involving an aromatic π-nucleophile

Article abstract of DOI:10.1016/S0040-4020(03)00418-6

Spiro 2-pyrrolidin-5-ones were obtained from N-substituted succinimides by a two-step procedure, involving 5- or 6-endo-trig cyclisation of N-acyliminium ion intermediates with a tethered aromatic π-nucleophile.

Full text of DOI:10.1016/S0040-4020(03)00418-6

Tetrahedron 59 (2003) 3369–3378
Spiro cyclisations of N-acyliminium ions involving an
aromatic p-nucleophile
†
Patrick D. Bailey,a Keith M. Morgan,a David I. Smithb and John M. Vernonc
,
,
*
aDepartment of Chemistry, Heriot-Watt University, Riccarton, Edinburgh EH14 4AS, UK
bSanofi-Synthelabo Research, Alnwick, Northumberland NE66 2JH, UK
cDepartment of Chemistry, University of York, Heslington, York YO10 5DD, UK
Received 21 October 2002; revised 17 February 2003; accepted 6 March 2003
Abstract—Spiro 2-pyrrolidin-5-ones were obtained from N-substituted succinimides by a two-step procedure, involving 5- or 6-endo-trig
cyclisation of N-acyliminium ion intermediates with a tethered aromatic p-nucleophile. q 2003 Elsevier Science Ltd. All rights reserved.
The importance of N-acyliminium ion chemistry in organic
synthesis is attested by numerous reviews.1,2 In the common
type of intramolecular reaction of N-acyliminium ions
represented by 1, the nucleophile may be heteroatom,
alkene, alkyne or aromatic groups; from cyclic iminium
ions, fused bicyclic or polycyclic products are obtained.
Much less common are intramolecular reactions of the type
represented by 2, which lead to the formation of spiro
products. Prior to our work in this area, the only examples of
such a,a-cyclisations involved alkene nucleophiles.3 The
reaction was applied in two syntheses of perhydrohistrio-
nicotoxin4 via the key intermediate 6,6-spiro lactam 3.
Recent examples of spiro cyclisation via N-acyliminium
ions include two syntheses of lepadiformine.5
Our own interest in spiro lactams was stimulated by
elucidation of the unexpected formation of 4 via a different
route,6 which prompted us to examine the possibility of a,a-
cyclisations 2 with an aromatic ring as the p-nucleophile.7
Two examples of this type were reported in the context of a
tandem thionium/N-acyliminium ion cascade cyclisation
sequence.8 Although an erythrinane synthesis achieved via
iminium ion cyclisation also involves the formation of a
spiro structure,9 the cyclisation step in this case corresponds
to type 1, not 2.
1. Results and discussion
The required cyclisation was first demonstrated with the
hydroxy lactam 7a, which afforded the 5,5-spiro lactam 9a
in 69% yield by dehydration in refluxing trifluoroacetic acid
(TFA). In the same way, the homologous hydroxy lactam 7b
was the intermediate in a two-step synthesis of the 5,6-spiro
lactam 9b (Scheme 1). 13C NMR DEPT spectra showed the
appropriate signals for CH3, CH2 (£4 in 9a, £5 in 9b) and
crucially for quaternary carbon (d 74.2 in 9a, d 65.8 in 9b).
Grignard addition to N-benzylsuccinimide 6, followed by
cyclisation in refluxing TFA, similarly afforded the N-
benzyl spiro lactams 10a,b, which showed the correspond-
ing 13C NMR resonances for quaternary carbon at d 74.9
and 67.1, respectively. However, we sought additional
evidence to confirm the spiro structures in these two cases
and specifically to exclude the alternative fused tricyclic
structures 11a,b, which could result from the intermediates
8a,b via the alternative N-acyliminium ion cyclisation 1
involving the N-benzyl group. Although these would be
relatively disfavoured 5-endo-trig cyclisations, there are
precedents in the formation of 12 and 13.10,11 The non-
Keywords: spiro lactams; N-acyliminium ion cyclisations.
*
Corresponding author. Tel.: þ44-1904-432541;
e-mail: jmv2@york.ac.uk
Present address: Department of Chemistry, UMIST, P.O. Box 88,
Manchester M60 1QD, UK.
1
†
equivalence of the N–CH2 signals in the H NMR spectra
(two doublets, d 3.85 and 4.67 in 10a and d 3.65 and 4.88 in
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00418-6

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P. D. Bailey et al. / Tetrahedron 59 (2003) 3369–3378
Scheme 1. Reagents: (i) Ph(CH2)nMgBr (ii) TFA, reflux.
10b) might have been interpreted as evidence for the fused
tricyclic structures 11a,b.
with substituents in both ortho positions of the N-benzyl
group, which served to block the alternative cyclisation to
11. The hydroxy lactam 26 obtained in low yield from N-
(2,6-difluorobenzyl)succinimide 24 was incompletely sep-
arated from by-products, but on heating in TFA it afforded
the 5,5-spiro lactam 28. Attempted Grignard addition to the
more sterically hindered succinimide 25 was unsuccessful,
and only the aldol condensation product 23 was obtained.
However, the alternative route shown in Scheme 3 afforded,
instead of the hydroxy lactam 27, the enamide 30. On
heating this in TFA the desired spiro product 29 was
obtained, although the reaction was slower than in other
cases and still incomplete after 4 days. Attempted
debenzylation of 29 with hydrogen and palladium resulted
only in hydrodehalogenation12 to give the N-benzyl spiro
lactam 10a. This series of experiments thus provides
conclusive proof of the correct assignment of spiro
structures 10a,b.
In the first place, and in order to develop applications of these
spiro cyclisations towards natural product targets, we
examined the cyclisation into a 3,4-methylenedioxy substi-
tuted benzene ring. This involved the preparation of bromides
19a,b as outlined in Scheme 2. Grignard reagents made from
19a,b were then added to N-benzyl succinimide 6 to give
hydroxy lactams 20a,b and, in one case, the by-product 22
from aldol condensation of 6. Heating of 20a,b in TFA
achieved cyclodehydration to give the spiro lactams 21a,b,
which showed 13C resonances for quaternary carbon at d 74.7
and67.1, respectively. 1HNMR Spectraof21a,bincludedtwo
singlets for aryl H adjacent to the OCH2O substituent, which
provides evidence to confirm the spiro structures rather than
fused tricyclic structures analogous to 11.
A variety of chiral control elements has been employed in
reactions via N-acyliminium ions.2 Among the simplest of
these is a chiral 1-arylethyl substituent on nitrogen, which
controls the stereochemistry of intermolecular additions to
N-acyliminium ions,13–15 although the changes in stereo-
selectivity resulting from changes in substituent, reactant or
conditions are not always understood. Hence, we were also
interested to explore the corresponding cyclisations of
hydroxy lactam precursors with a chiral N-substituent for
the possibility of stereochemical control of formation of
the spiro carbon centre. For this purpose, we took (R)-N-
(1-phenylethyl)succinimide 31, but found that steric hin-
drance reduced the reactivity towards Grignard addition
onto a succinimide carbonyl group, while the basicity of the
Grignard reagent resulted in aldol-type dimerisation of 31 to
give 36. This problem was circumvented by using a cerium-
moderated Grignard reagent of lower basicity,16 whereby
the ketoamide 32 and enamide 33b were obtained if the
Grignard reagent was prepared from Ph(CH2)nBr (n¼2 or
3), respectively. Treatment of 32 with TFA under very mild
conditions achieved recyclisation to the enamide 33a. In
A second approach to prove the correct assignment of spiro
structures 10a,b involved cyclisation of derivatives of 8a,b
Scheme 2. Reagents: (i) LiAlH4/THF; (ii) H2/Pd; (iii) PPh3þCBr4/MeCN.

P. D. Bailey et al. / Tetrahedron 59 (2003) 3369–3378
3371
Scheme 3. Reagents: (i) PhCH2CH2MgBr/THF; (ii) 2,6-Cl2C6H3CH2Br/Cs2CO3/MeCN; (iii) TFA, reflux; (iv) H2/Pd(OH)2–C/MeOH.
refluxing TFA 32 and 33a were separately converted into
the spiro lactam 34a, but with loss of the chiral N-
substituent (Scheme 4). TLC was used to monitor the
progress of reaction in TFA at lower temperatures, but this
did not indicate the formation of other spiro products (35a).
Moreover, and disappointingly, the product 34a was
racemic, implying that this debenzylation of the N-
acyliminium ion intermediate had occurred prior to spiro
cyclisation.
Spiro lactam 35b contains two benzylic groups attached to
nitrogen and it was problematic whether the side chain
1-phenylethyl group could be removed selectively. In fact,
no debenzylation of 35b was observed under the usual
conditions of hydrogen with palladium or Pearlman’s
catalyst, with or without addition of acid. In a small scale
experiment with sodium and liquid ammonia, 35b was
reduced with unexpected cleavage of the endocyclic
benzylic bond to give amide 37. This appeared to be a
single diastereoisomer (13C NMR spectrum7) and some of
35b remained (tlc analysis), which suggested that ring-
opening of 35b had occurred diastereoselectively.
