Synthetic applications of aminochlorocarbenes: A two-step conversion of N-methylformanilides into 3-arylamino-2-chloroindoles

Article abstract of DOI:10.1055/s-2002-35228

The thermal cyclisation of 1,2-diarylamino-1,2-dichloroethenes (dimers of arylaminochlorocarbenes) in DMF affords 3-arylamino-2-chloroindoles in good yields (70-91%).

Full text of DOI:10.1055/s-2002-35228

2426
PAPER
Synthetic Applications of Aminochlorocarbenes: A Two-step Conversion of
N-Methylformanilides into 3-Arylamino-2-chloroindoles
Synthetic
A
pplica
t
i
ionsof
n
A
minochlor
g
ocarbenes Cheng,*a Yu-Hua Zhan,a Hai-Xia Guan,a Hua Yang,a Otto Meth-Cohn*b
a
Chemistry Department, Beijing Normal University, Beijing 100875, China
E-mail: yincheng@95777.com
b
Chemistry Department, University of Sunderland, Sunderland SR1 3SD, UK
E-mail: otto.meth-cohn@sunderland.ac.uk
Received 29 July 2002
quiring storage at low temperature in many cases. At am-
bient temperature they decomposed on standing. While
examining the nature of this decomposition, we observed
in one case the conversion of the dimer 4 into an indole at
room temperature, as well as in the mass spectrometer
(see below). The dimers as highly nucleophilic alkenes,
were possibly in equilibrium with their ionic electrophilic
analogues, the keteniminium salts 4 , and the interaction
of these two systems would lead to oligomeric material.
With a view to studying the reactivity of aminochlorocar-
benes 3 and their derived dimers 4, we therfore thermoly-
sed a variety of 1,2-bis(arylamino)-1,2-dichloroethene 4
in refluxing DMF. Gratifyingly, these dimers did not de-
compose in hot DMF but instead cyclised to yield novel
indoles, namely 2-chloro-3-(N-arylamino)indoles 5 in
good yields (Scheme 2). Although the photo-cyclisation
of N-vinylanilines [ s+ s+ 2a] to indoles is well
Abstract: The thermal cyclisation of 1,2-diarylamino-1,2-dichlo-
roethenes (dimers of arylaminochlorocarbenes) in DMF affords 3-
arylamino-2-chloroindoles in good yields (70–91%).
Key words: cyclisation,
1,2-diarylamino-1,2-dichloroethenes,
arylaminochlorocarbenes, 3-arylamino-2-chloroindoles
We have shown in earlier work1 that Vilsmeier reagents 2
are readily deprotonated with mild bases to yield ami-
nochlorocarbenes (3, Scheme 1). Under these conditions,
nucleophilic carbenes 2 tend to react with the Vilsmeier
reagent to give, after deprotonation a 1,2-diamino-1,2-
dichloroethene 4. We showed that these systems are use-
ful precursors to isatins, 2,2-bis-indoles and to indolo-
quinolines.1 We herein demonstrate that the dimers 3
derived from N-methylformanilides undergo a facile ther-
mal cyclisation to give 3-arylamino-2-chloroindoles in
good yields.
2
2
documented4 the thermal equivalent is disallowed, sup-
porting the keteniminium-mediated mechanism.
Indoles are among the most important ring systems in the
alkaloids and thus are of considerable pharmacological in-
terest. Over one thousand such alkaloids are known.2 3-
Amino-2-chloroindoles are little known3 systems and ex-
amples of 3-arylamino-derivatives are unknown. The
above-mentioned dimers 4 proved of limited stability, re-
This unexpected result prompted us to optimise the
preparation of the dimers 4. In our earlier work,1 we ob-
tained N-methyl-N-(p-halophenylamino)-1,2-dichloro-
ethenes 4a c by treating the Vilsmeier’s reagents 2a–c
with Hünig’s base at 0–35 °C in chloroform or THF solu-
tion. The dimers 4, bearing electron-donating groups were
Scheme 1
Synthesis 2002, No. 16, Print: 14 11 2002.
Art Id.1437-210X,E;2002,0,16,2426,2430,ftx,en;P04102SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

PAPER
Synthetic Applications of Aminochlorocarbenes
2427
Scheme 2
Table 1 Optimised Reaction Conditions for Dimer 4 Formation and
their Yields
not isolated, being unstable under the reaction conditions.
