Oxidative aromatic C-N bond formation: Convenient synthesis of N-amino-3-nitrile-indoles via FeBr3-mediated intramolecular cyclization

Article abstract of DOI:10.1039/c1ob05069a

A variety of functionalized N-amino-3-nitrile-indole derivatives are obtained via an intramolecular hetero-cyclization of 2-aryl-3-substituted hydrazono-alkylnitriles using FeBr₃ as a single electron oxidant. This approach allows the N-moiety on the side-chain to be annulated to the benzene ring during the final synthetic step via direct oxidative aromatic C-N bond formation.

Full text of DOI:10.1039/c1ob05069a

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PAPER
Oxidative aromatic C–N bond formation: convenient synthesis of
N-amino-3-nitrile-indoles via FeBr3-mediated intramolecular cyclization†
Zisheng Zheng, Lina Tang, Yanfeng Fan, Xiuxiang Qi, Yunfei Du* and Daisy Zhang-Negrerie*
Received 13th January 2011, Accepted 2nd March 2011
DOI: 10.1039/c1ob05069a
A variety of functionalized N-amino-3-nitrile-indole derivatives are obtained via an intramolecular
hetero-cyclization of 2-aryl-3-substituted hydrazono-alkylnitriles using FeBr3 as a single electron
oxidant. This approach allows the N-moiety on the side-chain to be annulated to the benzene ring
during the final synthetic step via direct oxidative aromatic C–N bond formation.
Introduction
For a class of nitrogen heterocyclic compounds with particular
substitution patterns, N-amino substituted indole derivatives show
significant pharmacological properties,1 which include but are
not limited to analgesic,1a anticonvulsant,1b and antioxidative1c,d
effects. In addition, some N-pyridylamino indole derivatives have
found wide applications as acetylcholinesterase inhibitors for the
treatment of Alzheimer’s disease.2
Several methods for the construction of these compounds have
been developed (Fig. 1).3,4 A literature survey shows that those
Fig. 1 General strategies for the syntheses of N-aminoindoles.
methods can be generalized into following categories: (1) the N-
aminoindole compound was synthesized using N-functionalized
aniline (e.g. nitroso aniline, phenylhydrazine, or diphenyldiazene,
etc.) as starting material (Fig. 1, Path a).3b–f (2) N-Amination
of the indole skeletons, via the hygroscopic hydroxylamine-O-
sulfonic acid (HOSA) or related reagents remains overwhelmingly
as the most applied method for constructing this interesting class
of compounds (Fig. 1, Path b).1d,2a,3i,4 (3) The N-moiety was
annulated to the benzene ring with an indispensable ortho halogen
substituent as the last synthetic step. This approach can provide
efficient syntheses of N-aminoindole derivatives via transition
metal-catalyzed intramolecular cyclization (Fig. 1, Path c).3a,3g,h
In continuation of our work on the synthesis of indole com-
pounds with different substitution patterns,5 we reported herein
that N-amino-3-nitrile-indoles 2 can be achieved via a novel
iron(III)-mediated intramolecular oxidative hetero-cyclization of
2-aryl-3-substituted hydrazonoalkylnitriles 1 (Table 2), which
contains the following features: (1) the indole ring formation
allows the N-moiety to be annulated to the benzene ring during
the last synthetic step, which enables the functionalization of the
benzenoid part with a variety of substituents at an early stage. (2)
The annulation can be directly realized via oxidative C–N bond
formation. (3) The presence of a halogen substituent at the ortho
position to the side-chain is unnecessary.
Result and discussion
We firstly subjected hydrazone substrate 1a (Table 1) to FeCl3
in CH2Cl2 to test the feasibility of the reaction. To our delight,
the reaction did produce the desired N,N-dimethylaminoindole
2a. However, the yields (10–20%) at complete consumption of 1a
were far from satisfactory (Table 1, entries 1–4). In each case, a
significant amount of unisolated polar byproducts (baseline by
TLC) were formed, which were probably derived from strong
complexation of HCl or iron(III) salts (both are Lewis acids)
with the amino moiety in the hydrazone 1a (Lewis base). Further
optimization study by using 1a as the substrate (Table 1) showed
that 1,2-dichloroethane (DCE) is a more desirable solvent than
CH2Cl2 since 2.5 equiv. of FeCl3 in DCE provided a better yield
(36%) under the conditions (Table 1, entry 5). It was also found
that increasing the dosage of FeCl3 to 3 equivalents led to an
obvious decrease in the yield (Table 1, entries 3–6). Finally, we
found that the replacement of FeCl3 with FeBr3 provided the
cyclized products in much improved yields (Table 1, entries 11–
14). Attempts to counteract the complexation via the introduction
of a milder Lewis base, such as acetic anhydride or propylene
oxide (PO) only resulted in lower yields (Table 1, entries 12–13).
Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency,
School of Pharmaceutical Science and Technology, Tianjin University, Tian-
jin 300072, P. R. China. E-mail: duyunfeier@tju.edu.cn, daisy_negrerie@
tju.edu.cn; Fax: +86-22-27404031; Tel: +86-22-27404031
† Electronic supplementary information (ESI) available: NMR data.
CCDC reference number 772745. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c1ob05069a
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Table 1 Oxidative condition screening for the cyclization of substrate 1aa
give the N-methylpyrazole compound,9 we did not assume that
replacing 1-methylhydrazine with 1,1-dimethylhydrazine would
also afford the same pyrazole compound. However, to our surprise,
the reactions gave good yields, and furthermore, both the electron-
withdrawing and electron-donating aromatic substituents could be
tolerated (eqn (1)).
Entry
Oxidant (equiv.)
Solvent
Time/h
Yieldb (%)
1
2
3
4
5
6
7
8
FeCl3 (2.0)
FeCl3 (2.2)
FeCl3 (2.5)
FeCl3 (3.0)
FeCl3 (2.5)
FeCl3 (3.0)
FeCl3 (2.5)
FeCl3 (2.5)
FeCl3 (2.5)
FeCl3 (2.5)
FeBr3 (2.5)
FeBr3 (2.5)
FeBr3 (2.5)
FeBr3 (2.5)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
DCE
CHCl3
2c
1
10
16
20
15
36
30
32
10
5
23
60
51
43
57
(1)
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1
0.5
0.5
0.5
0.5
We propose the reason that condensation of b-ketonitrile 3 with
1,1-dimethylhydrazine can hardly occur at room temperature is
due to the steric hindrance. Raising the reaction temperature had
probably brought about the intramolecular cyclization followed
by a tautomerization to give intermediate 5, which led to the
formation of the pyrazole derivative 4 with the subsequent removal
of a methyl group on the quaternary nitrogen center by a
nucleophile (e.g. H2NNMe2, EtOH or acetate anion) (Scheme 1).
THF
9
toluene
CH3CN
DCE
DCE-Ac2O
DCE-PO
DCE-CH3NO2
10
11
12
13
14
a Reaction conditions: 1a (1 mmol) and iron(III) oxidant in 10 mL of solvent
at room temperature. b Yield of isolated product after chromatography.
c The substrate was not totally consumed, even though the reaction mixture
was refluxed for 12 h.
Moreover, the introduction of polar nitromethane to enhance the
solubility of FeBr3 did not benefit the yield (Table 1, entry 14).6
Under the most optimal reaction conditions (Table 1, entry 11),
the scope and limitations of this reaction were further explored.
It is expected that each hydrazone substrate 1, prepared from a-
aryl-b-ketonitrile 3 and 1,1-dimethylhydrazine via condensation,7
should possess two isomers. However, the 1H NMR spectra
indicated that only hydrazones 1a–b, 1i and 1o exist as a mixture of
trans and cis isomers, with the trans isomers predominating for 1c–
h, 1j–n and 1p–q.5b,8 The results listed in Table 2 demonstrate that
both the electron-withdrawing and electron-donating aromatic
substituents can be tolerated and all reactions proceed to afford a
variety of N,N-dimethylaminoindoles in moderate yields (Table 2,
entries 1–14). The reaction was also shown to be compatible with
multiple substituents on the benzene ring (Table 2, entries 3–4
and 12).
Meta-substituted aromatic reactants have the possibility of pro-
ducing two regioisomeric products. However, for substrates 1f–h,
only 2f–h were obtained, respectively, by silica gel chromatography
as the major regioisomeric products.
An extension of the application of this heterocyclization
methodology is to generate N-containing heterocycles containing
aromatic systems other than benzene. An example of this applica-
tion is the synthesis of the two unknown heterocycles 2m and 2n
with yields close to 50%.
Scheme 1 Proposed mechanism for the formation of pyrazole derivatives.
Considering that the two methyl groups on the hydrazono
moiety in the substrates are electron-donating in nature, we
initiated further studies by replacing the methyl groups with an
electron-withdrawing phthalyl group. The N,N-phthalyl hydra-
zone substrates 1o–q, whether the R2 group is a chained propyl,
bulkier benzyl or phenyl group, can be conveniently prepared by
the condensation of the b-ketonitriles and N-aminophthalimide.
