A simple route to N-ω-chloroalkylisatins from cyclic t-anilines, oxalyl chloride and DABCO

Article abstract of DOI:10.1055/s-2002-19290

para-Substituted N-phenylpyrrolidines, -piperidines, -perhydroazepines and -morpholines react with oxalyl chloride and DABCO to give the pharmaceutically useful intermediates, N-ω-haloalkylisatins, under mild conditions and generally good yields.

Full text of DOI:10.1055/s-2002-19290

34
PAPER
A Simple Route to N- -Chloroalkylisatins from Cyclic t-Anilines, Oxalyl
Chloride and DABCO
A
S
imple Route to
i
N
-
-
C
n
hloroalkylis
g
tins Cheng,*a Yu-Hua Zhan,a Otto Meth-Cohn*b
a
Chemistry Department, Beijing Normal University, Beijing 100875, China
E-mail: yincheng@public2east.net.cn
b
Chemistry Department, University of Sunderland, Sunderland SR1 3SD, U.K.
E-mail: otto.meth-cohn@sunderland.ac.uk
Received 7 September 2001; revised 29 October 2001
yield from para-substituted N,N-dimethylanilines 7 and
oxalyl chloride (8), catalysed by DABCO (Scheme 1), via
o-oxalylation, ring-closure and demethylation.
Abstract: para-Substituted N-phenylpyrrolidines, -piperidines,
-perhydroazepines and -morpholines react with oxalyl chloride and
DABCO to give the pharmaceutically useful intermediates, N- -ha-
loalkylisatins, under mild conditions and generally good yields.
Key words: cyclic t-anilines, oxalyl chloride, DABCO, N- -ha-
loalkylisatins
N- -Haloalkylisatins 1 are important intermediates in the
syntheses of pharmacologically important isatin deriva-
tives. These include anaphylactic asthma inhibitors 2,1
gastroduodenal ulcer inhibitors 3,2 cholinesterase inhibi-
tors 43 and acetylcholinesterase inhibitors 54 (which are
useful in the treatment of neurodegenerative and cognitive
dysfunction conditions such as Alzheimer’s disease) and
compounds 65 used in treating central nervous system dis-
order (Figure).
Methods for the synthesis of the N- -haloalkylisatins1,4,6
are limited to the monoalkylation of isatins by dihaloal-
kanes. This method has serious limitations due to the lack
of available isatins as starting materials and to poor yields
due to side-reactions. Very recently, we reported7 that 5-
substituted N-methylisatins 9 could be prepared in high
Scheme 1
We have now discovered that this method is also applica-
ble to para-substituted N-phenylheterocycles such as pyr-
rolidines, piperidines, morpholines and perhydroazepines
10–13, with ring-opening of the heterocycle to give 5-sub-
stituted N- -chloroalkylisatins 17–20 as the sole prod-
ucts. The formation of 17–20 can be explained by a
similar mechanism to that invoked for the formation of N-
methylisatins 97 (Scheme 2).
N-Methylisatins were prepared using DABCO in reflux-
ing chloroform under nitrogen. The reactions of para-sub-
stituted N-phenylheterocycles 10–13 with the oxalyl
Figure Some pharmacologically important isatin derivatives 1–6
Synthesis 2002, No. 1, 28 12 2001. Article Identifier:
1437-210X,E;2002,0,01,0034,0038,ftx,en;E06001SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

PAPER
A Simple Route to N- -Chloroalkylisatins
35
chloride/DABCO salt 14 required long reaction times time were decreased significantly. Furthermore, the yield
and/or gave poor yields under these conditions, while with of products, particularly when the para-substituted N-
acetonitrile as the solvent, the reaction temperature and
Table 1 Reactions Between para-Substituted N-Phenylheterocycles and Oxalyl Chloride/DABCO
N-Phenyl-Hetero- Solvent
cycle
Temp (°C)
