Synthesis of 3-acyl-1-hydroxy-1H-indole-5,6-dicarbonitriles

Article abstract of DOI:10.1016/j.mencom.2015.07.030

The Vilsmeier-Haack formylation of 4-(2-aryl-2-oxoethyl)-5-nitrophthalonitriles followed by reduction affords 3-acyl-1-hydroxy- 1H-indole-5,6-dicarbonitriles.

Full text of DOI:10.1016/j.mencom.2015.07.030

Mendeleev
Communications
Mendeleev Commun., 2015, 25, 315–317
Synthesis of 3-acyl-1-hydroxy-1H-indole-5,6-dicarbonitriles
Zhanna V. Chirkova,a Mariya V. Kabanova,a Sergey S. Sergeev,a Sergei I. Filimonov,*a
Igor G. Abramov,a Alexander V. Samet*b and Kyrill Yu. Suponitskyc
a Yaroslavl State Technical University, 150023 Yaroslavl, Russian Federation. Fax: +7 4852 44 0729;
e-mail: filimonovsi@ystu.ru
b N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian
Federation. Fax: +7 495 135 5328; e-mail: sametav@server.ioc.ac.ru
c A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: +7 499 135 9202; e-mail: kirshik@yahoo.com
DOI: 10.1016/j.mencom.2015.07.030
The Vilsmeier–Haack formylation of 4-(2-aryl-2-oxoethyl)-5-nitrophthalonitriles followed by reduction affords 3-acyl-1-hydroxy-
1H-indole-5,6-dicarbonitriles.
R
O
Cl
R
3-Acyl-1H-indoles can serve as starting components for bio-
logically active compounds1 and pharmaceutical substances
possessing antifungal and analgesic activity.2,3 N-Hydroxy-1H-
indoles exert bactericidal4,5 and antitumor6 activity. Therefore,
3-acyl-1-hydroxy-1H-indoles can be of this ‘joint’ interest.
Usually, 3-acylindoles are prepared by Friedel–Crafts acyla-
tion7,9 or Vilsmeier–Haack formylation10 of the already existing
indole cycle. Recently, Pd- and Rh-based catalysts were used
for the synthesis of substituted 3-acylindoles from o-(alkynyl)-
anilines.11–13 Metal-based catalysis is employed for addition of
nitriles to 3-unsubstituted indoles,14,15 formylation,16 or cycliza-
tion of ethenyl substrates with a nitro group in ortho-position4
and aminoacetylation using N-sulfonyltriazole intermediates.17
Earlier we reduced 4-(2-oxo-2-R-ethyl)-5-nitrophthalonitriles
1 into 1-hydroxy-2-R-1H-indole-5,6-dicarbonitriles 2 which were
further O-methylated to the corresponding 1-methoxy derivatives
i, POCl3/DMF
NC
NC
NC
NC
ii, NaHCO3
CHO SnCl2
HCl
NO2
NO2
1a–d
4a–d
O
R
O
R
NC
NC
NC
NC
MeI
K2CO3
N
N
OH
OMe
5a–d
6a–d
a R = Ph
b R = 4-MeC6H4
c R = 4-MeOC6H4
d R = 2-thienyl
Scheme 2
3
18 (Scheme 1). Such compounds with a phthalonitrile motif are
of interest, in particular, in the synthesis of macroheterocycles
and polymer chemistry (see ref. 18 and references therein).
data for similar compounds.23 Their structure was proved by IR
and NMR spectroscopy (including 2D NMR) and mass spectro-
metry. The NOESY spectrum of compound 4d featured a key
cross-peak of formyl proton with an H-5' proton of thiophene ring,
thus supporting the E-configuration of the major isomer. Based
on the HMBC spectrum of compound 4c, full assignment of
hydrogen and carbon atoms was fullfilled. Mass spectra of com-
pounds 4a–d feature molecular ion peak of low abundance as
two signals (3:1) according to the isotope composition of Cl.
