Electrocatalytic multicomponent transformation of cyclic 1,3-diketones, isatins, and malononitrile: facile and convenient way to functionalized spirocyclic (5,6,7,8-tetrahydro-4H-chromene)-4,3′-oxindole system

Article abstract of DOI:10.1016/j.tet.2007.07.080

An electrochemically induced catalytic multicomponent transformation of cyclic 1,3-diketones, isatins, and malononitrile in alcohols in an undivided cell in the presence of sodium bromide as an electrolyte results in the formation of spirooxindoles with f

Full text of DOI:10.1016/j.tet.2007.07.080

Tetrahedron 63 (2007) 10543–10548
Electrocatalytic multicomponent transformation of cyclic
,3-diketones, isatins, and malononitrile: facile and convenient
way to functionalized spirocyclic (5,6,7,8-tetrahydro-4H-
1
0
chromene)-4,3 -oxindole system
*
*
Michail N. Elinson, Alexey I. Ilovaisky, Alexander S. Dorofeev, Valentina M. Merkulova,
Nikita O. Stepanov, Fedor M. Miloserdov, Yuri N. Ogibin and Gennady I. Nikishin
N. D. Zelinsky Institute of Organic Chemistry, Leninsky prospect 47, 119991 Moscow, Russia
Received 13 April 2007; revised 9 July 2007; accepted 20 July 2007
Available online 31 July 2007
Abstract—An electrochemically induced catalytic multicomponent transformation of cyclic 1,3-diketones, isatins, and malononitrile in
alcohols in an undivided cell in the presence of sodium bromide as an electrolyte results in the formation of spirooxindoles with fused func-
tionalized 5,6,7,8-tetrahydro-4H-chromene system in 83–98% yields. The application of this efficient electrocatalytic method to the formation
0
of medicinally relevant spirocyclic (4H-chromene)-4,3 -oxindoles is beneficial from the viewpoint of diversity-oriented large-scale processes
and represents novel, facile, and environmentally benign synthetic concept for multicomponent reaction strategy.
Ó 2007 Elsevier Ltd. All rights reserved.
1
. Introduction
spirooxindole compounds have made them attractive syn-
6
6,7
thetic targets. Azaspiro derivatives are well-known, but
the preparation of the corresponding oxa analogues has
evolved at a relatively slow pace. Among the oxygen-con-
The development of multicomponent reactions (MCRs) de-
signed to produce elaborate biologically active compounds
has become an important area of research in organic, combi-
natorial, and medicinal chemistry. The MCR strategy offers
significant advantages over conventional linear-type synthe-
sis due to its flexible, convergent, and atom efficient nature.
In recent years, the synthesis of combinatorial small-mole-
cule heterocyclic libraries has emerged as a valuable tool
in the search for novel lead structures. Thus, the success
of combinatorial chemistry in the drug discovery process
is considerably dependent on further advances in heterocy-
clic MCR methodology and, according to current synthetic
requirements, environmentally benign multicomponent
procedures are particularly welcome.
8
taining heterocycles fused with spirooxindole ring system,
4H-chromenes are of particular utility as they belong to
‘privileged medicinal scaffolds’—certain molecular frame-
works serving for the generation of ligands for functionally
1
2
9
and structurally discreet biological receptors. Functionally
substituted 4H-chromenes have received considerable atten-
tion due to their wide range of useful biological properties,
which include spasmolitic-, diuretic-, anticoagulant-, anti-
3
1
0
cancer-, and antianaphylactic activities. The current inter-
est in 5,6,7,8-tetrahydro-4H-chromene derivatives bearing
nitrile functionality, especially 2-amino-5-oxo-5,6,7,8-tetra-
hydro-4H-chromene-3-carbonitriles, arises from their
potential application in the treatment of human neurodegen-
1
1
The heterocyclic spirooxindole ring system is a widely
distributed structural framework present in a number of
pharmaceuticals and natural products, including such cyto-
static alkaloids as spirotryprostatins A, B, and strychnophyl-
line. The unique structural array and the highly pronounced
pharmacological activity displayed by the class of
erative disorders.
4
To the best of our knowledge, there are only two reports on
multicomponent entries to the synthesis of spirooxindoles
with fused 2-amino-5-oxo-5,6,7,8-tetrahydro-4H-chromene-
3-carbonitrile systems. Both MCRs employ a three-compo-
nent condensation of cyclic 1,3-diketones, isatins, and
malononitile realized under two types of catalytic conditions.
The catalysis of dimedone, isatin, and malononitrile with
piperidine in ethanol affords spiro[(2-amino-3-cyano-5-
5
Keywords: Electrochemistry; Electrocatalysis; Multicomponent reactions;
Chromenes; Spirooxindoles.
