Cyclization of cyanoethylated ketones as a route to 6-substituted indole derivatives

Article abstract of DOI:10.1002/jhet.2048

δ-Cyanoketones are quickly cyclized with KOtBu to 3-aminocyclohex-2-enone derivatives, which in turn will give substituted indoles when treated with oxalyl chloride. Thus, 3-amino-6,6-dimethylcyclohex-2-enone gave 3-chloro-6,6-dimethyl-2,5,6,7-tetrahydroindole-2,5-dione, whose structure was corroborated by X-ray crystallography, whereas the corresponding molecule without the blocking gem-dimethyl groups, 3-aminocyclohex-2-enone, gave via hydrogen shifts 6-chloro-3-hydroxyoxindole.

Full text of DOI:10.1002/jhet.2048

January 2014
Cyclization of Cyanoethylated Ketones as a Route to 6-Substituted
Indole Derivatives
1
a
a†
*
Jan Bergman and Birgitta Stensland
KI, Unit of Organic Chemistry, Department of Biosciences at Novum, SE 141 57 Huddinge, Sweden
*
E-mail:jan.bergman@ki.se
†Retired
Received March 1, 2013
DOI 10.1002/jhet.2048
Published online 4 October 2013 in Wiley Online Library (wileyonlinelibrary.com).
d-Cyanoketones are quickly cyclized with KOtBu to 3-aminocyclohex-2-enone derivatives, which in turn
will give substituted indoles when treated with oxalyl chloride. Thus, 3-amino-6,6-dimethylcyclohex-2-enone
gave 3-chloro-6,6-dimethyl-2,5,6,7-tetrahydroindole-2,5-dione, whose structure was corroborated by
X-ray crystallography, whereas the corresponding molecule without the blocking gem-dimethyl groups,
3-aminocyclohex-2-enone, gave via hydrogen shifts 6-chloro-3-hydroxyoxindole.
J. Heterocyclic Chem., 51, 1 (2014).
INTRODUCTION
Cyanoethylation is a simple and synthetically useful
operation [1,2]. Thus, acetone and acrylonitrile plus a suitable
basic catalyst will readily give the tris-cyanoethylated product
1 because the reaction steps two and three proceed faster
than the first step. On an industrial scale, however, the 1:1
product 5-ketohexanenitrile 2a can readily be prepared,
and the substance is also commercially available. a,a-
Dialkylketones are regioselectively cyanoethylated at the
carbon atom bearing the alkyl groups. Thus, for instance,
methylisopropylketone readily regioselectively will give
compound 2b [3]. Enamine derivatives of ketones can
also be used to obtain 1:1 products. In this fashion, for
example, 3 is readily available by cyanoethylation of the
morpholino enamine derivative of cyclohexanone [2].
In spite of their ready availability at a low cost, very few
secondary transformations on 1 and 2 and related
molecules have been reported. In 1972, Cason et al.
reported incorrectly that base-induced condensation of 3,3-
biscyanoethylated octane-2-one will give rise to 4a [4], that
is, a Thorpe cyclization, which in principle should be evident
from work reported by Colonge [5] and by Pfleiderer [6]. In
fact, condensations leading to 3-aminocyclohex-2-enones 5
will invariably occur. Cason et al. also incorrectly contended
that 1 should be its cyclized isomer 4b.
RESULTS AND DISCUSSION
It has now been found that the monocyanoethylated
ketones 2a and 2b under the influence of potassium tert-
butoxide in hot THF (for 2b) or dioxane (for 2a) quickly
(5–10min) will give the potassium salts 8a and 8b,
respectively, as readily isolable solids in high yields. The
gem-dimethyl derivative 8b is rather insensitive and can
even be recrystallized from water. Acidic hydrolysis of 8b
gave the known molecule 3-hydroxy-6,6-dimethylcyclohex-
2-enone [14,15]. Alkylation of 8a with 3-chloro-2-butanone
followed by heating gave the expected and already known
indole derivative 9 [16,17], whereas treatment of 8b with
oxalyl chloride gave an unexpected indole derivative, 11,
as outlined in Scheme 1. The yield was high (90%).
In fact (as NMR data now clearly demonstrate), the
originally (1942) assigned structure is indeed correct [7].
Thus, condensation of 2b under basic conditions likewise
readily yields the condensation product 5b and not a
Thorpe product. The trinitrile 1 similarly yields 5c [8].
Molecule 5a is a commonly used starting material for syn-
thesis of various nitrogen heterocycles (e.g., 6 [9–11], 7a
[11], and 7b [12,13]).
The chlorine atom in 11 could readily be displaced by
nucleophiles, such as morpholine, which gave 13 (Scheme 1).
The known amino derivatives of dimedone, 14a and 14b,
when treated similarly gave the chlorine-free products 15a
and 15b. Under forcing conditions, 15b could be converted
to the mono chloro derivative 16. Obviously, the sterically
demanding gem-dimethyl group in 4-position is preventing
any transformation of the hydroxyl group in the 3-position.
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J. Bergman and B. Stensland
Vol 51
Scheme 1
The conventionally expected regioisomeric products
from 8b, 12a, or 12b were not formed at all that might
be explained in terms of a severely deactivated enaminone
system in the initial product 17a that will therefore react as
the enol 17b (Scheme 2).
3-Hydroxycyclohex-2-enone similarly gave an unstable
intermediate that readily eliminated CO and CO2 yielding
the known molecule 18 [18,19] rather than any cyclized
product. That the product of the reaction between 8b
and oxalyl chloride could not be 12b was clearly indicated
by the fact that the coupling constant between the CH2
group and the olefinic proton is very low (J = 0.1 Hz) in
Figure 1. The crystal structure of 11. [Color figure can be viewed in the
online issue, which is available at wileyonlinelibrary.com.]
1
the H NMR spectrum of 11. The correct structure was
finally corroborated by an X-ray analysis (Fig. 1). The crystal
structure of 11 crystallizes in the monoclinic space group
P21/n with four molecules in the unit-cell. The unit-cell axes
are as follows: a = 5.716(1), b = 29.947(2), and c = 5.934
(1) Å, b = 102.93(1).
in Scheme 1 seems to be without precedents, and the closest
example is due to Sha et al. [20] who found that the silylated
derivative 19 could be brominated by N-bromosuccinimide
in the presence of azo-bisisobutyronitrile to give the product
20,which subsequently could be cyclized to 21 [18].
Another intriguing example has been provided by Langer
et al. [21] who treated doubly silylated dimedone, 22 with
oxalyl chloride and obtained the benzofuranone derivative
23, obviously a cousin to 15a.