Treatment of compounds 4a–d with SnCl2 in HCl18 resulted
in reduction of the nitro group along with replacement of the
chlorine atom by the hydroxyl group and cyclization to the cor-
responding 3-acyl-1-hydroxy-1H-indole-5,6-dicarbonitriles 5a–d
in yields up to 80% (Scheme 2).† Reduction of the compounds
like 4 was not previously described in literature. Reductive
cyclization of unsymmetrical 2-(o-nitrophenyl)-1,3-dicarbonyl
R
O
NC
NC
NC
NC
SnCl2
HCl
R
N
NO2
OH
1
2
NC
NC
MeI
K2CO3
R
N
OMe
3
Scheme 1
Here, this strategy was developed for a synthesis of 3-acyl-
1-hydroxy-1H-indole-5,6-dicarbonitriles (Scheme 2). Noteworthy,
the examples of the 1-hydroxy-3-acyl-1H-indoles synthesis via
reductive cyclization are scarce,19–21 and there are no data on
preparation of 3-acyl-substituted 1-hydroxyindole-5,6-dicarbo-
nitriles. First, formyl derivatives 4a–d were prepared by the
Vilsmeier–Haack reaction22 (yields up to 72%). Using 3-fold
excess of POCl3 resulted in formylation with concomitant replace-
ment of enol hydroxyl group by chlorine atom.
†
IR spectra were measured on a Perkin-Elmer RX-1 spectrometer in the
range of 700–4000 cm–1 using suspensions of substances in Nujol. Mass
spectra were obtained using a FINNIGAN MAT INCOS 50 mass spectro-
meter; the ionization energy was 70 eV. NMR spectra were recorded on a
Bruker DRX-500 instrument at 30°C for solutions in DMSO-d6. Signals
1
of residual protons of the solvent in H NMR spectra (dH 2.50) or the
signal of DMSO-d6 in 13C spectra (dC 39.5) were used as references for
chemical shift measurements. Two-dimensional spectra were recorded using
standard Bruker techniques. The mixing time in NOESY spectra was 0.3 s.
Elemental analysis was carried out on a Perkin Elmer 2400 instrument.
Synthesis of compounds 1–3 was described earlier.18
Compounds 4a–d were formed as E/Z-isomeric mixtures with
predominant E-isomer (81–98%), in accordance with published
© 2015 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
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Mendeleev Commun., 2015, 25, 315–317
CHO
compounds was reported20 to produce a mixture of isomers.
NC
NC
NC
NC
POCl3/DMF
However, in the present work due to the use of b-chlorovinyl-
carbonyl compounds 4a–d the problem of regioselectivity was
solved leading exclusively to 5a–d. To prove the structure of
compounds 5a–d, they were converted to N-methoxy-1H-indoles
6a–d by methylation with MeI in the presence of K2CO3. Such
N-methoxy derivatives are more stable under EI mass spectrometry
conditions thus enabling the observation of molecular ion peaks.
The structure of products 5 and 6 was proved by IR and
NMR spectroscopy and mass spectrometry. On the basis of 2D
NMR 1H and 13C HSQC and HMBC of compound 5b the exact
structures of 5a–d, 6a–d were established and all the signals
of H and C atoms were assigned. Singlets of methoxy group
R
R
N
N
OMe
OMe
3a–d
7a–d
a R = Ph
c R = 4-MeOC6H4
d R = 2-thienyl
b R = 4-MeC6H4
Scheme 3
If the reaction sequence is changed, the reductive cyclization
of nitro ketones 1a–d carried out first, the resulting 1-hydroxy-
1H-indoles 2 methylated (see Scheme 1) and 1-methoxy-1H-
indoles 3 then treated with a Vilsmeier reagent, 2-substituted-
3-formyl-1H-indoles 7a–d are obtained instead of isomeric
3-acylindoles 6a–d (Scheme 3).‡ Note that treatment of N-hydroxy-
1H-indoles with chlorinating agents was reported25,26 to produce
3-chloroindoles with elimination of hydroxyl group. Similarly,
formylation of 2-aryl-1-hydroxy-1H-indoles was also accom-
panied by elimination of OH group and furnished 2-aryl-1H-
indoles.27 Thus, formylation at the 3-position with the retention
of N-substituent proceeds smoothly for O-methylated N-hydroxy-
1H-indoles only.
1
were observed at 4.0–4.3 ppm in H NMR spectra of 6a–d.
Mass spectra of the compounds 5a–d are characterized by low
abundance of the molecular ion peaks, [M+–O] being one of the
main fragment ions.24 On the contrary, for compounds 6a–d
molecular ion is one of the most abundant ones and [M+–OMe]
is the main fragment ion.
4-(2-Aryl-1-chloro-3-oxoprop-1-en-2-yl)-5-nitrophthalonitriles 4a–d
(general procedure). Compound 1a–d (6 mmol) was added to a solution
of POCl3 (18 mmol) in DMF (3 ml). The mixture was stirred at 80–90°C
for 2 h, cooled and poured into cold 5% aq. NaHCO3 solution. The resulting
precipitate was filtered, thoroughly washed with water and recrystallized
from EtOH.
