Reaction of 2-chloroindole-3-carbaldehyde with epihalogenohydrins. Tandem oxirane-opening - 1,3-oxazole-closure process

Article abstract of DOI:10.1016/j.tet.2011.09.015

Reaction of 2-chloroindole-3-carbaldehyde with epibromohydrin gives the expected 1-(oxiran-2-ylmethyl) derivative. However the analogous reaction with epichlorohydrin leads to the formation of the oxazolo[3,2-a]indole skeleton. Some chemical properties of this tricyclic system were investigated. Its reaction with secondary amines unexpectedly proceeds with the opening of the oxazole ring.

Full text of DOI:10.1016/j.tet.2011.09.015

Tetrahedron 67 (2011) 8775e8779
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Reaction of 2-chloroindole-3-carbaldehyde with epihalogenohydrins.
Tandem oxirane-openingd1,3-oxazole-closure process
,
a
a
b
Konstantin F. Suzdaleva , Sophia V. Den’kina , Gennadii S. Borodkin , Valerii V. Tkachev ,
*
Mikhail A. Kiskin c, Mikhail E. Kletsky d, Oleg N. Burov d
a Research Institute of Physical and Organic Chemistry of Southern Federal University, Stachki Street 194/2, 344090 Rostov-on-Don, Russian Federation
b Institute of Problems of Chemical Physics, Russian Academy of Sciences, N.N. Semyonov Street 1, 142432 Czernogolovka, Moscow region, Russian Federation
c N.S. Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences, Leninsky prosp. 31, 119991 Moscow, Russian Federation
d Chemical Department of Southern Federal University, Sorge Street 7, 344090 Rostov-on-Don, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 June 2011
Received in revised form 19 August 2011
Accepted 6 September 2011
Available online 10 September 2011
Reaction of 2-chloroindole-3-carbaldehyde with epibromohydrin gives the expected 1-(oxiran-2-
ylmethyl) derivative. However the analogous reaction with epichlorohydrin leads to the formation of
the oxazolo[3,2-a]indole skeleton. Some chemical properties of this tricyclic system were investigated. Its
reaction with secondary amines unexpectedly proceeds with the opening of the oxazole ring.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Indoles
Aldehydes
Epihalogenohydrins
Oxazolo[3,2-a]indole
1. Introduction
indole ring system 4 and occurs as a tandem oxirane-openingd1,3-
oxazole-closure process. It is obvious that this reaction proceeds by
It is known that indole, 2-phenylindole, and 4-hydroxy-1H-in-
dole-3-carbaldehyde undergo alkylation with epichlorohydrin to
form 1-(oxiran-2-ylmethyl) derivatives.1,2 Similar compounds react
with amines to produce derivatives having the 3-amino-2-
hydroxypropyl chain at the 1-position of the indole ring, and are
used as HIV-1 protease inhibitors3 and antitumor compounds.4
Reactions of 1-(oxiran-2-ylmethyl) indoles with phenols give
alcohols, which are inhibitors of human cytosolic phospholipase
N-alkylation by the methylene group of oxirane ring with the for-
mation of open-chain intermediate 3. Similar intermediates were
earlier observed in reactions of epichlorohydrin with other het-
erocyclic compounds.6 Next, nucleophilic substitution of the chlo-
rine atom in the intermediate 3 leads to the formation of tricyclic
system 4 (Scheme 1). Data about some other compounds having
the oxazolo[3,2-a]indole skeleton, which may be employed in the
manufacture of 5-HT4 receptor antagonists, were published.7
The 1H NMR spectrum of product 2 shows that the signals of
the methylene protons of the epoxide fragment are unequivalent
due to the presence of the chiral center. Therefore, the signals
of the protons of the OCH2-group appear at 2.52e2.54 and
2.79e2.82 ppm as two multiplets. The multiplet of the proton at the
chiral carbon atom is at 3.23e3.28 ppm. The signals of the protons
of the NCH2-group are characterized as two doublets of doublets at
4.22 and 4.53 ppm. The assignment of all protons in the 1H NMR
spectrum of substances 2 and 4 were carried out on the basis
of two-dimensional heteronuclear correlation spectroscopy NMR
{1H, 13C} using HSQC and HMBC experiments.
A .