Corresponding authors. Tel.: +7 495 137 3842; fax: +7 495 135 5328;
e-mail: elinson@ioc.ac.ru
*
0
oxo-5,6,7,8-tetrahydro-4H-chromene)-4,3 -oxindole] in 83%
0
040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.07.080

10544
M. N. Elinson et al. / Tetrahedron 63 (2007) 10543–10548
yield at ambient temperature, but the reaction has been
performed only on a single example with a lack of character-
solvents in the presence of sodium bromide as an electrolyte
(Scheme 1).
1
2
ization data. Recently Shanthi et al. reported a three-compo-
nent condensation of cyclic 1,3-diketones, isatin, and
malononitrile catalyzed by 20 mol % of indium(III) chlo-
First, to evaluate the synthetic potential of the procedure
proposed and to optimize the electrolysis conditions, the
electrocatalytic multicomponent transformation of 5,5-di-
methylcyclohexane-1,3-dione 1a, isatin 2a, and malononi-
1
3
ride. Although this catalytic MCR leads to corresponding
0
spiro[(4H-chromene)-4,3 -oxindoles] in 70–90% yields, it
0
necessitates either reflux in acetonitrile for 1.5 h or micro-
wave irradiation. Furthermore, column chromatography is
required for purification of desired products. Thus, each of
the known MCR procedures for the synthesis of correspond-
trile into spirocyclic (4H-chromene)-4,3 -oxindole 3a was
studied (Table 1).
Excellent conversions of the starting compounds were ob-
tained under 10 mA/cm and 15 mA/cm current densities
after 0.1 F/mol of electricity had been passed. The current
0
2
2
ing spiro[(4H-chromene)-4,3 -oxindole] system has its merits,
but the essence of facile and convenient multicomponent
methodology has yet to be developed.
2
density of 10 mA/cm (I¼50 mA, electrodes surface
2
5 cm ) was found to be optimal for the electrochemically in-
duced chain process and allowed for the highest yield of spi-
0
2
. Results and discussion
ro[(4H-chromene)-4,3 -oxindole] 3a. An increase in the
2
current density up to 15 mA/cm (I¼75 mA) resulted in
The advances in electrosynthesis in the last few decades have
provided organic chemists with a new versatile synthetic
a slight decrease in the reaction yield, and may be a result
of the activation of the undesired direct electrochemical pro-
cesses that lead to oligomerization of the starting material.
1
4
device of great promise. Despite the significant synthetic
potential and ecological advantages of electrochemical
methods, the practical usage of electrochemical procedure
is often limited on account of its technical complexity and
generally long processing times. In the course of our study
on the electrochemical transformation of organic com-
pounds, we have found a new type of electrochemical trans-
formation, namely the electrocatalytic chain transformation
of organic compounds induced by a catalytic amount of an
0
After electrolysis, spiro[(4H-chromene)-4,3 -oxindole] 3a
was directly crystallized from the reaction mixture. As for
the alcoholic solvent, the usage of either EtOH or n-PrOH
is preferred since the products can be filtered directly after
1
7
electrolysis. Under the optimal conditions (current density
10 mA/cm , 0.1 F/mol passed, EtOH as solvent) the electro-
2
lysis of cyclic 1,3-diketones 1a and 1b, isatins 2a–e, and
malononitrile in an undivided cell affords spiro[(4H-chro-
1
5
electrogenerated base in an undivided cell. Recently, we
have successfully applied this electrocatalytic procedure, de-
veloped by us, to the synthesis of a number of medicinally
relevant 4H-chromene derivatives bearing nitrile functional-
0
temperature over a 32 min reaction period (Table 2).
mene)-4,3 -oxindoles] 3a–i in yields of 83–98% at ambient
16
ity. These unique electrochemical procedures utilize a
simple undivided cell and are valuable for large-scale pro-
cesses because of their catalytic nature and the use of a cheap
and environmentally responsible chemical reagent—elec-
tricity. The use of the described electrocatalytic method-
ology in base-activated MCRs is highly promising as it
allows for the combination of the synthetic virtues of the
conventional MCR strategy with the ecological benefits
and convenience of the facile electrocatalytic procedure.
Table 1. Electrocatalytic transformation of 5,5-dimethylcyclohexane-
0
1,3-dione 1a, isatin 2a, and malononitrile into spiro[(4H-chromene)-4,3 -
oxindole] 3a
a
I (mA)
Current
density
(
Time
(min)
Alcohol
Electricity
passed
(F/mol)
Yield of
3a (%)
b
2
mA/cm )
5
10
1
2
4
10
15
10
10
320
160
80
32
22
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
n-PrOH
0.1
0.1
0.1
0.1
0.1
0.1
0.1
71
75
82
96
87
84
92
2
5
7
5
0
0
5
0
In the present study we report our results on electrocatalytic
multicomponent chain transformation of cyclic 1,3-dike-
tones, isatins, and malononitrile into spiro[(2-amino-3-
32
32
50
a
Reagents and conditions: 1a (10 mmol), 2a (10 mmol), malononitrile
0
cyano-5-oxo-5,6,7,8-tetrahydro-4H-chromene)-4,3 -oxindoles]
under neutral and mild conditions by electrolysis in an
undivided cell. The reaction is performed in alcoholic
2
10 mmol), NaBr (1 mmol), alcohol (20 mL), iron cathode (5 cm ),
(
graphite anode (5 cm ), 20 C.