We postulated that the reaction difference of this condensation
reaction from the previous case should be attributed to the
decreased nucleophilicity of the N-moiety in the N,N-phthalyl
hydrazone substrates, on which it was substituted by the electron-
withdrawing phthalyl group, thus preventing the formation of
the similar byproduct 5. To our delight, N,N-phthalyl hydrazone
substrates 1o–q can also afford the desired cyclized products 2o–
q in even better yields, although higher reaction temperature
and longer reaction time were required (Table 2, entries 15–
17). Similarly, the results also demonstrate that both electron-
withdrawing and electron-donating aromatic substituents can be
well tolerated in the process. It is worth noting that the removal of
It is worth noting that our attempt to achieve the hydrazone
substrate with R2 being a bulkier benzyl or phenyl group, or
chained alkyl group was unsuccessful, since the condensation
reaction of the corresponding 1,1-dimethylhydrazine and b-
ketonitrile did not occur at room temperature, while raising
the reaction temperature only led to the formation of either an
inseparable complex mixture (R2 = Bn, Ph) or an unexpected 5-
aminopyrazole compound 4 (R2 = n-Pr). Although the reaction
of b-ketonitrile and 1-methylhydrazine has been well known to
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a
Table 2 Oxidative intramolecular hetero-cyclization of 2-aryl-3-substituted hydrazono-alkylnitriles 1 mediated by FeBr3
Entry
1
Substrate 1
Product 2
Time/h
0.5
Yieldc (%)
60
2
0.5
0.5
0.5
0.5
0.5
0.5
49
61
63
57
51
43
3
4
5
6b
7b
8b
0.5
0.5
46
47
9
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Table 2 (Contd.)
Entry
10
Substrate 1
Product 2
Time/h
0.5
Yieldc (%)
51
11
12
0.5
50
52
0.75
13
14
15
16
1
1
2
3
48
47
79
70
17
2.5
67
a Reaction conditions: 1 (2 mmol) and FeBr3 (2.5 equiv.) in 20 mL of DCE at room temperature. b Major regioisomeric product was isolated by
chromatography. c Yield of isolated product after chromatography.
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the phthalyl group in products 2o–q may provide N-unsubstituted
aminoindole compounds, which might be used for the syntheses of
other functionalized N-substituted aminoindole derivatives. For
example, the hydrazinolysis of 2o can afford the N-amino-3-nitrile
indole 2o¢ in 88% yield (eqn (2)).10
substrates, this method provides access to a wide range of N-
aminoindoles that could only be synthesized by a limited number
of methods.3,4
Experimental
1H and 13C NMR spectra were recorded on a 400 MHz BRUKER
AVANCE spectrometer at 25 ◦C. Chemical shifts values are given
in ppm and referred to the internal standard TMS: 0.00 ppm.
The peak patterns are indicated as follows: s, singlet; d, doublet;
t, triplet; q, quartet; m, multiplet; br, broad and dd, doublet
of doublets. The coupling constants J, are reported in hertz
(Hz). GC-MS was performed by direct inlet on a Shimadazu
GCMS-QP2010 Plus instrument. IR were recorded on a Bruker
Tensor 27 infrared spectrometer as KBr pellets with absorption
in cm-1. High-resolution mass spectra (HRMS) were obtained
on a Q-TOF micro (Waters) spectrometer. Melting points were
determined with a national micromelting point apparatus without
corrections. TLC plates were visualized by exposure to ultraviolet
light. 1,2-Dichloroethane wasdried by CaH2 before use, other
reagents and solvents were purchased as reagent grade and were
used without further purification. Flash column chromatography
was performed over silica gel 200–300 m and the eluent was a
mixture of EtOAc and petroleum ether, or a mixture of MeOH
and CH2Cl2.
(2)
All the structures of the N-aminoindole products are deter-
mined by detailed study of their spectroscopic data and product
2a is further confirmed through X-ray crystallographic analysis
(Fig. 2).11
Fig. 2 X-Ray crystallography of 2a.
The mechanism of this intramolecular oxidative C–N bond
formation process was postulated (Scheme 2).12 Firstly, abstraction
of the benzylic hydrogen atom from 1 by a SET (single electron
transfer) process gives the carbon-based radical 6, with resonance
structure N-radical 7. Secondly, mediated by iron(III) bromide,
a second SET process occurs to convert the N-radical 7 to the
nitrenium ion 8. Finally, nucleophilic attack on the nitrenium ion
by the benzene ring results in carbocation 9, which undergoes
rearomatization via the loss of a proton, to afford title compound
2.5b
General procedure for the preparation of 17
A mixture of b-ketonitriles (10 mmol), 1,1-dimethylhydrazine or
N-aminophthalimide (15 mmol), p-toluenesulfonic acid (1 mmol)
˚
with several 4 A molecular sieves in 100 mL of toluene was
stirred at room temperature (if N-amino phthalimide was used,
the solution was heated to reflux) under nitrogen atmosphere, and
TLC was used to monitor the reaction process. After completion
of the reaction, it was filtered and the solvent was removed under
vacuum. The residue was purified by column chromatography
using a mixture of petroleum ether and EtOAc as eluent to afford
the substrate.
3-(2,2-Dimethylhydrazono)-2-phenylbutanenitrile (1a)
General procedure was followed (4 h), white solid,
1.53 g (10.0 mmol, 76% yield, cis : trans = 2 : 3), Rf 0.52
(EtOAc/petroleum ether = 30/70), mp 66–68 ◦C; 1H NMR
(400 MHz, CDCl3): major isomer (trans) d 7.41–7.18 (m, 5H,
Harom, peaks of two isomers overlapped), 5.59 (s, 1H, CH), 2.43 (s,
6H, NCH3), 2.34 (s, 3H, CH3); minor isomer (cis) d 7.41–7.18 (m,
5H, Harom, peaks of two isomers overlapped), 5.73 (s, 1H, CH),
2.56 (s, 6H, NCH3), 2.07 (s, 3H, CH3). 13C NMR (100 MHz,
CDCl3): major isomer (trans) d 157.0, 133.1, 129.4, 128.9, 127.2,
122.3, 78.8, 48.3, 17.3; minor isomer (cis) d 158.9, 134.5, 129.6,
128.4, 126.4, 120.4, 76.9, 48.5, 15.3; IR (KBr) 2183 s, 1593vs,
1495 m, 1393 m, 1361 m, 766 m, 704 m cm-1; GC-MS: Rt 4.2 min;
m/z (EI) 201 (M+, 100%), 169 (19), 157 (52), 142 (84), 130 (37),
115 (46), 103 (13), 89 (29), 77 (16), 59 (56), 44 (81), 42 (49);
HRMS-ESI (m/z): [M + Na]+ calcd for C12H15N3Na 224.1158;
found 224.1162.
Scheme 2 Proposed mechanistic pathway.
Conclusions
In summary, we have described an efficient synthesis of N-
aminoindole compounds, which allows the N-moiety on the
side-chain to be annulated to the substituted benzene ring via
FeBr3-mediated oxidative aromatic C–N bond formation. Via a
protection and subsequent deprotection step of the hydrazone
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3-(2,2-Dimethylhydrazono)-2-o-tolylbutanenitrile (1b)
114.7, 78.2, 55.2, 48.2, 17.1; IR (KBr) 2178 s, 1601 vs, 1511 s,
1387 s, 1359 m, 1247 s, 1036 s, 832 s cm-1; GC-MS: Rt 5.1 min;
m/z (EI) 231 (M+, 100%), 202 (1), 187 (50), 172 (69), 145 (36),
132 (14), 103 (12), 85 (34), 77 (15), 59 (16), 42 (40); HRMS-
ESI (m/z): [M + Na]+ calcd for C13H17N3NaO 254.1264; found
254.1272.
General procedure was followed (4.5 h), white solid, 1.35 g
(9.7 mmol, 65% yield, cis : trans = 1 : 3), Rf 0.44 (EtOAc/petroleum
ether = 30/70), mp 52–54 ◦C; 1H NMR (400 MHz, CDCl3): major
isomer (trans) d 7.28–7.12 (m, 4H, Harom, peaks of two isomers
overlapped), 4.85 (s, 1H, CH), 2.37 (s, 6H, NCH3), 2.33 (s, 3H,
CH3), 2.29 (s, 3H, CH3); minor isomer (cis) d 7.28–7.12 (m, 4H,
Harom, peaks of two isomers overlapped), 4.70 (s, 1H, CH), 2.56
(s, 6H, NCH3), 2.35 (s, 3H, CH3), 1.81 (s, 3H, CH3). 13C NMR
(100 MHz, CDCl3): major isomer (trans) d 157.2, 138.3, 131.8,
131.0, 128.5, 126.8, 126.0, 121.6, 77.6, 48.4, 19.5, 16.6; minor
isomer (cis) d 159.1, 138.3, 133.0, 131.1, 130.3, 127.9, 126.0, 119.6,
75.5, 48.5, 19.9, 15.1; IR (KBr) 2173 s, 1604 vs, 1489 m, 1394 m,
1362 w, 766 m cm-1; GC-MS: Rt 4.2 min; m/z (EI) 215 (M+,
100%), 185 (9), 156 (49), 130 (22), 103 (12), 77 (17), 59 (59), 44
(48), 42 (29); HRMS-ESI (m/z): [M + Na]+ calcd for C13H17N3Na
238.1315; found 238.1323.
