L. D. Jennings et al. / Bioorg. Med. Chem. 8 (2000) 897±907
905
398.0134. Found 398.0148. trans Isomer 4 isolated as a
2H), 8.10 (d, J=7.5 Hz, 1H); HRMS m/e calcd for C13
H17BrNO: 282.0494. Found: 282.0494.
white solid (39%): mp 142±144 ꢀC; H NMR (CDCl3) d
1
1.52 (d, J=6.8 Hz, 3H), 1.74 (s, 3H), 2.80±2.88 (m,
2H), 3.10±3.16 (m, 2H), 5.15 (m, 1H), 5.85 (br s, 1H),
7.19 (d, J=8.0 Hz, 2H), 7.31 (d, J=8.0 Hz, 2H); 19F
NMR (376 MHz, CDCl3) d 73.71 (s); irradiation at
73.71 ppm showed positive NOE enhancement on
C-3 methyl; HRMS m/e calcd for C15 H17BrClF3NO:
398.0134. Found. 398.0147.
cis-(R)-3-Chloro-3-methyl-N-[1-(4-bromophenyl)ethyl]-
cyclobutanecarboxamide (41). Method A, isolated as a
ꢀ
1
white solid (7%): mp 110±131 C; H NMR (300 MHz,
d6-DMSO) d 1.30 (d, J=7.13 Hz, 3H), 1.72 (s, 3H),
2.46±2.70 (m, 4H), 2.85±2.95 (m, 1H), 4.90±4.95 (m,
1H), 7.22 (d, J=8.4 Hz, 2H), 7.50 ppm (d, J=8.4 Hz,
2H), 8.30 (d,J=7.5 Hz, 1H); HRMS m/e calcd for
C14H18ClNO: 330.0260. Found: 330.0251.
trans-(R)-3-Chloro-3-methyl-1-tri¯uoromethy-N-[1-(4-
chlorophenyl)ethyl]cyclobutane carboxamide (37).
Method A, cis isomer isolated as a white solid (11%):
(R)-1,3,3-Trichloro-N-[1-(4-bromophenyl)ethyl]cyclobut-
anecarboxamide (42). Method A, isolated as a white
mp 129±130 ꢀC; H NMR (300 MHz, CDCl3) d 1.49 (d,
1
solid (42%): mp 149±151 ꢀC; H NMR (300 MHz, d6-
1
J=6.9 Hz, 3H), 1.67 (s, 3H), 2.82±3.05 (m, 4H), 5.05-
5.15 (m, 1H), 5.85 (br s, 1H), 7.20 (d, J=8.5 Hz, 2H),
7.32 (d, J=8.5 Hz, 2H); HRMS m/e calcd for C15H17Cl2
F3NO: 354.0639. Found: 354.0627. trans Isomer 37
isolated as a white solid (19%): mp 145±146 ꢀC; 1H
NMR (300 MHz, CDCl3) d 1.54 (d, J=6.9 Hz, 3H), 1.74
(s, 3H), 2.79±2.86 (m, 2H), 3.05±3.15 (m, 2H), 5.10±5.20
(m, 1H), 5.85 (br s, 1H), 7.23 (d, J=8.5 Hz, 2H), 7.31
(d, J=8.5 Hz, 2H); HRMS m/e calcd for C15H17
Cl2F3NO: 354.0639. Found: 354.0623.
DMSO) d 1.40 (d, J=6.9 Hz, 3H), 3.45±3.55 (m, 2H),
3.85±3.95 (m, 2H), 4.85±4.95 (m, 1H), 7.30 (d, J=
8.4 Hz, 2H), 7.50 (d, J=8.4 Hz, 2H), 8.85 (d, J=7.5 Hz,
1H); HRMS m/e calcd for C13H14Cl3BrNO: 383.9324.
Found: 383.9339.
(R)-3,3-Di¯uoro-1-methyl-N-[1-(4-bromophenyl)ethyl]-
cyclobutanecarboxamide (43). Method B, isolated as an
orange solid (72%): mp 120±122 ꢀC; H NMR (CDCl3,
1
300 MHz) d 1.48 (d, J=7.2Hz, 3H), 1.58 (s, 3H), 2.40 (m,
2H), 3.01 (m, 2H), 5.06 (m, 1H), 5.66 (d, J=7.2Hz, 1H),
7.17 (d, J=8.1Hz, 2H), 7.47 (d, J=8.1Hz, 2H); 19F
NMR (CDCl3, 282 MHz) d 93.3 (s), 87.4 (s); HRMS
m/e calcd for C14H17BrF2NO: 332.0462. Found: 332.0476.
trans-(R)-3-Chloro-3-methyl-1-tri¯uoromethy-N-[1-(2,4-
dichlorophenyl)ethyl]cyclobutanecarboxamide
(38).
