Synthetic applications of 3-(cyanoacetyl)indoles and related compounds

Article abstract of DOI:10.1002/jhet.5570420122

Various synthetic applications of 3-(cyanoacetyl)indoles, as well as syntheses of some related indoles, have been investigated. Diethyl 2-(1H-indol-3-yl)-2-oxoethylphosphonate and a methyl derivative thereof have been prepared in one step from indole. Moreover, it was demonstrated that 3-(cyanoacetyl)indoles are useful starting materials for the preparation of for example 3-(1H-indol-3-yl)-3-oxopropanamides, 3-heteroarylindoles or 3-heteroaroylindoles.

Full text of DOI:10.1002/jhet.5570420122

Jan-Feb 2005
141
Synthetic Applications of 3-(Cyanoacetyl)indoles and Related
Compounds
Johnny Slätt, Tomasz Janosik, Niklas Wahlström and Jan Bergman*
Unit for Organic Chemistry, Department of Biosciences, Karolinska Institute, Novum Research Park, SE-141
57 Huddinge, Sweden, and Södertörn University College, SE-141 04 Huddinge, Sweden
Fax +46 8 608920, E-mail: jabe@cnt.ki.se
Received June 9, 2004
Various synthetic applications of 3-(cyanoacetyl)indoles, as well as syntheses of some related indoles,
have been investigated. Diethyl 2-(1H-indol-3-yl)-2-oxoethylphosphonate and a methyl derivative thereof
have been prepared in one step from indole. Moreover, it was demonstrated that 3-(cyanoacetyl)indoles are
useful starting materials for the preparation of for example 3-(1H-indol-3-yl)-3-oxopropanamides, 3-het-
eroarylindoles or 3-heteroaroylindoles.
J. Heterocyclic Chem., 42, 141 (2005).
Recently, a facile procedure for the cyanoacetylation of
various indoles and pyrroles leading for example to com-
pounds 1a–d and 2–3 has been developed in our labora-
tory. This one-step approach, employing cyanoacetic acid
in acetic anhydride for the introduction of the cyanoacetyl
functionality, provides quick and easy access to cyano-
acetylated indoles, pyrroles, as well as some additional
heterocycles in high yields [1]. Cyanoacetylated com-
pounds and related ketones incorporating electron-with-
drawing groups at α-position to the carbonyl are versatile
precursors for the construction of more complex systems
[2]. Since these readily accessible compounds may also
undergo functional group transformations at the nitrile
and/or ketone moieties to afford further useful indole and
pyrrole derivatives which otherwise have to be prepared
using multi-step procedures, we became interested in
exploring the reactivity and synthetic applications of
cyanoacetylated heterocycles to further extend the scope
of our cyanoacetylation protocol.
acetic acids having other electron withdrawing α-sub-
stituents might also prove to be useful reagents for similar
applications. Therefore, the original acetylation protocol
was slightly modified in order to facilitate the acetylation
with diethylphosphonoacetic acid, which gave the corre-
sponding 3-acetylated indoles 1e–f. Such compounds are
rather rare and do possess properties similar to indole-3-
acetic acid, a well studied phytohormone [3]. Diethyl 2-(2-
methyl-1H-indol-3-yl)-2-oxoethylphosphonate (1f) has
previously been prepared in a multi-step sequence via the
corresponding 3-(chloroacetyl)indole by treatment with
triethyl phosphite. This ester, however, was never isolated,
but hydrolysed directly to the corresponding acid [4].
Reduction of 3-(cyanoacetyl)indole (1a) with sodium
borohydride followed by acidic workup gave selectively
(E)-3-(1H-indol-3-yl)acrylonitrile (4) in 78% yield. A
previously reported route for the preparation of 4 from
3-formylindole has been reported to afford a mixture of
(E)- and (Z)-isomers [5]. In this context it is interesting to
note that derivatives of 4, for instance the corresponding
5-bromo derivative, have been shown to possess antimi-
crobial properties [6]. Moreover, reduction of 4 with
hydrogen in the presence of Raney nickel is known to give
homo-tryptamine [7], which belongs to a versatile class of
compounds in natural product synthesis [8].
i. NaBH ; ii. HCl
4
It is well established that photocyclization reactions of
3-cyanovinyl-2-aryl- or 3-cyanovinyl-2-heteroarylin-
doles can be used to synthesize carbazoles [9–12].
