Preparation of N-heterocycles by radical cyclisation of enamides mediated by manganese(III) or copper(I). A comparison of cyclisation methods

Article abstract of DOI:10.1016/S0040-4020(00)00316-1

Reaction of enamides with manganese(III) acetate or copper(I) chloride/bipyridine has been investigated. In both cases, an initial 5-endo- trig radical cyclisation reaction took place to produce functionalised pyrrolidinones. The copper(I)-mediated cyclisations were very efficient and bicyclic dienes could be isolated in >80% yield, while the corresponding manganese(III) reactions were generally more problematic, giving related dienes in lower yield (35-52%). (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00316-1

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 3941±3949
Preparation of N-Heterocycles by Radical Cyclisation of
Enamides Mediated by Manganese(III) or Copper(I).
A Comparison of Cyclisation Methods
David T. Davies,a Neha Kapurb and Andrew F. Parsonsb,
*
aDepartment of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Third Avenue,
Harlow, Essex CM19 5AW, UK
bDepartment of Chemistry, University of York, Heslington, York YO10 5DD, UK
Received 29 February 2000; accepted 25 April 2000
AbstractÐReaction of enamides with manganese(III) acetate or copper(I) chloride/bipyridine has been investigated. In both cases, an initial
5-endo-trig radical cyclisation reaction took place to produce functionalised pyrrolidinones. The copper(I)-mediated cyclisations were very
ef®cient and bicyclic dienes could be isolated in .80% yield, while the corresponding manganese(III) reactions were generally more
problematic, giving related dienes in lower yield (35±52%). q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
double bond or halogen atom) is introduced into the product
after cyclisation. Whereas manganese(III)-based cyclisa-
tions6 commonly employ 1,3-dicarbonyl compounds
(which readily undergo enolisation), copper(I)-based reac-
tions7 require precursors with a particularly weak carbon±
halogen bond.
One important method for preparing 5-membered nitrogen
heterocycles is the radical cyclisation of unsaturated orga-
nohalides.1 Thus, for example, cyclisations proceeding by a
(favoured) 5-exo-trig pathway have been shown to provide a
mild and ¯exible approach to a variety of pyrrolidinones.2
More recently, however, an alternative approach to pyrroli-
dinones has been developed, which centres on the 5-endo-
trig radical cyclisation of halo-enamides.3 This cyclisation
is unusual (disfavoured) in that the initial carbamoylmethyl
radical reacts to form a 5- rather than a 4-membered (or b-
lactam) ring. The (favoured) 4-exo-trig cyclisation, to form
a b-lactam, is generally observed when radical-stabilising
(aromatic) groups are introduced on the enamide CvC
bond.4 These 5-endo cyclisations, which can be mediated
by tributyltin hydride, have been shown, for example, to
provide ef®cient approaches to substituted pyroglutamates.5
However, the use of tributyltin hydride is far from ideal as
tin-containing by-products are often dif®cult to remove and
the cyclisation leads to the reduction of two functional
groups (i.e. the C-halogen and CvC bonds). With a view
to developing a more straightforward and versatile approach
to functionalised pyrrolidinones, this paper describes the use
of manganese(III) or copper(I) reagents as initiators for 5-
endo-trig radical cyclisations. Both methods have a number
of advantages over the use of tributyltin hydride. Hence, the
reagents are cheaper, the metal by-products are more easily
removed and, importantly, a functional group (generally a
Results and Discussion
The formation and reaction of b-amido ester 1 with manga-
nese(III) acetate was ®rst investigated (Scheme 1).8 This
was prepared by N-acylation of the imine derived from
benzylamine and cyclohexanone, with methyl malonyl
chloride. Initial reactions of 1 with manganese(III) acetate
in boiling acetic acid, in the presence or absence of
²
copper(II) acetate, were disappointing as a number of
unidenti®able products were obtained in trace amounts
following column chromatography. However, when the
reaction was carried out in boiling methanol (in the absence
of copper(II) acetate) diene 2 was isolated. The yield of 2
was found to improve from 10 to 38% when the number of
equivalents of manganese(III) acetate was increased from 1
to 4, whereas addition of .4 equiv. was found to have a
detrimental effect on the product yield. In order to compare
the two different methods of cyclisation, reaction of dichlor-
³
oamide 3 with copper(I) chloride and bipyridine was inves-
tigated. This was prepared in 79% yield by chlorination of 1
²
Copper(II) acetate is often used as a co-oxidant in manganese(III)-
mediated cyclisations.
Keywords: manganese and compounds; copper and compounds; cyclisa-
tion; enamides.
* Corresponding author. Tel.: 144-1904-432608; fax: 144-1904-432516;
e-mail: afp2@york.ac.uk
³
Bipyridine is added to coordinate and solubilise the copper(I) chloride,
and alter the redox potential so that reactions can be carried out at reason-
able temperatures.
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00316-1

3942
D. T. Davies et al. / Tetrahedron 56 (2000) 3941±3949
Scheme 1.
Scheme 2.
using 2.2 equiv. of sodium hydride and N-chlorosuccini-
mide. Interestingly, on reaction of 3 with 0.5 equiv. of
copper(I) chloride/bipyridine in boiling (dry) toluene,
diene 2 was also isolated but in a much higher yield of
84% (Scheme 1).
ing to alkene 7 and/or 8. Further radical generation/oxida-
tion or loss of HCl (which could be mediated by bipyridine)
is then expected to produce diene 2.11 The fact that the best
yield of 2 was obtained when using 4 equiv. of mangane-
se(III) acetate could therefore be explained by two radical
generation and oxidation sequences.
Dichloroamide 3 could also be ef®ciently cyclised to diene 2
(in 76% yield) using 0.5 equiv. of dichlorotris(triphenylpho-
sphine)ruthenium(II) in boiling toluene. The ef®ciency of
both the copper(I) chloride/bipyridine and ruthenium(II)
cyclisation methods compare favourably with related halo-
amide cyclisations, which have been carried out using
nickel in acetic acid9 or an alternative copper(I) complex
(at room temperature).10
Trichloroamide 9 underwent a similar cyclisation, to form
diene 10 in 94% yield, when treated with 0.5 equiv. of
copper(I) chloride/bipyridine (Scheme 3). Both the forma-
tion of 2 and 10 was expected to require only a catalytic
amount of the copper(I) complex as the copper(II), formed
on generation of 4, is reduced back to copper(I) on reaction
with tertiary radical 5. However, when 9 was treated with
0.25 equiv. of copper(I) chloride/bipyridine the yield of 10
decreased to 84% and a small amount of starting material
(4%) was recovered. It is not clear, therefore, why more than
0.25 equiv. of the copper(I) complex is required although
the formation of 10 (and 2) requires the loss of HCl which
could disrupt the catalytic cycle.