More interestingly, the corresponding cyclisation of
homologous enamide 33b in refluxing TFA resulted in
formation of a mixture of NH and N-substituted 5,6-spiro
lactams 34b and 35b, in 58 and 25% yield, respectively;
34b, like 34a, was racemic and 35b was a ca. 3:1 mixture of
diastereoisomers, inseparable by chromatography. Spiro
lactam 34b was prepared independently in two steps by
Grignard addition to succinimide, followed by cyclisation in
refluxing TFA. Benzylation of 34a,b gave N-benzyl
derivatives (Scheme 4), which were identical with the
spiro lactams 10a,b obtained previously.
Scheme 4. Reagents: (i) Ph(CH2)nMgBr/CeCl3/THF; (ii) TFA/CH2Cl2/08C; (iii) TFA, reflux; (iv) PhCH2Br/Cs2CO3/MeCN.

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P. D. Bailey et al. / Tetrahedron 59 (2003) 3369–3378
In conclusion, we have demonstrated the formation of spiro
lactams by cyclisation of N-acyliminium ion intermediates
reacting intramolecularly with an arene p-nucleophile. In
subsequent work we have found that some of the
cyclisations, e.g. to 10a,b, can be achieved using aluminium
trichloride in 1,2-dichloroethane. We have also developed a
stereoselective approach17 to spiro lactams based on the use
of phenylglycinol as chiral auxiliary and a regioselective
debenzylation procedure18 to remove the side chain from
nitrogen.
MS m/z 203 (Mþ, 50%), 188 (6), 160 (100), 146 (9), 132 (6),
120 (7), 104 (24) and 77 (22). (S)-(2)-31 has been
reported:13,21 mp 39–418C, 67–68.58C; [a]D279.8,
268.9 (EtOH).
N-(2,6-Difluorobenzyl)succinimide 24 was prepared from
succinimide (2.39 g) and 2,6-difluorobenzyl bromide (5.0 g)
dissolved in acetonitrile (30 mL) and stirred with caesium
carbonate (10.0 g) for 24 h. The solution was filtered, the
solvent evaporated and the residue recrystallised to give the
imide 24 (4.22 g, 77%) as colourless platelets, mp 112–
1138C (methanol) (HREIMS Found Mþ m/z 225.0600.
C11H9F2NO2 requires M 225.0601); IR nmax/cm21 1780 and
2. Experimental
2.1. General
1
1710 (CvO); H NMR (90 MHz) d 2.70 (4H, s, 2£ring
CH2), 4.74 (2H, s, NCH2) and 6.72–7.39 (3H, m, aryl H);
13C NMR (22.5 MHz) d 28.1 (CH2), l30.6, 30.8, 31.0l
(CH2), l110.8, 111.9l (CH), l129.3, 129.7, 130.2l (CH),
l155.7, 156.1, 166.8, 167.2l (CF) and 176.3 (CvO); MS m/z
225 (Mþ, 100%), 196 (10), 169 (12), 140 (64) and 127
(ArCHþ2 , 51).
Optical rotations were recorded for solutions in dichloro-
methane (DCM) at 228C (Perkin–Elmer 141 polarimeter).
IR Spectra were recorded for solutions in chloroform
(Perkin–Elmer 1420 spectrophotometer). 1H NMR Spectra
were recorded at 90 MHz (JEOL FX90Q) or at 300 MHz
(Bruker MSL300) and 13C NMR spectra at 22.5 MHz
(JEOL FX90Q spectrometer) for solutions in deuterio-
chloroform (unless stated otherwise) with tetramethylsilane
as internal standard. In 13C NMR spectra lines enclosed in l l
are due to 19F splittings. Mass spectra were obtained by
electron impact at 70 eV (VG Autospec). Flash chromato-
graphy19 was performed using silica gel 60 (230–400
mesh) purchased from Camlab. Acetonitrile, diethyl ether
and THF were dried before use. DCM refers to
dichloromethane.
N-(2,6-Dichlorobenzyl)succinimide 25 was obtained in the
same way (36% yield) using 2,6-dichlorobenzyl bromide;
mp 116–1188C (methanol) (HRCIMS Found M·NHþ4 m/z
275.0356. C11H1335Cl2N2O2 requires 275.0354); IR nmax
/
cm21 1780 and 1710 (CvO); H NMR (90 MHz) d 2.67
(4H, s, 2£ring CH2), 4.89 (2H, s, NCH2) and 7.12–7.28
(3H, m, aryl H); 13C NMR (22.5 MHz) d 27.7 (CH2), 38.5
(CH2), 128.1 (CH), 129.3 (CH), 129.8 (C), 135.8 (C) and
176.3 (CvO); MS m/z 261, 259 and 257 (Mþ, all ,1%),
224 (31), 222 (M2Cl, 100), 172 (7), 161 (8), 159 (12) and
141 (21).
1
2.2. N-Substituted succinimides 6, 24, 25 and 31
2.3. 2-(3,4-Methylenedioxyphenyl)ethanol 16 and
1-bromo-2-(3,4-methylenedioxy-phenyl)ethane 19a;
3-(3, 4-methylenedioxyphenyl)propan-1-ol 18 and
1-bromo-3-(3,4-methylenedioxyphenyl)propane 19b
N-Benzylsuccinimide 6 was prepared by dropwise addition
of benzylamine (16.5 g, 150 mmol) to a stirred solution of
succinic anhydride (15.0 g, 150 mmol) in THF (150 mL).
The mixture was heated under reflux for 2 h, then cooled
and the solvent removed in vacuo. Acetic anhydride
(150 mL) was added and the mixture again heated under
reflux for 2 h, then cooled and poured onto crushed ice and
stirred. The precipitated solid was collected and recrystal-
lised to give the imide 6, mp 101–1038C (methanol) (lit.20
mp 103.5–1058C).
3,4-Methylenedioxyphenylacetic acid (5.0 g) was reduced
with aluminium lithium hydride (2.3 g) in THF at room
temperature. Aqueous work-up afforded the alcohol 16
(4.6 g) as a colourless oil. This was dissolved in acetonitrile
(50 mL) together with triphenylphosphine (6.9 g), to which
was added carbon tetrabromide (9.2 g) in portions, followed
by stirring overnight. The solvent was evaporated in vacuo
and the residue chromatographed on silica, from which
DCM eluted the bromide 19a (5.1 g, 80% over 2 steps),
colourless oil (HREIMS Found Mþ 227.9815. C9H979BrO2
requires M 227.9786); 1H NMR (90 MHz) d 3.05 (2H, br t,
J 7.3 Hz, ArCH2CH2), 3.50 (2H, br t, J 7.3 Hz, CH2Br), 5.91
(2H, s, OCH2O) and 6.57–6.80 (3H, m, aryl H); 13C NMR
(22.5 MHz) d 33.2 (CH2), 39.1 (CH2), 101.0 (CH2), 108.4
(CH), 109.0 (CH), 121.7 (CH), 132.7 (C), 146.5 (C) and
147.7 (C); MS m/z 230 and 228 (Mþ, 25%), 149 (M2Br,
20), 135 (ArCHþ2 , 100), 119 (9), 91 (16) and 77 (11).
(R)-(þ)-N-(1-Phenylethyl)succinimide 31 was prepared in
the same way from (R)-(þ)-1-phenylethylamine and
succinic anhydride. After pouring the acetic anhydride
solution onto crushed ice, the mixture was extracted three
times with DCM. The combined extracts were washed with
saturated sodium hydrogen carbonate solution, then with
brine, then dried (MgSO4), and the solvent evaporated to
afford a colourless oil. This was chromatographed on silica,
from which DCM eluted the imide 31 as a colourless oil
(60% yield) which crystallised after trituration with ether,
mp 64–658C (HREIMS Found Mþ m/z 203.0945.
C12H13NO2 requires M 203.0946); [a]Dþ91.9 (c 4.0,
DCM); IR nmax/cm21 3000, 1775, 1700, 1600, 1580,
3,4-Methylenedioxycinnamic acid (3.0 g) was dissolved in
THF (100 mL) and cooled to 08C during addition of
aluminium hydride (1.5 g) with stirring. The mixture was
allowed to warm to room temperature, then heated under
reflux for 24 h. Aqueous work-up afforded a mixture of
saturated and unsaturated alcohols 17 and 18, which was
redissolved in methanol (50 mL) and stirred overnight with
1
1490, 1450 and 1430; H NMR (90 MHz) d 1.81 (3H, d,
J 7.4 Hz, CHCH3), 2.62 (4H, s, 2£ring CH2), 5.42 (1H, q,
J 7.4 Hz, CHCH3) and 7.25–7.50 (5H, m, aryl H); 13C NMR
(22.5 MHz) d 16.6 (CH3), 28.1 (CH2), 50.3 (CH), 127.6
(CH), 127.8 (CH), 128.4 (CH), 139.7 (C) and 177.0 (CvO);

P. D. Bailey et al. / Tetrahedron 59 (2003) 3369–3378
3373
palladium on charcoal under an atmosphere of hydrogen.