Time (h)
Producta
Yield(%)
Mp (°C)
79–80
10a
10a
10b
10b
10b
10c
10c
10d
10d
10d
10e
10e
11a
11a
11b
11b
11d
11d
12a
12a
12b
12b
12d
12d
13a
13a
13b
13b
13c
13d
13d
13e
CH2Cl2
MeCN
CHCl3
70
30
10
2
17a
17a
17b
17b
17b
17c
17c
17d
17d
17d
17e
17e
18a
18a
18b
18b
18d
18d
19a
19a
19b
19b
19d
19d
20a
20a
20b
20b
20c
20d
20d
20e
79
81
60
37
72
41
44
37
48
37
36
40
48
59
35
44
27
30
50
52
42
42
16
33
25
47
22
52
0
64
10
46
6
86–87
toluene
MeCN
CHCl3
90–100
30
35
11
5
90–92
85–86
MeCN
CHCl3
35
64
11
23
9
Cl2CHCHCl2
MeCN
ClCH2CH2Cl
MeCN
CHCl3
110
80–85
82
47
10
16
11
19
11
40
11
8
77–78
48–50
95–97
84–86
45–47
69–71
70–72
74–76
87–89
82
64
MeCN
CHCl3
60
64
MeCN
CHCl3
60
64
MeCN
CHCl3
65
64
MeCN
ClCH2CH2Cl
MeCN
CHCl3
48
11
16
11
24
11
18
11
38
10
48
48
20
11
85
65
64
MeCN
CHCl3
65
64
MeCN
CHCl3
56
64
MeCN
CHCl3
58
64
–
CHCl3
64
0
170–171
MeCN
MeCN
85
9
82
8
113–114
a Satisfactory microanalyses obtained: C 0.34, H 0.35, N 0.36. Exceptions: 17b, C –0.68; 18b, C –0.47; 20a, C –0.47.
Synthesis 2002, No. 1, 34–38 ISSN 0039-7881 © Thieme Stuttgart · New York

36
Y. Cheng et al.
PAPER
est yield of isatin from N-(p-methoxyphenyl)pyrrolidine
(81%), while the N-(p-halophenyl)morpholines gave the
lowest yields.
We believe that this method is the simplest route for the
preparation of N-chloroalkylisatins, requiring only sim-
ple, cheap starting materials and reagents, and mild condi-
tions.
1
Melting points or boiling points and pressure are uncorrected. H
NMR and 13C NMR were obtained on a Bruker Avance 500. IR
spectra were recorded using a Avatar 360 FT-IR spectrometer.
Mass spectra were recorded on a KYKY-ZHT-5 instrument and el-
emental analyses were performed on a GMBH Vario EL instru-
ment.
para-Substituted N-Phenylheterocycles 10–13; General
Procedure
To a solution of 7 (50 mmol) in anhyd toluene (20 mL) were added
N,N-diisopropylethylamine (1.42 g, 11 mmol) and a dibromoalkane
(55 mmol) (The BrCH2CH2OCH2CH2Br was displaced by
TsOCH2CH2OCH2CH2OTs when para-substituted N-phenylmor-
pholines were prepared). The mixture was refluxed for 18–24 h un-
der N2. After cooling, the mixture was poured into H2O (100 mL)
and the toluene layer was separated. The aqueous solution was ex-
tracted with Et2O (3 50 mL) and the organic layers were com-
bined and dried (MgSO4). After removal of the solvent, the product
was obtained by distillation or chromatography on silica gel eluting
with variable amounts of hexane–EtOAc (Table 2).
Table 2 para-Substituted N-Phenylheterocycles 10–13 Prepared
Product
Yield (%)
Mp (°C) or Bp
(°C)/Torr
Found
Reported
46–478
10a
83
80
61
64
78
79
86
74
23
30
24
54
70
45
55
45–46
10b
38–40
39–409
122/1310
85–8611
10312
Scheme 2
10c
58–60/0.2
85–87
10d
phenylmorpholines were utilised, was improved
(Table 1).
10e
103–105
77–79/0.15
97–98/1
68–71
11a
3713,a
Methoxy- and methyl-substituted t-anilines 10–13 gave
higher yields of isatins than their halogen substituted ana-
logues, probably due to the electron-withdrawing effect of
the latter substituents on the oxalyl-ring-closure and ring-
opening reactions. However, the fluoro-substituted t-
aniline 10c was more reactive than the chloro- or bromo-
substituted analogues indicating that the reaction se-
quences are not so trivially explained. If the reaction of
fluoro derivative 10c with oxalyl chloride was carried out
above 60 °C, the reaction mixture became very dark. The
conversions of the halo t-anilines 10d and 10c into isatins
were not complete even after long reaction times.