The mechanism of these cyclisation reactions presumably
involves initial formation of carbamoylmethyl radical 4
(Scheme 2). Thus, reaction of 1 with manganese(III) is
expected to promote an oxidation leading to formal loss of
a hydrogen atom (together with manganese(II)), while reac-
tion of 3 with copper(I) (or ruthenium(II)) is expected to
lead to chlorine-atom abstraction (and the formation of
copper(II)). Radical 4 is then expected to undergo 5-endo
cyclisation to form tertiary radical 5, which is particularly
susceptible to oxidation by reaction with a further equiva-
lent of manganese(III) or by copper(II). The resultant N-
acyliminium ion 6 could then undergo deprotonation lead-
Reaction of related b-amido esters to 1, showed that the
ef®ciency of the manganese(III) promoted cyclisation was
affected by the nature of the N-protecting group. For exam-
ple, when the corresponding N-butyl (rather than N-benzyl)
enamide was reacted, the yield of the diene increased from
38 to 52%. Of particular note, however, was the reaction of
the N-allyl derivative 11, which has the option to undergo
ring closure by either a 5-endo or 5-exo pathway (by attack
at the enamide or N-allyl double bond, respectively)
(Scheme 4). Reaction of 11 with 4 equiv. of manganese(III)
acetate, unexpectedly, produced the oxindole 12 in 17%
yield. This yield could be increased to 46% when 8 equiv.
of manganese(III) acetate were added portionwise to 11
over 8 h. It seems likely therefore, that 5-endo cyclisation
leads to an intermediate diene (of type 2) and the presence of
Scheme 3.

D. T. Davies et al. / Tetrahedron 56 (2000) 3941±3949
3943
Scheme 4.
Scheme 5.
an N-allyl group encourages further oxidation to give an
oxindole, although the reason for this is unclear. The forma-
tion of oxindole 12 contrasts with the ef®cient formation of
bicyclic diene 14 from reaction of N-allyl trichloroamide 13
with copper(I) chloride/bipyridine. The presence of an N-
benzyl or N-allyl protecting group clearly has little in¯uence
on this copper(I)-mediated cyclisation.
N-acyliminium ion to form an alkene, which is then
converted to diene 19 or 20 on loss of HCl.
Surprisingly, when manganese(III) acetate was reacted with
b-amidoesters 21ab, bearing cycloheptene or cyclooctene
rings, respectively, no cyclised products were isolated. A
similar result was also obtained when using the correspond-
ing N-butyl precursors. In contrast, the copper(I)-mediated
cyclisation of dichloroesters 22a and 22b proceeded as
expected, and the bicyclic dienes 23a and 23b were isolated
in 86 and 90% yield, respectively.
A marked difference in reaction products was also observed
on cyclisation of enamides bearing a cyclopentene ring
(Scheme 5). On portionwise addition of 2 equiv. of manga-
nese(III) acetate (over 8 h) to 15, the methoxy derivative 16
was isolated in an optimum yield of 39% (as a single dia-
stereomer from the NMR spectra). Thus the intermediate N-
acyliminium ion (of type 6) reacts with methanol before
deprotonation can take place. The deprotonation may be
slower than for the 6-ring system because of the greater
strain associated with a 5,5- rather than a 5,6-bicyclic
ring. In contrast, when the related dichloroamide 17 or
trichloroamide 18 were reacted with 0.5 equiv. of copper(I)
chloride/bipyridine, the bicyclic dienes 19 and 20 were
formed, respectively. The presence of a non-nucleophilic
solvent (i.e. toluene) therefore allows deprotonation of the
The cyclisation of cyclohexene precursors, bearing a methyl
substituent, also produced an interesting contrast in reagent
reactivity. When a 1:1.5 mixture of (inseparable) alkene
isomers 24 and 25 was heated with 4 equiv. of mangan-
ese(III) acetate, bicyclic alkene 26 was isolated in 44%
yield (Scheme 6). This is presumably derived from cyclisa-
tion of the trisubstituted alkene 24 and no product derived
from cyclisation of 25 was recovered. This could be
explained by isomerisation of 25, to give the more stable
(tetrasubstituted) alkene 24, under the acid reaction condi-
tions. Indeed, when a 1:1.5 mixture of 24 and 25 was heated
Scheme 6.

3944
D. T. Davies et al. / Tetrahedron 56 (2000) 3941±3949
in methanol containing acetic acid (for 8 h), the alkene ratio
changed to 1.2:1 in favour of 24. In contrast, reaction of an
inseparable 2.6:1 mixture of 2- and 6-methylcyclohexenyl
dichlorides 27 and 28, with 0.5 equiv. of copper(I) chloride/
bipyridine, gave a mixture of oxindole 29 and alkene 26. It
is believed that alkene 26 is formed from cyclisation of 27,
following a similar mechanism to the related mangan-
ese(III) reaction. The presence of an a-hydrogen atom in
26 presumably results from chlorine-atom abstraction
followed by reaction with an (unidenti®ed§) hydrogen
atom donor. Oxindole 29 could be formed on hydrolysis
and decarboxylation (during silica gel chromatography) of
the corresponding a-methyl ester 30 as related esters are
known to be hydrolytically unstable.12 Therefore, introduc-
tion of a 6-methyl substituent in the enamide precursor,
leads to further oxidation of an intermediate diene (of type
2) to give an oxindole, while the introduction of a 2-methyl
substituent effectively prevents any further oxidation of
alkene 26.
This work has demonstrated that the 5-endo-trig cyclisation
of enamides can be initiated using either manganese(III)
acetate or copper(I) chloride/bipyridine. Whereas a variety
of precursors could be ef®ciently cyclised using copper(I)
chloride/bipyridine, reactions using manganese(III) acetate
were less predictable and proved to be very sensitive to the
nature of the substrate. However, both of these methods
provide a quick, easy and mild approach to a variety of
functionalised pyrrolidinones in one-pot transformations.
In all cases, the reactions are presumed to proceed via oxida-
tion of a tertiary radical to an N-acyliminium ion (of type 5
and 6, respectively). However, attempts to trap these inter-
mediates by reaction with a second double bond (in a
tandem cyclisation process13) were unsuccessful. Hence,
for example, reaction of 39 with manganese(III) acetate
produced diene 40, while reaction of 41 with copper(I)/
bipyridine produced diene 42 (Scheme 7). The rate of radi-
cal oxidation and cation deprotonation is therefore faster
than (radical or cationic) cyclisation onto electron-rich
double bonds.
Oxindole products were also obtained from enamide precur-
sors with different substituents at alternative positions of the
ring. For example, reaction of copper(I) chloride/bipyridine
with acetal 31 produced oxindole 32 (in 35% yield), while
carbamate 33 gave oxindoles 34 and 35 (in 15 and 19%
yield), together with diene 36 (in 59% yield). The introduc-
tion of these functional groups on the cyclohexene ring
clearly makes the intermediate diene more susceptible to
oxidation. However, further oxidation can be prevented
when using enamides with a more rigid ring system.
