Synthesis of the marine dibromooxoindoline convolutamydine C

Article abstract of DOI:10.1039/a700683g

A synthesis of the marine 4,6-dibromo-3-hydroxyoxoindoline convolutamydine C 3 is described. The key steps are the rhodium(II) perfluorobutyramide catalysed cyclisation of diazoamide 17 to give the oxoindoline 18, and the subsequent high yielding one-pot hydrolysis-decarboxylation-oxidation of 19 to 20. X-Ray crystal structures have been determined for the diazoamides 10 and 17 and for the oxoindolines 11 and 13.

Full text of DOI:10.1039/a700683g

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Synthesis of the marine dibromooxoindoline convolutamydine C
Soyfur Miah,a Christopher J. Moody,*,†,a Ian C. Richardsb and
Alexandra M. Z. Slawin‡,a
a
Department of Chemistry, Loughborough University, Loughborough, Leicestershire,
UK LE11 3TU
b AgrEvo Limited, Chesterford Park, Saffron Walden, Essex, UK CB10 1XL
A synthesis of the marine 4,6-dibromo-3-hydroxyoxoindoline convolutamydine C 3 is described. The
key steps are the rhodium(II) perfluorobutyramide catalysed cyclisation of diazoamide 17 to give the
oxoindoline 18, and the subsequent high yielding one-pot hydrolysis–decarboxylation–oxidation of 19 to
20. X-Ray crystal structures have been determined for the diazoamides 10 and 17 and for the oxoindolines
11 and 13.
Marine organisms continue to be a rich source of interesting
natural products,1 and recently a new family of alkaloids was
isolated from the Floridian bryozoan Amathia convoluta.2,3 The
compounds, named the convolutamydines, for example 1–4,
contain the novel 4,6-dibromo-3-hydroxyoxoindoline structure
and only differ from each other in the nature of the second
substituent at C-3. In continuation of our interest in oxoindo-
lines,4,5 we now report the details of the first synthesis of convo-
lutamydine C.
perfluorobutyramide did not result in the desired attack on
the aromatic ring to give an oxoindoline; rather attack on
the tert-butoxy carbonyl group occurred to give, after loss of
2-methylpropene, the oxazolidinedione 7 as the sole product
(by 1H NMR spectroscopy) in 77% isolated yield (Scheme
2).11
Br
Br
Br
N2
N
CO2Et
O
i
ii
Br
HO
R
1
2
3
4
R = CH2COMe
R = CH2CH2Cl
R = Me
convolutamydine A
convolutamydine B
convolutamydine C
convolutamydine D
Br
CO2H Br
NHBoc
Br
Boc
O
R = CH=CH2
5
N
H
6
Br
iii
Results and discussion
Br
Br
Although there are several methods for the synthesis of oxo-
indolines,6 we5 and others7 have been interested in developing
routes based on intramolecular aromatic C᎐H insertion reac-
tions of rhodium carbenoids (Scheme 1).8 In particular we have
O
O
Br
N
Br
N
–
CO2Et
CO2Et
O
O
+
ButO
Z
O
N2
Z
7
X
X
O
Scheme 2 Reagents and conditions: i, DPPA, Et3N, ButOH (82%);
ii, BunLi, THF, Ϫ78 ЊC, then EtO2CCN2COCl (46%; 100% based on
unconsumed 5); iii, cat. Rh2(NHCOC3F7)4, CH2Cl2 (77%)
N
R
N
R
O
Scheme 1
established that catalysts bearing perfluorinated carboxamide
ligands are particularly effective for such processes,5 and there-
fore we wished to apply this methodology to the synthesis of
the dibromooxoindoline ring of the convolutamydines.
The starting material was N-tert-butoxycarbonyl-3,5-
dibromoaniline 5, readily available in high yield from 3,5-
dibromobenzoic acid by reaction with diphenylphosphoryl
Given the failure of the N-tert-butoxycarbonyldiazoamide
6 to cyclise to the aromatic ring upon treatment with a
rhodium() catalyst, an alternative N-protecting group was
investigated. Hence the N-benzyldiazoamide 10 was prepared
as shown in Scheme 3. Diazoamide 10 is highly crystalline and
its structure was confirmed by X-ray crystallography (Fig. 1);12
the structure shows that, in common with related diazoamides,5
the diazo group adopts a conformation in which it is syn to the
amide carbonyl and anti to the ester carbonyl, thereby placing
the diazo carbon towards the N-aryl group. Treatment of
diazoamide 10 with a catalytic amount of rhodium() per-
fluorobutyramide resulted in intramolecular attack upon the
aromatic ring and formation of the oxoindoline 11 in 98%
yield (Scheme 3). The structure of oxoindoline 11 was con-
firmed by X-ray crystallography (Fig. 2).12 Oxoindoline 11 was
cleanly C-methylated to give 12. With the intention of remov-
ing the 3-ester group by hydrolysis and decarboxylation with
subsequent oxidation in a separate step of the resulting
3-methyloxoindoline, ideally by air oxidation,13 ester 12 was
azide (DPPA), triethylamine and tert-butyl alcohol in
a
modified Curtius rearrangement.9 Initially we attempted to
use the tert-butoxycarbonyl group as the N-protecting group
for the whole synthesis and therefore the carbamate 5 was con-
verted into the diazocarbonyl compound 6 directly by treat-
ment of its lithium anion with ethyl diazomalonyl chloride.5,10
However, treatment of diazo compound 6 with rhodium()
† Present address: Department of Chemistry, University of Exeter,
Stocker Road, Exeter, UK EX4 4QD.
‡ Author to whom all correspondence regarding the X-ray crystal-
lography should be addressed.
J. Chem. Soc., Perkin Trans. 1, 1997
2405

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Br
Br
i
ii
5
Boc
Br
N
Br
NHR
R
9
16
R = Bn
R = PMB
8
15
R = Bn
R = PMB
iii
Br
Br
CO2Et
N2
CO2Et
iv
O
N
Br
N
O
Br
R
R
11
18
R = Bn
R = PMB
10
17
R = Bn
R = PMB
v
Fig. 1 X-Ray crystal structure of the diazoamide 10
Br
Br
Me
HO
CO2Et
O
Me
vi
O
N
N
R
Br
Br
R
13
20
21
R = Bn
12
19
R = Bn
R = PMB
R = PMB
R = 4-HOBn
20
vii
viii
Br
Me
CO2Et
Br
AcO
Me
O
N
O
Bn
N
Br
14
R
24 R = PMB
25 R = H
ix
Fig. 2 X-Ray crystal structure of the oxoindoline-3-carboxylate 11
Scheme 3 Reagents and conditions: i, NaH, DMF, ArCH2X; ii,
CF3CO2H, CH2Cl2 (69% from 3,5-dibromobenzoic acid/77% from 5);
iii, EtO2CCN2COCl, Et3N (61%/66%); iv, cat. Rh2(NHCOC3F7)4,
CH2Cl2 (98%/99%); v, NaH, DMF, MeI (68%/66%); vi, NaOH, air, aq.
