[1,4]Diazepino[6,5ꢀb]indole
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 6, June, 2003
1395
The precipitate was filtered off and washed with MeOH to give
0.19 g of compound 5d.
mixture was kept for 16 h at 20 °C and ∼40 mL of ice water was
added. The precipitate was filtered off, washed with water, and
transferred into a beaker. Isopropyl alcohol was added, and the
mixture was heated to boiling. The suspension was cooled and
the precipitate was filtered off and washed with PriOH and ether
to give 1.17 g of compound 7b.
3ꢀ[NꢀChloroacetylꢀNꢀ(4ꢀnitrophenyl)amino]indole (5e). Anꢀ
hydrous Na2CO3 (0.23 g, 2.2 mmol) and chloroacetyl chloride
(0.18 mL, 2.2 mmol) were added to a suspension of compound 6e
(0.5 g, 1.97 mmol) in 50 mL of toluene. The mixture was stirred
at reflux for 6 h, left overnight at 20 °C (for 16 h), Na2CO3 and
chloroacetyl chloride (each 2.2 mmol) were added, and refluxed
for additional 7 h. The inorganic salts were filtered off, and the
solution was clarified by adding activated carbon, concentrated
to half its volume, and cooled. The precipitate was filtered off,
washed with toluene and water, and dried to give 0.29 g of
compound 5e. 1H NMR, δ: 4.24 (s, 2 H, COCH2Cl); 7.01, 7.14
(both t, each 1 H, H(5), H(6), J5,4 = J5,6 = J6,7 = 7.8 Hz); 7.34,
7.42 (both d, each 1 H, H(4), H(7), J4,5 = J7,6 = 7.8 Hz); 7.60
and 8.15 (AA´XX´, 4 H, C6H4NO2); 7.74 (d, 1 H, H(2), J =
2.8 Hz); 11.50 (br.s, 1 H, N(1)H).
When the charge was increased 10ꢀfold, the reaction gave a
mixture of monoꢀ and bis(chloroacyl) derivatives 5e and 12
whose 1H NMR spectrum exhibited signals corresponding to
pure compound 5e (see above) and 3ꢀ[Nꢀ(4ꢀnitrophenyl)ꢀ
Nꢀchloroacetylamino]ꢀ2ꢀchloroacetylindole (12), δ: 4.25 (s,
2 H, N´ꢀCOCH2Cl); 4.99 (s, 2 H, 2ꢀCOCH2Cl); 7.18, 7.43
(both t, each 1 H, H(5), H(6), J4,5 = J5,6 = J6,7 = 7.6 Hz);
7.56, 8.17 (m, 6 H, H(4), H(7), C6H4NO2); 12.50 (br.s,
1 H, N(1)H).
3ꢀ[Nꢀ(4ꢀCyanophenyl)amino]indole (6d). А. Triethylamine
(2.7 mL, 19 mmol) was added to a suspension of 1ꢀacetylꢀ3ꢀ
[Nꢀ(4ꢀcyanophenyl)amino]indole (3d) (4.8 g, 18 mmol) in 70 mL
of MeOH and the mixture was refluxed for 1.5 h. Activated
carbon (0.5 g) was added to the resulting solution and the mixꢀ
ture was refluxed for additional 10 min. The carbon was filtered
off and the solution was cooled. The precipitate was filtered off
and washed with MeOH to give 2.3 g of compound 6d. The
mother liquor was concentrated to a minimum volume and
cooled. The precipitate was filtered off to give additionally 1.25 g
of compound 6d. Overall yield 3.55 g. 1H NMR, δ: 6.78,
7.32—7.47 (both m, 7 H, H(2), H(4), H(7), C6H4CN); 6.99,
7.08 (both t, each 1 H, H(5), H(6), J5,4 = J5,6 = J6,7 = 7.6 Hz);
8.27 (br.s, 1 H, N´(3)H); 10.92 (br.s, 1 H, N(1)H).
3ꢀ[NꢀChloroacetylꢀNꢀ(4ꢀcyanophenyl)amino]ꢀ2ꢀformylindole
(7d). А. Anhydrous Na2CO3 1.13 g (10.5 mmol) and chloroacetyl
chloride (0.84 mL, 10.5 mmol) were added to a suspension of
2ꢀformylindole 9a (2.18 g, 8.4 mmol) in 200 mL of benzene, the
mixture was stirred at reflux for 3 h. Activated carbon (0.5 g) was
added, and the mixture was refluxed for 5—10 min. The carbon
was filtered off. The solution was cooled and the precipitate was
filtered off and washed with benzene. Then the precipitate was
transferred into a beaker and covered with ∼50 mL of water, and
the mixture was stirred for 30 min. The precipitate was filtered
off and washed with water and PriOH on a filter to give 1.77 g of
compound 7d. 1H NMR, δ: 4.27 (s, 2 H, COCH2Cl); 7.20, 7.41
(both t, each 1 H, H(5), H(6), J5,4 = J5,6 = J6,7 = 7.6 Hz);
7.54—7.83 (m, 6 H, H(4), H(7), C6H4CN); 10.00 (s, 1 H,
2ꢀCHO); 12.30 (br.s, 1 H, N(1)H).