Hence, reaction of decalene 37, prepared from a mixture
of cis- and trans-decalone, produced only diene 38 in 79%
yield (as a single (ring junction) isomer from the NMR
spectra) under the same reaction conditions; the ring strain
associated with the tricyclic ring of 38 presumably hinders
further oxidation.
Experimental
IR spectra were recorded on an ATI Mattison Genesis FT IR
1
spectrometer. H NMR and 13C spectra were recorded on a
Jeol EX 270 or BruÈker AMX 500 spectrometer. The carbon
spectra were assigned using DEPT experiments. Coupling
constants (J) were recorded in Hertz to the nearest 0.5 Hz.
Mass spectra were recorded on a Fisons Instruments VG
Analytical Autospec Spectrometer system. Thin layer chro-
matography (TLC) was performed on Merck aluminium-
backed silica gel plates. The Chemical Analytical Services
Unit, University of Newcastle performed microanalyses
using a Carlo Erba 1106 Elemental Analyser. Compounds
were visualised under a UV lamp, using alkaline potassium
Scheme 7.
§
When the reaction was carried out in d8-toluene no deuterium was incor-
porated into 26 (or 29).

D. T. Davies et al. / Tetrahedron 56 (2000) 3941±3949
3945
permanganate solution and/or iodine. Column chromato-
graphy was performed using silica gel (Matrix Silica 60,
70±200 mm Fisons or ICN ¯ash silica 60, 32±63 mm).
Petroleum ether refers to the fraction with b.p. 40±608C.
Toluene was dried over calcium hydride, distilled, and
added to the crude product. The organic layer was separated,
washed with water, brine, dried (MgSO4) and then evapo-
rated under reduced pressure. The resultant residue was
puri®ed by ¯ash column chromatography (silica) to afford
cyclic products.
Ê
stored over 3 A molecular sieves under a nitrogen atmo-
sphere. Enamide precursors for manganese (11, 15, 24/25,
39) and copper (9, 13, 17, 18, 22ab, 27/28, 31, 33, 37, 41)
mediated cyclisations were prepared using the general
procedures; the preparation of 1 and 3 are shown as repre-
sentative examples.
N-Benzyl-3-methoxycarbonyl-1,4,5,6-tetrahydro-indol-2-
one 2; 38%; colourless oil; Rf 0.28 (diethyl ether); nmax (thin
®lm) 3009 (w), 2929 (w), 1707 (s), 1650 (s), 1609 (w), 1437
(m), 1382 (m), 1138 (m) cm21; dH (270 MHz, CDCl3) 7.27±
7.14 (5H, m, aromatics), 5.75 (1H, t, Jˆ5 Hz, NCvCH),
4.72 (2H, s, NCH2) 3.82 (3H, s, CO2CH3), 2.97 (2H, t,
Jˆ6.5 Hz, CH2CvC), 2.29±2.20 (2H, m, CH2CHvC),
1.67 (2H, quin., Jˆ6.5 Hz, CH2CH2CH2); dC (67.5 MHz,
CDCl3) 163.4, 156.8 (CO2CH3 and NCO), 155.7
(CvCCO2CH3), 138.0, 137.0 (NCvCH and CvCH),
128.6, 127.4, 127.3 (CHvCH and CvCCO2CH3), 116.5
(NCvCH), 51.8 (CO2CH3), 42.8 (NCH2), 29.7, 24.4, 22.6
(CH2); m/z (CI, NH3) 284 (M1H1, 100%), 251 (23), 224
(18), 195 (10), 167 (17), 149 (16); Found: M1H1,
284.1287. C17H17NO3 requires for M1H1, 284.1287.
General procedure for enamide formation
To a stirred solution of the ketone (2.55±8.32 mmol) in
benzene or toluene (50±100 cm3) was added the appropriate
amine (2.55±8.32 mmol) and the solution was heated at
re¯ux under Dean±Stark conditions until no starting mate-
rial could be detected by TLC analysis (typically 7±10 h).
The solution was then cooled to 08C and methyl malonyl
chloride (2.55±8.32 mmol) added dropwise, followed by
the slow addition of N,N-diethylaniline (2.55±8.32 mmol).
The mixture was allowed to warm to room temperature and
left to stir for 2 h. Water was then added and the organic
phase separated and washed with more water, brine, dried
(MgSO4) and evaporated in vacuo to afford crude product
which was puri®ed using column chromatography (silica) to
give the enamides (24±76%), usually as oils.
Methyl N-allyl-3-hydroxy-2-oxo-3-indolinecarboxylate
12; 46%; colourless oil; Rf 0.31 (petroleum ether±diethyl
ether, 1:2); nmax (thin ®lm) 2933 (m), 1754 (s), 1711 (s),
1454 (w), 1405 (m) cm21; dH (270 MHz, CDCl3) 7.46±7.21
(3H, m, aromatics), 7.07±7.01 (1H, m, aromatics), 5.83±
5.71 (1H, m, CHvCH2), 5.35±5.18 (2H, m, CHvCH2),
4.40±4.31 (1H, ddt, Jˆ15.5, 4.5, 2 Hz, NCH2), 4.06±3.96
(1H, ddt, Jˆ15.5, 4.5, 2 Hz, NCH2), 3.41 (3H, s, CO2CH3),
[OH not observed]; dC (67.5 MHz, CDCl3) 172.7, 170.3
(CO2CH3 and NCO), 143.8 (NCvCH), 130.6
(CH2CHvCH2), 130.5, 126.7, 123.9 (CHvCH), 118.4
(CHvCH2), 109.8 (COH), 53.6 (CO2CH3), 42.5 (NCH2);
m/z (CI, NH3) 265 (M1NH14 , 100%), 248 (M1H1, 16),
191 (6), 174 (17); Found: M1H1, 248.0929. C13H13NO4
requires for M1H1, 248.0923.
Methyl [N-benzyl-N-(cyclohex-1-enyl)carbamoyl]ethano-
ate 1. Cyclohexanone (0.52 g, 0.55 cm3, 5.30 mmol) was
reacted with benzylamine (0.57 g, 0.58 cm3, 5.30 mmol),
methyl malonyl chloride (0.72 g, 0.57 cm3, 5.30 mmol)
and N,N-diethylaniline (0.79 g, 0.86 cm3, 5.30 mmol) in
benzene (100 cm3) following the general procedure.
