Temperature-dependent product selectivity in the Vilsmeier-Haack reaction on bis(phenylhydrazones) of bis(aroylmethyl) sulfides (=1,1'-[thiobis(methylene) ]bis[arylmethanone] bis(2-phenylhydrazones)): Synthesis of 3-aroylindoles (=aryl(1H-indol-3-yl)methanones)

Article abstract of DOI:10.1002/hlca.201200198

The bis(phenylhydrazone) of substituted diphenacyl sulfides (=1,1'-[thiobis(methylene)]bis[arylmethanone] bis(2-phenylhydrazones)) 1 underwent a tandem sequence of reactions upon treatment with Vilsmeier reagent, ultimately yielding 3-aroylindoles (=aryl(1H-indol-3-yl)methanones) 3 (Scheme 1 and Table 1). The reaction seems to be product selective depending upon the reaction temperature. Copyright

Full text of DOI:10.1002/hlca.201200198

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Helvetica Chimica Acta – Vol. 96 (2013)
Temperature-Dependent Product Selectivity in the VilsmeierꢀHaack
Reaction on Bis(phenylhydrazones) of Bis(aroylmethyl) Sulfides (¼1,1’-
[
Thiobis(methylene)]bis[arylmethanone] Bis(2-phenylhydrazones)):
Synthesis of 3-Aroylindoles (¼Aryl(1H-indol-3-yl)methanones)
by Nidhin Paul and Shanmugam Muthusubramanian*
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai-625021,
Tamil Nadu, India
(
phone/fax: þ 91-452-2459845; e-mail: muthumanian2001@yahoo.com)
The bis(phenylhydrazone) of substituted diphenacyl sulfides (¼1,1’-[thiobis(methylene)]bis[aryl-
methanone] bis(2-phenylhydrazones)) 1 underwent a tandem sequence of reactions upon treatment with
Vilsmeier reagent, ultimately yielding 3-aroylindoles (¼aryl(1H-indol-3-yl)methanones) 3 (Scheme 1
and Table 1). The reaction seems to be product selective depending upon the reaction temperature.
Introduction. – Since its discovery in 1927, the Vilsmeier (or VilsmeierꢀHaack)
reaction has been developed into a powerful synthetic tool, and it continues to attract
considerable attention [1]. Even though initially used for the introduction of a formyl
group in activated aromatic and heteroaromatic compounds, this reaction has also
found increasing application in formylating active methylene groups.
Results and Discussion. – In a recent publication, we have explored the possibility
of using the VilsmeierꢀHaack reaction in preparing different benzo[b]thiophenes [2]
from diphenacyl sulfides (¼1,1’-[thiobis(methylene)]bis[phenylmethanones]). With
this background, we now applied the Vilsmeier reaction to bis(phenylhydrazone) 1 of
diphenacyl sulfides (Scheme 1) with the expectation of getting S-linked bis[1H-
pyrazoles] 2. The starting materials were prepared by a known procedure [3]. Then, to
an ice-cold solution of bis(phenylhydrazone) 1 in DMF, POCl was added, and after
3
30 min, the temperature was raised to 808 and kept at that temperature for 2 h
(
Scheme 1). On completion of the reaction, 3-substituted indoles, i.e., aryl (1H-indol-3-
yl)methanones 3, and 1,3-diaryl-1H-pyrazole-4-carboxaldehydes 4 were obtained as the
products (Table 1). It was noticed that the temperature has a prominent effect on the
product selectivity. The formation of 3 was observed at higher temperature. On
keeping the reaction mixture for 24 h at room temperature without increasing the
temperature, only 4 was obtained (Table 1). The formation of 1H-pyrazolecarbox-
aldehydes 4 by the VilsmeierꢀHaack reaction of simple acetophenone arylhydrazones
has already been reported [4].
A mechanism for the formation of the 3-aroylindoles 3 and pyrazoles 4 from 1 is
proposed in Scheme 2. Monoformylation of 1a leads to compound 5 with concomitant
removal of the S-compound 6. Phenylhydrazone 5 rearranges to aminoaldehyde 7
ꢀ
2013 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 96 (2013)
453
Scheme 1. Synthesis of 3-Aroylindoles 3 and Pyrazoles 4. For R, see Table 1.