The cyclization of the enaminone 8b in 4-position (and
not in 2-position) relative the carbonyl function as outlined
Scheme 2
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Cyclization of Cyanoethylated Ketones as a Route to 6-Substituted Indole
Derivatives
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yielding 6-chloro-3-hydroxyoxindole 25, a reaction that
starts with a ring opening to 28, which subsequently will
lose the side chain followed by a recyclization to 25.
Compound 27a featured an aliphatic signal at 71.1 ppm,
whereas the ring-opened molecule 28 had a CH function
that resonated at 40.8 ppm. The final recyclization yielded
6-chloro-3-hydroxyoxindole that as a cyclic molecule
featured a aliphatic CH signal at 67.8 ppm. The structure of
25 was proven by an independent synthetic reduction of
6-chloroisatin with hypophosphorous acid. This reductive
agent previously had been used on one single occasion,
namely reduction of 5,7-diiodoisatin to 5,7-diiodo-3-
hydroxyoxindole a long time ago [23] (Scheme 4).
Reduction of 6-chloroisatin with sodium borohydride in
ethanol or acetic acid failed, and dimeric products were
obtained. Actually, hypophosphorous acid proved to be
a useful reductive agent as several isatin derivatives
could conveniently be reduced to 3-hydroxyoxindoles. In
connections with NMR studies of, for example, 5-fluoro-
3-hydroxyoxindole, it was observed that in a solution of
dimethylsulfoxide (DMSO), oxidative coupling to 3,30-di-
hydroxy-5,50-difluoro-3,30-bioxindole was complete within
24 h at room temperature.
Reaction of 8a, or equally well the corresponding acid,
3-aminocyclohex-2-enone, with oxalyl chloride gave a
product with a chlorine atom in the 6-membered and not in
the 5-membered ring as indicated in Scheme 3. The proposed
intermediate 24 contains chlorine in the 6-membered ring as
distinct from the corresponding intermediate, 17b, discussed
in Scheme 2, where the gem-dimethyl group is preventing a
chlorination process. In similarity with the previous case,
the intermediate 24 will cyclize to the 4-position rather
than to the 2-position, thus yielding, after transposition of
hydrogen atoms, the 6-chlorinated indole derivative 25,
which under the conditions will react with a second mole-
cule of oxalyl chloride to give 27a.
The final product 27 existed exclusively as the chain
tautomer 27a, rather than the ring tautomer 27b that
could be transformed to a pyridinium salt, which differed
very little from 27a when it comes to the signals in the
13C NMR spectrum. As expected, signal differences were
only clearly observable in the side chain. In connection with
the discussion of the intermediate 26 and the final product
27a, the isolation of 29, from treatment of oxindole with
oxalyl chloride, by Magnus is of considerable interest [22].
The side chain in 27a could be removed by hot water
Scheme 3
Scheme 4
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J. Bergman and B. Stensland
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The phenylamino derivative 30, readily prepared from
isomers was 2:1 with the 4-chloroisomer predominating,
which is in agreement with results reported by Senear
[27] but in disagreement with the relative yields reported
by Sadler, who reported the ratio 33/35 with the 6-iso-
mer slightly predominating [25,26]. The facile synthesis of
33 and 36 is in sharp contrast to a report by Kraynack et al.
[28]. These workers prepared 33 and 36 in a lengthy and
time-consuming way. The ring phenylated molecule 38
could be similarly cyclized to 39 with oxalyl chloride as
outlined in Scheme 7.
The 3-hydroxycyclohex-2-enone derivatives 25, 27,
and 31 could easily be ring-opened with piperidine or
morpholine. During that process also, oxidation took place
and the product, as illustrated in Scheme 8, was identical with
the product obtained by ring opening of the corresponding
isatin derivative. Isatin itself 41 undergoes a similar ring
opening to 42 [29].
1,3-cyclohexanedione and aniline, 130ꢀC/5 min, similarly
could by cyclized to 31, whose structure was proven by
phenylation of the anion of 6-chloroisatin 33 with
diphenyliodonium triflate as outlined in Scheme 5. This
new procedure appears to be general, and isatin itself could
be similarly transformed to N-phenylisatin. 4-Chloroisatin
similarly could be phenylated to 34, a molecule that also
could be isolated in small amounts from the mother liquor
of 31 after several days. Obviously, a “conventional”
cyclization of 30 induced by oxalyl chloride had to a
minor extent occurred, and subsequent aerial oxidation
led to 34. Ready aerial oxidation of N-substituted
(e.g., N-phenyl-3-hydroxy-oxindole) 3-hydroxyoxindoles
is a well-known process [24]. The two substituted isatins,
33 and 36, needed for the phenylation studies were
synthesized from the oxime 35 obtained via the classical
Sandmeyer procedure [25]. Separation of the mixture
of 33 and 36 was very easy, following literature proce-
dures [25,26] outlined in Scheme 6.
As expected, because of hindered rotation around the
amide bond, the CH2 groups in the piperidine ring featured
five signals in the 13C NMR spectra. From the transforma-
tion 10 ! 11, it is clear that hydroxyl groups in position 3
of the indole rings can be converted to the corresponding
chloro derivatives, and in order, to study the generality of
Acidification of the mother liquor with hydrochloric acid
after isolation of the 4-isomer, 36, gave, due to cyclization
of 37, the 6-isomer in pure form. The relative ratio of the
Scheme 5
Scheme 6
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Cyclization of Cyanoethylated Ketones as a Route to 6-Substituted Indole
Derivatives
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Scheme 7
Scheme 8
Scheme 9
Scheme 10
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2.35 (t, 2H, CH2); 13C NMR d:12.1 (t), 23.3 (t), 25.0 (q),
33.7 (q), 46.4 (s), 120.6 (s), 212.0 (s).
this reaction, 3-hydroxyindole 43 itself was treated with
oxalyl chloride in acetonitrile and the expected product,
the known molecule 3-chlorooxindole 44, was not formed
(Scheme 9). However, 44 could readily be prepared from
the diazo compound 45. 3,6-Dichlorooxindole could be
similarly prepared.
3-Amino-6,6-dimethylcyclohex-2-enone, potassium salt (8b).
The ketonitrile 2b (13.9 g, 0.1 mol) was added dropwise to a
stirred solution of potassium t-butoxide (11.2, 0.1 mol) in THF
(80 mL) under argon. The reaction mixture was heated at reflux
for 15 min and then allowed to cool. After 2 h, the solid formed
was collected and dried, 15.9 g (93%) of 8b mp >260 dec. This
potassium salt is not sensitive to water and can in fact be
recrystallized from this medium. Actually, evaporation of the THF
mother liquor followed by recrystallization from water gave an
additional quantity (1.0 g) of 8b. 1H NMR d: 0.93 (s, 6H,
2 CH3), 1.61 (q, 2H, CH2), 2.25 (q, 2H, CH2), 4.70 (s,
1H, CH), 4.91 (s, 1H, NH); 13C NMR d: 25.3 (q), 25.9
(t), 35.6 (t), 37.9 (s), 95.5 (d), 167.2 (s), 197.1 (s).