2a 5
2. Results and discussion
With the aim of obtaining 2-chloro-1-(oxiran-2-ylmethyl)-
1H-indole-3-carbaldehyde we investigated the reaction of
2-chloroindole-3-carbaldehyde 1 with epihalogenohydrins. We
found that the structure of the product depends on the kind of
halogenohydrin. The reaction of compound 1 with epibromohydrin
leads to desired compound 2. However, the analogous reaction with
epichlorohydrin leads to a derivative of the [1,3]oxazolo[3,2-a]
In the 1H NMR spectrum of compound 4 the hydrogen atoms of
the two methylene groups are magnetically unequivalent due to
the presence of a chiral center and each of them is observed as
a separate signal. The signals of the NCH2-protons appear as two
* Corresponding author. Fax: þ7 (863) 243 47 00; e-mail addresses: konsuz@
gmail.com (K.F. Suzdalev), sofia1984@inbox.ru (S.V. Den’kina).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.015

8776
K.F. Suzdalev et al. / Tetrahedron 67 (2011) 8775e8779
O
O
O
Cl
8
5
O
Cl
O
8a
Br
O
9a
1
7
6
9
Cl
Cl
O
N
N
-HCl
N
N
NaOH/ DMF
NaOH/ DMF
4a
H
OH
2
4
3
2
O
1
3
Cl
4
Cl
Scheme 1. Interaction of compound 1 with epihalogenohydrins.
doublets of doublets at 4.21 and 4.37 ppm. Evidence of the as-
signment of these signals as the NCH2-protons is the presence of
the two cross-peaks in the two-dimensional spectrum {1H, 15N}
with coordinates 4.21, 132.61, and 4.36, 132.61 ppm, showing the
interaction of each proton with the nitrogen atom. The signal of
protons of the ClCH2-group is at 3.91e3.97 ppm. For them, the
correlation between {1H, 15N} is absent. This data show that the
ClCH2-group is out of cycle. In the two-dimensional {1H, 13C} HMBC
spectrum, interaction between the proton at C-2 and the carbon
atom C(9a) (cross-peak with coordinates 1H, 13C at 5.58, 162.5 ppm)
is observed. Interaction of the protons of the NCH2-group with the
carbon atom C(9a) is observed as two cross-peaks with coordinates
1H, 13C at 4.21, 162.5 and at 4.37, 162.5 ppm, respectively.
N
O
NSO2Cl
O
O=C=NSO2Cl
PhH
N
CH2(CN)2
O
O
N
N
N
i-PrOH
5
4
Cl
Cl
Cl
6
R1
O
HNR1R2
N S N
R2
O
7a R1=H, R2= 4-MeC6H4
7b NR1R2= morpholine
O
N
7c NR1R2 = N- methylpiperazine
7(a-c)
Cl
Scheme 2. Reactions of compound
4 with malononitrile and chlorosulfonyl
isocyanate.
Finally the structure of compound 4 was determined on the
basis of X-ray analysis (Fig. 1). Cyclic atoms N(4), C(4a)eC9(a) are in
ꢀ
one plane accurate within 0.05 A. Atom C(2) and O(2) are over this
ꢀ
ꢀ
plane at 0.145 A and 0.264 A, respectively. Atom Cl(1) is under the
ꢀ
plane of the indole ring at 0.313 A. The torsion angle C(3)eC(2)e
C(10)eCl(1) is 47.1ꢀ. The torsion angle C(8a)eC(9)eC(11)eO(2)
is 1.6ꢀ.
Fig. 2. Molecular structure of compound 5 (thermal ellipsoids are drawn at the 30%
probability level).
In order to realize nucleophilic substitution of the chlorine
atom, we explored the reaction of compound 4 with secondary
amines. Unexpectedly we isolated another kind of compounds
having a chlorine atom, according to data elemental and mass-
spectral analyses. In the 1H NMR spectra of these products we
observed changes in the character of signals of the aliphatic protons
in comparison with initial compound 4, as well as observing the
CHO-group intact. Therefore we suggest the ring-opening process
is taking place with the formation of either 8(aec) or 9(aec),
having a chloropropyl chain at the indole nitrogen (Scheme 3).
Fig. 1. Molecular structure of compound 4 (thermal ellipsoids are drawn at the 30%
probability level).
We have investigated some chemical properties of compound 4.
Its reaction with malononitrile gives Knoevenagel condensation
product 5. Reaction with chlorosulfonyl isocyanate at the carbonyl
group with the extrusion of CO2,8 forms unstable product 6, which
may be isolated and reacted with amines to give sulfonamides
7(aec) (Scheme 2).
In the 1H NMR spectra of products 5, 6, 7(aec), the view and the
location of signals of the aliphatic protons do not change in com-
parison with the initial spectrum of compound 4.
R1
R1
O
O
HN
O
HN
R1
R2
R2
R2
OH
The structure of compound 5 was determined by X-ray analysis
(Fig. 2). Atoms of the indole ring N(4), C(4a)eC9(a) and atoms O(1)
N
R1
O
N
N
N
8(a-c)
N
R2
OH
9(a-c)
Cl
4
ꢀ
Cl
and C(2) are in one plane accurate within 0.04 A. Atom C(3) goes
8a NR1R2 = pyrrolidine
8b NR1R2 = morpholine
Cl
ꢀ
out of plane at 0.073 A. The torsion angle C(3)eC(2)eC(10)eCl(1) is
56.8ꢀ. In contrast to compound 4, atom Cl(1) goes out of indole
8c NR1R2 = N-methylpiperazine
ꢀ
plane at 2.66 A; the dihedral angle between planes O(1)eC(2)eC(3)
and C(2)eC(10)eCl(1) is practically right (87.6ꢀ).