Table 1. Yield of 3 and 4 at Different Temperatures
a
b
b
R
Yield [%] ) (80 – 838)
Yield [%] ) (59 – 638)
Yield [%] ) (258)
3
4
3
4
3
4
a
b
c
d
e
f
H
Me
Cl
Br
MeO
Ph
74
75
78
77
79
73
12
15
9
14
10
15
44
40
37
42
41
39
41
48
49
43
45
44
0
0
0
0
0
0
77
81
68
72
79
75
a) Yield after purification by column chromatography. ) Yield determined by H-NMR spectroscopy of
b
1
the crude product mixture.
which, on further tautomerization and condensation, yields 3a. The expected Fischer
indole cyclization of 5 does not occur. The second formylation of phenylhydrazone 5
results in pyrazole-4-carboxaldehyde 4a.
When the reaction was conducted at higher temperature, before the second
formylation takes place on 5, enolization followed by the 3,3-sigmatropic rearrange-
ment occurs resulting in 7. Again 5 could have undergone a Fischer indole-type reaction
to give indole 8, but once 9 is formed, the enolization is preferred at the formyl rather
than at the C¼NH group, thus leading the cyclization the other way. The formation of
the oxothial corresponding to 6 from diphenacyl sulfide has been proposed in a
different reaction studied by us [5].
Acetophenone phenylhydrazone can also act as precursor for 3-benzoylindole 3a by
the mechanism shown in Scheme 2. However, indoles 3 have not been isolated earlier
from this source [4]. To ascertain this fact, in a separate experiment, the
VilsmeierꢀHaack reaction of simple acetophenone phenylhydrazone 10 was conducted

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Helvetica Chimica Acta – Vol. 96 (2013)
Scheme 2. Mechanism of Formation of 3-Aroylindoles 3 and Pyrazole 4
with a slight variation from the reported procedure [4], i.e., 10 was subjected to the
Vilsmeier reaction as described for 1. NMR Analysis of the crude product revealed the
formation of 55% of 1H-pyrazole-4-carbaldehyde 4a along with 10% of 3-benzoyl-
indole 3a (Scheme 3).
Scheme 3. Formation of 3-Benzoylindole 3a from 10
The structure of indole 3c (R ¼ Cl) was confirmed by NMR, mass, and crystal
1
analysis and was in agreement with the reported values [6]. In the H-NMR spectrum
of 3c, the NH group appears as a broad s at d(H) 12.12 and HꢀC(2) as another broad s
13
at d(H) 7.96. In the C-NMR spectrum, the C-atom of the C¼O group resonates at
1
13
d(C) 188.2. The complete assignment of the H- and C-NMR signals along with the
þ
HMBC data are shown in Fig. 1. The mass spectrum of 3a (m/z 220.0768, [M ꢀ 1] ;
calc. 220.0841) was also in agreement with the proposed structure. The structure of the
3-aroylindoles 3 was finally confirmed by a single-crystal X-ray analysis of 3c (Fig. 2).
In the NMR spectra of 1H-pyrazole-4-carboxaldehyde 4e, the formyl H-atom appears
as a s at d(H) 10.02 and the formyl C-atom at d(C) 185.1; the H-atom of the pyrazole
ring gives rise to a s at d(H) 8.51.

Helvetica Chimica Acta – Vol. 96 (2013)
455
Fig. 1. HMBCs (H ! C) and NMR data of 3c
Fig. 2. ORTEP Diagram of 3c. Arbitrary atom numbering.
Conclusions. – We optimized a method for the preparation of 3-aroylindoles
¼aryl(1H-indol-3-yl)methanones) through an unusual VilsmeierꢀHaack pathway. The
(
remarkable product selectivity based on the reaction temperature is worth mentioning.
The authors thank DST, New Delhi, for funds under the IRHPA program towards high-resolution
NMR spectroscopy. Dr. N. Srinivasan, Thiagarajar College, Madurai, India, and Prof. J. C. Men e´ ndez,
Departamento de Quꢂmica Org a´ nica y Farmac e´ utica, Universidad Complutense de Madrid, Spain, are
acknowledged for the X-ray diffraction and mass analyses, respectively. Financial support from UGC,
New Delhi, to N.P. is gratefully acknowledged.