(E)-3-(2,2-Dimethylhydrazono)-2-(3-methoxyphenyl)butanenitrile
(1f)
General procedure was followed (5 h), white solid, 1.76 g
(10.0 mmol, 76% yield), Rf 0.50 (EtOAc/petroleum ether = 30/70),
mp 79–81 ◦C; 1H NMR (400 MHz, CDCl3): d 7.29 (t, J = 8.0 Hz,
1H, Harom), 6.89 (d, J = 8.0 Hz, 1H, Harom), 6.85 (s, 1H, Harom), 6.78
(d, J = 8.0 Hz, 1H, Harom), 5.71 (s, 1H, CH), 3.79 (s, 3H, OCH3),
2.44 (s, 6H, NCH3), 2.33 (s, 3H, CH3). 13C NMR (100 MHz,
CDCl3): d 160.3, 157.1, 134.5, 130.3, 122.3, 121.0, 114.3, 112.8,
78.5, 55.2, 48.3, 17.3; IR (KBr) 2180 s, 1601 vs, 1489 m, 1392 s,
1361 m, 1243 m, 1035 m cm-1; GC-MS: Rt 5.0 min; m/z (EI) 231
(M+, 100%), 207 (3), 188 (33), 171 (51), 143 (33), 128 (10), 116
(24), 103 (15), 85 (96), 77 (22), 59 (36), 44 (81), 42 (68); HRMS-
ESI (m/z): [M + Na]+ calcd for C13H17N3NaO 254.1264; found
254.1273.
(E)-2-(Benzo[d][1,3]dioxol-5-yl)-3-(2,2-dimethylhydrazono)-
butanenitrile (1c)
General procedure was followed (3 h), light yellow solid, 1.82 g
(9.8 mmol, 76% yield), Rf 0.55 (EtOAc/petroleum ether = 40/60),
mp 71–73 ◦C; 1H NMR (400 MHz, CDCl3): d 6.82 (d, J = 8.0 Hz,
1H Harom), 6.77–6.74 (m, 2H, Harom), 5.98 (s, 2H, CH2), 5.45 (s, 1H,
CH), 2.43 (s, 6H, NCH3), 2.31 (s, 3H, CH3). 13C NMR (100 MHz,
CDCl3): d 157.0, 148.4, 146.8, 126.4, 122.7, 122.2, 109.6, 109.0,
101.3, 78.5, 48.4, 17.1; IR (KBr) 2180 s, 1598 vs, 1500 s, 1392 s,
1359 m, 1218 s, 1039 s cm-1; GC-MS: Rt 5.4 min; m/z (EI) 245
(M+, 100%), 213 (8), 202 (46), 185 (22), 171 (94), 159 (39), 143
(97), 129 (17), 101 (22), 85 (53), 75 (23), 59 (20), 44 (74), 42 (50);
HRMS-ESI (m/z): [M + Na]+ calcd for C13H15N3NaO2 268.1056;
found 268.1064.
(E)-2-(3-Chlorophenyl)-3-(2,2-dimethylhydrazono)butanenitrile
(1g)
General procedure was followed (6 h), white solid, 1.99 g
(10.2 mmol, 83% yield), Rf 0.53 (EtOAc/petroleum ether = 30/70),
mp 62–63 ◦C; 1H NMR (400 MHz, CDCl3): d 7.34–7.30 (m, 2H,
Harom), 7.24–7.19 (m, 2H, Harom), 5.56 (s, 1H, CH), 2.45 (s, 6H,
NCH3), 2.35 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3): d 157.7,
135.1, 135.1, 130.5, 128.9, 127.3, 127.0, 121.9, 77.2, 48.3, 17.4; IR
(KBr) 2180 s, 1589 s, 1483 m, 1392 m, 1360 m, 781 m, 695 m cm-1;
GC-MS: Rt 4.8 min; m/z (EI) 235 (M+, 72%), 220 (9), 203 (5), 193
(28), 170 (9), 156 (51), 128 (12), 114 (24), 101 (7), 85 (39), 75 (12),
59 (48), 44 (100), 42 (58); HRMS-ESI (m/z): [M + Na]+ calcd for
C12H14ClN3Na 258.0768; found 258.0778.
(E)-2-(3,4-Dimethoxyphenyl)-3-(2,2-dimethylhydrazono)-
butanenitrile (1d)
General procedure was followed (3 h), white solid, 2.14 g
(10.0 mmol, 82% yield), Rf 0.45 (EtOAc/petroleum ether = 40/60),
mp 148–149 ◦C; 1H NMR (400 MHz, CDCl3): d 6.88 (d, J = 8.0 Hz,
1H, Harom), 6.85–6.82 (m, 2H, Harom), 5.49 (s, 1H, CH), 3.89 (s, 3H,
OCH3), 3.88 (s, 3H, OCH3), 2.43 (s, 6H, NCH3), 2.33 (s, 3H, CH3).
13C NMR (100 MHz, CDCl3): d 156.8, 149.5, 148.2, 125.3, 122.4,
121.4, 112.1, 110.7, 78.5, 55.9, 48.3, 17.1; IR (KBr) 2179 s, 1601
vs, 1515 s, 1391 s, 1367 m, 1244 s, 1028 s cm-1; GC-MS: Rt 5.7 min;
m/z (EI) 261 (M+, 92%), 246 (8), 203 (42), 186 (79), 175 (35), 159
(21), 131 (20), 104 (17), 85 (100), 77 (20), 63 (11), 44 (80), 42 (52);
HRMS-ESI (m/z): [M + Na]+ calcd for C14H19N3NaO2 284.1369;
found 284.1371.
(E)-3-(2,2-Dimethylhydrazono)-2-(3-(trifluoromethyl)phenyl)-
butanenitrile (1h)
General procedure was followed (6 h), white solid, 1.14 g
(7.0 mmol, 60% yield), Rf 0.47 (EtOAc/petroleum ether = 30/70),
mp 60–62 ◦C; 1H NMR (400 MHz, CDCl3): d 7.58 (s, 1H, Harom),
7.50 (s, 3H, Harom), 5.66 (s, 1H, CH), 2.45 (s, 6H, NCH3), 2.35 (s,
3H, CH3). 13C NMR (100 MHz, CDCl3): d 157.8, 134.3, 132.2,
131.6 (q, JC–F = 32.1 Hz), 129.8, 125.7 (d, JC–F = 3.5 Hz), 123.9
(q, JC–F = 270.6 Hz), 123.7 (d, JC–F = 3.4 Hz), 77.0, 48.0, 17.4; IR
(KBr) 2185 s, 1588 vs, 1492 w, 1390 m, 1362 w, 1329 s cm-1;
GC-MS: Rt 3.9 min; m/z (EI) 269 (M+, 100%), 239 (5), 227
(29), 223 (6), 205 (44), 185 (17), 177 (7), 156 (16), 134 (9), 115
(10), 107 (2), 85 (22), 70 (11), 59 (59), 44 (79), 42 (67); HRMS-
ESI (m/z): [M + Na]+ calcd for C13H14F3N3Na 292.1032; found
292.1041.
(E)-3-(2,2-Dimethylhydrazono)-2-(4-methoxyphenyl)butanenitrile
(1e)
General procedure was followed (4.5 h), white solid, 1.9 g
(9.5 mmol, 87◦% yield), Rf 0.56 (EtOAc/petroleum ether = 40/60),
1
mp 103–104 C; H NMR (400 MHz, CDCl3): d 7.20 (d, J =
2-(4-Bromophenyl)-3-(2,2-dimethylhydrazono)butanenitrile (1i)
8.0 Hz, 2H, Harom), 6.90 (d, J = 8.0 Hz, 2H, Harom), 5.49 (s, 1H,
CH), 3.78 (s, 3H, OCH3), 2.40 (s, 6H, NCH3), 2.30 (s, 3H, CH3).
13C NMR (100 MHz, CDCl3): d 158.7, 156.7, 130.3, 124.9, 122.4,
General procedure was followed (5.5 h), yellow solid, 2.15 g
(10.0 mmol, 77% yield, cis:trans = 3 : 4), Rf 0.52 (EtOAc/petroleum
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◦
1
ether = 30/70), mp 117–119 C; H NMR (400 MHz, CDCl3):
major isomer (trans) d 7.44 (d, J = 8.4 Hz, 2H, Harom), 7.12 (d,
J = 8.4 Hz, 2H, Harom), 5.58 (s, 1H, CH), 2.56 (s, 6H, NCH3), 2.06
(s, 3H, CH3); minor isomer (cis) d 7.51 (d, J = 8.4 Hz, 2H, Harom),
7.20 (d, J = 8.4 Hz, 2H, Harom), 5.52 (s, 1H, CH), 2.44 (s, 6H,
NCH3), 2.33 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3): major
isomer (trans) d 157.4, 132.2, 131.6, 131.1, 120.9, 120.2, 77.6, 48.5,
17.3; minor isomer (cis) d 159.1, 133.6, 132.5, 130.6, 121.9, 120.0,
75.6, 48.3, 15.3; IR (KBr) 2182 s, 1593 s, 1485 m, 1382 m, 1359
m, 826 s cm-1; GC-MS: Rt 5.2 min; m/z (EI) 279 (M+, 57%), 264
(4), 239 (22), 237 (25), 221 (3), 207 (13), 170 (18), 155 (94), 128
(18), 114 (39), 101 (8), 85 (51), 70 (11), 59 (44), 44 (100), 42 (77);
HRMS-ESI (m/z): [M + Na]+ calcd for C12H14BrN3Na 302.0263;
found 302.0274.