The solution was filtered, the solvent evaporated, and the
residue chromatographed on silica, from which DCM eluted
3-(3,4-methylenedioxyphenyl)propan-1-ol 18 (1.5 g, 53%),
colourless oil (HREIMS Found Mþ 180.0787. C10H12O3
8.8 mmol) according to the general procedure. The crude
product was a yellow oil (3.3 g) which by flash chromato-
graphy on silica and elution with a solvent gradient (ether/
DCM 40:60 to methanol/ether/DCM 2:40:58) afforded
5-hydroxy-1-methyl-5-(2-phenylethyl)pyrrolidin-2-one 7a
(1.01 g, 52%) as a pale yellow foam (HREIMS Found Mþ
219.1244. C13H17NO2 requires M 219.1259); Rf 0.20
(methanol/chloroform 1:9); IR nmax/cm21 3580 (O–H),
1
requires M 180.0787); IR nmax/cm21 3605 (OH); H NMR
(90 MHz) d 1.72–1.96 (2H, m, ArCH2CH2CH2), 2.43 (1H,
s, OH), 2.51–2.68 (2H, m, ArCH2CH2), 3.61 (2H, t,
J 6.4 Hz, CH2OH), 5.88 (2H, s, OCH2O) and 6.54–6.76
(3H, m, aryl H); 13C NMR (22.5 MHz) d 31.7 (CH2), 34.3
(CH2), 61.8 (CH2), 100.7 (CH2), 108.1 (CH), 108.8 (CH),
121.1 (CH), 135.7 (C), 145.6 (C) and 147.5 (C); MS m/z 180
(Mþ, 66%), 162 (5), 136 (60), 135 (ArCHþ2 , 100), 106 (10),
91 (8) and 77 (17).
1
3000, 1675 (CvO), 1600, 1490, 1455 and 1410; H NMR
(90 MHz) d 2.75 (3H, s, CH3), 1.83–2.90 (8H, m, 4£CH2),
5.26 (1H, br, s, OH) and 7.11–7.40 (5H, m, aryl H); 13C
NMR (22.5 MHz) d 24.1 (CH3), 29.3 (CH2), 30.1 (CH2),
31.6 (CH2), 39.9 (CH2), 91.6 (spiro C), 126.1 (CH), 128.2
(CH), 128.5 (CH), 141.0 (C) and 175.0 (CvO); MS m/z 219
(Mþ, 2%), 201 (M2H2O, 100), 200 (45), 186 (3), 172 (12),
124 (42), 114 (32) and 91 (51).
Alcohol 18 (1.3 g) and triphenylphosphine (1.8 g) were
dissolved in acetonitrile (20 mL) and stirred during addition
of carbon tetrabromide (2.4 g) in portions. Stirring was
continued overnight, after which the solvent was evaporated
in vacuo and the residue chromatographed on silica, from
which DCM eluted 1-bromo-3-(3,4-methylenedioxyphe-
nyl)-propane 19b (1.25 g, 71%), colourless oil (HREIMS
Found Mþ 243.9901. C10H1181BrO2 requires M 243.9902);
IR O–H absorption absent; 1H NMR (90 MHz) d 1.92–2.28
(2H, m, ArCH2CH2CH2), 2.69 (2H, t, J 7.3 Hz, ArCH2CH2),
3.37 (2H, t, J 6.3 Hz, CH2Br), 5.92 (2H, s, OCH2O) and
6.56–6.82 (3H, m, aryl H); 13C NMR (22.5 MHz) d 32.9
(CH2), 33.7 (CH2), 34.3 (CH2), 100.8 (CH2), 108.2 (CH),
108.9 (CH), 121.4 (CH), 134.2 (C), 145.9 (C) and 147.7 (C);
MS m/z 244 and 242 (Mþ, 19%), 162 (5), 135 (ArCHþ2 ,
100), 105 (5) and 77 (15).
After heating the hydroxy lactam 7a (500 mg, 2.28 mmol)
in TFA (20 mL) under reflux for 48 h, the mixture was
worked up to afford a crude product of a yellow oil (425 mg)
and after flash chromatography and elution with ether/DCM
(5:95) 2,3-dihydro-10-methylspiro[1H-indene-1,20-pyrrol-
idin]-50-one 9a (318 mg, 69%) as colourless needles, mp
44–458C (from methanol) (Found: C, 77.6; H, 7.5; N, 7.0.
C13H15NO requires C, 77.6; H, 7.5; N, 6.9%); Rf 0.27 (ether/
chloroform 1:9); IR nmax/cm21 3000, 1670 (CvO), 1475,
1
1450, 1435, 1420 and 1395; H NMR (90 MHz) d 1.94–
2.58 (6H, m, 3£CH2), 2.58 (3H, s, CH3), 2.96 (2H, t,
J 7.1 Hz, ArCH2) and 7.01–7.26 (4H, m, aryl H); 13C NMR
(22.5 MHz) d 25.3 (CH3), 29.4 (CH2), 30.2 (CH2), 33.8
(CH2), 34.9 (CH2), 74.2 (spiro C), 122.7 (CH), 125.0 (CH),
127.2 (CH), 128.3 (CH), 142.7 (C), 144.2 (C) and 174.7
(CvO); MS m/z 201 (Mþ, 100%), 200 (37), 186 (8), 172
(30), 158 (34), 144 (29), 129 (16) and 115 (16).
2.4. General procedures for Grignard reactions and for
cyclisations in TFA
The Grignard reagent was freshly prepared from the
required bromide in ether with an equimolar quantity of
magnesium; reaction was initiated, if necessary, by addition
of a small crystal of iodine and completed by heating under
reflux for 1 h. The required imide dissolved in THF was
added to the Grignard reagent in ether at room temperature
with stirring and the mixture stirred overnight. Saturated
aqueous ammonium chloride was added and the mixture
extracted with 2 portions of chloroform. The combined
extracts were washed 3 times with brine, then dried
(MgSO4); the solution was filtered, the solvent evaporated
in vacuo, and the residue purified by flash chromatography
on silica to yield hydroxy lactam and other products
described below.
The Grignard reagent was prepared from 1-bromo-3-
phenylpropane (3.7 g, 20 mmol) and reacted with N-
methylsuccinimide (1.0 g, 8.8 mmol) according to the
general procedure. The crude product was a yellow oil
(3.05 g) which by flash chromatography on silica and
elution with a solvent gradient (ether/DCM 10:90 to
methanol/ether/DCM 2:10:88) afforded the hydroxy lactam
7b (536 mg) [Rf 0.44 (ether/chloroform 1:9)] contaminated
by some baseline material. This product was dissolved in
TFA (15 mL) and heated under reflux for 48 h. The usual
work-up procedure afforded 1,2,3,4-tetrahydro-10-methyl-
spiro[naphthalene-1,20-pyrrolidin]-50-one 9b as a colourless
oil (474 mg, 25% from N-methylsuccinimide) (HREIMS
Found Mþ 215.1318. C14H17NO requires M 215.1310); Rf
0.39 (ether/chloroform 1:9); IR nmax/cm21 3000, 1670
1
The hydroxy lactam was dissolved in TFA and heated under
reflux for 1–3 days. The solution was cooled and poured
dropwise into saturated NaHCO3 solution in presence of an
excess of solid NaHCO3. The mixture was extracted twice
with chloroform, the extracts washed with brine, then dried
(MgSO4); the solution was filtered, the solvent evaporated
in vacuo, and the residue purified by flash chromatography
on silica to yield spiro products described below.
CvO), 1490, 1450, 1420 and 1400; H NMR (90 MHz) d
1.75–2.50 (8H, m, 4£CH2), 2.57 (3H, s, CH3), 2.65–2.90
(2H, m, ArCH2) and 7.00–7.24 (4H, m, aryl H); 13C NMR
(22.5 MHz) d 20.0 (CH2), 25.7 (CH3), 29.3 (CH2), 29.5
(CH2), 32.2 (CH2), 35.8 CH2), 65.8 (spiro C), 126.0 (CH),
126.7 (CH), 127.2 (CH), 129.3 (CH), 137.6 (C), 139.1 (C) and
175.1 (CvO); MS m/z 215 (Mþ, 100%), 200 (29), 186 (60),
172 (44), 158 (24), 144 (19), 124 (19), 115 (17) and 91 (9).