THF (99%/99%) [the first yield quoted refers to the N-benzyl deriv-
ative; the second to the N-(4-methoxybenzyl) derivative]; vii, H2–PdCl2,
HOAc, EtOAc (30%); viii, Ac2O, Et3N, DMAP, CH2Cl2 (99%); ix,
CAN, aq. MeCN (82%)
All attempts to debenzylate oxoindoline 13 using either Li–
NH3,15 aluminium chloride16 or trifluoroacetic acid 17 were
unsuccessful. Likewise attempts to debenzylate the ester 12
using formic acid 18 or catalytic hydrogenation 19 also failed. In
the latter case, slow selective mono-debromination at C-6
occurred to give ethyl 1-benzyl-4-bromo-3-methyl-2-oxoindol-
ine-3-carboxylate 14.
heated in aqueous alkali in air. Under these conditions, not
only was the ester group removed, but also the hydroxy group
was introduced, to give the desired N-protected natural prod-
uct, the 3-hydroxyoxoindoline 13 in 99% yield (Scheme 3). The
structure of this key oxoindoline 13 was confirmed by X-ray
crystallography (Fig. 3).12 The ease of the decarboxylative oxi-
dation of oxoindoline 12 is remarkable; in a related example
of such an aerial oxidation to give a 3-hydroxyoxoindole,13a the
3-position already contains a hydrogen, i.e. no prior hydrolysis–
decarboxylation is necessary, although there is an example of
a hydrolysis–decarboxylation–oxidation sequence (55%) in pyr-
roloquinolines.13b Related oxidations of oxoindoles to the 3-
hydroxy derivatives usually require conditions such as oxygen–
Rose Bengal–NaOMe.14
With the failure to remove the N-benzyl protecting group, the
sequence was repeated using the more labile p-methoxybenzyl
(PMB) group (Scheme 3). Thus the carbamate 5 was converted
into the diazoamide 17 by an analogous route; again the diazo-
amide 17 was highly crystalline and its X-ray crystal structure
(Fig. 4) showed a very similar conformation to the diazoamide
10.12 Diazoamide 17 was converted into the 3-hydroxyoxo-
indoline 20 without incident, with the decarboxylative oxid-
ation step again proceeding in excellent yield (Scheme 3). Frus-
tratingly all attempts to remove the PMB group from 20 under
oxidative conditions using ceric ammonium nitrate (CAN) were
unsuccessful;20 likewise oxidation of the corresponding N-(4-
hydroxybenzyl) derivative 21, readily obtained by boron tri-
bromide demethylation of 20, with DDQ 21 did not result in
2406
J. Chem. Soc., Perkin Trans. 1, 1997

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cerium ammonium nitrate proceeded smoothly in 82% yield
to give O-acetyl convolutamydine C 25 (Scheme 3). Finally
hydrolysis of the acetate gave convolutamydine C 3 in 91%
yield.
Since the submission of this manuscript, a synthesis of
convolutamydine A has appeared (S. J. Garden, J. C. Torres,
A. A. Ferreira, R. B. Silva and A. C. Pinto, Tetrahedron Lett.,
1997, 38, 1501).
Experimental
Commercially available reagents were used throughout without
further purification; solvents were dried by standard pro-
cedures. Ether refers to diethyl ether and light petroleum to the
fraction with bp 40–60 ЊC. Analytical thin layer chrom-
atography was carried out using aluminium-backed plates
coated with Merck Kieselgel 60 GF254. Plates were visualised
under UV light (at 254 and/or 360 nm). Flash chromatography
was carried out using Merck Kieselgel 60 H silica or Matrex
silica 60. Fully characterised compounds were chromato-
graphically homogeneous. IR spectra were recorded in the
range 4000–600 cmϪ1 using a Nicolet FT-205 spectrometer,
Fig. 3 X-Ray crystal structure of the 3-hydroxyoxoindoline 13
1
with internal calibration. H and 13C spectra were recorded in
deuteriochloroform (unless otherwise stated) using Bruker
AC-250 and Bruker DPX-400 instruments: J values were
recorded in Hz. High and low resolution mass spectra were
recorded on a Kratos MS80 instrument and at the EPSRC
Mass Spectrometry Service at Swansea. In the mass spectra of
dibromo compounds, the molecular ion is taken as the 79Br81Br
peak unless otherwise stated.
3,5-Dibromo-N-(tert-butoxycarbonyl)aniline 5
A mixture of 3,5-dibromobenzoic acid (4.94 g, 17.65 mmol),
triethylamine (2.56 ml, 18.34 mmol) and diphenylphosphoryl
azide (5.05 g, 17.65 mmol) in tert-butyl alcohol (30 ml) was
heated under reflux for 18 h. The mixture was cooled and con-
centrated under reduced pressure to give a viscous yellow oil
which was taken up in dichloromethane (200 ml) and washed
with aqueous sodium hydroxide (10%; 200 ml), water (2 × 200
ml) and brine (200 ml). Drying over MgSO4 followed by con-
centration under reduced pressure afforded the crude product
which could be used without further purification, or purified
by flash chromatography on silica gel (9:1 then 7:1 light
petroleum–ether) to give the title compound 5 (5.08 g, 82%) as a
crystalline, colourless solid, mp 112 ЊC (n-pentane) (Found: C,
37.5; H, 3.5; N, 3.85. C11H13Br2NO2 requires C, 37.6; H, 3.7;
N, 4.0%) (Found: Mϩ, 350.9296. C11H13Br2NO2 requires M,
350.9294); νmax(CHCl2)/cmϪ1 3423, 3057, 1735, 1513 and 1154;
δH (250 MHz; CDCl3) 1.51 (9H, s), 6.49 (1H, br s), 7.31 (1H, t, J
1.6) and 7.51 (2H, d, J 1.6); δC(100.6 MHz; CDCl3) 28.23 (CH3),
81.55 (C), 119.90 (CH), 123.04 (C), 128.39 (CH), 140.62 (C)
Fig. 4 X-Ray crystal structure of the diazoamide 17
Br
Br
Me
CO2Et
O
COCH3
NH2
ii
i
+
3
19
N
H
Br
Br
and 152.02 (C᎐O); m/z 351 (Mϩ, 2%), 295 (4), 251 (7) and 57
᎐
22
23
(100).
Scheme 4 Reagents and conditions: i, CAN, aq. MeCN (95%); ii,
NaOH, air, aq. THF (18% of 3 ϩ 63% of 23)
Ethyl 2-diazo-3-(3,5-dibromo-N-tert-butoxycarbonylanilino)-3-
oxopropionate 6
N-deprotection. However, treatment of the oxoindoline 19 with
CAN did result in clean removal of the PMB group, and gave
the oxoindoline 22 in 95% yield (Scheme 4). However, as
expected, the decarboxylative oxidation of 22 proved much
more difficult than with the N-protected derivative 20. Never-
theless the desired oxidation did proceed to give convolut-
amydine C 3 in 18% yield, although the major product was
the acetophenone 23 resulting from further hydrolysis and
oxidation under the reaction conditions.
In view of the poor yield of the natural product, an altern-
ative route incorporating additional protection–deprotection
steps was adopted. Thus the tertiary alcohol 20 was protected
(99%) as its acetate 24 by treatment with acetic anhydride under
standard conditions. Oxidative removal of the PMB group with
A solution of the carbamate 5 (0.500 g, 1.42 mmol) in dry THF
(12.5 ml) was cooled to Ϫ78 ЊC and then treated with BunLi (1.6
 in hexanes; 0.99 ml, 1.58 mmol). The resulting mixture was
stirred at Ϫ78 ЊC for 20 min and then treated dropwise with
ethyl 2-diazomalonyl chloride (0.280 g, 1.58 mmol) and stirring
maintained for a further 2 h. The reaction was then quenched
with water (10 ml) and allowed to warm to room temperature.
The organic layer was set aside and the aqueous extracted with
ether (20 ml) and dichloromethane (20 ml). The organic
extracts were combined, washed with brine (20 ml) and dried
over MgSO4 before preadsorbing on silica and subjecting to
flash chromatography to give recovered starting carbamate 5
(0.269 g, 54%) and the title compound 6 (0.317 g, 46%) as a
colourless solid, mp 63–65 ЊC (Found: MHϩ, 491.9588.
