Benzocarbapenems from indoles

Article abstract of DOI:10.1039/a800278i

The 8,8a-dihydroazeto[1,2-a]indol-2(1H)-ones (benzocarbapenems) 1a, 16, 17, 22, 27, 35 and 36 have been prepared by cyclodehydration of the corresponding β-amino acids, these amino acids being obtained by reduction of the analogous 2-substituted or 2,7-disubstituted indoles. The hydroxy group of compound 36 is designed to mimic the carboxylic acid function of the carbapenems on the basis of molecular modelling. The azetidinones 1a and 27, which are unsubstituted at the methylene group of the four-membered ring, are unstable and highly susceptible to ring opening by nucleophiles but the compounds 22,35 and 36 with two methyl substituents at this position are much more stable. The carbonyl stretching frequency in the IR is close to 1770 cm^-1 for all the azetidinones except the phenol 36 for which the absorption is at 1735 cm^-1. An X-ray crystal structure of compound 36 is reported.

Full text of DOI:10.1039/a800278i

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Benzocarbapenems from indoles1
Steven Coulton,a Thomas L. Gilchrist*,b and Keith Grahamb
a SmithKlineBeecham Pharmaceuticals, New Frontiers Science Park (North),
Coldharbour Road, The Pinnacles, Harlow, Essex, UK CM19 2JE
b Chemistry Department, University of Liverpool, Liverpool, UK L69 7ZD
The 8,8a-dihydroazeto[1,2-a]indol-2(1H)-ones (benzocarbapenems) 1a, 16, 17, 22, 27, 35 and 36 have been
prepared by cyclodehydration of the corresponding â-amino acids, these amino acids being obtained by
reduction of the analogous 2-substituted or 2,7-disubstituted indoles. The hydroxy group of compound
36 is designed to mimic the carboxylic acid function of the carbapenems on the basis of molecular
modelling. The azetidinones 1a and 27, which are unsubstituted at the methylene group of the four-
membered ring, are unstable and highly susceptible to ring opening by nucleophiles but the compounds
22, 35 and 36 with two methyl substituents at this position are much more stable. The carbonyl stretching
frequency in the IR is close to 1770 cmϪ1 for all the azetidinones except the phenol 36 for which the
absorption is at 1735 cmϪ1. An X-ray crystal structure of compound 36 is reported.
We have been investigating syntheses of bicyclic and tricyclic
β-lactams in which aromatic heterocycles are used as the pre-
cursors. Because of the high stability and predictable chemistry
of these heterocycles it should be possible to devise short routes
to new or little known ring systems or to introduce new substi-
tution patterns. The synthesis of carbapenams from pyrroles
has been described in an earlier paper.2 In this paper we give the
results of an investigation of the synthesis of 8,8a-dihydro-
azeto[1,2-a]indol-2(1H)-ones (benzocarbapenems) 1 from in-
doles. A related route to benzocarbacephems from quinolines is
described in the following paper.3
in the second, the side chain is introduced at a late stage by
alkylation of indole6 or by modification of an existing 2-
substituent.7 After considerable experimentation with several
of the literature procedures we chose to use a route of the first
type involving an intramolecular Wittig reaction as the key
step5d (Scheme 2) since it proved to be reliable when carried out
OH
NH2
PPh3+ Br–
NH2
i
88%
We chose as our initial target the parent unsubstituted benzo-
carbapenem 1a, in order to establish a viable synthetic route to
more biologically relevant molecules.† The starting point for
the synthesis of 1a is an indole-2-acetic acid and the route is, in
principle, very simple (Scheme 1). The two steps are the reduc-
ii 71%
PPh3+ Br–
O
iii
70%
N
CO2Et
CO2Et
N
H
H
8
3
8a
1
Scheme 2 Reagents: i, PPh3ؒHBr; ii, EtO2CCH2COCl; iii, KOBut
N
N
4
O
on a large scale. Ethyl indole-2-acetate 3 was prepared from
2-aminobenzyl alcohol in three steps and in an overall yield of
44% by this method.
The reduction of ethyl indole-2-acetate to the corresponding
indoline ester 4a was carried out (82%) by dissolving the ester in
R
CO2R
O
2a R = H
b R = CH2COMe
1a R = H
b R = OH
1a
N
N
N
CO2R
CO2R
O
PO
H
H
N
H
O
CO2R
3
Scheme 1
5
4 a R = Et
b R = H
tion of the double bond in the five-membered ring and the
cyclisation of the β-amino acid derivative to the β-lactam. The
synthesis therefore required a route to indole-2-acetic acid or to
one of its esters that could subsequently be used for the corre-
sponding 7-hydroxyindole-2-acetic acid (for reasons given
below), and reliable methods for carrying out the reduction and
cyclisation steps.
There are two general routes to indole-2-acetic acid deriv-
atives. The first requires the construction of the five-membered
ring of the indole skeleton with the side chain already in place;5
R1
R2
N
CO2Et
CO2But
6 R1 = R2 = H
7 R1 = Me, R2 = H
8 R1 = R2 = Me
TFA then adding trimethylamine–borane complex to the sol-
ution at 0 ЊC over a period of five minutes. Similar reductions of
indoles by pyridine–borane complex have been described.8 The
† The parent compound 1a had been synthesised once before but not
fully characterised.4
J. Chem. Soc., Perkin Trans. 1, 1998
1193

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ester was hydrolysed to the corresponding carboxylic acid 4b in
concentrated HCl, the product being isolated (60%) and char-
acterised as its crystalline hydrochloride. As in the earlier
work,2 the cyclising agent used to produce the β-lactam 1a from
the carboxylic acid 4b was tris(2-oxobenzoxazolin-3-yl)phos-
phine oxide 5.9 This proved to be more efficient than other
cyclising agents [dicyclohexylcarbodiimide (DCCI) or dipyridyl
disulfide with triphenylphosphine]. The β-lactam 1a was
isolated as a crystalline solid (37%) after purification by sub-
limation. It shows a carbonyl stretching absorption in the IR
spectrum at 1773 cmϪ1 and its NMR spectrum is consistent
with that reported earlier.4
H2/Rh
N
CO2But
H
12
2
Me
3' O 4'
2'
5'
O
Fig. 1 Addition of hydrogen to the indole 7 in its lowest energy
conformation
7
The benzocarbapenem 1a starts to decompose within a few
hours when left in air at room temperature but it was stored for
up to a month under nitrogen at Ϫ20 ЊC without significant
decomposition. It is highly susceptible to ring opening by
nucleophiles. An attempt to obtain a mass spectrum of a
sample dissolved in methanol gave only a spectrum consistent
with a product of ring opening, methyl 2,3-dihydro-1H-indole-
2-acetate. An electron impact mass spectrum of the purified
solid gave a molecular ion; the major breakdown pathway is its
cleavage to indole and ketene.
Route A
i
88%
88%
iii
Route B
N
CO2Et
H
9
The high reactivity of the compound should be moderated by
substitution of the methylene group of the four membered ring
since this is likely to lower the internal angle strain. In order to
establish this the synthesis was applied to derivatives bearing
one and two methyl substituents in the four membered ring.
Two approaches were considered: (i) to incorporate the methyl
substituents into the precursors for the intramolecular Wittig
reaction and (ii) to alkylate the side chain methylene group of
ethyl indole-2-acetate. Since the second approach appeared
to be potentially more versatile this was the method adopted.
The nitrogen atom of ethyl indole-2-acetate was protected by
introduction of a tert-butoxycarbonyl (Boc) group and the
protected ester 6 was methylated by reaction with potassium
hexamethyldisilazide (KHMDS) and iodomethane to give the
α-methyl ester 7 in 92% yield. By repeating the methyl-
ation procedure without isolation of the intermediate 7, the
dimethylated ester 8 was obtained in 83% yield from ethyl
indole-2-acetate.
The ester 7 was deprotected by reaction with TFA (Scheme 3,
route A). Reduction of the double bond of the product 9 with
trimethylamine–borane complex was inefficient but reduction
by sodium cyanoborohydride in TFA gave the corresponding
dihydroindole esters 10 and 11 in a combined yield of 79%. As
expected, the reduction was unselective and the isomers were
obtained in a 1:1 ratio, as estimated from the NMR spectrum
of the mixture. The components could not be separated by
column chromatography.
H
H
+
N
N
CO2Et
CO2But
CO2Et
CO2But
13
ii
79%
12
88%
i
H
H
+
N
H
CO2R
N
CO2R
+
H
10
11
iv
H
H
+
N
CO2H
–OCOCF3
N
CO2H
–OCOCF3
H2
H2
14
15
v
H
H
+
N
N
The Boc protected ester 7 was also reduced directly to the
corresponding dihydroindoles 12 and 13 by catalytic hydro-
genation at 200 psi over rhodium in a mixture of ethanol and
acetic acid10 (route B in Scheme 3). The esters were isolated
in a combined yield of 88% as a 5:1 mixture of diastereo-
isomers. The major isomer was subsequently shown to be 12.