Work-up afforded crude product which was puri®ed using
column chromatography (silica; petroleum ether±diethyl
ether, 1:3) to afford 1 (0.85 g, 56%) as a yellow oil; Rf
0.24 (petroleum ether±diethyl ether, 1:3); nmax (thin ®lm)
2929 (s), 2858 (s), 1743 (s), 1653 (s), 1495 (w), 1437 (m),
1406 (m), 1329 (w), 1154 (w) cm±1; dH (270 MHz, CDCl3)
7.26-7.17 (5H, m, aromatics), 5.40 (1H, s, NCvCH), 4.60
(2H, s, NCH2), 3.69 (3H, s, CO2CH3), 3.43 (2H, s, CH2CO),
1.95 (4H, br s, CH2CH and CH2CNCH2), 1.65±1.45 (4H, m,
CH2CH2); dC (67.5 MHz, CDCl3) 168.3, 165.2 (CO2CH3
and NCO), 137.8, 137.3 (NCvCH and CH2CvCH),
129.1, 128.4, 128.1, 127.0 (CHvCH and NCvCH), 52.1
(CO2CH3), 49.3 (CH2CO), 40.9 (NCH2), 27.7, 24.5 (CH2CH
and CH2CNCH2), 22.4, 21.1 (CH2CH2); m/z (CI, NH3) 288
(M1H1, 100%), 230 (6), 198 (21), 188 (12), 108 (10), 98
(16), 91 (8), 35 (56); Found: M1H1, 288.1595. C17H21NO3
requires for M1H1, 288.1599.
Methyl N-benzyl-6a-methoxy-2-oxo-octapenta[a,b]pyr-
role-3-carboxylate 16; 39%; colourless oil; Rf 0.53 (petro-
leum ether±ethyl acetate, 1:1); nmax (thin ®lm) 2927 (m),
1739 (s), 1696 (s), 1432 (w), 1403 (m) cm21; dH (270 MHz,
CDCl3) 7.38±7.21 (5H, m, aromatics), 4.70 (1H, d,
Jˆ15 Hz, NCH2), 4.16 (1H, d, Jˆ15 Hz, NCH2), 3.81
(3H, s, CO2CH3), 3.20 (1H, d, Jˆ5 Hz, CHCO), 3.06 (3H,
s, NCOCH3), 2.99±2.93 (1H, m, CHCHCO), 2.09±2.04
(2H, m, CH2COCH3), 1.74±1.44 (4H, m, CH2CH2); dC
(67.5 MHz, CDCl3) 170.2, 169.9 (CO2CH3 and NCO),
137.4 (CvCH), 128.4, 128.0, 127.9, 127.5, 127.3
(CHvCH), 105.0 (COCH3), 52.8 (COCH3), 50.8
(CO2CH3), 45.6 (CHCO), 43.5 (NCH2), 41.4 (CHCHCO),
38.1 (CH2COCH3), 33.6, 21.9 (CH2CH2); m/z (CI, NH3) 304
(M1H1, 83%), 272 (100), 214 (7); Found: M1H1,
304.1544. C17H21NO4 requires for M1H1, 304.1549.
General procedure for manganese(III) acetate mediated
cyclisation
Methyl
N-benzyl-3a-methyl-2-oxo-2,3,3a,4,5,6-hexa-
hydro-indole-3-carboxylate 26; 44%; colourless oil; Rf
0.23 (petroleum ether±diethyl ether, 1:1); nmax (thin ®lm)
2925 (m), 1758 (s), 1693 (s), 1435 (m), 1403 (w) cm21; dH
(270 MHz, CDCl3) 7.35±7.21 (5H, m, aromatics), 4.79 (1H,
t, Jˆ3.5 Hz, NCvCH), 4.70 (2H, s, NCH2), 3.72 (3H, s,
CO2CH3), 3.30 (1H, s, CHCO), 2.08±1.73 (6H, m,
CH2CH2), 1.28 (3H, s, CCH3); dC (67.5 MHz, CDCl3)
To a stirred solution of the alkene (0.26±0.84 mmol) in
methanol (5±15 cm3) under nitrogen was added a suspen-
sion of Mn(OAc)3´2H2O (2±8 equiv.) in methanol (10±
20 cm3), in one portion or dropwise. The mixture was heated
at re¯ux until no starting material could be detected by TLC
analysis. The solvent was then removed under reduced pres-
sure and ethyl acetate (15 cm3) and water (15 cm3) was

3946
D. T. Davies et al. / Tetrahedron 56 (2000) 3941±3949
173.0, 168.7 (CO2CH3 and NCO), 143.4 (NCvCH), 138.2
(CH2CvCH), 128.7, 128.6, 128.5, 128.4, 127.3, 127.1
(CHvCH and NCvCH), 59.2 (CHCO), 52.1 (CO2CH3),
43.4 (NCH2), 40.2 (CCH3), 30.2 (CH2CH), 22.4
(CH2CCH3), 21.6 (CH2CH2CH2), 15.1 (CCH3); m/z (CI,
NH3) 317 (M1NH14 , 45%), 300 (M1H1, 100); Found:
M1H1, 300.1602. C18H21NO3 requires for M1H1,
300.1599.
m/z (CI, NH3) 358 (35,37M1H1, 57%), 356 (35M1H1, 89),
320 (69), 286 (100), 271 (51), 254 (11), 226 (19), 186 (24),
108 (7), 91 (20); Found: 35M1H1, 356.0814. C17H19Cl2NO3
requires for 35M1H1, 356.0820.
General procedure for copper(I) chloride mediated
cyclisation
To a stirred solution of the alkene (0.22 mmol) and
copper(I) chloride (0.11 mmol) in dry degassed toluene
(1.5 cm3) under an atmosphere of nitrogen was added a
solution of 2,20-bipyridine (0.11 mmol) in toluene
(0.5 cm3). The mixture was heated at re¯ux until no starting
material could be detected by TLC analysis. The solvent
was removed under reduced pressure and the residue puri-
®ed by column chromatography (silica) to afford cyclic
product(s), typically as oils.
Methyl N-[2-(1-cyclohex-1-enyl)ethyl]-2-oxo-2,4,5,6-tetra-
hydro-indole-3-carboxylate 40; 57%; colourless oil; Rf
0.23 (petroleum ether±diethyl ether, 1:2); nmax (thin ®lm)
2932 (m), 1736 (s), 1709 (s), 1440 (m), 1402 (m) cm21; dH
(270 MHz, CDCl3) 5.97 (1H, t, Jˆ5 Hz, NCvCH), 5.46
(1H, s, CvCH), 3.93 (3H, s, CO2CH3), 3.70 (2H, t,
Jˆ6.5 Hz, NCH2), 3.10 (2H, t, Jˆ6.5 Hz, CH2CvC),
2.53±2.47 (1H, m, CH2CHvCN), 2.23 (2H, t, Jˆ7.5 Hz,
NCH2CH2), 1.98±1.89 (6H, m, CH2CCH2, CH2CH and
CH2CH2CvC), 1.69±1.58 (4H, m, CH2CH2); dC
(67.5 MHz, CDCl3) 165.5, 163.4 (CO2CH3 and NCO),
155.1 (CvCCO2CH3), 138.2 (NCvCH), 123.4
(CvCCO2CH3), 116.9 (CH2CvCH), 115.2 (NCvCH),
51.6 (CO2CH3), 38.0 (NCH2), 36.6 (CH2CvC), 28.3,
25.2, 24.4 (CH2CvCH and CHCH2), 22.8, 22.1
(CH2CH2CH2); m/z (CI, NH3) 296 (M1NH14 , 23%), 279
(M1H1,100); Found: M1H1, 279.1604. C15H23NO3
requires for M1H1, 279.1606.