J. Chem. Soc., Perkin Trans. 1, 1997
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C12H18Br2N3O5 requires M, 491.9594); νmax(CHCl3)/cmϪ1 2985,
2142, 1731, 1663, 1373, 1152 and 1071; δH (250 MHz; CDCl3)
1.34 (3H, t, J 7.1), 1.44 (9H, s), 4.31 (2H, q, J 7.1), 7.36 (2H, d, J
1.6) and 7.63 (1H, t, J 1.6); δC(100.6 MHz; CDCl3) 14.36 (CH3),
27.84 (CH3), 61.95 (CH2), 84.36 (C), 122.48 (C), 130.43 (CH),
J 5.3), 6.67 (2H, d, J 1.6), 6.96 (1H, t, J 1.6) and 7.40–7.24
(5H, m); δC(100.6 MHz; CDCl3) 48.33, 114.69, 123.05, 123.88,
127.85, 128.06, 129.23, 138.41 and 150.42; m/z 341 (Mϩ, 11%),
91 (100) and 28 (53).
133.66 (CH), 140.11 (C), 151.32 (C᎐O), 160.63 (C᎐O) and
Ethyl 2-diazo-3-(N-benzyl-3,5-dibromoanilino)-3-oxopropionate
10
᎐
᎐
164.61 (C᎐O); m/z 492 (MHϩ, <1%), 464 (M Ϫ N , <1%), 407
᎐
2
(18), 392 (12), 335 (10), 291 (8), 262 (16) and 57 (100).
A solution of N-benzyl-3,5-dibromoaniline 9 (0.240 g, 5.57
mmol) in dichloromethane (80 ml) was treated with triethyl-
amine (1.24 g, 12.26 mmol, 1.71 ml) and ethyl 2-diazomalonyl
chloride (0.984 g, 5.57 mmol). The mixture was stirred at room
temperature for 4 h, and then heated under reflux for 40 min.
The solution was allowed to cool, preadsorbed onto silica
and subjected to flash chromatography (9:1 then 8:1 light
petroleum–ether) to give recovered starting aniline 9 (0.649 g,
34%) and the title compound 10 (1.625 g, 61%) as a bright yellow
crystalline solid, mp 119–120 ЊC (light petroleum–ether)
(Found: C, 44.7; H, 2.95; N, 8.7. C18H15Br2N3O3 requires C,
44.9; H, 3.1; N, 8.7%) (Found: MHϩ, 479.9558. C18H15Br2N3O3
requires M, 479.9558); νmax(CH2Cl2)/cmϪ1 2134, 1719, 1580 and
1374; δH (250 MHz; CDCl3) 1.15 (3H, t, J 7.1), 4.04 (2H, q,
J 7.1), 4.97 (2H, s), 7.22 (2H, d, J 1.6), 7.40–7.24 (5H, m) and
7.49 (1H, t, J 1.6); δC(100.6 MHz; CDCl3) 14.58 (CH3), 54.87
Ethyl 3-(3,5-dibromophenyl)-2,4-dioxo-4,5-dihydrooxazole-5-
carboxylate 7
A solution of the diazoamide 6 (0.032 g, 0.065 mmol) in di-
chloromethane (2 ml) was treated with rhodium() perfluoro-
butyramide (1 mg, 1 mol%) and the mixture was stirred for
2 h. When all the diazoamide had been consumed (1H NMR
spectroscopy) the mixture was filtered through Celite, concen-
trated under reduced pressure to give an oil, which was tritur-
ated with n-pentane–ether and recrystallised to give the title
compound 7 (20 mg, 77%), mp 109–110 ЊC (n-pentane–ether)
(Found: C, 35.0; H, 2.0; N, 3.3. C12H9Br2NO5 requires C, 35.4;
H, 2.2; N, 3.4%) (Found: Mϩ, 406.8823. C12H9Br2NO5 requires
M, 406.8829); νmax(CH2Cl2)/cmϪ1 2987, 1838, 1755, 1566, 1447,
1338, 1191, 1168 and 1105; δH (250 MHz; CDCl3) 1.39 (3H, t, J
7.1), 4.40 (2H, q, J 7.1), 5.38 (1H, s), 7.63 (2H, t, J 1.6) and 7.75
(1H, t, J 1.6); δC(100.6 MHz; CDCl3) 14.02 (CH3), 64.04 (CH2),
76.50 (CH), 123.24 (C), 127.05 (CH), 132.23 (C), 134.98 (CH),
152.03 (C᎐O), 161.79 (C᎐O) and 164.29 (C᎐O); m/z 407 (Mϩ,
(NCH ), 62.02 (OCH ), 68.68 (C᎐N ), 123.05 (C), 128.17 (CH),
᎐
2
2
2
128.23 (CH), 128.32 (CH), 129.09 (CH), 132.56 (CH), 136.58
(C), 145.65 (C), 161.18 (C᎐O) and 161.94 (C᎐O); m/z 480
᎐
᎐
(MHϩ, 75%), 340 (10) and 108 (8).
᎐
᎐
᎐
13%), 335 (8), 278 (10), 170 (9), 57 (13) and 29 (100).
Ethyl 1-benzyl-4,6-dibromo-2-oxoindoline-3-carboxylate 11
A solution of the diazoamide 10 (0.150 g, 0.312 mmol) in
dry dichloromethane (2.6 ml) was added to a suspension of
rhodium() perfluorobutyramide (6.6 mg, 2 mol%) in dry
dichloromethane (3.8 ml) and the mixture stirred at room tem-
perature for 0.5 h. The reaction mixture was filtered through
Celite and concentrated under reduced pressure to give pure
oxoindoline 11 (0.138 g, 98%) as a colourless solid, mp 152–
153 ЊC (ethanol) (Found: C, 47.9; H, 3.2; N, 3.1. C18H15Br2NO3
requires C, 47.7; H, 3.3; N, 3.1%) (Found: MHϩ, 452.9410.
C18H15Br2NO3 requires M, 452.9400); νmax(CH2Cl2)/cmϪ1 1751,
1742 and 1605; δH (250 MHz; CDCl3) 1.13 (3H, t, J 7.1), 4.30
(2H, m), 4.43 (1H, s), 4.78 (1H, d, J 15.8), 4.97 (1H, d, J 15.8),
6.80 (1H, d, J 1.35) and 7.40–7.20 (6H, m); δC(100.6 MHz;
CDCl3) 14.09 (CH3), 44.38 (NCH2), 54.10 (CH), 62.59 (OCH2),
111.84 (CH), 120.05, 123.37, 123.74, 127.06 (CH), 127.30 (CH),
128.10 (CH), 128.43 (CH), 129.05 (CH), 134.36 (C), 146.12 (C),
164.80 (C᎐O) and 169.74 (C᎐O); m/z 452 (Mϩ, 17%), 380 (12),
N-Benzyl-3,5-dibromo-N-(tert-butoxycarbonyl)aniline 8
A solution of crude carbamate 5 (3.06 g, 8.72 mmol) in DMF
(18 ml) was added to a suspension of sodium hydride (60%
dispersion in mineral oil; 0.384 g, 9.59 mmol) in DMF (18 ml)
whilst cooling in an ice bath, and the resulting mixture was
stirred for 4 h, then treated with benzyl bromide (1.491 g, 8.72
mmol). After stirring for a further 0.5 h, the mixture was
quenched with water (180 ml) and extracted with ether (1 × 180
ml, 2 × 90 ml). The ether extracts were combined and washed
with brine (2 × 90 ml), dried over MgSO4 and concentrated
under reduced pressure to give the crude title compound 8 as a
pale yellow solid (≈3.85 g) which was taken on to the next step
without purification. A sample was recrystallised to give a
colourless solid, mp 64–65 ЊC (light petroleum) (Found: C,
49.0; H, 4.3; N, 3.2. C18H19Br2NO2 requires C, 48.9; H, 4.2;
N, 3.4%) (Found: Mϩ, 440.9764. C18H19Br2NO2 requires M,
440.9764); νmax(CH2Cl2)/cmϪ1 2981, 1702, 1583 and 1158;
δH (400 MHz; CDCl3) 1.43 (9H, s), 4.80 (2H, s), 7.35–7.15 (7H,
m) and 7.44 (1H, t, J 1.6); δC(100.6 MHz; CDCl3) 28.18 (CH3),
53.65 (CH2), 81.59 (C᎐O), 122.24 (C), 127.13 (CH), 128.09
(CH), 128.62 (CH), 131.20 (CH), 137.69 (C), 144.95 (C) and
᎐
᎐
110 (8) and 91 (100).