Yield of isolated product obtained by filtration of the reaction mixture.
2
ꢀ
b
O
R3
O
R2
N
R2
O
CN
CN
electrolysis, 0.1 F/mol
O
+
O
+
CN
R1
R1
4
R OH, NaBr
O
N
R1
R
R3
R4 = Me, Et, n-Pr
1
O
NH2
1a,b
2a-e
3a-i
1
a R = H, R = H;
2
2
3
3
3
3
1
1
1
1
2
2
2
3
3
3
3
1
2
3
3
a R = Me
a R = Me, R = H, R = H; b R = Me, R = Br, R = H;
1
b R = Br, R = H;
1
2
b R = H
c R = Me, R = H, R = Me; d R = Me, R = H, R = Ac;
2
1
2
3
c R = H, R = Me;
e R = Me, R = H, R = Bn; f R = H, R = H, R = H;
2
2
1
2
3
d R = H, R = Ac;
g R = H, R = Br, R = H; h R = H, R = H, R = Me;
2
3
1
2
3
e R = H, R = Bn;
i R = H, R = H, R = Ac;
Scheme 1.

M. N. Elinson et al. / Tetrahedron 63 (2007) 10543–10548
Table 2. Electrocatalytic transformation of cyclic 1,3-diketones 1, isatins 2,
10545
the regeneration of the alkoxide anion as the last step. The
catalytic chain process then continues by the interaction of
the alkoxide with the next molecule of malononitrile
(Scheme 3). Thus, under the conditions of developed elec-
trocatalytic process, the generation of even a single alkoxide
anion at the cathode is theoretically sufficient for the total
conversion of equimolar quantities of cyclic 1,3-diketone,
isatin, and malononitrile into the corresponding spiro[(4H-
0
a
and malononitrile into spiro[(4H-chromene)-4,3 -oxindoles] 3
Cyclic
1,3-diketone
Isatin Current
density
Time Electricity Product Yield
b
(min) passed
(F/mol)
of 3a–i
(%)
2
mA/cm )
(
1a
1a
1a
1a
1a
1b
1b
1b
1b
2a
2b
2c
2d
2e
2a
2b
2c
2d
10
10
10
10
10
10
10
10
10
32
32
32
32
32
32
32
32
32
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
3a
3b
3c
3d
3e
3f
3g
3h
3i
96
87
97
90
91
89
83
98
87
0
chromene)-4,3 -oxindole].
3
. Conclusions
a
Reagents and conditions: 1 (10 mmol), 2 (10 mmol), malononitrile
In conclusion, the simple electrocatalytic system can
produce, under neutral and mild conditions, a fast and selec-
tive multicomponent transformaton of cyclic 1,3-diketones,
2
10 mmol), NaBr (1 mmol), EtOH (20 mL), iron cathode (5 cm ), graph-
(
ite anode (5 cm ), 20 C.
Yield of isolated product obtained by filtration of the reaction mixture.
2
ꢀ
b
isatins, and malononitrile into spiro[(2-amino-3-cyano-
0
5-oxo-5,6,7,8-tetrahydro-4H-chromene)-4,3 -oxindoles] in
With the above results taken into consideration and the
mechanistic data on the electrocatalytic chain cyclizations
previously performed by us,
for the electrocatalytic chain transformation of cyclic 1,3-
excellent yields. This novel electrocatalytic chain process
offers an efficient and convenient way to create spirocyclic
oxindole systems with fused cyano-functionalized 4H-chro-
mene fragment—the hybridized ‘privileged drug scaffold’
for human neurodegenerative disorders therapy and different
biomedical applications. The electrocatalytic procedure
utilizes simple equipment and an undivided cell, and is
easily carried out. This efficient electrocatalytic approach
1
5,16
the following mechanism
diketones 1, isatins 2, and malononitrile into substituted
0
spiro[(4H-chromene)-4,3 -oxindoles] 3 is proposed. The ini-
tiation step of the catalytic cycle begins with the deprotona-
tion of a molecule of alcohol at the cathode, which leads to
the formation of an alkoxide anion. The subsequent reaction
between the alkoxide anion and malononitrile gives rise to
the malononitrile anion (Scheme 2).
0
to spirocyclic (5,6,7,8-tetrahydro-4H-chromene)-4,3 -oxin-
dole ring system represents a novel synthetic concept for
multicomponent reactions, and allows for the combination
of the synthetic virtues of conventional MCRs with ecolo-
gical benefits and convenience of facile electrocatalytic
procedure. Therefore, this novel MCR strategy brings us
4
4
cathode:
R OH + 1e
R O + 1/2 H2
CH(CN)2 + R OH
4
4
in solution:
CH (CN)2 + R O
19
2
a step closer to the notion of ‘ideal synthesis’.