Copper(I) mediated cyclisation of N-benzyl-2,2,2-
trichloro-N-(cyclohex-1-enyl)ethanamide 3. Enamide 3
(73 mg, 0.22 mmol), copper(I) chloride (6 mg, 0.06 mmol)
and 2,20-bipyridine (9 mg, 0.06 mmol) were reacted
together in dry toluene (2 cm3) following the general proce-
dure. Column chromatography (silica; petroleum ether±
diethyl ether, 3:1) afforded 2 (47 mg, 84%) as a pale yellow
oil. The spectral data for 2 was identical to that reported
earlier.
N-Benzyl-3-chloro-1,4,5,6-tetrahydro-indol-2-one 10; 94%;
pale yellow oil; Rf 0.32 (petroleum ether±diethyl ether, 3:1);
(Found: C, 64.06; H, 5.54; N, 4.96. C15H14ClNO requires C,
64.31; H, 5.83; N, 5.09%); nmax (thin ®lm) 2912 (w), 1714
(s), 1692 (m), 1438 (w), 1399 (w), 1246 (w) cm21; dH
(270 MHz, CDCl3) 7.65±7.22 (5H, m, aromatics), 5.59
(1H, t, Jˆ4.5 Hz, NCvCH), 4.80 (2H, s, NCH2), 2.62
(2H, t, Jˆ6.5 Hz, CH2CvC), 2.31±2.26 (2H, m,
CH2CHvC), 1.81 (2H, q, Jˆ6.5 Hz, CH2CH2CH2); dC
(67.5 MHz, CDCl3) 164.8 (NCO), 137.1, 137.0 (2£
CvCH and NCvCH), 128.7, 127.5, 127.2 (CHvCH and
ClCvC), 111.7 (NCvCH), 43.5 (NCH2), 24.3, 22.6, 22.3
(CH2CH2); m/z (CI, NH3) 262 (37M1H1, 34%), 260
(35M1H1, 100), 226 (11), 170 (9); Found: 35M1H1,
260.0837. C15H14ClNO requires for 35M1H1, 260.0842.
General procedure for chlorination of alkenes
To a stirred solution of the alkene (0.52±1.95 mmol) in dry
tetrahydrofuran (10±15 cm3) at 08C, under an atmosphere of
nitrogen, was added sodium hydride (1.15±4.29 mmol). The
solution was allowed to stir for 1 h after which N-chloro-
succinimide (1.15±4.29 mmol) was added, the solution
allowed to warm to room temperature and stirred for a
further 2 h. The solvent was then evaporated under reduced
pressure and water (10 cm3) and ethyl acetate (10 cm3) were
added. The organic phase was separated, washed with more
water, brine, dried (MgSO4) and then evaporated under
reduced pressure to afford crude product which was puri®ed
using column chromatography (silica) to afford the chlori-
nated products (69±84%), usually as oils.
Methyl [N-benzyl-N-(cyclohex-1-enyl)carbamoyl]-2,2-
dichloroethanoate 3. Enamide 1 (150 mg, 0.52 mmol),
sodium hydride (28 mg, 47 mg of a 60% dispersion in
mineral oil, 1.15 mmol) and N-chlorosuccinimide
(154 mg, 1.15 mmol) were reacted together in dry tetrahy-
drofuran (8 cm3) following the general procedure. Column
chromatography (silica; petroleum ether±diethyl ether, 1:1)
afforded the desired product 3 (146 mg, 79%) as a colourless
oil; Rf 0.45 (petroleum ether±diethyl ether, 1:1); nmax (thin
®lm) 2935 (s), 1767 (s), 1744 (m), 1679 (s), 1452 (m), 1437
(m), 1393 (w) cm21; dH (270 MHz, CDCl3) 7.32±7.21 (5H,
m, aromatics), 5.40 (1H, br s, NCvCH), 5.05 (1H, d,
Jˆ14 Hz, NCH), 4.25 (1H, d, Jˆ14 Hz, NCH), 3.84 (3H,
s, CO2CH3), 2.17±1.83 (4H, m, CH2CH and CH2CCH),
1.54±1.25 (4H, m, CH2CH2); dC (67.5 MHz, CDCl3)
164.1, 161.5 (CO2CH3 and NCO), 136.3, 135.9 (NCvCH
and CvCH), 131.4, 128.4, 128.3, 127.5 (CHvCH and
NCvCH), 80.5 (CCl2), 54.4 (CO2CH3), 51.6 (NCH2),
27.2, 24.6 (CH2CH and CH2CCH), 22.2, 20.9 (CH2CH2);
N-Allyl-3-chloro-1,4,5,6-tetrahydro-indol-2-one 14; 91%;
colourless oil; Rf 0.36 (petroleum ether±diethyl ether,
3:1); nmax (thin ®lm) 2929 (w), 1705 (s), 1656 (m), 1437
(w), 1411 (w), 1317 (w) cm21; dH (270 MHz, CDCl3) 5.85±
5.71 (1H, m, CHvCH2), 5.68 (1H, t, Jˆ4 Hz, NCvCH),
5.17±5.13 (2H, m, CHvCH2), 4.25 (2H, s, NCH2), 2.63
(2H, t, Jˆ6.5 Hz, CH2CvC), 2.39±2.33 (2H, m,
CH2CHC), 1.83 (2H, q, Jˆ6.5 Hz, CH2CH2CH2); dC
(67.5 MHz, CDCl3) 164.4 (NCO), 139.7, 137.2 (ClCvC
and NCvCH), 132.9 (CHvCH2), 119.3 (ClCvC), 116.8
(CHvCH2), 111.5 (NCvCH), 42.2 (NCH2), 24.3, 22.6,
22.3 (CH2CH2); m/z (CI, NH3) 212 (37M1H1, 32%), 210
(35M1H1, 100), 176 (9); Found: 35M1H1, 210.0684.
C11H12ClNO requires for 35M1H1, 210.0686.