After 3 h, the violet-red reaction solution from 43 and
oxalyl chloride deposited indirubin 46 in a respectable
yield (76%). In Scheme 10, a speculative rationalization
is offered, which involves the classical intermediate
indolon 51 as the crucial intermediate. Traditionally,
indirubin 46 has been prepared in excellent yields by
reacting indoxyl 49 (or N-acetylindoxyl) with a product
obtained by treating isatin with PCl5 in hot benzene. This
orange-red product was a long time considered to be 47
but is in fact largely its dimer 48 [30]. However, they are in-
terrelated via an equilibrium. As indicated in Scheme 10, for-
mation of indirubin from 3-hydroxyoxindole and oxalyl
chloride seems to involve similar types of transformations.
Finally, it should be added that indirubin 46 and some
of its derivatives have attracted considerable attention
among biochemists ever since it was reported that indirubin
46 and several of its derivatives selectively inhibit cyclin-
dependent kinases [31–34].
3-Amino-6,6-dimethylcyclohex-2-enone (5b). The potassium salt
8b (1.77 g, 10 mmol) was stirred in water (10 mL) containing acetic
acid (1.0 mL) for 0.5 h, whereupon the mixture was extracted with
ether (2ꢂ 50 mL). The extract was dried and evaporated.
Crystallization from benzene gave the title compound, 1.11 g (80%)
mp 208–210ꢀC; IR 3343, 3138, 2956, 2919, 1649 (w), 1530, 1469,
1440, 1388, 1211, 1162, 824 cmꢃ1 1H NMR d: 0.95 (s, 6H, 2
;
CH3), 1.64 (q, 2H, CH2), 2.27 (q, 2H, CH2), 4.80 (s, 1H, CH), 6.62
(2H, NH2); 13C NMR d: 25.0 (t), 25.1 (q), 35.3 (t), 38.3 (s), 95.5
(d), 165.5 (s), 199.3 (s). Anal. Calcd for C8H13NO: C 69.03; H
9.41; N 10.06. Found: C 68.90; H 9.62; N 10.12.
3-Hydroxy-6,6-dimethylcyclohex-2-enone. The potassium salt
8b (2mmol) was added to ethanol (5 mL) containing
hydrochloric acid (0.5 mL). After a period of reflux (20 min),
the solution was evaporated and the residue extracted with
ether. After a drying period over MgSO4, the solvent was
evaporated, and the residue, 1.5 mmol, (75%) was identified as
the title compound. The 13C data were identical with those
reported by Maini et al. [14]
3-Amino-6,6-bis-cyanoethylcyclohexene-2-one (5c). The
trisnitrile 1 (10.85 g, 0.05 mol) was dissolved in DMF
(90 mL) plus THF (80 mL), and potassium t-butoxide (5.6 g)
was added to the stirred solution under argon at 55ꢀC. After
1 h at this temperature, the reaction mixture was concentrated and
poured into water and acidified with acetic acid. The solid formed
was collected after 4 h, 9.05 (83%) mp 215–217ꢀC (lit. [5] mp
215–217ꢀC); 1H NMR d: 1.73 (m, 6H), 2.37 (m, 6H), 4.87 (s,
1H), 6.76 + 6.99 (2s, 2NH); 13C NMR d: 11.5 (t), 23.8 (t), 29.9
(t), 31.2 (t), 43.5 (s), 96.5 (d), 121.0 (s), 166.2 (s), 195.4 (s).
3-Aminocyclohexene-2-one, potassium salt (8a). The same
procedure as for 8b was used except that protection with
nitrogen (or preferably argon) was necessary. Yield 75%; 13C
NMR d: 22.6 (t), 34.0 (t), 35.6 (t), 96.5 (d), 176.2 (s), 183.2 (s).
3-Aminocyclohexene-2-one (5a). The potassium salt 8a (1 mmol)
was treated with water containing acetic acid as described for the
gem-dimethyl derivative. Yield 65%, mp 133–134ꢀC (lit. [35]
mp 133–134ꢀC). The NMR data were in agreement with data
reported in the literature [35].
CONCLUSIONS
A novel but limited synthetic method to substituted indole
derivatives has been developed. As spin-offs, a simple (and
fast) method to the valuable synthon 3-aminocyclohex-2-
enone has been found, and perhaps most importantly, a
one-step method to indirubin has been realized.
EXPERIMENTAL
General.
1H and 13C NMR spectra were recorded on a
1
Bruker DPX 300 instrument at 300.1 MHz for H and 75.5 for
13C, respectively, using the residual (DMSO-d6) resonances as
reference, unless otherwise stated. The IR spectra were
performed on an Avatar 300 FT-IR spectrometer (Thermo
Nicolet). The elemental analyses were performed by H. Kolbe
Mikroanalytisches Laboratorium, Mülheim an der Ruhr,
Germany. All chemicals originated from commercial sources and
were used as received, except THF, which was distilled from
sodium and benzophenone. 5-Ketohexanenitrile 2a was
purchased from TCI Europe, Belgium.
a,a,a-Triscyanoethylacetone (1). This molecule was prepared
as described in the literature [3]. Yield: 92%, mp 166–167ꢀC;
3-Chloro-5,5-dimethyl-2,4,5,6-tetrahydro-2,6-dioxoindole (11).
Oxalyl chloride (5.0 mL) in acetonitrile (20mL) was added
dropwise to a stirred solution of 6,6-dimethyl-3-aminocyclohexene-
2-one (2.78 g, 0.02 mol) in acetonitrile (70 mL). This operation
resulted in the formation of a precipitate of an acid chloride, which
quickly went in solution during the following period (4 h) of reflux.
After filtration, the solution was evaporated and treated with
methyl acetate, 3.80 g (90%); mp 207–208ꢀC. IR 3219, 2968 (w),
1
IR 2957, 2250 (CꢁN), 1695 (C=O), 1474, 1361, 1171 cm1; H
NMR d: 1.87 (t, CH2), 2.17 (s, CH3), 2.32 (t, CH2); 13C NMR
d: 11.4 (t, CH2), 25.6 (q, CH3), 27.3 (t, CH2), 52.2 (s), 120.2
(s, CꢁN), 211.1 (s, C=O).