Scheme 3. Interaction of compound 4 with secondary amines.

K.F. Suzdalev et al. / Tetrahedron 67 (2011) 8775e8779
8777
It was impossible to make distinguish between structures 8 or 9
only on the basis of NMR and IR spectra. The ultimate proof of
structure of substances 8(aec) was made by X-ray analysis of
product 8a (Fig. 3).
Reaction of compound 4 with malononitrile proceeds at the
carbon atom of the carbonyl group to give the Knoevenagel con-
densation product 5. However, interaction of starting material 4
with secondary amines proceeds at C(9a). In order to explain ex-
perimental facts and compare the stability of reaction product 8a
and hypothetical molecule 10, obtained by two alternative path-
ways, quantum-chemical calculations for reaction of compound 4
with pyrrolidine were carried out. Results, shown in Table 1,
indicate that the energy of compound 10 is higher than the starting
reaction point energy by15.1 kJ molꢁ1. This result demonstrates
endothermic character of the attack at the aldehyde group of 4 by
the pyrrolidine molecule. At the same time the addition of pirro-
lidine leads to the formation of compound 8a, which is more
preferable by 28.9 kJ molꢁ1
.
Table 1
Total (E) and relative (
6-311 G(d) method
DE) energies calculated in the gas phase by the B3LYP/
Structure
E, a.u
D
E, kJ molꢁ1
4þPyrrolidine
ꢁ1341.26388
ꢁ1341.27488
ꢁ1341.25815
0.0
8a
10
ꢁ28.9
þ15.1
3. Experimental section
3.1. General
Fig. 3. Molecular structure of compound 8a (thermal ellipsoids are drawn at the 30%
probability level).
Due to the presence of a chiral center [C(9) or C(90)] the X-ray
crystal structure of molecule 8a (Fig. 3) displays several interesting
structural features. Both enantiomers have the composition of
a monocrystal. In the unit cell, one quarter of atoms C(90), H(90),
and O(10) are situated in positions (unshaded lines), which differ
from other molecules. In residual molecules, the fragment C(9),
H(9), O(1) is located inversely (drawn by shaded lines). It is
noteworthy that atom H(1) is common for both oxygen atoms O(1)
and O(10). The carbon atoms of the indole ring are in one plane
All commercially available compounds were used without fur-
ther purification. 2-Chloroindole-3-carbaldehyde was obtained by
the known protocol.10 IR spectra were taken on Varian 3100 FT-IR,
Excalibur Series instrument by means of Attenuated Total Re-
flectance (ATR) method. 1H and 13C NMR spectra were recorded on
a Bruker DPX-250 instrument. Two-dimensional heteronuclear
correlation NMR spectra {1H, 13C} and {1H, 15N} using HSQC and
HMBC experiments for compounds 2 and 4 were recorded on an
Avance-600 (Bruker 600 MHz) spectrometer. Mass-spectra were
obtained on a Varian MAT-44 spectrometer.
ꢀ
accurate within 0.005 A, nitrogen atoms N(1) and N(2) go out of
ꢀ
plane in different directions at 0.018 A, atoms C(15) and O(2) move
ꢀ
The X-ray data sets for 4 and 5 were collected on a Bruker APEX
II diffractometer equipped with a CCD camera (Mo Ka,
aside at 0.092 A as N(2). In the pyrrolidine ring, atoms C(12) and
ꢀ
C(13) go out of plane N(2)C(11)C(14) at 0.39 and ꢁ0.24 A. Torsion
ꢀ
l
¼0.71073 A).11 The X-ray diffraction study of 8a was carried out on
angles O(2)eC(15)eC(3)eC(2)¼179.1, C(15)eC(3)eC(2)eN(2)¼4.5,
C(3)eC(2)eN(2)eC(14)¼4.3ꢀ. The sum of angles at N(1)¼359.5
and at N(2)¼359.7ꢀ. The fact that the indole and pyrrolidine rings
ꢀ
a Bruker P4 diffractometer (Mo Ka,
l
¼0.71073 A). For compound 5
semiempirical absorption correction was applied.12 The structures
were solved by direct methods and using Fourier techniques and
were refined by the full-matrix least squares against F2 with an-
isotropic thermal parameters for all non-hydrogen atoms. The hy-
drogen atoms were positioned geometrically and refined using the
riding model. All calculations were carried out with the use of the
SHELX97 program package.13
are situated near one plane indicate the presence of n-
p
conju-
gation between a lone pair of N(2) and the aromatic
p-system. In
the unit cell, the indole and pyrrolidine rings are located in a ‘head
to tail’ manner with an intermolecular hydrogen bond between
the O(2) atoms of one molecule and the hydrogen atom of the OH-
group of another one.