Methyl N-benzyl-2-oxo-1,2,4,5-tetrahydro-cyclopenta[a,b]-
pyrrole-3-carboxylate 19; 89%; colourless oil; Rf 0.18
(petroleum ether±diethyl ether, 1:4); (Found: C, 70.31; H,
5.68; N, 4.99. C16H15NO3 requires C, 70.11; H, 5.61; N,

D. T. Davies et al. / Tetrahedron 56 (2000) 3941±3949
3947
5.20%); nmax (thin ®lm) 2951 (w), 1739 (s), 1711 (s), 1648
(m), 1437 (m), 1351 (w) cm21; dH (270 MHz, CDCl3) 7.34±
7.23 (5H, m, aromatics), 5.76 (1H, t, Jˆ3 Hz, NCvCH),
4.82 (2H, s, NCH2), 3.87 (3H, s, CO2CH3), 3.04±2.98 (2H,
m, CH2CH2), 2.90±2.85 (2H, m, CH2CH2); dC (67.5 MHz,
CDCl3) 169.9, 163.0 (CO2CH3 and NCO), 144.4
(CvCCO2CH3), 138.9, 136.6 (NCvCH and CvCH),
128.7, 127.9, 127.7 (CHvCH), 120.3 (NCvCH), 112.5
(CvCCO2CH3), 51.7 (CO2CH3), 44.6 (NCH2), 35.8, 26.4
(CH2CH2); m/z (CI, NH3) 269 (M1H1, 34%), 237 (17), 208
(27), 181 (44), 91 (100); Found: M1H1, 269.1059.
C16H15NO3 requires for M1H1, 269.1052.
Copper(I) mediated cyclisation of methyl [N-benzyl-N-
(2-methyl-cyclohex-1-enyl)carbamoyl]-2,2-dichloro-
ethanoate 27 and methyl [N-benzyl-N-(6-methyl-cyclo-
hex-1-enyl)carbamoyl]-2,2-dichloroethanoate 28.
A
2.6:1 mixture of enamides 27 and 28 (81 mg, 0.22 mmol),
copper (I) chloride (10 mg, 0.11 mmol) and 2,20-bipyridine
(16 mg, 0.11 mmol) were reacted together in dry toluene
(2 cm3) following the general procedure. Column chromato-
graphy (silica; petroleum ether±diethyl ether, 1:2) afforded
an inseparable mixture of 26 (20 mg, 30%) and N-benzyl-7-
methyl-1,3-dihydro-indol-2-one 29 (6 mg, 11%), as a
colourless oil; Rf 0.43 (petroleum ether±diethyl ether,
1:2); nmax (thin ®lm) 2953 (w), 1710 (s), 1604 (s), 1471
(m), 1446 (w) cm21. 29; dH (270 MHz, CDCl3) 7.34±7.21
(5H, m, aromatics), 7.17±7.10 (3H, m, aromatics), 5.20 (2H,
s, NCH2Ph), 3.65 (2H, s, CH2CON), 1.61 (3H, s, CCH3); dC
(67.5 MHz, CDCl3, mixture with 26) 176.0, 170.1, 169.2
(CO2CH3 and NCO), 142.3 (NCvCH), 137.8, 136.8,
136.0 (NCvCCH3, NCvCCH3 and CvCH), 128.8,
128.5, 127.1, 125.6, 125.0, 122.4, 122.3, 119.8 (CHvCH
and NCvCH), 60.8 (CHCO2CH3), 52.1 (CO2CH3), 45.0,
44.8 (NCH2), 40.1 (CCH3), 35.6 (CH2CON), 30.1, 22.5,
21.5 (CH2CH2), 18.6, 17.9 (CCH3); m/z (CI, NH3) 238
(M1H1, 100%), 91 (17); Found: M1H1, 238.1232.
C16H15NO requires for M1H1, 238.1231.
N-Benzyl-3-chloro-4,5-dihydro-cyclopenta[a,b]pyrrol-2-
one 20; 92%; colourless oil; Rf 0.29 (petroleum ether±
diethyl ether, 4:1); nmax (thin ®lm) 2921 (m), 1711 (s),
1650 (m), 1454 (w), 1436 (w), 1402 (w), 1327 (w), 1246
(w) cm21; dH (270 MHz, CDCl3) 7.34±7.23 (5H, m,
aromatics), 5.47 (1H, t, Jˆ3 Hz, NCvCH), 4.82 (2H, s,
NCH2), 2.83±2.74 (4H, m, CH2CH2); dC (67.5 MHz,
CDCl3) 169.2 (NCO), 153.6 (ClCvC), 143.3 (NCvCH),
136.5 (CvCH), 128.6, 127.7, 127.6 (CHvCH), 114.4
(NCvCH), 45.3 (NCH2), 34.6, 23.2 (CH2CH2); m/z (CI,
NH3) 248 (37M1H1, 34%), 246 (35M1H1, 100), 212
(100), 91 (9); Found: 35M1H1, 246.0683. C14H12ClNO
requires for 35M1H1, 246.0685.
N-Benzyl-5-(3-hydroxy-2,2-dimethylpropoxy)-1,3-dihydro-
indol-2-one 32; 35%; colourless oil; Rf 0.25 (petroleum
ether±ethyl acetate, 1:2); nmax (thin ®lm) 3471 (s), 2957
(m), 1703 (s), 1694 (s), 1598 (m), 1493 (m), 1453 (w),
1366 (m) cm21; dH (270 MHz, CDCl3) 7.27±7.22 (5H, m,
aromatics), 6.87 (1H, s, CH2CvCH), 6.67 (1H, dd,
Jˆ8.5 Hz, 2.5, NCCHCH), 6.55 (1H, d, Jˆ8.5 Hz,
NCCH), 4.87 (2H, s, NCH2), 3.68 (2H, s, COCH2), 3.56
(OCH2), 3.51 (2H, s, CH2OH), 0.99 (6H, s, C(CH3)2); dC
(67.5 MHz, CDCl3) 174.0 (NCO), 155.3 (CHCOCH2),
144.4 (NCCH), 135.9 (CvCH), 128.7 (CHvCH), 127.9
(COCH2CCH), 127.5, 127.3 (CHvCH), 113.0, 112.6
(NCCHCH and NCCHCH), 109.3 (COCH2CCH), 75.8
(CHCOCH2C), 69.9 (CH2OH), 43.8 (NCH2), 36.2
(COCH2), 36.1 (CCH3), 22.5, 21.6 (CH3); m/z (CI, NH3)
326 (M1H1, 100%), 308 (3), 239 (12), 91 (15); Found:
M1H1, 326.1764. C20H23NO3 requires for M1H1,
326.1758.