ESI (m/z): [M + Na]+ calcd for C15H21N3NaO3 314.1475; found
314.1477.
(E)-3-(2,2-Dimethylhydrazono)-2-(naphthalen-2-yl)butanenitrile
(1m)
General procedure was followed (8 h), light yellow solid, 1.18 g
(8.1 mmol, 58% yield), Rf 0.55 (EtOAc/petroleum ether = 30/70),
◦
1
mp 106–108 C. H NMR (400 MHz, CDCl3): d 7.86–7.76 (m,
4H, Harom), 7.50–7.24 (m, 3H, Harom), 5.72 (s, 1H, CH), 2.42 (s, 6H,
NCH3), 2.38 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3): d 157.3,
133.7, 132.3, 130.6, 129.2, 127.8, 127.8, 127.7, 126.8, 126.6, 126.3,
122.4, 78.8, 48.4, 17.4; IR (KBr) 2180 s, 1586 vs, 1503 m, 1434
m, 1398 m, 1363 w cm-1; GC-MS: Rt 6.2 min; m/z (EI) 251 (M+,
87%), 219 (8), 206 (57), 192 (73), 179 (23), 165 (61), 140 (25), 139
(37), 115 (11), 103 (3), 85 (86), 77 (8), 59 (13), 44 (100), 42 (49);
HRMS-ESI (m/z): [M + Na]+ calcd for C16H17N3Na 274.1315;
found 274.1323.
(E)-3-(2,2-Dimethylhydrazono)-2-(2-methoxyphenyl)butanenitrile
(1j)
General procedure was followed (4.5 h), white solid, 1.96 g
(11.4 mmol, 75% yield), Rf 0.47 (EtOAc/petroleum ether = 30/70),
mp 94–95 ◦C; 1H NMR (400 MHz, CDCl3): d 7.32–7.25 (m,
2H, Harom), 7.00–6.93 (m, 2H, Harom), 5.17 (s, 1H, CH), 3.85 (s,
3H, OCH3), 2.41 (s, 6H, NCH3), 2.34 (s, 3H, CH3). 13C NMR
(100 MHz, CDCl3): d 157.4, 156.5, 131.7, 129.3, 122.4, 121.4,
121.2, 111.8, 74.5, 55.5, 48.4, 17.0; IR (KBr) 2171 s, 1600 vs, 1493
m, 1397 s, 1360 m, 1260 m, 1054 m, 755 s cm-1; GC-MS: Rt 4.7 min;
m/z (EI) 231 (M+, 100%), 216 (7), 185 (14), 172 (26), 146 (30), 132
(11), 103 (13), 85 (75), 77 (16), 59 (64), 44 (94), 42 (42); HRMS-
ESI (m/z): [M + Na]+ calcd for C13H17N3NaO 254.1264; found
254.1275.
(E)-3-(2,2-Dimethylhydrazono)-2-(naphthalen-1-yl)butanenitrile
(1n)
General procedure was followed (6.5 h), light yellow liquid, 1.74 g
(11.0 mmol, 63% yield), Rf 0.42 (EtOAc/petroleum ether = 20/80);
1H NMR (400 MHz, CDCl3): d 7.94–7.91 (m, 1H, Harom), 7.87–
7.81 (m, 2H, Harom), 7.52–7.44 (m, 4H, Harom), 4.92 (s, 1H, CH), 2.47
(s, 3H, CH3), 2.28 (s, 6H, NCH3). 13C NMR (100 MHz, CDCl3): d
158.1, 134.2, 131.4, 129.5, 129.1, 128.9, 128.7, 126.7, 126.4, 126.0,
125.0, 122.2, 75.6, 48.2, 16.9; IR (KBr) 2180 s, 1585 vs, 1505 m,
1432 m, 1396 m, 1360 w cm-1; GC-MS: Rt 6.3 min; m/z (EI) 251
(M+, 93%), 219 (11), 206 (65), 192 (75), 179 (28), 165 (63), 140 (27),
139 (39), 115 (15), 103 (4), 85 (89), 77 (6), 59 (10), 44 (100), 42 (55);
HRMS-ESI (m/z): [M + Na]+ calcd for C16H17N3Na 274.1315;
found 274.1324.
(E)-2-(4-Chlorophenyl)-3-(2,2-dimethylhydrazono)butanenitrile
(1k)
General procedure was followed (6 h), white solid, 1.86 g
(10.0 mmol, 79% yield), Rf 0.53 (EtOAc/petroleum ether = 30/70),
◦
1
mp 110–112 C; H NMR (400 MHz, CDCl3): d 7.36 (d, J =
8.4 Hz, 2H, Harom), 7.25 (d, J = 8.4 Hz, 2H, Harom), 5.50 (s, 1H,
CH), 2.44 (s, 6H, NCH3), 2.34 (s, 3H, CH3). 13C NMR (100 MHz,
CDCl3): d 157.4, 132.9, 131.6, 130.3, 129.5, 121.9, 77.6, 48.4,
17.3; IR (KBr) 2181 s, 1594 vs, 1489 m, 1383 m, 1359 m, 831
m cm-1; GC-MS: Rt 4.8 min; m/z (EI) 235 (M+, 88%), 220 (9),
203 (7), 193 (28), 170 (10), 156 (93), 149 (16), 128 (14), 114
(30), 101 (8), 85 (37), 75 (10), 59 (46), 44 (100), 42 (60); HRMS-
ESI (m/z): [M + Na]+ calcd for C12H14ClN3Na 258.0768; found
258.0779.
3-(1,3-Dioxoisoindolin-2-ylimino)-2-phenylhexanenitrile (1o)
General procedure was followed (8 h), white solid,
2.38 g (10.0 mmol, 72% yield, cis : trans = 1 : 5), Rf 0.50
◦
1
(EtOAc/petroleum ether = 40/60), mp 157–159 C; H NMR
(400 MHz, CDCl3): major isomer (trans) d 7.84–7.80 (m, 2H,
Harom, peaks of two isomers overlapped), 7.79–7.76 (m, 2H, Harom),
7.44 (d, J = 7.6 Hz, 2H, Harom), 7.36–7.28 (m, 3H, Harom), 6.37 (s,
1H, CH), 2.50 (t, J = 7.8 Hz, 2H, CH2), 1.71 (sxt, J = 7.6 Hz,
2H, CH2), 1.03 (t, J = 7.4 Hz, 3H, CH3); minor isomer (cis)
d 7.96–7.94 (m, 2H, Harom), 7.84–7.80 (m, 2H, Harom, peaks of
two isomers overlapped), 7.18–7.14 (m, 3H, Harom), 6.52 (s, 1H,
CH), 2.21 (t, J = 8.0 Hz, 2H, CH2), 1.62–1.53 (sxt, J = 7.6 Hz,
2H, CH2), 0.83 (t, J = 7.4 Hz, 3H, CH3). 13C NMR (100 MHz,
CDCl3): major isomer (trans) d 165.6, 158.3, 134.9, 131.7, 129.9,
129.4, 128.8, 128.1, 124.3, 123.9,87.5, 33.1, 21.8, 13.8; minor
isomer (cis) d 165.7, 158.4, 135.1, 131.7, 129.7, 129.3, 128.7,
127.9, 124.5, 120.0, 87.6, 31.3, 21.7, 13.7; IR (KBr) 2193 s, 1793
m, 1743 vs, 1613 s, 1536 s, 1422 m cm-1; GC-MS: Rt 4.3 min; m/z
(EI) 331 (M+, 100%), 303 (40), 286 (8), 274 (20), 249 (1), 207 (5),
183 (25), 169 (2), 155 (26), 147 (3), 130 (35), 115 (15), 104 (28),
89 (9), 76 (35), 43 (5); HRMS-ESI (m/z): [M + Na]+ calcd for
C20H17N3NaO2 354.1213; found 354.1215.