2.4.1. Hydroxy lactam 7a,b and spiro products 9a,b
derived from N-methylsuccinimide. The Grignard reagent
was prepared from 1-bromo-2-phenylethane (3.7 g,
20 mmol) and reacted with N-methylsuccinimide (1.0 g,
2.4.2. Hydroxy lactam 8a,b and 20a,b and spiro products
10a,b and 21a,b derived from N-benzylsuccinimide. The
Grignard reagent was prepared from 1-bromo-2-phenyl-
ethane (5.3 mmol) and reacted with N-benzylsuccinimide 6

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P. D. Bailey et al. / Tetrahedron 59 (2003) 3369–3378
(0.77 g, 4.1 mmol) according to the general procedure. The
crude product was a yellow oil (1.4 g) which by flash
chromatography on silica and elution with a solvent gradient
(ether/DCM 40:60 to methanol/ether/DCM 2:40:58)
afforded 1-benzyl-5-hydroxy-5-(2-phenylethyl)pyrrolidin-
2-one 8a (0.81 g, 67%) as a colourless oil (HREIMS
Found Mþ 295.1570. C19H21NO2 requires M 295.1572); Rf
0.53 (methanol/chloroform 1:9); IR nmax/cm21 3575, 3000,
3000, 2950, 1670, 1600, 1485, 1450, 1430, 1405 and 1355;
1H NMR (90 MHz) d 1.62–1.87 (4H, m, 2- and 3–CH2),
2.13 and 2.20 (each 1H, dt, J 13.0, 8.0 Hz, 30 –CH2),
2.63 (2H, t, J 8.0 Hz, 40 –CH2), 2.71–2.77 (2H, m, 4–CH2),
3.65 and 4.88 (each 1H, d, J 15.6 Hz, NCH2Ph) and
7.03–7.27 (9H, m, aryl H); 13C NMR (22.5 MHz) d 20.1
(CH2), 29.3 (2 lines, CH2), 35.4 (CH2), 36.3 (CH2), 44.5
(CH2), 67.1 (spiro C), 125.9 (CH), 126.6 (CH), 127.0 (CH),
127.4 (CH), 128.4 (CH), 128.8 (CH), 129.6 (CH), 137.8 (C),
138.7 (C), 139.3 (C) and 176.3 (CvO); MS m/z 291 (Mþ,
1%), 248 (15), 200 (10), 163 (35), 146 (35), 106 (30) and 91
(83).
1
1675 (CvO), 1600, 1490, 1455, 1410 and 1355; H NMR
(90 MHz) d 1.75–2.80 (8H, m, 4£CH2), 3.67 (1H, br s,
OH), 4.30 and 4.64 (each 1H, apparent s, outer lines of AB
system not seen, NCH2) and 7.28–7.88 (10H, m, aryl H);
13C NMR (22.5 MHz) d 29.2 (CH2), 30.2 (CH2), 32.5
(CH2), 41.0 (CH2), 42.5 (CH2), 92.7 (C), 126.1 (CH), 127.4
(CH), 128.2 (CH), 128.5 (CH), 128.7 (CH), 138.4 (C), 140.9
(C) and 175.6 (CvO); MS m/z 295 (Mþ, 2%), 277
(M2H2O, 84), 248 (16), 186 (65), and 91 (100).
The Grignard reagent was prepared from 1-bromo-2-(3,4-
methylenedioxyphenyl)ethane 19a (1.0 g, 4.4 mmol) and
reacted with N-benzylsuccinimide 6 (0.28 g, 1.5 mmol)
according to the general procedure. After flash
chromatography on silica and elution with ether/DCM
(1:9) 1-benzyl-5-hydroxy-5-{2-(3,4-methylenedioxyphe-
nyl)ethyl}pyrrolidin-2-one 20a (0.43 g, 85%) was obtained
as a pale yellow foam; Rf 0.42 (methanol/chloroform 1:9);
1H NMR (90 MHz) d 1.85–2.85 (8H, m, 4£CH2), 3.20 (1H,
br, OH), 4.28–4.85 (2H, m, NCH2), 5.88 (2H, s, OCH2O),
6.28–6.70 (3H, m, aryl H) and 7.25 (5H, br, aryl H); 13C
NMR (22.5 MHz) d 21.3 (CH2), 28.1 (CH2), 28.8 (CH2),
32.2 (CH2), 43.7 (CH2), 100.8 (CH2), 108.1 (CH), 108.5
(CH), 120.5 (CH), 127.1 (CH), 127.3 (CH), 128.6 (CH),
134.7 (C), 136.0 (C), 139.9 (C), 145.7 (C), 147.6 (C) and
175.5 (CvO); MS m/z Mþ absent, 321 (M2H2O, 80%),
292 (4), 230 (41), 186 (55), 135 (34), 91 (100) and 77 (10).
This hydroxy lactam 20a (0.26 g) was dissolved in TFA
(10 mL) and heated under reflux for 24 h. After work-up,
flash chromatogra0phy on silica and elution with ether/DCM
(1:9) afforded 1 -benzyl-5,6-methylenedioxy-2,3-dihydro-
spiro[1H-indene-1:20-pyrrolidin]-50-one 21a (70 mg, 28%)
as a colourless foam (HREIMS Found Mþ 321.1364.
C20H19NO3 requires M 321.1365); Rf 0.45 (ether/chloro-
form 1:9); 1H NMR (90 MHz) d 1.96–2.23 (4H, m,
2£CH2), 2.52–2.77 (4H, m, 2£CH2), 3.92 and 4.56 (each
1H, d J 15.3 Hz, NCH2), 5.90 (2H, s, OCH2O), 6.37 and
6.63 (each 1H, s, H-4 and H-7) and 7.04–7.28 (5H, m, aryl
H); 13C NMR (22.5 MHz) d 29.3 (CH2), 30.0 (CH2), 34.6
(CH2), 37.5 (CH2), 43.6 (CH2), 74.7 (spiro C), 101.2 (CH2),
103.3 (CH), 104.9 (CH), 126.9 (CH), 127.6 (CH), 128.1
(CH), 136.3 (C), 136.7 (C), 138.5 (C), 147.2 (C), 148.3 (C)
and 175.0 (CvO); MS m/z 321 (Mþ, 92%), 292 (15), 264
(18), 230 (7), 187 (34), 174 (100) and 91 (42). A repeat of
the experiment using a less pure sample of hydroxy lactam
20a gave, in addition to the spiro compound 21a, a
small quantity of N-benzyl-3-(1-benzyl-5-oxopyrrolidin-5-
ylidene)succinimide 22 as a colourless foam (HREIMS
Found Mþ 360.1477. C22H20N2O3 requires M 360.1474); Rf
0.35 (ether/chloroform 1:9); IR nmax/cm21 3000, 1740 and
1690 (CvO), 1625 and 1430; 1H NMR (300 MHz) d 2.69–
2.74 and 3.44–3.49 (each 2H, m, CH2CH2), 3.26 (2H, br s,
CH2), 4.64 and 4.94 (each 2H, s, NCH2), 7.03–7.06 (2H, m,
aryl H) and 7.25–7.38 (8H, m, aryl H); 13C NMR (75 MHz)
d 25.5 (CH2), 27.6 (CH2), 33.0 (CH2), 42.0 (CH2), 44.5
(CH2), 92.2 (C), 125.1 (CH), 127.6 (CH), 127.7 (CH), 128.6
(CH), 128.8 (CH), 129.3 (CH), 135.8 (C), 136.1 (C), 152.4
(C), 170.9 (CvO), 173.5 (CvO) and 177.6 (CvO); MS
m/z 360 (Mþ, 40%), 269 (16), 241 (10), 198 (7), 171 (7), 149
(8), 137 (20) and 91 (100).
The hydroxy lactam 8a (100 mg) was dissolved in TFA and
heated under reflux for 72 h. After the usual work-up, flash
chromatography on silica and elution with ether/DCM
(5:95) afforded 10-benzyl-2,3-dihydrospiro[1H-indene-1:20-
pyrrolidin]-50-one 10a (35 mg, 37%) as a colourless oil
(HREIMS Found Mþ 277.1498. C19H19NO requires M
277.1467); Rf 0.54 (ether/chloroform 1:9); IR nmax/cm21
3000, 2950, 1670, 1600, 1490, 1450, 1430, 1400 and 1355;
1H NMR (90 MHz) d 1.95–2.30 (4H, m, 2£CH2), 2.50–
2.90 (4H, m, CH2CO and CH2Ph), 3.85 and 4.67 (each 1H,
d, J 15.4 Hz, NCH2) and 6.95–7.25 (9H, m, aryl H); 13C
NMR (22.5 MHz) d 29.4 (CH2), 30.1 (CH2), 34.8 (CH2),
37.1 (CH2), 43.9 (CH2), 74.9 (spiro C), 123.2 (CH), 125.1
(CH), 127.0 (CH), 127.1 (CH), 127.7 (CH), 128.3 (CH),
128.5 (CH), 138.5 (C), 143.0 (C), 144.2 (C) and 175.5
(CvO); MS m/z 277 (Mþ, 100%), 248 (13), 200 (8), 186
(10), 146 (23), 130 (32) and 91 (50).