4,4-Dimethyl-5-ketohexanenitrile (2b). Methyl isopropyl
ketone was cyanoethylated following a literature procedure
[3]. Yield: 88%, bp 132–134ꢀC/18 mm; 1H NMR d: 1.08
(s, 6H, 2CH3), 1.80 (t, 2H, CH2), 2.11 (s, 3H, COCH3),
2928 (w), 1732, 1694, 1642, 1630, 1139, 1123, 1053, 870 cmꢃ1
;
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Cyclization of Cyanoethylated Ketones as a Route to 6-Substituted Indole
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7
1H NMR d: 1.11 (s, 6H, 2 CH3), 2.82 (s, 2H, CH2, J =0.1), 5.61 (s,
1H, CH, J= 0.1), 11.0 (s, 1H, NH); 13C NMR d: 26.0 (q), 34.4 (s).
42.6 (t), 104.9 (d), 123.8 (s), 140.0 (s), 149.2 (s), 165.0 (s), 201.5
(s); Anal. Calcd for C10H10ClNO2: C 56.91; H 4.73; N 6.03.
Found: C 56.88; H 4.79; N 5.99.
3-Chloro-5,5-bis-cyanoethyl-2,4,5,6-tetrahydro-2,6-dioxoindole.
The procedure given for 11 was followed starting with 5c. Yield:
77%, mp 210ꢀC, dec. 1H NMR except for a CH-singlet at
5.61 ppm, a complex pattern of multiplets; 13C NMR d: 11.7 (t)
29.4 (t), 31.1 (t), 47.9 (s), 105.5 (d), 120.3 (s), 124.7 (s), 138.8 (s),
149.5 (s), 164.9 (s), 198.3 (s). Anal. Calcd for C14H12ClN3O2: C
58.25; H 4.17; N 4.84. Found: C 57.99; H 4.25; N 4.73.
at 70ꢀC. The solid formed on cooling was collected 225 mg
(62%) mp >260ꢀC; 13C NMR d: 70.5 (d), 110.2 (d), 121.7 (d),
123.2 (s), 124.8 (d), 126.7 (d), 134.5 (s), 138.9 (d), 144.6 (s),
147.5 (d), 159.4 (s), 160.2 (s), 172.7 (s).
Hydrolysis of 27a. Preparation of 28. Compound 27a
(256 mg, 1 mmol) was heated for 0.5 h at 80ꢀC in dioxan (5 mL)
and water (3 mL). After filtration, the filtrate was concentrated,
and the crystals formed were collected, 160 mg (54%), mp
1
160ꢀC dec.; H NMR d: 4.50 (s, 1H), 5.7 (br s, OH), 6.78–6.86
(m, 3H), 10.4 (s, 1H). No clear assignments of the OH groups
in the carboxyl functions could be made. 13C NMR d: 40.8 (d),
108.6 (d), 111.5 (s), 120.4 (d), 123.9 (d), 129.6 (s), 131.0 (s),
144.5 (s), 162.6 (s), 178.2 (s). Anal. Calcd for C10H8ClNO6: C
43.87; H 2.92; N 5.13. Found: C 43.55; H 3.06; N 4.97.
3-Hydroxy-4,4-dimethyl-2,4,5,6-tetrahydro-2,6-dioxoindole (15a).
The same procedure as for 11 was used, starting with compound
14a, a known molecule [36]. Yield 82%, mp 190ꢀC, dec. IR 3350,
6-Chloro-3-hydroxyoxindole (25). A mixture of 6-chloroisatin
(1.86 g) dioxane (6 mL), water (4 mL), and H3PO2 (50%, in
water, 6 mL) was heated under nitrogen at reflux temperature
for 1 h. The solution obtained was allowed to cool and the
whitish solid collected after 24 h, 1.49 g (79%) mp 190–195ꢀC.
1706, 1615, 1480, 1449, 1326, 1180, 1068, 923, 868 cmꢃ1 1H
;
NMR d: 1.28 (s, 6H, 2CH3), 2.44 (s, 2H, CH2), 3.90 (br s, 1H, OH),
5.54 (s, 1H, CH), 10.4 (s, 1H, NH); 13C NMR d: 27.7 (q), 32.5 (s),
52.1 (t), 104.2 (d), 118.3 (s), 144.3 (s), 152.6 (s), 166.7 (s), 196.5
(s). Anal. Calcd for C10H11NO3: C 62.16; H 5.74; N 7.25. Found: C
61.85; H 5.90; N 7.11.
IR 3300–3100, 1708, 1616, 1181, 1069, 920 cmꢃ1 13C NMR d:
;
68.8 (d), 109.7 (d), 121.4 (d), 126.2 (d), 128.3 (s), 133.4 (s),
143.8 (s), 177.9 (s); Anal. Calcd for C8H6ClNO2: C, 52.40; H
3.27; N 7.63. Found; 52.17; H 3.40; N 7.49.
Hydrolysis (3h) of compound 27a. Compound 10 (2.22 g,
10 mmol) was heated at reflux temperature in water (30 mL) and
dioxane (30 mL) for 3 h, whereupon the mixture was filtered and
the solid formed on cooling (after concentration) was collected
1.05 g (56%). The spectral data showed its identity with 6-chloro-
3-hydroxyoxindole 25.
3-Morpholino-5,5-dimethyl-2,4,5,6-tetrahydro-2,6-dioxoindole
(13). 3-Chloro-5,5-dimethyl-2,4,5,6-tetrahydro-2,6-dioxoindole 11
(212mg, 1 mmol) was heated at reflux for 10min in dioxane
(5mL) containing morpholine (200 mg). After completed reaction,
the mixture was poured into water, and the yellowish solid was
1
collected and dried, 220 mg (83%) mp 187–188ꢀC. H NMR d:
1.15 (s, 6H, 2CH3), 2.68 (s, 2H, CH2), 3.52 (s, 4H, 2CH3), 3.64
(s, 4H, 2CH2O), 5.25 (s, 1H, CH), 10.4 (s, 1H, NH); 13C NMR d:
26.0 (q), 35.7 (t), 41.9 (s), 48.1 (t), 66.1 (t), 100.1 (d), 109.8 (s),
138.3 (s), 152.5 (s), 167.5 (s), 201.2 (s). Anal. Calcd for
C14H18N2O3; C 63.10; H 6.92; N 10.68. Found: C 63.22; H. 6.99;
N 10.72.
2,3-Dimethyl-4-oxo-4,5,6,7-tetrahydroindole (9). The potassium
salt 8a (1.49 g, 10mmol) and 3-bromo-2-butanone (1.51 g,
10mmol) were heated at reflux temperature in dioxane for 1 h.
After filtration and evaporation, the residue was crystallized from
toluene, 1.29 g (79%); mp 226–227ꢀC (lit. [16] mp 226–227ꢀC);
13C NMR d: 9.8 (q), 9.9 (q), 22.2 (t), 23.7 (t), 38.3 (t), 111.5 (s),
117.9 (s), 123.7 (s), 141.5 (s), 193.3 (s).