Indeed, we now find that these dimers are unstable even
in chloroform solution. Furthermore, they are sensitive to
oxygen, heat, acidic conditions, and silica gel. The most
stable dimers are the 4-bromo- and 4-chloro-derivatives,
4b and 4c, which can be kept at room temperature for sev-
eral days. The others, 4a and 4d–h are only stable below
–10 °C. The dimers 4d–g prove to be particularly unsta-
ble, becoming dark in a few hours at room temperature.
With these observations in mind, we prepared the dimers
4 under more appropriate reaction conditions. The best re-
sults are shown in Table 1. The structures of the dimers
have been identified by their IR, 1H NMR, 13C NMR, MS,
CHN analysis or HRMS. All the dimers are white solids
except 4g, which is a colourless oil and partly cyclises to
give the indole 10g even at room temperature in about half
an hour. Consequently, this oily dimer did not give satis-
factory elemental analysis data, and the HRMS of 4g also
1–4
X
Solvent
Temp.
(°C)
Time
(h)
Product Yield
(%)
p-F
CHCl3
CHCl3
CHCl3
THF
–10 to 25
–10 to25
–10 to 25
–10 to 25
–78 to 25
–78 to 25
–10 to 25
–10 to 25
3
4
4
3
6
6
4
3
4a
4b
4c
4d
4e
4f
72
52
68
85
76
50
55
85
p-Cl
p-Br
H
p-Me
p-OMe
m-Cl
m-Br
xylene
THF
CHCl3
CHCl3
4g
4h
revealed the molecular weight of 5g, not 4g, suggesting (as a hydrochloric acid trap) proved effective (Table 2).
that this dimer cyclised under HRMS conditions.
While the symmetrical, para-substituted phenylamino-
ethenes 4a–f afforded only one type of indoles 5a–f, the
cyclization of meta-substituted dimers 4g and 4h, gave
both possible regioisomeric indoles. The major products
are those from cyclisation at the less hindered position, the
ratio of two products being about 5:3 (Scheme 3).
We initially obtained the indole derivative 5b from dimer
4b in refluxing DMF. When we used the same conditions
to prepare the other indoles, we found many of the dimers
were not stable and the reaction mixture became very
dark. However, lower temperatures and added piperidine
Scheme 3
Synthesis 2002, No. 16, 2426–2430 ISSN 0039-7881 © Thieme Stuttgart · New York

2428
Y. Cheng et al.
PAPER
Table 2 Optimised Reaction Conditions for the Formation of the Indoles 5 and their Yields
Starting material Base
Solvent
Temp.
(°C)
Time
(h)
Product
Yield
(%)
4a
4b
4c
4d
4e
4f
piperidine
DMF
DMF
DMF
DMF
DMF
DMF
DMF
110–120
140–160
140–160
100–110
100–110
100–110
140–150
7
7
5a
5b
5c
5d
5e
5f
91
79
70
73
81
78
–
–
5
piperidine
piperidine
piperidine
piperidine
8
8
8
4g
10
5g-1
5g-2
51
30
4h
piperidine
DMF
140–150
18
5h-1
5h-2
51
32
Table 3 Spectroscopic Data for the Dimers 4
Dimers 4 Mp (°C)
IR (cm–1)
1H NMR (C6D6) , J (Hz)
13C NMR (C6D6)
MS (EI) m/z (%)
4a