(E)-3-(2,2-Dimethylhydrazono)-2-(trimethoxyphenyl)butanenitrile
(1l)
General procedure was followed (3 h), light yellow solid, 1.85 g
(7.2 mmol, 88◦% yield), Rf 0.48 (EtOAc/petroleum ether = 50/50),
1
mp 107–109 C; H NMR (400 MHz, CDCl3): d 6.53 (s, 2H,
Harom), 5.65 (s, 1H, CH), 3.85 (s, 9H, OCH3), 2.47 (s, 6H, NCH3),
2.33 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3): d 157.1, 153.8,
137.0, 128.4, 122.1, 106.0, 78.6, 60.8, 56.1, 48.3, 17.1; IR (KBr)
2181 s, 1593 vs, 1508 m, 1391 s, 1365 m, 1244 s, 1023 m cm-1;
GC-MS: Rt 6.1 min; m/z (EI) 291 (M+, 67%), 262 (3), 248
(58), 233 (80), 216 (41), 201 (22), 173 (20), 158 (10), 132 (7),
104 (7), 85 (100), 77 (10), 59 (6), 44 (77), 42 (30); HRMS-
3720 | Org. Biomol. Chem., 2011, 9, 3714–3725
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(E)-2-(4-Bromophenyl)-3-(1,3-dioxoisoindolin-2-ylimino)-3-
1-(Dimethylamino)-2,4-dimethyl-1H-indole-3-carbonitrile (2b)
phenylpropanenitrile (1p)
General procedure was followed (0.5 h), white solid, 0.23 g
General procedure was followed (10 h), light yellow solid, 2.80 g
(9.6 mmol, 66% yield), Rf 0.40 (EtOAc/petroleum ether = 30/70),
mp 69–71 ◦C; 1H NMR (400 MHz, CDCl3): d 7.82–7.80 (m, 2H,
Harom), 7.73–7.70 (m, 4H, Harom), 7.32 (d, J = 7.2 Hz, 2H, Harom),
7.24–7.22 (m, 3H, Harom), 7.23 (d, J = 8.8 Hz, 2H, Harom), 6.88 (d, J =
8.4 Hz, 2H, Harom), 6.50 (s, 1H, CH). 13C NMR (100 MHz, CDCl3):
d 165.4, 158.4, 134.8, 131.4, 131.1, 131.1, 131.0, 129.6, 129.3, 129.0,
128.8, 124.0, 123.8, 121.0, 88.9; IR (KBr) 2190 s, 1794 m, 1737
vs, 1609 m, 1517 m, 1405 m cm-1; MS (ESI+): m/z 332 (M+1,
100%); HRMS-ESI (m/z): [M + Na]+ calcd for C23H14BrN3NaO2
466.0162; found 466.0170.
(2.2 mmol, 49◦% yield), Rf 0.46 (EtOAc/petroleum ether = 20/80),
1
mp 120–122 C; H NMR (400 MHz, CDCl3): d 7.38 (d, J =
8.0 Hz, 1H, Harom), 7.12 (t, J = 8.0 Hz, 1H, Harom), 6.96 (d, J =
8.0 Hz, 1H, Harom), 3.07 (s, 6H, NCH3), 2.73 (s, 3H, CH3), 2.56 (s,
3H, CH3). 13C NMR (100 MHz, CDCl3): d 147.3, 132.8, 130.9,
124.5, 122.9, 122.6, 118.0, 109.2, 81.8, 44.8, 18.5, 11.6; IR (KBr)
2213 s, 1549 m, 1497 w, 1456 m cm-1; GC-MS: Rt 4.9 min; m/z
(EI) 213 (M+, 67%), 198 (100), 183 (7), 169 (46), 157 (22), 140 (10),
115 (14), 89 (3), 77 (10), 63 (3), 42 (11); HRMS-ESI (m/z): [M +
Na]+ calcd for C13H15N3Na 236.1158; found 236.1167.
5-(Dimethylamino)-6-methyl-5H-[1,3]dioxolo[4,5-f ]-indole-7-
carbonitrile (2c)
(E)-3-(1,3-Dioxoisoindolin-2-ylimino)-2-(4-methoxy-phenyl)-4-
phenylbutanenitrile (1q)
General procedure was followed (0.5 h), white solid, 0.30 g
(2.0 mmol, 61% yield), Rf 0.40 (EtOAc/petroleum ether = 25/75),
mp 175–176 ◦C; 1H NMR (400 MHz, CDCl3): d 7.03 (s, 1H, Harom),
7.00 (s, 1H, Harom), 6.00 (s, 2H, CH2), 3.03 (s, 6H, NCH3), 2.50 (s,
3H, CH3). 13C NMR (100 MHz, CDCl3): d 145.2, 144.8, 144.4,
127.6, 120.2, 116.4, 101.2, 98.6, 92.6, 82.8, 44.7, 11.8; IR (KBr)
2209 s, 1549 m, 1499 m, 1467 s, 1257 m, 1036 s cm-1; GC-MS: Rt
6.0 min; m/z (EI) 243 (M+, 48%), 228 (100), 213 (12), 199 (43),
187 (10), 157 (1), 143 (16), 133 (1), 114 (15), 88 (4), 63 (4), 43 (3),
42 (14); HRMS-ESI (m/z): [M + Na]+ calcd for C13H13N3NaO2
266.0900; found 266.0902.
General procedure was followed (7 h), white solid, 2.78 g
(10.6 mmol, 64% yield), Rf 0.46 (EtOAc/petroleum ether = 40/60),
mp 167–169 ◦C; 1H NMR (400 MHz, CDCl3): d 7.69–7.67 (brd,
4H, Harom), d 7.44 (d, J = 7.6 Hz, 2H, Harom), 7.13–7.12 (m, 5H,
Harom), 6.85 (d, J = 7.6 Hz, 2H, Harom), 6.38 (s, 1H, CH), 3.95 (s,
2H, CH2), 3.72 (s, 3H, OCH3). 13C NMR (100 MHz, CDCl3): d
165.1, 159.6, 155.6, 134.7, 134.6, 130.8, 129.2, 128.7, 128.3, 127.2,
123.6, 123.3, 120.1, 114.9, 89.4, 55.3, 37.6; IR (KBr) 2190 m, 1795
m, 1742 vs, 1599 s, 1513 s, 1356 s, 1255 s, 1031 m cm-1; GC-MS:
Rt 8.0 min; m/z (EI) 409 (M+, 100%), 394 (5), 376 (1), 355 (2), 332
(9), 281 (2), 262 (6), 234 (1), 205 (2), 176 (1), 165 (13), 147 (2), 115
(3), 91 (14), 76 (14), 65 (3), 43 (8); HRMS-ESI (m/z): [M + Na]+
calcd for C25H19N3NaO3 432.1319; found 432.1329.
1-(Dimethylamino)-5,6-dimethoxy-2-methyl-1H-indole-3-
carbonitrile (2d)
General procedure for the preparation of 25
General procedure was followed (0.5 h), white solid, 0.35 g
(2.1 mmol, 63% yield), Rf 0.50 (EtOAc/petroleum ether = 40/60),
mp 150–151 ◦C; 1H NMR (400 MHz, CDCl3): d 7.08 (s, 1H, Harom),
6.99 (s, 1H, Harom), 3.94 (s, 6H, OCH3), 3.07 (s, 6H, NCH3), 2.54
(s, 3H, CH3). 13C NMR (100 MHz, CDCl3): d 147.0, 146.6, 144.6,
127.1, 119.0, 116.7, 101.0, 95.1, 82.2, 56.5, 56.3, 44.8, 11.9; IR
(KBr) 2210 s, 1551 m, 1492 s, 1268 s, 1026 s cm-1; GC-MS: Rt
6.1 min; m/z (EI) 259 (M+, 45%), 244 (100), 229 (4), 215 (30), 200
(16), 187 (2), 171 (19), 145 (4), 116 (24), 103 (3), 63 (1), 42 (10);
HRMS-ESI (m/z): [M + Na]+ calcd for C14H17N3NaO2 282.1213;
found 282.1222.
To
a
stirring solution of the 2-aryl-3-dimethylhydrazo-
noalkylnitriles 1 (2.0 mmol) in DCE (20 mL) was added one
portion of the FeBr3 powder (5.0 mmol) at room temperature
under a N2 atmosphere. TLC was used to monitor the reaction
process until the total consumption of 1. To the solution was
then added H2O (20 mL), and stirring was continued for an
additional 5 min. The reaction mixture was extracted with CH2Cl2
(30 mL ¥ 3) and the organic layer was dried over anhydrous sodium
sulfate. The solvent was removed under reduced pressure and the
given residue was purified by column chromatography by using a
mixture of petroleum ether and EtOAc as eluent to afford the pure
compounds.
1-(Dimethylamino)-6-methoxy-2-methyl-1H-indole-3-carbonitrile
(2e)
1-(Dimethylamino)-2-methyl-1H-indole-3-carbonitrile (2a)
General procedure was followed (0.5 h), white solid, 0.26 g
(2.0 mmol, 57% yield), Rf 0.45 (EtOAc/petroleum ether = 25/75),
mp 104–105 ◦C; 1H NMR (400 MHz, CDCl3): d 7.53 (d, J = 8.8 Hz,
1H, Harom), 7.01 (s, 1H, Harom), 6.88 (dd, J = 2.0 Hz, J = 8.4 Hz, 1H,
Harom), 3.87 (s, 3H, OCH3), 3.07 (s, 6H, NCH3), 2.53 (s, 3H, CH3).