Scheme 2.
4. Experimental section
The following process in the solution represents a typical
cascade reaction. Knoevenagel condensation of the malono-
nitrile anion with isatin 2 takes place with the elimination of
a hydroxide anion and formation of isatylidenemalononitrile
4.1. General remarks
All melting points were measured with a Gallenkamp melt-
1
8
1
13
4
.
The subsequent hydroxide-promoted Michael addition
ing point apparatus and are uncorrected. H and C NMR
spectra were recorded with Bruker AC-200, Bruker WM-
250, and Bruker AC-300 spectrometers at ambient tempera-
of cyclic 1,3-diketone 1 to electron deficient Knoevenagel
adduct 4 followed by intramolecular cyclization leads to
0
corresponding spiro[(4H-chromene)-4,3 -oxindoles] 3 with
ture. Chemical shifts values are relative to Me Si. IR spectra
4
O
NC
NC
R3
O
CN
O
O
CN
O
N
R2
R1
R
R2
R2
R2
O
O
CH(CN)2
1
O
- OH
O
CN
CN
OH
N
N
N
R1
R
R3
R3
R3
O
1
2
4
R3
R3
O
O
R3
R2
R2
R2
N
N
N
O
O
4
O
R OH
O
4
CN
CN
CN
CN
R O
+
1
1
R1
1
R1
R
R
R
O
NH2
O
N
O
R1
3
The beginning of
new catalytic cycle
Scheme 3.

10546
M. N. Elinson et al. / Tetrahedron 63 (2007) 10543–10548
were registered with a SPECORD M82 spectrometer in KBr
pellets. Mass spectra (EI¼70 eV) were obtained directly
with a Finningan MAT INCOS 50 spectrometer.
(CH ), 27.1 (CH ), 27.6 (CH ), 32.0 (CH ), 39.9 (C), 46.5
3 3 3 2
(C), 50.0 (CH ), 57.1 (C), 108.2 (CH), 110.8 (C), 117.2
2
(C), 122.5 (CH), 122.8 (CH), 128.5 (CH), 133.6 (C), 143.6 (C),
1
58.9 (C), 164.3 (C), 176.6 (C), 194.9 (C) ppm. MS
+
4
.2. Typical electrolysis procedure
(70 eV) m/z (relative intensity %): 349 ([M] , 42), 334 (8),
23 (22), 295 (12), 265 (100), 223 (17), 140 (11), 89 (12),
55 (13), 44 (16). IR (KBr): nmax 3368, 3324, 3176, 2960,
3
A solution of cyclic 1,3-diketone (10 mmol), isatin
10 mmol), malononitrile (0.66 g, 10 mmol), and sodium
bromide (0.1 g, 1 mmol) in the appropriate alcoholic solvent
20 mL) was electrolyzed in an undivided cell equipped with
ꢁ
2200, 1712, 1672, 1356, 1224, 1052 cm . C H N O
20 19 3 3
1
(
calcd: C 68.75, H 5.48, N 12.03; found: C 68.69, H 5.52,
N 11.97.
(
a magnetic stirrer, a graphite anode, and an iron cathode at
ꢀ
2
0 0
4.2.4. 1 -Acetyl-2-amino-7,7-dimethyl-2 ,5-dioxo-
1 ,2 ,5,6,7,8-hexahydrospiro[chromene-4,3 -indole]-
2
0 C under a constant current density of 10 mA/cm
2
0
0
0
(
I¼50 mA, electrodes square 5 cm ) until the catalytic quan-
tity of 0.1 F/mol of electricity was passed (time: 32 min).
After the electrolysis was finished, the solution was filtered
to isolate the solid product, which was then twice rinsed with
an ice-cold ethanol/water solution (9:1, 5 mL), and dried
under reduced pressure.
3-carbonitrile (3d). White solid, yield 3.40 g (97%), mp
233–234 C (from EtOH). dH (300 MHz, DMSO-d ) 1.01
ꢀ
(3H, s, CH ), 1.05 (3H, s, CH ), 2.12–2.21 (2H, m, CH ),
6
3
3
2
2.58 (2H, s, CH ), 2.63 (3H, s, CH CO), 7.18–7.25 (2H,
2
3
m, Ar), 7.28–7.38 (1H, m, Ar), 7.55 (2H, s, NH ), 8.08
2
(
1H, d, J 7.8 Hz, Ar) ppm; d (63 MHz, DMSO-d ) 26.0
C 6
0
hydrospiro[chromene-4,3 -indole]-3-carbonitrile (3a).
0
0
4
.2.1. 2-Amino-7,7-dimethyl-2 ,5-dioxo-1 ,2 ,5,6,7,8-hexa
0
(CH ), 27.1 (CH ), 27.6 (CH ), 32.2 (CH ), 39.8 (C), 47.5
3 3 3 2
(C), 49.5 (CH ), 57.1 (C), 110.9 (C), 115.4 (CH), 117.1
2
(C), 123.4 (CH), 125.6 (CH), 128.8 (CH), 132.8 (C), 139.3 (C),
158.7 (C), 164.9 (C), 170.4 (C), 177.9 (C), 195.5 (C) ppm.