Ethyl 1-Benzyl-4,6-dibromo-3-methyl-2-oxoindoline-3-carb-
oxylate 12
153.95 (C᎐O); m/z 441 (Mϩ, 1%), 341 (25), 277 (21), 91 (100)
A solution of the oxoindoline 11 (0.100 g, 0.220 mmol) in dry
DMF (3 ml) was added slowly to a stirred, ice-cooled suspen-
sion of sodium hydride (60% dispersion in mineral oil; 0.0096 g,
0.240 mmol) in dry DMF (2 ml) and stirred for 1 h after which
time evolution of hydrogen had ceased. Iodomethane (0.035 g,
0.240 mmol, ≈15 µl) was added and stirring was continued for a
further 3 h whilst allowing the reaction to reach ambient tem-
perature. The reaction mixture was diluted with ether (20 ml)
and water (20 ml). The aqueous layer was extracted with ether
(20 ml then 50 ml); the combined ethereal extracts were washed
with brine, dried (MgSO4), concentrated under reduced pres-
sure and subjected to flash silica gel column chromatography
and recrystallisation to afford the title compound 12 (0.070 g,
68%) as colourless crystals, mp 99–101 ЊC (n-pentane–ether)
(Found: C, 48.7; H, 3.7; N, 3.0. C19H17Br2NO3 requires C,
48.85; H, 3.7; N, 3.0%); νmax(CH2Cl2)/cmϪ1 1752, 1723, 1599,
1572, 1340 and 1110; δH (250 MHz; CDCl3) 1.20 (3H, t, J 7.1),
1.80 (3H, s), 4.21 (2H, dq, J 7.1 and 2.0), 4.77 (1H, d, J 15.9),
5.03 (1H, d, J 15.9), 6.80 (1H, d, J 1.4) and 7.35–7.22 (6H, m);
δC(100.6 MHz; CDCl3) 14.41 (CH3), 18.05 (CH3), 44.45
᎐
and 57 (43).
N-Benzyl-3,5-dibromoaniline 9
A solution of the crude carbamate 8 (≈3.85 g, 8.72 mmol) in
dichloromethane (30 ml), cooled in an ice bath was treated with
trifluoroacetic acid (30 ml). The mixture was stirred at room
temperature for 16 h then concentrated under reduced pressure,
diluted with dichloromethane (50 ml) and washed with aqueous
sodium hydroxide (2 ; 50 ml). The aqueous layer was extracted
with dichloromethane, the organic extracts were combined and
washed with water (50 ml) and brine (50 ml). The solution was
dried (Na2SO4), preadsorbed onto silica and subjected to flash
chromatography and crystallisation to afford the title compound
9 (2.061 g, 69% from 3,5-dibromobenzoic acid) as large yellow
prisms, mp 60–61 ЊC (n-pentane–ether) (Found: C, 45.5; H, 3.0;
N, 4.2. C13H11Br2N requires C, 45.5; H, 3.25; N, 4.1%) (Found:
Mϩ, 340.9246. C13H11Br2N requires M, 340.9240); νmax(CH2Cl2)/
cmϪ1 3445, 3422, 2860, 1590, 1496, 1358, 1109, 1089, 1070, 981
and 822; δH (250 MHz; CDCl3) 4.12 (1H, br s), 4.26 (2H, d,
2408
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
(NCH2), 57.00 (C), 62.75 (OCH2), 112.28 (CH), 119.45 (C),
123.17 (C), 127.26 (CH), 128.41 (CH), 129.24 (CH), 129.38
H, 4.2; N, 2.95. C19H21Br2NO3 requires C, 48.4; H, 4.5; N, 3.0%)
(Found: Mϩ, 470.9871. C19H21Br2NO3 requires M, 470.9869);
νmax(CH2Cl2)/cmϪ1 3048, 2934, 2840, 1699, 1583, 1556, 1514,
1440, 1369, 1266, 1160, 1034, 909 and 858; δH (250 MHz;
CDCl3) 1.44 (9H, s), 3.80 (3H, s), 4.74 (2H, s), 6.88–6.80 (2H,
m), 7.15–7.08 (2H, m), 7.26 (2H, d, J 1.7) and 7.44 (1H, t, J 1.7);
δC(100.6 MHz; CDCl3) 28.62 (CH3), 53.44 (NCH2), 55.65
(OCH2), 81.85 (OC), 114.42 (CH), 122.59 (C), 128.77 (CH),
(CH), 130.05 (C), 134.90 (C), 145.79 (C), 167.48 (C᎐O) and
᎐
174.61 (C᎐O); m/z 469 (Mϩ, 13%), 394 (28) and 91 (100).
᎐
1-Benzyl-4,6-dibromo-3-hydroxy-3-methylindolin-2-one 13
A stirred solution of the ester 12 (18 mg, 0.038 mmol) in THF–
water (3:1; 3.1 ml) was treated with sodium hydroxide pellets
(16 mg, 0.4 mmol) and the resulting mixture heated under reflux
for 18 h under an atmosphere of air. After allowing to cool to
ambient temperature, the suspension was acidified with hydro-
chloric acid (2 ) and the THF was removed under reduced
pressure. The aqueous concentrate was extracted with ether (10
ml and 5 ml). The organic extracts were combined and washed
with water (5 ml), brine (5 ml) and dried over MgSO4. Concen-
tration under reduced pressure gave pure title compound 13 (16
mg, 99%) as colourless prisms, mp 148–149 ЊC (Found: C, 46.4;
H, 2.8; N, 3.2. C16H13Br2NO2 requires C, 46.75; H, 3.2; N, 3.4%)
(Found: Mϩ, 410.9296. C16H13Br2NO2 requires M, 410.9294);
νmax(CH2Cl2)/cmϪ1 3567, 1735, 1600, 1574, 1344, 1164, 1036,
937 and 839; δH (250 MHz; CDCl3) 1.80 (3H, s), 2.67 (1H, br s;
removed by D2O exchange), 4.8 (1H, d, J 15.8), 4.90 (1H, d, J
15.8), 6.80 (1H, d, J 1.6) and 7.38–7.20 (6H, m); δC(100.6 MHz;
CDCl3) 21.71 (CH3), 43.05 (CH2), 73.96 (C), 111.16 (CH),
118.81 (C), 122.68 (C), 126.21 (CH), 127.23 (CH), 127.50 (C),
128.20 (CH), 128.48 (CH), 133.64 (C), 143.93 (C) and 176.46
129.04 (CH), 130.10 (C), 131.64 (CH), 145.28 (C), 154.36 (C᎐O)
᎐
and 159.39 (C); m/z 471 (Mϩ, 2%), 415 (20), 371 (13), 251 (8),
121 (100), 57 (74) and 41 (42).