3.2. 2-Chloro-1-(oxiran-2-ylmethyl)-1H-indole-3-
carbaldehyde (2)
2.1. Results of quantum-chemical calculations
According to the calculation of Fukui indices fþ, compound 4 has
two reaction centersdthe carbon atom of the aldehyde group and
atom C(9a) (Scheme 4).9
To 2-chloroindole-3-carbaldehyde (1.8 g, 0.01 mol) in DMF
(10 mL) was added sodium hydroxide (0.5 g, 0.01 mol) in water
(1 mL). The reaction mixture was stirred for 1 h. To this solution was
added epibromohydrin (2.5 mL, 0.03 mol). The reaction mixture
was stirred for 30 min and then slowly heated up to 50 ꢀC. The
mixture was poured into water (300 mL) and retained overnight.
The crude product was filtered off and dried, then dissolved in
benzene and passed through a filter funnel, containing Al2O3 (20 g).
The solvent was evaporated to volume (10e15 mL). The formed
precipitate was filtered off to give the title compound 2 (705 mg,
30%) as a white powder, mp 114e118 ꢀC; [Found: C, 60.92; H, 4.26;
Cl, 15.04; N, 5.94. C12H10ClNO2 requires C, 61.16; H, 4.28; Cl, 15.04;
HO
0.18
O
0.27
0.00
N
0.03
O
HN
0.03
0.00
0.27
O0.04
O
N
N
0.01 N
N
0.04
Cl
0.04
0.00Cl
0.00
0.00
HO
8a
10
4
Cl
Scheme 4. Fukui indices fþ of compound 4 and its reactions with pyrrolidine.

8778
K.F. Suzdalev et al. / Tetrahedron 67 (2011) 8775e8779
N, 5.93%]; nmax 1648, 1613, 1581, 1512 cmꢁ1
;
dH (600 MHz, CDC13)
3.5. {(1Z)-[2-(Chloromethyl)-2,3-dihydro[1,3]oxazolo[3,2-a]
2.52e2.54 (1H, m, OCH2), 2.79e2.82 (1H, m, OCH2), 3.23e3.28 (1H,
m, CH), 4.22 (1H, dd, J 15.6, 5.3 Hz, NCH2), 4.53 (1H, dd, J 15.6,
3.3 Hz, NCH2), 7.26e7.37 (3H, m, H-5,6,7), 8.21e8.27 (1H, m, H-4),
10.07 (1H, s, CH]O); dC (150 MHz, CDCl3) 45.0(C-10), 45.1(C-8),
49.7(C-9), 109.9(C-7), 113.2(C-3), 121.1(C-4), 123.5(C-5),124.1(C-3a),
124.2(C-6), 135.8(C-7a), 136.1(C-2), 183.8 (C-11);m/z (Mþ) 235
(100), 192 (63%).
indol-9-yl]methylene}sulfamoyl chloride (6)
To compound 4 (904 mg, 0.004 mol) in dry benzene (10 mL) was
added dropwise chlorosulfonyl isocyanate (0.35 mL, 0.004 mol).
This was retained at room temperature for 10e15 min. The formed
precipitate was filtered off, washed with diethyl ether and dried to
give crude product 6 (1 g, 75%). It was recrystallized from a mixture
of benzene and acetonitrile (1:1) to give the title compound 6
(360 mg, 27%) as a light yellow powder, mp 165e168 ꢀC; [Found: C,
43.43; H, 3.04; Cl, 21.37; N, 8.45; S, 9.66. C12H10Cl2N2O3S requires C,
43.26; H, 3.03; Cl, 21.28; N, 8.41; S, 9.62%]; nmax 1619, 1576, 1539,
3.3. 2-(Chloromethyl)-2,3-dihydro[1,3]oxazolo[3,2-a]indole-
9-carbaldehyde (4)
1525, 1475 cmꢁ1
; dH (250 MHz, DMSO-d6) 4.23e4.38 (3H, m, CH2Cl,
To 2-chloroindole-3-carbaldehyde (23.5 g, 0.13 mol) in DMF
(40 mL) was added sodium hydroxide (5.24 g, 0.131 mol) in water
(5 mL). The reaction mixture was stirred for 1 h. To this solution
was added epichlorohydrin (30.50 mL, 0.39 mol). The reaction
mixture was stirred for 3 h and then slowly heated up to 50 ꢀC.
The mixture was poured into water (500 mL) and retained over-
night. The crude product was filtered off and dried, then dissolved
in benzene and passed through a filter funnel, containing Al2O3
(50 g). The solvent was evaporated to volume (15e20 mL). The
formed precipitate was filtered off to give the crude product
(15.0 g, 49%). Substance 4 was recrystallized from propan-2-ol to
give the title compound 4 (8 g, 26%) as a white powder, mp
161e165 ꢀC; [Found: C, 61.40; H, 4.30; Cl, 15.10; N, 5.96.