The stereoselectivity of the reduction can be ascribed to reac-
tion through a conformer (Fig. 1) that was found by molec-
ular mechanics to be the lowest energy of those examined. The
same stereoselectivity was observed in the catalytic hydrogen-
ation of analogous pyrroles to pyrrolidines.2 The Boc protect-
ing group was removed by reaction with TFA to give the
esters 10 and 11.
The mixed esters obtained by each of the two reduction
procedures were hydrolysed to the corresponding amino
acids, which were characterised as the TFA salts 14 and 15.
The salts (as mixtures) were then cyclised (56–63% yield) by
reaction with the phosphine oxide 5 and triethylamine. The
mixtures of β-lactams 16 and 17 were obtained as low melt-
ing point crystalline solids and were characterised without
being separated. The mixture obtained by the catalytic hydro-
O
O
16
17
Scheme 3 Reagents: i, TFA; ii, NaCNBH3, TFA; iii, H2, Rh/C; iv, aq.
KOH then TFA; v, 5, Et3N
genation route proved to contain 16 as the predominant
component and this established the isomer 12 as the major
product in the hydrogenation step. The β-lactams 16 and 17
were distinguished by the signals for H-1 in the NMR spec-
trum. The signal for 16 appears at lower field than that for
17 (at δ 3.70 for 16, close to δ 3.17 for 17) and shows cis
coupling to the bridgehead hydrogen H-8a (J 5.5 Hz; J 2.8
Hz for 17). These β-lactams are somewhat more stable than
the unsubstituted compound 1a; they could be stored under
nitrogen below 0 ЊC without decomposition.
The ester 8 was converted into the β-lactam 22 by an anal-
ogous route, shown in Scheme 4. The final cyclisation step pro-
ceeded in 73% yield and gave the product 22 as a crystalline
solid that was significantly more stable than 1a. The carbonyl
1194
J. Chem. Soc., Perkin Trans. 1, 1998

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Table 1 Observed and calculated geometries of the azetidinones 2b,
2a and 1b
A
N
a
c
b
B
θ
N
O
O
r
HO
Structure
2ba
2ab
1bb
C
HO
O
O
Pyramidality (Њ)
Torsion angle, θ (Њ)
Cohen distance, r (Å)
35.8
152.7
3.61
45.0
143.0
3.67
44.6
138.9
3.71
(a)
(b)
Fig. 2 (a) Pyramidality 360Њ Ϫ (a ϩ b ϩ c)Њ; Cohen distance (Å) = r;
(b) through space torsion angle between the ring plane ABN and
carbon atom C = θЊ
a Observed. b Calculated.
8
i
98%
iii
66%
N
CO2Et
CO2But
N
CO2Et
H
18
19
89%
i
ii
69%
N
H
CO2Et
20
iv 88%
Fig. 3 Molecular modelling (a) of the carboxylic acid 2a; (b) of the
phenol 1b; (c) superposition of the two structures
v
73%
N
N
CO2H
–OCOCF3
oxyanion hole and the serine hydroxy group. The degree of
β-lactam pyramidality is interpreted as increasing the reactivity
towards nucleophilic attack, by perturbation of β-lactam
amide resonance.
H2
O
22
21
Scheme 4 Reagents: i, TFA; ii, NaCNBH3, TFA; iii, H2, Rh/C; iv, aq.
KOH then TFA; v, 5, Et3N
After construction and geometry optimisation using the
molecular mechanics within SYBYL,13 molecules 1b and
2a were submitted for full geometry optimisation within
MOPAC14 using AM1 Hamiltonians. The minimum energy
conformations thus obtained were validated by comparison of
the optimised structure for 2a with the X-ray structure of the
carbapenem ester 2b, imported from the Cambridge Crystallo-
graphic Database (Table 1). The observed values for the
pyramidality and the Cohen distance (the distance between the
oxygen atom of the β-lactam and the carbon atom of the carb-
oxylate or phenolic oxygen functionality) all lie in the range
that is found in biologically active compounds.12 Indeed, the
fully optimised structures of 1b and 2a can be overlaid such that
the functional groups in the two compounds are essentially
superimposable (Fig. 3). This raised the possibility that the
hydroxy function in the benzocarbapenem 1b might mimic the
role of the carboxy function in the carbapenems. Although
β-lactams bearing phenolic hydroxy groups have been prepared
before,15 their structures have not been specifically matched to
those of biologically active compounds.
The Bartoli indole synthesis provides an attractive route to 7-
substituted indoles16 and 7-(benzhydryloxy)indole 23 has been
prepared in two steps from 2-nitrophenol by this route.17 This
preparation, in combination with the radical alkylation of
indole introduced by Baciocchi et al.,6 offered a short synthesis
of ethyl 7-(benzhydryloxy)indole-2-acetate 24, a suitably pro-
tected precursor to 1b.
The indole 23 was prepared by a slight modification of the
literature procedure in an overall yield of 38% from 2-
nitrophenol. Radical alkylation of indole by ethyl iodoacetate
as described by Baciocchi et al. is a synthetically valuable and
stretching frequency in the IR spectrum was at 1771 cmϪ1
,
almost the same as that of 1a.
It was perhaps no surprise that benzocarbapenems 1a, 16, 17
and 22 lacked any useful antibacterial and/or β-lactamase
inhibitory activity. It is generally believed that the presence of
an acidic functionality is essential for good antibacterial activ-
ity. The free carboxylate of β-lactam antibiotics anchors the
nuclei electrostatically by binding to an unstabilised lysine or
histidine residue in the basal cleft, while an oxyanion hole
locates and activates the β-lactam carbonyl oxygen atom by way
of two hydrogen bonds.11 These primary anchorages present the
carbonyl carbon atom to the active-site serine hydroxy group,
prior to acylation.
We therefore proposed to introduce an appropriate acidic
functionality into the C-7 position of the benzocarbapenem
ring system. Preliminary comparison of the three-dimensional
structure of the benzocarbapenem ring system with that of
the carbapenem carboxylic acid 2a identified the phenol deriv-
ative 1b as an appropriate candidate. Further encouragement
was provided by performing a more detailed conformational
analysis of 1b. Early work by Rao and Vasudevan and by
Cohen identified that the degree of β-lactam nitrogen
pyramidality and the position of the carboxylate group, par-
ticularly the Cohen distance, (Fig. 2) are pivotal features for
penicillin binding protein (PBP) inhibition.12 Cohen argued
that when the ‘Cohen’ distance is greater than 3.95 Å, the β-
lactam derivative is inactive, due to its inability to fit the cata-
lytic triad of active-site residues: the unstabilised lysine, the
J. Chem. Soc., Perkin Trans. 1, 1998
1195

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i
ii
iii
N
N
N
N
39%
CO2Et
CO2Et
CO2H
91%
74%
H
H
H
H
Ph
O
Ph
O
Ph
O
Ph
O
Ph
Ph
Ph
Ph
23
24
25
26
v
92%
iv 32%
CO2But
CO2Et
N
CO2But
N
H
Ph
O
O
Ph
O
Ph
Ph
27
28
Scheme 5 Reagents: i, ICH2CO2Et, FeSO4, DMSO, H2SO4, urea–H2O2; ii, NaCNBH3, AcOH; iii, aq. KOH then citric acid; iv, 5, Et3N;
v, (ButOCO)2O, DMAP
Table 2 Selected bond lengths and bond angles for 36a
unusual reaction since it provides a rare example of preferential
2-substitution. We explored the reaction of the indole 23 and
Bond lengths (Å)
Bond angles (Њ)
ethyl iodoacetate under a variety of conditions. The desired
alkylation product 24 was obtained in acceptable yield only
when the indole was used in three- or four-fold excess. The use
of urea–hydrogen peroxide complex in place of aqueous hydro-
gen peroxide resulted in a slight improvement in the yield
(Scheme 5). In our hands, the product was obtained in the
highest yield (39%) when the reaction was carried out on a
modest scale (5 mmol ethyl iodoacetate). The reaction mixture
was relatively clean, most of the remainder being the precursor
indole 23 which could be recovered by column chromatography
and recycled.
N1᎐C2
N1᎐C3
N1᎐C6
C1᎐C2
C1᎐C3
C6᎐C7
O1᎐C7
O2᎐C2
1.379(4)
C2᎐N1᎐C3
N1᎐C2᎐C1
C2᎐C1᎐C3
N1᎐C3᎐C1
N1᎐C6᎐C7
C11᎐C1᎐C12
O1᎐C7᎐C6
N1᎐C2᎐O2
93.1(2)
93.7(3)
85.1(2)
1.505(4)
1.426(4)
1.532(5)
1.567(5)
1.379(4)
1.369(4)
1.214(4)
87.6(2)
127.8(3)
111.8(3)
118.8(3)
131.6(3)
a Atom numbering corresponds to that in Fig. 4.