However, all attempts to react 4 with dimethyl
The ready preparation of the sulfone 1d [1] by treatment
of indole with (methanesulfonyl)acetic acid suggested that

142
J. Slätt, T. Janosik, N. Wahlström and J. Bergman
Vol. 42
acetylenedicarboxylate or various maleimides under
thermal conditions in refluxing toluene or xylenes failed.
The limited solubility of the substrate 4 in these solvents
may account for the low reactivity.
with sodium nitrite in acetic acid gave as expected the
interesting oxime 7. The reactivity of the methylene moi-
ety of 1a was further demonstrated by its facile condensa-
tion with salicylaldehyde, followed by a subsequent attack
of the o-hydroxyl group on the cyano group to generate an
intermediate iminocoumarine (not isolated), which was
directly hydrolyzed with dilute hydrochloric acid to the
final coumarine derivative 8.
In connection with the easy preparation of the oxime 7,
it is worth mentioning that the closely related imine 9 has
been employed as a key intermediate in the synthesis of
cypridinaluciferin (10) [18].
Previous hydrolyses of 3-cyanoindole derivatives have
been shown, depending on the reaction conditions, to give
the corresponding amides [13] or the carboxylic acids
[14]. Thus heating of 3-(cyanoacetyl)indoles 1a–c at 100
°C for 2 h in polyphosphoric acid (PPA) [15], followed by
addition of water produced the desired amides 5a–c in
good yields. Since the previous synthesis of the amide 5c
was not practical due to the limited scale (0.25 mmol), and
required a rather long reaction time (14 h) [13a], our
approach constitutes a considerable improvement.
Interestingly, certain diketo indoles having structures
related to 5a–c have been shown to exhibit HIV-inhibiting
properties [16].
During all experiments outlined so far, we noticed that
the carbonyl group of 1a displayed rather low reactivity
due to the electron-releasing properties of the indole nitro-
gen atom. The prospect of accessing further interesting
derivatives by reactions at the carbonyl part of the cyano-
acetyl group prompted us to activate the carbonyl group by
attaching an electron-withdrawing group to the indole
nitrogen. Thus, Boc-protection of 1a under standard con-
i. PPA, 100 °C, 2 h
The activated methylene group in 1a readily takes part
in numerous reactions providing access to more complex
molecules. Thus for example, condensation of 1a with
N,N-dimethylformamide dimethyl acetal (DMFDMA)
proceeded smoothly to give the previously known com-
pound 6 [17] in good yield. Likewise, nitrosation of 1a
ditions (Boc O, DMAP) produced 11 in good yield. As
2
anticipated, treatment of compound 11 with hydroxy-
lamine hydrochloride in the presence of base gave the
interesting isoxazole 12. Similar transformations of cyano-
acetyl moieties to 5-aminoisoxazoles have been reported
previously [19].
i. Boc O, DMAP, THF, rt; ii. HONH ·HCl, NaOAc, CH Cl , MeOH
2
2
2
2
In conclusion, we have developed a convenient one-step
procedure for the synthesis of 2-(1H-indol-3-yl)-2-
oxoethylphosphonates. Several transformations of
3-(cyanoacetyl)indoles have also been investigated, lead-
ing to easy access to (E)-3-(1H-indol-3-yl)acrylonitrile
i. DMFDMA; ii. NaNO , AcOH; iii. salicylaldehyde; iv. aq. HCl
2

Jan-Feb 2005
Synthetic Applications of 3-(Cyanoacetyl)indoles and Related Compounds
143
129.8 Hz) 61.6 (d, J
= 6.3 Hz), 111.3, 113.7 (d, J
= 4.1 Hz),
and 3-(1H-indol-3-yl)-3-oxopropanamides. Moreover, 3-
(cyanoacetyl)indoles also proved to be useful starting
materials for the synthesis of various 3-heteroarylindoles
and 3-heteroaroylindoles.
C–P
C–P
120.7, 121.6, 122.1, 126.9, 134.7, 145.1, 186.5 (d, J
= 7.8 Hz);
C–P
31
+
P nmr (DMSO-d ): δ 22.4 ppm; ms: (ESI+) m/z 310 [M + H] .
6
Anal. Calcd. for C H NO P: C, 58.25; H, 6.52; N, 4.53.