Experimental Part
General. TLC: silica gel G plates (SiO
in open capillary tubes; uncorrected. H-, C-, and 2D-NMR Spectra: BrukerAvance 300 MHz NMR
2
13
; Merck); petroleum ether (60 – 808)/AcOEt as eluant. M.p.:
1
instrument; d in ppm rel. to Me Si as internal standard, J in Hz. Elemental analyses: PerkinꢀElmer-2400-
4
II CHNS elemental analyzer.
Aryl(1H-indol-3-yl)methanones 3 and 1,3-Diaryl-1H-pyrazole-4-carboxaldehydes 4: General Proce-
dure. Bis(aroylmethyl)sulfide bis(phenylhydrazone) 1 (1 mmol) is dissolved in DMF (5 ml), and the
soln. is cooled to 08. To the ice-cold soln., POCl (2 mmol) is added dropwise, and the mixture is stirred
3
for 30 min. The temp. is gradually increased to 808 and maintained for 2 h. After completion of the
reaction (TLC), the mixture is cooled to r.t., and poured into ice-cold H O. The obtained solid is
2
separated and purified by CC (SiO , petroleum ether (60 – 808)/AcOEt 5 :1): 3 and 4 (see Table 1).
2

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Helvetica Chimica Acta – Vol. 96 (2013)
1
(
1H-Indol-3-yl)phenylmethanone (3a): Colorless solid. M.p. 2428 ([6a]: 242 – 2458). H-NMR: 7.23 –
7
.31 (m, 2 arom. H); 7.55 – 7.64 (m, 4 arom. H); 7.81 (d, J ¼ 7.2, 2 arom. H); 7.95 (d, J ¼ 2.7, 1 arom. H); 8.28
13
(
1
dd, J ¼ 6.3, 1.8, 1 arom. H); 12.13 (s, NH). C-NMR: 111.6; 114.5; 120.8; 121.2; 122.5; 125.7; 127.7 (2 C);
30.3; 135.0; 136.1; 140.0; 189.3.
1H-Indol-3-yl)(4-methylphenyl)methanone (3b): Colorless solid. M.p. 1808 ([7]: 179 – 1808).
(
1
H-NMR: 2.41 (s, Me); 7.24 – 7.28 (m, 2 arom. H); 7.35 (d, J ¼ 8.1, 2 arom. H); 7.54 (dd, J ¼ 6.6, 1.8, 1
arom. H); 7.72 (d, J ¼ 8.1, 2 arom. H); 7.95 (d, J ¼ 3.0, 1 arom. H); 8.26 (dd, J ¼ 6.6, 1.8, 1 arom. H); 12.07
13
(s, NH). C-NMR: 20.4; 111.5; 114.6; 120.8; 121.1; 122.4; 125.7; 127.9; 128.3; 134.6; 136.1; 137.3; 140.4;
1
89.1.
4-Chlorophenyl)(1H-indol-3-yl)methanone (3c): Colorless solid. M.p. 2408 ([6c]: 239 – 2428).
H-NMR: 7.19 – 7.27 (m, 2 arom. H); 7.51 (dd, J ¼ 7.5, 2.1, 1 arom. H); 7.57 (d, J ¼ 8.4, 2 arom. H); 7.79
(
1
13
(
1
d, J ¼ 8.4, 2 arom. H); 7.96 (br. s, 1 arom. H); 8.24 (dd, J ¼ 7.5, 2.1, 1 arom. H); 12.12 (s, NH). C-NMR:
11.8; 114.3; 120.9; 121.5; 122.7; 125.7; 128.0; 129.8; 135.3; 135.5; 136.2; 138.6; 188.2.
4-Bromophenyl)(1H-indol-3-yl)methanone (3d): Colorless solid. M.p. 2378. 1H-NMR: 7.21 – 7.29
(
(
m, 2 arom. H); 7.52 (dd, J ¼ 6.9, 1.8, 1 arom. H); 7.67 – 7.87 (m, 4 arom. H); 7.97 (d, J ¼ 3.3, 1 arom. H);
13
8
1
5
.24 (d, J ¼ 6.9, 1.8, 1 arom. H); 12.18 (s, NH). C-NMR: 111.6; 114.2; 120.8; 121.3; 122.6; 124.0; 125.5;
29.7; 130.7; 135.2; 136.1; 138.9; 188.1. Anal. Calc. for C H BrNO: C 60.02, H 3.36, N 4.67; found: C
15
10
9.98, H 3.33, N 4.64.