The indole 24 was reduced to the dihydroindole 25 (91%) by
sodium cyanoborohydride in acetic acid. This was hydrolysed
to the acid 26 under basic conditions and the cyclisation of the
acid gave the desired β-lactam 27 in 32% yield. IR and NMR
spectra of the product were consistent with the proposed struc-
ture but the product was not fully characterised because it was
extremely unstable. The analogous unsubstituted β-lactam 1a
was purified by vacuum sublimination but this technique failed
with compound 27.
Since methylation of the acetate side chain had produced
more stable compounds 16, 17 and 22 in the earlier series, the
same procedure was attempted with the 7-substituted indole
24. This required protection of the indole nitrogen atom of
the ester 24 before alkylation. Unfortunately it proved impos-
sible to introduce the Boc protecting group on to the nitrogen
atom. Instead a disubstituted compound, to which the
structure 28 has been assigned, was produced in high yield.
Evidently the bulky substituent at C-7 prevents the normal
substitution at nitrogen. Attempts to introduce other protect-
ing groups (TBDMS, SEM) were also unsuccessful, and this
approach was abandoned in favour of one based on the
intramolecular Wittig reaction for the construction of the
required indole.
The route is shown in Scheme 6. 2-Amino-3-methoxybenzyl
alcohol 29 was prepared in two steps from commercially avail-
able 3-methoxy-2-nitrobenzoic acid. This amine was then
converted into the indole ester 32 by way of the isolated inter-
mediates 30 and 31. The indole ester was reduced to the indol-
ine 33 by sodium cyanoborohydride in acetic acid. The ester
was hydrolysed to the acid 34 which was cyclised in good yield
to the azetidinone 35. This compound is a stable crystalline
solid. It was purified by column chromatography and fully char-
acterised. The final step, the cleavage of the methyl ether, was
achieved with boron tribromide to give the phenol 36 as a
Fig. 4 Structure of compound 36
crystalline solid. An X-ray crystal structure of the product was
obtained (Fig. 4). Selected bond lengths and bond angles are
listed in Table 2.‡
The carbonyl stretching absorption in the IR spectrum of the
Ϫ1 whereas that of the ether 35 is at 1774
phenol 36 is at 1735 cm
cmϪ1. This lowering of the frequency is also observed in other
azetidinones bearing an adjacent phenolic substituent.15 It can
‡ Full crystallographic details, excluding structure factor tables, have
been deposited at the Cambridge Crystallographic Data Centre
(CCDC). For details of the deposition scheme, see ‘Instructions for
Authors’, J. Chem. Soc., Perkin Trans. 1, available via the RSC Web
page (http://www.rsc.org/authors). Any request to the CCDC for this
material should quote the full literature citation and the reference
number 207/194.
1196
J. Chem. Soc., Perkin Trans. 1, 1998

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Microanalyses were performed in the University of Liverpool
OH
NH2
PPh3+ Br–
NH2
i
Microanalysis Laboratory. Melting points (mp) were deter-
mined on a Kofler block and are uncorrected. Flash chrom-
atography was carried out using Kieselgel 60 and water pump
vacuum. Thin layer chromatography (TLC) was carried out on
Merck 10 × 2 cm aluminium-backed plates with a 0.2 mm layer
of Kieselgel 60 F254. Light petroleum refers to the fraction bp
60–80 ЊC and ether refers to diethyl ether.
88%
O
O
29
30
ii
87%
2-Aminobenzyltriphenylphosphonium bromide5d
Triphenylphosphonium hydrogen bromide (37.48 g, 0.109 mol)
was added to a stirred and boiling solution of 2-aminobenzyl
alcohol (13.45 g, 0.109 mol) in acetonitrile (750 cm3). The reac-
tion mixture was heated under reflux for 7 h then allowed to
cool. The solid precipitate was filtered off and the filtrate was
reduced in volume to give a further crop; total 43.17 g (88%);
δH(200 MHz; CDCl3) 5.21 (2 H, d, J 12.2) and 7.26–7.76 (19 H,
m).
PPh3+ Br–
O
iii
58%
CO2Et
N
H
N
CO2Et
H
O
O
31
32
76%
iv
[2-(Ethoxycarbonylacetamido)benzyl]triphenylphosphonium
bromide5d
Ethyl malonyl chloride (7.43 g, 49 mmol) was added to a stirred
solution of 2-aminobenzyltriphenylphosphonium bromide
(22.1 g, 49.0 mmol) in dichloromethane (100 cm3). After 3 h the
solvent was distilled off and the residue was crystallised from
hot ethanol (20 cm3) to give the phosphonium bromide (19.64 g,
71%); νmax(Nujol)/cmϪ1 3481, 1765 and 1688; δH(200 MHz;
CDCl3) 1.24 (3 H, t, J 7.1), 3.49 (2 H, s), 4.14 (2 H, q, J 7.1),
5.52 (2 H, d, J 14.4), 7.24–7.77 (19 H, m) and 10.51 (1 H, br s,
NH).
v
99%
N
CO2H
N
CO2Et
H
H
O
O
33
34
72%
vi
Ethyl 1H-indole-2-acetate 35d
Freshly prepared potassium tert-butoxide (5.00 g) was slowly
added to a stirred suspension of the phosphonium bromide
(8.05 g, 14 mmol) in toluene (35 cm3) under reflux. After 15 min
the reaction mixture was filtered hot and the filtrate was evap-
orated to dryness. The residue was purified by flash chrom-
atography which gave (with dichloromethane) ethyl 1H-indole-
2-acetate 3 (2.07 g, 70%) as an oil; νmax(film)/cmϪ1 3395 and
1726; δH(200 MHz; CDCl3) 1.28 (3 H, t, J 7.1), 3.81 (2 H, s),
4.22 (2 H, q, J 7.1), 6.34 (1 H, s), 7.03–7.56 (5 H, m) and 8.67 (1
H, br s).
vii
62%
N
N
OH
O
O
O
36
35
Scheme 6 Reagents: i, PPh3ؒHBr; ii, EtO2CCMe2COCl; iii, KOBut; iv,
NaCNBH3, AcOH; v, aq. KOH then citric acid; vi, 5, Et3N; vii, BBr3
be ascribed to intramolecular hydrogen bonding, although the
X-ray structure of compound 36 shows no evidence for either
intramolecular or intermolecular hydrogen bonding in the
crystal.
Ethyl 2,3-dihydro-1H-indole-2-acetate 4a
To an ice-cooled solution of ethyl 1H-indole-2-acetate 3 (1.12 g,
5.5 mmol) in TFA (10 cm3) was added trimethylamine–borane
complex (3.00 g) in small amounts during 5 min. The mixture
was stirred for a further 15 min then aq. sodium hydrogen
carbonate (8 g in 50 cm3 water) was added. The aqueous layer
was washed with toluene. The toluene extract was washed with
saturated aqueous sodium chloride and dried over Na2SO4. The
solvent was distilled off and the residue was subjected to flash
chromatography, which gave [with light petroleum–ethyl acetate
(19:1)] ethyl 2,3-dihydro-1H-indole-2-acetate 4a (0.93 g, 82%)
(Found: C, 70.2; H, 7.4; N, 6.85. C12H15NO2 requires C, 70.2; H,
7.4; N, 6.8%); νmax(film)/cmϪ1 3374 and 1729; δH(200 MHz;
CDCl3) 1.28 (3 H, t, J 7.1), 2.62 (2 H, d, J 6.6, CH2CO2Et), 2.69
(1 H, dd, J 8.2 and 15.4, 3-H), 3.18 (1 H, dd, J 8.2 and 15.4,
3-H), 4.17 (2 H, q, J 7.1), 4.12–4.30 (1 H, m, 2-H), 6.59–6.73
(2 H, m) and 6.98–7.33 (2 H, m); m/z 205 (Mϩ, 17%) and 118
(100).
In summary, routes to several azeto[1,2-a]indol-2(1H)-ones
have been devised. Those derivatives lacking substitution at the
C-1 position in the benzocarbapenem ring system are isolable
but very unstable. Chemical stability is significantly increased
by the presence of one or two methyl substituents at this pos-
ition. These compounds, as well as the 7-hydroxy derivative 36,
are devoid of any useful biological activity. Introduction of an
(R)-hydroxyethyl substituent at the C-1 position (as in thien-
amycin) may improve the possibility of achieving antibacterial
activity in this novel series of tricyclic β-lactam derivatives and
will be the focus of future chemistry.
Experimental
General
1H NMR spectra were recorded on Bruker AC 200 (200 MHz),
Varian Gemini 2000 (300 MHz) and Bruker AMX (400 MHz)
spectrometers. Multiplicities are recorded as broad peaks (br),
singlets (s), doublets (d), triplets (t), quartets (q) and multiplets
(m). J Values are in Hz. Infrared spectra were recorded either
on a Perkin-Elmer 298 or on a Perkin-Elmer 1720-X FTIR
spectrometer. Solid samples were run as Nujol mulls, and
liquids as thin films. Mass spectra were recorded on a VG
Micromass 7070E machine as electron impact spectra (70 eV).
