European Journal of Organic Chemistry
10.1002/ejoc.201600933
FULL PAPER
O-4-Chloro-2-cyano-3-(2-cyanopropan-2-yl)phenyl
N,N-
(t, J = 7.1 Hz, 3H) ppm. 13C NMR (100.6 MHz, DMSO-d6): δ = 161.6 (dd,
J = 7.8, 3.2 Hz, C), 150.3 (dd, J = 6.7, 2.0 Hz, C), 145.9 (dd, J = 243.5,
14.7 Hz, C), 142.9 (dd, J = 236.7, 12.9 Hz, C), 117.0 (d, J = 18.1, Hz,
CH), 115.2 (dd, J = 18.0, 3.1 Hz, C), 111.2 (dd, J = 10.3, 7.1 Hz, C), 42.5
(CH2), 38.7 (CH2), 14.0 (CH3), 12.8 (CH3) ppm. LRMS (EI): m/z (%) =
229 (M, 60), 210 (37), 157 (100), 58 (73). HRMS (EI): calcd. for
C11H13F2NO2 [M]+ 229.0914; found 229.0921.
diethylcarbamate (11b): The reaction of O-3,4-dichlorophenyl N,N-
diethylcarbamate (2b) (131 mg, 0.5 mmol) following the general
procedure yielded 11b as a white solid (31% yield); m.p. 102–104 ºC. 1H
NMR (300 MHz, CDCl3): δ = 7.66 (d, J = 8.9 Hz, 1H), 7.34 (d, J = 8.8 Hz,
1H), 3.50 (q, J = 7.1 Hz, 2H), 3.38 (q, J = 7.1 Hz, 2H), 2.10 (s, 6H), 1.28
(t, J = 7.1 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (75.4 MHz,
CDCl3): δ = 154.9 (C), 152.1 (C), 139.5 (C), 136.8 (CH), 131.5 (C), 124.2
(CH), 122.4 (C), 114.0 (C), 106.8 (C), 42.8 (CH2), 42.3 (CH2), 37.7 (C),
28.5 (2 CH3), 14.1 (CH3), 13.2 (CH3) ppm. LRMS (EI): m/z (%) = 321
(M2, 1), 319 (M, 3), 100 (100), 72 (30). HRMS (EI): calcd. for
C16H18ClN3O2 [M]+ 319.1088; found 319.1101.
N,N-Diethyl-3,6-difluoro-2-hydroxybenzamide (13c): The reaction of
O-2,6-difluorophenyl N,N-diethylcarbamate (1c) (115 mg, 0.5 mmol)
following the general procedure yielded 13c as a white solid (81% yield);
m.p. 153–155 ºC. 1H NMR (400 MHz, DMSO-d6): δ = 10.44 (br s, 1H),
7.25–7.17 (m, 1H), 6.74–6.67 (m, 1H), 3.42 (q, J = 7.1 Hz, 2H), 3.10 (q, J
= 7.1 Hz, 2H), 1.10 (t, J = 7.1 Hz, 3H), 0.97 (t, J = 7.1 Hz, 3H) ppm. 13C
NMR (100.6 MHz, DMSO-d6): δ = 161.7 (s, C), 154.2 (d, J = 239.0, C),
148.0 (d, J = 236.2, C), 141.9 (dd, J = 17.6, 9.1 Hz, C), 116.6 (d, J = 2.5,
2.4 Hz, C), 116.0 (dd, J = 21.2, 10.5 Hz, CH), 105.8 (dd, J = 24.4, 7.0 Hz,
CH), 42.5 (CH2), 38.7 (CH2), 14.0 (CH3), 12.9 (CH3) ppm. LRMS (EI): m/z
(%) = 229 (M, 31), 210 (21), 157 (100), 58 (58). HRMS (EI): calcd. for
C11H13F2NO2 [M]+ 229.0914; found 229.0917.