11b
57–60/0.59
6914
11d
12a
94–96/0.3
76–80/0.2
84–85/0.3
71–73
87/0.215
62/0.1215
75/0.215
71–7316
91/0.417
71–7218
112–11319
12b
12d
13a
13b
95/0.5b
13d
71–73
The pyrrolidines 10 gave the highest yields of isatins com-
pared to their piperidine 11, perhydroazepine 12, and mor-
pholine 13 analogues due probably to the easier ring-
opening of the strained spiro-5,5-intermediate. Combina-
tion of these two effects, as expected, resulted in the high-
13e
115–117
a Melting point.
b Melting point 44–45 °C.
Synthesis 2002, No. 1, 34–38 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Simple Route to N- -Chloroalkylisatins
37
N- -Chloroalkylisatins 17–20; General Procedure
the residue was neutralized with 10% aq NaHCO3. The products
were extracted with CHCl3 (3 100 mL) and dried (MgSO4). After
removal of solvent, the isatins were purified by chromatography on
silica gel, eluting with variable amounts of hexane–EtOAc
(Table 3).
Oxalyl chloride (1.75 mL, 2.55 g, 20 mmol) was added dropwise to
a solution of DABCO (11 mmol) in the appropriate solvent (10 mL)
(see Table 1) cooled in an ice-bath under N2 to form a pale yellow
solid salt. To this salt was added slowly with ice-bath cooling, the
para-substituted N-phenylheterocycle 10 (10 mmol) in the same
solvent (50 mL) and the mixture was stirred for the period of time
and at the temperature shown in Table 1. After removal of solvent,
Table 3 Spectroscopic Data of Isatins 17–20
Product IR (cm–1)
1H NMR (CDCl3/TMS)
, J (Hz)
13C NMR (CDCl3/TMS)
MS (EI) (rel. intensity, %)
149 (95), 162 (100), 176 (39),
17a
17b
1730, 1616,
1599, 1490
7.18 (1 H, s), 7.17(1 H, d, J = 7.6), 6.87 (1 184.2, 158.7, 157.0, 145.0, 125.1,
H, d, J = 7.9), 3.84 (3 H, s, OCH3), 3.77 (2 118.5, 111.5, 110.2, 56.4, 44.6, 39.7, 177 (38),
H, t, J = 6.5, NCH2), 3.63 (2 H, t, J = 5.8,
CH2Cl), 1.90 (4 H, m, CH2CH2)
29.9, 24.9
267 (M+, 60)/269 (20)
1739, 1621,
1594, 1490
7.44 (1 H, s), 7.42 (1 H, d, J = 8.2), 6.84 (1 184.0, 158.7, 148.9, 139.2, 134.0,
133 (100), 146 (90), 160 (37),
H, d, J = 8.0), 3.77 (2 H, t, J = 6.5, NCH2), 126.3, 118.1, 110.3, 44.6, 39.7, 29.9, 251 (M+, 60)/253 (20)
3.62 (2 H, t, J = 5.9, CH2Cl), 2.36 (3 H, s, 24.9, 21.0
CH3), 1.89 (4 H, m, CH2CH2)
17c
17d
1741, 1728,
1618, 1606,
1485, 1464
7.29–7.37 (2 H, m), 6.91–6.94 (2 H, m),
3.79 (2 H, t, J = 6.6, NCH2), 3.63 (2 H, t, J 125.2, 125.0, 118.7, 113.1, 112.9,
= 5.9, CH2Cl), 1.89 (4 H, m, CH2CH2) 111.7, 111.6, 44.5, 39.9, 29.8, 24.8
183.1, 160.7, 158.7, 158.4, 147.1,
137 (37), 150 (100), 255 (M+,
9)/257 (3)
1751, 1735,
1605, 1592,
1474, 1445
