TABLE 1. Synthesis of N-Acyl Indolines with 2-Aminophenethyl
N-Trifluoroacetylindoline (3a). 3a was obtained as a white solid
Ethanols and Carboxylic Acids
in 97% yield by column chromatography (4:1 hexane:ethyl acetate)
1
on neutral aluminum oxide: mp 51-52 °C; H NMR (500 MHz,
pKa of
acid
yield of 3 + 4 (%)a
CDCl3, ppm) δ 8.14 (d, J ) 8.0 Hz, 1H), 7.07-7.23 (m, 3H), 4.22
entry
R1
R2
CF3
CCl3
CF2H
H
R3
(t, J ) 8.5 Hz, 2H), 3.20 (t, J ) 8.5 Hz, 2H); 13C NMR (125 MHz,
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
0.50
0.52
1.33
3.75
4.21
4.31
4.75
4.82
4.85
0.50
1.33
4.31
0.50
4.87
0.50
4.31
0.50
0.50
3a
3b
3c
3d + 4d
3e
3f
3g + 4g
3h + 4h
3i + 4i
3j
3k
3l
3m
3n + 4n
3o
97
2
CDCl3) δ 154.4 (q, JC-F ) 37.5 Hz), 141.8, 131.8, 128.0, 126.1,
40b
94
1
4
125.0, 118.1, 116.3 (q, JC-F ) 286.3 Hz), 47.9 (q, JC-F ) 4.2
Hz), 28.6; 19F NMR (470 MHz, CFCl3) δ -75.69 (s); IR (KBr,
cm-1) 3023, 1683, 1606, 1492, 1433, 1222, 1201, 1138, 765.
N-Difluoroacetylindoline (3c). 3c was obtained as a yellow solid
in 94% yield by column chromatography (4:1 hexane:ethyl acetate)
74c
83
Ph
PhCH2
CH3
C3H7
C5H11
80
79c
77c
75c
95
1
on neutral aluminum oxide: mp 63-64 °C; H NMR (500 MHz,
CDCl3, ppm) δ 8.20 (d, J ) 8.0 Hz, 1H), 7.10-7.26 (m, 3H), 6.12
(t, J ) 53.5 Hz, 1H), 4.26 (t, J ) 8.5 Hz, 2H), 3.24 (t, J ) 8.5 Hz,
5-OCH3 CF3
5-OCH3 CF2H
5-OCH3 PhCH2
5-F
5-F
H
91
81
2
2H); 13C NMR (125 MHz, CDCl3) δ 159.7 (t, JC-F ) 25.0 Hz),
1
142.0, 131.6, 127.8, 125.4, 124.9, 117.7, 110.1 (t, JC-F ) 252.5
CF3
C2H5
CF3
PhCH2 3-CH3
CF3
CF3
89
79d
92
Hz), 46.7, 28.5; 19F NMR (470 MHz, CFCl3) δ -124.25 (d, J )
53.5 Hz); IR (KBr, cm-1) 3018, 1675, 1489, 1458, 1148, 1043,
759; HRMS calcd for (M+) C10H9F2NO:197.0652, found 197.0656.
N-Trifluoroacetyl-5-methoxyindoline (3j). 3j was obtained as
a white solid in 95% yield by column chromatography (4:1 hexane:
ethyl acetate) on neutral aluminum oxide: mp 96-98 °C; 1H NMR
(500 MHz, CDCl3, ppm) δ 8.12 (d, J ) 8.5 Hz, 1H), 6.77-6.81
(m, 2H), 4.27 (t, J ) 8.0 Hz, 2H), 3.81 (s, 3H), 3.23 (t, J ) 8.0
3-CH3
H
H
H
3p
3q
3r
83
2-Ph
90
3-CH3, 2-Ph
82e
a All the yields listed here are isolated yields. b 3b is N-dichloroacetyl-
1
indoline. c The ratio of 3 and 4 is determined by H NMR: 3d:4d ) 82:
18, 3g:4g )85:15, 3h:4h ) 89:11, 3i:4i ) 90: 11. d The ratio of 3n and
4n is determined by 19F NMR: 3n:4n ) 93:7. e Only threo 3r was detected
and isolated.
Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 158.0, 153.7 (q, 2JC-F
)
37.5 Hz), 135.3, 133.5, 118.8, 116.4 (q, 1JC-F ) 286.3 Hz), 112.6,
4
111.0, 55.8, 48.1 (q, JC-F ) 3.8 Hz), 28.8; 19F NMR (470 MHz,
mixture, and only N-dichloroacetyl indoline product (3b) was
obtained in 40% yield.
CFCl3) δ -72.32 (s); IR (KBr, cm-1) 3016, 2954, 2847, 1682, 1607,
1494, 1437, 1233, 1200, 1142, 1078, 832; HRMS calcd for (M+)
C11H10F3NO2 245.0664, found 245.0665.
The starting 2-aminophenethyl alcohols (1) are commercially
available. For specific structure demands, such as 1r, the desired
product can also be simply prepared through a reaction of
1-alkyl-2-nitrobenzene with aldehyde,10 followed by the reduc-
tion of the nitro group.11
The cyclized indoline products can further be simply oxidized
to the biologically important indoles and oxindoles according
to the known procedures.12,13
In conclusion, a unique and concise one-pot synthesis of
N-acyl indolines from of 2-aminophenethyl alcohols and car-
boxylic acids has been developed. This new approach provides
an efficient, scalable, low-cost, and direct access to the
biologically important indolines which are further oxidizable
to indoles and oxindoles.