Found: C, 58.08; H, 6.16; N, 4.63.
15 20
4
(E)-3-(1H-Indol-3-yl)acrylonitrile (4).
EXPERIMENTAL
General.
To a suspension of 3-(cyanoacetyl)-1H-indole (1a) (2.34 g,
12.7 mmol) in methanol (60 mL) was added sodium borohydride
(1.44 g, 38.1 mmol) in small portions to give a clear solution. The
mixture was allowed to cool (30 minutes) and was thereafter
acidified with concentrated hydrochloric acid to pH < 2. The
resulting mixture was stirred for 1 h and was then diluted with
water to give a precipitate, which was collected by filtration and
dried to give 4 (1.68 g, 78%) as a beige solid, mp 143–144 °C
(Lit. [5] 143–144 °C).
1
13
H nmr and C nmr spectra were recorded on a Bruker DPX
300 spectrometer operating at 300 MHz and 75.5 MHz, respec-
31
tively. The P nmr data were acquired using a JEOL Eclipse 500
spectrometer operating at 202.5 MHz employing 85% H PO as
3
4
external standard. The ir spectra were recorded on a Thermo
Nicolet Avatar 330 FT-IR. Mass spectra (ESI) were obtained
using a Perkin Elmer API 150 EX spectrometer or a Waters
Micromass ZQ system. Elemental analyses were performed by
H. Kolbe Mikroanalytisches Laboratorium, Mülheim an der
Ruhr, Germany. Melting points were taken on a Büchi B-545
apparatus in open capillary tubes and are uncorrected.
Chromatography was performed on Merck Silica Gel 60. All sol-
vents and reagents were of analytical grade and were used as
received, except THF, which was distilled from sodium and
benzophenone.
3-(1H-Indol-3-yl)-3-oxopropanamide (5a).
3-(Cyanoacetyl)-1H-indole (1a) (2.5 g, 13.6 mmol) was added
to PPA (20 mL), and the resulting mixture was heated at 100 °C
for 2 h, whereupon the mixture was poured on ice. The precipi-
tate formed was collected by filtration and washed with water to
afford 5a (2.5 g, 82%) as a beige solid, mp 208 °C (dec); ir (neat):
3408, 3189, 1641, 1597, 1579, 1519, 1430, 1377, 1237, 1144,
-1
1
962, 742 cm ; H nmr (DMSO-d ): δ 3.70 (s, 2H), 7.05 (br s,
6
Diethyl 2-(1H-Indol-3-yl)-2-oxoethylphosphonate (1e).
1H), 7.16–7.24 (m, 2H), 7.46–7.49 (m, 1H), 7.54 (br s, 1H),
8.16–8.20 (m, 1H), 8.34–8.35 (m, 1H), 12.00 (br s, 1H); C nmr
13
Indole (1.17 g, 10 mmol) dissolved in acetic acid (5 mL) was
added slowly to a hot (100 °C) mixture of diethylphospho-
noacetic acid (1.96 g, 10 mmol) and acetic anhydride (20 mL).
After complete addition, the reaction mixture was heated for 4 h
and was then allowed to cool. The solvent was evaporated.
Addition of diisopropyl ether to the residue gave a precipitate,
which was collected by filtration and dried to afford 1e as a
colourless solid (0.8 g, 29%), mp 170–171 °C; ir (neat): 3114,
(DMSO-d ): δ 47.8, 112.2, 117.5, 121.3, 121.9, 122.9, 125.4,
6
+
135.1, 136.7, 169.0, 189.1; ms: (ESI+) m/z 203 [M + H] .
Anal. Calcd. for C H N O : C, 65.34; H, 4.98; N, 13.85.
11 10
2 2
Found: C, 65.24; H, 5.10; N, 13.76.
3-(2-Methyl-1H-indol-3-yl)-3-oxopropanamide (5b).
3-(Cyanoacetyl)-2-methyl-1H-indole (1b) (2.25 g, 11.3.
mmol) was added to PPA (18 mL) and the resulting mixture was
heated at 100 °C for 2 h, and thereafter poured on ice. The pre-
cipitate formed was collected by filtration and washed with water
to give 5b (2.14 g, 87%) as a beige solid, mp 196–197 °C (Lit.
