Syntheses of spiro[cyclopropane-1,3′-oxindole]-2-carboxylic acid and cyclopropa[c]quinoline-7b-carboxylic acid and their derivatives

Article abstract of DOI:10.1016/j.tet.2006.11.051

The synthesis of spiro[cyclopropane-1,3′-oxindole]-2-carboxylic acid, including novel 3-(2- and 3-pyridyl)-substituted analogues and the novel cyclopropa[c]quinoline-7b-carboxylic acid and their ester and amide derivatives is described. These syntheses in

Full text of DOI:10.1016/j.tet.2006.11.051

Tetrahedron 63 (2007) 1191–1199
0
Syntheses of spiro[cyclopropane-1,3 -oxindole]-2-carboxylic
acid and cyclopropa[c]quinoline-7b-carboxylic acid and
their derivatives
a
Sarah R. Yong, Alison T. Ung, Stephen G. Pyne, Brian W. Skelton and Allan H. White
a,*
a,*
b
b
a
Department of Chemistry, University of Wollongong, Wollongong, New South Wales 2522, Australia
Department of Chemistry, University of Western Australia, Crawley, Western Australia 6009, Australia
b
Received 3 October 2006; revised 4 November 2006; accepted 16 November 2006
Available online 11 December 2006
0
Abstract—The synthesis of spiro[cyclopropane-1,3 -oxindole]-2-carboxylic acid, including novel 3-(2- and 3-pyridyl)-substituted analogues
and the novel cyclopropa[c]quinoline-7b-carboxylic acid and their ester and amide derivatives is described. These syntheses involve
diastereoselective cyclopropanation reactions of methyl 2-(2-nitrophenyl)acrylate and (3E)-(pyridin-2-ylmethylene)- and (3E)-(pyridin-
3
-ylmethylene)-1,3-dihydro-2H-indol-2-one with ethyl (dimethyl sulfuranylidene) acetate (EDSA). The synthesis of methyl cyclopropa[c]-
quinoline-7b-carboxylate involves a regioselective reductive cyclization of a nitro-diester precursor. The relative stereochemistry of key
compounds has been determined by single-crystal X-ray structural analysis.
Ó 2006 Published by Elsevier Ltd.
X
3
1. Introduction
2
2
HO C
CO2R
1
0
3 -Spirocyclo-oxindoles, of synthetic or natural origin, have
a range of biological activities.
O
1
–3
N
H
N
O
As part of a medicinal
chemistry project, we have been focusing on the synthesis
H
0
discovery. We recently reported the preparation of 3 -spiro-
1, X = H, R = H
, X = 2- or 3-pyridyl, R = Et
3
of novel 3 -spirocyclo-oxindoles as scaffolds for new drug
0
pentacyclo-oxindole derivatives using phosphine-catalyzed
2
X
4
CO Et
2
[3+2]-cycloaddition reactions. As an extension of this
project, we required the synthesis of 3 -spirocyclopropyl-
COR
0
oxindole-2-carboxylic acid 1, and its 3-(2-pyridyl)- and
Y
X
O
O
N
H
N
H
3-(3-pyridyl)-substituted analogues 2, and the novel cyclo-
propa[c]quinoline-7b-carboxylic acid 3.
4
; R = OH, O-alkyl or NHR;
8
X = H, Y = H or Br
5
; R = OEt; X = Ph, Y = H
2
a
During the courseof this projectHe et al. reported that some
6; R = Ph; X = Ar; Y = H
7; R = Ph; X = H; Y = H
0
0
ester and amide derivativesof 5 -bromo-3 -spirocyclopropyl-
oxindole-2-carboxylic acid 4 (R¼OH, Y¼Br) were po-
tent HIV-1 non-nucleoside reverse transcriptase inhibitors
R
Cl
CO2Et
(
NNRTIs) on both wild-type and drug resistant mutant
viruses. The ethyl ester of compound 4 (R¼OEt, X¼H,
Y¼Br) was prepared from 3-carboethoxymethylene deriva-
tive of5-bromoisatin(8, X¼Br)bytreatment withdiazometh-
ane to generate the cyclopropanated product, via its diazo
intermediate. Similar reactions have been utilized earlier to
N
H
O
9
; R = alkyl
0
3,3-diphenyl-3 -spirocyclopropyloxindole-2-carboxylic ester
5
,6
3 -spirocyclopropyloxindole-2-carboxylic ester (5) and
0
prepare the ethyl ester of 1 (R¼Et), and 2-substituted-
0
5
3
-spirocyclopropyloxindole-2-carboxylic esters. 3-Phenyl-
have also been prepared from 8 (X¼H) using phenyldiazo-
5
6
7
methane and diphenyldiazomethane, respectively. Indeed
prior to thework disclosed here, no methods were available to
Keywords: Cyclopropanation; Sulfur ylide; Spirocyclic compounds; Ox-
indole; Quinoline.
0
prepare 3-aryl-3 -spirocyclopropyloxindole-2-carboxylic
esters, including the desired 3-(2- and 3-pyridyl)-substituted
*
Corresponding authors. E-mail addresses: aung@uow.edu.au; spyne@
uow.edu.au
0
040–4020/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tet.2006.11.051

1192
S. R. Yong et al. / Tetrahedron 63 (2007) 1191–1199
analogues 2 that did not employ potentially hazardous diazo
of the nitro-diester 11. Based on literature precedent of
related but non-cyclopropanated nitro-diesters, cyclization
should favour the formation of a quinoline ring system
8
9
compounds. Earlier work by Croce et al., however, showed
that the related phenyl ketone derivatives, 6 and 7, could be
prepared by the reaction of dimethylsulfonium phenacylide
1
1
over an oxindole ring structure. However, at the onset of
this study, the effect of the cyclopropane moiety in 11 on
the regioselectivity of such a reductive cyclization reaction
was not certain. Nitro-diester 11 was prepared in 80% yield
in a completely diastereoselective fashion by treatment of
(
Me S]CHC(O)Ph) with 8 (X¼H) or 3-methylene-indo-
2
line-2-one, respectively. The former products were formed
as a mixture (1.5–3.5:1) of diastereomers.
1
0
4,12
In 2006 He et al., disclosed that derivatives of ethyl
cyclopropa[c]quinoline-1c-carboxylate 9, closely related
structures to our target molecule 3, also had potent HIV
antiviral activities as NNRTIs. We report here our own
the acrylate 10 with ethyl (dimethyl sulfuranylidene) ace-
tate (EDSA, 1.5 equiv) in anhydrous toluene for 20 h at rt.
Single X-ray crystallographic analysis of 11 showed that
the two polar ester groups had a trans-stereochemical rela-
tionship (Fig. 1). This stereochemical outcome was expected
0
efforts for preparing 3 -spirocyclopropyloxindole deriva-
1
4
tives related to 1 and a method for preparing, for the first
time, 3-pyridyl-substituted analogues 2 using stabilized
sulfur ylides. Furthermore, we report an efficient and highly
diastereoselective synthesis of cyclopropa[c]quinoline-7b-
carboxylic acid 3, a new isomer of He’s compound 9, and
its ester and benzamide derivatives.
based on literature precedent of related reactions.