3,5-Dibromo-N-(4-methoxybenzyl)aniline 16
A solution of the crude carbamate 15 (3.92 g, 8.32 mmol) in
dichloromethane (30 ml) was cooled in an ice bath and treated
with trifluoroacetic acid (30 ml). The mixture was stirred at
room temperature for 80 min, then concentrated under reduced
pressure to give an oil which was taken up in dichloromethane
(50 ml) and washed with dilute aqueous sodium hydroxide
(10%; 50 ml). The aqueous layer was extracted with dichloro-
methane (25 ml). The organic extracts were combined, washed
with water (50 ml), brine (50 ml), dried over Na2SO4, pre-
adsorbed onto silica and subjected to flash chromatography to
give the title compound 16 (2.39 g, 77% for the two steps) as a
colourless crystalline solid, mp 73–74 ЊC (n-pentane–ether)
(Found: C, 45.1; H, 3.2; N, 3.6. C14H13Br2NO requires C, 45.3;
H, 3.5; N, 3.8%); νmax(CH2Cl2)/cmϪ1 3423, 2840, 1590, 1560,
1514, 1264, 1176, 1034, 895 and 821; δH (250 MHz; CDCl3) 3.81
(3H, s), 4.06 (1H, br s), 4.19 (2H, d, J 4.8), 6.67 (2H, d, J 1.6),
6.85–6.91 (2H, m), 6.96 (1H, t, J 1.6) and 7.27–7.20 (2H, m);
δC(100.6 MHz; CDCl3) 47.85 (CH2), 55.71 (OCH3), 114.65
(CH), 114.68 (CH), 122.97 (CH), 123.86 (C), 129.19 (CH),
130.39 (C), 150.45 (C) and 159.60 (C); m/z 371 (Mϩ, 30%), 251
(8), 121 (100) and 78 (19).
(C᎐O); m/z 411 (Mϩ, 14%), 302 (7), 155 (7), 113 (7), 91 (100)
᎐
and 57 (18).
Ethyl 1-benzyl-4-bromo-3-methyl-2-oxoindoline-3-carboxylate
14
A solution of the oxoindoline 12 (0.036 g, 0.0077 mmol) in ethyl
acetate–acetic acid (4:1; 5 ml) was treated with PdCl2 (0.0087 g,
0.049 mmol) and the resulting suspension stirred under an
atmosphere of hydrogen gas. The reaction was monitored by
TLC; after 3 h further PdCl2 (0.0168 g) was added and the
mixture stirred for 18 h under hydrogen. The resulting suspen-
sion was filtered through Celite, washed with saturated aqueous
NaHCO3, water and brine. After drying over MgSO4, the
mixture was preadsorbed onto silica and subjected to flash
chromatography to give unreacted starting oxoindoline 12
(0.025 g, 69%) and the title compound 14 (0.009 g, 30%) as a
sticky solid (Found: Mϩ, 387.0469. C19H1879BrNO3 requires M,
387.04705); νmax(CHCl3)/cmϪ1 1750, 1717, 1605, 1456, 1377,
1237, 1217 and 1169; δH (250 MHz; CDCl3) 1.20 (3H, t, J 7.1),
1.83 (3H, s), 4.20 (2H, dq, J 7.1 and 1.8), 4.81 (1H, d, J 15.9),
5.07 (1H, d, J 15.9), 6.66 (1H, dd, J 7.9 and 7.6), 7.06 (1H, t, J
7.9), 7.15 (1H, d, J 7.6) and 7.40–7.18 (5H, m); δC(100.6 MHz;
CDCl3) 14.41 (CH3), 18.14 (CH3), 44.35 (NCH2), 57.29 (C),
62.56 (OCH2), 108.88 (CH), 119.02 (C), 127.05 (CH), 127.31
(CH), 128.18 (CH), 129.23 (CH), 130.27 (C), 130.39 (CH),
Ethyl 2-diazo-3-[3,5-dibromo-N-(4-methoxybenzyl)anilino]-3-
oxopropionate 17
A solution of the aniline 16 (1.00 g, 2.695 mmol) in dichloro-
methane (39 ml) was treated with triethylamine (5.93 mmol,
0.83 ml) and ethyl 2-diazomalonyl chloride (0.476 g, 2.695
mmol); the mixture was stirred at room temperature for 70 h.
The solution was washed with dilute hydrochloric acid (2 ; 50
ml), water (20 ml) and brine (20 ml). Drying over Na2SO4 fol-
lowed by preadsorption onto silica and flash chromatography
(gradient elution from 8:1 to 6:1 light petroleum–ether) gave
recovered starting aniline 16 (0.30 g, 30%) and the title com-
pound 17 (0.907 g, 66%) as a bright yellow crystalline solid,
mp 95 ЊC (n-pentane–ether–EtOAc) (Found: C, 44.5; H, 3.05;
N, 8.1. C19H17Br2N3O4 requires C, 44.6; H, 3.35; N, 8.2%)
(Found: Mϩ, 510.9567. C19H17Br2N3O4 requires M, 510.9546);
νmax(CH2Cl2)/cmϪ1 2839, 2133, 1718, 1633, 1580, 1557, 1514,
1436, 1422, 1374, 1320 and 1107; δH (250 MHz; CDCl3) 1.14
(3H, t, J 7.1), 3.78 (3H, s), 4.03 (2H, q, J 7.1), 4.90 (2H, s), 6.84–
6.80 (2H, m), 7.18–7.14 (2H, m), 7.20 (2H, d, J 1.6) and 7.49
(1H, t, J 1.6); δC(100.6 MHz; CDCl3) 14.21 (CH3), 54.00
135.43 (C), 144.84 (C), 168.06 (C᎐O) and 174.795 (C᎐O); m/z
᎐
᎐
387 (Mϩ, 7%), 314 (8), 155 (4), 119 (4), 91 (100) and 65 (8).
3,5-Dibromo-N-(tert-butoxycarbonyl)-N-(4-methoxybenzyl)-
aniline 15
(NCH ), 55.28 (OCH ), 61.60 (OCH ), 68.16 (C᎐N ), 114.08
᎐
2
3
2
2
A solution of carbamate 5 (3.00 g, 8.55 mmol) in dry DMF (18
ml) was added to a stirred suspension of sodium hydride (60%
dispersion in mineral oil; 0.376 g, 9.40 mmol) in dry DMF (18
ml) whilst cooling in an ice bath and the resulting mixture was
stirred for 20 min. 4-Methoxybenzyl chloride (1.16 ml, 1.34 g,
8.55 mmol) was then added and the mixture stirred for a further
21 h. The reaction was quenched with water (180 ml) and
extracted with ether (180 ml then 2 × 90 ml). The combined
ether extracts were washed with brine (2 × 90 ml), dried over
MgSO4 and concentrated under reduced pressure to give essen-
tially pure product as a pale yellow solid (4.03 g, 100%) used
without further purification. A sample was recrystallised from
light petroleum–ether to give the title compound 15 as colourless
crystals, mp 82–84 ЊC (light petroleum–ether) (Found: C, 48.4;
(CH), 122.64 (C), 128.18 (CH), 128.28 (C), 129.59 (CH), 132.22
(CH), 145.14 (C), 159.25 (C), 160.86 (C) and 161.46 (C); m/z
511 (Mϩ, <1%), 483 (M Ϫ N2, 4%), 410 (9), 277 (5), 206 (35),
161 (13), 134 (11) and 121 (100).
