C. D. Gabbutt et al. / Tetrahedron 62 (2006) 737–745
743
The cooled mixture was poured into water (100 mL) and the
organic layer was separated. The aqueous layer was
extracted with ethyl acetate (3!100 mL) and the combined
organic phases were washed with water (6!50 mL), dried
(anhyd Na2SO4) and evaporated to afford the crude product.
Purification was effected by elution from silica with 30%
EtOAc in hexane. The following benzophenones were
prepared in this manner:
3.7.4. 2-Fluoro-4-pyrrolidinobenzophenone 11d. From
2,4-difluorobenzophenone 8d, elution from silica gave
two fractions. Fraction 1. 2-Fluoro-4-pyrrolidinobenzo-
phenone 11d as yellow microcrystals (2.3 g, 37%), mp
86–90 8C, nmax 1645, 1609, 1579 cmK1, dH 2.06 (4H, m,
(CH2)2), 3.36 (4H, m, N(CH2)2), 6.18 (1H, dd, JZ14.0,
2.3 Hz,03-H), 6.35 (1H, dd, JZ8.8, 2.3 Hz, 5-H), 7.44 (2H,
m, 50,3 -H), 7.53 (1H, m, 040-H), 7.58 (1H, d, JZ8.6 Hz,
6-H), 7.60 (2H, m, 20,6 -H), dC 25.4, 47.7, 97.9 (d,
JZ26.9 Hz), 107.3 (d, JZ1.3 Hz), 113.2 (d, JZ12.5 Hz),
128.0, 129.2 (d, JZ1.6 Hz), 131.8, 133.5 (d, JZ4.5 Hz),
139.9, 152.1 (d, JZ12.3 Hz), 161.9, 164.4, 192.7. (Found:
C, 75.3; H, 6.2; N, 5.4; C17H16NOF requires C, 75.8; H, 6.0;
N, 5.2%).
3.7.1. 2-Iodo-4-pyrrolidinobenzophenone 11a. From
4-chloro-2-iodobenzophenone 8a, elution from silica
gave three fractions. Fraction 1. 2-Iodo-4-pyrrolidino-
benzophenone 11a as yellow microcrystals (2.60 g, 30%),
mp 117–120 8C, nmax 1642, 1593 cmK1, dH 1.90 (4H, m,
(CH2)2), 3.12 (4H, m, N(CH2)2), 6.64 (1H, dd, JZ8.3,
1.9 Hz, 5-H), 6.81 (1H, d, JZ1.9 Hz, 3-H), 7.17 (1H, d,
JZ8.3 Hz, 6-H), 7.47 (2H, m, 30,50-H), 7.56 (1H, m, 40-H),
7.91 (2H, m, 20,60-H), dC 26.3, 51.7, 114.1, 115.1, 122.8,
128.8, 130.8, 133.0, 133.2, 137.9, 138.5, 149.1, 196.2.
(Found: C, 54.0; H, 4.3; N, 3.8; C17H16NOI requires C, 54.1;
H, 4.2; N, 3.7%).
Fraction 2. 4-Fluoro-2-pyrrolidinobenzophenone 10a as
yellow microcrystals (1.7 g, 28%).
3.8. Preparation of 2-substituted 4-pyrrolidinobenzo-
phenones (Method 2)
The halogenobenzophenone 8 (23 mmol) was dissolved in a
mixture of pyrrolidine (5.85 mL, 70 mmol) and anhyd
DMSO (30 mL) and stirred at room temperature for 10 min
and then heated under reflux until TLC examination of the
reaction mixture indicated that no further changes were
apparent (w4 days). The cooled mixture was poured into
water (300 mL) and the organic layer was separated. The
aqueous layer was extracted with ethyl acetate (3!100 mL)
and the combined organic phases were washed with water
(6!50 mL), dried (anhyd Na2SO4) and evaporated to afford
the crude product. Purification was effected by elution from
silica with 30% EtOAc in hexane. The following
benzophenones were prepared in this manner:
Fraction 2. 4-Chloro-2-pyrrolidinobenzophenone 10b
(0.26 g, 4%), dH 2.05 (4H, m, (CH2)2), 3.36 (4H, m,
N(CH2)2), 6.42 (1H, dd, JZ8.7 Hz, 2.3, 5-H), 6.57 (1H, d,
JZ2.4 Hz, 3-H), 7.36 (1H0 , d, JZ8.6 Hz, 6-H), 7.43 (2H, m,
30,50-H), 7.54 (1H, m, 4 -H), 7.78 (2H, m, 20,60-H).
Fraction 3. 2,4-Dipyrrolidinobenzophenone 9 (0.29 g, 4%).