C12H10ClNO2 requires C, 61.16; H, 4.28; Cl, 15.04; N, 5.93%]; nmax
NCH2), 4.59e4.73 (1H, m, NCH2), 6.06e6.25 (1H, m, CH), 7.11e7.55
(3H, m, H-5,6,7), 8.25e8.53 (2H, m, H-4, CH]).
3.6. N-{(1Z)-[2-(Chloromethyl)-2,3-dihydro[1,3]oxazolo[3,2-
a]indol-9-yl]methylene}-N0-(4-methylphenyl)sulfamide(7a)
To 4-methylaniline (107 mg, 0.001 mol) in dry acetonitrile
(3 mL) and triethylamine (0.14 mL, 0.001 mol) was added com-
pound 6 (333 mg, 0.001 mol). To the precipitate of triethylamine
hydrochloride was added water (20 mL). The remaining precipitate
was filtered off and dried to give the crude product 7a (400 mg,
99%). It was recrystallized from butan-1-ol (3 mL) to give the title
compound 7a (100 mg, 25%) as a white powder, mp 235e238 ꢀC;
[Found: C, 56.72; H, 4.51; Cl, 8.82; N, 10.44; S, 7.97. C19H18ClN3O3S
requires C, 56.50; H, 4.49; Cl, 8.78; N, 10.40; S, 7.94%]; nmax 3245,
1635, 1614, 1562, 1562 cmꢁ1
; dH (600 MHz, CDC13) 3.91e3.96 (2H,
m, OCH2), 4.21 (1H, dd, J 9.5, 6.4 Hz, NCH2), 4.37 (1H, dd, J 9.5,
8.4 Hz, NCH2), 5.67e5.71 (1H, m, CH), 7.06e7.37 (3H, m, H-5,6,7),
8.11 (1H, d, J 7.7 Hz, H-8), 9.88 (1H, s, CH]O); dC (150 MHz, CDCl3)
43.9(C-10), 45.0(C-3), 87.7(C-2), 94.0(C-9), 109.0(C-5), 121.5(C-8),
122.4(C-6), 123.2(C-7), 128.7(C-8a), 128.8(C-4a), 162.3(C-9a),
180.6(C-11); m/z (Mþ) 235 (100), 200 (50), 172 (30), 144 (68), 117
(35%). The crystallographic parameters for 4 at T¼296(2) K are as
follows: C12H10ClNO2, fw¼235.66, triclinic system, space group
1615, 1576, 1513, 1475 cmꢁ1
;
dH (250 MHz, CDC13þ0.1 mL DMSO-d6)
1.83 (3H, s, Me), 3.51e3.74 (2H, m, CH2Cl), 3.79e3.91 (1H, m, NCH2),
4.03e4.18 (1H, m, NCH2), 5.40e5.54 (1H, m, CH), 6.51e6.88 (7H, m,
ArH), 7.51e7.63 (1H, m, H-8), 8.37 (1H, s, NH), 8.84 (1H, s, CH]); dC
(60 MHz, DMSO-d6); 21.2, 46.0, 46.3, 88.1, 91.0, 111.4, 120.6 (2C),
122.1, 123.7, 123.8, 128.5, 130.3 (2C), 130.6, 133.1, 137.1, 158.2, 165.4.
3.7. N-{(1Z)-[2-(Chloromethyl)-2,3-dihydro[1,3]oxazolo[3,2-a]
indol-9-yl]methylene}morpholine-4-sulfonamide (7b)
Pꢁ1, a¼7.795(9) A, b¼8.067(9) A, c¼8.250(10) A,
a
¼94.236(19)ꢀ,
ꢀ
ꢀ
ꢀ
3
ꢀ
b
¼92.663(17)ꢀ,
g
¼93.488(19)ꢀ,
V¼515.7(10)
A ,
Z¼2,
rcalcd¼1.518 g cmꢁ3
,
m
¼3.52 cmꢁ1, 3054 measured reflections, 976
To morpholine (0.1 mL, 0.001 mol) in dry acetonitrile (3 mL) and
triethylamine (0.14 mL, 0.001 mol) was added compound 6 (333 mg,
0.001 mol). To the precipitate of triethylamine hydrochloride was
added water (20 mL). The remaining precipitate was filtered off and
dried to give the crude product 7b (258 mg, 67%). It was recrystal-
lized from butan-1-ol (3 mL) to give the title compound 7b (112 mg,
29%) as a white powder, mp 195e198 ꢀC; [Found: C, 49.87; H, 4.71;
Cl, 9.20; N,10.91; S, 8.32. C16H18ClN3O4S requiresC, 50.07; H, 4.73; Cl,
reflections with I>2.0
s
(I), Rint¼0.1222, GooF¼0.974, R1 (I>2 (I))¼
s
0.0727, wR2 (I>2
s(I))¼0.1788. CCDC 831061.