5-Methyl-3-aminocyclohex-2-enone. 5-Methyl-3-hydroxycyclohex-2-
enone (2.52g, 20 mmol) was dissolved in concentrated aqueous
ammonia (8mL). After 24h at room temperature, the solvent was
evaporated to yield a white solid, 2.40g (100%) mp 146–148ꢀC
(lit. [37] mp 146–148ꢀC); 13C NMR d: 20.7 (q), 28.7 (d), 36.0 (t),
49.0 (t), 96.8 (d), 167.5 (s), 194.9 (s).
2-Amino-4-chloroglyoxylylpiperidide (40) from 6-chloroisatin.
A mixture of 6-chloroisatin (1.86 g), water (8 mL), dioxane (8 mL),
and piperidine (0.6 g) was heated at reflux temperature for 5 min.
After concentration, additional water was added, and the light
yellow solid formed was collected, 2.36 g (80%), mp 132–133ꢀC.
IR: 3418, 3295, 2939, 2855, 1601, 15540, 1473, 1431, 1240,
1
1209, 969, 920, 851cmꢃ1; H NMR d: 1.41 (m, 2H), 1.60 (dd,
4H), 3.18 (dd, 2H), 3.54 (dd, 2H), 6.60 (dd, 1H, J1 = 1.83,
J2 = 8.71), 6.91 (d, 1H, J1 = 1.83), 7.30 (d, 1H, J2 = 8.71), 7.52 (br
s, 2H, NH2); 13C NMR d: 23.7 (t), 25.0 (t), 25.7 (t), 41.1 (t), 46.3
(t), 111.7 (s), 115.1 (d), 115.8 (d), 134.7 (d), 140.4 (s), 153.0 (s),
164.5 (s), 193.2 (s); Anal. Calcd for C13H15ClN2O2: C 58.70; H
5.74; N 10.53. Found: C 58.63; H 5.81; N 10.40.
2-Amino-4-chloroglyoxylylpiperidide from 27a. Compound
27a (256mg, 1 mmol) and piperidine (0.25 mL) were heated at
reflux in dioxane (5mL) for 0.5 h, whereupon the reaction mixture
was concentrated and treated with water. The light yellow solid
formed was collected, washed with water, and dried, yield 85%.
This sample was identical with a sample from the previous
preparation.
Synthesis of compound 27a. Oxalyl chloride (6.34g, 50mmol)
was added dropwise to a stirred solution of 3-aminocyclohex-2-
enone (2.22 g, 20mmol) or an equivalent suspension of the
potassium salt 8a in acetonitrile (80mL) at 50ꢀC. A period of
reflux (2.5h) finalized the conversion to the product that was
isolated after filtration (hot), evaporation, and titruation with
methyl acetate, and dried, 5.75g(93%) mpꢄ 200ꢀC dec.; IR
3300–3000 (br), 1744, 1725, 1671, 1616, 1485, 1172, 921,
3-Hydroxyoxindole. Isatin (14.7 g, 0.1 mol) was reduced with
sodium dithionate following a literature procedure [38]. Yield:
1
73%, mp 167–168ꢀC (lit. [39] mp 167–168ꢀC); H NMR d: 4.85
(d, 1H, 3-H, J= 6.6), 6.20 (d, 1H, OH, J= 6.6), 6.80 (d, 1H, 7-H),
6.95 (dd, 1H, 5-H), 7.18 (dd, 1H, 6-H), 7.29 (d, 1H, 4-H), 10.2 (s,
1H, NH); 13C NMR d: 69.2 (d), 109.5 (d), 121.6 (d), 124.8 (d),
128.9 (d), 129.3 (s), 142.1 (s), 178.0 (s).
817 cmꢃ1 1H NMR d: 6.08 (s, 1H, 3-H), 6.91 (d, 1H, 7-H,
;
J1 = 1.98), 6.99 (dd, 1H, 5-H, J1 = 1.98, J2 = 7.93), 7.33 (d, 1H, 4-
H, J2 = 7.93), 10.9 (s, 1H, OH); 13C NMR d: 70.9 (d), 110.3 (d),
121.7 (d), 122.8 (s), 126.8 (d), 133.6 (s), 144.6 (s), 158.1 (s),
158.2 (s), 172.4 (s); Anal. Calcd for C10H6ClNO5: C 47.21; H
2.36; N 5.52. Found: C 46.98; H 2.44; N 5.47.
5-Fluoro-3-hydroxyoxindole. 5-Fluoroisatin (8.25g, 50mmol)
was added in portions to a stirred solution of hypophosphorous
acid (aq., 25%, 70 mL) at 65ꢀC. After 0.5 h at this temperature,
the mixture was allowed to cool and the whitish solid collected
6.8 g (81%) mp 200–201ꢀC; IR 3300–3100, 1697, 1631, 1484,
Pyridinium salt of 27a. Compound 27a (256 mg, 1 mmol) and
pyridine (79 mg, 1 mmol) were dissolved in acetonitrile (10 mL)
1
1463, 1263, 1192, 1137, 1106, 1054, 946, 878, 819 cmꢃ1; H
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

8
J. Bergman and B. Stensland
Vol 51
NMR d: 4.85 (s, 1H, 3H), 6.2 (br s, 1H, OH), 6.71 (m, 1H), 7.01
(m, 1H), 7.12 (m, 1H); 13C NMR d: 69.4 (d, 3C, JCF = 1.6 Hz),
110.2 (d, 7-C, JCF = 7.7 Hz), 112.4 (d, 6-C, JCF = 24.7 Hz),
115.1 (d, 4-C, JCF = 23.5 Hz), 131.1 (d, 3a-C, JCF = 7.7 Hz),
138.2 (d, 7a-C, JCF = 2.2 Hz), 157.9 (d, 5-C, JCF = 237.7 Hz),
177.9 (s, C=O). Anal. Calcd for C8H6FNO2: C 57.50; H 3.59;
N 8.39. Found: C 57.23; H 3.65; N 8.30.
3-Chlorocyclohex-2-enone (18). Oxalyl chloride (6.5mL) was
added in portions to 3-hydroxycyclohex-2-enone (4.48 g,
40mmol) in acetonitrile (40mL) at 20ꢀC. The solid part of the
starting material quickly went into solution under vigorous
evolution of hydrogen chloride. After 2 h, the solvent was
evaporated, leaving the product as viscous oil, 4.90 g (92%). The
NMR data were identical with those in the literature [19].
