A facile synthesis of 1-alkyl-7-azaisatins

Article abstract of DOI:10.3987/COM-99-8792

1-Alkyl-7-azaisatins are synthesized from the reaction of 1-alkyl-7- azaindoles with bromine in dichloromethane and subsequent oxidation with N- bromosuccinimide - dimethyl sulfoxide reagent. 1-Alkyl-7-azaindoles are readily available in high yields from

Full text of DOI:10.3987/COM-99-8792

HETEROCYCLES, Vol. 53, No. 5, 2000, pp. 1145 - 1150, Received, 25th October, 1999
A FACILE SYNTHESIS OF 1-ALKYL-7-AZAISATINS
Jiro Tatsugi,* Tong Zhiwei, Tomohiro Amano, and Yasuji Izawa
Department of Applied Chemistry, Aichi Institute of Technology, Yachigusa,
Yakusa-cho, Toyota 470-0392, Japan
Abstract - 1-Alkyl-7-azaisatins are synthesized from the reaction of 1-alkyl-7-
azaindoles with bromine in dichloromethane and subsequent oxidation with N-
bromosuccinimide - dimethyl sulfoxide reagent. 1-Alkyl-7-azaindoles are readily
available in high yields from the reaction of sodium salt of 7-azaindole with the
appropriate alkyl halides in dimethylacetamide.
In the course of our studies on the photochemical behavior of cyclic vicinal polycarbonyl compounds,1 we
needed to prepare 1-alkyl-7-azaisatins as structurally related compounds for study on the photochemical
reactions of heterocyclic vicinal polycarbonyl compounds. 7-Azaisatin was first obtained by treatment
of 7-azaoxindole (1) with nitrous acid to give its 3-oxime, followed by hydrolysis of the oxime.2 Another
route for the preparation of 7-azaisatin from 1 in five steps was reported in 1989.3 Recently, we
reported one-pot synthesis of vicinal polycarbonyl compounds via α-bromo carbonyl derivatives from
α-methylene carbonyl compounds by NBS-DMSO oxidation.4 This oxidation method with NBS-
DMSO reagent prompted us to explore an improved synthesis of 1-alkyl-7-azaisatins from 1-alkyl-7-
azaindoles . We have examined to apply this NBS-DMSO oxidation to the conversion of 3-bromo-1-
methyl-7-azaindole (3a) into 1-methyl-7-azaisatin (4a) as shown in Scheme 1. Initially, we prepared 1-
O
Br
Br
NBS
1) NaH
2) RX
2
O
CH Cl
N
N
N
N
2
2
DMSO
N
N
N
N
R
R
H
R
DMAc
3a,b,c
4a,b,c
2a,b,c
a: R=Me b: R=Et c: R=Bn
Scheme 1
1
X = Br, I

methyl-7-azaindole (2a) from the reaction of sodium salt of 1 with methyl iodide in dimethylacetamide
(DMAc). The preparation of 3a was carried out by the reaction of 2a with bromine in dichloromethane.
Finally, it was found that the oxidation of 3a with NBS in DMSO to 4a was carried out at 60 ℃ for 6 h
under ambient pressure and then at above 80 ℃ for 20 h under reduced pressure to remove the generated
hydrogen bromide. In this paper, we wish to describe this improved method for preparation of the 1-
alkyl-7-azaisatins (4) from 1.
1-Alkyl-7-azaindoles (2a, b, and c) were prepared in excellent yields by the reaction of sodium salt of 1
with appropriate alkyl halides in DMAc at room temperature. Bromination of 2 with Br2 in CH2Cl2
produced 1-alkyl-3-bromo-7-azaindoles (3a, b, and c) in high yields. The resulting bromo derivatives (3)
were subsequently oxidized to 4 with NBS-DMSO reagent. When oxidation of 3a with NBS in anhydrous
DMSO was carried out at room temperature for 12 h, a small amount of 4a was detected by GC-MS
analysis. Unfortunately, when this oxidation reaction was performed at above 80 ℃ under ambient
pressure, rapid decomposition of DMSO by the generated hydrogen bromide predominantly proceeded.5
Therefore, it was necessary in the present oxidation reaction to prevent the acid-catalyzed decomposition
of DMSO. In order to remove the generated hydrogen bromide, the oxidation with NBS in DMSO at
above 80 ℃ was carried out under reduced pressure. Thus, the desired 4a was obtained in 90% yield by
treatment of 3a with NBS in DMSO at 60 ℃ for 6 h under ambient pressure and then at above 80 ℃ for
20 h under reduced pressure to remove the generated hydrogen bromide. Similarly, 3-bromo-1-ethyl- and
3-bromo-1-benzyl-7-azaindoles (3b and 3c) were converted to the corresponding 1-alkylated 7-azaisatins
(4b and 4c) in 87 and 88% yields, respectively.
A plausible mechanism for the formation of 4 is illustrated in Scheme 2. The initial bromination of 3
Br
Br
Br
Br
Me
S
Br
Me
DMSO
H O
2
NBS
O
O
4
3
Br
N
R
N
N
DMSO
N
- Me S
N
N
2
- HBr
R
R
C
A
B
Scheme 2
would yield 2,3-dibromo derivative (A), which would react further with DMSO to yield intermediate (B).
Intermediate (B) would lead to 4 via intermediate (C). To confirm the reaction pathway to 4, the