2,3-Dihydro-1H-indole-2-acetic acid 4b
Method A. To a stirred solution of the ester 4a (0.422 g, 2
mmol) in dioxan (4 cm3) was added potassium hydroxide (0.4 g)
followed by water (1 cm3). The progress of the reaction was
followed by TLC until no starting material remained. The sol-
vent was removed and the residue was acidified by the addition
of 10% aq. citric acid (20 cm3). The solution was extracted with
dichloromethane (3 × 30 cm3) and ether (2 × 30 cm3), then
J. Chem. Soc., Perkin Trans. 1, 1998
1197

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dried over MgSO4. The solvent was removed in vacuo to give the
acid 4b as an oil; δH(200 MHz; CDCl3) 2.72 (2 H, d, J 6.6,
CH2CO2Et), 2.73 (1 H, dd, J 8.8 and 15.4, 3-H), 3.21 (1 H, dd,
J 8.8 and 15.4, 3-H), 4.16–4.31 (1 H, m, 2-H), 6.23 (1 H, br s,
NH), 6.65–6.79 (2 H, m) and 7.01–7.25 (2 H, m); m/z 177 (Mϩ,
13%), 130 (24), 118 (100) and 117 (38).
Method B. A solution of the ester 4a (1.15 g, 5.6 mmol) in
concentrated hydrochloric acid (30 cm3) was stirred for 1 h at
room temperature (RT). The solution was diluted with water
(20 cm3) and was stirred for a further 24 h. The solution was
evaporated to dryness and the solid residue was crystallised to
give the hydrochloride of compound 4b (0.72 g, 60%), mp
139 ЊC (from ethanol–light petroleum) (Found: C, 56.1; H, 5.7;
N, 6.5. C10H12ClNO2 requires C, 56.2; H, 5.7; N, 6.6%);
νmax(Nujol)/cmϪ1 2919 and 1714; δH(200 MHz; D2O) 3.03 (2 H,
d, J 8.8, CH2CO2Et), 3.06 (1 H, dd, J 8.2 and 16.5, 3-H), 3.48
(1 H, dd, J 8.2 and 16.5, 3-H), 4.50–4.57 (1 H, m, 2-H) and
7.36–7.44 (4 H, m); m/z 177 (Mϩ, 26%) and 118 (100).
(0.45 g, 1.4 mmol) in dichloromethane (4 cm3) at RT. After 3 h
the solution was poured into saturated aq. sodium hydrogen
carbonate (30 cm3). The mixture was extracted with dichloro-
methane (2 × 20 cm3) and the extracts were combined, dried
(MgSO4) and evaporated under reduced pressure. The residue
was purified by flash chromatography (dichloromethane) to
give the ester 9 (0.27 g, 88%) as an oil; δH(200 MHz; CDCl3)
1.27 (3 H, t, J 7.1), 1.60 (3 H, d, J 7.1), 3.93 (1 H, q, J 7.1), 4.19
(2 H, q, J 7.1), 6.35–6.37 (1 H, m, 3-H), 7.03–7.19 (1 H, m),
7.31–7.36 (1 H, m), 7.53–7.57 (1 H, m) and 8.56 (1 H, br s, NH).
Ethyl 2-(2,3-dihydro-1H-indol-2-yl)propanoates 10 and 11
(i) By route A. Sodium cyanoborohydride (0.55 g) was added
slowly in small portions to TFA (10 cm3) at 0 ЊC under N2.
After 15 min the ester 9 (0.35 g, 1.6 mmol) was added slowly.
The mixture was allowed to warm to RT and, after 1 h, add-
itional sodium cyanoborohydride (0.60 g) was added in por-
tions. The mixture was stirred for a further 1 h before water (30
cm3) was added. The resulting reaction mixture was added to
saturated aq. sodium hydrogen carbonate and the mixture was
extracted with dichloromethane (3 × 25 cm3). The organic
product was subjected to flash chromatography [dichloro-
methane–hexane (1:1)] to give the esters 10 and 11 (0.28 g,
79%) as an oil (Found: C, 71.5; H, 7.9; N, 6.5. C18H25NO4
requires C, 71.2; H, 7.8; N, 6.4%); νmax(film)/cmϪ1 3373 and
1724; δH(200 MHz; CDCl3) 1.22 (d, J 7.1, CHCH3 of 11), 1.23
(d, J 7.1, CHCH3 of 10), 1.26 (t, J 7.1, CH2CH3 of 10), 1.28 (t,
J 7.1, CH2CH3 of 11) (these four signals together, 6 H; ratio
10:11 = 1:1), 2.54–2.88 (2 H, m, 3-H and CHCH3), 3.14 (1 H,
dd, J 8.6 and 14.8, 3-H of both isomers), 3.95–4.11 (1 H, m,
2-H), 4.08–4.23 (2 H, m, CH2CH3), 6.57–6.71 (2 H, m) and
6.96–7.10 (2 H, m); m/z 233 (Mϩ, 6%) and 118 (100).
8,8a-Dihydroazeto[1,2-a]indol-2(1H)-one 1a
To a stirred suspension of the hydrochloride of 4b (0.21 g, 1.0
mmol) in dry acetonitrile (100 cm3) was added tris(2-oxo-
benzoxazolin-3-yl)phosphine oxide 5 (0.45 g, 1.0 mmol) and
dry triethylamine (0.41 g, 4.0 mmol). The reaction mixture was
heated under reflux for 6 h. The solvent was removed under
reduced pressure and the crude product was subjected to flash
chromatography (dichloromethane) and sublimation (70 ЊC
and 0.2 mmHg) to give 8,8a-dihydroazeto[1,2-a]indol-2(1H)-
one 1a (0.06 g, 37%), mp 77 ЊC (Found: C, 75.3; H, 5.7; N, 8.7.
C10H9NO requires C, 75.45; H, 5.7; N, 8.8%); νmax(Nujol)/cmϪ1
1773, 1645 and 1600; δH(200 MHz; CDCl3) 2.98 (1 H, dd, J 3.3
and 16.5, 1-H), 3.15 (1 H, dd, J 7.8 and 16.8, 8-H), 3.37 (1 H,
dd, J 8.8 and 16.8, 8-H), 3.53 (1 H, dd, J 5.2 and 16.5, 1-H),
4.32–4.44 (1 H, m, 8a-H) and 7.03–7.25 (4 H, m); m/z 159 (Mϩ,
33%) and 117 (100, Mϩ Ϫ CH2CO).
(ii) By route B. TFA (7 cm3) was added to a stirred solution of
the mixture of esters 12 and 13 (0.38 g, 1.2 mmol) in dichloro-
methane (4 cm3) at room temperature. After 3 h, the products
were poured into saturated aqueous sodium hydrogen carb-
onate (50 cm3). The organic products were extracted with
dichloromethane (3 × 40 cm3), and the extracts were combined,
dried (MgSO4) and evaporated under reduced pressure. Flash
chromatography gave (with dichloromethane) a mixture of the
esters 10 and 11 (0.23 g, 88%) as an oil νmax(film)/cmϪ1 3373 and
1724. The NMR spectrum showed the same signals as those in
the spectrum of the product from method (i) but in the ratio
10:11 = 5:1.
Ethyl 1-tert-butoxycarbonyl-1H-indole-2-acetate 6
To a stirred solution of ethyl 1H-indole-2-acetate 3 (0.51 g, 2.5
mmol) in dry dichloromethane (40 cm3) was added 4-dimethyl-
aminopyridine (0.31 g, 2.5 mmol) followed by di-tert-butyl
dicarbonate (0.82 g, 3.8 mmol). The solution was stirred at
room temperature for 3 h. Evaporation of the solvent followed
by flash chromatography [dichloromethane–hexane (1:1)] gave
the ester 6 as an oil (0.76 g, 100%) (Found: C, 67.7; H, 7.0; N,
4.6. C17H21NO4 requires C, 67.3; H, 7.0; N, 4.6%); νmax(film)/
cmϪ1 1734; δH(200 MHz; CDCl3) 1.25 (3 H, t, J 7.1), 1.66 (9 H,
s), 4.03 (2 H, s), 4.18 (2 H, q, J 7.1), 6.47 (1 H, s, 3-H), 7.19–7.28
(2 H, m), 7.47–7.52 (1 H, m) and 8.08 (1 H, d, J 8.8); m/z 303
(Mϩ, 16%) and 130 (100).
Ethyl 2-(1-tert-butoxycarbonyl-2,3-dihydro-1H-indol-2-yl)-
propanoates 12 and 13
The ester 7 (0.17 g, 0.5 mmol) in ethanol (4 cm3) and acetic
acid (0.5 cm3) was hydrogenated at 200 psi over rhodium
(5% on alumina, 300 mg). Flash chromatography gave (with
dichloromethane) a mixture of the esters 12 and 13 (0.15 g,
88%) as an oil (Found: C, 67.4; H, 7.9; N, 4.35. C18H25NO4
requires C, 67.7; H, 7.9; N, 4.4%); δH(200 MHz; CDCl3) 0.95 (3
H, t, J 7.2), 1.16 (3 H, d, J 7.2), 1.61 (9 H, s), 2.99 (1 H, dd, J 2.2
and 16.5, 3-H), 3.24 (1 H, dd, J 9.4 and 16.5, 3-H), 3.80 (2 H, q,
J 7.2), 3.59–4.19 (2 H, m), 6.86–6.94 (2 H, m), 7.08–7.16 (2 H,
m); m/z 319 (Mϩ, 2%), 219 (11) and 118 (100).