1H-Indol-3-yl)(4-methoxyphenyl)methanone (3e): Colorless solid. M.p. 2028 ([6b]: 203 – 2058).
(
1
H-NMR: 3.83 (s, MeO); 7.05 (d, J ¼ 8.7, 2 arom. H); 7.19 – 7.25 (m, 2 arom. H); 7.49 (dd, J ¼ 6.9, 1.8, 1
arom. H); 7.79 (d, J ¼ 8.7, 2 arom. H); 7.93 (br. s, 1 arom. H); 8.20 (dd, J ¼ 6.9, 1.8, 1 arom. H); 12.01 (s,
13
NH). C-NMR: 55.7; 112.5; 114.0; 115.4; 121.8; 122.0; 123.3; 126.8; 130.9; 133.3; 135.2; 136.9; 162.1;
1
88.2.
[1,1’-Biphenyl]-4-yl)(1H-indol-3-yl)methanone (3f): Colorless solid. M.p. 2218. H-NMR: 7.22 – 7.26
m, 2 arom. H); 7.40 (t, J ¼ 7.2, 1 arom. H); 7.47 – 7.52 (m, 3 arom. H); 7.73 (d, J ¼ 7.8, 2 arom. H); 7.80 (d,
J ¼ 8.4, 2 arom. H); 7.86 (d, J ¼ 8.4, 2 arom. H); 8.00 (d, J ¼ 3.0, 1 arom. H); 8.07 (dd, J ¼ 6.6, 1.8, 1 arom.
1
(
(
13
H); 12.09 (s, NH). C-NMR: 111.6; 114.5; 120.8; 121.2; 122.5; 125.7; 125.9; 126.2; 127.4; 128.4; 128.5;
1
34.9; 136.1; 138.7; 138.8; 142.0; 188.8. Anal. calc. for C H NO: C 84.82, H 5.08, N 4.71; found: C 84.79,
21 15
H 5.05, N 4.67.
1
1,3-Diphenyl-1H-pyrazole-4-carboxaldehyde (4a): Colorless solid. M.p. 1388 ([4a]: 1408). H-NMR:
7
.36 (t, J ¼ 7.2, 1 arom. H); 7.45 – 7.52 (m, 5 arom. H); 7.77 (d, J ¼ 7.8, 2 arom. H); 7.82 (dd, J ¼ 7.8, 1.5, 2
13
arom. H); 8.55 (s, 1 arom. H); 10.03 (s, CHO). C-NMR: 119.6; 122.4; 127.8; 128.6; 128.9; 129.2; 129.5;
1
31.0; 131.3; 138.9; 154.6; 185.0.
3
-(4-Methylphenyl)-1-phenyl-1H-pyrazole-4-carboxaldehyde (4b): Colorless solid. M.p. 1218 ([4d]:
1
1
20 – 1228). H-NMR: 2.42 (s, Me); 7.52 (d, J ¼ 8.1, 2 arom. H); 7.38 (t, J ¼ 7.5, 1 arom. H); 7.49 (t, J ¼ 7.5, 2
arom. H); 7.71 (d, J ¼ 8.1, 2 arom. H); 7.78 (d, J ¼ 8.1, 2 arom. H); 8.52 (s, 1 arom. H); 10.04 (s, CHO).
13
C-NMR: 21.3; 119.7; 122.4; 127.8; 128.4; 128.8; 129.4; 129.6; 130.9; 139.0; 139.3; 154.8; 185.2.
3
-(4-Chlorophenyl)-1-phenyl-1H-pyrazole-4-carboxaldehyde (4c): Colorless solid. M.p. 1118 ([4d]:
1
1
7
10 – 1138). H-NMR: 7.37 – 7.42 (m, 1 arom. H); 7.51 (d, J ¼ 8.4, 2 arom. H); 7.64 (d, J ¼ 8.4, 2 arom. H);
13
.70 – 7.76 (m, 4 arom. H); 8.51 (s, 1 arom. H); 10.04 (s, CHO). C-NMR: 119.5; 122.4; 123.9; 128.0;
1
29.6; 130.4; 130.9; 132.3; 132.8; 138.8; 153.2; 184.6.
-(4-Bromophenyl)-1-phenyl-1H-pyrazole-4-carboxaldehyde (4d): Colorless solid. M.p. 1408.