O-5-Chloro-2-cyano-3-(2-cyanopropan-2-yl)phenyl
diethylcarbamate (11c): The reaction of O-3,5-dichlorophenyl N,N-
diethylcarbamate (2c) (131 mg, 0.5 mmol) following the general
N,N-
procedure yielded 11c as
a yellow oil (58% yield); Rf = 0.43
(hexane/EtOAc, 4:1). 1H NMR (300 MHz, CDCl3): δ = 7.44 (q, J = 1.7 Hz,
2H), 3.47 (q, J = 7.1 Hz, 2H), 3.38 (q, J = 7.2 Hz, 2H), 1.71 (s, 6H), 1.29
(t, J = 7.1 Hz, 3H), 1.21 (t, J = 7.2 Hz, 3H) ppm. 13C NMR (75.4 MHz,
CDCl3): δ = 154.8 (C), 151.6 (C), 148.2 (C), 137.5 (C), 123.1 (CH), 122.5
(C), 118.8 (CH), 112.3 (C), 107.7 (C), 42.7 (CH2), 42.3 (CH2), 37.4 (C),
28.5 (2 CH3), 14.0 (CH3), 13.0 (CH3) ppm. LRMS (EI): m/z (%) = 321
(M2, 1), 319 (M, 3), 100 (100), 72 (33). HRMS (EI): calcd. for
C16H18ClN3O2 [M]+ 319.1088; found 319.1095.
3-Chloro-N,N-diethyl-2-fluoro-6-hydroxybenzamide
(13d):
The
reaction of O-4-chloro-3-fluorophenyl N,N-diethylcarbamate (1d) (123 mg,
0.5 mmol) following the general procedure yielded 13d as a white solid
1
(85% yield); m.p. 122–124 ºC. H NMR (300 MHz, DMSO-d6): δ = 10.49
(s, 1H), 7.38–7.32 (m, 1H), 6.74–6.71 (m, 1H), 3.41 (q, J = 7.3 Hz, 2H),
3.10 (q, J = 7.0 Hz, 2H), 1.10 (t, J = 7.1 Hz, 3H), 0.97 (t, J = 7.1 Hz, 3H)
ppm. 13C NMR (75.4 MHz, DMSO-d6): δ = 161.7 (C), 153.8 (d, J = 7.7 Hz,
C), 153.6 (d, J = 244.0 Hz, C), 130.2 (CH), 115.1 (d, J = 21.4 Hz, C),
112.8 (d, J = 3.0 Hz, CH), 109.0 (d, J = 18.2 Hz, C), 42.4 (CH2), 38.7
(CH2), 14.0 (CH3), 12.8 (CH3) ppm. LRMS (EI): m/z (%) = 247 (M+2, 5),
245 (M+, 18), 210 (40), 173 (100), 58 (65). HRMS (EI): calcd. for
C11H13ClFNO2 [M]+ 245.0619; found 245.0610.
O-6-Chloro-2-cyano-3-(2-cyanopropan-2-yl)phenyl
diethylcarbamate (11d): The reaction of O-2,5-dichlorophenyl N,N-
diethylcarbamate (2d) (131 mg, 0.5 mmol) following the general
N,N-
1
procedure yielded 11d as a white solid (30% yield); m.p. 99–101 ºC. H
NMR (300 MHz, CDCl3): δ = 7.66 (d, J = 8.6 Hz, 1H), 7.58–7.65 (d, J =
8.7 Hz, 1H), 3.52 (q, J = 7.1 Hz, 2H), 3.41 (q, J = 7.1 Hz, 2H), 1.95 (s,
6H), 1.34 (t, J = 7.1 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (75.4
MHz, CDCl3): δ = 152.2 (C), 151.2 (C), 143.1 (C), 134.4 (CH), 129.3 (C),
124.7 (CH), 122.4 (C), 113.5 (C), 108.1 (C), 43.0 (CH2), 42.5 (CH2), 37.8
(C), 27.3 (2 CH3), 14.1 (CH3), 13.3 (CH3) ppm. LRMS (EI): m/z (%) =
321 (M2, 1), 319 (M, 3), 100 (100), 72 (26). HRMS (EI): calcd. for
C16H18ClN3O2 [M]+ 319.1088; found 319.1095.