3.4. {[2-(Chloromethyl)-2,3-dihydro[1,3]oxazolo[3,2-a]indol-
9-yl]methylene}malononitrile (5)
To compound 4 (235 mg, 0.001 mol) in propan-2-ol (2 mL) and
triethylamine (0.14 mL, 0.001 mol) was added malononitrile
(100 mg). The reaction mixture was refluxed for 2 h. The yellow
precipitate was filtered off and dried to give the crude product
(100 mg, 35%), which was recrystallized from propan-2-ol to give
the title compound 5 (80 mg, 28%) as a yellow powder, mp
180e182 ꢀC; [Found: C, 63.75; H, 3.56; Cl, 12.55; N, 14.87.
C15H10ClN3O requires C, 63.50; H, 3.55; Cl, 12.50; N, 14.81%]; nmax
9.24; N, 10.95; S, 8.35%]; nmax 1620, 1577, 1510, 1475 cmꢁ1
; dH
(250 MHz, CDC13) 3.14e3.26 (4H, m, N(CH2)2morpholine), 3.68e3.83
(4H, m, O(CH2)2morpholine), 3.87e4.02 (2H, m, CH2Cl), 4.22e4.34 (1H,
m, NCH2), 4.41e4.52 (1H, m, NCH2), 5.69e5.83 (1H, m, CH),
7.05e7.32 (3H, m, H-5,6,7), 8.00e8.15 (1H, m, H-8), 8.83 (1H, s,
CH]); dC (60 MHz, DMSO-d6); 46.2, 46.3, 47.2 (2C), 66.1 (2C), 88.7,
91.2, 111.5, 122.4, 123.9, 124.0, 128.5, 130.8, 159.4, 165.6.
2211, 1617, 1588, 1529, 1468 cmꢁ1
; dH (250 MHz, CDC13) 3.90e4.05
(2H, m, CH2Cl), 4.28e4.40 (1H, m, NCH2), 4.43e4.54 (1H, m, NCH2),
5.75e5.88 (1H, m, CH), 7.07e7.33 (3H, m, H-5,6,7), 7.64 (1H, s,
CH]), 7.70e7.80 (1H, m, H-8); dC (60 MHz, CDCl3) 45.3, 45.8, 67.9,
89.7, 89.8, 110.7, 116.0, 117.6, 121.1, 123.6, 123.8, 129.1, 130.3, 148.4,
162.3; m/z (Mþ) 283 (25), 75 (73), 39 (100%). The crystallographic
parameters for 5 at T¼296(2) K are as follows: C15H10ClN3O,
3.8. N-{(1Z)-[2-(Chloromethyl)-2,3-dihydro[1,3]oxazolo[3,2-a]
indol-9-yl]methylene}-4-methylpiperazine-1-sulfonamide (7c)
To N-methylpiperazine (0.12 mL, 0.00106 mol) in dry acetoni-
trile (3 mL) and triethylamine (0.15 mL, 0.00106 mol) was added
compound 6 (354 mg, 0.00106 mol). To the precipitate of triethyl-
amine hydrochloride was added water (20 mL). The remaining
precipitate was filtered off and dried to give the crude product 7c
(308 mg, 73%). It was recrystallized from butan-1-ol (3 mL) to give
the title compound 7c (170 mg, 40%) as a white powder, mp
131e135 ꢀC; [Found: C, 51.24; H, 5.30; Cl, 8.89; N, 14.06; S, 8.05.
C17H21ClN4O3S requires 51.45; H, 5.33; Cl, 8.93; N, 14.12; S, 8.08%];
ꢀ
fw¼283.71, monoclinic system, space group P21/n, a¼8.711(5) A,
3
ꢀ
ꢀ
ꢀ
ꢀ
b¼10.988(7) A, c¼14.230(9) A,
b
¼103.854(10) , V¼1322.5(14) A ,
Z¼4, rcalcd¼1.425 g cmꢁ3
,
m
¼2.87 cmꢁ1, 11,510 measured re-
flections, 2166 reflections with I>2.0
s
(I), Rint¼0.031, GooF¼0.968,
R1 (I>2
s
(I))¼0.0446, wR2 (I>2 (I))¼0.1389, Tmin/max¼0.9719/
s
0.9830. CCDC 831062.

K.F. Suzdalev et al. / Tetrahedron 67 (2011) 8775e8779
8779
nmax 1620, 1575, 1507, 1475 cmꢁ1
;
dH (250 MHz, CDC13) 2.28 (3H, s,
(0.14 mL, 0.001 mol) and the reaction mixture was refluxed for 2 h.