4b
4c
4d
132a
1506, 1468
6.96 (2 H, t, J = 8.7 Hz), 6.71 (2 H, 159.2, 157.3, 141.5,
272 (82), 291 (59), 306 (100),
432 (15) [M+]
m), 2.79 (3 H, s)
134.3, 116.7/116.8 (d),
116.2/116.0 (d), 37.2
168a
1592, 1490
7.29 (2 H, d, J = 8.9 Hz), 6.80 (2
H, d, J = 8.9 Hz), 3.17 (3 H, s)
143.3, 133.6, 129.2,
125.9, 116.0, 37.1
111 (100), 222 (65)/224 (60),
338 (60)/340 (55), 374 (30)
[M+]/376 (35)/378 (20)/380 (10)
144–146a
129–132a
1589, 1488,
1465
7.33 (2 H, d, J = 9.0 Hz), 6.41 (2
H, d, J = 8.9 Hz), 2.94 (3 H, s)
148.1, 133.6, 132.1,
125.4, 114.8, 39.5
312 (47)/314 (46),
426 (43) [M+ – HCl]/ 428 (100)/
430 (70)
1595, 1579,
1495,1471
7.18 (2 H, t, J = 7.7 Hz), 6.91 (1 H, 146.2, 137.1, 129.5,
t, J = 7.8 Hz), 6.77 (2 H, d, J = 8.5 120.8, 115.5, 37.5
Hz), 2.63 (3 H, s)
117 (93), 219 (100)/220 (93),
234 (88)/235 (60)/236 (32), 270
(94)/272 (30), 306 (6.2) [M+]/
308 (3.6)
4e
4f
130a
132a
Oilb
1611, 1512
7.15 (2 H, d, J = 8.4 Hz), 6.97 (2
H, d, J = 8.4 Hz), 2.95 (3 H, s),
2.26 (3 H, s)
143.3, 134.7, 130.8,
91 (90), 298 (100), 334 (70)
130.2, 115.7, 37.1, 20.7 [M+]/336 (40)/338 (10)
1509, 1470,
1442
6.98 (2 H, d, J = 9.2 Hz), 6.94 (2
H, d, J = 9.2 Hz), 3.49 (3 H, s),
2.97 (3 H, s)
155.2, 139.5, 134.7,
77 (100), 92 (85), 315 (60), 330
117.3, 115.2, 55.3, 37.5 (85)/332 (30), 366 (10) [M+]/368
(8)
4g
1594, 1571,
1482
7.21 (1 H, t, J = 8.1 Hz), 6.91(1 H, 147.1, 136.3, 135.5,
111 (75), 268 (100)/270 (30),
338 (50)/336 (45), 376 (8) [M+]/
378(4)
d, J = 7.9 Hz), 6.81 (1 H, s), 6.72
(1 H, dd, J = 8.2, 1.7 Hz), 2.96 (3
H, s)
130.5, 120.8, 115.4,
113.4, 38.0
4h
81–83a
1589, 1480,
1561
7.14 (1 H, t, J = 8.0 Hz), 7.05 (1 H, 147.3, 136.5, 131.2,
461.8900 [M+]
d, J = 8.3 Hz), 6.95 (1 H, s), 6.75
(1 H, dd, J = 8.2, 1.4 Hz), 2.95 (3
H, s)
123.5, 123.0, 118.0,
114.4, 37.8
a Elemental analysis: C 0.4, H 0.5, N 0.2.
b HRMS: m/z calcd for C16H14Br2Cl2N2, 461.8894; found: 461.8900.
In summary, we herein have discovered a very simple and meier reagents, conversion into aminochlorocarbenes
efficient method for preparing 3-arylamino-2-chloroin- with Hünig’s base and thermal cyclisation of the derived
doles in a two-step route from N-methylformanilides. dimers of these carbenes.
These steps involve formation of the corresponding Vils-
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Synthetic Applications of Aminochlorocarbenes
2429
1
Melting points are uncorrected. H NMR and 13C NMR were ob-
tained on a Bruker Avance 500. IR spectra were recorded using an
AVATAR 360 FT-IR spectrometer. Mass spectra were recorded on
a Trace MS instrument (EI-MS) or Bruker APEX-2 (HRMS) and el-
emental analyses were performed on a GMBH Vario EL instru-
ment. Light petroleum refers to the fraction bp 60–80 °C.