Ethyl 2-(1-tert-butoxycarbonyl-1H-indol-2-yl)propanoate 7
To a solution of the ester 6 (0.53 g, 1.7 mmol) in dry THF (5
cm3) at Ϫ78 ЊC was added slowly dropwise KHMDS (3.4 cm3,
0.5  in toluene, 1.7 mmol). After 1 h iodomethane (0.30 g, 2
mmol) was added dropwise. The reaction mixture was stirred
for 30 min then allowed to warm to RT. Saturated aq. ammon-
ium chloride was added and the organic components were
extracted with ether (3 × 30 cm3). The ether extracts were
washed with water (3 × 30 cm3) and brine (30 cm3) and dried
over MgSO4. The solvent was removed and the crude residue
was subjected to flash chromatography [dichloromethane–
hexane (1:1)] to give the ester 7 (0.51 g, 92%) as an oil (Found:
C, 68.3; H, 7.3; N, 4.4. C18H23NO4 requires C, 68.1; H, 7.3; N,
4.4%); νmax(film)/cmϪ1 3052, 1734 and 1453; δH(200 MHz;
CDCl3) 1.07 (3 H, t, J 7.1), 1.50 (3 H, d, J 7.1), 1.51 (9 H, s),
4.00 (2 H, q, J 7.1), 4.27 (1 H, q, J 7.1), 6.38 (1 H, s, 3-H), 6.99–
7.14 (2 H, m), 7.34 (1 H, dd, J 2.2 and 6.0) and 7.89 (1 H, dd,
J 2.2 and 7.1); m/z 317 (Mϩ, 7%) and 57 (100).
2-(2,3-Dihydro-1H-indolium-2-yl)propanoic acid
trifluoroacetates 14 and 15
(i) By route A. Potassium hydroxide (150 mg) dissolved in the
minimum amount of water was slowly added to a stirred sol-
ution of the 1:1 mixture of esters 10 and 11 (80 mg) in ethanol
(2 cm3). The reaction vessel was flushed with nitrogen and the
solution was stirred until the starting material could no longer
be detected by TLC. The ethanol was distilled off and the
remaining aqueous solution was extracted with ethyl acetate
(3 × 25 cm3). The extracts were combined, dried over MgSO4
and concentrated. The residue was then dissolved in TFA and
the excess TFA was removed by rotary evaporation to leave the
Ethyl 2-(1H-indol-2-yl)propanoate 918
TFA (0.5 cm3) was added to a stirred solution of the ester 8
1198
J. Chem. Soc., Perkin Trans. 1, 1998

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trifluoroacetates 14 and 15 (90 mg, 81%) as a solid; νmax(Nujol)/
cmϪ1 2950 and 1719; δH(200 MHz; TFA–C6D6) 1.24 and 1.27
(together 3 H, each d, J 7.1, CHCH3), 2.98–3.14 (2 H, m,
CHCH3 and 3-H), 3.40 (1 H, dd, J 8.8 and 16.5, 3-H), 4.20–4.43
(1 H, m, 2-H) and 7.30–7.40 (4 H, m); m/z 191 (Mϩ, 9%) and
118 (100).
(3 H, t, J 7.1), 1.66 (6 H, s), 4.17 (2 H, q, J 7.1), 6.31–6.35 (1 H,
m), 7.03–7.19 (2 H, m), 7.32–7.36 (1 H, m), 7.53–7.57 (1 H, m)
and 8.57 (1 H, br s); m/z 231 (Mϩ, 17%) and 158 (100).
Ethyl 2-(1-tert-butoxycarbonyl-2,3-dihydro-1H-indol-2-yl)-2-
methylpropanoate 19
(ii) By route B. Potassium hydroxide (180 mg) dissolved in the
minimum amount of water was added to a stirred solution of
the esters 10 and 11 (140 mg) in ethanol (2 cm3). The reaction
vessel was flushed with nitrogen and the solution was stirred
until the starting material could no longer be detected by TLC.
The ethanol was removed in vacuo and the remaining aqueous
solution was extracted with ethyl acetate (3 × 25 cm3). The
extracts were combined, dried over MgSO4 and concentrated.
The residue was then dissolved in TFA and the excess TFA was
removed by rotary evaporation to give the trifluoroacetate salts
14 and 15 (180 mg, 92%) as a solid.
The ester 8 (0.09 g, 0.3 mmol) was hydrogenated by the same
procedure as described for the preparation of the indolines 12
and 13. The ester 19 was isolated (0.06 g, 66%) as an oil (Found:
Mϩ, 333.194. C19H27NO4 requires M, 333.194); νmax(film)/cmϪ1
2977, 1704 and 1603; δH(200 MHz; CDCl3) 0.96 (3 H, s), 1.18
(3 H, t, J 7.1), 1.25 (3 H, s), 1.56 (9 H, s), 2.72 (1 H, dd, J 1.7
and 16.5, 3-H), 3.33 (1 H, dd, J 9.4 and 16.5, 3-H), 3.89–4.10 (2
H, m), 4.85 (1 H, dd, J 1.7 and 9.4, 2-H), 6.93–6.98 (1 H, m),
7.07–7.14 (2 H, m) and 7.50–7.56 (1 H, br m); m/z 333 (Mϩ, 3%)
and 118 (100).
Ethyl 2-(2,3-dihydro-1H-indol-2-yl)-2-methylpropanoate 20
(i) From the ester 18. Sodium cyanoborohydride (0.30 g) was
added slowly and in small portions to TFA (10 cm3) at 0 ЊC
under N2. After 15 min the ester 18 (0.20 g, 0.9 mmol) was
added slowly. The mixture was allowed to warm to RT and,
after 1 h, additional sodium cyanoborohydride (0.30 g) was
added in portions. The mixture was stirred for a further 1 h
before water (30 cm3) was added. The product was extracted
and purified as described for compound 9. Flash chrom-
atography gave the ester 20 (0.14 g, 69%) as an oil (Found: C,
72.1; H, 8.2; N, 6.0. C14H19NO2 requires C, 72.1; H, 8.2; N,
6.0%); νmax(Nujol)/cmϪ1 3374 and 1719; δH(200 MHz; CDCl3)
1.18 (3 H, s), 1.22 (3 H, s), 1.26 (3 H, t, J 7.1), 2.84 (1 H, dd,
J 9.3 and 15.9, 3-H), 3.02 (1 H, dd, J 9.4 and 15.9, 3-H), 4.14
(2 H, q, J 7.1), 4.18 (1 H, t, J 9.4, 2-H), 6.55–6.69 (2 H, m) and
6.96–7.07 (2 H, m); m/z 233 (Mϩ, 6%) and 118 (100).
8,8a-Dihydro-1-methylazeto[1,2-a]indol-2(1H)-ones 16 and 17
(i) By route A. Tris(2-oxobenzoxazol-3-yl)phosphine oxide 5
(0.27 g, 0.6 mmol) and dry triethylamine (0.25 g, 2.4 mmol)
were added to a stirred suspension of the TFA salt (0.19 g, 0.6
mmol) in dry acetonitrile (100 cm3). The reaction mixture was
heated under reflux for 6 h. The solvent was removed under
reduced pressure and the crude product was subjected to flash
chromatography (dichloromethane) and sublimation (70 ЊC, 0.2
mmHg) to give 8,8a-dihydro-1-methylazeto[1,2-a]indol-2(1H)-
ones 16 and 17 (60 mg, 56%), mp 35–40 ЊC (Found: C, 76.0; H,
6.4; N, 8.05%; Mϩ, 173.084. C11H11NO requires C, 76.3; H, 6.4;
N, 8.1%; M, 173.084); νmax(Nujol)/cmϪ1 1778 and 1601; δH(200
MHz; CDCl3) (ratio 16:17 = 1:1) 1.26 (d, J 7.7, 1-Me of 16),
1.51 (d, J 7.7, 1-Me of 17), 3.02–3.26 (m, 2 × 8-H of 16 and 8-H
of 17), 3.17 (dq, J 2.8 and 7.7, 1-H of 17), 3.34 (dd, J 9.3 and
16.8, 8-H of 17), 3.70 (dq, J 5.5 and 7.7, 1-H of 16), 4.03 (ddd,
J 2.8, 7.7 and 9.3, 8a-H of 17), 4.46 (ddd, J 5.5, 8.2 and 9.4,
8a-H of 16) and 7.01–7.25 (m, Ar-H); m/z 173 (Mϩ, 21%), 130
(20) and 117 (100, Mϩ Ϫ MeCHCO).