4-Chloro-N,N-diethyl-2-fluoro-6-hydroxybenzamide
(13e):
The
reaction of O-3-chloro-5-fluorophenyl N,N-diethylcarbamate (1e) (123 mg,
0.5 mmol) following the general procedure yielded 13e as a white solid
1
(87% yield); m.p. 120–122 ºC. H NMR (300 MHz, DMSO-d6): δ = 10.72
(br s, 1H), 6.89 (dd, J = 9.0, 1.8 Hz, 1H), 6.74–6.73 (m, 1H), 3.43–3.37
(m, 2H), 3.09 (q, J = 6.9 Hz, 2H), 1.08 (t, J = 7.1 Hz, 3H), 0.97 (t, J = 7.1
Hz, 3H) ppm. 13C NMR (75.4 MHz, DMSO-d6): δ = 162.0 (C), 158.8 (d, J
= 244.7 Hz, C), 155.7 (d, J = 10.2 Hz, C), 133.7 (d, J = 14.2 Hz, C), 113.0
(d, J = 22.0 Hz, C), 111.9 (d, J = 2.9 Hz, CH), 106.8 (d, J = 26.0 Hz, CH),
42.5 (CH2), 38.8 (CH2), 14.0 (CH3), 12.9 (CH3) ppm. LRMS (EI): m/z (%)
= 247 (M+2, 6), 245 (M+, 21), 210 (41), 173 (100), 58 (76). HRMS (EI):
calcd. for C11H13ClFNO2 [M]+ 245.0619; found: 245.0624.
General Procedure for the Synthesis of Dihalosalicylamides 13 and
14: A solution of the corresponding carbamate 1 or 2 (0.5 mmol) in THF
(2 mL) at –78 ºC under nitrogen, was treated with s-BuLi (0.39 mL of a
1.4 M solution in cyclohexane, 0.55 mmol, for 1a-f and 2a-d) or LDA (1.2
equiv, for 1g-i and 2e). The resulting solution was allowed to reach –65
ºC for 5 min, and stirred at this temperature for 90 min. The mixture was
allowed to warm slowly to room temperature and then stirred for 60 min.
The reaction mixture was quenched with HCl (1 N) solution, the acidic
aqueous solution was then extracted with EtOAc (3 10 mL), and the
combined organic layers were dried over anhydrous Na2SO4 and
concentrate under reduced pressure. The residue was purified by silica
gel column chromatography (hexane/EtOAc, 1:1) affording the
salicylamides 13 and 14 as white solids.
3-Chloro-N,N-diethyl-6-fluoro-2-hydroxybenzamide
(13f):
The
reaction of O-2-chloro-5-fluorophenyl N,N-diethylcarbamate (1f) (123 mg,
0.5 mmol) following the general procedure yielded 13f as a white solid
1
(86% yield); m.p. 123–125 ºC. H NMR (300 MHz, DMSO-d6): δ = 10.21
(br s, 1H), 7.40 (dd, J = 8.9, 6.1 Hz, 1H), 6.82–6.77 (m, 1H), 3.44–3.39
(m, 2H), 3.09 (q, J = 7.0 Hz, 2H), 1.11 (t, J = 7.1 Hz, 3H), 0.97 (t, J = 7.1
Hz, 3H) ppm. 13C NMR (75.4 MHz, DMSO-d6): δ = 162.5 (C), 157.8 (d, J
= 243.0 Hz, C), 150.6 (d, J = 8.7 Hz, C), 130.6 (d, J = 10.3 Hz, CH),
117.3 (C), 117.1 (d, J = 23.3 Hz, C), 108.3 (d, J = 23.3 Hz, CH), 42.6
(CH2), 38.7 (CH2), 13.8 (CH3), 12.7 (CH3) ppm. LRMS (EI): m/z (%) =
247 (M+2, 10), 245 (M+, 31), 175 (33), 173 (100), 58 (74). HRMS (EI):
calcd. for C11H13ClFNO2 [M]+ 245.0619; found 245.0619. C11H13ClFNO2
(245.6778): calcd. C 53.78, H 5.33, N 5.70; found C 53.67, H 5.38, N
5.76.