The structure of compounds 7a–d was established by IR and
NMR spectroscopy and mass spectrometry and confirmed by
X-ray diffraction data for 7b. H NMR spectra of indoles 7a–d
1
4-[1-Chloro-1-(4-methoxyphenyl)-3-oxoprop-1-en-2-yl]-5-nitrobenzene-
1,2-dicarbonitrile 4c: yield 66%, mp 191–193°C (ethanol). IR (n/cm–1):
2241 (CºN), 1664 (C=O), 1600 (Ar), 1531, 1349 (NO2). 1H NMR
(DMSO-d6) d: E-isomer >98%, 3.88 (s, 3H, OMe), 7.18 (d, 2H, H-3',
H-5', J 8.7 Hz), 7.66 (d, 2H, H-2', H-6', J 8.7 Hz), 8.60 (s, 1H, H-3), 9.03
(s, 1H, H-6), 9.44 (s, 1H, COH). 13C NMR (DMSO-d6) d: 187.07, 162.42,
155.29, 150.05, 138.39, 134.39, 134.15, 132.42 (2C), 130.19, 125.95,
119.48, 116.76, 114.60 (2C), 114,58 114.42, 55.73. MS, m/z (%): 367
[M+] (21), 338 [M–COH] (11), 303 (56), 294 (57), 259 (50), 251 (49),
233 (53), 215 (42), 202 (68), 189 (74), 165 (86), 169 (34), 155 (52), 142
(41), 135 (51), 119 (48), 107 (51), 92 (80), 76 (39), 64 (100). Found
(%): C, 58.52; H, 2.65; N, 11.34. Calc. for C18H10ClN3O4 (%): C, 58.79;
H, 2.74; N, 11.43.
feature a low-field singlet corresponding to the formyl proton at
9.80–10.12 ppm.
An asymmetric unit cell contains one molecule of 7b
(Figure 1).§ The p-tolyl and methoxy substituents are out of
O(1)
C(16)
C(4)
N(2)
C(5)
C(2)
C(1)
C(3)
C(17)
C(14)
C(11)
C(13)
C(12)
C(6)
C(9)
C(15)
C(8)
N(1)
C(10)
C(7)
C(18)
3-Acyl-1-hydroxy-1H-indole-5,6-dicarbonitriles 5a–d (general pro-
cedure). Compound 4a–d (3 mmol) was added to a solution of SnCl2
(0.01 mol) in conc. HCl (2 ml) and EtOH (2 ml), and the mixture was
stirred at 50°C for 0.5–1 h. The precipitate formed upon cooling of the
solution was filtered and recrystallized from EtOH.
N(3)
O(2)
C(19)
Figure 1 Molecular structure of compound 7b. Displacement ellipsoids
are drawn at the 50% probability level.
1-Hydroxy-3-(4-methylbenzoyl)-1H-indole-5,6-dicarbonitrile 5b: yield
79%, mp 272–273°C (ethanol). IR (n/cm–1): 3561 (OH), 2230 (CºN),
1635 (C=O), 1585 (Ar). 1H NMR (DMSO-d6) d: 2.42 (s, 3H, Me), 7.38
(d, 2H, H-3', H-5', J 8.0 Hz), 7.77 (d, 2H, H-2', H-6', J 8.0 Hz), 8.44 (s,
1H, H-4), 8.61 (s, 1H, H-2), 8.80 (s, 1H, H-7), 12.87 (s, 1H, OH). 13C NMR
(DMSO-d6) d: 188.26 (C=O), 142.46 (C-1'), 137.61 (C-2), 136.05 (C-4'),
133.73 (C-7a), 129.26 (C-3', C-5'), 128.92 (C-2', C-6'), 128.52 (C-7),
124.72 (C-3), 117.11 (6-CN), 116.91 (C-4), 116.82 (5-CN), 110.70 (C-3a),
107.46 (C-5), 106.81 (C-6), 21.16 (Me). MS, m/z (%): 301 (1), 285 [M+– O]
(6), 154 (11), 139 (15), 119 (100), 91 (97). Found (%): C, 71.53; H, 3.52;
N, 13.88. Calc. for C18H11N3O2 (%): C, 71.75%; H, 3.68; N, 13.95.
3-Acyl-1-methoxy-1H-indole-5,6-dicarbonitriles 6a–d (general proce-
dure). MeI (1.1 mmol) and K2CO3 (1.3 mmol) were added to a solution
of compounds 5a–d (1 mmol) in DMF (5 ml) and the mixture was stirred
at 30–40°C for 1–2 h. Then it was cooled, the resulting precipitate was
filtered and recrystallized from EtOH.