(ii) From the ester 19. TFA (2 cm3) was added to a stirred
solution of the ester 19 (1.22 g, 3.7 mmol) in dichloromethane
(5 cm3) at RT. After 3 h, the products were poured into satur-
ated aq. sodium hydrogen carbonate (50 cm3). Extraction
(dichloromethane) followed by flash chromatography gave the
ester 20 (0.76 g, 89%) as an oil.
(ii) By route B. The salts 14 and 15 (0.28 g, 0.9 mmol) were
cyclised as in (a) to give the azetidinones 16 and 17 (100 mg,
63%), mp 40–68 ЊC (Found: C, 76.1; H, 6.4; N, 8.05.
C11H11NO requires C, 76.3; H, 6.4; N, 8.1%); the NMR spec-
trum showed the same signals as those in (a) in the ratio
16:17 = 5:1.
2-(2,3-Dihydro-1H-indolium-2-yl)-2-methylpropanoic acid
trifluoroacetate 21
A solution of potassium hydroxide (250 mg) in the minimum
amount of water was added to a stirred solution of the ester 20
(200 mg) in ethanol (2 cm3). After the starting ester had been
consumed (TLC) the ethanol was distilled off and the remain-
ing aqueous solution was extracted with ethyl acetate (3 × 25
cm3). The extracts were combined, dried and evaporated to
dryness. The residue was dissolved in TFA and the excess TFA
was removed by rotary evaporation to give the trifluoroacetate
21 (0.24 g, 88%) as a solid; νmax(Nujol)/cmϪ1 2924 and 1724;
δH(200 MHz; TFA–C6D6) 2.05 (3 H, s), 2.18 (3 H, s), 3.81 (1 H,
dd, J 9.4 and 15.9, 3-H), 4.00–4.12 (1 H, dd, J 8.2 and 16.5,
3-H), 4.88–5.02 (1 H, m, 2-H) and 7.97–8.07 (4 H, m); m/z 205
(Mϩ, 6%) and 118 (100).
Ethyl 2-(1-tert-butoxycarbonyl-1H-indol-2-yl)-2-methyl-
propanoate 8
KHMDS (0.5  in toluene, 7.20 cm3, 3.6 mmol) was added at
Ϫ78 ЊC to a solution of the ester 6 (0.74 g, 2.4 mmol) in dry
THF (10 cm3). After 30 min iodomethane (0.57 g, 4.0 mmol) in
THF (5 cm3) was added. The reaction mixture was allowed to
warm to RT then, after 30 min, it was again cooled to Ϫ78 ЊC.
KHMDS (9.00 cm3, 4.5 mmol) was added then, after 30 min,
iodomethane (0.85 g, 6 mmol) in THF (5 cm3). The reaction
mixture was quenched and the product was extracted as
described for the ester 7. Flash chromatography gave [with
dichloromethane–hexane (1:1)] the ester 8 (0.67 g, 83%) as
colourless crystals mp 92 ЊC (Found: C, 68.8; H, 7.6; N, 4.2.
C19H25NO4 requires C, 68.9; H, 7.6; N, 4.2%); νmax(Nujol)/cmϪ1
1735; δH(200 MHz; CDCl3) 1.60 (3 H, t, J 7.1), 1.68 (15 H, s, But
and CMe2), 4.10 (2 H, q, J 7.1), 6.59 (1 H, s, 3-H), 7.20–7.28
(2 H, m), 7.48–7.53 (1 H, m) and 7.98 (1 H, d, J 7.2); m/z 331
(Mϩ, 6%), 231 (29) and 158 (100).
8,8a-Dihydro-1,1-dimethylazeto[1,2-a]indol-2(1H)-one 22
The phosphine oxide 5 (0.41 g, 0.9 mmol) and dry triethylamine
(0.32 g, 3.7 mmol) were added to a stirred suspension of the salt
21 (0.28 g, 0.9 mmol) in dry acetonitrile (100 cm3). The reaction
mixture was heated under reflux for 6 h. The solvent was
removed under reduced pressure and the crude product was
subjected to flash chromatography (dichloromethane) and sub-
limation (70 ЊC, 0.2 mmHg) to give the azetidinone 22 (0.12 g,
73%), mp 82–83 ЊC (Found: C, 77.1; H, 7.0; N, 7.5. C12H13NO
requires C, 77.0; H, 7.0; N, 7.5%); νmax(Nujol)/cmϪ1 1771, 1600
and 1585; δH(400 MHz; CDCl3) 1.23 (3 H, s), 1.51 (3 H, s), 3.11
(1 H, dd, J 9.5 and 17.0, 8-H), 3.20 (1 H, dd, J 7.9 and 17.0,
8-H), 4.15 (1 H, dd, J 7.9 and 9.5, 8a-H), 7.03–7.07 (1 H, m) and
Ethyl 2-(1H-indol-2-yl)-2-methylpropanoate 18
TFA (1.5 cm3) was added to a stirred solution of the ester 8
(1.88 g, 5.7 mmol) in dichloromethane (5 cm3) at room temper-
ature. Extraction of the product and flash chromatography gave
the ester 18 (1.29 g, 98%), mp 111–114 ЊC (Found: C, 72.5; H,
7.5; N, 6.0. C14H17NO2 requires C, 72.7; H, 7.4; N, 6.1%);
νmax(Nujol)/cmϪ1 3359 and 1696; δH(200 MHz; CDCl3) 1.25
J. Chem. Soc., Perkin Trans. 1, 1998
1199

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7.16–7.23 (3 H, m); δC(100 MHz, CDCl3) 16.11 (1-Me), 23.46
(1-Me), 30.56 (8-C), 53.66 (1-C), 63.61 (8a-C), 116.73 (4-C),
124.90 (Ar-C), 125.56 (Ar-C), 127.61 (Ar-C), 136.93 (7a-C),
141.93 (3a-C) and 161.01 (2-C); m/z 187 (Mϩ, 59%), 144 (100),
118 (87) and 70 (71).
J 9.3 and 15.4, 3-H), 4.11–4.29 (1 H, m, 2-H), 6.42 (1 H, m),
6.64–6.70 (2 H, m), 7.21–7.37 (7 H, m) and 7.51–7.61 (4 H, m);
m/z 359 (Mϩ, 1%) and 167 (100).
4-Benzhydryloxy-8,8a-dihydroazeto[1,2-a]indol-2(1H)-one 27
The acid 26 (0.23 g, 0.64 mmol) was cyclised by the method
described for the preparation of the azetidinone 1a. Flash
chromatography gave [with dichloromethane–hexane (1:1)] the
azetidinone 27 (70 mg, 32%) as an amorphous solid that was
not fully characterised; νmax(Nujol)/cmϪ1 1773, 1610 and 1582;
δH(200 MHz; CDCl3) 2.99 (1 H, dd, J 2.7 and 16.5, endo 1-H),
3.13 (1 H, dd, J 8.2 and 16.5, 8-H), 3.30 (1 H, dd, J 8.8 and 16.5,
8-H), 3.54 (1 H, dd, J 5.5 and 16.5, exo 1-H), 4.31–4.44 (1 H, m,
8a-H), 6.38 (1 H, m) and 7.16–7.44 (13 H, m); m/z 341 (Mϩ,
0.3%), 167 (100, Ph2CHϩ) and 165 (24).
7-(Benzhydryloxy)-1H-indole 2317
2-(Benzhydryloxy)nitrobenzene was prepared (87%) from
2-nitrophenol and benzhydryl bromide with potassium car-
bonate in DMF, mp 97 ЊC (from dichloromethane–hexane);
νmax(Nujol)/cmϪ1 1604; δH(200 MHz; CDCl3) 6.36 (1 H, s), 6.96
(1 H, t, J 7.7, 3-H), 7.03 (1 H, d, J 8.2, 6-H), 7.20–7.40 (7 H, m),
7.47 (4 H, dd, J 1.7 and 8.2) and 7.83 (1 H, dd, J 1.6 and 8.2);
m/z 305 (Mϩ, 3%) and 167 (100). Vinylmagnesium bromide
(70 cm3, 1  in THF, 70 mmol) was added portionwise at
Ϫ40 ЊC to a stirred solution of 2-(benzhydryloxy)nitrobenzene
(6.10 g, 20 mmol) in dry THF (100 cm3) under N2. After 1 h the
reaction mixture was quenched with saturated aq. ammonium
chloride. Extraction and flash chromatography gave [with
dichloromethane–hexane (1:1)] the indole 23 (2.62 g, 44%), mp
110–112 ЊC (from cyclohexane) (lit.,17 110–112 ЊC); νmax(Nujol)/
cmϪ1 3436 and 3030; δH(200 MHz; CDCl3) 6.33 (1 H, s), 6.47 (1
H, dd, J 2.5 and 3.3, 3-H), 6.53 (1 H, d, J 7.7, 6-H), 6.85 (1 H, t,
J 7.8, 5-H), 7.00 (1 H, t, J 2.7, 2-H), 7.10–7.49 (11 H, m) and
8.32 (1 H, br s, NH); m/z 299 (Mϩ, 16%) and 167 (100).