Method A, cis isomer isolated as a white solid (9%):
mp 149±150 ꢀC; 1H NMR (CDCl3) d 1.54 (d, J=7.5 Hz,
3H), 1.70 (s, 3H), 2.82±3.05 (m, 4H), 5.30±5.40 (m, 1H),
6.05 (br s, 1H), 7.18±7.28 (m, 3H); HRMS m/e calcd for
C15H16Cl3F3NO: 388.0250. Found: 388.0253. trans
Isomer 38 isolated as a white solid (9%): mp 180±
cis- and trans-(R)-1,3-Dichloro-3-methyl-N-[1-(4-bromo-
phenyl)ethyl]cyclobutanecarboxamide (44). Method A,
isolated in 13% yield as a 1:1 mixture of two isomers
181 ꢀC; H NMR (CDCl3) d 1.52 (d, J=7.5 Hz, 3H),
which were not separated: mp 109±113 ꢀC; H NMR
1
1
1.74 (s, 3H), 2.80±2.90 (m, 2H), 3.10±3.20 (m, 2H),
5.30±5.40 (m, 1H), 6.05 (br s, 1H), 7.22 (s, 2H), 7.40 (s,
1H); HRMS m/e calcd for C15H16Cl3F3NO: 388.0250.
Found: 388.0268.
(CDCl3, 300 MHz) d 1.40 (d, J=7.0 Hz, 3H), 1.80 (s,
3H), 2.85±2.95 (m, 2H), 3.30±3.40 (m, 2H), 4.90±5.00
(m, 1H), 7.30 (d, J=8.5 Hz, 2H), 7.55 (d, J=8.5 Hz,
2H), 8.70 (d, J=7.5 Hz, 1H).
trans-(R)-3-Chloro-3-methyl-1-tri¯uoromethy-N-[3-(2-
¯uorophenyl)oxy-2-propyl] cyclobutanecarboxamide (39).
Method A, cis isomer isolated as a white solid (27%):
cis-(R)-3-Chloro-1,3-dimethyl-N-[1-(4-bromophenyl)ethyl]-
cyclobutanecarboxamide (45). Method A, isolated as an
orange solid (3%): mp 128±139 ꢀC; 1H NMR (300 MHz,
d6-DMSO) d 1.30 (overlapping doublet and singlet, 6H),
1.75 (s, 3H), 2.25±2.35 (m, 2H), 2.90±3.00 (m, 2H),
4.85±4.95 (m, 1H), 7.25 (d, J=8.5 Hz, 2H), 7.45 (d, J=
8.4 Hz, 2H), 8.09 (d, J=7.5 Hz, 1H).
mp 70±72 ꢀC, H NMR (300 MHz, CDCl3) d 1.37 (d,
1
J=7.2 Hz, 3H), 1.67 (s, 3H), 2.83±2.90 (m, 1H), 2.97±
3.05 (m, 3H), 4.0±4.10 (m, 2H), 4.35±4.45 (m, 1H), 6.05
(br s, 1H), 6.90±6.98 (m, 2H), 7.01±7.12 (m, 2H), 19F
NMR (282 MHz, CDCl3) d 73.59(s), 135.08 (s);
HRMS m/e calcd for C16H19ClF4NO2: 368.1040.
Found: 368.1033. trans isomer 39 isolated as a white
solid (35%): mp 145±146 ꢀC; 1H NMR (400 MHz,
CDCl3) d 1.40 (d, J=7.2 Hz, 3H), 1.75 (s, 3H), 2.80±
2.85 (m, 2H), 3.05±3.20 (m, 2H), 4.0±4.12 (m, 2H), 4.42±
4.52 (m, 1H), 6.10 (br s, 1H), 6.90±7.0 (m, 2H), 7.01±
7.12 (m, 2H), 19F NMR (376 MHz, CDCl3) d 73.98
(s), 135.195 (s), Irradiation at 73.98 ppm showed
positive NOE enhancement on C-3 methyl. HRMS m/e
calcd for C16H19ClF4NO2: 368.1040. Found: 368.1034.
cis- and trans-(R)-3-Chloro-3-(chloromethyl)-1-methyl-
N-[1-(4-bromophenyl)ethyl] cyclobutanecarboxamide (46
and 47). Method A, trans isomer 46 isolated as a white
solid (24%): mp 96±103 ꢀC; 1H NMR (CDCl3,
300 MHz) d 1.47 (d, J=7.0 Hz, 3H), 1.61 (s, 3H), 2.38±
2.44 (m, 2H), 3.00±3.06 (m, 2H), 3.80 (d, J=3.75 Hz,
2H), 4.97±5.07 (m, 1H), 5.61 (br s, 1H), 7.18 (d,
J=8.5 Hz, 2H), 7.48 (d, J=8.5 Hz, 2H); irradiation at
3.80 ppm showed no NOE enhancement on C-1 methyl;
HRMS m/e calcd for C15H19Cl2BrNO: 378.0027.
Found: 378.0036. cis Isomer 47 isolated as a white solid
ꢀ
1
(R)-N-[1-(4-Bromophenyl)ethyl]cyclobutanecarboxamide
(40). Method A, isolated as a white solid (83%): mp
(24%): mp 102±117 C; H NMR (CDCl3, 300 MHz) d
1.39 (s, 3H), 1.50 (d, J=7.0 Hz, 3H), 2.57±2.62 (m, 2H),
2.88±2.95 (m, 2H), 3.77 (s, 2H), 5.07±5.17 (m, 1H), 5.81
(br s, 1H), 7.20 (d, J=8.5 Hz, 2H), 7.44 (d, J=8.5 Hz,
2H); irradiation at 3.77 ppm showed positive NOE
140±150 ꢀC; H NMR (300 MHz, d6-DMSO) d 1.30 (d,
1
J=6.9 Hz, 3H), 1.75±2.18 (m, 6H), 3.05 (m, 1H), 4.85
(m, 1H), 7.23 (d, J=8.4 Hz, 2H), 7.49 (d, J=8.4 Hz,