RSS-Feed abonnieren
DOI: 10.1055/s-0030-1289515
Synthesis of Substituted 3-Cyano- and 3-(Arenesulfonyl)indoles from o-Nitrobenzyl Cyanides and Sulfones
Publikationsverlauf
Publikationsdatum:
06. Oktober 2011 (online)
![](https://www.thieme-connect.de/media/synlett/201117/lookinside/thumbnails/10.1055-s-0030-1289515-1.jpg)
Abstract
Formation of enamines, in the reaction of o-nitrophenylacetonitriles with Vilsmeier reagents, followed by reductive cyclization using Zn in acetic acid, leads to variously substituted 3-cyanoindoles, possessing aryl, alkyl, and aminoalkyl substituents at C-2. The method, when starting from the appropriate o-nitrobenzylsulfones, allows the synthesis of substituted 3-(arenesulfonyl)-indoles.
Key words
indoles - amides - cyclization - nitriles - sulfones
- 1
Dhar TGM.Shen Z.Gu HH.Chen P.Norris D.Watterson SH.Ballentine SK.Fleener CA.Rouleau KA.Barrish JC.Townsend R.Hollenbaugh DL.Iwanowicz E. J. Bioorg. Med. Chem. Lett. 2003, 13: 3557 - 2
Owa T.Yoshino H.Okauchi T.Okabe T.Ozawa Y.Sugi NH.Yoshimatsu K.Nagasu T.Koyanagi N.Kitoh K. Bioorg. Med. Chem. Lett. 2002, 12: 2097 - 3
Yokoi A.Kuromitsu J.Kawai T.Nagasu T.Sugi NH.Yoshimatsu K.Yoshino H.Owa T. Mol. Cancer Ther. 2002, 1: 275 - 4
Turner SC.Carroll WA.White TK.Gopalakrishnan M.Coghlan MJ.Shieh C.-C.Zhang X.-F.Parihar AS.Buckner SA.Milicic I.Sullivan JP. Bioorg. Med. Chem. Lett. 2003, 13: 2003 - 5
Garg NK.Stoltz BM. Tetrahedron Lett. 2005, 46: 1997 - 6
Miyake FY.Yakushijin K.Horne DA. Org. Lett. 2000, 2: 2121 - 7
Mąkosza M.Winiarski J. J. Org. Chem. 1984, 49: 1494 - 8
Mąkosza M.Wojciechowski K. Chem. Rev. 2004, 104: 2631 -
9a
Mąkosza M.Danikiewicz W.Wojciechowski K. Liebigs Ann. Chem. 1988, 203 -
9b
Macor JE.Forman JT.Post RJ.Ryan K. Tetrahedron Lett. 1997, 38: 1673 -
9c
Macor JE.Wehner JM. Tetrahedron Lett. 1993, 34: 349 -
9d
Marino JP.Hurt CR. Synth. Commun. 1994, 24: 839 - 10
Macor JE.Wehner JM. Tetrahedron Lett. 1991, 32: 7195 -
11a
Wróbel Z.Mąkosza M. Synlett 1993, 597 -
11b
Wróbel Z.Mąkosza M. Tetrahedron 1997, 53: 5501 -
12a
Suh JT.Puma BM. J. Org. Chem. 1965, 30: 2253 -
12b
Suh JT. inventors; US 3370063. -
13a
Söderberg BCG.Banini SR.Turner MR.Minter AR.Arrington AK. Synthesis 2008, 903 -
13b
Banini SR.Turner MR.Cummings MM.Söderberg BCG. Tetrahedron 2011, 67: 3603 -
14a
Yu W.Du Y.Zhao K. Org. Lett. 2009, 11: 2417 -
14b
Li X.Du Y.Liang Zh.Li X.Pan Y.Zhao K. Org. Lett. 2009, 11: 2643 -
14c
El-Araby ME.Bernacki RJ.Makara GM.Pera PJ.Anderson WK. Bioorg. Med. Chem. 2004, 12: 2867 -
14d
Orlemans EOM.Schreunder AH.Conti PGM.Verboom W.Reinhoudt DN. Tetrahedron 1987, 43: 3817 -
14e
Wacker DA.Kasireddy P. Tetrahedron Lett. 2002, 43: 5189 -
15a
Batcho AD.Leimgruber W. Org. Synth. 1985, 63: 214 ; Org. Synth., Coll. Vol. VII 1990, 34 -
15b
Clark RD.Repke DB. Heterocycles 1984, 22: 195 -
15c
Gribble GW. J. Chem. Soc., Perkin Trans. 1 2000, 1045 -
16a
Clark CI.White JM.Kelly DP.Martin RF.Lobachevsky P. Aust. J. Chem. 1998, 51: 243 -
16b
Prashad M.Vecchia LL.Prasad K.Repic O. Synth. Commun. 1995, 25: 95 -
16c
Coe JW.Vetelino MG.Bradlee MJ. Tetrahedron Lett. 1996, 37: 6045 - 17
Mąkosza M.Wróbel Z. Rev. Roum. Chim. 1991, 36: 563 ; Chem. Abstr. 1992, 117, 26036 - 19
Mąkosza M.Goliński J.Baran J. J. Org. Chem. 1984, 49: 1488 -
20a
Wojciechowski K.Mąkosza M. Tetrahedron Lett. 1984, 25: 4793 -
20b
Wojciechowski K.Mąkosza M. Synthesis 1986, 651 - 21
Heffernan GD.Coghlan RD.Manas ES.McDevitt RE.Li Y.Mahaney PE.Robichaud AJ.Huselton C.Alfinito P.Bray JA.Cosmi SA.Johnston GH.Kenney T.Koury E.Winneker RC.Deecher DC.Trybulski EJ. Bioorg. Med. Chem. 2009, 17: 7802 - 22
Bernotas R.Lenicek S.Antane S.Zhang GM.Smith D.Coupet J.Harrison B.Schechter LE. Bioorg. Med. Chem. Lett. 2004, 14: 5499 - 23
Bernotas RC.Antane S.Shenoy R.Le V.-D.Chen P.Harrison BL.Robichaud AJ.Zhang GM.Smith D.Schechter LE. Bioorg. Med. Chem. Lett. 2010, 20: 1657 - 24
Wróbel Z.Wojciechowski K.Kwast A.Gajda N. Synlett 2010, 2435
References and Notes
General Procedure
for the Synthesis of Enamines 3a,e,k
The amide 2 (3 mmol) dissolved in dry MeCN (10 mL)
was cooled to -40 ˚C and treated with oxalyl chloride
(3 mmol). The cooling bath was removed, and the reaction mixture allowed
to reach r.t. After evolution of gas ceased (ca. 30 min) the reaction
mixture was cooled to -40 ˚C and treated with
a solution of substrate 1 (1 mmol) and
Et3N (5 mmol) in dry MeCN (10 mL). (In the case of less
soluble sulfones they were added in powdered form to the cooled
Vilsmeier reagent followed by the addition of Et3N).