MS (70 eV) m/z (relative intensity %): 377 ([M] , 35), 362
ꢀ
285–287 C, from DMF/EtOH). dH
White solid, yield 3.22 g (96%), mp 305–307 C (from
EtOH; lit. mp
1
2
ꢀ
300 MHz, DMSO-d ) 1.00 (3H, s, CH ), 1.03 (3H, s, CH ),
+
(
6
3
3
2
.08–2.19 (2H, m, CH ), 2.56 (2H, s, CH ), 6.78 (1H, d,
2
(8), 348 (9), 334 (100), 251 (25), 223 (10), 140 (11), 89
(8), 55 (9), 43 (75). IR (KBr): nmax 3332, 3192, 2960,
2
J 7.3 Hz, Ar), 6.89 (1H, t, J 7.3 Hz, Ar), 6.97 (1H, d,
J 7.3 Hz, Ar), 7.14 (1H, t, J 7.3 Hz, Ar), 7.23 (2H, s, NH2),
1
ꢁ
1
2204, 1756, 1724, 1672, 1352, 1272, 1052 cm
C H N O calcd: C 66.83, H 5.07, N 11.13; found: C
.
0.40 (1H, s, NH) ppm; dC (63 MHz, DMSO-d ) 27.1
6
21 19 3 4
(
CH ), 27.7 (CH ), 32.0 (CH ), 40.0 (C), 46.9 (C), 50.1
3
66.78, H 5.14, N 11.04.
3
2
(
1
CH ), 57.5 (S), 109.3 (SH), 110.9 (C), 117.4 (C),
2
0
1 ,2 ,5,6,7,8-hexahydrospiro[chromene-4,3 -indole]-
0
21.8 (CH), 123.1 (CH), 128.2 (CH), 134.5 (C), 142.1 (C),
58.9 (C), 164.2 (C), 178.1 (C), 194.9 (C) ppm. MS (70 eV)
4.2.5. 2-Amino-1 -benzyl-7,7-dimethyl-2 ,5-dioxo-
0
3-carbonitrile (3e). White solid, yield 3.87 g (91%), mp
0
0
1
m/z (relative intensity %): 335 ([M] , 30), 309 (9), 290 (9),
+
ꢀ
2
(
51 (100), 209 (26), 140 (11), 83 (25), 55 (31), 44 (45), 39
41). IR (KBr): nmax 3376, 3312, 3144, 2928, 2196, 1724,
280–281 C (from EtOH). dH (250 MHz, DMSO-d ) 1.03
6
(6H, s, 2 CH ), 2.14–2.21 (2H, m, CH ), 2.61 (2H, m, CH ),
3
2
2
ꢁ1
1
H 5.11, N 12.53; found: C 67.94, H 5.17, N 12.42.
656, 1348, 1224, 1056 cm . C H N O calcd: C 68.05,
4.92 (2H, s, CH Ph), 6.65–6.73 (1H, m, Ar), 6.87–7.70
2
1
9
17
3
3
(10H, m, Ar, NH ) ppm; d (63 MHz, DMSO-d ) 27.1
2
C
6
(CH ), 27.7 (CH ), 32.0 (CH ), 40.0 (C), 43.4 (CH ), 46.7
(C), 49.9 (CH ), 57.3 (C), 108.9 (CH), 110.7 (C), 117.5
3 3 2 2
0
,2 ,5,6,7,8-hexahydrospiro[chromene-4,3 -indole]-
0
4
1
3
.2.2. 2-Amino-5 -bromo-7,7-dimethyl-2 ,5-dioxo-
2
0
-carbonitrile (3b). White solid, yield 3.60 g (87%), mp
0
0
(C), 122.6 (CH), 123.0 (CH), 127.2 (3 CH), 128.3 (CH),
128.4 (2 CH), 133.7 (C), 136.2 (C), 142.7 (C), 159.0 (C),
164.6 (C), 176.8 (C), 195.1 (C) ppm. MS (70 eV) m/z
ꢀ
305–307 C (from EtOH). d (200 MHz, DMSO-d ) 1.02 (6H,
s, 2 CH ), 2.16 (2H, s, CH ), 2.45–2.65 (2H, m, CH ),
H
6
+
(relative intensity %): 425 ([M] , 26), 397 (12), 341 (12),
334 (84), 234 (17), 222 (10), 140 (10), 91 (100), 83 (13),
3
2
2
6
.76 (1H, d, J 8.1 Hz, Ar), 7.19 (1H, s, Ar), 7.24–7.36
3H, m, Ar, NH ), 10.52 (1H, s, NH) ppm; dC (63 MHz,
(
DMSO-d ) 27.3 (CH ), 27.6 (CH ), 32.1 (CH ), 39.9 (C),
65 (22). IR (KBr): nmax 3380, 3300, 3208, 2964, 2200,
2
ꢁ
1716, 1660, 1352, 1220, 1052 cm . C H N O calcd: C
26 23 3 3
1
6
3
3
2
4
1
1
7.1 (C), 50.0 (CH ), 56.8 (C), 110.3 (C), 111.3 (CH),
2
73.39, H 5.45, N 9.88; found: C 73.28, H 5.48, N 9.82.