B. A solution of chloroacyl derivative 5d (0.48 g, 1.6 mmol)
was added with stirring at 15—20 °C to the Vilsmeier complex
prepared by the usual procedure from DMF (0.4 mL, 4.8 mmol)
and POCl3 (0.45 mL, 4.8 mmol). The solution was kept for 4 h
at 25—30 °C, for 2 h at 45—50 °C, and for 16 h at 20—25 °C.
The reaction solution was poured on ice water (∼50 mL). The
precipitate was filtered off, washed with water, and dried to
give 0.46 g of compound 7d containing 3ꢀ[Nꢀchloroacetylꢀ
Nꢀ(4ꢀcyanophenyl)amino]ꢀ1,2ꢀdiformylꢀindole 13b and
3ꢀ[NꢀchloroacetylꢀNꢀ(4ꢀcyanophenyl)amino]ꢀ1ꢀformylindole
14 as impurities, the product ratio being 70 : 6 : 24 (according to
1H NMR data). 1H NMR (of the mixture), δ: 4.29 (s, 2 H,
COCH2Cl), 9.99 (s, 1 H, 2ꢀCHO), 12.42 (br.s, 1 H, N(1)H)
(7d); 4.43 (s, 2 H, COCH2Cl), 8.43 (d, 1 H, H(7), J7,6 = 8.2 Hz),
9.98 (s, 1 H, 1ꢀCHO), 10.29 (s, 1 H, 2ꢀCHO) (13b); 4.39 (s,
2 H, COCH2Cl), 8.24 (d, 1 H, H(7), J7,6 = 7.6 Hz), 8.29 (s, 1 H,
H(2)), 9.40 (s, 1 H, 1ꢀCHO) (14). All other signals of comꢀ
pounds 7d, 13b, and 14 formed a complex multiplet at about
δ 7.00—8.00.
B. Triethylamine (0.28 mL, 2 mmol) was added at 25—30 °C
to a solution of N,N´ꢀdiacyl derivative 4d, the resulting soluꢀ
tion was kept for 3 days at 20—25 °C and concentrated to
dryness, and the residue was triturated with MeOH. The
precipitate was filtered off and washed with MeOH to give
0.08 g of compound 6d. The melting point of a mixed sample
consisting of compounds prepared by procedures А and B
was undepressed. The IR spectra of these compounds were
identical.
3ꢀ[NꢀChloroacetylꢀNꢀ(4ꢀRꢀphenyl)amino]ꢀ2ꢀformylindoles
(7a,c) were prepared by a known method9 but with a ratio of
compound 5a or 5c to the Vilsmeier complex equal to 1 : 1. This
gave 80% of compound 7a, m.p. 176—178 °C (cf. Ref. 9: m.p.
177—178 °C) and 65% of compound 7c, m.p. 184—185 °C
(cf. Ref. 9: m.p. 185—186 °C).
3ꢀ[NꢀChloroacetylꢀNꢀ(4ꢀnitrophenyl)amino]ꢀ2ꢀformylindole
(7e). Anhydrous Na2CO3 (2.07 g, 19.5 mmol) and chloroacetyl
chloride (1.57 mL, 19.5 mmol) were added to a suspension of
2ꢀformylindole 9b (5 g, 17.8 mmol) in 500 mL of toluene. The
mixture was refluxed for 3 h, portions (2.07 g) of sodium carꢀ
bonate and chloroacetyl chloride (1.57 mL) being added every
hour. Activated carbon (5 g) was added, the mixture was reꢀ
fluxed for 10 min, the carbon was filtered off, and the solution
was cooled. The precipitate was filtered off, washed with toluene
and water, and dried at 110 °C at a constant weight to give
6.2 g of compound 7e. 1H NMR, δ: 4.33 (s, 2 H, COCH2Cl);
7.21, 7.42 (both t, each 1 H, H(5), H(6), J5,4 = J5,6 = J6,7
=
8.2 Hz); 7.55 (d, 1 H, H(4), J4,5 = 8.2 Hz); 7.67, 8.22 (both m,
5 H, H(7), C6H4NO2); 10.00 (s, 1 H, 2ꢀCHO); 12.50 (br.s,
1 H, N(1)H).
3ꢀ[NꢀChloroacetylꢀNꢀ(4ꢀethoxyphenyl)amino]ꢀ2ꢀformylꢀ
indole (7b). A solution of N´ꢀchloroacetyl derivative 5b (1.4 g,
4.3 mmol) in 3.5 mL of DMF was added dropwise at 15—20 °C
to the Vilsmeier complex prepared by a standard procedure from
DMF (1.0 mL, 12 mmol) and POCl3 (0.44 mL, 4.8 mmol). The
3ꢀ[NꢀChloroacetylꢀNꢀ(4ꢀnitrophenyl)amino]ꢀ2ꢀformylindole
diisopropyl acetal (16b). Activated carbon (0.1 g) was added to a
solution of 2ꢀformylindole 7e (0.6 g, 1.7 mmol) in 40 mL of
PriOH, the mixture was refluxed for 10 min, filtered, cooled,
and kept for 24 h in a refrigerator (7 °C). The precipitate was