Reductive cyclization of 11 using zinc and HCl under reflux-
ing conditions, led to the formation of the expected products,
12 and 13. This reaction was highly regioselective (12/
13¼12:1) in favour of the formation of the quinoline 12
(70% isolated yield) over the indolone 13 (5% isolated
yield). In contrast, catalytic hydrogenation of 11 using Pd/
C and H led to a less regioselective reaction providing
2
. Results and discussion
2
a 4:1 mixture of 12 and 13, in favour of the quinoline product
12 (61% isolated yield). The higher regioselectivity found in
The synthesis of the corresponding esters of 1 and 3, i.e., 13
and 12, respectively (Scheme 1) could in principle be
achieved by regioselective reductive cyclization reactions
2
+
the former method may be due to Zn activation of the less
hindered ester carbonyl by coordination, leading to more of
the quinoline product 12. Compounds 12 and 13 were readily
separated by column chromatography and their structures
were established by single-crystal X-ray crystallographic
CO2Et
CO Me
a)
CO2Me
13
1
2
analysis (Fig. 2). The H NMR spectral data of 13 at
300 MHz were similar to that reported in 1978 by Bennett
et al. for the same compound at 60 MHz. We thus assume
NO2
NO2
5
10
11
that the same diastereomeric compound was produced
from these two different synthetic routes. Furthermore, the
H NMR spectral data for the cyclopropane resonances of
b)
MeO2C
1
CO2Et
1
3 matched very closely to that of the analogous N-methyl
O
+
7
analogue of 13 that were recently reported. Saponification
of 12 and 13 gave the carboxylic acids, 3 (structure confirmed
by X-ray structural analysis) and 1, respectively, which
were converted to their respective amide derivatives 14 and
N
N
O
H
H
1
3
12
13
c)
HO2C
c)
1
5, under EDCI/HOBT coupling conditions with aniline.
CO2H
O
+
N
H
N
O
H
3
1
d)
d)
O
O
HN
N
H
O
+
N
H
O
N
H
14
15
Scheme 1. Reagents and conditions: (a) Me
DBU (1.5 equiv), anhydrous toluene, 20 h, 80%; (b) Zn dust (40 equiv),
EtOH, H O, HCl, reflux, 3 h (12:1 of 12/13), 70% (12), 5% (13) or H
2 2 2
SCH CO Et$Br (2 equiv),
2
2
,
Pd/C, 2 days (4:1 of 12/13), 61% (12), 18% (13); (c) K
ꢀ
2
CO
3
, (2 equiv),
O, sealed tube, 60 C, 18 h, 50% (3), 80% (1); (d) aniline
Figure 1. Molecular projection of 11. This and subsequent figures depict
50% probability amplitude displacement envelopes for the non-hydrogen
˚
atoms and hydrogen atoms having arbitrary radii of 0.1 A; crystallographic
numbering is also shown.
MeOH/H
(1.6 equiv), HOBT (1 equiv), EDCI (1 equiv), anhydrous MeCN, rt,
2
3
days, 77% (14), 18% (15) (Compounds 1, 2 and 11–15 are racemic).

S. R. Yong et al. / Tetrahedron 63 (2007) 1191–1199
1193
Figure 2. Molecular projection of 12 (left) and 13 (right).
A more direct method to synthesize the indolone amide 15,
involved cyclopropanation of the acrylate 10 with the amide-
stabilized ylide derived from the sulfonium salt 19, which
was readily prepared in three synthetic steps from chloro-
acetyl chloride 16, as outlined in Scheme 2. Although far
less common than their ester-sulfonium analogues, amide-
sulfonium salts like 19 have been previously used for the
cyclopropanation reactions of electron deficient alkenes,
CH Cl for 2 days at rt yielded solely the trans product 20
2 2
in 39% yield. The structure of 20 was unequivocally estab-
lished by single-crystal X-ray structural analysis (Fig. 3).
1
3
The reductive cyclization of 20, using the methods described
in Scheme 1, however, was not productive. Previously, it was
found that reduction of aromatic nitro compounds can pro-
1
6
ceed using iron with acetic acid under sonication. This
method successfully yielded the desired product 15 in a yield
of 60%.
1
5
however, normally as their tertiary amide derivatives.
For the preparation of target molecules 2, the a-methylene
indolinones 21a and 21b were prepared according to the
literature. Their E-geometries were unequivocally estab-
O
Cl
O
a)
b)
Cl
Cl
17
HN
16
17
lished by single-crystal X-ray structural analysis (structures
not shown). The cyclopropanation reactions of either 21a
or 21b with EDSA in anhydrous acetonitrile (compounds
1
3
I
O
Me S
O
MeS
c)
2
21a,b were not soluble in toluene) for 24 h at rt yielded
a mixture of three diastereomeric cyclopropane products
HN
HN
19
1
(
Scheme 3). For the reaction using 21a, H NMR analysis
18
of the crude reaction mixture revealed a 5.6:1.8:1 mixture
of the diastereomeric products, 22a, 23a and 24a, respec-
tively. In contrast, the cyclopropanation reaction using 21b
proved to be a much more diastereoselective reaction giving
a 43:7:1 mixture of the diastereomeric products, 22b, 23b
and 24b, respectively. Separation of these diastereomeric
O
N
H
d)
e)
CO2Me
NO2
20
O
O
N
H
N
H
15
Scheme 2. Reagents and conditions: (a) aniline (1.1 equiv), pyridine
ꢀ
(1.5 equiv), anhydrous CH
anhydrous MeOH, rt, 15 min, 98%; (c) MeI (10 equiv), anhydrous CH
rt, 2 days, 52%; (d) 10, 19 (1.5 equiv), DBU (1.1 equiv), anhydrous CH
2
Cl
2
, 0 C/rt, 1 h, 74%; (b) MeSNa (1.1 equiv),
2
Cl
Cl
2
,
,
2
2
rt, 2 days, 39%; (e) Fe (8 equiv), AcOH, EtOH, sonication, 2 h, 60% (Com-
pounds 15 and 20 are racemic).
The cyclopropanation reaction of the acrylate 10 and the
amide-stabilized ylide generated in situ from the sulfonium
salt 19 (1.5 equiv) with DBU (1.1 equiv) in anhydrous
Figure 3. Molecular projection of 20.

1194
S. R. Yong et al. / Tetrahedron 63 (2007) 1191–1199
products by column chromatography proved to be difficult
and only compounds 22a and 24a could be isolated as dia-
stereomerically pure in yields of 27 and 12%, respectively.
The remaining chromatographic fractions consisted of mix-
tures of all three isomers. In contrast, the major trans-isomer
shifts and appeared almost like an ABq (d 3.86 and 3.82).
While one methine for the isomer 24a had the most upfield
signal (d 3.08) and one at d 3.57. The cyclopropane vicinal
coupling constants for two of the products, 22a and 24a,
3
were found to be the same, Jw8 Hz. This was in contrast
to isomer 23a, which had a vicinal coupling constant of
2
6
2b was readily isolated in diastereomerically pure form in
1% yield from 21b. Diastereomerically pure samples of the
other isomers, 23b and 24b, however, could not be obtained
3
Jw10 Hz. Since in cyclopropanes, cis-vicinal coupling con-
3
stants ( J 6–10 Hz) are usually larger than trans-vicinal
coupling constants ( J
cis
3
18
from the inseparable mixtures.
3–6 Hz), the diastereomers
trans
2
the cis-isomer. While the synthesis of 5 was reported in
2a and 24a were assigned as the trans-isomers and 23a as
Ar
5
1
978, the relative stereochemistry of the 3-phenyl substitu-
EDSA, MeCN
1
ent was not defined. A comparison of the H NMR data of 5
(d 3.73, d, J 8 Hz; d 3.20, d, J 8 Hz) with that of 22a suggests
that they have the same relative stereochemistries.
O
Ar =
24 h
N
N
H
N
b
a
21
1
4c
Pedregal and Monn reported that the reaction of EDSA
with acyclic enones in toluene gave the trans-cyclopropane
isomers (ester and ketone groups are trans) as the exclusive
products. The cis-cyclopropanated products were formed as
minor isomers in more polar chloroform solution. In some
cases a small amount (10%) of another trans-isomer was
formed from epimerization of the minor cis-isomer under
the basic reaction conditions. Based upon this report, we
speculate that our minor trans-isomers 24a,b may arise
from epimerization of their respective cis-isomers 23a,b.
In this case, we assign the stereochemistry of 23a,b as shown
in Scheme 3. Unfortunately pure samples of 23a,b could not
be obtained to examine this possibility or to perform mean-
ingful NOESY NMR experiments.