Dimers 4; General Procedure
Under a nitrogen atmosphere, oxalyl chloride (1.40 g, 0.96 mL,
0.011 mol) was added dropwise to an N-methylformanilide 1 (0.01
mol) cooled in an ice-bath to form a solid Vilsmeier’s reagent. A
soln of Hünig’s base (1.42 g, 1.92 mL, 0.011 mol) in an appropriate
solvent (50 mL) was added slowly to the Vilsmeier’s reagent below
Table 4 Spectroscopic Data of the Indoles 5
Indole
Mp (°C)
67–68a
IR (cm–1)
1H NMR
, J (Hz)
13C NMR
MS (EI)
m/z (%)
5a
1550,1508, 7.26–7.28 (1 H, m), 6.99–7.03 (1 H, m),
1487
159.4, 157.5, 157.2, 145.6, 95 (57), 241 (50), 255
(55)/256 (85),
(d), 113.9/114.0 (d), 111.2, 291(65), 306 (100)
6.90–6.96 (3 H, m), 6.59–6.62 (2 H, m), 3.80 131.5, 124.9, 115.7/115.8
(3 H, s), 3.32 (3 H, s)c
110.9, 110.6/110.7 (d),
[M+]/308 (35)
103.6/103.8 (d), 39.7, 30.6
5b
5c
5d
5e
5f
101–102a
136–137a
68–69a
1599,1549, 7.63 (1 H, d, J = 8.7 Hz), 7.26 (1 H, dd, J =
1493, 1469 8.7, 1.7 Hz), 7.21 (1 H, s), 7.17 (2 H, d, J =
148.2, 133.7, 129.5, 125.9, 268 (100)/270 (35),
125.1, 124.4, 123.1, 121.7, 338 (97) [M+]/340
8.9 Hz), 6.57 (2 H, d, J = 8.9 Hz), 3.80 (3 H, 118.9, 117.2, 114.9, 113.2, (85)/342 (35)
s), 3.26 (3 H, s)d
39.8, 31.2
1589,1489, 7.43 (1 H, d, J = 1.6 Hz), 7.35 (1 H, dd, J =
148.1, 133.6, 132.1, 125.7, 314 (40)/316 (41),
125.4, 124.8, 120.8, 119.1, 426 (45) [M+] /428
1466
8.7, 1.8 Hz), 7.27 (2 H, d, J = 9.5 Hz), 7.22
(1 H, d, J = 8.7 Hz), 6.57 (2 H, d, J = 9.0 Hz), 114.8, 114.2, 111.4, 109.8, (100)/430 (70)
3.79 (3 H, s), 3.32 (3 H, s)c
39.5, 30.6
1599,1576, 7.46 (1 H, d, J = 7.9 Hz), 7.24–7.31 (3 H, m), 149.3, 135.0, 129.3, 124.0, 220 (95), 235 (50),
1499, 1465 7.12 (1 H, t, J = 7.5 Hz), 7.01 (1 H, d, J = 8.2 123.4, 122.6, 120.4, 120.1, 255 (40), 270 (100)
Hz), 6.87–6.92 (3 H, m)e
118.7, 117.5, 113.2, 109.7, [M+]/272 (30)
39.4, 30.3
80–81a
1617, 1515 7.29 (1 H, d, J = 8.5 Hz), 7.04 (1 H, d, J = 8.3 147.5, 133.7, 130.0, 129.7, 247 (65), 262 (100),
Hz), 7.05 (1 H, s), 6.92 (2 H, d, J = 8.3 Hz), 129.5, 126.0, 124.2, 122.8, 298 (38) [M+]/300
6.55 (2 H, d, J = 8.5 Hz), 3.71 (3 H, s), 3.28 119.8, 117.9, 113.1, 110.0, (14)
(3 H, s), 2.32 (3 H, s), 2.19 (3 H, s)f
39.0, 29.8, 21.1, 20.0
80–81a
1619,1510, 7.39 (1 H, d, J = 9.0 Hz), 6.86 (1 H, dd, J =
154.9, 152.3, 143.9, 130.4, 280 (55), 300 (50),
127.3, 124.5, 123.0, 120.3, 515 (85), 330 (100)
1488
8.9, 2.1 Hz), 6.76 (2 H, d, J = 9.0 Hz), 6.70
(1 H, s), 6.59 (2 H, d, J = 8.9 Hz), 3.78 (3 H, 115.0, 114.7, 114.1, 112.4, [M+]/332 (65)
s), 3.70 (6 H, s), 3.29 (3 H, s)f
111.2, 100.0, 55.4, 55.3,
39.1, 29.9
5g-1
5g-2
5h-1
107–108a
102–104a
119–120a
1596,1562, 7.33 (1 H, d, J = 1.5 Hz), 7.17 (1 H, d, J = 8.4 150.3, 135.4, 135.2, 130.3, 253 (60), 268 (100)/
1487, 1469 Hz), 7.04 (2 H, m), 6.70 (1 H, d, J = 8.7 Hz), 129.0, 124.0, 122.3, 121.5, 270 (55), 338 (90)/
6.62 (1 H, t, J = 2.2 Hz), 6.48 (1 H, d, J = 8.4 119.6, 119.4, 117.7, 113.0, 340 (87)/342 (30)
Hz), 3.75 (3 H, s), 3.30 (3 H, s)c
111.5, 110.0, 39.5, 30.6
1594,1564, 7.27 (1 H, t, J = 8.0 Hz), 7.19 (1 H, t, J = 7.8 151.3, 136.3, 135.3, 130.3, 268 (100)/270 (45),
1486