The Grignard reagent was prepared from 1-bromo-3-
phenylpropane (1.85 g, 10 mmol) and reacted with N-
benzylsuccinimide 6 (1.50 g, 7.94 mmol) with stirring
overnight. Work-up according to the general procedure
gave a crude product as a yellow oil (3.75 g) and flash
chromatography on silica and elution with a solvent gradient
(ether/DCM 50:50 to methanol/ether/DCM 5:50:45)
afforded 1-benzyl-5-hydroxy-5-(3-phenylpropyl)pyrrolidin-
2-one 8b (1.55 g, 50%) as a pale yellow oil (HREIMS
Found Mþ 309.1704. C20H23NO2 requires M 309.1732); Rf
0.50 (methanol/chloroform 1:9); IR nmax/cm21 3575, 3000,
1
1675 (CvO), 1600, 1490, 1455, 1410 and 1355; H NMR
(90 MHz) d 1.02–1.61 (10H, m, 5£CH2), 4.15–4.60 (2H,
m, NCH2) and 6.92–7.25 (10H, m aryl H); 13C NMR
(22.5 MHz) d 25.8 (CH2), 29.0 (CH2), 32.0 (CH2), 35.6
(CH2), 38.9 (CH2), 42.4 (CH2), 92.8 (C), 125.9 (CH), 127.3
(CH), 128.2 (CH), 128.3 (CH), 128.5 (CH), 138.5 (C), 141.7
(C) and 175.5 (CvO); MS m/z 309 (Mþ, ,1%), 291
(M2H2O, 2%), 200 (100) and 91 (55).
The hydroxy lactam 8b (240 mg) was dissolved in TFA and
heated under reflux for 72 h. After the usual work-up, flash
chromatography on silica and elution with ether/DCM
(5:95) afforded 10-benzyl-1,2,3,4-tetrahydrospiro[naphtha-
lene-1:20-pyrrolidin]-50-one 10b (80 mg, 35%) as a colour-
less oil (HREIMS Found Mþ 291.1632. C20H21NO requires
M 291.1623); Rf 0.52 (ether/chloroform 1:9); IR nmax/cm21

P. D. Bailey et al. / Tetrahedron 59 (2003) 3369–3378
3375
The Grignard reagent was prepared from 1-bromo-3-(3,4-
methylenedioxyphenyl)propane 19b (0.63 g, 2.6 mmol) and
reacted with N-benzylsuccinimide 6 (0.35 g, 1.85 mmol)
according to the general procedure. After flash chromato-
graphy on silica and elution with a solvent gradient [ether/
DCM (1:9) to methanol/ether/DCM (2:10:88)] 1-benzyl-5-
hydroxy-5-[3-(3,4-methylenedioxyphenyl)propyl]pyrrol-
idin-2-one 20b (125 mg, 19%) was obtained as a pale
yellow foam (HREIMS Found m/z 353.1614. C21H23NO4
requires M 353.1627); Rf 0.30 (methanol/chloroform 1:9);
IR nmax/cm21 3575 (OH), 3000, 2920, 1670 (CvO), 1600,
NMR (22.5 MHz) d 30.7 (CH2), 31.2 (CH2), l32.6, 32.8,
33.0l (CH2), 36.5 (CH2), 36.6 (CH2), 76.7 (spiro C), l111.8,
112.1, 113.0, 113.2l (CH), l113.8, 114.5, 115.2l (C), 124.5
(CH), 126.2 (CH), 127.1 (C), 128.1 (CH), 129.7 (CH),
l130.5, 131.0, 131.5l (CH), 144.5 (C), l157.4, 157.6, 168.4,
168.8l (CF) and 177.6 (CvO); MS m/z 313 (Mþ, 51%), 186
(14), 143 (89), 142 (86), and 127 (100).
The Grignard reagent was prepared from 1-bromo-2-
phenylethane (2.2 g, 12 mmol) and reacted with N-(2,6-
dichlorobenzyl)succinimide 25 (1.0 g, 3.9 mmol) according
to the general procedure. The crude product was again a
complex mixture, from which flash chromatography on
silica and elution with a solvent gradient (ether/DCM 1:4 to
methanol/ether/DCM 2:20:78) separated a mixture of low-
running components as a yellow oil (0.33 g). This was
dissolved in TFA and heated under reflux for 48 h. After the
usual work-up and flash chromatography on silica, elution
with ether/DCM (1:19) afforded N-(2,6-dichlorobenzyl)-2-
[1-(2,6-dichlorobenzyl)-5-oxopyrrolidin-5-ylidene]succin-
imide 23 (33 mg), mp 185–1888C (HREIMS Found
[M2Cl]þ 461.0009. C22H1635Cl3N2O3 requires 461.0015);
IR nmax/cm21 3000, 1740 and 1690 (CvO), 1620, 1570,
1
1500 and 1485; H NMR (90 MHz) d 1.15–2.65 (10H, m,
5£CH2), 3.74 (1H, s, OH), 4.14–4.63 (2H, m, NCH2), 5.88
(2H, s, OCH2O), 6.37–6.74 (3H, m, aryl H) and 7.27 (5H, s,
aryl H); 13C NMR (22.5 MHz) d 26.0 (CH2), 29.0 (CH2),
32.0 (CH2), 35.3 (CH2), 38.7 (CH2), 42.4 (CH2), 92.8 (C),
100.7 (CH2), 108.0 (CH), 109.0 (CH), 121.1 (CH), 127.1
(CH), 128.1 (CH), 128.5 (CH), 135.5 (C), 138.5 (C), 145.6
(C), 147.5 (C) and 175.5 (CvO); MS m/z 353 (Mþ, 1%),
335 (M2H2O, 5), 200 (95), 148 (30) and 91 (100).
The hydroxy lactam 20b (80 mg) was dissolved in TFA
(10 mL) and heated under reflux for 48 h. After the usual
work-up, flash chromatograph0y on silica and elution with
ether/DCM (20:80) afforded 1 -benzyl-6,7-methylenedioxy-
1,2,3,4-tetrahydrospiro[naphthalene-1,20-pyrrolidin]-50-
one 21b (24 mg, 32%) as a pale yellow foam (HREIMS
Found 335.1540. C12H21NO3 requires M 335.1521); Rf 0.68
(ether/chloroform 1:9); IR nmax/cm21 3000, 1780, 1710,
1585, 1570, 1440, 1400, 1350 and 1330; 1H NMR (90 MHz)
d 1.62–1.87 (4H, m, 2£CH2), 2.01–2.26 (2H, m, CH2),
2.47–2.88 (4H, m, 2£CH2), 3.72 and 4.80 (each 1H, d
J 15.5 Hz, NCH2), 5.89 (2H, s, OCH2O), 6.47 and 6.55
(each 1H, s, H-5 and H-8) and 7.15–7.26 (5H, m, aryl H);
13C NMR (22.5 MHz) d 20.4 (CH2), 29.4 (CH2), 29.5
(CH2), 35.1 (CH2), 36.1 (CH2), 44.3 (CH2), 67.1 (spiro C),
101.0 (CH2), 105.8 (CH), 108.7 (CH), 125.3 (CH), 126.9
(CH), 127.9 (CH), 128.3 (CH), 131.4 (C), 132.4 (C), 138.7
(C), 146.4 (C), 146.9 (C) and 175.9 (CvO); MS m/z 335
(Mþ, 70%), 292 (30), 278 (9), 202 (8), 188 (100), 174 (8),
163 (19), 149 (12) and 91 (83).
1
1550, 1430 and 1390; H NMR (300 MHz) d 2.51–2.56
(2H, m, CH2), 3.36–3.39 (4H, m, 2£CH2), 4.98 and 5.13
(each 2H, s, NCH2), 7.14–7.21 (2H, m aryl H) and 7.29–
7.33 (4H, m, aryl H); 13C NMR (22.5 MHz) d 25.8 (CH2),
27.4 (CH2), 33.1 (CH2), 38.7 (CH2), 42.6 (CH2), 95.9 (C),
128.4 (CH), 129.3 (CH), 130.5 (C), 130.6 (C), 134.9 (C), 136.2
(C), 153.0 (C) and 170.3, 172.5 and 177.7 (CvO); MS Mþ
peaks absent, m/z 465/463/461 (M2Cl, 30/91/91%), 234 (25),
232 (77), 161 (64), 159 (100), 123 (15) and 91 (20).