tert-Butyl ethyl 2-(7-benzhydryloxy-3-tert-butoxycarbonyl-2,3-
dihydro-1H-indol-2-ylidene)malonate 28
DMAP (0.16 g, 1.3 mmol) and di-tert-butyl dicarbonate (0.48
g, 2.2 mmol) were added to a stirred solution of the ester 24
(0.43 g, 1.1 mmol) in dichloromethane (10 cm3). After 12 h the
solvent was removed and the residue was subjected to flash
chromatography which gave (with dichloromethane) the ester
28 (0.59 g, 92%), mp 106 ЊC (Found: C, 71.55; H, 6.75; N,
2.4%; Mϩ, 585.273. C35H39NO7 requires C, 71.8; H, 6.7; N,
2.4%; M, 585.273); νmax(film)/cmϪ1 3431, 1741 and 1685; δH(200
MHz; CDCl3) 1.28 (3 H, t, J 7.1), 1.47 (9 H, s), 1.63 (9 H, s),
4.15–4.35 (2 H, m), 6.11 (1 H, s), 6.38 (1 H, s), 6.62 (1 H, d,
J 7.7), 6.98 (1 H, dd, J 7.7 and 8.2), 7.25–7.46 (10 H, m), 7.65
(1 H, d, J 8.2) and 9.71 (1 H, br s, NH); m/z 585 (Mϩ, 0.2%), 484
(0.4) and 167 (100).
Ethyl 7-(benzhydryloxy)-1H-indole-2-acetate 24
7-(Benzhydryloxy)-1H-indole (5.98 g, 20 mmol), ethyl iodo-
acetate (1.07 g, 5 mmol) and iron() sulfate heptahydrate (1.30
g, 4.5 mmol) were dissolved in DMSO (50 cm3) with water
(1 cm3) and concentrated H2SO4 (1 cm3) and the solution was
stirred at RT. Urea–hydrogen peroxide (6.00 g) was added in
portions over 2 h. The reaction mixture was diluted with brine
(60 cm3) then extracted with ether (3 × 50 cm3). Flash chrom-
atography gave [with dichloromethane–hexane(1:1)] the ester
24 (0.76 g, 39%), mp 108 ЊC (Found: C, 77.8; H, 6.1; N, 3.5.
C25H23NO3 requires C, 77.9; H, 6.0; N, 3.6%); νmax(Nujol)/cmϪ1
3307 and 1711; δH(250 MHz; CDCl3) 1.29 (3 H, t, J 7.2), 3.82
(2 H, s), 4.21 (2 H, q, J 7.2), 6.85 (1 H, t, J 7.8, 5-H), 7.00 (1 H,
t, J 2.7, 3-H), 7.10–7.49 (11 H, m) and 8.32 (1 H, br s, NH); m/z
385 (Mϩ, 9%) and 167 (100).
2-Amino-3-methoxybenzyl alcohol 29
2-Amino-3-methoxybenzoic acid19 (10.70 g, 64 mmol) was
placed in the thimble of a Soxhlet extractor. Lithium alum-
inium hydride (10 g) in dry ether (500 cm3) was placed in the
attached reaction flask and the ether was heated under reflux
until all the acid had been consumed. The excess of lithium
aluminium hydride was decomposed by careful addition of
water. To the reaction mixture was added 10% sodium hydrox-
ide solution (250 cm3). The ether layer was separated off and
the aqueous layer was extracted with ether (2 × 100 cm3). The
ether extracts were combined, dried over MgSO4 and concen-
trated under reduced pressure to give the alcohol 29 (8.69 g,
89%) as an oil (Found: Mϩ, 153.079. C8H11NO2 requires M,
153.079); νmax(film)/cmϪ1 3372 and 1618; δH(200 MHz; CDCl3)
3.85 (3 H, s), 4.66 (2 H, s) and 6.63–6.81 (3 H, m); m/z 153 (Mϩ,
59%) and 122 (100).
Ethyl 7-benzhydryloxy-2,3-dihydro-1H-indole-2-acetate 25
Sodium cyanoborohydride (1.00 g) was added in one portion to
a stirred solution of ethyl 7-(benzhydryloxy)-1H-indole-2-
acetate 24 (0.57 g, 1.5 mmol) in acetic acid (5 cm3) at 15–17 ЊC
under N2. Water (15 cm3) was added and the reaction mixture
was neutralised with saturated aq. sodium hydrogen carbonate.
Extraction with ether and flash chromatography gave (with
dichloromethane) the ester 25 (0.52 g, 91%), mp 86–87 ЊC
(Found: C, 77.8; H, 6.6; N, 3.45. C25H25NO3 requires C, 77.5; H,
6.5; N, 3.6%); νmax(Nujol)/cmϪ1 3362 and 1721; δH(200 MHz;
CDCl3) 1.26 (3 H, t, J 7.1), 2.65 (2 H, d, J 7.7), 2.73 (1 H, dd,
J 8.2 and 15.9, 3-H), 3.21 (1 H, dd, J 8.2 and 15.9, 3-H), 4.16 (2
H, q), 4.11–4.31 (1 H, m, 2-H), 6.17 (1 H, m), 6.48–6.72 (3 H,
m) and 7.25–7.44 (10 H, m); m/z 387 (Mϩ, 5%), 300 (5), 220 (24)
and 167 (100).
(2-Amino-3-methoxybenzyl)triphenylphosphonium bromide 30
To a stirred and boiling solution of 2-amino-3-methoxybenzyl
alcohol 29 (8.69 g, 57 mmol) in acetonitrile (500 cm3) was added
triphenylphosphonium hydrogen bromide (19.50 g, 57 mmol).
The reaction mixture was heated under reflux for 7 h then
allowed to cool. The solvent was removed to leave the crude
phosphonium salt 30 (23.89 g, 88%) as a solid; νmax(Nujol)/cmϪ1
3441, 3306 and 1627; δH(200 MHz; CDCl3) 3.77 (3 H, s), 5.35
(2 H, d, J 13.7), 6.13–6.18 (1 H, m), 6.41 (1 H, t, J 8.0), 6.64–
6.72 (1 H, m) and 7.55–7.78 (15 H, m).
7-Benzhydryloxy-2,3-dihydro-1H-indole-2-acetic acid 26
Potassium hydroxide (0.54 g, 10 mmol) in water (1 cm3) was
added to a solution of ethyl 7-benzhydryloxy-2,3-dihydro-1H-
indole-2-acetate 25 (0.48 g, 1.2 mmol) in ethanol (3 cm3). The
reaction mixture was stirred at RT for 12 h and evaporated to
dryness. The residue was taken up in water (20 cm3) and washed
with ethyl acetate (20 cm3). The aqueous layer was cooled in an
ice bath and acidified with 10% aq. citric acid. Extraction with
ethyl acetate (3 × 25 cm3) gave the acid 26 (0.33 g, 74%) as an
oil (Found: Mϩ, 359.152. C23H21NO3 requires M, 359.152);
νmax(Nujol)/cmϪ1 3381 and 1701; δH[200 MHz; (CD3)2CO)] 2.66
(2 H, d, J 6.6), 2.70 (1 H, dd, J 8.8 and 15.4, 3-H), 3.18 (1 H, dd,
[2-(2-Ethoxycarbonyl-2-methylpropanamido)-3-methoxy-
benzyl]triphenylphosphonium bromide 31
A solution of ethyl 3-chloro-2,2-dimethyl-3-oxopropanoate20
(4.47 g, 25 mmol) in dichloromethane (30 cm3) was slowly
added to a stirred mixture of the phosphonium salt 30 (11.00 g,
23 mmol) in dichloromethane (150 cm3). Pyridine (2.68 g, 2.75
cm3, 34 mmol) was then added dropwise, and the mixture was
heated under reflux for 30 min. After cooling to room temper-
ature the reaction mixture was washed with 5% aq. phosphoric
1200
J. Chem. Soc., Perkin Trans. 1, 1998

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acid and 15% aq. Na2CO3. The organic layer was washed with
water (2 × 60 cm3), dried over MgSO4 and evaporated to leave
the phosphonium salt 31 (12.43 g, 87%) as a solid; νmax(Nujol)/
cmϪ1 3404, 1728 and 1671; δH(200 MHz; CDCl3) 1.25 (3 H, t,
J 7.1), 1.49 (6 H, s), 3.78 (3 H, s), 4.16 (2 H, q, J 7.1), 5.18 (2 H,
d, J 14.1), 6.35–6.39 (1 H, m), 6.81–6.99 (2 H, m), 7.49–7.79
(15 H, m) and 8.58 (1 H, br s, NH).
ether 35 (72 mg, 0.40 mmol) in dry dichloromethane (10 cm3) at
Ϫ78 ЊC under N2. After 24 h the reaction mixture was quenched
by the addition of water (5 cm3). Extraction with dichloro-
methane and evaporation gave a solid that was recrystallised to
give the azetidinone 36 (42 mg, 62%), mp 125–126 ЊC (from
ether) (Found: C, 70.8; H, 6.5; N, 6.9. C12H13NO2 requires C,
70.9; H, 6.45; N, 6.9%); νmax(Nujol)/cmϪ1 3294, 1735, 1626 and
1588; δH(200 MHz; CDCl3) 1.26 (3 H, s, endo 1-Me), 1.52 (3 H,
s, exo 1-Me), 3.10–3.22 (2 H, m, 8-H), 4.18 (1 H, dd, J 7.7 and
8.8, 8a-H), 5.77 (1 H, br s, OH), 6.76–6.85 (2 H, m) and 6.91–
7.06 (1 H, m); m/z 203 (Mϩ, 34%) and 133 (100).