5-Fluoro-3-hydroxy-2-oxo-3-biindole. 5-Fluoro-3-hydroxyoxindole
(1.67 g, 10 mmol) was dissolved in DMSO (10 mL) and the solution
kept at 40ꢀC for 24 h and then poured into water to yield a grayish
solid, 1.55 g (94%) mp >260ꢀC; IR 3317, 3208, 1697, 1684, 1628,
6-Chloro-4-methyl-3-hydroxyoxindole. The procedure given for
6-chloro-3-hydroxy-oxindole was followed. Yield 45%, mp 112–
1
115ꢀC. H NMR d: 2.26 (s, 3H, CH3), 4.82 (s, 1H, 3-H), 5.51
(br s, 1H, OH), 6.60 (d, 1H, J= 1.25), 6.78 (d, 1H, J= 1.25),
10.3 (s, 1H, NH). 13C NMR d: 17.1 (q), 68.4 (d), 107. (d),
122.5 (d), 124.3 (s), 133.0 (s), 137.7 (s), 143.7 (s), 177.8 (s).
Anal. Calcd for C9H8ClNO2; C 54.60; H 4.05; N 7.08. Found:
C 54.43; H 4.11; N 6.96.
6-Chloro-4-methylisatin. A solution of 6-chloro-4-metyl-3-
hydroxyoxindole (1 mmol) in DMSO (8 mL) was prepared. After
3 days, the solution was poured into water, and the yellow solid
formed (0.8 mmol) was collected, mp 230ꢀC dec. 1H NMR d: 2.40
(s, 3H, CH3), 6.70 (d, 1H, J= 1.25), 6.93 (d, 1H, J= 1.25), 11.1 (s,
1H, NH). 13C NMR d: 17.2 (q), 109.6 (d), 124.3 (d), 141.5 (s),
141.7 (s), 145.5 (s), 151.9 (s), 159.2 (s), 183.5 (s). Anal. Calcd for
C9H6ClNO2; C 55.04; H, 3.06; N 7.16. Found: C 54.86; H 3.17;
N 7.00.
1482, 1463, 1345, 1261, 1197, 1147, 1122, 869, 828 cmꢃ1 1H
;
NMR d: 5.8 (br s, 1H, OH), 6.60 (m, 1H), 6.78 (m, 1H), 7.07 (m,
1H), 10.4 (s, NH); 13C NMR d: 77.6 (d, 3-C, JCF = 1.6 Hz), 110.4
(d, 6-C, JCF = 7.8 Hz), 113.0 (d, 6-C, JCF = 25.2 Hz), 116.3 (d, 4-C,
JCF = 23.1 Hz), 128.5 (d, 3a-C, JCF = 7.7 Hz), 138.7 (d, 7a-C,
JCF = 1.9 Hz), 157.5 (d, 5-C, JCF = 240.0 Hz), 176.0 (s, C=O). Anal.
Calcd for C16H10F2N2O4; C 58.08; H 3.08; N 8.47. Found: C
57.97; H 3.16; N 8.42.
3-Phenylaminocyclohex-2-enone (30). A mixture of 3-
hydroxycyclohex-2-enone (11.2 g, 0.1 mol) and aniline
(10.5 g, 0.11 mol) was heated under nitrogen for 10 min at
140ꢀC. The solid formed was treated with 2-propanol, and the
beige title compound was collected 14.6 g (78 %) mp 178–179ꢀC
1
(lit. [36] mp 176–177ꢀC); H NMR d: 1.87 (m, 2H, CH2), 2.18
6-Chloro-N-phenyl-3-hydroxyoxindole (31). 3-Phenylaminocyclohex-
2-enone 30 (1.87g, 10mmol) was dissolved in acetonitrile (40 mL),
and oxalyl chloride (3.17 g, 25mmol) in acetonitrile (20 mL) was
added dropwise during 15min. After a period (10min) of reflux,
the solution was evaporated and the residue dissolved in warm
2-propanol. The crystals formed on cooling were collected,
1.42 g (57%), mp 199–200ꢀC. 1H NMR d: 5.13 (s, 1H, 3-H),
6.63 (d, 1H, 7-H, J1 = 1.98), 7.14 (dd, 1H, 5-H, J1 = 1.98,
J2 =7.93), 7.56 (1H, 4-H, J1 = 7.93), 7.40–7.60 (m, 5H), 6.5 (br s,
1H, OH). IR 3343, 1715, 1614, 1587, 1502, 1480, 1422, 1372, 1179,
(m, 2H, CH2), 2.51 (m, 2H, CH2), 5.37 (s, 1H, CH), 7.1–7.4 (m,
5H, arom CH), 8.9 (s, 1H, NH); 13C NMR d: 21.5 (t), 28.5 (t),
36.4 (t), 97.9 (d), 122.9 (d), 124.3 (d), 129.1 (d), 139.1 (s), 162.0
(s), 195.8 (s).
5,5-Dimethyl-3-phenylaminocyclohex-2-enone (14b). The
procedure described earlier was used, starting with dimedone
(0.1 mol). Yield: 85%, lit. [36,40]. The NMR spectra were in
agreement with data given by Edmondson et al. [41].
3-Chlorooxindole (42). 3-Diazooxindole 43, (1.59 g, 10 mmol)
[42,43] was added in portions to conc. hydrochloric acid
(10 mL) diluted with water (5 mL) at 30ꢀC. Vigorous evolution
of N2 ensued, and the product separated was collected after
0.5 h, yield 1.55 g (92%), mp 163–164ꢀC (lit. [44] mp 163ꢀC).
IR 3148, 3086, 1730, 1681, 1619, 1468, 1206, 1188, 740,
1115, 1064, 926, 864 cmꢃ1 13C NMR d: 68.5 (d), 108.8 (d), 122.5
.
(d), 126.5 (d), 126.6 (d), 127.5 (s), 128.3 (d), 129.8 (d), 133.4 (s),
133.8 (s), 144.9 (s), 175.5 (s). Anal. Calcd for C14H10ClNO2; C
64.96; H 3.87; N 5.42. Found: C 64.84; H 3.98; N 5.24.
6-Chloro-N-phenylisatin (32). 6-Chloro-N-phenyl-3-hydroxyoxindole
31 (263 mg, 1 mmol) was dissolved in acetonitrile (10 mL), and
thionyl chloride (195 mg, 1.5 mmol) was added at 25ꢀC.
After approx. 5 min, the solution became turbid. Heating at
reflux temperature for 15 min completed the oxidation, and
the orange product was collected after cooling and a storage
period of 2 h, 220 mg (84%), mp 230ꢀC dec. IR 3075 (w),
1736, 1603, 1596, 1497, 1427, 1365, 1263, 1155, 1069, 938,
1
6.81 cmꢃ1; H NMR d: 5.57, (s, 1H, 3-H), 6.85 (d, 1H), 7.01
(dd, 1H), 7.27 (dd, 1H), 7.35 (d, 1H), 10.8 (s, 1H, NH). 13C
NMR d: 52.2 (d), 110.2 (d), 122.3 (d), 125.6 (d), 126.5 (s),
130.3 (d), 142.4 (s), 173.2 (s).