13C NMR (100 MHz, CDCl3): d 156.5, 146.0, 133.8, 119.9, 119.8,
116.4, 110.7, 95.9, 82.3, 55.8, 44.6, 11.9; IR (KBr) 2209 s, 1621 s,
1557 m, 1494 s, 1460 s, 1268 s, 1037 m cm-1; GC-MS: Rt 5.4 min;
m/z (EI) 229 (M+, 70%), 214 (100), 199 (8), 185 (64), 171 (18), 157
(4), 142 (36), 127 (4), 115 (13), 89 (5), 75 (5), 63 (3), 43 (5), 42 (14);
HRMS-ESI (m/z): [M + Na]+ calcd for C13H15N3NaO 252.1107;
found 252.1116.
General procedure was followed (0.5 h), white solid, 0.24 g
(2.0 mmol, 60% yield), Rf 0.52 (EtOAc/petroleum ether = 20/80),
mp 85–87 ◦C; 1H NMR (400 MHz, CDCl3): d 7.68–7.66 (m, 1H,
Harom), 7.56–7.53 (m, 1H, Harom), 7.23 (d, J = 8.0 Hz, 1H, Harom),
7.23 (dd, J = 4.0 Hz, 1H, Harom), 3.09 (s, 6H, NCH3), 2.56 (s, 3H,
CH3). 13C NMR (100 MHz, CDCl3): d 146.9, 132.8, 126.1, 122.6,
121.9, 119.5, 116.3, 111.6, 82.4, 44.9, 11.7; IR (KBr) 2211 s, 1609
w, 1552 m, 1460 s cm-1; GC-MS: Rt 4.5 min; m/z (EI) 199 (M+,
75%), 184 (100), 169 (9), 155 (47), 143 (18), 128 (29), 118 (9), 101
(20), 77 (11), 63 (5), 42 (12); HRMS-ESI (m/z): [M + Na]+ calcd
for C12H13N3Na 222.1002; found 222.1011.
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1-(Dimethylamino)-5-methoxy-2-methyl-1H-indole-3-carbonitrile
(2f)
(14), 87 (10), 75 (9), 63 (7), 44 (21), 42 (44); HRMS-ESI (m/z):
[M + Na]+ calcd for C12H12BrN3Na 300.0107; found 300.0118.
General procedure was followed (0.5 h), white solid, 0.22 g
1-(Dimethylamino)-4-methoxy-2-methyl-1H-indole-3-carbonitrile
(2j)
(1.9 mmol, 51◦% yield), Rf 0.44 (EtOAc/petroleum ether = 25/75),
1
mp 105–106 C; H NMR (400 MHz, CDCl3): d 7.42 (d, J =
8.8 Hz, 1H, Harom), 7.11 (s, 1H, Harom), 6.86 (dd, J = 8.8 Hz, 1H,
Harom), 3.86 (s, 3H, OCH3), 3.06 (s, 6H, NCH3), 2.53 (m, 3H, CH3).
13C NMR (100 MHz, CDCl3): d 155.7, 146.7, 127.4, 127.1, 116.5,
112.7, 112.4, 101.3, 82.0, 55.7, 45.0, 11.7; IR (KBr) 2213 s, 1617
m, 1581 m, 1545 m, 1467 s, 1238 s, 1025 m cm-1; GC-MS: Rt
5.5 min; m/z (EI) 229 (M+, 52%), 214 (100), 199 (9), 171 (17),
158 (5), 142 (27), 127 (3), 115 (12), 89 (4), 75 (4), 63 (3), 42 (8);
HRMS-ESI (m/z): [M + Na]+ calcd for C13H15N3NaO 252.1107;
found 252.1115.
General procedure was followed (0.5 h), white solid, 0.22 g
(1.9 mmol, 51% yield), Rf 0.52 (EtOAc/petroleum ether = 25/75),
mp 118–120 ◦C; 1H NMR (400 MHz, CDCl3): d 7.14 (d, J = 4.4 Hz,
2H, Harom), 6.61 (t, J = 4.2 Hz, 1H, Harom), 3.98 (s, 3H, OCH3), 3.08
(s, 6H, NCH3), 2.55 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3):
d 153.4, 146.3, 134.2, 123.5, 117.2, 115.6, 104.5, 101.9, 80.7, 55.6,
44.8, 11.5; IR (KBr) 2217 s, 1615 w, 1589 m, 1548 m, 1505 m, 1459
m, 1270 s, 1048 m cm-1; GC-MS: Rt 5.6 min; m/z (EI) 229 (M+,
100%), 214 (91), 199 (18), 185 (38), 171 (19), 142 (24), 116 (15),
89 (11), 63 (4), 42 (16); HRMS-ESI (m/z): [M + Na]+ calcd for
C13H15N3NaO 252.1107; found 252.1118.
5-Chloro-1-(dimethylamino)-2-methyl-1H-indole-3-carbonitrile
(2g)
6-Chloro-1-(dimethylamino)-2-methyl-1H-indole-3-carbonitrile
General procedure was followed (0.5 h), white solid, 0.20 g
(2.0 mmol, 43% yield), Rf 0.43 (EtOAc/petroleum ether = 20/80),
mp 134–136 ◦C; 1H NMR (400 MHz, CDCl3): d 7.63 (s, 1H, Harom),
7.45 (d, J = 8.8 Hz, 1H, Harom), 7.19 (dd, J = 8.8 Hz, 1H, Harom), 3.07
(s, 6H, NCH3), 2.56 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3):
d 148.1, 131.2, 127.9, 127.1, 123.0, 119.0, 115.5, 112.4, 82.4, 44.9,
11.8; IR (KBr) 2217 s, 1608 w, 1571 m, 1555 m, 1446 s cm-1; GC-
MS: Rt 5.4 min; m/z (EI) 233 (M+, 65%), 218 (100), 203 (5), 189
(29), 177 (13), 153 (14), 127 (22), 114 (7), 99 (7), 87 (5), 75 (8),
63 (4), 44 (9), 42 (19); HRMS-ESI (m/z): [M + Na]+ calcd for
C12H12ClN3Na 256.0612; found 256.0613.
(2k)
General procedure was followed (0.5 h), white solid, 0.23 g
(2.0 mmol, 50◦% yield), Rf 0.52 (EtOAc/petroleum ether = 20/80),
1
mp 158–160 C; H NMR (400 MHz, CDCl3): d 7.56 (d, J =
8.4 Hz, 1H, Harom), 7.54 (s, 1H, Harom), 7.20 (dd, J = 8.4 Hz, 1H,
Harom), 3.07 (s, 6H, NCH3), 2.56 (s, 3H, CH3). 13C NMR (100 MHz,
CDCl3): d 147.7, 133.3, 128.6, 124.4, 122.6, 120.4, 115.7, 111.4,
83.0, 44.9, 11.9; IR (KBr) 2211 s, 1610 w, 1553 m, 1469 s cm-1;
GC-MS: Rt 5.2 min; m/z (EI) 233 (M+, 67%), 218 (100), 203 (6),
189 (42), 177 (16), 153 (18), 127 (22), 114 (7), 87 (4), 75 (8), 45 (10),
42 (20); HRMS-ESI (m/z): [M + Na]+ calcd for C12H12ClN3Na
256.0612; found 256.0621.
1-(Dimethylamino)-2-methyl-5-(trifluoromethyl)-1H-indole-3-
carbonitrile (2h)
1-(Dimethylamino)-5,6,7-trimethoxy-2-methyl-1H-indole-3-
carbonitrile (2l)
General procedure was followed (0.5 h), white solid, 0.26 g
(2.1 mmol, 46% yield), Rf 0.50 (EtOAc/petroleum ether = 25/75),
mp 119–120 ◦C; 1H NMR (400 MHz, CDCl3): d 7.96 (s, 1H, Harom),
7.64 (d, J = 8.4 Hz, 1H, Harom), 7.48 (d, J = 8.8 Hz, 1H, Harom), 3.10
(s, 6H, NCH3), 2.60 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3):
General procedure was followed (0.75 h), light yellow solid, 0.32 g
(2.1 mmol, 52% yield), Rf 0.44 (EtOAc/petroleum ether = 20/80),
mp 93–95 ◦C; 1H NMR (400 MHz, CDCl3): d 6.83 (s, 1H, Harom),
4.15 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 2.93
(s, 6H, NCH3), 2.49 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3):
d 150.9, 147.8, 139.4, 139.0, 123.4, 120.3, 116.7, 95.6, 81.6, 61.1,
60.5, 56.3, 45.2, 11.9; IR (KBr) 2212 s, 1577 m, 1486 s, 1462 s,
1253 s, 1058 s cm-1; GC-MS: Rt 6.2 min; m/z (EI) 289 (M+, 37%),
274 (100), 258 (4), 244 (15), 230 (30), 200 (5), 172 (8), 149 (4), 117
(10), 89 (2), 75 (3), 58 (3), 42 (11); HRMS-ESI (m/z): [M + Na]+
calcd for C15H19N3NaO3 312.1319; found 312.1321.
d 148.9, 134.5, 125.5, 124.7 (q, JC-F = 270.1 Hz), 124.4 (q, JC-F
=
2.2 Hz), 119.5 (q, JC-F = 3.3 Hz), 117.0 (q, JC-F = 3.9 Hz), 115.2,
111.8, 83.7, 44.9, 11.9; IR (KBr) 2213 s, 1621 w, 1556 m, 1465
m cm-1; GC-MS: Rt 4.6 min; m/z (EI) 267 (M+, 79%), 266 (86),
252 (100), 225 (30), 223 (40), 203 (10), 176 (12), 157 (13), 133 (9),
112 (3), 87 (2), 75 (4), 45 (12), 42 (24); HRMS-ESI (m/z): [M +
Na]+ calcd for C13H12F3N3Na 290.0876; found 290.0886.