Ethyl 4,6-dibromo-1-(4-methoxybenzyl)-2-oxoindoline-3-
carboxylate 18
A solution of the diazoamide 17 (0.415 g, 0.812 mmol) in dry
dichloromethane (18 ml) was treated with rhodium() per-
fluorobutyramide (0.0086 g, 1 mol%) and the mixture stirred at
room temperature for 1.5 h. The reaction mixture was rapidly
filtered through Celite and concentrated under reduced pres-
sure to give pure title compound 18 (0.390 g, 99%) as an unstable
colourless foam/solid (Found: Mϩ, 482.9496. C19H17Br2NO4
J. Chem. Soc., Perkin Trans. 1, 1997
2409

View Article Online
requires M, 482.9506); νmax(CH2Cl2)/cmϪ1 2987, 2939, 2840,
1750, 1723, 1605, 1515, 1250, 1178, 1157, 1034 and 836; δH (250
MHz; CDCl3) 1.31 (3H, t, J 7.1), 3.79 (3H, s), 4.29 (2H, dq, J
7.1 and 2.5), 4.41 (1H, s), 4.72 (1H, d, J 15.6), 4.89 (1H, d, J
15.6), 6.82 (1H, d, J 1.3), 6.86 (2H, d, J 8.7), 7.20 (2H, d, J 8.7)
and 7.34 (1H, d, J 1.3); δC(100.6 MHz; CDCl3) 13.93 (CH3),
43.71 (NCH2), 53.90 (CH), 55.13 (OCH3), 62.04 (OCH2),
111.69 (CH), 114.24 (CH), 119.82 (C), 123.15 (C), 123.55 (C),
126.18 (C), 128.16 (CH), 128.34 (CH), 145.93 (C), 159.21 (C),
164.68 (C᎐O) and 169.52 (C᎐O); m/z 483 (Mϩ, 1%), 121 (100),
dichloromethane (1 ml) and the solution was cooled to Ϫ80 ЊC
in a dry ice–acetone bath, then treated slowly with BBr3 (1 
solution in dichloromethane; 0.37 ml, 0.37 mmol). The mixture
was stirred for 16 h whilst allowing to warm slowly to 8 ЊC;
water and dichloromethane (5 ml) were added and the suspen-
sion stirred. The organic layer was washed twice with water and
dried (MgSO4). Concentration under reduced pressure yielded
the title compound 21 (0.050 g, 99%) as a colourless solid, mp
167 ЊC (n-pentane–light petroleum–ethyl acetate) (Found: Mϩ,
426.9245. C16H13Br2NO3 requires M, 426.9244); νmax(CH2Cl2)/
cmϪ1 3686, 3576, 2930, 1735, 1601, 1516, 1162 and 839; δH (250
MHz; CDCl3) 1.78 (3H, s), 2.85 (1H, br s), 4.72 (1H, d, J 15.6),
4.81 (1H, d, J 15.6), 5.25 (1H, br s), 6.78 (2H, m), 6.82 (1H, d,
J 1.5), 7.11 (2H, m) and 7.34 (1H, d, J 1.5); δC(100.6 MHz;
CDCl3) 22.84 (CH3), 43.86 (CH2), 75.38 (C), 112.56 (CH),
116.38 (CH), 120.07 (C), 123.99 (C), 126.73 (C), 128.67 (C),
129.05 (CH), 129.84 (CH), 145.03 (C), 155.96 (C) and 178.00
᎐
᎐
78 (6), 45 (13) and 31 (29).
Ethyl 4,6-dibromo-1-(4-methoxybenzyl)-3-methyl-2-oxoindoline-
3-carboxylate 19
A solution of the oxoindoline 18 (0.390 g, 0.808 mmol) in dry
DMF (12 ml) was added slowly to a stirred, ice-cooled suspen-
sion of sodium hydride (60% dispersion in mineral oil; 0.036 g,
0.890 mmol) in dry DMF (18 ml) and stirring was main-
tained for 0.5 h, when evolution of hydrogen subsided. Then
iodomethane (0.126 g, 0.890 mmol, ≈55.5 µl) was added and
stirring was continued for a further 3 h whilst allowing the reac-
tion to reach ambient temperature. The reaction mixture was
diluted with ether (120 ml) and water (120 ml). The aqueous
layer was extracted with ether (120 ml then 300 ml); the com-
bined ethereal extracts were washed with brine, dried (MgSO4),
concentrated under reduced pressure and subjected to flash
chromatography on silica gel to yield the title compound 19
(0.265 g, 66%) as a colourless oil which crystallised on cooling,
mp 120–120.5 ЊC (n-pentane) (Found: C, 48.3; H, 3.7; N, 2.8.
C20H19Br2NO4 requires C, 48.3; H, 3.7; N, 2.8%) (Found: Mϩ,
496.9665. C20H19Br2NO4 requires M, 496.9662); νmax(CH2Cl2)/
cmϪ1 1752, 1723, 1600, 1515, 1112 and 838; δH (250 MHz;
CDCl3) 1.20 (3H, t, J 7.1), 1.79 (3H, s), 3.79 (3H, s), 4.20 (2H,
dq, J 7.1 and 2.0), 4.77 (1H, d, J 15.9), 5.03 (1H, d, J 15.9), 6.82
(1H, d, J 1.4), 6.86 (2H, d, J 8.6), 7.18 (2H, d, J 8.6) and 7.31
(1H, d, J 1.4); δC(100.6 MHz; CDCl3) 14.40 (CH3), 18.03 (CH3),
44.00 (NCH2), 55.68 (OCH3), 56.99 (C), 62.68 (OCH2), 112.32
(CH), 114.79 (CH), 119.39 (C), 123.125 (C), 126.93 (C), 128.71
(CH), 129.13 (CH), 129.38 (C), 129.33 (C), 145.84 (C), 159.765
(C), 167.49 (C᎐O) and 174.56 (C᎐O); m/z 497 (Mϩ, 22%), 304
(C᎐O); m/z 427 (Mϩ, <1%), 121 (100) and 78 (5).
᎐
Ethyl 4,6-dibromo-3-methyl-2-oxoindoline-3-carboxylate 22
The oxoindoline 19 (0.050 g, 0.101 mmol) was dissolved in
acetonitrile (1.21 ml) and water (0.40 ml) was added. The solu-
tion was treated with ceric ammonium nitrate (0.221 g, 0.402
mmol), stirred for 2.5 h, poured into water and extracted with
ethylacetate(2 × 10ml;brinewasadded to help clear emulsions).
The organic extracts were combined, washed with water, brine
and dried (MgSO4). Preadsorption on silica followed by flash
column chromatography gave the title compound 22 (0.036 g,
95%) as a colourless powder, mp 175–176 ЊC (n-pentane–ethyl
acetate) (Found: C, 37.9; H, 2.8; N, 4.0. C12H11Br2NO3 requires
C, 38.2; H, 2.9; N, 3.7%) (Found: Mϩ, 376.9092. C12H11Br2NO3
requires M, 376.9087); νmax(CH2Cl2)/cmϪ1 3417, 2959, 1755,
1735, 1610, 1426 and 1112; δH (250 MHz; CDCl3) 1.20 (3H, t, J
7.15), 1.77 (3H, s), 4.10–4.30 (2H, m), 7.06 (1H, d, J 1.5), 7.36
(1H, d, J 1.5) and 8.07 (1H, br s); δC(100.6 MHz; CDCl3) 14.12
(CH3), 57.46 (C), 62.84 (CH2), 113.13 (CH), 119.62 (C), 123.21
(C), 129.28 (CH), 129.86 (C), 143.65 (C), 167.38 (C᎐O) and
᎐
176.3 (C᎐O); m/z 377 (Mϩ, 15%), 304 (100), 223 (30), 195 (13),
᎐
155 (33), 116 (24), 89 (23) and 29 (81).
᎐
᎐
(4), 121 (100), 91 (10) and 78 (16).
Convolutamydine C 3
A stirred solution of the ester 22 (0.0240 g, 0.0637 mmol)
in THF–water (3:1; 5 ml) was treated with sodium hydroxide
pellets (0.025 g, 0.610 mmol), and the resulting mixture heated
under reflux for 50 h under an atmosphere of oxygen. After
allowing to cool to ambient temperature, the suspension was
acidified carefully with aqueous hydrochloric acid (2 ) and the
THF was removed under reduced pressure. The aqueous con-
centrate was extracted with ether (2 × 10 ml). The organic
extracts were combined and washed with water, brine and dried
(MgSO4). Preadsorption on silica, followed by flash column
chromatography (3:1 then 2:1 light petroleum–EtOAc) gave (i)
the title compound 3 as a colourless solid (2.4 mg, 18%), mp
>160 ЊC (decomp.) (light petroleum–ethyl acetate) (lit.,3 175–
180 ЊC from acetone) (Found: Mϩ, 318.8844. Calc. for
C9H779Br79BrNO2: M, 318.8845) (Found: Mϩ, 320.8829. Calc.