Methyl N-benzyl-2-oxo-1,2,4,5,6,7-hexahydro-cyclohep-
ta[a,b]pyrrole-3-carboxylate 23a; 86%; pale yellow oil;
Rf 0.32 (petroleum ether±diethyl ether, 1:4); nmax (thin
®lm) 2950 (w), 1736 (s), 1711 (s), 1648 (m), 1437 (m),
1399 (w) cm21; dH (270 MHz, CDCl3) 7.33±7.20 (5H, m,
aromatics), 5.88 (1H, t, Jˆ6 Hz, NCvCH), 4.85 (2H, s,
NCH2), 3.90 (3H, s, CO2CH3), 3.16 (2H, m, CH2CvC),
2.48±2.42 (2H, m, CH2CH), 1.81±1.77 (4H, m,
CH2CH2CH2); dC (67.5 MHz, CDCl3) 165.2, 163.0
(CO2CH3 and NCO), 158.9 (CvCCO2CH3), 138.9, 137.1
(NCvCH and CvCH), 128.2, 127.3, 127.0 (CHvCH),
122.3 (NCvCH), 117.0 (CvCCO2CH3), 52.0 (CO2CH3),
42.8 (NCH2), 28.9, 28.7 (CH2CvC and CH2CH), 26.7,
24.1 (CH2CH2CH2); m/z (CI, NH3) 298 (M1H1, 100%),
256 (9), 242 (15), 91 (10); Found: M1H1, 298.1442.
C18H19NO3 requires for M1H1, 298.1443.
Methyl N-benzyl-2-oxo-2,4,5,6,7,8-hexahydro-cycloocta-
[a,b]pyrrole-3-carboxylate 23b; 90%; colourless oil; Rf
0.43 (petroleum ether±diethyl ether, 1:4); nmax (thin ®lm)
2931 (w), 1723 (s), 1694 (m), 1496 (m), 1437 (m), 1382
(w) cm21; dH (270 MHz, CDCl3) 7.33±7.20 (5H, m,
aromatics), 5.65 (1H, t, Jˆ9 Hz, NCvCH), 4.87 (2H, s,
NCH2), 3.90 (3H, s, CO2CH3), 3.23 (2H, t, Jˆ7 Hz,
CH2CvC), 2.58 (2H, quin., Jˆ7 Hz, CH2CH), 1.79±1.72
(2H, m, CvCCH2CH2 or CvCHCH2CH2), 1.56±1.49
(2H, m, CvCCH2CH2 or CvCHCH2CH2), 1.43±1.38
(2H, m, CH2CH2); dC (67.5 MHz, CDCl3) 165.6, 163.7
(CO2CH3 and NCO), 156.9 (CvCCO2CH3), 141.7, 136.9
(NCvCH and CvCH), 128.6, 127.3, 126.8 (CHvCH),
122.2 (NCvCH), 116.7 (CvCCO2CH3), 52.0 (CO2CH3),
42.6 (NCH2), 26.5, 25.3 (CH2CvC and CH2CH), 24.9,
24.5 (CvCCH2CH2 and CvCHCH2CH2), 21.2
(CH2CH2); m/z (CI, NH3) 312 (M1H1, 100%); Found:
M1H1, 312.1597. C19H21NO3 requires for M1H1,
312.1599.
Copper(I) chloride mediated cyclisation of methyl N-
[benzyl(4-{[(benzyloxy)carbonyl]amino}-N-cyclohex-1-
enyl)carbamoyl]-2,2-dichloroethanoate 33. To a stirred
solution of dichloride 33 (111 mg, 0.22 mmol) and
copper(I) chloride (10 mg, 0.11 mmol) in dry degassed
toluene (1.5 cm3) under an atmosphere of nitrogen was
added a solution of 2,20-bipyridine (16 mg, 0.11 mmol) in
toluene (0.5 cm3). The mixture was heated at re¯ux until no
starting material could be detected by TLC analysis. The
solvent was removed under reduced pressure and the residue
puri®ed by column chromatography (silica; petroleum
ether±diethyl ether, 2:1), which afforded 34 (16 mg,
19%), 35 (7 mg, 15%) and 36 (56 mg, 59%) as colourless
oils.
Benzyl N-benzyl-2-oxo-2,3-dihydro-indol-5-yl carba-
mate 34; Rf 0.11 (petroleum ether±diethyl ether, 2:1);
nmax (thin ®lm) 2920 (w), 1711 (m), 1675 (s), 1609 (m),

3948
D. T. Davies et al. / Tetrahedron 56 (2000) 3941±3949
1493 (m), 1452 (m), 1366 (w), 1358 (m) cm21; dH
(270 MHz, CDCl3) 7.28±7.22 (5H, m, aromatics), 7.03
(1H, m, COCH2CCH), 6.60 (2H, m, NCCH and NCCHCH),
5.16 (2H, s, OCH2), 4.87 (2H, s, NCH2), 3.58 (2H, s,
COCH2); dC (67.5 MHz, CDCl3) 174.8 (NCO), 153.6
(NCO2CH2), 144.5, 140.5 (NCCH and CNCO2), 136.0,
135.7 (CvCH), 128.8, 128.6, 128.3, 128.1, 127.6, 127.3
(CHvCH), 125.3 (COCH2CCH), 118.7, 116.8 (NCCHCH
and NCCHCH), 109.1 (COCH2CCH), 67.1 (OCH2), 43.8
(NCH2), 36.0 (COCH2); m/z (CI, NH3) 373 (M1H1,
45%), 256 (100), 239 (49), 108 (14), 91 (24); Found:
M1H1, 372.1468. C23H21N2O3 requires for M1H1,
372.1471.
90%), 312 (100), 137 (24), 121 (35); Found: M1H1,
368.1856. C22H25NO4 requires for M1H1, 368.1861.
N-(But-3-enyl)-3-chloro-1,4,5,6-tetrahydro-indol-2-one
42; 89%; pale yellow oil; Rf 0.29 (petroleum ether±diethyl
ether, 3:1); nmax (thin ®lm) 2937 (w), 1704 (s), 1654 (m),
1623 (w), 1439 (w), 1411 (w), 1341 (w) cm21; dH
(270 MHz, CDCl3) 5.81±5.72 (1H, m, CH2CHvCH2),
5.69 (1H, t, Jˆ4.5 Hz, NCvCH), 5.10±5.02 (2H, m,
CH2CHvCH2), 3.65 (2H, t, Jˆ14.5 Hz, NCH2), 2.62 (2H,
t, Jˆ6.5 Hz, CH2CvC), 2.42±2.35 (4H, m, CH2CvCH and
NCH2CH2), 1.85 (2H, q, Jˆ6.5 Hz, CH2CH2CH2); dC
(67.5 MHz, CDCl3) 164.6 (NCO), 139.4 (ClCvC), 137.3
(NCvCH), 134.6 (CHvCH2), 117.2 (CHvCH2), 110.7
(NCvCH), 39.2 (NCH2), 33.2 (NCH2CH2), 24.4, 22.7,
22.2 (CH2CH2); m/z (CI, NH3) 226 (37M1H1, 32%), 224
(35M1H1, 100), 206 (5), 190 (16), 170 (12); Found:
35M1H1, 224.0841. C12H14ClNO requires for 35M1H1,
224.0842.