The Grignard reagent was prepared from 1-bromo-2-
phenylethane (1.5 g, 8 mmol) and reacted with succinimide
(0.20 g, 2 mmol) according to the general procedure. The
crude product was a brown oil (0.40 g), which was
redissolved in acetonitrile and stirred with caesium
carbonate (4.0 g) during addition of 2,6-dichlorobenzyl
bromide (2.0 g) and for further 4 days. The mixture was
filtered, the filtrate evaporated in vacuo, and the residue
chromatographed on silica, from which ether/DCM (1:19)
eluted 1-(2,6-dichlorobenzyl)-5-(2-phenylethylidene)-pyr-
rolidin-2-one 30, colourless oil (0.53 g, 77% from succini-
mide), as a mixture of stereoisomers (HREIMS Found Mþ
345.0687. C19H1735Cl2NO requires 345.0687); Rf 0.69
(ether/chloroform 1:9); IR nmax/cm21 3010, 1710, 1675,
2.4.3. Enamide 30 and spiro products 28 and 29 derived
from N-2,6-difluoro- and N-2,6-dichlorobenzylsuccini-
mide. The Grignard reagent was prepared from 1-bromo-2-
phenylethane (3.3 g, 18 mmol) and reacted with N-(2,
6-difluorobenzyl)succinimide 24 (1.0 g, 4.4 mmol) accord-
ing to the general procedure. The crude product was a
complex mixture. Flash chromatography on silica and
elution with a solvent gradient (ether/DCM 1:9 to
methanol/ether/DCM 2:10:88) afforded a mixture of low-
running components as a yellow oil (250 mg). This was
dissolved in TFA and heated under reflux for 48 h. After
the usual work-up and flash chromatography on silica,
elution with ether/DCM (1:9) afforded 2,3-dihydro-10-(2,6-
difluorobenzyl)spiro[1H-indene-1,20-pyrrolidin]-50-one 28
(52 mg), mp 62–668C (DCM) (HREIMS Found Mþ
313.1287. C19H17F2NO requires M 313.1278); Rf 0.50
(ether/chloroform 1:9); IR nmax/cm21 3000, 1675 (CvO),
1
1605, 1580, 1520, 1495, 1475, 1440 and 1405; H NMR
(90 MHz) d 2.50–2.85 (4H, m, 2£ring CH2), 3.24 (2H, t,
J 7.7 Hz, PhCH2CH), 4.51–5.01 (3H, m, PhCH2CH and
NCH2) and 6.82–7.34 (8H, m, aryl H); 13C NMR
(22.5 MHz) d 21.1 (CH2), 28.8 (CH2), 32.4 (CH2), 40.0
(CH2), 100.4 (CH), 125.7 (CH), 127.6 (CH), 128.2 (CH),
128.3 (CH), 128.8 (CH), 129.1 (CH), 13.9 (C), 135.8 (C),
136.3 (C), 139.5 (C), 140.8 (C) and 175.3 (CvO); MS m/z
349/347/345 (Mþ, 1/8/13%), 312/310 (M2Cl, 22/66), 224/
222 (15/46), 220/218 (19/55), 186 (9), 161 (44), 159 (68),
143 (8), 141 (18), 123 (15) and 91 (100). Additional 13C
NMR signals attributable to the minor stereoisomer d 28.0,
29.6, 38.8, 136.6 and 176.2.
1
1630, 1595, 1470 and 1400; H NMR (300 MHz) d 2.05–
2.45 (4H, m, 2£CH2), 2.55–2.65 (2H, m, CH2CO), 2.85–
2.95 (2H, m, (CH2Ar), 4.30–4.70 (2H, m, NCH2), 6.62 (1H,
t, J 8.0 Hz, aryl H) and 6.60–7.30 (6H, m, aryl H); 13C
The enamide 30 (140 mg) was dissolved in TFA (15 mL)
and heated under reflux for 4 days. The usual work-up was

3376
P. D. Bailey et al. / Tetrahedron 59 (2003) 3369–3378
followed by flash chromatography on silica and elution with
ether/DCM (1:19) to give 2,3-dihydro0-10-(2,6-dichloro-
benzyl)spiro[1H-indene-1,20-pyrrolidin]-5 -one 29, colour-
less oil (38 mg, 27%), together with recovered starting
material 30 (35 mg). Data for 29: (HREIMS Found
[M2Cl]þ 310.0995, C19H1735ClNO requires 310.0999); Rf
0.57 (ether/chloroform 1:9); IR nmax/cm21 3000, 1710,
with rapid stirring. After stirring for 30 min, the cerium
chloride was further activated by sonication for 1 h at room
temperature.22 The Grignard reagent was prepared from 1-
bromo-2-phenylethane (185 mg, 1.0 mmol) in ether (3 mL)
and added to the flask containing cerium chloride, which
was stirred for 2 h, then cooled to 2788C. N-(1-Pheny-
lethyl)succinimide 31 (101 mg, 0.50 mmol) in dry THF
(6 mL) was added with stirring and the mixture was allowed
to warm slowly to room temperature with stirring overnight.
After the usual work-up, a colourless oil (188 mg) was
obtained, which was flash chromatographed on silica.
Elution with a solvent gradient (DCM to ether/DCM 1:9)
separated N-(1-phenylethyl)-4-oxo-6-phenylhexanamide 32
(94 mg, 61%), unreacted succinimide 31 (17 mg) and still
unresolved mixture of these two (42 mg). Data for 32:
(HREIMS Found Mþ 309.1740. C20H23NO2 requires M
309.1729); Rf 0.35 (ether/chloroform 1:9); IR nmax/cm21
3430, 3080, 3060, 3000, 1710, 1665, 1600, 1510, 1455,
1420 and 1375; 1H NMR (90 MHz) d 1.44 (3H, d, J 7.0 Hz,
CHCH3), 2.32–2.95 (8H, m, 4£CH2), 5.06 (1H, dq, J 7.3,
7.0 Hz, CHCH3), 6.17 (1H, br d, J 7.3 Hz, NH) and 7.13–
7.28 (10H, m aryl H); 13C NMR (22.5 MHz) d 21.9 (CH3),
29.7 (CH2), 30.0 (CH2), 37.8 (CH2), 44.2 (CH2), 48.8 (CH),
126.1 (CH), 127.3 (CH), 128.2 (CH), 128.5 (CH), 128.6
(CH), 140.9 (C), 143.3 (C), 170.9 (CvO) and 209.1
(CvO); MS m/z 309 (Mþ, 50%), 208 (22), 188 (10), 177
(10), 161 (9), 152 (29), 133 (7), 121 (74), 107 (94), 106
(100), 101 (15), 92 (79), 79 (15), 78 (23) and 57 (13).
1
1675, 1580, 1560, 1440 and 1390; H NMR (90 MHz) d
1.96–2.87 (8H, m, 4£ring CH2), 4.55 and 5.03 (each 1H, d,
J 15.0 Hz, NCH2) and 6.68–7.26 (7H, m, aryl H); 13C NMR
(22.5 MHz) d 29.3 (CH2), 29.9 (CH2), 33.4 (CH2), 35.4
(CH2), 39.0 (CH2), 74.9 (spiro C), 123.2 (CH), 124.6 (CH),
126.2 (CH), 127.8 (CH), 128.1 (CH), 128.7 (CH), 132.7 (C),
136.4 (C), 142.6 (C), 143.2 (C) and 174.9 (CvO); MS Mþ
peaks absent, m/z 312/310 (M2Cl, 34/100%), 201 (7), 163
(9), 159 (14), 151 (24) and 113 (20).
The spiro compound 29 (30 mg) was dissolved in methanol
(10 mL) and shaken with Pearlman’s catalyst (palladium
hydroxide on charcoal) under an atmosphere of hydrogen
for 24 h. After filtration and removal of solvent, the residue
was flash chromatographed on silica. Elution with ether/
DCM (1:19) afforded the chlorine-free N-benzyl spiro
1
lactum 10a (17 mg), which was identical by tlc and H
NMR spectrum with the sample obtained by cyclisation
of 8a.
2.4.4. Ketoamide 32, hydroxy lactum 33a,b and spiro
products 34a,b and 35b derived from N-(1-phenylethyl)-
succinimide. The Grignard reagent was prepared from
1-bromo-2-phenylethane (0.74 g, 4 mmol) and reacted
with N-(1-phenylethyl)succinimide 31 (0.30 g, 1.5 mmol)
according to the general procedure. After the usual work-up,
flash chromatography on silica eluted with a solvent
gradient (ether/DCM 5:95 to methanol/ether/DCM 2:5:93)
afforded the dimer N-(1-phenylethyl)-4-[1-(1-phenylethyl)-
2,5-dioxopyrrolidin-3-yl]-4-oxobutanamide 36 (0.25 g, 84%)
as a pale yellow foam (HREIMS Found Mþ406.1900.