EtO2C 2'
EtO C
EtO C
2
2
3'
Ar
Ar
O
Ar
O
+
+
O
N
N
H
N
H
H
22
23
24
2
2a : 23a : 24a = 5.6 : 1.8 : 1
2b : 23b : 24b = 43 : 7 : 1
2
Scheme 3. All compounds are racemic.
The structure of 22b was unequivocally established by
1
3
single-crystal X-ray structural analysis (Fig. 4). The as-
signment of the relative stereochemistries of the diastereo-
meric products produced in Scheme 3 is based on the
coupling constants observed for the cyclopropane methines,
For cyclopropanation reactions of electron deficient alkenes
1
4b
(RCH]CHW) using EDSA, DeLuca and Curley
proposed a mechanism that involves equilibration of the ini-
tially formed syn-betaines (Me
have
0
0
CH-3 and CH-2 . The chemical shifts and coupling con-
stants for the major isomers of both reactions (22a and
S(+) and CH(ꢁ)W are syn
2
22b) and corresponding minor isomers according to preva-
lence ((23a and 23b) and (24a and 24b)) were almost iden-
due to electrostatic attraction) and then subsequent collapse
of these betaines, via their corresponding anti-conforma-
tions, to the cyclopropanated products. Of the four possible
racemic anti-betaine intermediates that could be involved
in the cyclopropanation reactions of 21a/b, conformation A
(Scheme 4) would be expected to be favoured in terms of
minimizing unfavourable steric and repulsive dipole–dipole
interactions (between the ester group (E) and the oxindole
tical, indicative of their same relative configurations. For the
isomeric set 22a–24a, the methine cyclopropane H NMR
resonances appeared as doublets for all diastereomers,
with one methine of the major isomer 22a having the most
downfield signal (d 3.93) and one at d 3.46. For the isomer
1
2
3a both cyclopropane methines had very similar chemical
1
4b,19
carbonyl dipole).
Indeed, this betaine would give rise
to the major diastereomeric products 22a and 22b. The lower
diastereoselectivity found in the cyclopropanation of 21a
compared to 22b, may be a result of a more unfavourable di-
pole–dipole interaction in betaine A between the oxindole
carbonyl group and the pyridine nitrogen atom, in the 2-pyr-
idyl series (A, X¼N, Y¼CH) compared to the 3-pyridyl
series (A, X¼CH, Y¼N). Such an interaction would destabi-
lize A relative to other reactive trans-betaine conformations
Y
E
H
X
H
H
Me2S
Y
X
C
O
H
O
N
N
H
E
2
2
3a, X = N, Y = CH
3b, X = CH, Y = N
A
Figure 4. Molecular projection of 22b.
Scheme 4.

S. R. Yong et al. / Tetrahedron 63 (2007) 1191–1199
1195
-
4
(
for example, one in which oxindole carbonyl group is anti
and recovered 10 (41.8 mg, 2ꢂ10 mol, 6%). MS (ESI+ve)
+
+
to the pyridine ring) leading to an erosion of product dia-
stereoselectivity by increased formation of the cis-isomer
2
m/z 294 (100%) [MH ], 248 (43%) [M ꢁOEt]. HRMS
+
(ESI+ve) Calcd for C H NO [MH ]: 294.0978; found:
1
4
16
6
1
3a.
294.0981. H NMR d 8.06 (br d, J 6.6 Hz, 1H, ArCH-3),
.62 (br d, J 7.5 Hz, 1H, ArCH), 7.51–7.46 (m, 2H, ArCH
and ArCH-4), 3.92 (q, J 7.0 Hz, 2H, CH CH ), 3.64 (s,
3H, OCH ), 3.02 (br s, 1H, CH-2), 2.02–1.99 (m, 2H,
3
CH -3), 1.08 (t, J 7.0 Hz, 3H, CH CH ). C NMR d 171.3
2 3 2
7
0
In conclusion, the synthesis of spiro[cyclopropane-1,3 -ox-
indole]-2-carboxylic acid 1, including novel 3-(2- and
3
2
3
1
3
-pyridyl)-substituted analogues 22–24 and the novel cyclo-
propa[c]quinoline-7b-carboxylic acid 3 and the ester
and amide derivatives of these acids has been achieved.
These syntheses involve diastereoselective cyclopropana-
tion reactions of methyl 2-(2-nitrophenyl)acrylate and
(CO Me), 169.5 (CO Et), 149.2 (ArC-1), 133.5 (ArCH-5
2 2
and ArCH-6), 131.0 (ArC-2), 128.9 (ArCH-4), 124.8
0
(ArCH-3), 61.2 (CH CH ), 53.0 (OCH ), 36.1 (C-1 ), 29.7
2
3
3
(CH-2), 22.1 (CH -3), 13.8 (CH CH ). The structure of 11
2
2
3
(
3E)-(pyridin-2-ylmethylene)- and (3E)-(pyridin-3-ylmethyl-
was confirmed by X-ray crystallography (Fig. 1).
ene)-1,3-dihydro-2H-indol-2-one with ethyl (dimethyl sul-
furanylidene) acetate (EDSA). The synthesis of methyl
cyclopropa[c]quinoline-7b-carboxylate 12 involves the regio-
selective reductive cyclization of a nitro-diester precursor 11.
The relative stereochemistry of key compounds has been
unequivocally determined by single-crystal X-ray structural
analysis.
3.3. Methyl (1aR*,7bR*)-2-oxo-1,1a,2,3-tetrahydro-
7bH-cyclopropa[c]quinoline-7b-carboxylate (12)
0
0
[cyclopropane-1 ,3-indole]-2 -carboxylate (13)
and ethyl (1 R*,2 R*)-2-oxo-1,2-dihydrospiro-
0
0
The title compounds were prepared using two methods.
Method 1: to a solution of 11 (493.8 mg, 1.68 mmol) in
EtOH/H O (12.8 mL:3.2 mL) were added activated Zn
2
3
. Experimental
dust (2.627 g, 40 mmol) and 8.9 M HCl (2.54 mL). The mix-
ture was stirred and heated at reflux for 3 h. The mixture was
filtered through a bed of Celite and washed with EtOH. H
1
3
.1. General
NMR analysis of the crude reaction mixture revealed
a 12:1 mixture of 12 and 13, respectively. The crude product
was purified by column chromatography using 20–50%
EtOAc/petrol as eluent and then further purified using
CH Cl /petrol/EtOAc (2:2:1) as eluent to yield 12, as white
Petrol refers to the fraction of petroleum spirit with a boiling
point of 40–60 C. All H NMR spectra were performed
ꢀ
1
1
3
at 300 MHz and all C NMR (DEPT) spectra at 75 MHz
in CDCl3 solution, unless otherwise noted. All spectra
were referenced to CDCl ( H d 7.26 ppm and C NMR
2
2
1
13
3
needles (253.6 mg, 1.17 mmol, 70%), and 13, as white nee-
dles (19.3 mg, 8.3ꢂ10 mol, 5%). Method 2: to a solution
1
ꢁ5
d 77.00 ppm). H NMR assignments were achieved with
the aid of gCOSY, and in some cases with NOESY and
ꢁ
4
of 11 (167.6 mg, 5.7ꢂ10 mol) in EtOAc (8.6 mL) was
1
3
TOCSY experiments. C NMR assignments were based
upon DEPT, gHSQC and gHMBC experiments. All solvents
were dried over anhydrous magnesium sulfate, unless stated
otherwise. The atom numbering for compounds 12 and 13
and their derivatives is as indicated below.
added 10% Pd/C (33 mg). The system was flushed with H
gas and left to stir under a H atmosphere (balloon) for
2
2
1
2
days. H NMR analysis of the crude reaction mixture re-
vealed a 4:1 mixture of 12 and 13, respectively. The crude
product was purified by column chromatography and then
by PTLC using 30% EtOAc/petrol as eluent to yield 12 as
ꢁ
4
3
`
white needles (76.1 mg, 3.5ꢂ10 mol, 61%, R ¼0.15 in
MeO2C
1
7b 1aH
2
CO Et
f
2
4
7
ꢀ
2`
7a
3a
30% EtOAc/petrol, mp166–170 C) and 13 as white needles
(23.9 mg, 0.1 mmol, 18%, R
6
3
O
¼0.3 in 30% EtOAc/petrol, mp
f
3a
7a N
H
13
ꢀ
5
ꢀ
N
O
4
136–138 C (lit. mp 154–156 C).