3.7.2. 2-Bromo-4-pyrrolidinobenzophenone 11b. From
2-bromo-4-chlorobenzophenone 8b, elution from silica
gave two fractions. Fraction 1. 2-Bromo-4-pyrrolidino-
benzophenone 11b as yellow microcrystals (2.95 g, 39%),
mp 117–120 8C, nmax 1642, 1593 cmK1, dH 1.90 (4H, m,
(CH2)2), 3.12 (4H, m, N(CH2)2), 6.64 (1H, dd, JZ8.3,
1.9 Hz, 5-H), 6.81 (1H, d, JZ1.9 Hz, 3-H), 7.17 (1H, d, JZ
8.3 Hz, 6-H),0 7.46 (2H, m, 50,30-H), 7.56 (1H, m, 40-H), 7.91
(2H, m, 20,6 -H), dC 25.8, 51.3, 113.6, 114.7, 122.3, 127.3,
128.3, 130.4, 132.6, 132.8, 137.5, 138.1, 148.7, 195.8.
(Found: C, 61.7; H, 5.3; N, 4.6; C17H16NOBr requires C,
61.8; H, 4.9; N, 4.2%).
3.8.1. 2-Methoxy-4-pyrrolidinobenzophenone 11f. From
4-chloro-2-methoxybenzophenone 8f, elution from silica
gave two fractions. Fraction 1. 2-Methoxy-4-pyrrolidino-
benzophenone 11f as yellow microcrystals (1.16 g, 18%),
mp 83–85 8C, nmax 1630, 1592 cmK1, dH 2.02 (4H, m,
(CH2)2), 3.35 (4H, m, N(CH2)2), 3.69 (3H, s, OCH3), 6.01
(1H, d, JZ2.0 Hz, 3-H), 6.14 (1H, dd, JZ8.6, 2.1 Hz, 5-H),
7.39 (2H, m, 6-H, Ar-H), 7.46 (2H, m, Ar-H), 7.70 (2H, m,
20,60-H), dC 25.9, 48.1, 55.7, 94.7, 104.0, 115.9, 128.1,
129.8, 131.6, 134.4, 141.0, 152.2, 161.3, 195.5. (Found: C,
76.7; H, 6.9; N, 4.9; C18H19NO2 requires C, 76.8; H, 6.8; N,
5.0%).
Fraction 2. 4-Chloro-2-pyrrolidinobenzophenone 10b
(0.33 g, 5%).
3.7.3. 2-Chloro-4-pyrrolidinobenzophenone 11c. From
2-chloro-4-fluorobenzophenone 8c, elution from silica
gave three fractions. Fraction 1. 2-Chloro-4-pyrrolidino-
benzophenone 11c as yellow microcrystals (3.35 g, 51%),
mp 95–98 8C, nmax 1650, 1591 cmK1, dH 2.04 (4H, m,
(CH2)2), 3.33 (4H, m, N(CH2)2), 6.41 (1H, dd, JZ8.6,
2.4 Hz, 5-H), 6.56 (1H, d, JZ2.4 Hz, 3-H), 7.35 (1H, d, JZ
8.6 Hz, 6-H),0 7.43 (2H, m, 50,30-H), 7.52 (1H, m, 40-H), 7.77
(2H, m, 20,6 -H), dC 25.8, 48.0, 109.4, 113.2, 124.2, 128.6,
130.4, 132.7, 133.5, 135.0, 139.2, 150.4, 195.2. (Found: C,
71.3; H, 5.7; N, 4.9; C17H16NOCl requires C, 71.5; H, 5.6;
N, 4.9%).
Fraction 2. 2-Hydroxy-4-pyrrolidinobenzophenone 11e as
green microcrystals (1.17 g, 19%), mp 55–58 8C, nmax 3435,
1628, 1549, 1522 cmK1, dH 2.02 (4H, m, (CH2)2), 3.38 (4H,
m, N(CH2)2), 6.05 (2H, m, 3,5-H), 7.38 (1H, d, JZ8.6 Hz,
6-H), 7.48 (3H, m, Ar-H), 7.61 (2H, m, 20,60-H), 13.04 (1H,
s, OH), dC 25.3, 47.6, 97.8, 104.3, 109.2, 128.1, 128.7,
130.7, 135.4, 139.0, 153.4, 166.0, 198.1. (Found: C, 76.0; H,
6.1; N, 4.9; C17H17NO2 requires C, 76.4; H, 6.4; N, 5.2%).
3.8.2. 2-Methyl-4-pyrrolidinobenzophenone 11g. From
4-chloro-2-methylbenzophenone 8g. As yellow micro-
crystals (2.5 g, 41%), mp 65–67 8C, nmax 1631, 1608,
1577 cmK1, dH 2.02 (4H, m, (CH2)2), 2.53 (3H, s, CH3),
3.35 (4H, m, N(CH2)2), 6.31 (1H, dd, JZ8.6, 2.3 Hz, 5-H),
6.42 (1H, d, JZ2.2 Hz, 3-H), 7.33 (1H, d, JZ8.6 Hz, 6-H),
Fraction 2. 4-Fluoro-2-pyrrolidinobenzophenone 10a
(60 mg, 1%).
Fraction 3. 2,4-Dipyrrolidinobenzophenone 9 (0.37 g, 5%).