C24H26N2O4 requires M 406.1893); Rf 0.59 (methanol/
chloroform 1:9); IR nmax/cm21 3000, 1775, 1700, 1675,
1600, 1500, 1450 and 1400; 1H NMR (90 MHz) d 1.44 (3H,
d, J¼6.8 Hz, NCH(CH3)Ph), 1.75 (3H, dd, J¼6.8, 2.4 Hz,
NHCH(CH3)Ph), 2.15–2.61 (4H, m, 2£CH2), 2.97–3.15
(2H, m, CH2CH), 3.80–4.00 (1H, m, CH2CH), 5.03 (1H,
apparent quintet, J 7.2 Hz, NHCH(CH3)Ph), 5.36 (1H, q,
J 6.8 Hz, NCH(CH3)Ph), 5.98 (1H, br d, J 7.2 Hz, NH) and
7.05–7.49 (10H, m, aryl H); 13C NMR (22.5 MHz) d 16.4
(CH3), 21.8 (CH3), 30.0 (CH2), 35.9 (CH2), 38.0 (CH2), 49.0
(CH), 50.7 (CH), 52.8 (CH), 126.1 (CH), 127.3 (CH), 127.9
(CH), 128.5 (CH), 128.6 (CH), 139.1 (C), 143.2 (C), 170.3
(CvO), 172.5 (CvO), 175.4 (CvO) and 201.5 (CvO);
MS m/z 406 (Mþ, 6%), 285 (3), 219 (19), 201 (9), 160 (15),
120 (91) and 105 (100).
The ketoamide 32 (31 mg) was dissolved in dry chloroform
(5 mL) and treated with successive addition of small
quantities of TFA, with monitoring by tlc. With 5 equiv.
of TFA (40 mL) slow appearance of a new product was
observed. The solution was worked up after 3 days at room
temperature and a pale yellow oil is obtained (31 mg). Flash
chromatography of this on silica, eluting with a solvent
gradient (ether/DCM 5:95 to methanol/ether/DCM 2:5:95),
separated (R)-1-(1-phenylethyl)-5-(2-phenylethylidene)pyr-
rolidin-2-one 33a (11 mg, 39%) as a mixture of E and Z
stereoisomers and unreacted ketoamide 32 (18 mg). Data
for 33a: (HREIMS Found Mþ 291.1623. C20H21NO
requires M 291.1623); Rf 0.63 (ether/chloroform 1:9); IR
n
max/cm21 3000, 2940, 1700, 1660, 1520, 1490, 1450 and
1400; 1H NMR (90 MHz) d 1.74 (3H, d, J 7.2 Hz, CHCH3),
2.61 (4H, br s, 2£ring CH2), 3.22 (2H, d, J 7.7 Hz, CHCH2),
4.66 (1H, br t, J 7.7 Hz, CHCH2), 5.71 (1H, q, J 7.2 Hz,
CHCH3) and 6.82–7.49 (10H, m aryl H); 13C NMR
(22.5 MHz) d 15.6 (CH3), 21.4 (CH2), 29.0 (CH2), 32.8
(CH2), 49.1 (CH), 102.2 (CH), 125.9 (CH), 126.6 (CH),
127.0 (CH), 127.9 (CH), 128.3 (CH), 128.5 (CH), 138.4 (C),
139.8 (C), 141.0 (C) and 175.9 (CvO), and additional lines
due to the minor stereoisomer d 16.6 (CH3), 28.2 (CH2),
50.4 (CH) and 97.3 (CH); MS m/z 291 (Mþ, 28%), 203 (26),
200 (7), 187 (41), 160 (46), 105 (100), 91 (55), 84 (36) and
77 (43).
Anhydrous cerium(III) chloride was prepared from the
trihydrate (373 mg, 1.0 mmol) in a 3-neck flask equipped
with a magnetic stirring bar suspended above the solid by
means of a second magnet external to the flask. The flask
was heated to 135–1408C and evacuated to 2 mm Hg
pressure. After 1 h the external magnet was removed to free
the internal stirring bar and the solid was stirred for further
2 h to afford a free-flowing white powder. The flask was
cooled to 2208C and dry THF (2 mL) added via syringe
The ketoamide 32 (60 mg) was dissolved in TFA (10 mL)
and heated under reflux for 48 h. After work-up, yellow oil
was obtained (57 mg) and flash chromatographed on silica.
Elution w0ith ether/DCM afforded 2,3-dihydrospiro[1H-
indene-1,2 -pyrrolidin]-50-one 34a (25 mg, 69%), colour-
less cubic crystals, mp 131–1328C (methanol) (Found: C,
77.0; H, 7.0; N, 7.5. C12H13NO requires C, 77.0; H, 7.1; N,

P. D. Bailey et al. / Tetrahedron 59 (2003) 3369–3378
3377
7.4%); Rf 0.18 (ether/chloroform 1:9); IR nmax/cm21 3430
(N–H), 3000, 1690 (CvO), 1600, 1520, 1480, 1460, 1400
and 1350; 1H NMR (300 MHz) d 2.13–2.38 (4H, m,
2£CH2), 2.49–2.54 (2H, m, 40-CH2), 2.89–2.95 (2H, m,
3-CH2), 6.36 (1H, br s, NH) and 7.22–7.30 (4H, m, aryl H);
13C NMR (75 MHz) d 29.1 (CH2), 30.6 (CH2), 35.1 (CH2),
40.3 (CH2), 69.6 (spiro C), 122.3 (CH), 124.9 (CH), 127.2
(CH), 128.2 (CH), 142.1 (C), 146.3 (C) and 177.6 (CvO);
MS m/z 187 (M, 100%), 158 (42), 144 (77), 131 (71), 115
(23), 103 (15), 91 (12), 86 (29), 84 (54), 77 (17) and 49 (60).
In another experiment the enamide 33a (21 mg) was
dissolved in TFA and changes monitored by tlc. No reaction
was observed over 3 days at room temperature, so the
solution was heated at 508C for 48 h and then at 708C for
48 h, when conversion to the spiro compound 34a was
complete. After flash chromatography 34a (13 mg, 92%)
was isolated and shown to be identical to the sample
obtained directly from the ketoamide 32.
colourless oil (HREIMS Found Mþ 201.1161. C13H15NO
requires M 201.1154); Rf 0.58 (methanol/chloroform 1:9);
[a]D0.0; IR nmax/cm21 3420 (N–H), 3000, 2940, 2870,
1
1690, 1600, 1520, 1490, 1420, 1400 and 1340; H NMR
(90 MHz) d 1.86–2.56 (8H, m, 4£CH2), 2.72–2.78 (2H, m,
4–CH2), 6.57 (1H, br s, NH) and 7.04–7.41 (4H, m, aryl H);
13C NMR (22.5 MHz) d 20.2 (CH2), 29.2 (CH2), 29.9
(CH2), 36.8 (CH2), 37.1 (CH2), 60.8 (spiro C), 126.1 (CH),
126.5 (CH), 127.2 (CH), 129.0 (CH), 136.7 (C), 141.2 (C)
and 177.6 (CvO); MS m/z 201 (Mþ, 86%), 173 (100), 158
(19), 144 (66), 130 (45), 117 (33), 105 (18), 91 (15) and 77
(15). Data for 35b: colourless oil; ca. 3:1 mixture of two
diastereoisomers; Rf 0.60 (ether/chloroform 1:9); IR nmax
/
cm21 3000, 2940, 2300, 1670, 1600, 1520, 1450, 1420 and
1350; 1H NMR (300 MHz) (minor distereoisomer in italics)
d 1.67 and 1.80 (3H, d, J 7.2 Hz, CH3CH), 1.64–2.27 (6H,
m, 3£CH2), 2.49–2.62 (2H, m, 40-CH2), 2.73–2.85 (2H, m,
4-CH2), 3.92 and 4.22 (1H, q, J 7.2 Hz, CH3CH) and 6.90–
7.38 (9H, m, aryl H); 13C NMR (22.5 MHz) d 20.3 and 20.7
(CH2), 20.1 and 21.1 (CH3), 29.5 and 29.7 (CH2), 30.4 and
30.5 (CH2), 33.5 and 35.1 (CH2), 36.4 and 36.6 (CH2), 54.2
and 55.0 (CH), 68.5 and 68.8 (spiro C), 125.9 and 126.6
(CH), 126.7 (CH), 126.8 (CH), 127.0 and 127.1 (CH), 127.4
and 127.7 (CH), 128.3 (CH), 128.8 and 129.5 (CH), 137.7
and 138.0 (C), 139.3 and 140.2 (C), 142.7 and 144.3 (C) and
175.7 and 176.1 (CvO); MS m/z 305 (Mþ, 100%), 214 (8),
200 (12), 185 (10), 173 (14), 161 (53), 160 (52), 146 (37),
129 (27), 128 (26), 120 (32), 105 (81), 91 (13) and 77 (27).