[13b] 197 °C); ir (neat): 3408, 1667, 1595, 1577, 1435, 1382,
2981, 2922, 1634, 1522, 1437, 1215, 1183, 1018, 945, 749, 719,
-1 1
658 cm ; H nmr (DMSO-d ): δ 1.20 (t, J = 7.0 Hz, 6H), 3.62 (d,
6
J = 22.2 Hz, 2H), 4.03 (q, J = 7.2, 4H), 7.17–7.25 (m, 2H),
7.45–7.50 (m, 1H), 8.16–8.20 (m, 1H), 8.42–8.43 (m, 1H), 12.05
13
(br s, 1H); C nmr (DMSO-d ): δ 16.1 (d, J
= 6.1 Hz), 38.6
6
C–P
-1
1
1239, 1154, 1056, 988, 743 cm ; H nmr (DMSO-d ): δ 2.69 (s,
(d, J
= 126.1 Hz), 61.6 (d, J
= 6.2 Hz), 112.1, 116.7 (d,
6
C–P
C–P
3H), 3.73 (s, 2H), 7.04 (br s, 1H), 7.08–7.16 (m, 2H), 7.32–7.40
(m, 1H), 7.47 (br s, 1H), 7.98–8.02 (m, 1H), 11.89 (br s, 1H);
J
J
= 2.9 Hz) 121.3, 121.9, 123.0, 125.4, 136.1, 136.6, 185.9 (d,
C–P
13
31
C
= 6.2 Hz); P nmr (DMSO-d ): δ 22.7 ppm; ms: (ESI+) m/z
C–P
6
+
nmr (DMSO-d ): δ 14.9, 49.8, 111.2, 113.3, 120.5, 121.4, 121.9,
296 [M + H] .
6
126.8, 134.7, 144.7, 169.0, 189.6.
Anal. Calcd. for C H NO P: C, 56.95; H, 6.14; N, 4.74.
14 18
4
Found: C, 57.07; H, 6.22; N, 4.65.
3-(1-Methyl-1H-indol-3-yl)-3-oxopropanamide (5c).
Diethyl 2-(2-Methyl-1H-indol-3-yl)-2-oxoethylphosphonate (1f).
3-(Cyanoacetyl)-1-methyl-1H-indole (1c) (3.5 g, 17.7 mmol)
was added to PPA (20 mL) and the resulting mixture was heated
at 100 °C for 2 h, and was thereafter poured on ice. The precipi-
tate formed was collected by filtration and washed with water to
afford 5c (3.56 g, 93%) as a beige solid, mp 181 °C (Lit. [13a]
179.5–181.5 °C); ir (neat): 3554, 3326, 1672, 1614, 1530, 1376,
2-Methylindole (1.31 g, 10 mmol) dissolved in acetic acid (10
mL) was added slowly to a hot (100 °C) mixture of diethylphos-
phonoacetic acid (1.96 g, 10 mmol) and acetic anhydride (15
mL). After complete addition the reaction mixture was heated at
100 °C for 2 h and was then allowed to cool. The solvent was
evaporated. Trituration of the residue with diisopropylether gave
a precipitate, which was collected by filtration and dried to afford
1f (1.05 g, 35%) as a colourless solid, mp 132–133 °C; ir (neat):
3165, 3131, 3097, 3040, 2975, 2913, 1616, 1582, 1488, 1457,
-1
1
1234, 1126, 1087, 902, 731 cm ; H nmr (DMSO-d ): δ 3.66 (s,
6
2H), 3.87 (s, 3H), 7.02 (br s, 1H), 7.21–7.32 (m, 2H), 7.50 (br s,
13
1H), 7.53–7.56 (m, 1H), 8.17–8.20 (m, 1H), 8.36 (s, 1H);
C
nmr (DMSO-d ): δ 33.5, 47.8, 111.0, 115.6, 121.7, 122.6, 123.4,
6
-1 1
+
1435, 1406, 1389, 1235, 1190, 1018, 990, 959, 916, 755 cm ; H
126.0, 137.6, 138.9, 169.5, 189.0; ms: (ESI+) m/z 217 [M + H] .
nmr (DMSO-d ): δ 1.20 (t, J = 7.0 Hz, 6H), 2.73 (s, 3H), 3.61 (d,
6
2-Cyano-3-(dimethylamino)-1-(1H-Indol-3-yl)propen-1-one (6).