H
1
2
ꢃ
+
Compound 12: MS (EI) m/z 217 (55%) [M ], 202 (58%)
+
+
[
M ꢁMe], 158 (53%) [M ꢁCO Me]. HRMS (EI) Calcd
2
ꢃ
+
1
3
cyclopropane-1 ,2 -dicarboxylate (11)
.2. (1R*,2R*)-2-Ethyl-1-methyl-1-(2-nitrophenyl)-
0
for C H NO [M ]: 217.0739; found: 217.0735.
12 11 3
H
0
NMR d 8.75 (br s, 1H, NH), 7.72 (dd, J 8.1, 1.2 Hz, 1H,
ArCH-4), 7.20 (dt, J 7.8, 1.5 Hz, 1H, ArCH-6), 7.07 (dt,
J 7.5, 1.5 Hz, 1H, ArCH-5), 6.81 (dd, J 8.1, 1.0 Hz, 1H,
A solution of ethyl dimethylsulfonium acetate bromide
(
(
1.56 g, 6.8 mmol) and 1,8-diazobicyclo[5.4.0]undec-7-ene
DBU) (0.76 mL, 5.1 mmol) in anhydrous toluene (30 mL)
ArCH-7), 3.80 (s, 3H, CH ), 2.58 (ddd, J 10.5, 5.1, 1.3 Hz,
3
1H, CH-1a), 2.43 (dd, J 4.2, 10.5 Hz, 1H, CH H -1), 1.03
A
B
1
3
was stirred under an N atmosphere at rt for 30 min. A solu-
2
(dd, J 5.7, 4.8 Hz, 1H, CH H -1). C NMR d 170.4
B A
tion of 10 (709.7 mg, 3.4 mmol) in anhydrous toluene
(CO Me), 167.2 (C-2), 134.3 (ArC-7a), 129.8 (ArCH-4),
2
(10 mL) was added and stirring was continued for 20 h.
The reaction mixture was washed with 10% HCl solution
127.8 (ArCH-6), 123.0 (ArCH-5), 119.2 (ArC-3a), 115.7
(ArCH-7), 52.7 (CH ), 29.9 (C-7b), 28.6 (CH-1a), 17.9
3
(
2ꢂ40 mL) and the aqueous washings were extracted with
(CH -1). The structure of 12 was confirmed by X-ray crys-
2
tallography (see Fig. 2).
EtOAc (3ꢂ100 mL). The combined extracts were dried,
filtered and evaporated under reduced pressure. The crude
mixture was purified by column chromatography, elution
with 10–25% EtOAc/petrol yielded 11 as a light-yellow
semicrystalline oil, which crystallized upon standing
ꢃ
+
Compound 13: MS (EI) m/z 231 (68%) [M ], 186 (32%)
+
ꢃ
+
[M ꢁOEt]. HRMS (EI+ve) Calcd for C H NO [M ]:
1
3
13
3
1
231.0895; found: 231.0896. H NMR (500 MHz) d 9.26
(br s, 1H, NH), 7.34 (d, J 7.5 Hz, 1H, ArCH-4), 7.22 (dt,
(
799.7 mg, 2.7 mmol, 80%, R ¼0.5 in 20% EtOAc/petrol),
f

1196
S. R. Yong et al. / Tetrahedron 63 (2007) 1191–1199
ꢀ
J 7.5, 1.5 Hz, 1H, ArCH-6), 7.00 (dt, J 8.0, 1.0 Hz, 1H,
ArCH-5), 6.98 (d, J 7.5 Hz, 1H, ArCH-7), 4.08–4.21 (m,
0 C (ice-bath) was added aniline (0.04 mL, 4.1ꢂ
ꢁ4
ꢀ
10 mol). The solution was stirred for 10 min at 0 C before
0
dd, J 7.5, 4.5 Hz, 1H, CH CH -3 ), 2.03 (dd, J 8.5,
ꢁ4
2
(
H, CH CH ), 2.72 (dd, J 8.5, 7.5 Hz, 1H, CH-2 ), 2.17
2
the addition of EDCI (49.5 mg, 2.6ꢂ10 mol) and left to stir
3
0
.5 Hz, 1H, CH CH -3 ), 1.21 (t, J 7.3 Hz, 3H, CH ).
ꢀ
at rt for 2 h, then at 50 C for 18 h and then again at rt for
A
B
0
C NMR (125 MHz) d 177.2 (C-2), 168.6 (CO Et), 141.5
4
3 days. The solvent was then removed, and the residue was
diluted with CH Cl (15 mL) and washed successively with
10 mL of 10% HCl, H O and brine. The organic extracts
were then combined, dried and evaporated invacuo. Purifica-
tion of the crude product by column chromatography using
10% MeOH/CHCl as the eluent yielded 14 as an amber col-
B
A
3
1
3
2
2
2
(
4
(
ArC-7a), 127.7 (ArCH-6), 126.2 (ArC-3a), 122.9 (ArCH-
), 122.2 (ArCH-5), 110.0 (ArCH-7), 61.3 (CH CH ), 34.0
2
2
3
0 0
C-3), 32.9 (CH-2 ), 20.8 (CH -3 ), 14.1 (CH ). The struc-
2 3
ture of 13 was confirmed by X-ray crystallography (Fig. 2).
3
ꢁ4
oured oil (56 mg, 2.0ꢂ10 mol, 77%, R ¼0.28 in 50%
f
ꢃ
+
3.4. (1aR*,7bR*)-2-Oxo-1,1a,2,3-tetrahydro-7bH-cyclo-
propa[c]quinoline-7b-carboxylic acid (3)
EtOAc/petrol). MS (EI) m/z 278 (63%) [M ], 263 (26%),
206 (12%), 186 (27%), 158 (47%), 130 (94%). HRMS (EI)
ꢃ
+
Calcd for C H N O [M ]: 278.1055; found: 278.1051.
1
H NMR (500 MHz) d 9.57 (br s, 1H, NH-3), 8.23 (br s,
7 14 2 2
1
To a solution of 12 (91.5 mg, 0.4 mmol) in MeOH (1.5 mL)
contained within a sealed tube was added a solution of
K CO (109 mg, 0.8 mmol) in H O (1 mL). The tube was
1H, NHPh), 7.56–7.54 (m, 3H, ArCH-7 and ArCH-o), 7.33
(t, J 8.0 Hz, 2H, ArCH-m), 7.16 (t, J 7.0 Hz, 1H, ArCH-5),
7.13 (t, J 7.3 Hz, 1H, ArCH-p), 7.06 (t, J 7.7 Hz, 1H,
ArCH-6), 6.90 (d, J 8.0 Hz, 1H, ArCH-4), 2.58 (dd, J 10.7,
4.7 Hz, 1H, CH CH -1), 2.18 (dd, J 10.5, 5.7 Hz, 1H,
2
3
2
ꢀ
sealed and the mixture was left stirring at 60 C for 18 h.