The precipitate was filtered off and dried to give the crude product
8c (186 mg, 55%). It was recrystallized from mixture benzene with
acetonitrile (10:1) to give the title compound 8c (70 mg, 21%) as
a white powder, mp 160e164 ꢀC; [Found: 60.56; H, 6.57; Cl, 10.52;
N, 12.46. C17H22ClN3O2 requires C, 60. 80; H, 6.60; Cl, 10.56; N,
Me), 2.42e2.61 (4H, m, N(CH2)2piperazine), 3.17e3.32 (4H, m,
N(CH2)2piperazine), 3.85e4.02 (2H, m, CH2Cl), 4.19e4.30 (1H, m,
NCH2), 4.37e4.50 (1H, m, NCH2), 5.67e5.82 (1H, m, CH), 7.02e7.30
(3H, m, H-5,6,7), 8.00e8.13 (1H, m, H-8), 8.79 (1H, s, CH]); dC
(60 MHz, CDCl3); 44.4, 45.7, 46.2, 46.9 (2C), 54.5 (2C), 88.6, 89.2,
109.8, 123.3, 123.5, 123.9, 128.8, 129.9, 160.3, 164.2.
12.51%]; nmax 3059,1659, 1610,1524, 1506, 1456 cmꢁ1
; dH (250 MHz,
CDC13) 2.35 (3H, s, Me), 2.46e2.67 (4H, m, N(CH2)2piperazine),
3.06e3.52 (5H, m, N(CH2)2piperazine, OH), 3.52e3.74 (2H, m, CH2Cl),
4.11e4.42 (3H, NCH2, CH), 7.18e7.38 (3H, m, H-5,6,7), 8.16e8.33
(1H, m, H-4), 10.26 (1H, s, CH]O); dC (60 MHz, CDCl3); 46.2, 46.8,
47.5 (2C), 52.9 (2C), 55.7, 69.8, 110.7, 110.9, 121.9, 123.5, 124.1, 125.5,
134.6, 156.1, 184.2.
3.9. 1-(3-Chloro-2-hydroxypropyl)-2-pyrrolidin-1-yl-1H-
indole-3-carbaldehyde (8a)
To compound 4 (235 g, 0.001 mol) in propan-2-ol (2 L) was added
pyrrolidine (0.1 mL, 0.0013 mol) and triethylamine (0.14 L, 0.001 mol)
and the reaction mixture was refluxed for 1 h. The precipitate was
filtered off and dried to give the crude product (90 mg, 29%). The
precipitatewasrecrystallized from benzeneto give the titlecompound
8a (52 mg,17%) as a white powder, mp 125e128 ꢀC; [Found: C, 62.89;
H, 6.26; Cl, 11.61; N, 9.17. C16H19ClN2O2 requires C, 62.64; H, 6.24; Cl,
References and notes
1. Buchman, G.; Graul, K. H. Pharmazie 1971, 26, 21e27.
2. Somei, M.; Iwasa, E.; Yamada, F. Heterocycles 1986, 24, 3065e3069.
3. Di Santo, R.; Costi, R.; Artico, M.; Massa, S.; Rango, R.; Marshall, G. R.; La Colla, P.
Bioorg. Med. Chem. 2002, 10, 2511e2526.
11.56; N, 9.13%]; nmax 3237, 1597, 1581, 1533 cmꢁ1
; dH (250 MHz,
CDC13) 1.98e2.18 (4H, m, (CH2)2pyrrolidine), 3.42e3.72 (6H, m, CH2Cl,
NCH2, CH, OH), 4.18e4.47 (4H, m, N(CH2)2pyrrolidine), 7.16e7.40 (3H, m,
H-5,6,7), 8.13e8.25 (1H, m, H-4), 9.75 (1H, s, CH]O); dC (60 MHz,
CDCl3) 26.5 (2C), 47.2, 48.0, 54.5 (2C), 69.7, 107.3, 110.0, 121.0, 123.0,
123.1,126.9,135.7,155.4,183.1. The crystallographic parameters for 8a
at T¼296(2) K are as follows: C16H19ClN2O2, fw¼306.78, triclinic
4. (a) Caballero, E.; Adeva, A.; Caldero, S. Bioorg. Med. Chem. 2003, 11, 3413e3421;
(b) Maya, A. B.; Perez-Melero, C.; Salvado, N. Bioorg. Med. Chem. 2005, 13,
2097e2107.
€
5. (a) Bovens, S.; Elfringhoff, A. S.; Kaptur, M.; Reinhardt, D.; Schafers, M.; Lehr, M.
J. Med. Chem. 2010, 53, 8298e8308; (b) Drews, A.; Bovens, S.; Roebrock, K. J.
Med. Chem. 2010, 53, 5165e5178; (c) Hess, M.; Elfringhoff, A. S.; Lehr, M. Bioorg.
Med. Chem. 2007, 15, 2883e2891.
6. (a) Korotkih, N. I.; Shvaika, O. P. Russ. J. Org. Chem. 1996, 32, 1076; (b) Sehgal, R.
K.; Webb, M. W.; Agrawal, K. C. J. Med. Chem. 1981, 24, 601e604.
7. (a) Hayami, M.; Seiko, T. Patent GB 1522173, 1975; Chem. Abstr. 1976, 85, 7280;
(b) Gaster, L. M.; Wyman, P. A. Patent WO 9,318,036, 1993; Chem. Abstr. 1994,
120, 134454; (c) Gaster, L. M.; Wyman, P. A.; Ellis, E. S.; Young, T. J. J. Bioorg. Med.