for C9H779Br81BrNO2: M, 320.8825); νmax(CHCl3)/cmϪ1 3691,
3607, 2928, 1749 and 1602; δH (250 MHz; CDCl3) 1.76 (3H, s,
Me), 2.67 (1H, br, OH), 7.00 (1H, d, J 1.5), 7.38 (1H, d, J 1.5)
and 7.45 (1H, NH); δC(100.6 MHz; [2H6]acetone) 19.9 (Me),
73.0 (C3), 110 (C7), 118.3 (C6), 121.1 (C4), 126.5 (C5), 143.3
(C7a) and 176.9 (C2); C3a not observed; m/z 321 (Mϩ, 24%),
306 (38), 278 (33), 170 (11), 90 (19), 74 (12), 63 (29) and 43
(100); and (ii) 2-amino-4,6-dibromoacetophenone 23 as a pale
yellow solid (10.0 mg, 63%), mp 89–91 ЊC (Found: Mϩ,
292.8877. C8H7Br2NO requires M, 292.8876); νmax(CHCl3)/
cmϪ1 3502, 3399, 3093, 3011, 2928, 2856, 1680, 1604, 1581,
1539, 1409, 1355 and 1253; δH (250 MHz; CDCl3) 2.63 (3H, s),
4.68 (2H, br s, exchangeable with D2O), 6.80 (1H, d, J 1.7) and
7.09 (1H, d, J 1.7); δC(100.6 MHz; CDCl3) 32.4 (CH3), 118.8
4,6-Dibromo-3-hydroxy-1-(4-methoxybenzyl)-3-methylindolin-2-
one 20
A stirred solution of the ester 19 (0.245 g, 0.493 mmol) in
THF–water (3:1; 40 ml) was treated with sodium hydroxide
pellets (0.203 g, 5.075 mmol) and the resulting mixture heated
under reflux for 21 h under an atmosphere of air. After allowing
the mixture to cool to ambient temperature, the suspension was
acidified carefully with aqueous hydrochloric acid (2 ) and the
THF was removed under reduced pressure. The aqueous con-
centrate was extracted with ether (60 ml and 30 ml). The
organic extracts were combined, washed with water (60 ml),
brine (30 ml) and dried over MgSO4. Concentration under
reduced pressure gave the title compound 20 (0.214 g, 99%) as an
amorphous, colourless solid, mp 168–169 ЊC (Found: C, 46.3;
H, 3.1; N, 2.9. C17H15Br2NO3 requires C, 46.3; H, 3.4; N, 3.2%);
νmax(CH2Cl2)/cmϪ1 3413, 2934, 2840, 1735, 1601, 1574, 1514,
1343, 1161 and 1034; δH (250 MHz; CDCl3) 1.79 (3H, s), 2.67
(1H, br s), 3.79 (3H, s), 4.72 (1H, d, J 15.5), 4.86 (1H, d, J 15.5),
6.83 (1H, d, J 1.5), 6.86 (2H, m), 7.18 (2H, m) and 7.34 (1H, d, J
1.5); δC(100.6 MHz; CDCl3) 22.97 (CH3), 43.82 (NCH2), 75.26
(C), 112.48 (CH), 114.85 (CH), 120.02 (C), 123.96 (C), 126.85
(C), 128.67 (C), 128.92 (CH), 129.96 (CH), 145.17 (C), 159.77
(C) and 177.66 (C᎐O); m/z 441 (Mϩ, 6%), 320 (1), 155 (2) and
᎐
121 (100).
4,6-Dibromo-3-hydroxy-1-(4-hydroxybenzyl)-3-methylindolin-2-
one 21
The oxoindoline 20 (0.052 g, 0.118 mmol) was taken up in dry
2410
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
¯
(CH), 121.6 (C), 125.2 (CH), 125.4 (C), 147.8 (C) and 203.9
᎐
(17) and 43 (37).
2θ < 74.78Њ, λ = 1.541 78 Å, T = 20 ЊC), space group P1 (no. 2),
(C᎐O); m/z 293 (Mϩ, 8%), 278 (100), 250 (5), 170 (8), 90 (5), 63
Z = 2, Dc = 1.70 g cmϪ3, clear plate, dimensions 0.15 × 0.15 ×
0.21 mm, µ(Cu-Kα) = 47 cmϪ1, F(000) = 476.
Compound 11: C18H15Br2NO3, M = 453.13. Monoclinic,
a = 11.281(1), b = 13.438(2), c = 12.424(1) Å, β = 109.85(1)Њ,
V = 1771.5(3) Å3 (by least-squares refinement for 25 centred
reflections with 72.67 < 2θ < 74.87Њ, λ = 1.541 78 Å, T = 20 ЊC),
space group P21/a (no. 14), Z = 4, Dc = 1.70 g cmϪ3, clear
4,6-Dibromo-1-(4-methoxybenzyl)-3-methyl-2-oxo-2,3-dihydro-
1H-indol-3-yl acetate 24
Tertiary alcohol 20 (0.025 g, 0.057 mmol) was taken up in dry
dichloromethane (2 ml) and treated with triethylamine (≈0.024
g, 0.24 mmol), acetic anhydride (≈0.015 g, 0.14 mmol), along
with a catalytic amount of 4-dimethylaminopyridine. After
stirring at room temperature for 25 h the solvent was removed
under reduced pressure. The residue was taken up in ether (10
ml), washed sequentially with hydrochloric acid (2 ; 2 × 5 ml),
water and brine. The ether solution was dried (MgSO4), filtered,
then concentrated under reduced pressure to yield the title
compound 24 (0.028 g, 99%) as an oily, colourless solid which
was used directly without crystallisation (Found: Mϩ, 482.9519.
C19H17Br2NO4 requires M, 482.9506); νmax(film)/cmϪ1 3081,
2998, 2934, 2837, 1739, 1602, 1515, 1164, 1105, 1043 and 734;
δH (250 MHz; CDCl3) 1.74 (3H, s), 2.14 (3H, s), 3.79 (3H, s),
4.75 (1H, d, J 15.7), 4.93 (1H, d, J 15.7), 6.76 (1H, d, J 1.5), 6.88
(2H, m) and 7.20–7.36 (3H, m); δC(100.6 MHz; CDCl3) 20.01
(CH3), 20.60 (CH3), 43.64 (CH2), 55.27 (CH3), 77.62 (C), 112.13
(CH), 114.38 (CH), 117.83 (C), 123.46 (C), 126.28 (C), 126.50
(C), 128.48 (CH), 128.81 (CH), 144.89 (C), 159.30 (C), 169.20
(C᎐O) and 174.48 (C᎐O); m/z 483 (Mϩ, 2%), 423 (23), 394 (2),
plate, dimensions 0.20 × 0.20 × 0.20 mm, µ(Cu-Kα) = 60 cmϪ1
F(000) = 896.
,
Compound 13: C16H13Br2NO2, M = 411.09. Monoclinic,
a = 11.698(2), b = 25.230(4), c = 11.023(2) Å, β = 104.19(2)Њ,
V = 3154.4(9) Å3 (by least-squares refinement for 25 centred
reflections with 45.91 < 2θ < 56.76Њ, λ = 1.541 78 Å, T = 20 ЊC),
space group Cc (no. 9), Z = 8 (two independent molecules),
Dc = 1.73 g cmϪ3, clear plate, dimensions 0.03 × 0.10 × 0.24
mm, µ(Cu-Kα) = 66 cmϪ1, F(000) = 1616.
Compound 17: C19H17Br2N3O4, M = 511.17. Monoclinic,
a = 18.542(12), b = 9.728(9), c = 23.971(11) Å, β = 100.30(5)Њ,
V = 4254.1(5) Å3 (by least-squares refinement for 25 centred
reflections with 65.00 < 2θ < 73.56Њ, λ = 1.541 78 Å, T = 20 ЊC),
space group C2/c (no. 15), Z = 8, Dc = 1.60 g cmϪ3, clear plate,
dimensions 0.18 × 0.18 × 0.20 mm, µ(Cu-Kα) = 51 cmϪ1
F(000) = 2032.