5-Amino-N-benzyl-1,3-dihydro-indol-2-one 35; Rf 0.27
(petroleum ether±diethyl ether, 2:1); nmax (thin ®lm) 1707
(m), 1614 (m), 1489 (m), 1466 (m), 1378 (w), 1358
(m) cm21; dH (270 MHz, CDCl3) 7.32±7.20 (7H, m,
CHvCH), 7.17 (1H, t, Jˆ7.5 Hz, CHvCH), 7.00 (1H, t,
Jˆ7.5 Hz, CHvCH), 6.72 (1H, d, Jˆ7.5 Hz, CHvCH),
4.92 (2H, s, NCH2), 3.63 (2H, s, COCH2); dC (67.5 MHz,
CDCl3) 175.1 (NCO), 144.4 (NCCH), 135.8 (CvCH),
128.7, 127.8, 127.8, 127.6, 127.3, 124.4 (CHvCH), 124.3
(COCH2CCH), 43.7 (NCH2), 35.7 (COCH2); m/z (CI, NH3)
224 (M1H1, 100%), 91 (9); Found: M1H1, 224.1070.
C15H14NO requires for M1H1, 224.1075.
Acknowledgements
We thank the BBSRC and SmithKline Beecham Pharma-
ceuticals for a research studentship.
Methyl N-benzyl-5-{[(benzyloxy)carbonyl]amino}-2-oxo-
2,4,5,6-tetrahydro-indole-3-carboxylate 36; Rf 0.15
(diethyl ether); nmax (thin ®lm) 3323 (m), 2952 (m), 1734
References
(s), 1719 (s), 1655 (s), 1528 (w), 1453 (m), 1438 (w) cm21
;
È
1. (a) Giese, B.; Kopping, B.; Gobel, T.; Dickhaut, J.; Thoma, G.;
dH (270 MHz, CDCl3) 7.65±7.18 (10H, m, aromatics), 5.66
(1H, t, Jˆ5 Hz, NCvCH), 5.08 (2H, s, OCH2), 5.03 (1H, br
s, NH), 4.82 (1H, d, Jˆ15 Hz, NCHPh), 4.74 (1H, d,
Jˆ15 Hz, NCHPh), 4.10 (1H, br s, NCH), 3.87 (3H, s,
CO2CH3), 3.46 (1H, dd, Jˆ4, 18 Hz, NHCHCH), 2.89
(1H, dd, Jˆ9.5, 18, NHCHCH), 2.68 (1H, dt, Jˆ18, 5 Hz,
NCvCHCH), 2.37±2.30 (1H, m, NCvCHCH); dC
(67.5 MHz, CDCl3) 165.8, 162.9 (CO2CH3 and NCO),
155.5, 152.7 (CO2CH2 and CvCCO2CH3), 137.8, 136.6,
136.1 (NCvCH and CvCH), 128.6, 128.3, 128.2, 127.6,
127.3 (CHvCH), 118.6 (CvCCO2CH3), 112.7 (NCvCH),
66.9 (OCH2), 51.9 (CO2CH3), 46.9 (CHNH), 43.0
(NCH2Ph), 31.1, 30.9 (CH2); m/z (CI, NH3) 433 (M1H1,
9%), 224 (64), 152 (11), 108 (34), 91 (100); Found:
M1H1, 433.1757. C25H24N2O5 requires for M1H1,
433.1763.
Kulicke, K. J.; Trach, F. Organic Reactions 1996, 48, 301; (b)
Aldabbagh, F.; Bowman, W. R. Contemp. Org. Synth. 1997,
261; (c) Bowman, W. R.; Bridge, C. F.; Brookes, P. J. Chem.
Soc., Perkin Trans. 1 2000, 1.
2. (a) Bryans, J. S.; Large, J. M.; Parsons, A. F. J. Chem. Soc.,
Perkin Trans. 1 1999, 2897; (b) Bryans, J. S.; Large, J. M.; Parsons,
A. F. J. Chem. Soc., Perkin Trans. 1 1999, 2905; (c) Ishibashi, H.;
So, T. S.; Okochi, K.; Sato, T.; Nakamura, N.; Nakatani, H.; Ikeda,
M. J. Org. Chem. 1991, 56, 95; (d) Ozaki, S.; Matsushita, H.;
Ohmori, H. J. Chem. Soc., Perkin Trans. 1 1993, 2339; (e) Cardi-
llo, B.; Galeazzi, R.; Mobbili, G.; Orena, M.; Rossetti, M. Hetero-
cycles 1994, 38, 2663; (f) Stork, G.; Mah, R. Heterocycles 1989,
28, 723.
3. For recent examples see: (a) Baker, S. R.; Burton, K. I.; Parsons,
A. F.; Pons, J.-F.; Wilson, M. J. Chem. Soc., Perkin Trans. 1 1999,
427; (b) Ishibashi, H.; Higuchi, M.; Ohba, M.; Ikeda, M.
Tetrahedron Lett. 1998, 39, 75; (c) Ikeda, M.; Ohtani, S.;
Yamamoto, T.; Sato, T.; Ishibashi, H. J. Chem. Soc., Perkin
Trans. 1 1998, 1763.
Methyl N-(4-methoxybenzyl)-2-oxo-2,4,4a,5,6,7,8,8a-octa-
hydro-benzo-indole-3-carboxylate 38; 79%; colourless
oil; Rf 0.29 (petroleum ether±diethyl ether, 1:2); nmax
(thin ®lm) 2928 (m), 1735 (m), 1709 (s), 1685 (s), 1513
(m), 1440 (w) cm21; dH (270 MHz, CDCl3) 7.15 (2H, d,
Jˆ9 Hz, CHvCOCH3), 6.82 (2H, d, Jˆ9 Hz,
CHvCOCH3), 5.82 (1H, br s, NCvCH), 4.72 (2H, s,
NCH2), 3.89 (3H, s, OCH3), 3.78 (3H, s, OCH3), 2.58±
2.49 (4H, m, CH2CH and 2£ CHCH2), 2.17±1.59 (8H, m,
CH2CH2); dC (67.5 MHz, CDCl3) 165.1, 163.3 (CO2CH3
and NCO), 158.8 (CHvCOCH3), 138.6, 136.9, 133.5
(NCvCH, CvCH and CCO2CH3), 129.0, 128.8, 128.6
(CHvCH), 114.0 (NCvCH), 55.0, 53.4 (COCH3 and
CO2CH3), 42.3 (NCH2), 36.3, 33.5 (CHCH2), 28.9, 26.5,
20.6 (CH2CH2 and CHCH2); m/z (CI, NH3) 368 (M1H1,
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3949
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