reaction of 2,3-dibromo-1-methyl-7-azaisatin prepared by the bromination of 2a with two equivalents of
bromine used in dichloromethane with DMSO was carried out under above similar oxidation conditions
afforded 4a in excellent yield. The results indicate that the formation of 4 is considered to proceed via A.
In addition, we describe the scope and limitations of the present oxidation of certain brominated 7-
azaindoles. Although bromination of 1-acetyl- and 1-benzoyl-7-azaindoles took place readily, the
oxidation of the corresponding brominated 1-acyl-7-azaindoles did not proceed, and a deacylation reaction
took place under the present oxidation conditions.
In summary, a convenient synthesis of 1-alkyl-7-azaisatins from commercially available 7-azaindole in a
three-step sequence (alkylation, bromination, and oxidation with NBS-DMSO reagent) is described.
EXPERIMENTAL
General: Melting points were determined on a Yanagimoto hot-stage apparatus and are uncorrected. IR
1
spectra were recorded on a Nihon Bunko 7300 FT-IR spectrometer in KBr with absorptions in cm－1. H
1
and 13C NMR spectra were recorded on a Varian Gemini-200 from a solution CDCl3 of the product. H
chemical shifts are expressed as δ values (ppm) relative to TMS as an internal standard. MS spectra
and HRMS were recorded on Hitachi 80-B spectrometer. Elemental analyses were performed at the
Center of Instrumental Analysis, Meijo University, Nagoya, Japan. For column chromatography, SiO2
(nacalai tesque, 230－400 mesh) was used. Commercal dimethyl sulfoxide was purified by drying over
calcium hydride and distillation. 7-Azaindole (Aldrich), methyl iodide, ethyl iodide, benzyl bromide,
and NBS were commercially available and were used without purification.
1-Methyl-7-azaindole (2a): Sodium hydride (0.1 g, 4 mmol) free of mineral oil was added to 7-azaindole
(1) (0.35 g, 3 mmol) in dimethylacetamide (DMAc) (10 mL) under an inert atmosphere. After 30 min,
methyl iodide (0.5 g, 3.5 mmol) was added slowly as a solution in DMAc (2 mL), and the solution was
stirred at rt for 12 h to give a pale yellow solution. The reaction is quenched by careful addition of water
(20 mL) and 1-methyl-7-azaindole was extracted with dichloromethane. The dichloromethane layer was
washed with distilled water. After drying the dichloromethane layer and removal of the solvent, the
residue was chromatographed on SiO2 with dichloromethane as an eluent to give 1a (0.375 g, 95%): pale
1
yellow oil; IR (neat) 1596, 1571, 1516, 1440, 1410, 1348, 1315, 1279, 797, 773, 719 cm－1; H NMR
(CDCl3) δ: 3.86 (s, 3H), 6.42 (d, 1H, J= 3.6 Hz), 7.02 (dd, 1H, J=4.8, 7.8 Hz), 7.13 (d, J=3.6 Hz), 7.88
13
(dd, 1H, J=1.6, 7.8 Hz), 8.33 (dd, 1H, J=1.6, 4.8 Hz); C NMR (CDCl3) δ: 31.07, 99.17, 115.33,