The solvent was removed by evaporation in vacuo, and the
residue was dissolved in H O (15 mL) and washed with
2
A
B
1
3
Et O (15 mL). The aqueous solution was then acidified
2
CH-1a), 0.89 (t, J 5.7 Hz, 1H, CH CH -1). C NMR
B A
to wpH 1 with 10% HCl and extracted with Et O
(125 MHz) d 168.8 (C-2), 166.7 (CONHPh), 137.7 (ArC-i),
135.3 (ArC-3a), 129.1 (ArCH-m), 128.4 (ArCH-7), 128.3
(ArCH-5), 124.6 (ArCH-p), 123.7 (ArCH-6), 120.0 (ArC-
7a), 119.6 (ArCH-o), 116.6 (ArCH-4), 33.3 (C-7b), 27.6
2
(
3ꢂ20 mL). The combined extracts were dried to yield 3
ꢁ4
as a white powder (40.3 mg, 2.0ꢂ10 mol, 50%, R ¼0 in
f
ꢀ
3
0% EtOAc/petrol, mp 152–156 C). MS (EI) m/z 203
ꢃ
+
(
35%) [M ], 159 (24%), 130 (30%), 111 (32%), 97
45%), 71 (60%), 57 (97%), 43 (87%). HRMS (EI) Calcd
(CH-1a), 15.1 (CH -1).
2
(
for C H NO [M ]: 203.0582; found: 203.0580. H NMR
ꢃ
+
1
0
0
0
0
0
3.7. (1 R*,2 R*)-2 -Oxo-N-phenyl-1 ,2 -dihydrospiro-
0
1
1
9
3
(
CD OD) d 7.77 (dd, J 7.8, 1.5 Hz, 1H, ArCH-4), 7.17 (dt,
3
[cyclopropane-1,3 -indole]-2-carboxamide (15)
J 7.5, 1.2 Hz, 1H, ArCH-6), 7.03 (dt, J 7.5, 1.2 Hz, 1H,
ArCH-5), 6.87 (dd, J 8.1, 0.9 Hz, 1H, ArCH-7), 2.46 (dd,
J 10.5, 5.4 Hz, 1H, CH-1a), 2.36 (dd, J 10.5, 3.9 Hz, 1H,
CH CH -1), 0.92 (dd, J 5.8, 4.0 Hz, 1H, CH CH -1).
The title compound was prepared using two methods.
Method 1: the title compound was prepared using a similar
method to that described above for the synthesis of 14 start-
A
B
B
A
1
3
ꢁ4
C NMR (CD OD, 125 MHz) d 173.3 (CO H), 169.6
3
ing from 1 (25.9 mg, 1.3ꢂ10 mol). The crude product
2
(
1
(
C-2), 136.2 (ArC-7a), 131.0 (ArCH-4), 128.6 (ArCH-6),
23.7 (ArCH-5), 121.1 (ArC-3a), 116.8 (ArCH-7), 30.8
C-7b), 29.3 (CH-1a), 18.3 (CH -1). The structure of 3
after acidic workup was purified initially by column chro-
matography using 10% MeOH/CHCl as eluent and then
3
further purified on a Chromatotron (0–1% MeOH/CHCl )
3
2
1
3
ꢁ5
was confirmed by X-ray crystallography.
to yield 15 as a beige powder (6.4 mg, 2.3ꢂ10 mol,
1
8%, R ¼0.23 in 50% EtOAc/petrol). MS (EI) m/z 278
f
0
0
ꢃ
+
3
1
.5. (1 R*,2 R*)-2-Oxo-1,2-dihydrospiro[cyclopropane-
0
(94%) [M ], 263 (31%), 206 (13%), 186 (34%), 158
(64%). HRMS (EI) Calcd for C H N O [M ]:
17 14 2 2
0
ꢃ
+
,3-indole]-2 -carboxylic acid (1)
2
78.1055; found: 278.1051. Method 2: to a solution of
ꢁ
5
The title compound was prepared using a similar method
to that described above for the synthesis of 3 starting with
20 (15.7 mg, 4.6ꢂ10 mol) in a mixture of H O (1 mL),
2
AcOH (2 mL) and EtOH (2 mL), contained within a sealed
ꢁ
4
1
3 (38.2 mg, 0.16 mmol) to yield 1 as white needles
tube, was added Fe (20 mg, 3.6ꢂ10 mol). The mixture
was subjected to sonication for 2 h. The mixture was diluted
with CH Cl (100 mL) and washed successively with satd
(
25.4 mg, 0.13 mmol, 80%, R ¼0 in 30% EtOAc/petrol,
f
ꢀ
ꢃ
+
mp 142–145 C). MS (EI) m/z 203 (29%) [M ]. HRMS
(
2
2
2
ꢃ
+
EI) Calcd for C H NO [M ]: 203.0582; found:
3
K CO solution (20 mL) and H O (100 mL). The solution
2 3 2
1
1
9
1
03.0579. H NMR (CD OD) d 7.27 (dd, J 7.5, 1.0 Hz,
3
was dried, filtered and the solvent was removed in vacuo.
The crude product was purified on a Chromatotron us-
ing 40–100% EtOAc/petrol and then MeOH to yield 15, as
1
H, ArCH-4), 7.21 (dt, J 7.5, 1.3 Hz, 1H, ArCH-6), 6.96
d, J 7.5 Hz, 1H, ArCH-7), 6.95 (dt, J 7.5, 1.2 Hz, 1H,
(
ArCH-5), 2.48 (dd, J 8.5, 7.3 Hz, 1H, CH-2 ), 2.00 (dd,
0
J 7.2, 4.3 Hz, 1H, CH CH -3 ), 1.82 (dd, J 8.4, 4.5 Hz,
ꢁ5
light brown solid (7.8 mg, 2.8ꢂ10 mol, 60 %), and recov-
0
H, CH CH -3 ). C NMR (CD OD, 125 MHz) d 178.7
ꢁ6
ered 20 (0.4 mg, 1.2ꢂ10 mol, 2%). MS (EI) m/z 278
A
B
0
13
ꢃ
+
1
(34%) [M ], 235 (15%), 223 (10%), 185 (47%)
[M ꢁNHPh], 157 (30%) [M ꢁCONHPh], 146 (42%), 130
(96%), 103 (30%). HRMS (EI) Calcd for C H N O
7 14 2 2
[M ]: 278.1055; found: 278.1049. H NMR (500 MHz,
CH OD) d 7.47 (d, J 7.5 Hz, 2H, ArCH-o), 7.30 (d,
B
A
3
+
+
(
CO H), 171.2 (C-2), 143.5 (ArC-7a), 128.8 (ArCH-6),
2
1
27.6 (ArC-3a), 123.6 (ArCH-4), 123.0 (ArCH-5), 111.0
0
1
0
ꢃ
+
1
(
ArCH-7), 34.7 (C-3), 33.9 (CH-2 ), 21.0 (CH -3 ).
2
3
3
7
.6. (1aR*,7bR*)-2-Oxo-N-phenyl-1,1a,2,3-tetrahydro-
bH-cyclopropa[c]quinoline-7b-carboxamide (14)
J 8.0 Hz, 1H, ArCH-4), 7.25 (t, J 8.3 Hz, 2H, ArCH-m),
7.18 (dt, J 7.0, 1.0 Hz, 1H, ArCH-6), 7.04 (t, J 7.8 Hz, 1H,
ArCH-p), 6.95 (d, J 8.0 Hz, 1H, ArCH-7), 6.92 (t, J
ꢁ
4
0
To a solution of 3 (52.4 mg, 2.6ꢂ10 mol) and HOBT
8.0 Hz, 1H, ArCH-5), 2.81 (dd, J 8.5, 7.5 Hz, 1H, CH-2 ),
0
(
34.9 mg, 2.6ꢂ10ꢁ4 mol) in anhydrous MeCN (3 mL) at
2.25 (dd, J 7.3, 4.3 Hz, 1H, CH CH -3 ), 1.91 (dd, J 8.7,
A
B

S. R. Yong et al. / Tetrahedron 63 (2007) 1191–1199
1197
0
13
4
.3 Hz, 1H, CH CH -3 ). C NMR (125 MHz, CH OD)
B
NMR data for this salt proved impossible to assign due to
peak broadening.