Anhydrous cerium(III) chloride was prepared from the
trihydrate (5.4 g, 14.5 mmol) as before, suspended in dry
THF (20 mL) and further activated by sonication.22 The
Grignard reagent was prepared from l-bromo-3-phenyl-
propane (2.0 g, 10 mmol) in ether (10 mL) and added to the
cerium chloride suspension, which was stirred at room
temperature for 2 h, then cooled to 2788C. N-(1-Phenyl-
ethyl)succinimide 31 (1.01 g, 5 mmol) in THF (20 mL) was
added dropwise with stirring, the mixture was allowed to
warm slowly to room temperature and stirred overnight.
After the usual work-up procedure involving some trouble-
some separation of precipitated solids, then flash chroma-
tography on silica eluting with a solvent gradient (ether/
DCM 5:95 to methanol/ether/DCM 5:5:90) afforded (R)-1-
(1-phenylethyl)-5-(3-phenylpropylidene)pyrrolidin-2-one
33b, colourless oil (0.38 g, 25%). The aqueous phase from
work-up together with precipitates was acidified to pH 1 by
addition of hydrochloric acid (6 M) and extracted with
chloroform. The extract afforded further crude material
(0.60 g) from which flash chromatography on silica eluting
with a solvent gradient (DCM to ether/DCM 5:95) separated
more of the enamide 33b (0.10 g, total yield 32%) and
unreacted imide 31 (225 mg). Data for 33b: (HREIMS
Found Mþ 305.1781. C21H23NO requires M 305.1780); Rf
0.77 (ether/chloroform 1:9); [a]Dþ23.1 (c¼4.0, DCM); IR
Spiro lactam 35b (31 mg) was dissolved in TFA (10 mL)
and heated under reflux overnight. Tlc analysis indicated
that no more than a trace amount of the debenzylated lactam
34b was formed.
The Grignard reagent prepared from magnesium (1.94 g)
and 1-bromo-3-phenylpropane (15.92 g, 80 mmol) in dry
THF was added to succinimide (1.98 g, 20 mmol) in THF.
The mixture was stirred for 3 days at room temperature
before work-up, which gave a crude product contaminated
with 1-phenylpropane and unreacted 1-bromo-3-phenylpro-
pane. This crude material was dissolved in TFA (25 mL)
and heated under reflux for 62 h, then cooled and worked up
in the usual way. The crude product was washed with light
petroleum and the residue recrystallised to afford 10-(1-
phenylethyl)-1,2,3,4-tetrahydrospiro[naphthalene-1,20-pyr-
rolidin]-50-one 34b (2.28 g, 57% from succinimide), mp
166–1688C (from ethanol), identical (tlc, 1H NMR and
mass spectra) with the sample obtained above from 33b.
n
max/cm21 3050, 2980, 2300, 1700, 1665, 1600, 1520, 1470
1
and 1420; H NMR (90 MHz) d 1.65 (3H, d, J 7.2 Hz,
CH3CH), 2.08–2.53 (8H, m, 4£CH2), 4.41 (1H, br t,
J 7.6 Hz, CHCH2), 5.62 (1H, q, J 7.2 Hz, CH3CH) and
6.86–7.37 (10H, m, aryl H); 13C NMR (22.5 MHz) d 15.6
(CH3), 21.0 (CH2), 28.9 (CH2), 29.2 (CH2), 36.1 (CH2), 48.8
(CH), 102.7 (CH), 125.6 (CH), 126.5 (CH), 126.8 (CH),
128.0 (CH), 128.2 (CH), 128.5 (CH), 137.6 (C), 139.7 (C),
141.5 (C) and 175.7 (CvO); MS m/z 305 (Mþ, 3%), 214
(37), 110 (100), 105 (78), 91 (13) and 77 (13).
Spiro lactam 34b (40 mg, 0.20 mmol) was dissolved in
acetonitrile and stirred with caesium carbonate (750 mg)
during addition of benzyl bromide (500 mg). The mixture
was heated under reflux for 48 h, then cooled, filtered, and
the filtrate evaporated in vacuo. The residue was flash
chromatographed on silica, eluting with ether/DCM (1:9), to
give the N-benzyl spiro lactam 10b identical (by TLC and
1H NMR spectrum) with the material obtained previously
by cyclisation of hydroxy lactam 8b.
The enamide 33b (227 mg) was dissolved in TFA (10 mL)
and heated under reflux for 48 h. The usual work-up was
followed by flash chromatography on silica, eluting with a
solvent gradient (DCM to ether/DCM 1:9 to methanol/
ether/DCM 5:10:85), to afford 10-(1-phenylethyl)-1,2,3,4-
tetrahydrospiro[naphthalene-1,20-pyrrolidin]-50-one 34b
(380 mg, 25%) and 1,2,3,4-tetrahydrospiro[naphthalene-
1,2 -pyrrolidin]-50-one 35b (57 mg, 58%). Data for 34b:
Spiro lactam 35b (15 mg) was dissolved in THF (1 mL) and
added to liquid ammonia (10 mL). Freshly cut sodium
(23 mg) was added in small portions with stirring to
maintain a blue colouration for 1 h. Solid ammonium

3378
P. D. Bailey et al. / Tetrahedron 59 (2003) 3369–3378
3. (a) Schoemaker, H. E.; Speckamp, W. N. Tetrahedron Lett.
1978, 1515. (b) Evans, D. A.; Thomas, E. W. Tetrahedron
Lett. 1979, 411. (c) Inoue, Y.; Tazawa, N.; Watanabe, A.;
Aoki, Y.; Kakisawa, H. Bull. Chem. Soc. Jpn 1992, 65, 2866.
4. (a) Schoemaker, H. E.; Speckamp, W. N. Tetrahedron 1980,
36, 951. (b) Evans, D. A.; Thomas, E. W.; Cherpeck, R. E.
J. Am. Chem. Soc. 1982, 104, 3695.
chloride was then added to quench the reaction, and
the ammonia allowed to evaporate. Brine was added to
the residue, which was then extracted with ethyl acetate; the
organic extract was dried (MgSO4), filtered, and the filtrate
evaporated to give yellow oil. Flash chromatography on
silica eluting with a solvent gradient (DCM to ether/DCM
1:9) afforded N-(1-phenylethyl)-3-(1,2,3,4-tetrahydro-
naphth-1-yl)propanamide 37 as a colourless oil (9 mg,
59%) (HREIMS Found Mþ 307.1929. C20H25NO requires
5. (a) Sun, P.; Sun, C.; Weinreb, S. M. Org. Lett. 2001, 3, 3507.
(b) Abe, H.; Aoyagi, S.; Kibayashi, C. Angew. Chem. Int. Ed.
2002, 41, 3017.
M 307.1936); Rf 0.71 (methanol/chloroform 1:9); IR nmax
/
cm21 3425, 3000, 2925, 2860, 1660, 1600, 1500, 1450,
1420 and 1375; 1H NMR (90 MHz) d 1.48 (3H, d, J 6.8 Hz,
CH3CH), 1.62–2.81 (11H, m, 5£CH2 and CH), 5.14 (1H,
dq, J 7.6, 6.8 Hz, CH3CHNH), 5.65 (1H, br d, J 7.6 Hz, NH)
and 7.05–7.36 (9H, m, aryl H); 13C NMR (22.5 MHz) d
19.8 (CH2), 21.7 (CH3), 27.5 (CH2), 29.6 (CH2), 32.2 (CH2),
34.5 (CH2), 37.1 (CH), 48.6 (CH), 125.6 (CH), 125.7 (CH),
126.2 (CH), 127.4 (CH), 128.7 (2 lines, CH), 129.1 (CH),
137.1 (C), 140.2 (C), 143.2 (C) and 171.9 (CvO); MS m/z
307 (Mþ, 15%), 202 (3), 176 (13), 163 (91), 143 (10), 131
(22), 115 (13), 105 (100), 91 (21), 77 (15) and 59 (24). As 37
was a single diastereoisomer (13C NMR spectrum), the yield
is effectively 79% (from the major diastereoisomer of 35b).
Tlc analysis showed the presence of unreacted 35b (the
minor diastereoisomer?) in the crude product before
chromatography.
6. Bahajaj, A. A.; Hitchings, G. J.; Moore, M. H.; Vernon, J. M.
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7. Bailey, P. D.; Morgan, K. M.; Smith, D. I.; Vernon, J. M.
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8. Padwa, A.; Heidelbaugh, T. M.; Kuethe, J. T.; McClure, M. S.
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10. Winn, M.; Zaugg, H. E. J. Org. Chem. 1968, 33, 3779.
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1990, 1757.
12. Pandey, P. N.; Purkayasha, M. L. Synthesis 1982, 877.
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1990, 55, 215.
14. (a) Polniaszek, R. P.; Belmont, S. E. J. Org. Chem. 1990, 55,
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16. Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.;
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