120.42, 128.61, 128.87, 142.52, 147.54; MS m/z (%) 132 ( M+, 93), 131 (100), 103 (63), 65 (57). Anal.
Calcd for C8H8N2: C, 72.70; H, 6.10; N, 21.20. Found: C, 72.25; H, 6.22; N, 20.97.
1-Ethyl-7-azaindole (2b): Yield 92%, pale yellow oil; IR (neat) 1594, 1569, 1508, 1428, 1403, 1358,
1
1347, 1319, 1305, 1268, 1206, 797 cm－1; H NMR (CDCl3) δ: 1.45 (t, 3H, H=7.2 Hz), 4.32 (q, 2H,
J=7.2 Hz), 6.42 (d, 1H, J= 3.6 Hz), 7.02 (dd, 1H, J=4.8, 7.8 Hz), 7.19 (d, J=3.6 Hz), 7.87 (dd, 1H, J=1.6,
7.8 Hz), 8.32 (dd, 1H, J=1.6, 4.8 Hz); 13C NMR (CDCl3) δ: 15.51, 39.13, 99.22, 115.34, 120.55, 127.13,
128.55, 142.38, 146.97; MS m/z (%) 146 ( M+, 58), 131 (41), 118 (100), 91(10), 65(11). Anal. Calcd for
C9H10N2: C, 73.94; H, 6.89; N, 19.16. Found: C, 73.47; H, 7.01; N, 18.89.
1-Benzyl-7-azaindole (2c): Yield 96%, pale yellow oil; IR (neat) 1592, 1568, 1511, 1494, 1454, 1435,
1421, 1349, 1314, 1211, 800, 749, 733 cm－1; 1H NMR (CDCl3) δ: 5.50 (s, 2H), 6.47 (d, 1H, J= 3.6 Hz),
7.02 (dd, 1H, J=4.8, 7.8 Hz), 7.13 (d, J=3.6 Hz), 7.88 (dd, 1H, J=1.6, 7.8Hz), 8.33 (dd, 1H, J=1.6, 4.8
13
Hz); C NMR (CDCl3) δ: 47.86, 100.17, 115.82, 120.62, 127.46, 127.61, 127.97, 128.70, 129.04,
137.69, 142.71, 147.37; MS m/z (%) 208 (M+, 95), 207 (100), 131 (43), 103 (12), 91 (95), 66 (32). Anal.
Calcd for C14H12N2: C, 80.74; H, 5.81; N, 13.45. Found: C, 80.31; H, 5.89; N, 13.36.
3-Bromo-1-methyl-7-azaindole (3a): Bromine (0.48 g, 3.0 mmol) was added to 1-methyl-7-azaindole
(2a) (0.35 g, 2.7 mmol) in dichloromethane (10 mL). The mixture was stirred at 0 ℃ for 1 h and then rt.
for 12 h. The mixture was poured onto crushed ice (30 g) and 3-bromo-1-methyl-7-azaindole was extracted
with dichloromethane (3 × 20 mL). The combined organic layer was washed with distilled water. After
drying the organics layer and removal of the solvent, the residue was chromatographed on SiO2 with
dichloromethane as an eluent to give a pale yellow oil 3a (0.54 g, 94%); IR (neat) 1598, 1566, 1519, 1440,
1405, 1322, 1305, 1297, 947, 791, 766 cm－1; 1H NMR (CDCl3) δ: 3.86 (s, 3H), 7.35 (dd, 1H, J=5.1, 8.0
13
Hz), 7.92 (s, 1H), 8.10 (dd, 1H, J=1.4, 8.0 Hz), 8.46 (dd, 1H, J=1.4, 5.1 Hz); C NMR (CDCl3) δ:
32.59, 87.51, 116.63, 120.49, 130.75, 131.04, 140.76, 143.42; MS m/z (%) 212 (M+ + 2, 98), 210 (M+,
100), 131 (76), 102 (36), 65 (27). Anal. Calcd for C8H7N2Br: C, 45.53; H, 3.34; N, 13.27. Found:
C, 45.33; H, 3.45; N, 13.17.
3-Bromo-1-ethyl-7-azaindole (3b): Yield 91%, pale yellow oil; IR (neat) 1597, 1566, 1514, 1422, 1322,
1
1305, 1139, 933, 791, 766 cm－1; H NMR (CDCl3) δ: 1.41 (t, 3H, J=7.2 Hz), 4.28 (q, 2H, J=7.2 Hz),
13
7.07 (dd,1H, J=4.8, 8.0 Hz), 7.20 (s,1H), 7.80 (dd, 1H, J=1.6, 8.0 Hz), 8.33 (dd, 1H, J=1.6, 4.8 Hz); C
NMR (CDCl3) δ: 15.45, 45.39, 87.52, 115.98, 119.73, 126.06, 127.15, 143.50, 145.90, MS m/z (%) 226
(M+ + 2, 90), 224 (M+, 93), 196 (100), 145 (20), 116 (62), 89 (59), 65 (51). Anal. Calcd for C9H9N2Br:

C, 48.03; H, 4.03; N, 12.45. Found: C, 47.78; H, 4.10; N, 12.29.
1-Benzyl-3-bromo-7-azaindole (3c): Yield 95%, mp 56 - 58 ℃ (dichloromethane); IR (KBr) 1594,
1565, 1513, 1438, 1421, 1317, 1302, 940, 792, 767, 739, 704 cm－1; 1H NMR (CDCl3) 5.48 (s, 2H), 7.15
(dd, 1H, J=4.0, 8.0 Hz), 7.19 (s, 1H), 7.2～7.3 (m, 5H), 7.87 (dd, 1H, J=1.6, 8.0 Hz), 8.38 (dd, 1H, J=1.6,
13
4.0 Hz); C NMR (CDCl3) δ: 48.17, 88.82, 116.45, 120.20, 126.93, 127.70, 127.91, 128.06, 128.79,
136.80, 143.53, 146.08; MS m/z (%) 288 (M+ + 2, 23), 286 (M+, 25), 207 (18), 115 (6), 91 (100), 66 (18).
Anal. Calcd for C14H11N2Br: C, 58.56; H, 3.86; N, 9.76. Found: C, 58.24; H, 3.86; N, 9.59.
1-Methyl-7-azaisatin (4a): A mixture of 3-bromo-1-methyl-7-azaindole (3a) (0.50 g, 2.4 mmol), NBS
(0.45 g, 2.5 mmol) and anhydrous DMSO (20 mL) was stirred at 60 ℃ for 6 h and then above 80 ℃ for
20 h under reduced pressure. The progress of the reaction was monitored by GC and GC-MS. After
disappearance of the 3-bromo derivative, the reaction mixture was poured into water (50 mL), followed by
extracting with dichloromethane (10 mL × 3). The extract was washed with distilled water and dried
(MgSO4). After removal of the solvent, the residue was chromatographed on SiO2 with dichloromethane
as an eluent. The first fraction was evaporated to afford a mixture (0.034 g) of 2,3-dibromo-1-methyl-7-
azaindole and 3,3-dibromo-1-methyl-7-azaoxindole in 3.2% and 2.2% yields respectively. The ratio of
1
this mixture was estimated by using H-NMR, and their structures were established on the basis of
spectral data. 2,3-Dibromo-1-methyl-7-azaindole was confirmed by the comparison with the compound
which was prepared by bromination of 2a with two equivalents of bromine used in dichloromethane.
2,3-Dibromo-1-methyl-7-azaindole: yield 80%, mp 90 - 92 ℃ (CH2Cl2); IR(KBr) 1566, 1497, 1482,
1403, 1318, 1296, 947, 791, 766, 552 cm－1;1H NMR (CDCl3) δ 3.36 (s, 3H), 7.11 (dd, 1H, J=5.2, 7.8
13
Hz), 7.81 (dd, 1H, J=1.6, 7.8 Hz), 8.26 (dd, 1H, J=1.6, 5.2 Hz); C NMR δ: 26.31, 116.50, 119.70,
125.96, 128.11, 133.20, 150.13, 152.49; MS m/z (%) 292 (M＋+ 2, 70), 290 (M＋, 100), 288 (M＋- 2, 68),
211 (38), 209 (40), 130 (50). 3,3-Dibromo-1-methyl-7-azaoxindole: IR(KBr) 1739, 1607, 1464, 1104,
910, 642, 538, 500 cm－1; 1H NMR (CDCl3) δ 3.92 (s, 3H), 7.15 (dd, 1H, J=4.8, 7.4 Hz), 7.84 (dd, 1H,
J=1.6, 7.4 Hz), 8.33 (dd, 1H, J=1.6, 4.8 Hz); 13C NMR δ: 30.89, 90.80, 116.97, 120.14, 126.87, 143.76,
146.63, 169.31; MS m/z (%) 308 (M＋+ 2, 5), 306 (M＋, 10), 304 (M＋- 2, 6), 292 (5), 290 (8), 288 (6), 227
(100), 225 (98), 118 (45). The second fraction collected was evaporated and the residue was
recrystallized from dichloromethane to give 0.35 g (90%) of 1-methyl-7-azaisatin (4a). Yellow plates; mp
160 - 161℃ (CH2Cl2); IR(KBr) 1750, 1607, 1594, 1458 cm－1; 1H NMR (CDCl3) δ 3.36 (s, 3H), 7.10
(dd, 1H, J=7.2, 7.5 Hz), 7.84 (d, 1H, J=7.5 Hz), 8.47 (d, 1H, J=7.2 Hz); 13C NMR δ: 25.03, 111.95,