13.4 (C), 117.3 (C), 126.0 (CH), 131.0 (CH), 136.9 (C),
41.5 (C), 158.9 (C), 164.7 (C), 177.7 (C), 195.2 (C) ppm.
0
[chromene-4,3 -indole]-3-carbonitrile (3f). White solid,
0
0
4.2.6. 2-Amino-2 ,5-dioxo-1 ,2 ,5,6,7,8-hexahydrospiro-
+
0
yield 2.73 g (89%), mp 312–313 C (from EtOH; lit. mp
MS (70 eV) m/z (relative intensity %): 415 ([M] , 35), 413
+
ꢀ
304–305 C, from AcOH). d (300 MHz, DMSO-d ) 1.91–
21
([M] , 38), 387 (20), 371 (19), 329 (100), 289 (27), 251
(30), 152 (19), 83 (31), 55 (42), 44 (49). IR (KBr): nmax
ꢀ
H
6
3
1
1
360, 3288, 3160, 2956, 2200, 1728, 1656, 1352, 1224,
056 cm . C H BrN O calcd: C 55.09, H 3.89, N
0.14; found: C 54.93, H 3.97, N 10.02.
2.00 (2H, m, CH ), 2.10–2.30 (2H, m, CH ), 2.62–2.73
2 2
(2H, m, CH ), 6.78 (1H, d, J 7.4 Hz, Ar), 6.88 (1H, t,
2
ꢁ1
1
9
16
3
3
J 7.4 Hz, Ar), 7.00 (1H, d, J 7.4 Hz, Ar), 7.14 (1H, t,
J 7.4 Hz, Ar), 7.23 (2H, s, NH ), 10.40 (1H, s, NH) ppm;
2
0
0
0
0
4.2.3. 2-Amino-1 ,7,7-trimethyl-2 ,5-dioxo-1 ,2 ,5,6,7,8-
hexahydrospiro[chromene-4,3 -indole]-3-carbonitrile
d (63 MHz, DMSO-d ) 19.8 (CH ), 26.8 (CH ), 36.4 (CH ),
C
6
2
2
2
0
3c). White solid, yield 3.39 g (97%), mp 248–250 C (from
46.9 (C), 57.6 (C), 109.2 (CH), 111.9 (C), 117.4 (C), 121.8
(CH), 123.3 (CH), 128.2 (CH), 134.6 (C), 142.0 (C), 158.7
(C), 166.1 (C), 178.2 (C), 195.1 (C) ppm. MS (70 eV) m/z
ꢀ
EtOH; lit. mp 225 C, from CH CN). d (300 MHz,
(
2
0
ꢀ
DMSO-d ) 1.03 (6H, s, 2 CH ), 2.12 (2H, s, CH ), 2.57 (2H,
3
H
+
(relative intensity %): 307 ([M] , 38), 281 (9), 262 (28),
251 (100), 209 (26), 140 (8), 89 (6), 55 (9), 44 (15), 39 (9). IR
(KBr): nmax 3352, 3296, 3176, 2952, 2204, 1712, 1656, 1352,
6
3
2
s, CH ), 3.14 (3H, s, NCH ), 6.93–7.04 (3H, m, Ar), 7.15–
2
7
3
.30 (3H, m, Ar, NH ) ppm; d (63 MHz, DMSO-d ) 26.4
C
2
6

M. N. Elinson et al. / Tetrahedron 63 (2007) 10543–10548
10547
ꢁ
1
1
1
216, 1076 cm . C H N O calcd: C 66.44, H 4.26, N
3.67; found: C 66.38, H 4.31, N 13.60.
to Russian Science Support Foundation for postgraduate
scholarship in 2007.
1
7 13 3 3
0 0 0 0
.2.7. 2-Amino-5 -bromo-2 ,5-dioxo-1 ,2 ,5,6,7,8-hexa
hydrospiro[chromene-4,3 -indole]-3-carbonitrile (3g).
4
0
References and notes
ꢀ
White solid, yield 3.20 g (83%), mp 273–275 C (from
EtOH). d (250 MHz, DMSO-d ) 1.78–2.08 (2H, m, CH ),
1. For selected reviews, see: (a) Orru, R. V. A.; de Greef, M.
Synthesis 2003, 1471–1499; (b) Balme, G.; Bossharth, E.;
Monteiro, N. Eur. J. Org. Chem. 2003, 4101–4111; (c) Br €a se,
S.; Gil, C.; Knepper, K. Bioorg. Med. Chem. 2002, 10, 2415–
2437; (d) D €o mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000,
39, 3168–3210.