6-Bromo-1-(dimethylamino)-2-methyl-1H-indole-3-carbonitrile
1-(Dimethylamino)-2-methyl-1H-benzo[g]indole-3-carbonitrile
(2i)
(2m)
General procedure was followed (0.5 h), white solid, 0.26 g
(2.0 mmol, 47% yield), Rf 0.53 (EtOAc/petroleum ether = 20/80),
mp 167–168 ◦C; 1H NMR (400 MHz, CDCl3): d 7.70 (s, 1H, Harom),
7.51 (d, J = 8.4 Hz, 1H, Harom), 7.33 (d, J = 8.4 Hz, 1H, Harom), 3.07
(s, 6H, NCH3), 2.55 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3):
d 147.6, 133.7, 125.2, 124.8, 120.7, 116.2, 115.6, 114.3, 83.1, 44.9,
11.9; IR (KBr) 2210 s, 1607 w, 1550 m, 1466 s cm-1; GC-MS: Rt
5.6 min; m/z (EI) 277 (M+, 66%), 262 (100), 247 (4), 235 (46), 221
(11), 198 (14), 183 (27), 169 (4), 154 (60), 153 (15), 127 (66), 113
General procedure was followed (1 h), light yellow liquid, 0.25 g
(2.0 mmol, 48% yield), Rf 0.53 (EtOAc/petroleum ether = 30/70);
1H NMR (400 MHz, CDCl3): d 9.15 (d, J = 8.4 Hz, 1H, Harom),
7.95 (d, J = 8.0 Hz, 1H, Harom), 7.70 (d, J = 8.4 Hz, 1H, Harom),
7.65–7.60 (m, 2H, Harom), 7.52 (t, J = 7.8 Hz, 1H, Harom), 3.19 (s,
6H), 2.82 (s, 3H). 13C NMR (100 MHz, CDCl3): d 143.8, 131.8,
128.9, 128.3, 126.2, 124.6, 123.6, 122.5, 121.5, 121.5, 117.8, 116.0,
86.8, 44.5, 13.3; IR (KBr) 2211 s, 1529 m, 1451 m cm-1; GC-MS:
Rt 6.7 min; m/z (EI) 249 (M+, 46%), 234 (100), 219 (10), 205 (40),
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193 (10), 164 (7), 151 (20), 125 (4), 103 (1), 87 (2), 75 (2), 63 (2), 42
(7); HRMS-ESI (m/z): [M + Na]+ calcd for C16H15N3Na 272.1158;
found 272.1169.
2-Benzyl-1-(1,3-dioxoisoindolin-2-yl)-6-methoxy-1H-indole-3-
carbonitrile (2q)
General procedure was followed (2.5 h), white solid, 0.54 g
(2.0 mmol, 67% yield), Rf 0.42 (EtOAc/petroleum ether = 40/60),
mp 265–267 ◦C; 1H NMR (400 MHz, CDCl3): d 7.90 (brd, s, 4H,
Harom), 7.65 (d, J = 8.8 Hz, 1H, Harom), 7.05–6.96 (m, 6H, Harom), 4.19
(s, 2H, CH2), 3.74 (s, 3H, OCH3). 13C NMR (100 MHz, CDCl3): d
162.9, 159.5, 146.1, 138.2, 136.5, 135.3, 134.6, 129.2, 128.7, 127.3,
124.4, 120.7, 118.7, 116.4, 115.0, 113.0, 88.0, 55.3, 32.3; IR (KBr)
2219 s, 1799 m, 1754 vs, 1625 m, 1561 m, 1498 m, 1317 m, 1234 m,
1037 m cm-1; GC-MS: Rt 6.7 min; m/z (EI) 407 (M+, 96%), 392
(2), 364 (1), 330 (2), 287 (1), 269 (1), 261 (100), 245 (68), 229 (18),
217 (33), 190 (11), 165 (3), 147 (2), 115 (3), 91 (7), 65 (3), 42 (1);
HRMS-ESI (m/z): [M + Na]+ calcd for C25H17N3NaO3 430.1162;
found 430.1173.
3-(Dimethylamino)-2-methyl-3H-benzo[e]indole-1-carbonitrile
(2n)
General procedure was followed (1 h), light yellow liquid, 0.24 g
(2.0 mmol, 47% yield), Rf 0.45 (EtOAc/petroleum ether = 20/80);
1H NMR (400 MHz, CDCl3): d 8.81 (d, J = 8.4 Hz, 1H, Harom),
7.90 (d, J = 8.0 Hz, 1H, Harom), 7.65 (dd, J = 21.2 Hz, 2H, Harom),
7.61 (t, J = 7.6 Hz, 1H, Harom), 7.48 (t, J = 7.4 Hz, 1H, Harom), 3.190
(s, 6H), 2.815 (s, 3H). 13C NMR (100 MHz, CDCl3): d 145.0, 130.1,
129.7, 128.6, 127.3, 126.6, 124.7, 123.8, 122.5, 119.8, 118.1, 111.9,
82.9, 45.3, 11.7; IR (KBr) 2213 s, 1527 m, 1454 m cm-1; GC-MS:
Rt 6.8 min; m/z (EI) 249 (M+, 61%), 234 (100), 219 (19), 205 (60),
177 (18), 164 (8), 151 (27), 125 (5), 96 (1), 75 (3), 56 (3), 42 (41);
HRMS-ESI (m/z): [M + Na]+ calcd for C16H15N3Na 272.1158;
found 272.1166.
10
General procedure for the preparation of 2o¢
A solution of phthalimidoindole compound 2o (1 mmol) in 10 mL
of absolute EtOH was treated with vigorous stirring with 1.1 equiv.
of hydrazine monohydrate at room temperature. After the mixture
was stirred for 2 h, the precipitate was filtered and the filtrate was
concentrated under reduced pressure. The residue was partitioned
between CH2Cl2 and H2O, and the aqueous phase was extracted
with 50 mL of CH2Cl2 three times. The combined organic phase
was dried over anhydrous Na2SO4, concentrated under reduced
pressure, and chromatographed to afford the desired compound
2o¢.
1-(1,3-Dioxoisoindolin-2-yl)-2-propyl-1H-indole-3-carbonitrile
(2o)
General procedure was followed (2 h), white solid, 0.55 g
(2.1 mmol, 79% yield), Rf 0.58 (EtOAc/petroleum ether = 40/60),
◦
1
mp 132–133 C; H NMR (400 MHz, CDCl3): d 8.08–8.05 (m,
2H, Harom), 8.00–7.98 (m, 1H, Harom), 8.08–8.05 (m, 2H, Harom),
8.00–7.98 (m, 1H, Harom), 7.97–7.94 (m, 2H, Harom), 7.87–7.85 (m,
1H, Harom), 7.75 (d, J = 8.0 Hz, 1H, Harom), 7.04 (d, J = 8.0 Hz,
1H, Harom), 2.77 (t, J = 7.6 Hz, 2H, CH2), 1.73 (sxt, J = 7.6 Hz,
2H, CH2), 0.98 (t, J = 7.4 Hz, 3H, CH3). 13C NMR (100 MHz,
CDCl3): d 163.8, 149.7, 135.8, 135.0, 129.2, 125.3, 124.9, 124.8,
123.6, 119.7, 115.1, 108.8, 87.0, 27.5, 21.8, 13.7; IR (KBr) 2222 s,
1799 m, 1744 vs, 1607 w, 1553 m, 1467 m, 1396 m, 1322 s cm-1;
GC-MS: Rt 4.1 min; m/z (EI) 329 (M+, 100%), 314 (10), 300 (87),
273 (6), 254 (4), 229 (2), 207 (1), 183 (61), 182 (88), 155 (47), 154
(19), 130 (53), 114 (7), 104 (20), 90 (7), 76 (26), 63 (6), 42 (1);
HRMS-ESI (m/z): [M + Na]+ calcd for C20H15N3NaO2 352.1056;
found 352.1065.
1-Amino-2-propyl-1H-indole-3-carbonitrile (2o¢)
General procedure was followed (8 h), light yellow solid, 0.18 g
(1.0 mmol, 88% yield), Rf 0.54 (EtOAc/petroleum ether = 30/70),
mp 51–53 ◦C; 1H NMR (400 MHz, CDCl3): d 7.66 (d, J = 7.2 Hz,
1H, Harom), 7.41 (d, J = 8 Hz, 1H, Harom), 7.34–7.25 (m, 2H, Harom),
4.61 (s, 2H, NH2), 3.02 (t, J = 7.6 Hz, 2H, CH2), 1.81 (sxt, J =
7.6 Hz, 2H, CH2), 1.04 (t, J = 7.4 Hz, 3H, CH3). 13C NMR
(100 MHz, CDCl3): d 151.2, 136.3, 125.2, 123.2, 122.3, 119.1,
116.5, 108.9, 82.1, 27.3, 22.6, 13.8; IR (KBr) 3325 s, 3221 m,
2207 s, 1633 m, 1533 m, 1478 m, 1462 w cm-1; GC-MS: Rt 5.6 min;
m/z (EI) 199 (M+, 78%), 184 (53), 170 (88), 155 (100), 143 (34),
116 (26), 103 (17), 89 (8), 77 (12), 63 (6), 43 (2); HRMS-ESI (m/z):
[M + Na]+ calcd for C12H13N3Na 222.1002; found 222.1012.