J = 21.4 Hz, 2H), 4.04 (q, J = 7.3, 4.4 Hz, 4H), 7.12–7.17 (m,
13
To a solution of 3-(cyanoacetyl)-1H-indole (1a) (4.63 g, 25.0
mmol) in DMF (30 mL) was added DMFDMA (3.0 g, 25.2
2H), 7.34–7.39 (m, 1H), 8.05–8.08 (m, 1H), 11.94 (br s, 1H);
nmr (DMSO-d ): δ 15.0, 16.2 (d, J = 5.9 Hz), 40.5 (d, J
C
=
6
C–P
C–P

144
J. Slätt, T. Janosik, N. Wahlström and J. Bergman
Vol. 42
mmol) and the mixture was heated at 60 °C for 4 h. After cooling,
the mixture was left overnight. The crystals which separated from
the solution were collected by filtration and washed with ethanol
to give 6 (5.34 g, 89%) as a yellow solid, mp 187–188 °C. (Lit.
[17] 187–188 °C); ir (neat): 3299, 2191, 1625, 1558, 1512, 1436,
after slow concentration of the mother liquors. Total yield: 15.12
g (89%). Colourless solid, mp 241 °C (dec); ir (neat): 1756, 1735,
1672, 1449, 1375, 1364, 1310, 1236, 1138, 1107, 898, 836, 764,
-1
1
750 cm ; H nmr (CDCl ): δ 1.72 (s, 9H), 3.97 (s, 2H),
3
7.35–7.45 (m, 2H), 8.10–8.13 (m, 1H), 8.26 (s, 1H), 8.28–8.31
-1
1
13
1422, 1346, 1298, 1240, 1132, 748 cm ; H nmr (DMSO-d ): δ
(m, 1H); C nmr (CDCl ): δ 28.3, 30.2, 86.5, 114.2, 115.3,
6
3
3.25 (s, 3H), 3.35 (s, 3H), 7.12–7.22 (m, 2H), 7.48–7.50 (m, 1H),
8.00 (s, 1H), 8.17–8.20 (m, 1H), 8.32 (s, 1H), 11.78 (br s, 1H);
118.2, 122.6, 125.1, 126.4, 127.0, 133.0, 135.6, 148.8, 182.2; ms:
(ESI–) m/z 283 [M – H] .
–
13
C nmr (DMSO-d ): δ 38.5, 47.4, 77.7, 111.9, 114.7, 121.2,
Anal. Calcd. for C H N O : C, 67.59; H, 5.67; N, 9.85.
6
16 16
2 3
121.8, 121.8, 122.6, 126.8, 131.2, 135.9, 158.7, 181.8; ms:
(ESI+) m/z 239 [M + H] .
Found: C, 67.68; H, 5.73; N, 9.81.
+
1-(tert-Butoxycarbonyl)-3-(5-aminoisoxazol-3-yl)-1H-indole
(12).
2-(Hydroxyimino)-3-(1H-indol-3-yl)-3-oxopropanenitrile (7).
To a warm (60 °C) mixture of 3-(cyanoacetyl)-1H-indole (1a)
(1.0 g, 5.34 mmol) in acetic acid (15 mL) sodium nitrite (3.5 g,
52.2 mmol) was added slowly over 30 minutes. After complete
addition, the mixture was heated to 120 °C to give a clear solu-
tion and was then allowed to cool. The mixture was thereafter
poured into water to give a precipitate, which was collected by
filtration and washed with water to afford 7 (0.72 g, 62%) as a
yellow solid, mp 216 °C (dec); ir (neat): 3226, 2243, 1591, 1580,
A mixture of 11 (1.12 g, 3.9 mmol), hydroxylamine hydrochlo-
ride (0.84 g, 12.1 mmol), and sodium acetate (1.32 g, 16.1 mmol)
in anhydrous CH Cl (20 mL) and methanol (20 mL) was stirred
2
2
at 40–50 °C under N for 24 h, and thereafter at room tempera-
2
ture for an additional period of 18 h. After concentration, the
residue was partitioned between ethyl acetate (100 mL) and
water (100 mL). The organic layer was washed with water (50
mL), brine (50 mL) and dried over MgSO . Removal of the sol-
4
-1 1
vent at reduced pressure gave a yellow foam, which was sub-
jected to column chromatography on silca gel [hexane–ethyl
acetate (3:2)] to afford 12 (1.07 g, 92%) as a cream-coloured
solid, mp 165–166 °C; ir (neat): 3457, 3421, 3333, 3132, 1713,
1434, 1226 1144, 1119, 1085, 1038, 937, 879, 837, 741, cm ; H
nmr (DMSO-d ): δ 7.22–7.30 (m, 2H), 7.51–7.56 (m, 1H),
6
8.19–8.24 (m, 1H), 8.35–8.36 (m, 1H), 12.44 (br s, 1H), 14.7 (br
13
s, 1H); C nmr (DMSO-d ): δ 109.6, 112.3, 112.6, 121.2, 122.6,
6
-1 1
1637, 1447, 1371, 1308, 1254, 1145, 748 cm ; H nmr (CDCl ):
123.5, 126.2, 133.6, 136.2, 137.0, 177.6; ms: (ESI+) m/z 214
3
+
δ 1.69 (s, 9H), 4.65 (br s, 2H), 5.44 (s, 1H), 7.29–7.40 (m, 2H),
[M + H] .