A
3
d 179.0 (C-2), 167.1 (CONH), 143.5 (ArC-7a), 139.7 (ArC-
i), 129.7 (ArCH-m), 128.6 (ArCH-6), 128.0 (ArC-3a),
0
0
0
(2-nitrophenyl)cyclopropanecarboxylate (20)
0
1
25.2 (ArCH-p), 123.5 (ArCH-5), 123.0 (ArCH-4), 121.2
0
3.11. Methyl (1 R*,2 R*)-2 -(anilinocarbonyl)-1 -
(
(
ArCH-o), 110.9 (ArCH-7), 36.2 (CH-2 ), 35.0 (C-3), 20.1
0
CH -3 ).
2
-5
To a solution of 19 (214.3 mg, 6.6ꢂ10 mol) in anhydrous
ꢁ
4
3
.8. 2-Chloro-N-phenylacetamide (17)
CH Cl (3 mL) was added DBU (0.07 mL, 4.7ꢂ10 mol)
2
2
and the solution was stirred under an N atmosphere at rt
2
ꢁ4
To a solution of pyridine (0.46 mL, 5.6 mmol) and aniline
(
for 30 min. A solution of 10 (91.5 mg, 4.4ꢂ10 mol) in
0.38 mL, 4.1 mmol) in anhydrous CH Cl (100 mL) at
2
CH Cl (2 mL) was added and stirring was continued for
2
2
2
ꢀ
0
C was added chloroacetyl chloride (0.3 mL, 3.8 mmol).
2 days. The reaction mixture was diluted with CH Cl
2 2
The mixture was allowed to warm to rt and left for stirring
at rt for 1 h. The crude mixture was washed with 50 mL of
citric acid and then with satd K CO solution, dried and
(50 mL) and the solution was washed with 1 M HCl solution
(2ꢂ40 mL). The aqueous layers were back-extracted with
CH Cl (2ꢂ50 mL). The combined extracts were then dried
2
3
2
2
the solvent was removed in vacuo to yield a white solid
796.5 mg, 4.7 mmol), which was recrystallized from
EtOAc/petrol to yield off-white crystalline plates
and evaporated under reduced pressure to yield a brown yel-
low solid. The crude product was purified by column chro-
matography using 20–50% EtOAc/petrol as eluent to yield
(
ꢁ
4
(
mp 122–125 C, lit. mp 132–134 C (from MeOH)). The
465.5 mg, 2.8 mmol, 74%, R ¼0.61 in 30% EtOAc/PS,
20 as a white solid (59 mg, 1.7ꢂ10 mol, 39%, R ¼0.4 in
f
f
ꢀ
NMR data for 17 were not reported. MS (EI) m/z 169
20
ꢀ
ꢀ
(51.5 mg) and 19 (60 mg). MS (EI) m/z 340 (40%) [M ],
30% EtOAc/petrol, mp 226–228 C) and recovered 10
ꢃ
+
ꢃ
+
+
+
(
(
1
70%), 171 (36%) [M ], 120 (54%) [M ꢁCH Cl]. HRMS
294 (90%) [M ꢁNO ]. HRMS (EI) Calcd for C H N O
2
2
18 16 2 5
3
5
ꢃ
+
ꢃ
+
1
EI) Calcd for C H NO Cl [M ]: 169.0294; found:
8
[M ]: 340.1058; found: 340.1055. H NMR d 8.04 (dd,
J 8.1, 1.3 Hz, 1H, ArCH-3), 7.65–7.54 (m, 2H, ArCH-5
and ArCH-6), 7.45 (dt, J 7.5, 1.6 Hz, 1H, ArCH-4), 7.24–
8
1
69.0295. H NMR d 8.30 (br s, 1H, NH), 7.54 (dd, J 7.5,
.2 Hz, 2H, ArCH-o), 7.35 (dt, J 7.8, 1.9 Hz, 2H, ArCH-
1
m), 7.16 (tt, J 7.2, 1.2 Hz, 1H, ArCH-p), 4.17 (s, 2H,
7.19 (m, 4H, ArCH-o and ArCH-m), 7.07–7.02 (m, 1H,
ArCH-p), 3.65 (s, 3H, CH ), 3.01 (br s, 1H, CH-2 ), 2.28
1
3
0
(br s, 1H, CH CH -3 ), 1.98 (dd, J 8.4, 4.8 Hz, 1H,
CH2). C NMR d 163.9 (CO), 136.6 (ArC-i), 129.0
ArCH-m), 125.2 (ArCH-p), 120.1 (ArCH-o), 42.8 (CH2).
3
0
CH CH -3 ). C NMR d 171.9 (CO Me), 165.3 (CONH),
(
A
B
0
13
B
A
2
3
.9. 2-(Methylsulfanyl)-N-phenylacetamide (18)
149.0 (ArC-1), 137.4 (ArC-i), 133.4 (ArCH-5 and ArCH-
), 130.8 (ArC-2), 129.0 (ArCH-4), 128.8 (ArCH-o),
125.2 (ArCH-3), 124.5 (ArCH-p), 120.0 (ArCH-m),
6
To a solution of 17 (257 mg, 1.52 mmol) in anhydrous
MeOH (35 mL) was added sodium thiomethoxide (95%,
0 0 0
53.0 (OCH ), 35.9 (C-1 ), 32.8 (CH-2 ), 21.0 (CH -3 ).
3 2
1
1
23.7 mg, 1.68 mmol). The reaction was stirred at rt for
5 min. The solvent was removed in vacuo in a fume cup-
The structure of 20 was confirmed by X-ray crystallography
(Fig. 3).
board. The residue was diluted with CH Cl (25 mL) and
2
2
0 0 0 0
3.12. Ethyl (1 R*,2 R*,3 R*)-2-oxo-3 -pyridin-2-yl-1,2-
washed with satd K CO solution (15 mL) and dried to yield
2
3
0 0
dihydrospiro[cyclopropane-1 ,3-indole]-2 -carboxylate
a cream solid (270.1 mg, 1.5 mmol, 98%, R ¼0.52 in 30%
f
1
0 0 0 0
(22a), ethyl (1 R*,2 R*,3 S*)-2-oxo-3 -pyridin-2-yl-1,2-
EtOAc/petrol). H NMR data were in close agreement
with the literature values. MS (EI) m/z 181 (49%) [M ],
135 (45%) [MH ꢁSMe]. HRMS (EI) Calcd for
C H NOS [M ]: 181.0561; found: 181.0562. H NMR
2
1
ꢃ
+
0 0
dihydrospiro[cyclopropane-1 ,3-indole]-2 -carboxylate
(23a) and ethyl (1 R*,2 S*,3 S*)-2-oxo-3 -pyridin-
+
0
0
0
0
ꢃ
+
1
0
2-yl-1,2-dihydrospiro[cyclopropane-1 ,3-indole]-
0
9
11
d 8.85 (br s, 1H, NH), 7.54 (d, J 7.5 Hz, 2H, ArCH-o),
.29 (t, J 7.9 Hz, 2H, ArCH-m), 7.09 (t, J 7.4 Hz, 1H,
ArCH-p), 3.28 (s, 2H, CH ), 2.14 (s, 3H, CH ). C NMR
2 -carboxylate (24a)
7
1
3
To a solution of ethyl dimethylsulfonium acetate bromide
(173.6 mg, 7.6ꢂ10 mol) in anhydrous MeCN (3.7 mL)
2
3
ꢁ
4
d 167.0 (CO), 137.4 (ArC-i), 128.7 (ArCH-m), 124.3
(
ꢁ
4
ArCH-p), 119.7 (ArCH-o), 38.7 (CH ), 16.0 (CH ).
2
was added DBU (0.07 mL, 4.7ꢂ10 mol) and the solution
3
was stirred under an N atmosphere at rt for 30 min. A solu-
2
1
7
ꢁ4
3.10. 2-Anilino-2-oxoethyl-(dimethyl)sulfonium
iodide (19)
tion of 21a (108.8 mg, 4.7ꢂ10 mol) was added and stir-
ring was maintained for 24 h. The reaction mixture was
diluted with EtOAc (50 mL) and washed with 10% HCl
solution (2ꢂ40 mL). The organic extracts were dried and
evaporated under reduced pressure to yield a crude product
To a solution of 18 (270.1 mg, 1.5 mmol) in anhydrous DCM
2 mL) was added MeI (0.94 mL, 15 mmol). The flask was
(
ꢁ
4
sealed and the Superseal was tightly wrapped with Parafilm
and left for stirring at rt for 2 days. The reaction was found to
be incomplete by TLC analysis and further MeI (0.94 mL,
as a peach coloured solid (155.6 mg, 5.0ꢂ10 mol).