H-NMR: 7.39 (t, J ¼ 7.5, 1 arom. H); 7.52 (t, J ¼ 7.5, 2 arom. H); 7.62 (d, J ¼ 8.7, 2 arom. H); 7.74 – 7.79
3
1
13
(
m, 4 arom. H); 8.53 (s, 1 arom. H); 10.03 (s, CHO). C-NMR: 119.7; 122.5; 123.7; 128.1; 129.7; 130.3;
1
30.4; 131.8; 132.0; 138.9; 153.1; 184.3. Anal. calc. for C H BrN O: C 58.74, H 3.39, N 8.56; found C
16 11 2
5
8.71, H 3.36, N 8.52.
3
-(4-Methoxyphenyl)-1-phenyl-1H-pyrazole-4-carboxaldehyde (4e): Colorless solid. M.p. 1028 ([4d]:
1
1
2
1
00 – 1028). H-NMR: 3.86 (s, MeO); 7.02 (d, J ¼ 8.7, 2 arom. H); 7.37 (t, J ¼ 7.2, 1 arom. H); 7.49 (t, J ¼ 7.2,
13
arom. H); 7.76 – 7.81 (m, 4 arom. H); 8.51 (s, 1 arom. H); 10.02 (s, CHO). C-NMR: 55.3; 114.1; 119.6;
22.3; 123.8; 127.8; 129.6; 130.2; 131.2; 139.0; 154.4; 160.5; 185.1.
3
-([1,1’-Biphenyl]-4-yl)-1-phenyl-1H-pyrazole-4-carboxaldehyde (4f): Colorless solid. M.p. 1978.
H-NMR: 7.36 – 7.42 (m, 2 arom. H); 7.45 – 7.54 (m, 4 arom. H); 7.66 (d, J ¼ 7.5, 2 arom. H); 7.73 (d, J ¼ 8.4,
arom. H); 7.81 (d, J ¼ 7.5, 2 arom. H); 7.93 (d, J ¼ 8.4, 2 arom. H); 8.56 (s, 1 arom. H); 10.10 (s, CHO).
1
2

Helvetica Chimica Acta – Vol. 96 (2013)
457
13C-NMR: 119.7; 122.6; 127.1; 127.4; 127.6; 128.0; 128.9; 129.3; 130.0; 130.2; 131.3; 139.0; 140.4; 142.1;
1
54.3; 185.0. Anal. calc. for C H N O: C 81.46, H 4.97, N 8.64; found: C 81.42, H 4.94, N 8.61.
22 16 2
1
Crystallographic Investigations ). Single crystals of 3c for crystallographic studies were prepared in
DMF. Crystallographic data for 3c is given in Table 2.
Table 2. Crystal Data of 3c
C H ClNO Absorption coefficient [mmꢀ1]
Empirical formula
Mr
0.286
528
15
10
255.70
F(000)
Temperature [K]
Wavelength [ꢃ]
Crystal system
Space group
Unit-cell dimensions:
a [ꢃ]
b [ꢃ]
c [ꢃ]
a [8]
b [8]
295(2)
0.71073
monoclinic
Crystal size [mm]
q Range for data collection [8] 2.79 to 26.56
Index ranges
0.20 ꢁ 0.17 ꢁ 0.13
ꢀ 17 ꢂ h ꢂ 17, ꢀ 8 ꢂ k ꢂ 8,
P2 /c
1
ꢀ 13 ꢂ l ꢂ 17
Reflections collected
13134
14.1025(6)
7.1469(3)
14.3196(6)
90.000
118.234(2)
90.000
Independent reflections
Completeness to q ¼ 60.008
Max. and min. transmission
Data, restraints, parameters
Goodness-of-fit on F
Final R indices (I > 2s(I))
R Indices (all data)
2637 (Rint ¼ 0.0228)
99.8%
0.94 and 0.96
2637, 0, 163
1.018
2
g [8]
Volume [ꢃ ]
R ¼ 0.0398, wR ¼ 0.1267
1
2
3
1271.54(9)
4
R ¼ 0.0544, wR ¼ 0.1413
1
2
Z
Largest diff. peak and hole
0.295 and ꢀ 0.396
3
ꢀ3
Density (calc.) [Mg/m ] 1.336
[e ꢃ
]
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[
[
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Received April 17, 2012
1)
CCDC-824833 contains the supplementary crystallographic data (excluding structure factors) for
c. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/data_request/cif.
3