7.61 (1 H, s), 7.60 (1 H, d, J = 10.8), 6.91 (1 182.7, 158.1, 149.3, 138.2, 130.1,
153(85), 166 (100)/168 (55),
H, d, J = 8.2), 3.80 (2 H, t, J = 6.5, NCH2), 125.9, 118.9, 111.8, 44.5, 39.9, 29.8, 180 (22), 271 (M+, 7)/273 (4)/
3.63 (2 H, t, J = 5.8, CH2Cl), 1.91 (4 H, m, 24.8
275 (2)
CH2CH2)
17e
18a
1735, 1599,
1472, 1441
7.74 (2 H, m), 6.86 (1 H, d, J = 8.9), 3.79 (2 182.5, 157.9, 149.8, 141.0, 128.7,
H, t, J = 6.5, NCH2), 3.62 (2 H, t, J = 5.8,
197 (100)/199 (80), 210 (75)/
119.2, 117.0, 112.2, 44.5, 39.9, 29.8, 212 (73), 315 (M+, 9)/317
CH2Cl), 1.89 (4 H, m, CH2CH2)
24.8
(10)/319 (4)
1747, 1722,
1632, 1595,
1491, 1470
7.16 (1 H, s), 7.15(1 H, dd, J = 8.2, 2.7),
184.2, 158.6, 156.9, 145.1, 125.0,
149 (60), 162 (100), 176 (50),
6.81 (1 H, d, J = 8.2), 3.81 (3 H, s, OCH3), 118.5, 111.5, 110.2, 56.4, 45.0, 40.4, 177 (49), 190 (75), 218 (80),
3.71 (2 H, t, J = 7.2, NCH2), 3.54 (2 H, t, J 32.4, 27.0, 24.5
= 6.5, CH2Cl), 1.83 (2 H, m, CH2), 1.73 (2
H, m, CH2), 1.53 (2 H, m, CH2)
281 (83)/283 (53)
18b
18d
19a
1737, 1725,
1620, 1597,
1492
7.44 (1 H, s), 7.41 (1 H, d, J = 8.0), 6.81 (1 184.1, 158.7, 149.1, 139.1, 133.9,
146 (100), 175 (24), 265 (M+,
H, d, J = 8.0), 3.74 (2 H, t, J = 7.2, NCH2), 126.5, 118.1, 110.3, 45.0, 40.3, 32.4, 15)/267 (5)
3.56 (2 H, t, J = 6.5, CH2Cl), 2.36 (3 H, s, 27.0, 24.5, 21.0
CH3), 1.86 (2 H, m, CH2), 1.76 (2 H, m,
CH2), 1.56 (2 H, m, CH2)
1752, 1735,
1605, 1475,
1446
7.59 (1 H, s), 7.58 (1 H, d, J = 9.2), 6.89 (1 182.9, 158.0, 149.5, 138.1, 130.0,
H, d, J = 8.1), 3.76 (2 H, t, J = 7.2, NCH2), 125.9, 118.8, 111.7, 45.0, 40.6, 32.3, 9)/287 (7)/289 (2)
3.56 (2 H, t, J = 6.5, CH2Cl), 1.86 (2 H, m, 26.9, 24.5
CH2), 1.75 (2 H, m, CH2), 1.56 (2 H, m,
166 (100)/168 (40), 285 (M+,
CH2)
1732, 1618,
1598, 1491
7.17 (1 H, s), 7.16 (1 H, d, J = 7.3), 6.83 (1 184.4, 158.6, 156.8, 145.2, 125.1,
149 (35), 162 (100), 177 (40),
H, d, J = 8.9), 3.83 (3 H, s, OCH3), 3.72 (2 118.4, 111.5, 110.1, 56.4, 45.3, 40.5, 295 (M+, 16)/297 (10)
H, t, J = 7.2, NCH2), 3.52 (2 H, t, J = 6.5,
CH2Cl), 1.80 (2 H, m, CH2), 1.74 (2 H, m,
CH2), 1.52 (2 H, m, CH2), 1.42 (2 H, m,
CH2)
32.7, 27.5, 26.8, 26.6
19b
1744, 1725,
1619, 1596,
1491
7.43 (1 H, s), 7.41(1 H, d, J = 8.1), 6.81 (1 184.2, 158.7, 149.2, 139.1, 133.9,
133 (54), 146 (100), 175 (45),
H, d, J = 8.0), 3.73 (2 H, t, J = 7.3, NCH2), 126.2, 118.1, 110.3, 45.3, 40.4, 32.8, 279 (M+, 45)/281 (15)
3.55 (2 H, t, J = 6.6, CH2Cl), 2.36 (3 H, s), 27.6, 26.8, 26.6, 21.0
1.79 (2 H, m, CH2), 1.73 (2 H, m, CH2),
1.52 (2 H, m, CH2), 1.42 (2 H, m, CH2)
Synthesis 2002, No. 1, 34–38 ISSN 0039-7881 © Thieme Stuttgart · New York