N-Difluoroacetyl-5-methoxyindoline (3k). 3k was obtained as
a pink solid in 91% yield by column chromatography (4:1 hexane:
ethyl acetate) on neutral aluminum oxide: mp 97-99 °C; 1H NMR
(500 MHz, CDCl3, ppm) δ 8.11 (d, J ) 8.5 Hz, 1H), 6.75-6.81
(m, 2H), 6.12 (t, J ) 53.5 Hz, 1H), 4.26 (t, J ) 8.5 Hz, 2H), 3.80
(s, 3H), 3.22 (t, J ) 8.5 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ
159.1 (t, 2JC-F ) 25.0 Hz), 157.7, 135.7, 133.3, 118.4, 112.4, 111.0,
110.6 (t, 1JC-F ) 252.5 Hz), 55.8, 47.0 (t, 4JC-F ) 5 Hz), 28.8; 19
F
NMR (470 MHz, CFCl3) δ -123.91 (d, J ) 53.5 Hz); IR (KBr,
cm-1) 2972, 2923, 2845, 1678, 1495, 1438, 1272, 1197, 1148, 1087,
1048, 823; HRMS calcd for (M+) C11H11F2NO2 227.0758, found
227.0763.
N-Benzoacetyl-5-methoxyindoline (3l). 3l was obtained as a
white solid in 81% yield by column chromatography (4:1 hexane:
1
ethyl acetate) on neutral aluminum oxide: mp 159-161 °C; H
Experimental Section
NMR (500 MHz, CDCl3, ppm) δ 8.18 (d, J ) 8.5 Hz, 1H), 7.24-
7.36 (m, 5H), 6.71 (m, 2H), 4.05 (t, J ) 8.5 Hz, 2H), 3.79 (s, 2H),
3.77 (s, 3H), 3.12 (t, J ) 8.5 Hz, 2H); 13C NMR (125 MHz, CDCl3)
δ 168.5, 156.5, 137.0, 134.6, 132.9, 129.2 (2 carbon), 128.9 (2
carbon), 127.1, 117.9, 112.0, 111.0, 55.8, 48.5, 43.5, 28.4; IR (KBr,
cm-1) 3031, 3010, 2972, 2837, 1652, 1592, 1487, 1399, 1267, 815,
746, 708; HRMS calcd for (M+) C17H17NO2 267.1259, found
267.1268.
General Procedure. To a 100-mL three-necked round-bottomed
flask equipped with a condenser and a magnetic stir bar was added
Ph3P (7.86 g, 30 mmol), NEt3 (4.2 mL, 30 mmol), CCl4 (40 mL,
419 mmol), and carboxylic acid (10 mmol) at 0 °C under nitrogen
atmosphere and the solution was then stirred for 10 min. A solution
of 2-aminophenethyl alcohol (10 mmol) dissolved in CCl4 (21 mL,
220 mmol) was added dropwisely to the reaction mixture. Once
the addition was completed, the reaction mixture was allowed to
reflux for 3-12 h. After cooling, the solvent was removed by rotary
evaporator, the residue was then carefully washed with mixture
solvent (4:1 hexane:ethyl acetate) 3 times, and the precipitate was
removed via filtration. The filtrate was combined and concentrated
by rotary evaporator. The residue was then purified by column
chromatography or distillation under reduced pressure to offer the
product 3.
N-Trifluoroacetyl-5-fluoroindoline (3m). 3m was obtained as
a golden solid in 89% yield by column chromatography (4:1 hexane:
ethyl acetate) on neutral aluminum oxide: mp 52-54 °C; 1H NMR
(500 MHz, CDCl3, ppm) 8.17 (dd, J ) 8.5, 4.5 Hz, 1H), 6.93-
6.98 (m, 2H), 4.31 (t, J ) 8.5 Hz, 2H), 3.26 (t, J ) 8.5 Hz, 2H);
1
13C NMR (125 MHz, CDCl3) δ 160.7 (d, JC-F ) 245 Hz), 154.1
(q, 2JC-F ) 37.5 Hz), 137.9 (d, 4JC-F ) 2.5 Hz), 134.0 (d, 3JC-F
)
3
1
8.8 Hz), 119.1 (d, JC-F ) 8.8 Hz), 116.3 (q, JC-F ) 286.3 Hz),
2
2
114.4 (d, JC-F ) 22.5 Hz), 112.3 (d, JC-F ) 22.5 Hz), 48.2 (q,
4JC-F ) 4.2 Hz), 28.6; 19F NMR (470 MHz, CFCl3) δ -72.51 (s),
-116.04 (m); IR (KBr, cm-1) 2926, 2855, 1693, 1610, 1487, 1428,
1246, 1208, 1146, 1077, 832; HRMS calcd for (M+) C10H7F4NO
233.0464, found 233.0466.
(10) Morimoto, T.; Hashimoto, I.; Yamaoka, H. Japanese patent 77108941,
1977; Chem. Abstr. 1978, 88, 104878.
(11) Bavin, P. M. G. Org. Synth. 1973, 5, 30.
(12) Dunetz, J. R.; Danheiser, R. L. J. Am. Chem. Soc. 2005, 127, 5776-
5777.
(13) Yadav, J. S.; Subba, Reddy, B. V.; Suresh Reddy, Ch.; Krishna, A.
D. Tetrahedron Lett. 2007, 48, 2029-2032.
N-Propionyl-5-fluoroindoline (3n). 3n was obtained as a pink
solid in 79% yield by column chromatography (4:1 hexane:ethyl
9366 J. Org. Chem., Vol. 72, No. 24, 2007