3,6-Dichlorooxindole. 6-Chloro-3-diazo-oxindole (3.90 g,
20 mmol) was added in portions under stirring to conc. HCl
(20 mL) kept at 60–65ꢀC. When the evolution of nitrogen had
ceased (0.5 h), the mixture was allowed to cool and the light-
beige product collected, 3.81 g (91%), mp 157–158ꢀC (lit. [45]
mp 157–158ꢀC). 1H NMR d: 5.53 (s, 1H, 3-H), 6.88 (d, 7-H,
J1 = 2.0), 7.04 (dd, 1H, 5-H, J1 = 2.0, J2 = 8.1), 7.34 (d, 1H, 4-H,
J2 = 8.1), 10.9 (s, NH). 13C NMR d: 51.6 (d), 110.5 (d), 122.2 (d),
125.5 (s), 127.2 (d), 134.7 (s), 144.0 (s), 173.3 (s).
877 cmꢃ1 13C NMR d: 6.78 (d, 1H, 7-H, J1 = 1.5), 7.23
.
(dd, 1H, 5-H, J1 = 1.5, J2 = 8.1), 7.68 (d, 1H, 4-H, J2 = 8.1),
7.5–7.6 (m, 5H). 13C NMR d: 110.8 (d), 116.6 (s), 123.6
(d), 126.3 (d), 126.6 (d), 128.8 (d), 129.9 (d), 133.0 (s),
142.2 (s), 152.3 (s), 157.6 (s), 181.4 (s). Anal. Calcd for
C14H8ClNO2; C 65.36; H 3.13; N 5.47. Found: C 65.13; H
3.28; N 5.42.
6-Chloro-4,4-dimethyl-N-phenyl-3-hydroxy-2,4-dihydro-2-
oxoindole (16). The procedure given for (11) was used starting with
15b. The light-beige product crystallized directly from the reaction
medium. Yield 85%, mp 215–216ꢀC. IR: 3210, 1675, 1637, 1619,
4-Chloro-N-phenylisatin (34). The 2-propanol mother liquor
from the preparation of 31 was allowed to be in a beaker, in
free contact with the air, for several days. Pale orange
crystals of the title compound slowly separated, 0.65 (26%),
mp 190–191ꢀC. IR 3030 (w), 1731, 1590, 1584, 1351, 1255,
1
1403, 1321, 1159, 952, 855 cmꢃ1. H NMR d: 1.40 (s, 6H, 2CH3),
5.38 (d, 1H, J= 1.20) 5.80 (d, 1H, J=1.20), 7.32–7.53 (m, 5H), 10.7
(br s, 1H, OH). 13C NMR d: 25.8 (q), 37.1 (s), 102.1 (d), 119.1 (s),
124.3 (s), 127.0 (d), 127.7 (d), 129.4 (d), 131.6 (d), 133.6 (s), 138.2
(s), 142.9 (s), 163.6 (s). Anal. Calcd for C16H14ClNO2; C 60.35; H
4.92; N 4.88. Found: C 60.12; H 5.10; N 4.75.
1
1168, 931 877 cmꢃ1. H NMR d: 6.78 (dd, 1H, 7-H, J1 = 0.7,
J2 = 7.9), 7.12 (dd, 1H, 5-H, J1 = 0.7, J2 = 7.9), 7.58 (dd, 1H, 6-H,
J1 = J2 = 7.9), 7.3–7.7 (m, 5H). 13C NMR d: 109.5 (d), 114.7 (s),
124.5 (d), 126.8 (d), 128.7 (d), 129.8 (d), 131.2 (s), 133.1 (s),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2014
Cyclization of Cyanoethylated Ketones as a Route to 6-Substituted Indole
Derivatives
9
138.5 (d), 152.6 (s), 156.8 (s), 179.3 (s). Anal. Calcd for
C14H8ClNO2; C 65.36; H 3.13; N 5.47. Found: C 65.08; H 3.26;
N 5.39.
of 4-chloroisatin was collected, 16.7 g (47%). 4-Chloroisatin 36
gave the following data, mp 257–258ꢀC (lit. [27] mp 256.5–
1
258ꢀC). IR 3280, 1731, 1608, 1439, 1245, 1160, 915cmꢃ1. H
N-Phenylisatin. Isatin (1.47 g, 10 mmol) was dissolved in dry
DMF (25 mL), whereupon under stirring and N2-protection,
sodium hydride (0.30 g, 80% in oil) was added at 25ꢀC. After
completed addition, diphenyliodonium triflate [46] (4.26 g,
10mmol) was added and the mixture stirred at 40ꢀC for 1 h when
water was added to the mixture, which was extracted with ether.
This extract in turn was treated with a solution (5%) of sodium
hydroxide in water. The water phase was separated and acidified
with hydrochloric acid, and the orange-red solid formed was
collected 1.95 g (82%), mp 138–139ꢀC (lit. [24,47] mp 138ꢀC;
mp 137–139ꢀC). IR 1735, 1608, 1454, 1361, 1299, 1180,
NMR d: 6.83 (dd, 1H, 7-H, J1 = 0.8, J2 = 8.3), 7.01 (dd, 1H, 5-H,
J1 = 0.8, J2 = 8.3), 7.52 (dd, 1H, 6-H, J1 = J2 = 8.3), 11.2 (s, 1H,
NH). 13C NMR d: 110.9 (d), 114.7 (s), 123.6 (d), 131.1 (s), 139.0
(d), 152.1 (s), 158.6 (s), 181.2 (s).
6-Chloroisatin (33). The mother liquor from the preparation
earlier was acidified with hydrochloric acid, and the orange solid
formed was collected after 1 h, 7.7g (22%), mp 258–259ꢀC (lit.
[27] mp 258–259ꢀC). IR 3180, 1742, 1715, 1609, 1443, 1326,
1
1207, 1098, 1064, 953, 920, 892cmꢃ1. H NMR d: 6.87 (d, 1H,
7-H, J1 = 2.0), 7.05 (dd, 1H, 5-H, J1 = 2.0, J2 = 8.1), 7.47 (d, 1H,
4-H, J2 = 8.1), 11.2 (s, 1H, NH). 13C NMR d: 112.2 (d), 116.6 (s),
122.7 (d), 126.1 (d), 142.4 (s), 151.8 (s), 159.4 (s), 183.6 (s).