1
H NMR analysis of the crude reaction mixture revealed
a 5.6:1.8:1 mixture of 22a, 23a and 24a, respectively. The
crude mixture was purified by column chromatography
using 30–50% EtOAc/petrol as eluent to yield 22a as clear
1
2
5 mmol) was added and the mixture was left for further
days at rt. The mixture was diluted with CH Cl (5 mL)
2
2
ꢁ
4
and 19 was filtered off as an off-white solid (253.3 mg,
.84ꢂ10 mol, 52%, R ¼0 in 30% EtOAc/petrol) and the
needle-like crystals (41.3 mg, 1.3ꢂ10 mol, 27%, R ¼
f
-
4
ꢀ
7
starting material 18 was recovered from the filtrate
0.24 in 50% EtOAc/petrol, mp 178–180 C) and 24a as a
f
ꢁ5
cream oil (17.4 mg, 5.6ꢂ10 mol, 12%, R ¼0.31 in 50%
f
ꢁ4
(
(
105.1 mg, 5.8ꢂ10 mol, 39%). MS (ESI+ve) m/z 196
EtOAc/petrol). Compound 23a was unable to be isolated
as a pure sample but was identified as the cis-isomer and
+
ꢁ
100%) [M ꢁI], (ESIꢁve) m/z 127 (100%) [I ]. The

1198
S. R. Yong et al. / Tetrahedron 63 (2007) 1191–1199
1
0
1
had: H NMR d 3.57 (d, J 9.9 Hz, 1H, CH-2 ) and 3.08 (d,
0
H NMR (500 MHz) d 9.40 (br s, 1H, NH), 8.57 (br s, 1H,
00 00
ArCH-2 ), 8.49 (br s, 1H, ArCH-4 ), 7.66 (d, J 8.5 Hz,
H, ArCH-6 ), 7.46 (d, J 7.5 Hz, 1H, ArCH-4), 7.22 (t,
00
J 10.2 Hz, 1H, CH-3 ).
0
J 7.7 Hz, 2H, ArCH-6 and ArCH-5 ), 7.03 (t, J 7.5 Hz,
0
1
ꢃ
+
Compound 22a: MS (EI) m/z 308 (26%) [M ], 262 (46%),
35 (94%), 217 (31%), 205 (44%). HRMS (EI+ve) Calcd
2
for C H N O [M ]: 308.1161; found: 308.1165.
1H, ArCH-5), 6.82 (d, J 7.7 Hz, 1H, ArCH-7), 4.27–4.15
(m, 2H, CH ), 3.73 (d, J 8.0 Hz, 1H, CH-2 ), 3.34 (d,
+
1
0
J 8.0 Hz, 1H, CH-3 ), 1.26 (t, J 7.7 Hz, 3H, CH ).
H
NMR (500 MHz) d 8.88 (br s, 1H, NH), 8.52 (d, J 4.0 Hz,
1
8
16
2
3
2
0
C NMR (125 MHz) d 173.7 (C-2), 167.9 (CO Et), 150.4
3
0
d, J 7.5 Hz, 1H, ArCH-4), 7.33 (d, J 7.5 Hz, 1H, ArCH-
0
00
13
1
H, ArCH-3 ), 7.62 (dt, J 7.5, 1.5 Hz, 1H, ArCH-5 ), 7.45
2
0
0
00
(ArCH-6 ), 128.8 (ArC-1 ), 127.9 (ArCH-6), 125.9 (ArC-
(
(ArCH-2 ), 148.4 (ArCH-4 ), 141.5 (ArC-7a), 136.6
0
.7 Hz, 1H, ArCH-5), 6.74 (d, J 7.5 Hz, 1H, ArCH-7),
0
00
00 00
6
7
4
3
), 7.18–7.14 (m, 2H, ArCH-4 and ArCH-6), 6.99 (t, J
0
0
3a), 122.8 (ArCH-5 ), 122.6 (ArCH-4), 122.1 (ArCH-5),
110.0 (ArCH-7), 61.7 (CH CH ), 39.5 (C-3), 37.0 (CH-2 ),
0
.46 (d, J 8.0 Hz, 1H, CH-3 ), 1.25 (t, J 7.0 Hz, 3H, CH ).
0
36.6 (CH-3 ), 14.1 (CH CH ). The structure of 22b was
.26–4.14 (m, 2H, CH ), 3.93 (d, J 8.0 Hz, 1H, CH-2 ),
2
2
3
0
C NMR (125 MHz) d 173.8 (C-2), 168.1 (CO Et), 153.1
0
confirmed by X-ray crystallography (Fig. 4).
3
3
2
1
3
2
0
0
ArCH-5 ), 127.7 (ArCH-6), 126.1 (ArC-3a), 123.9
00
(
(
(
(
(
ArC-1 ), 149.1 (ArCH-3 ), 141.4 (ArC-7a), 136.1
0
0
0
0
ArCH-5), 109.8 (ArCH-7), 61.5 (CH ), 40.7 (CH-2 ), 39.5
00
Acknowledgements
ArCH-6 ), 122.8 (ArCH-4), 122.4 (ArCH-4 ), 122.1
0
2
0
We thank the University of Wollongong for financial support
and the Australian Research Council for a Ph.D. scholarship
to S.R.Y.
C-3), 36.8 (CH-3 ), 14.1 (CH ).
3
1
Compound 24a: H NMR d 8.60 (br s, 1H, NH), 8.55 (dm, J
00
.8 Hz, 1H, ArCH-3 ), 7.51 (dt, J 7.5, 1.9 Hz, 1H, ArCH-
), 7.19 (t, J 4.0 Hz, 1H, ArCH-6 ), 7.11 (ddd, J 7.5, 4.8,
4
5
1
6
0
0
00
Supplementary data
00
.2 Hz, 1H, ArCH-4 ), 7.03 (dt, J 7.5, 1.5 Hz, 1H, ArCH-
), 6.80 (d, J 7.8 Hz, 1H, ArCH-7), 6.75 (d, J 7.5 Hz, 1H,
Details of the X-ray crystal/refinement data (2 pages).
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2006.11.051.
ArCH-4), 6.68 (dt, J 7.2, 1.0 Hz, 1H, ArCH-5), 4.21–4.13
(
0
J 8.1 Hz, 1H, CH-3 ), 1.21 (t, J 7.0 Hz, 3H, CH ).
m, 2H, CH ), 3.86 (d, J 8.1 Hz, 1H, CH-2 ), 3.82 (d,
2
0
C NMR d 174.7 (C-2), 167.2 (CO Et), 152.9 (ArC-1 ),
3
1
3
00
48.8 (ArCH-3 ), 141.3 (ArC-7a), 136.5 (ArCH-5 ), 127.5
2
0
0
00
ArCH-6), 126.1 (ArC-3a), 125.6 (ArCH-6 ), 122.6
1
References and notes
00
(
(
(
0
ArCH-7), 61.4 (CH ), 40.2 (CH-2 ), 40.1 (C-3), 35.7 (CH-
0
ArCH-4 ), 122.5 (ArCH-4), 121.8 (ArCH-5), 109.7
0
1. Williams, R. M.; Cox, R. J. Acc. Chem. Res. 2003, 36, 127–139;
Lopez-Gresa, M. P.; Gonzalez, M. C.; Ciavatta, L.; Ayala, I.;
Moya, P.; Primo, J. J. Agric. Food Chem. 2006, 54, 2921–
2
0
3
), 14.2 (CH3).