Lett. 1994, 5, 667e668; (d) Gaster, L. M.; Joiner, G. F.; King, F. D.; Wyman, P. A.;
Sutton, J. M.; Bingham, S.; Ellis, E. S.; Sanger, G. J.; Wardle, K. A. J. Med. Chem.
1996, 38, 4760e4763; (e) Gaster, L. M.; Wyman, P. A. U.S. Patent 5,852,014, 1998;
Chem. Abstr. 1999, 130, 81518; (f) Fedouloff, M.; Hossnera, F.; Voylea, M.; Ran-
sonb, J.; Powlesb, J.; Rileyb, G.; Sangerb, G. J. Bioorg. Med. Chem. 2001, 8,
2119e2128; (g) Zeng, C.-C.; Liu, F.-J.; Ping, D.-W.; Hu, L.-M.; Cai, Y.-L.; Zhong, R.-G.
J. Org. Chem. 2009, 74, 6386e6389.
ꢀ
ꢀ
ꢀ
system, space group Pꢁ1, a¼7.799(2) A, b¼9.829(2) A, c¼10.526(2) A,
3
ꢀ
a
¼67.500(10)ꢀ,
b
¼81.63(2)ꢀ,
g
¼81.18(2)ꢀ, V¼733.3(3) A , Z¼2,
rcalcd¼1.389 g cmꢁ3
,
m
¼2.67 cmꢁ1, 3143 measured reflections, 1969
reflections with I>2.0
0.0478, wR2 (I>2
s
(I), Rint¼0.0303, GooF¼1.053, R1 (I>2 (I))¼
s
s(I))¼0.1252. CCDC 831063.
3.10. 1-(3-Chloro-2-hydroxypropyl)-2-morpholin-4-yl-1H-
indole-3-carbaldehyde (8b)
8. Dhar, D. N.; Murthy, K. S. K. Synthesis 1986, 437e439.
To compound 4 (470 mg, 0.002 mol) in propan-2-ol (3 mL) was
added morpholine (0.18 mL, 0.002 mol) and the reaction mixture was
refluxed for 2 h. The precipitate was filtered off and recrystallized
from benzene with charcoal to give the title compound 8b (60 mg, 9%)
as a white powder, mp 125e127 ꢀC; [Found: C, 59.30; H, 5.91; Cl,
10.94; N, 8.65. C16H19ClN2O3 requires C, 59.54; H, 5.93; Cl, 10.98; N,
9. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, J. A.; Vreven, T., Jr.; Kudin, K. N.; Burant, J. C.;
Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken,
V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A.
J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G.
A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.;
Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Fores-
man, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov,
B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.;
Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P.
M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian
03; Gaussian: Wallingford CT, 2004.
8.68%]; nmax 3350, 1620,1582,1534,1461 cmꢁ1
; dH (250 MHz, CDC13)
2.67e2.79 (1H, m, OH), 3.20e3.51 (4H, N(CH2)2morpholine), 3.52e3.75
(2H, m, CH2Cl), 3.77e4.08 (4H, m, O(CH2)2morpholine), 4.18e4.53 (3H,
m, NCH2, CH), 7.26e7.40 (3H, m, H-5,6,7), 8.13e8.33 (1H, m, H-4),
10.33 (1H, s, CH]O); dC (60 MHz, CDCl3) 46.8, 47.3, 53.6 (2C), 67.8
(2C), 69.9, 88.4,109.6,110.9,121.9,123.0,123.6,124.2,125.5,181.1; m/z
(Mþ) 322 (64), 305 (82), 130 (78), 89 (70), 43 (100%).
10. Showalter, H. D. H.; Sercel, A. D.; Leja, D. M.; Wolfangel, C. D.; Ambroso, L. A.;
Elliot, W. L.; Fry, D. W.; Kraker, A. J.; Howard, C. T.; Lu, G. H.; Moore, C. W.;
Nelson, J. M.; Roberts, B. J.; Vinsent, P. W.; Denny, W. A.; Thompson, A. M. J. Med.
Chem. 1997, 40, 413e426.
3.11. 1-(3-Chloro-2-hydroxypropyl)-2-(4-methylpiperazin-1-
11. SMART (Control) and SAINT (Integration) Software, Version 5.0; Bruker AXS:
yl)-1H-indole-3-carbaldehyde (8c)
Madison, WI, 1997.
12. Sheldrick, G. M. SADABS, Program for Scanning and Correction of Area Detector
Data; Gottingen University: Gottingen, Germany, 2004.
13. Sheldrik, G. M. Acta Crystallogr. 2008, A64, 112e122.
To compound 4 (235 mg, 0.001 mol) in propan-2-ol (2 mL) were
added N-methylpiperazine (0.11 mL, 0.001 mol) and triethylamine
€
€