13
7.92 (s, 1H), 8.12–8.18 (m, 2H); C nmr (CDCl ): δ 28.3, 78.7,
Anal. Calcd. for C H N O : C, 61.97; H, 3.31; N, 19.71.
3
11
7 3 2
84.6, 111.3, 115.3, 122.1, 123.6, 125.2, 125.7, 127.8, 135.8,
149.6, 159.0, 168.5; ms: (ESI+) m/z 300 [M + H] .
Found: C, 62.02; H, 3.26; N, 19.63.
+
1-(Chromene-2-one-3-yl)-1-(1H-indol-3-yl)methanone (8).
Anal. Calcd. for C H N O : C, 64.20; H, 5.72; N, 14.04.
16 17
3 3
To a mixture of 3-(cyanoacetyl)-1H-indole (1a) (0.74 g, 4.0
mmol) and o-salicylaldehyde (0.49 g, 4 mmol) in ethanol (60
mL), piperidine (5 drops) was added. The reaction mixture turned
yellowish immediately. The reaction was monitored with TLC
and after about 2.5 h no starting material could be detected. The
solvent was evaporated to give a residue which was treated with
ethanol (30 mL) and concentrated hydrochloric acid (1 mL). This
mixture was heated at reflux for 30 minutes. After cooling, a pre-
cipitate formed and was collected by filtration to give 8 (0.8 g,
73%) as a white solid, mp 294–295 °C; ir (neat): 3304, 1719,
1709, 1596, 1513, 1432, 1243, 1141, 1130, 1118, 957, 886, 873,
Found: C, 64.11; H, 5.64; N, 13.96.
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-1
1
773 cm ; H nmr (DMSO-d ): δ 7.23–7.30 (m, 2H), 7.38–7.43
6
(m, 1H), 7.46–7.53 (m, 2H), 7.67–7.72 (m, 1H), 7.80–7.83 (m,
13
1H), 8.21–8.24 (m, 2H), 8.29 (s, 1H), 12.18 (br s, 1H); C nmr
(DMSO-d ): δ 112.4, 115.8, 116.2, 118.6, 121.3, 122.3, 123.4,
6
124.7, 125.6, 128.4, 129.3, 132.7, 137.0, 137.7, 142.2, 153.8,
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+
158.3, 184.8; ms: (ESI+) m/z 290 [M + H] .
Anal. Calcd. for C H NO : C, 74.73; H, 3.83; N, 4.84.
18 11
3
Found: C, 74.50; H, 3.61; N, 4.97.
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[1-(tert-Butoxycarbonyl)-1H-indol-3-yl]-1-oxopropanenitrile
(11).
To a suspension of 3-(cyanoacetyl)-1H-indole (1a) (11.04 g,
60.0 mmol) in anhydrous THF (200 mL) was added di-tert-butyl
dicarbonate (16.38 g, 75.0 mmol), followed by DMAP (70 mg,
0.57 mmol). The mixture was stirred at room temperature under
N for 42 h, and was thereafter concentrated in vacuo. Trituration
2
of the residue with Et O (~200 mL) gave a precipitate, which was
2
collected by filtration and dried to afford 11 (12.4 g) as a colour-
less solid. Two additional crops (2.2 g and 0.52 g) were obtained

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