Ethyl 2-(7-methoxy-1H-indol-2-yl)-2-methylpropanoate 32
Freshly prepared potassium tert-butoxide (2.50 g) was slowly
added to a stirred suspension of the phosphonium bromide 31
(6.00 g, 10 mmol) in toluene (100 cm3) under reflux. After 30
min the reaction mixture was concentrated to a volume of 20
cm3 and ether (100 cm3) was added to precipitate most of the
triphenylphosphine oxide. The reaction mixture was filtered
and the filtrate was evaporated to dryness. The residue was
purified by flash chromatography which gave (with dichloro-
methane) the indole 32 (1.47 g, 58%) as an oil (Found: Mϩ,
261.136. C15H19NO3 requires M, 261.136); νmax(film)/cmϪ1 3377,
1727 and 1628; δH(200 MHz; CDCl3) 1.25 (3 H, t, J 7.1), 1.66
(6 H, s), 3.95 (3 H, s), 4.17 (2 H, q, J 7.1), 6.35 (1 H, d, J 2.2,
3-H), 6.61 (1 H, d, J 7.7), 6.99 (1 H, d, J 7.7), 7.16 (1 H, d, J
8.2) and 8.67 (1 H, br s, NH); m/z 261 (Mϩ, 30%) and 188
(100).
Crystal data for 36
C12H13NO2, M = 203.24. Monoclinic, a = 9.832(9), b =
8.687(5), c = 12.932(6) Å, β = 108.52(4)Њ, V = 1047(1) Å3,
F(000) 432, λ = 0.710 69 Å, T = 153(2) K, space group P21/c
(no. 14), Z = 4, Dc = 1.289 g cmϪ3, colourless prism, 0.15 ×
0.10 × 0.25 mm.
Data collection and processing. Rigaku AF6S diffractometer,
graphite-monochromated Mo-Kα radiation, ω Ϫ 2θ scans to a
maximum 2θ value of 50.1Њ with ω scan width (1.52 ϩ 0.30 tan
θ)Њ; 2108 reflections collected of which 1989 were unique
(Rint = 0.026). The intensities of three representative reflections
which were measured after every 150 reflections remained con-
stant throughout data collection; no decay correction was
applied.
Structure solution and refinement. Automatic direct
methods21 (all non-H atoms). Non-H atoms were refined either
anisotropically or isotropically. The final cycle of full-matrix
least-squares refinement was based on 1006 observed reflections
[I > 3.00σ(I)] and 136 variable parameters and converged
(largest parameter shift was 0.02 times its esd) with weighted
and unweighted agreement factors of:
Ethyl 2-(2,3-dihydro-7-methoxy-1H-indol-2-yl)-2-methyl-
propanoate 33
Sodium cyanoborohydride (0.70 g) was added in one portion to
a stirred solution of the indole 32 (0.60 g, 2.3 mmol) in acetic
acid (5 cm3) at 15–17 ЊC under N2. After 3 h, water (15 cm3) was
added and the reaction mixture was neutralised with saturated
aq. sodium hydrogen carbonate. Extraction with ether and flash
chromatography gave (with dichloromethane) the indoline
33 (0.46 g, 76%) as an oil (Found: Mϩ, 263.152. C15H21NO3
requires M, 263.152); νmax(film)/cmϪ1 3395, 1719 and 1618;
δH(200 MHz; CDCl3) 1.25 (3 H, t, J 7.1), 1.19 (3 H, s), 1.25 (3
H, s), 2.87 (1 H, dd, J 10.5 and 15.9, 3-H), 3.02 (1 H, dd, J 9.4
and 15.9, 3-H), 3.80 (3 H, s), 4.14 (2 H, q, J 7.1), 4.12–4.27 (1 H,
m, 2-H) and 6.59–6.75 (3 H, m); m/z 263 (Mϩ, 8%) and 148
(100).
R = Σ Fo| Ϫ |Fc /Σ|Fo| = 0.045
¹
2
²
2
Rw = [(Σw(|Fo| Ϫ |Fc|) /ΣwFo )] = 0.047
The standard deviation of an observation of unit weight was
1.48. The weighting scheme was based on counting statistics
and included a factor (ρ = 0.03) to downweight the intense
reflections. The maximum and minimum peaks on the final
difference Fourier map corresponded to 0.17 and Ϫ0.23
e ÅϪ3, respectively. All calculations were performed using the
TEXSAN crystallographic structure package of the Molecular
Structure Corporation.22
2-(2,3-Dihydro-7-methoxy-1H-indol-2-yl)-2-methylpropanoic
acid 34
The ester 33 (0.50 g, 1.9 mmol) in ethanol (3 cm3) was hydro-
lysed with aq. potassium hydroxide as described for the ester 25.
This gave the acid 34 (0.45 g, 99%) as an oil (Found: Mϩ,
235.121. C13H17NO3 requires M, 235.121); δH(200 MHz;
CD3COCD3) 1.22 (3 H, s), 1.26 (3 H, s), 2.77 (1 H, dd, J 10.9
and 15.8, 3-H), 3.11 (1 H, dd, J 9.4 and 15.8, 3-H), 3.77 (3 H, s),
4.10 (1 H, dd, J 9.4 and 10.9, 2-H) and 6.67–6.74 (3 H, m); m/z
235 (Mϩ, 13%) and 148 (100).
Molecular mechanics calculations
After building and geometry optimisation using the molecular
mechanics within SYBYL13 the molecule 7 was submitted for
full geometry optimisation using the AM1 method in
MOPAC.14 The following conformational searches were then
performed using the Tripos force field within SYBYL: (i) a ran-
dom conformational search around 9 bonds, with 1000 con-
formations considered and using Gasteiger–Hückel charges;
(ii) a gridsearch, rotating C2᎐C2Ј through 360Њ in 15Њ intervals,
without charges; (iii) as in (ii) and using Gasteifer–Hückel
charges; (iv) a gridsearch with Gasteiger–Hückel charges, rotat-
ing bonds C2᎐C2Ј, C2Ј᎐C3Ј, C3Ј᎐O4Ј and O4Ј᎐C5Ј (numbering as in
Fig. 1) through 360Њ in 60Њ intervals. In all searches the
minimum energy conformation was similar to that depicted in
Fig. 1, with the methyl group eclipsing the plane of the indole
ring.
8,8a-Dihydro-1,1-dimethyl-4-methoxyazeto[1,2-a]indol-2(1H)-
one 35
The acid 34 (0.42 g, 1.8 mmol) was cyclised by the procedure
described for the cyclisation of the salt 21. Flash chrom-
atography gave [with dichloromethane–hexane (1:1)] the azet-
idinone 35 (280 mg, 72%), mp 73–75 ЊC (Found: C, 71.8; H,
6.9; N, 6.5%; Mϩ, 217.110, C13H15NO2 requires C, 71.9; H, 7.0;
N, 6.45%; M, 217.110); νmax(Nujol)/cmϪ1 1774, 1609 and 1586;
δH(300 MHz; CDCl3) 1.26 (3 H, s, endo 1-Me), 1.53 (3 H, s, exo
1-Me), 3.09 (1 H, dd, J 9.3 and 16.8, 8-H), 3.20 (1 H, dd, J 8.2
and 16.8, 8-H), 3.92 (3 H, s), 4.16 (1 H, dd, J 8.2 and 9.3, 8a-H),
6.77–6.85 (2 H, m) and 6.99–7.07 (1 H, m); m/z 217 (Mϩ, 44%),
147 (34) and 118 (100).
Acknowledgements
8,8a-Dihydro-1,1-dimethyl-4-hydroxyazeto[1,2-a]indol-2-(1H)-
one 36
We thank the EPSRC and SmithKline Beecham Pharm-
aceuticals for a CASE Studentship (to K. G.). We also thank
Mr J. V. Barkley (University of Liverpool) for determining the
X-ray crystal structure of 36.
Boron tribromide (0.50 cm3, 1.0  in dichloromethane, 0.5
mmol) was added dropwise to a stirred solution of the methyl
J. Chem. Soc., Perkin Trans. 1, 1998
1201

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12 V. S. R. Rao and T. K. Vasudevan, CRC Crit. Rev. Biochem., 1983,
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Paper 8/00278I
Received 9th January 1998
Accepted 5th February 1998
1202
J. Chem. Soc., Perkin Trans. 1, 1998