Hz), 7.07–7.12 (2 H, m), 6.69 (1 H, d, J = 7.8 126.2, 124.6, 123.4, 121.9, 338 (80)/340 (65)/
Hz), 6.57 (1 H, s), 6.44 (1 H, d, J = 8.4 Hz), 121.6, 118.4, 117.1, 112.7, 342 (35)
3.82 (3 H, s), 3.29 (3 H, s)c
111.1, 108.5, 40.4, 30.8
1593,1567, 7.53 (1 H, s), 7.22 (1 H, dd, J = 8.4, 0.85 Hz), 150.4, 135.6, 130.6, 124.1, 312 (75)/314 (700,
1485
7.16 (1 H, d, J = 8.4 Hz), 7.03 (1 H, t, J = 8.1 123.7, 122.6, 120.6, 119.8, 426 (40) [M+] /428
Hz), 6.88 (1 H, d, J = 7.8 Hz), 6.82 (1 H, s), 119.7, 116.5, 115.9, 113.0, (100)/430 (65)
6.55 (1 H, dd, J = 8.4, 2.2 Hz), 3.78 (3 H, s), 112.0, 39.5, 30.6
3.33 (3 H, s)c
5h-2
120–121b
1592,1559, 7.31 (2 H, d, J = 7.9 Hz), 7.14 (1 H, t, J = 7.9 151.4, 136.0, 130.5, 126.5, 427.9105 [M + 1]
1484
Hz), 7.04 (1 H, t, J = 8.1 Hz), 6.85 (1 H, d, J 125.2, 123.8, 123.6, 123.0, (FAB)
= 7.8 Hz), 6.75 (1 H, s), 6.47 (1 H, d, J = 7.7 120.0, 118.8, 115.4, 111.9,
Hz), 3.82 (3 H, s), 3.31 (3 H, s)c
111.6, 109.0, 40.4, 30.7
a Elemenatal analysis: C 0.4, H 0.6, N 0.5.
b HRMS: m/z calcd for C16H13Br2ClN2 (M + 1)+, 427.9108; found, 427.9108.
c CDCl3.
d DMSO-d6.
e C6D6.
f CD3COCD3.
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Y. Cheng et al.
PAPER
–10 °C or – 78 °C (see Table 1) and the mixture was stirred for the
period of time and at the temperature shown in Table 1. After re-
moval of most of solvent, the residue (about 5–10 mL) was filtered
through a pad of neutral alumina, washed with Et2O (about 300 mL)
and evaporated to give the crude product, which was further puri-
fied by chromatography through neutral alumina, and eluted using
light petroleum–EtOAc, 10:1. The properties of the products are re-
corded in Table 3.
Acknowledgements
This work was supported by the National Natural Science Founda-
tion of China and the Excellent Young Teachers Program of MOE,
P. R. C. We thank to the analytical centre of Beijing Normal Uni-
versity for their help with the spectroscopic analyses.
References
Indoles 5; General Procedure
(1) (a) Cheng, Y.; Goon, S.; Meth-Cohn, O. Chem. Commun.
1996, 1395. (b) Cheng, Y.; Goon, S.; Meth-Cohn, O. J.
Chem. Soc., Perkin Trans. 1 1998, 1619.
(2) Review: Sundberg, R. J. In The Chemistry of Indoles;
Academic Press: New York, 1970.
(3) (a) Marinone, F. A.; Oberti, R.; Caramella, P. J. Chem. Res.,
Miniprint 1983, 0417. (b)Velezheva, V. S.; Ryabova, S. Yu.
Chem. Heterocycl. Compd. 1990, 617. (c)Velezheva, V. S.;
Ryabova, S. Yu.; Mel’man, A. I.; Polshakov, V. I. Chem.
Heterocycl. Compd. 1992, 43.
Under a nitrogen atmosphere, 1,2-diarylamino-1,2-dichloroethenes
4 (0.005 mol) were dissolved in DMF (15 mL) and piperidine (5
mL). The mixture was heated for a period of time at the temperature
shown in Table 2. After removal of DMF and piperidine under vac-
uum, the product was isolated by chromatography on silica gel, and
eluted using light petroleum–EtOAc, 10:1. The properties of the
products are recorded in Table 4.
(4) Sundberg, R. J. In Indoles; Meth-Cohn, O., Ed.; Academic
Press: London, 1996, 39–41; and references therein.
Synthesis 2002, No. 16, 2426–2430 ISSN 0039-7881 © Thieme Stuttgart · New York