Indirubin (46). 3-Oxo-2-(2-oxo-3-indolylidene)-indole. 3-
Hydroxyoxindole (1.49 g, 10 mmol) was dissolved in
acetonitrile (35 mL) and oxalyl chloride (3.0 mL) added. The
mixture was heated at reflux for 2 h and then left in repos for
24 h. The dark violet-red solid was collected and identified as
1
929 cmꢃ1. H NMR d: 6.82 (d, 1H, 7-H, J1 = 8.0), 7.19 (dd, 1H,
7-H, J1 = J2 = 8.0), 7.48–7.67 (m, 8H). 13C NMR d: 110.8 (d),
117.7 (s), 123.7 (d), 124.7 (d), 126.5 (d), 128.5 (d), 129.7 (d),
133.4 (s), 138.1 (d), 151.3 (s), 157.5 (s), 182.8 (s).
Phenylation of 6-chloroisatin. The procedure described
earlier was used. Yield: 80% of (32). This product was
identical with a sample from oxidation of 6-chloro-3-hydroxy-
N-phenyl-oxindole described earlier.
Phenylation of 4-chloroisatin. The procedure described earlier
was used. Yield: 75% of 34. This product was identical with a
sample from oxidation of 4-chloro-3-hydroxy-N-phenyl-
oxindole described earlier.
5-Phenyl-3-phenylaminocyclohex-2-enone (38). The procedure
described for 30 was used. Yield: 93%, mp 210ꢀC dec. 1H NMR d:
2.30–2.35 (m, 5H), 5.45 (s, 1H, 2-H), 7.11–7.41 (m, 10H), 9.1 (s,
NH). 13C NMR d: 36.0 (t), 39.4 (d), 43.7 (t), 97.6 (d), 123.1 (d),
124.5 (d), 126.6 (d), 127.0 (d), 128.5 (d), 129.3 (d), 139.1 (s),
143.9 (s), 161.2 (s), 195.2 (s). Anal. Calcd for C18H17NO: C 82.10;
H 6.51; N 5.32. Found: C 81.86; H 6.58; N 5.09.
N,4-Diphenyl-6-chloro-3-hydroxyoxindole (39). The procedure
described for 31 was used. Yield: 66%, mp 198ꢀC dec. IR
3300–3100, 1718, 1593, 1571, 1499, 1411, 1356, 1235, 1093,
868 cmꢃ1. 1H NMR d: 5.40 (s, 1H, 3-H), 6.62 (d, 1H, 4-H, J=1.8),
7.14 (d, 1H, 6-H, J=1.8), 7.38–7.71 (m, 10H). 13C NMR d: 68.1
(d), 107.8 (d), 123.1 (d), 124.2 (s), 126.8 (d), 127.7 (d), 128.3 (d),
128.5 (d), 128.6 (d), 129.8 (d), 133.8 (s), 133.9 (s), 137.6 (s), 141.1
(s), 146.1 (s), 175.5 (s). Anal. Calcd for C20H14ClNO2: C 71.60; H
4.19; N 4.16. Found: C 71.43; H 4.31; N 4.11.
1
indirubin [29] 0.99 g (76%) mp >260ꢀC. H NMR d: 6.89 (d,
1H), 7.00 (dd, 2H), 7.23 (dd, 1H), 7.35 (d, 1H), 7.40–7.65 (m,
2H), 8.76 (d, 1H, 4-H), 10.9 (s, 1H, NH), 11.0 (s, 1H, NH).
13C NMR d: 107.5 (s), 110.5 (d), 114.3 (d), 119.9 (s), 122.1
(d), 122.2 (d), 122.3 (s), 125.2 (d), 125.5 (d), 130.1 (d), 138.0
(d), 139.2 (s), 141.8 (s), 153.4 (s), 171.8 (s), 189.5 (s). These
spectroscopic data are in principal agreement with the data in
the literature [48] except that the signal at 189.5ppm in the 13C
NMR spectrum was not reported. This signal emanates from the
carbonyl group in 3-position of the indole ring. The doublet at
1
8.76ppm in the H NMR spectrum emanates from the hydrogen
atom in 4-position in the indole ring. In the literature, this signal
was incorrectly assigned as one of the NH groups. This
reassignment is in principle in agreement with work published
by Adachi et al. [49].
REFERENCES AND NOTES
[1] Bruson, H. A. Org React 1949, 5, 79.
[2] Fleming, F.; Wang, Q. F. Chem Rev 2003, 103, 2035.
[3] Campbell, A. D.; Carter, C. L.; Slater, S. N. J Chem Soc 1948,
1741.
Preparation of 4-chloroisatin and 6-chloroisatin by Sandmeyer
synthesis. Chloral hydrate (33.0g, 0.2 mol) was dissolved in water
(450mL), and sodium sulfate decahydrate (200 g) was added
followed by 3-chloroaniline (25.4g, 0.2 mol) dissolved in water
(80 mL) plus conc. hydrochloric acid (15mL), which resulted in
partial precipitation of 3-chloro-anilinium sulfate. Finally,
hydroxylamine hydrochloride (16.5g, 0.22mol) in water (60mL)
was added. The mixture was heated to 55ꢀC and then kept
between 65 and 70ꢀC for 10 min. During that period, the organic
sulfate dissolved and was gradually replaced by the desired oxime.
The reaction was finalized by a heating period (10 min) at 70–
75ꢀC. The precipitate was collected, washed with water, and dried.
For the second step, the oxime was added in portions to sulfuric
acid (180 mL) at 60ꢀC. The temperature rose slightly and was kept
at 65–70ꢀC. After completed addition, the temperature was kept at
80ꢀC for 10 min. The red reaction mixture was allowed to cool and
added to crushed ice. The precipitate formed was collected after 1 h
and dissolved in 5% sodium hydroxide, whereupon to pH was
adjusted to 8–9 and the mixture was filtered. The filtrate was
acidified with acetic acid, and the orange-red solid formed
[4] Cason, J.; Koch, C. W.; Fisher, R. P.; Kow, R.; Kutas, M. G.;
Teranishi, A. Y.; Walba, D. M. J Org Chem 1972, 37, 2573.
[5] Colonge, J.; Vuillemet, R. Bull Chim Soc France 1961, 1757.
[6] Zondler, H.; Pfleiderer, W. Liebigs Ann Chem 1972, 759, 84.
[7] Bruson, H. A.; Riener, T. W. J Am Chem Soc 1942, 64, 2850.
[8] Brandopadhyay, M.; Abu Dagga, F. J Prakt Chem 1980, 322,
491.
[9] Dubas-Sluyter, M. A.; Speckamp, T. W.; Huisman, H. O. N.
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[10] Albright, J. A.; Du, X. J. J Heterocycl Chem 2000, 37, 41.
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Chiong, K. N. J Org Chem 1978, 43, 3541.
[12] Gonzalez, F. G.; Sanchez, A. G.; de Rey, G. Carbohydr Res
1965, 1, 261.
[13] Sanchez, A. G.; Guillen, M. G.; Scheidegger, V. Carbohydr
Res 1967, 3, 486.
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