2
925; Mugishima, T.; Tsuda, M.; Yuu, K.; Haruaki, I.;
0
dihydrospiro[cyclopropane-1,3 -indole]-2-carboxylate
0
0
0
0
0
3
.13. Ethyl (1 R*,2 R*,3 R*)-2 -oxo-3-pyridin-3-yl-1 ,2 -
0
Fukushi, E.; Kawabata, J.; Watanabe, M.; Akao, K.;
Kobayashi, J. J. Org. Chem. 2005, 70, 9430–9435.
0
dihydrospiro[cyclopropane-1,3 -indole]-2-carboxylate
0
0
0
0
0
(
22b), ethyl (1 R*,2 R*,3 S*)-2 -oxo-3-pyridin-3-yl-1 ,2 -
2. (a) Jiang, T.; Kuhen, K. L.; Wolff, K.; Yin, H.; Bieza, K.;
Caldwell, J.; Bursulaya, B.; Wu, T. Y.-H.; He, Y. Bioorg.
Med. Chem. Lett. 2006, 16, 2105–2108; (b) Ding, K.; Lu, Y.;
Nikolovska-Coleska, Z.; Wang, G.; Qiu, S.; Shangary, S.;
Gao, W.; Qin, D.; Stuckey, J.; Krajewski, K.; Roller, P. P.;
Wang, S. J. Med. Chem. 2006, 49, 3432–3435; (c)
Rajeswaran, W. G.; Labroo, R. B.; Cohen, L. A. J. Org.
Chem. 1999, 64, 1369–1371; (d) Robertson, D. W.;
Krushinski, J. H.; Pollock, G. D.; Wilson, H.; Kauffman,
R. F.; Hayes, J. S. J. Med. Chem. 1987, 30, 824–829.
3. For some recent synthetic studies, see: Alcaide, B.; Almendros,
P.; Rodriguez-Acebes, R. J. Org. Chem. 2006, 71, 2346–2351;
Poornachandran, M.; Muruganantham, R.; Raghunathan, R.
Synth. Commun. 2006, 36, 141–150; Nair, V.; Vellalath, S.;
Poonoth, M.; Mohan, R.; Suresh, E. Org. Lett. 2006, 8, 507–
509; Alcaide, B.; Almendros, P.; Rodriguez-Acebes, R.
Chem.–Eur. J. 2005, 11, 5708–5712.
0
23b) and ethyl (1 R*,2 S*,3 S*)-2 -oxo-3-pyridin-
0
0
0
0
(
3
2
0
0
0
-yl-1 ,2 -dihydrospiro[cyclopropane-1,3 -indole]-
-carboxylate (24b)
The title compounds were prepared using a method similar
to that described above for the synthesis of 22a–24a except
1
7
ꢁ4
using 21b (104.4 mg, 4.7ꢂ10 mol). After extraction the
crude product was a peach coloured powder (101.7 mg,
ꢁ
4
1
3
.3ꢂ10 mol, 70%). H NMR analysis of the crude reac-
tion mixture revealed a 43:7:1 mixture of 22b, 23b and
4b, respectively. The crude product was purified by column
chromatography using 40–60% EtOAc/petrol as eluent to
2
ꢁ
4
yield 22b as cream needles (88.2 mg, 2.9ꢂ10 mol, 61%,
ꢀ
pounds 23b and 24b could not be isolated as pure samples
R ¼0.38 in 10% MeOH/CHCl , mp 208–210 C). Com-
f
3
but were identified as the cis and trans-isomers, respectively.
Compound 23b: H NMR d 3.45 (dd, J 9.6, 0.6 Hz, 1H,
4. Yong, S. R.; Williams, M. C.; Pyne, S. G.; Ung, A. T.; Skelton,
B. W.;White, A. H.;Turner, P. Tetrahedron 2005, 61, 8120–8129.
5. Bennett, G. B.; Mason, R. B.; Shapiro, M. J. J. Org. Chem.
1978, 43, 4383–4385.
1
0
0
CH-2 ) and 3.05 (d, J 9.6 Hz, 1H, CH-3 ). Compound 24b:
0
J 5.1 Hz, 1H, CH-3 ).
1
H NMR d 3.65 (d, J 5.7 Hz, 1H, CH-2 ) and 3.63 (d,
0
6. Franke, A. Liebigs Ann. Chem. 1978, 5, 717–725.
7
. For the synthesis of N-alkyl derivatives of 4 employing a reduc-
tive cyclization reaction to prepare the cyclopropane ring,
see: Shanmugam, P.; Vaithiyanathan, V.; Viswambharan, B.
Tetrahedron 2006, 62, 4342–4348.
ꢃ
+
Compound 22b: MS (EI) m/z 308 (46%) [M ], 262 (57%)
+
+
[M ꢁOEt], 235 (96%) [M ꢁCO Et]. HRMS (EI) Calcd
for C H N O [M ]: 308.1161; found: 308.1158.
2
ꢃ
+
18 16 2 3

S. R. Yong et al. / Tetrahedron 63 (2007) 1191–1199
1199
8
9
. 2-Pyridyl and 3-pyridyldiazomethane are known compounds
but have found little synthetic application, see: Eistert, B.;
Kurze, W.; Mueller, G. W. Liebigs Ann. Chem. 1970, 732,
1–6; Chapman, O. L.; Sheridan, R. S.; LeRoux, J. P. J. Am.
Chem. Soc. 1978, 100, 6245–6247.
14. (a) Payne, G. B. J. Org. Chem. 1967, 32, 3351–3355; (b)
Curley, R. W., Jr.; DeLuca, H. F. J. Org. Chem. 1984, 49,
1944–1946; (c) Collado, I.; Dominguez, C.; Ezquerra, J.;
Pedregal, C.; Monn, J. A. Tetrahedron Lett. 1997, 38, 2133–
2136.
15. See for example: Ma, D.; Jiang, Y. Tetrahedron: Asymmetry
2000, 11, 3727–3736; Heras-Lopez, A. M.; Pino-Gonzalez,
M. S.; Sarabia-Garcia, F.; Lopez-Herrera, F. J. J. Org. Chem.
1998, 63, 9630–9634.
16. Gamble, A. B.; Keller, P. A. Unpublished work, University of
Wollongong, 2006.
17. Walker, G. N.; Smith, R. T.; Weaver, B. N. J. Med. Chem. 1965,
8, 626–637.
18. Friebolin, H. Basic One- and Two-dimensional NMR
Spectroscopy; VCH: Weinheim, 1991; p 81.
19. Trost, B. M. J. Am. Chem. Soc. 1967, 89, 138–142.
20. Jaszay, Z. M.; Petnehazy, I.; Toke, L. Synthesis 1989, 745–747.
21. Tamura, Y.; Uenishi, J.-I.; Maeda, H.; Choi, H.-D.; Ishibashi,
H. Synthesis 1981, 534–537.
. Chiericato, M.; Croce, P. D.; Licandro, E. J. Chem. Soc., Perkin
Trans. 1 1979, 211–213.
1
0. Ellis, D.; Kuhen, K. L.; Anaclerio, B.; Wu, B.; Wolff, K.; Yin,
H.; Bursulaya, B.; Caldwell, J.; Karanewsky, D.; He, Y. Bioorg.
Med. Chem. Lett. 2006, 16, 4246–4251.
1
1. Walker, G. N. J. Am. Chem. Soc. 1956, 78, 3698–3701;
Selvakumar, N.; Reddy, B. Y.; Kumar, G. S.; Iqbal, J.
Tetrahedron Lett. 2001, 42, 8395–8398; Hinman, R. L.;
Bauman, C. P. J. Org. Chem. 1964, 29, 2431–2437.
12. Selvakumar, N.; Azhagan, A. M.; Srinivas, D.; Krishna, G. G.
Tetrahedron Lett. 2002, 43, 9175–9178.
13. CCDC deposition numbers for compounds 3, 11, 12, 13, 20,
21a, 21b and 22b are 622516–622523, respectively, see
Supplementary data for crystal/refinement data.