38
Y. Cheng et al.
PAPER
Table 3 Spectroscopic Data of Isatins 17–20 (continued)
Product IR (cm–1)
1H NMR (CDCl3/TMS)
13C NMR (CDCl3/TMS)
MS (EI) (rel. intensity, %)
, J (Hz)
19d
20a
20b
1752, 1731,
1608, 1589,
1473, 1447
7.57 (1 H, s), 7.56 (1 H, d, J = 8.6), 6.86 (1 182.9, 158.0, 149.6, 138.1, 129.9,
153 (40), 166 (100)/168 (40),
H, d, J = 8.2), 3.73 (2 H, t, J = 7.2, NCH2), 125.8, 118.8, 111.7, 45.2, 40.6, 32.7, 299 (M+, 12)/301 (5)/303 (2)
3.53 (2 H, t, J = 6.5, CH2Cl), 1.78 (2 H, m, 27.5, 26.8, 26.5
CH2), 1.72 (2 H, m, CH2), 1.51 (2 H, m,
CH2), 1.41 (2 H, m, CH2)
1730, 1616, 7.12 (1 H, s), 7.13 (1 H, d, J = 9.1), 7.03 (1 184.1, 159.0, 156.8, 145.9, 125.2, 162 (100), 177 (20), 283
H, d, J = 8.3), 3.91 (2 H, t, J = 5.1, OCH2),
1601, 1491
118.3, 113.0, 109.4, 71.5, 69.4, (M+, 10)/285 (4)
56.4, 43.3, 40.9
3.81 (3 H, s, OCH3), 3.77 (2 H, t, J = 5.1,
NCH2), 3.71 (2 H, t, J = 5.5, OCH2), 3.56 (2
H, t, J = 5.5, CH2Cl)
1743, 1729,
1618, 1598,
1492
7.39 (1 H, s), 7.38 (1 H, d, J = 9.7), 6.99 (1 184.0, 159.0, 149.7, 139.1, 133.9,
146 (100), 161 (23), 267 (M+,
H, d, J = 7.9), 3.92 (2 H, t, J = 5.1, OCH2), 125.8, 118.0, 111.6, 71.6, 69.2, 43.2, 17)/269 (7)
3.78 (2 H, t, J = 5.1, NCH2), 3.71 (2 H, t, J 40.8, 21.0
= 5.5, OCH2), 3.56 (2 H, t, J = 5.5, CH2Cl),
2.33 (3 H, s, CH3)
20d
20e
1750, 1731,
1607, 1475,
1448
7.57(1 H, s), 7.56(1 H, d, J = 7.9), 7.13 (1 182.8, 158.4, 150.3, 138.1, 129.9,
107 (70), 166 (10), 168 (80),
H, d, J = 8.5), 3.96 (2 H, t, J = 4.9, OCH2), 125.3, 118.7, 113.5, 71.6, 69.6, 43.3, 181 (80)/183 (45), 287 (M+,
3.80 (2 H, t, J = 5.1, NCH2), 3.73 (2 H, t, J 41.2
= 5.2, OCH2), 3.60(2 H, t, J = 5.6, CH2Cl)
50)/289 (34)/291 (6)
1747, 1731,
1604, 1473,
1440
7.71 (1 H, s), 7.70 (1 H, d, J = 7.2), 7.09 (1 182.6, 158.2, 150.7, 140.9, 128.2,
H, d, J = 9.0), 3.96 (2 H, t, J = 5.0, OCH2), 119.0, 116.9, 113.9, 71.6, 69.5, 43.3, 210 (100)/212 (98), 225 (85)/
3.80 (2 H, t, J = 5.0, NCH2), 3.73 (2 H, t, J 41.2
= 5.2, OCH2), 3.58 (2 H, t, J = 5.5, CH2Cl)
107 (80), 155 (60)/157 (55),
227 (82), 331 (M+, 52)/333
(60)/335 (20)
(8) Venuti, M. C.; Ort, O. Synthesis 1988, 985.
Acknowledgement
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This work was supported by the Scientific Research Foundation for
the Returned Overseas Chinese Scholars, State Education Ministry,
China.
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Synthesis 2002, No. 1, 34–38 ISSN 0039-7881 © Thieme Stuttgart · New York