2. (a) Weber, L. Drug Discov. Today 2002, 7, 143–147; (b)
D €o mling, A. Curr. Opin. Chem. Biol. 2002, 6, 306–313.
3. (a) Nefzi, A.; Ostresh, J. M.; Houghten, R. A. Chem. Rev. 1997,
97, 449–472; (b) Thompson, L. A. Curr. Opin. Chem. Biol.
2000, 4, 324–337.
4. For reviews, see: (a) Williams, R. M.; Cox, R. J. Acc. Chem.
Res. 2003, 36, 127–139; (b) Da Silva, J. F. M.; Garden, S. J.;
Pinto, A. C. J. Braz. Chem. Soc. 2001, 273–324.
5. (a) Cui, C.-B.; Kakeya, H.; Osada, H. Tetrahedron 1996, 52,
12651–12666; (b) Cui, C.-B.; Kakeya, H.; Osada, H.
J. Antibiot. 1996, 49, 832–833; (c) Leclercq, J.; De Pauw-
Gillet, M.-C.; Bassleer, R.; Angenot, L. J. Ethnopharmacol.
1986, 15, 305–316.
6. (a) Fischer, C.; Meyers, C.; Carreira, E. M. Helv. Chim. Acta
2000, 83, 1175–1181; (b) Alper, P. B.; Meyers, C.; Lerchner,
A.; Siegel, D. R.; Carreira, E. M. Angew. Chem., Int. Ed.
1999, 38, 3186–3189 and references cited therein; (c)
Ashimori, A.; Bachand, B.; Overmann, L. E.; Poon, D. J.
J. Am. Chem. Soc. 1998, 120, 6477–6487; (d) Matsuura, T.;
Overmann, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120,
6500–6503.
7. For selected recent examples, see: (a) Ding, K.; Lu, Y.;
Nikolovska-Coleska, Z.; Qiu, S.; Ding, Y.; Gao, W.; Stuckey,
J.; Krajewski, K.; Roller, P. P.; Tomita, Y.; Parrish, D. A.;
Deschamps, J. R.; Wang, S. J. Am. Chem. Soc. 2005, 127,
10130–10131; (b) Chen, C.; Li, X.; Neumann, C. S.; Lo,
M. M.-C.; Schreiber, S. L. Angew. Chem., Int. Ed. 2005, 44,
2249–2252; (c) Bella, M.; Kobbelgaard, S.; Jorgensen, K. A.
J. Am. Chem. Soc. 2005, 127, 3670–3671.
H
6
2
2
.10–2.35 (2H, m, CH ), 2.56–2.79 (2H, m, CH ), 6.75
2 2
(
1H, d, J 7.3 Hz, Ar), 7.14–7.61 (4H, m, Ar, NH ), 10.55
2
(
1H, s, NH) ppm; dC (63 MHz, DMSO-d ) 19.8 (CH ),
6
2
2
1
1
6.8 (CH ), 36.4 (CH ), 47.2 (C), 56.9 (C), 111.2 (CH, C),
2 2
13.4 (C), 117.3 (C), 126.2 (CH), 130.9 (CH), 137.0 (C),
41.4 (C), 158.8 (C), 166.7 (C), 177.9 (C), 195.3 (C) ppm.
+
MS (70 eV) m/z (relative intensity %): 387 ([M] , 24), 385
+
([M] , 23), 342 (14), 329 (66), 289 (37), 273 (100), 248
(75), 151 (39), 89 (27), 55 (67), 44 (50). IR (KBr): nmax
3
1
1
424, 3304, 3180, 2956, 2204, 1708, 1672, 1352, 1176,
080 cm . C H BrN O calcd: C 52.87, H 3.13, N
0.88; found: C 52.85, H 3.08, N 10.84.
ꢁ
1
1
7
12
3 3
0
0
0
0
4.2.8. 2-Amino-1 -methyl-2 ,5-dioxo-1 ,2 ,5,6,7,8-hexa
hydrospiro[chromene-4,3 -indole]-3-carbonitrile (3h).
0
White solid, yield 3.15 g (98%), mp 247–248 C (from
ꢀ
EtOH). d (300 MHz, DMSO-d ) 1.78–2.05 (2H, m, CH ),
H
6
2
2
s, NCH ), 6.85–7.10 (3H, m, Ar), 7.18–7.36 (3H, m, Ar,
.08–2.34 (2H, m, CH ), 2.56–2.89 (2H, m, CH ), 3.14 (3H,
2 2
3
NH ) ppm; d (63 MHz, DMSO-d ) 19.8 (CH ), 26.4
2
C
6
2
(
(
(
CH ), 26.8 (CH ), 36.4 (CH ), 46.6 (C), 57.2 (C), 108.1
3 2 2
CH), 111.9 (C), 117.3 (C), 122.5 (CH), 123.0 (CH), 128.4
CH), 133.7 (C), 143.6 (C), 158.8 (C), 166.2 (C), 176.7 (C),
1
(
95.1 (C) ppm. MS (70 eV) m/z (relative intensity %): 321
[M] , 63), 295 (15), 265 (100), 236 (11), 223 (23), 193 (7),
+
1
3
1
40 (11), 89 (8), 55 (13), 44 (19). IR (KBr): nmax 3564,
464, 3365, 3148, 2964, 2200, 1704, 1676, 1352,
216 cm . C H N O calcd: C 67.28, H 4.71, N 13.08;
ꢁ
1
1
8 15 3 3
found: C 67.22, H 4.80, N 12.97.