,
Data collection and processing. Rigaku AFC7S diffract-
ometer, graphite monochromated Cu-Kα radiation, ω–2θ scan
method, corrections for Lorentz and polarisation factors,
absorption were applied in all cases (DIFABS),22 as were cor-
rections for linear isotropic crystal decay where noted.
10: 2939 reflections measured (5.3 р 2θ р 120.4Њ, h, ±k, ±l)
2861 unique (Rint = 0.13, decay of standards 14.4%), giving
2395 observed [I > 3.00σ(I)] which were used in all further
calculations.
11: 2929 reflections measured (5.3 р 2θ р 120.1Њ, h, k, ±l)
2774 unique (Rint = 0.27), giving 2067 observed [I > 2.00σ(I)]
which were used in all further calculations.
13: 2548 reflections measured (5.4 р 2θ р 120.2Њ, h, k, ±l)
2417 unique (Rint = 0.12), giving 1402 observed [I > 3.00σ(I)]
which were used in all further calculations.
᎐
᎐
121 (100) and 43 (28).
4,6-Dibromo-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl acetate
25
N-4-Methoxybenzyloxindolone 24 (0.026 g, 0.054 mmol) was
dissolved in acetonitrile (0.65 ml) and then water (0.22 ml) was
added. The solution was treated with ceric ammonium nitrate
(0.118 g, 0.215 mmol), stirred for 3.5 h, then water (10 ml) was
added and the mixture extracted with ethyl acetate (2 × 10 ml).
The organic extracts were combined, washed with brine and
dried (MgSO4). Preadsorption on silica followed by flash silica
gel column chromatography afforded the title compound 25
(0.016 g; 82%) as colourless needles, mp 155–165 ЊC (decomp.)
(light petroleum–ethyl acetate) (Found: Mϩ, 362.8929.
C11H9Br2NO3 requires M, 362.8930); νmax(CH2Cl2)/cmϪ1 3420,
1756, 1743, 1612, 1578, 1372, 1172, 1104, 1022, 950 and 841;
δH (250 MHz; CDCl3) 1.73 (3H, s), 2.13 (3H, s), 7.00 (1H, d, J
1.5), 7.31 (1H, d, J 1.5) and 8.30 (1H, br s); δC(66 MHz; CDCl3)
20.00 (CH3), 20.23 (CH3), 77.72 (C), 112.97 (CH), 118.12 (C),
17: 3498 reflections measured (5.4 р 2θ р 120.5Њ, h, k, ±l)
3373 unique (Rint = 0.03, decay of standards 10.2%), giving
1677 observed [I > 3.00σ(I)] which were used in all further
calculations.
Structure solution and refinement.23 The structures were
solved by direct methods (10, 13 and 17 all non-H atoms) and
heavy atom methods (11). Full-matrix least-squares refinement
on F, with all non H-atoms anisotropic except in 17, where
Br(17) was refined in three positions to model disorder. The
highest weight (0.5) occupancy position was refined aniso-
tropically and the two minor weight positions (0.25) were
refined isotropically. In 13, solution and refinement were
attempted in C2/c, but proved unsuccessful. Hydrogen atoms
were placed in idealised positions. All R indices were as defined
in ref. 23. All calculations were carried out using the TEXSAN
crystallographic software package of Molecular Structure
Corporation.23 Atomic coordinates, bond lengths, angles and
thermal parameters have been deposited with the Cambridge
Crystallographic Data Centre (CCDC).12
123.55 (C), 126.57 (C), 128.93 (CH), 142.83 (C), 169.39 (C᎐O)
᎐
and 176.00 (C᎐O); m/z 363 (Mϩ, 41%), 320 (15), 304 (34), 278
᎐
(12), 225 (4) and 43 (100).
Convolutamydine C 3 (alternative method)
The acetate 25 (0.0075 g, 0.0207 mmol) was taken up in ethanol
(0.5 ml) and treated with excess aqueous sodium hydroxide (1
; 5 drops) and the mixture stirred for 3 h. TLC showed clean
conversion to the desired product. Thus the mixture was cooled
in an ice bath and acidified with dilute hydrochloric acid (4%; 10
drops), saturated with brine and extracted with ethyl acetate
(3 × 10 ml). The combined extracts were dried (NaSO4), fil-
tered and concentrated under reduced pressure to give essen-
10: R = 0.038, Rw = 0.041. An extinction parameter was
1
included and refined to 2.94 × 10Ϫ6. Maximum peak in the final
tially pure (by H NMR spectroscopy) convolutamydine C 3.
∆F map was 0.41 e ÅϪ3
.
The solid was preadsorbed on silica and subjected to flash silica
column chromatography (2:1 light petroleum–ethyl acetate) to
yield pure convolutamydine C 3 (0.0061 g, 91%) as a colourless
solid; data as given previously.
11: R = 0.055, Rw = 0.054. An extinction parameter was
included and refined to 3.65 × 10Ϫ7. Maximum peak in the final
∆F map was 0.58 e ÅϪ3
.
13: R = 0.030, Rw = 0.024. An extinction parameter was
X-Ray crystallography
included and refined to 2.98 × 10Ϫ7. Maximum peak in the final
Crystal data. Compound 10: C18H15Br2N3O3, M = 481.14.
Triclinic, a = 11.176(3), b = 10.440(3), c = 10.007(3) Å, α =
118.18(2), β = 68.45(2), γ = 100.20(2)Њ, V = 957.2(5) Å3 (by least-
squares refinement for 25 centred reflections with 74.09 <
∆F map was 0.19 e ÅϪ3
.
17: R = 0.067, Rw = 0.069. An extinction parameter was
included and refined to 8.63 × 10Ϫ8. Maximum peak in the final
∆F map was 0.55 e ÅϪ3
.
J. Chem. Soc., Perkin Trans. 1, 1997
2411

View Article Online
10 J. P. Marino, M. H. Osterhout, A. T. Price, S. M. Sheehan and
Acknowledgements
A. Padwa, Tetrahedron Lett., 1994, 35, 849.
We thank the EPSRC and AgrEvo Ltd. for a CASE award
(to S. M.), Dr D. J. Mansfield for helpful discussions, and the
EPSRC Mass Spectrometry Centre at Swansea for mass spectra.
11 The formation and subsequent reaction of carbonyl ylides, by
intramolecular attack of rhodium carbenoids on carbonyl groups, is
well known: A. Padwa and S. F. Hornbuckle, Chem. Rev., 1991, 91,
263; A. Padwa and K. E. Krumpe, Tetrahedron, 1992, 48, 5385;
A. Padwa and D. J. Austin, Angew. Chem., Int. Ed. Engl., 1994, 33,
1797; A. Padwa and M. D. Weingarten, Chem. Rev., 1996, 96, 223.
12 See Instructions for Authors, J. Chem. Soc., Perkin Trans. 1, 1997,
Issue 1. Any request to the CCDC for this material should quote the
full literature citation and the reference number 207/119.
13 (a) Q. Yu, Y. Li, W. Luo and A. Brossi, Heterocycles, 1993, 36, 1791;
(b) M. Watanabe, M. Kodera, T. Kinoshita and S. Furukawa, Chem.
Pharm. Bull., 1975, 23, 2598.
14 T. Nishio, J. Chem. Soc., Perkin Trans. 1, 1991, 1717.
15 M. Y. Kin, J. E. Starett and S. M. Weinreb, J. Org. Chem., 1981, 46,
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16 Y. Murakami, T. Watanabe, A. Kobayashi and Y. Yokoyama,
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17 A. B. Smith III, T. A. Rano, N. Chida, G. A. Sulikowski and
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Paper 7/00683G
Received 29th January 1997
Accepted 8th May 1997
2412
J. Chem. Soc., Perkin Trans. 1, 1997