6-Bromo-1-(1,3-dioxoisoindolin-2-yl)-2-phenyl-1H-indole-3-
carbonitrile (2p)
General procedure for the preparation of 49
General procedure was followed (3 h), light yellow solid, 0.62 g
(2.0 mmol, 70% yield), Rf 0.39 (EtOAc/petroleum ether = 30/70),
mp 131–133 ◦C; 1H NMR (400 MHz, CDCl3): d 7.97–7.95 (m, 2H,
Harom), 7.89–7.87 (m, 2H, Harom), 7.72 (d, J = 8.4 Hz, 1H, Harom),
7.58–7.55 (m, 2H, Harom), 7.52 (dd, J = 8.4 Hz, 1H, Harom), 7.44–7.42
(m, 3H, Harom), 7.32 (s, 1H, Harom). 13C NMR (100 MHz, CDCl3): d
163.6, 148.8, 136.8, 135.7, 130.8, 129.3, 129.0, 128.8, 127.6, 126.2,
124.8, 124.7, 121.5, 119.2, 114.4, 112.7, 88.1; IR (KBr) 2224 s,
1799 m, 1751 vs, 1612 m, 1549 w, 1467 s, 1379 m, 1301 s cm-1;
GC-MS: Rt 6.4 min; m/z (EI) 441 (M+, 100%), 398 (3), 363 (4),
334 (1), 317 (6), 297 (14), 294 (14), 268 (6), 249 (1), 230 (1), 216
(39), 201 (4), 189 (19), 181 (4), 153 (3), 130 (17), 113 (5), 104 (38),
90 (5), 76 (24), 63 (3), 45 (6); HRMS-ESI (m/z): [M + Na]+ calcd
for C23H12BrN3NaO2 464.0005; found 464.0016.
To
a stirring solution of b-ketonitriles (10 mmol), 1,1-
dimethylhydrazine (20 mmol) in anhydrous ethanol (50 mL) was
added acetic acid (1 mmol). The mixture was heated to reflux
with a condenser under nitrogen atmosphere until TLC indicated
the total consumption of the b-ketonitriles. The solvent was
removed under vacuum and the residue was purified by column
chromatography using a mixture of CH2Cl2 and MeOH as eluent
to afford the substrate.
1-Methyl-4-phenyl-3-propyl-1H-pyrazol-5-amine (4a)
General procedure was followed (8 h), light yellow solid, 1.34 g
(10.4 mmol, 60% yield), Rf 0.55 (MeOH/CH2Cl2 = 2.5/97.5), mp
139–141 C; H NMR (400 MHz, CDCl3): d 7.42–7.38 (m, 2H,
◦
1
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Harom), 7.29–7.23 (m, 3H, Harom), 3.67 (s, 3H, NCH3), 3.55 (s, 2H,
NH), 2.56 (t, J = 7.9 Hz, 2H, CH2), 1.57 (sxt, J = 7.6 Hz, 2H, CH2),
0.89 (t, J = 7.4 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3): d
149.2, 142.0, 134.0, 128.9, 128.1, 126.0, 104.9, 34.2, 29.3, 22.7,
14.2; IR (KBr) 3316 s, 3190 s, 1641 s, 1601 s, 1561 s, 1543 s, 1500
m, 1452 m cm-1; GC-MS: Rt 4.7 min; m/z (EI) 215 (M+, 55%), 200
(13), 187 (100), 169 (7), 145 (13), 115 (19), 103 (4), 89 (7), 77 (8),
57 (6), 42 (2); HRMS-ESI (m/z): [M + Na]+ calcd for C13H17N3Na
238.1315; found 238.1317.
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4-(4-Methoxyphenyl)-1-methyl-3-propyl-1H-pyrazol-5-amine (4b)
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General procedure was followed (6 h), light yellow solid, 1.66 g
(10.1 mmol, 67% yield), Rf 0.54 (MeOH/CH2Cl2 = 4/96), mp 138–
139 ◦C; 1H NMR (400 MHz, CDCl3): d 7.19 (d, J = 8.0 Hz, 2H,
Harom), 6.95 (d, J = 8.0 Hz, 2H, Harom), 3.83 (s, 3H, OCH3), 3.67
(s, 3H, NCH3), 3.49 (s, 2H, NH), 2.53 (t, J = 8.0 Hz, 2H, CH2),
1.56 (sxt, J = 7.6 Hz, 2H, CH2), 0.88 (t, J = 7.2 Hz, 3H, CH3).
13C NMR (100 MHz, CDCl3): d 158.0, 149.3, 141.8, 130.1, 126.1,
114.3, 104.7, 55.3, 34.2, 29.3, 22.7, 14.1; IR (KBr) 3320 s, 3192 s,
1640 m, 1566 s, 1540 s, 1513 s, 1464 m, 1249 s, 1019 m cm-1; GC-
MS: Rt 5.6 min; m/z (EI) 245 (M+, 74%), 230 (13), 217 (100), 202
(8), 175 (8), 158 (6), 130 (5), 107 (4), 91 (3), 77 (5), 57 (4), 42 (2);
HRMS-ESI (m/z): [M + Na]+ calcd for C14H19N3NaO 268.1420;
found 268.1429.
4-(4-Chlorophenyl)-1-methyl-3-propyl-1H-pyrazol-5-amine (4c)
General procedure was followed (10 h), white solid, 1.34 g
(10.0 mmol, 54% yield), Rf 0.48 (MeOH/CH2Cl2 = 4/96), mp
162–164 ◦C; 1H NMR (400 MHz, CDCl3): d 7.37 (d, J = 8.4 Hz,
2H, Harom), 7.21 (d, J = 8.0 Hz, 2H, Harom), 3.68 (s, 3H, NCH3), 3.55
(s, 2H, NH), 2.53 (t, J = 8.0 Hz, 2H, CH2), 1.56 (sxt, J = 7.6 Hz,
2H, CH2), 0.88 (t, J = 7.4 Hz, 3H, CH3). 13C NMR (100 MHz,
CDCl3): d 149.1, 142.0, 132.4, 131.8, 130.1, 129.1, 103.9, 34.3,
29.3, 22.6, 14.1; IR (KBr) 3316 s, 3193 s, 1642 m, 1599 w, 1569 s,
1540 s, 1494 s, 1452 m cm-1; GC-MS: Rt 5.5 min; m/z (EI) 249
(M+, 48%), 234 (11), 221 (100), 198 (4), 179 (7), 149 (7), 128 (5),
115 (14), 92 (8), 77 (3), 57 (6), 42 (4); HRMS-ESI (m/z): [M +
Na]+ calcd for C13H16ClN3Na 272.0925; found 272.0934.
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Chem., 2000, 65, 6922; (b) J. E. Johnson, A. Ghafouripour, Y. K. Haug,
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9 For recent synthesis of 5-aminopyrazole derivatives: (a) L. Q. He, P. J.
Gilligan, R. Zaczek, L. W. Fitzgerald, J. McElroy, H. S. L. Shen, J. A.
Saye, N. H. Kalin, S. Shelton, D. Christ, G. Trainor and P. Hartig,
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Acknowledgements
Y.D. acknowledges the National Natural Science Foundation of
China (#20802048) and Cultivation Foundation (B) for Young
Faculty of Tianjin University (TJU-YFF-08B68) for financial
support. X.Q. is grateful for financial support by the China
Postdoctoral Science Foundation (200904507610) for this project.
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3724 | Org. Biomol. Chem., 2011, 9, 3714–3725
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¯
11 Compound 2a: Crystallized in the triclinic space group P1 with cell
˚
˚
˚
dimensions: ◦a = 8.8268(18) A, b = 8.9764(18) A, c = 16.501(3) A,
◦
◦
3
˚
a = 99.27(3) , b = 96.72(3) , g = 118.09(3) , V = 1110.1(4) A , Dc =
1.192 g cm-3, Z = 4. CCDC: 772745†.
12 One reviewer has proposed a following alternative mechanism, which
features: (i) FeBr3 plays a role of Lewis acid to coordinate with the cyano
group, which assists the tautomerization of imine 1¢ into enamine A; (ii)
the formation of a N–Fe bond between A and FeBr3, with the release
of HBr, will give imine intermediate B; (iii) the abstraction of [FeBr]
from B will give ammonium intermedidate C, which will undergo the
same cyclization and aromatization process we have described; (iv) the
released [FeBr] species will be oxidized by FeBr3 to give FeBr2.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 3714–3725 | 3725
©