0 0 0 0
.2.9. 1 -Acetyl-2-amino-2 ,5-dioxo-1 ,2 ,5,6,7,8-hexa
hydrospiro[chromene-4,3 -indole]-3-carbonitrile (3i).
4
0
ꢀ
White solid, yield 3.04 g (87%), mp 252–254 C (from
EtOH). d (300 MHz, DMSO-d ) 1.80–2.09 (2H, m, CH ),
H
6
2
2
.13–2-42 (2H, m, CH ), 2.57 (3H, s, CH CO), 2.59–2.85
2
8. Alcaide, B.; Almendros, P.; Rodriguez-Acebes, R. J. Org.
Chem. 2006, 71, 2346–2351 and references cited therein.
9. The term ‘privileged scaffolds or structures’ was originally
introduced by Merck researchers in their work on benzodiaze-
pins: (a) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo,
R. M.; Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.;
Veber, D. F.; Anderson, P. S.; Chang, R. S. L.; Lotti, V. J.;
Cerino, D. J.; Chen, T. B.; Kling, P. J.; Kunkel, K. A.;
Springer, J. P.; Hirshfield, J. J. Med. Chem. 1988, 31, 2235–
2246 also, see: (b) Patchett, A. A.; Nargund, R. P. Annu. Rep.
Med. Chem. 2000, 35, 289–298; (c) DeSimone, R. W.;
Currie, K. S.; Mitchell, S. A.; Darrow, J. W.; Pippin, D. A.
Comb. Chem. High Throughput Screen. 2004, 7, 473–493.
3
(2H, m, CH ), 7.15–7.28 (2H, m, Ar), 7.28–7.41 (1H, m,
2
Ar), 7.54 (2H, m, NH ), 8.07 (1H, d, J 7.5 Hz, Ar) ppm; d
2
C
(
50 MHz, DMSO-d ) 19.7 (CH ), 25.9 (CH ), 26.6 (CH ),
6 2 3 2
3
1
1
5.9 (CH ), 47.5 (C), 57.1 (C), 111.9 (C), 115.3 (CH),
2
17.0 (C), 123.6 (CH), 125.5 (CH), 128.6 (CH), 132.9 (C),
39.2 (C), 158.6 (C), 166.8 (C), 170.4 (C), 178.0 (C), 195.6
+
(
C) ppm. MS (70 eV) m/z (relative intensity %): 349 ([M] ,
2
8
2
8), 334 (4), 321 (3), 306 (100), 251 (19), 222 (6), 140 (5),
8 (3), 55 (5), 43 (29). IR (KBr): nmax 3412, 3324, 3184,
204, 1748, 1716, 1668, 1352, 1272, 1204 cm
ꢁ
1
.
C H N O calcd: C 65.32, H 4.33, N 12.03; found: C
1
9 15 3 4
6
5.28, H 4.41, N 11.94.
1
0. (a) Skommer, J.; Wlodkowic, D.; M €a tt €o , M.; Eray, M.;
Pelkonen, J. Leuk. Res. 2006, 30, 322–331; (b) Yu, N.;
Aramini, J. M.; Germann, M. W.; Huang, Z. Tetrahedron
Lett. 2000, 41, 6993–6996; (c) Bonsignore, L.; Loy, G.;
Secci, D.; Calignano, A. Eur. J. Med. Chem. 1993, 28,
517–520; (d) Witte, E. C.; Neubert, P.; Roesch, A. Ger.
Offen. DE 3427985, 1986; Chem. Abstr. 1986, 104,
224915f; (e) Andreani, L. L.; Lapi, E. Boll. Chim. Farm.
1960, 99, 583–587.
Acknowledgements
The authors gratefully acknowledge the financial support
of the Russian Foundation for Basic Research (Project No.
06-03-32181a) and of the Presidential Scholarship Program
for State Support of Leading Science Schools of Russian
Federation (Project No. 5022.2006.3). A.S.D. is indebted

10548
M. N. Elinson et al. / Tetrahedron 63 (2007) 10543–10548
1
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1
1
1
2. Abdel-Latif, F. F.; Mashaly, M. M.; El-Gawish, E. H. J. Chem.
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1
1
6. (a) Elinson, M. N.; Dorofeev, A. S.; Feducovich, S. K.;
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