N,N-Diethyl-2,3-difluoro-6-hydroxybenzamide (13a): The reaction of
O-3,4-difluorophenyl N,N-diethylcarbamate (1a) (115 mg, 0.5 mmol)
following the general procedure yielded 13a as a white solid (81% yield);
m.p. 172–174 ºC. 1H NMR (400 MHz, DMSO-d6): δ = 10.72 (br s, 1H),
6.64 (td, J = 9.6, 2.2 Hz, 1H), 6.49 (d, J = 10.7 Hz, 1H), 3.42–3.36(m, 2H),
3.11–3.06 (m, 2H), 1.08 (t, J = 7.0 Hz, 3H), 0.96 (t, J = 7.1 Hz, 3H) ppm.
13C NMR (100.6 MHz, DMSO-d6): δ = 162.4 (dd, J = 244.6, 16.4 Hz, C),
162.2 (dd, J = 3.2, 1.1 Hz, C), 159.1 (dd, J = 242.8, 16.4 Hz, C), 156.0
(dd, J = 13.8, 11.3 Hz, C), 110.5 (dd, J = 22.3, 3.9 Hz, C), 99.1 (dd, J =
24.7, 7.8 Hz, CH), 94.7 (dd, J = 8.1, 3.7 Hz, CH), 42.5 (CH2), 38.7 (CH2),
14.0 (CH3), 12.9 (CH3) ppm. LRMS (EI): m/z (%) = 229 (M, 24), 157
(100), 101 (24), 58 (55). HRMS (EI): calcd. for C11H13F2NO2 [M]+
229.0914; found 229.0909. C11H13F2NO2 (229.2232): calcd. C 57.64, H
5.72, N 6.11; found C 57.53, H 5.75, N 6.06.
3-Bromo-N,N-diethyl-2-fluoro-6-hydroxybenzamide
(13g):
The
reaction of O-4-bromo-3-fluorophenyl N,N-diethylcarbamate (1g) (145 mg,
0.5 mmol) following the general procedure yielded 13g as a white solid
(91% yield); m.p. 161–163 ºC. 1H NMR (300 MHz, DMSO-d6): δ = 7.38 (t,
J = 8.7 Hz, 1H), 6.62 (d, J = 8.8 Hz, 1H), 5.60 (br s, 1H), 3.41 (q, J = 7.0
Hz, 2H), 3.15–3.06 (m, 2H), 1.10 (t, J = 7.1 Hz, 3H), 0.97 (t, J = 7.1 Hz,
3H) ppm. 13C NMR (75.4 MHz, DMSO-d6): δ = 162.7 (C), 155.4 (d, J =
3.6 Hz, C), 155.3 (d, J = 242.5 Hz, C), 133.4 (CH), 115.5 (d, J = 21.6 Hz,
C), 113.9 (CH), 96.6 (d, J = 21.6 Hz, C), 42.6 (CH2), 38.8 (CH2), 13.9
(CH3), 12.7 (CH3) ppm. LRMS (EI): m/z (%) = 291 (M2, 12), 289 (M,
12), 219 (50), 217 (52), 210 (100), 58 (37). HRMS (EI): calcd. for
C11H13BrFNO2 [M]+ 289.0114; found 289.0108.
N,N-Diethyl-2,4-difluoro-6-hydroxybenzamide (13b): The reaction of
O-3,5-difluorophenyl N,N-diethylcarbamate (1b) (115 mg, 0.5 mmol)
following the general procedure yielded 13b as a white solid (88% yield);
m.p. 168–170 ºC. 1H NMR (400 MHz, DMSO-d6): δ = 10.16 (br s, 1H),
7.21 (dt, J = 18.8, 9.4 Hz, 1H), 6.64 (ddd, J = 9.1, 3.5, 1.8 Hz, 1H), 3.41
(q, J = 7.0 Hz, 2H), 3.10 (q, J = 6.9 Hz, 2H), 1.09 (t, J = 7.1 Hz, 3H), 0.97
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