119.59, 132.76, 155.84, 158.31, 163.81, 181.86; MS m/z (%) 162 (M＋, 58), 134 (34), 105 (40), 75 (100);
HRMS calcd for C8H6N2O2 162.0428, found 162.0429. Anal. Calcd for C8H6N2O2: C, 59.26; H, 3.73;
N, 17.28. Found: C, 59.79; H, 3.86; N, 17.00.
1-Ethyl-7-azaisatin (4b): Yield 87%, yellow plates; mp 127 - 128 ℃ (CH2Cl2); IR(KBr), 1742, 1607,
1593, 1358 cm－1; 1H NMR (CDCl3) δ: 1.36 (t, 3H, J=7.2 Hz), 3.93 (q, 2H, J=7.2 Hz), 7.11 (dd, 1H,
13
J=7.2, 7.5 Hz), 7.85 (d, 1H, J=7.5 Hz), 8.47 (d, 1H, J=7.2 Hz); C NMR δ: 12.80, 34.12, 111.96,
119.37, 132.83, 155.64, 157.91, 163.55, 182.10; MS m/z (%) 176 (M＋, 74), 147 (10), 133 (46), 120 (100);
HRMS calcd for C9H8N2O2 176.0585, found 176.0561. Anal. Calcd for C9H8N2O2: C, 61.36; H, 4.58;
N, 15.90. Found: C, 61.58; H, 4.50; N, 15.91.
1-Benzyl-7-azaisatin (4c): Yield 88%, yellow plates; mp 187 - 188 ℃ (CH2Cl2), IR(KBr) 1742, 1603,
1592, 1443 cm－1; 1H NMR (CDCl3) δ: 5.03 (s, 2H), 7.08 (dd, 1H, J=7.2, 7.5 Hz), 7.26 - 7.52 (m, 5H),
13
7.82 (d, 1H, J=7.5 Hz), 8.46 (d, 1H, J=7.2 Hz); C NMR δ: 42.69, 112.14, 119.64, 128.08, 128.71,
128.84, 132.93, 135.41, 155.72, 158.05, 163.47, 181.83; MS m/z (%) 238 (M＋, 20), 210 (16),
181 (49), 147 (78), 119 (22), 92 (100); HRMS calcd for C14H10N2O2 238.0741, found 238.0736. Anal.
Calcd for C14H10N2O2: C, 70.58; H, 4.23; N, 11.76. Found: C, 70.30; H, 4.28; N, 11.72.
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2. H. Kägi, Helv. Chim. Acta, 1941, 24,141E.
3. J. Parrick, A. Yahya , A. S. Ijaz, and J. Yizun, J. Chem. Soc., Perkin Trans. 1, 1989, 2009.
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