3-Benzoyl-1-methoxy-1H-indole-5,6-dicarbonitrile 6a: yield 78%,
mp 251–253°C (ethanol). IR (n/cm–1): 2237 (CºN), 1659 (C=O), 1615
(Ar). 1H NMR (DMSO-d6) d: 4.26 (s, 3H, OMe), 7.60 (t, 2H, H-3',
H-5', J 7.7 Hz), 7.69 (t, 1H, H-4', J 7.7 Hz), 7.90 (d, 2H, H-2', H-6',
J 7.7 Hz), 8.65 (s, 1H, H-4), 8.84 (s, 1H, H-2), 8.91 (s, 1H, H-7). 13C NMR
(DMSO-d6) d: 188.66, 138.39, 137.08, 132.26 (2C), 128.71 (2C), 128.67
(2C), 128.49, 124.59, 116.81, 116.79, 116.53, 111.22, 108.08, 107.42,
68.00. MS, m/z (%): 301 [M+] (13), 224 (25), 215 (15), 165 (26), 105 (44),
77 (100). Found (%): C, 71.52; H, 3.57; N, 13.89. Calc. for C18H11N3O2
(%): C, 71.75; H, 3.68; N, 13.95.
‡
3-Formyl-1-methoxy-2-R-1H-indole-5,6-dicarbonitriles 7a–d (general
procedure). Compound 3a–d (1 mmol) was added to a solution of POCl3
(0.279 ml, 460 mg, 3 mmol) in DMF (5 ml). The reaction mixture was
stirred at 80–90°C for 2 h. The solution was cooled and poured into
10-fold excess of ice water. The resulting precipitate was filtered, washed
with 1% NaHCO3 solution and crystallized from EtOH.
3-Formyl-1-methoxy-2-phenyl-1H-indole-5,6-dicarbonitrile 7a: yield
53%, mp 236–238°C (decomp.). IR (n/cm–1): 2227 (CºN), 1664 (C=O),
1607 (Ar). H NMR (DMSO-d6) d: 3.93 (s, 3H, OMe), 7.68 (m, 3H,
1
H-3', H-4', H-5'), 7.87 (d, 2H, H-2', H-6', J 7.4 Hz), 8.71 (s, 1H, H-4),
8.81 (s, 1H, H-7), 9.81 (s, 1H, COH). 13C NMR (DMSO-d6) d: 185.35, 149.12,
132.09, 131.31, 130.88 (2C), 129.09 (2C), 127.45, 124.49, 122.90, 116.92,
116.69, 116.56, 110.74, 108.65, 108.20, 67.19. MS, m/z (%): 301 [M+] (30),
270 [M+ –OMe] (100), 241 (13), 215 (36), 77 (11). Found (%): C, 71.62;
H, 3.76; N, 13.89. Calc. for C18H11N3O2 (%): C, 71.75; H, 3.68; N, 13.95.
For characteristics of compounds 7b–d, see Online Supplementary
Materials.
§
Crystal data for 7b. Crystals of C19H13N3O2 are triclinic, space group
–
P1: a = 8.5169(4), b = 8.6573(4) and c = 12.2902(6) Å, a = 103.3990(10)°,
b = 97.4720(10)°, g = 109.8100(10)°, V = 807.54(7) Å3, Z = 2, M = 315.32,
dcalc = 1.297 g cm–3, m = 0.087 mm–1, wR2 = 0.1286 calculated on F2hkl for
5135 independent reflections (Rint = 0.0237) with 2q < 62° [GOF = 1.010,
R = 0.0451 calculated on Fhkl for 4283 reflections with I > 2s(I)].
CCDC 1037901 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via http://www.ccdc.cam.ac.uk.
For characteristics of compounds 4a,b,d, 5a,c,d and 6b–d, see Online
Supplementary Materials.
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Mendeleev Commun., 2015, 25, 315–317
9 J. H. Wynne, Ch. T. Lloyd, S. D. Jensen, S. Boson and W. M. Stalick,
the plane of the indole cycle due evidently to sterical reasons
while the formyl substituent is coplanar to the cycle. It should
be noted that in spite of the absence of the acidic H-atoms in
molecule 7b, the O(1) atom of the formyl group forms relatively
strong hydrogen bond C(7)–H(7A)···O(1) [C···O 3.1694(13) Å,
H···O 2.25 Å, ÐCHO 162°], that links molecules into chains along
crystallographic axis a. All the other intermolecular interactions
are of ordinary van-der-Waals type.
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Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2015.07.030.
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Received: 18th December 2014; Com. 14/4535
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