After stirring for 1 h the reaction mixture was poured into sat.
NH4Cl solution (20 mL), extracted with EtOAc (3 × 20
mL), the extract was dried (Na2SO4), filtered,
evaporated and purified by chromatography.
Enamines 3b-d and 3f-i were
synthesized according to the procedure described previously.¹7
General Procedure for the Synthesis of 3-Cyanoindoles
4
Enamine 3 (1 mmol) in glacial
AcOH (20 mL) was treated with Zn powder (10 mmol) (Note:
a slight exotherm was observed). After stirring for 1 h at r.t.
the mixture was heated to reflux for 1 h. After cooling the solvent
was evaporated to dryness, the residue was dissolved in EtOAc (20
mL), and treated cautiously with sat. NaHCO3 (3 mL).
After filtering through Celite® the solution
was evaporated, and the residue purified by chromatography.
Representative Analytical Data(2
E
,
Z
)-2-(5-Chloro-2-nitrophenyl)-3-(dimethylamino)-3-phenylacrylonitrile
(3a)
White solid, mp 103-106 ˚C. ¹H
NMR (600 MHz, DMSO-d
6): two
isomers, M (major)/N (minor) = 1.2. δ = 2.65
(s, 6 H, M), 3.18 (s, 6 H, N), 7.07 (dd, J = 8.7,
2.2 Hz, 1 H, M), 7.10-7.12 (m,
2 H, M), 7.20-7.24 (m, 2 H, M), 7.29-7.32 (m, 1 H, M), 7.33 (dd, J = 8.7,
2.2 Hz, 1 H, N), 7.43 (d, J = 2.2 Hz,
1 H, M), 7.48-7.55 (m, 5 H, N), 7.51 (d, J = 8.7
Hz, 1 H, M), 7.58 (d, J = 2.2
Hz, 1 H, N), 7.79 (d, J = 8.7
Hz, 1 H, N). MS (EI, 70 eV): m/z (%) = 327
(36), 283 (9), 187 (55), 148 (20), 118 (100), 105 (40). HRMS (EI): m/z calcd for C17H14N3O2
³5Cl:
327.0774; found: 327. 0771.
2-{1-[(4-Methoxyphenyl)methyl]-2-methyl-5-nitro-1
H
-indol-4-yl}-2-[(2
E
,
Z
)-1-methylpyrrolidin-2-ylidene]-acetonitrile
(3d)
Yellow crystals, mp 165-166 ˚C
(hexane-EtOAc).
¹H NMR (500
MHz, DMSO-d
6): two isomers, M (major)/N (minor) = 2.5. δ = 7.74
(d, J = 8.9
Hz, 1 H, M), 7.70 (d, J = 8.9
Hz, 1 H, N), 7.57 (d, J = 8.9
Hz, 1 H, M), 7.56 (d, J = 8.9
Hz, 1 H, N), 6.97-7.01 (m, 2
H, N), 6.93-6.97 (m, 2 H, M), 6.85-6.89 (m, 2 H, M + 2 H, N),
6.45-6.46 (m, 1 H, N), 6.39-6.40
(m, 1 H, M), 5.37-5.47 (m, 2
H, M + 2 H, N), 3.70
(s, 3 H, N), 3.69 (s, 3 H, M), 3.42-3.55 (m, 2 H, M + 2 H, N),
3.34 (s, 3 H, N), 2.92-3.08
(m, 2 H, M), 2.41 (d, J = 0.9
Hz, 3 H, N), 2.41 (d, J = 0.9
Hz, 3 H, M), 2.18 (s, 3 H, M), 2.08-2.22 (m, 2 H, N), 1.96-2.05 (m, 2 H, M), 1.70-1.76 (m, 2 H, N). MS (EI, 70 eV): m/z (%) = 416
(11), 121 (100). HRMS (EI): m/z calcd
for C24H24N4O3: 416.1848; found:
416.1860.
(2
E
,
Z
)-2-(5-Chloro-2-nitrophenyl)-3-pyrrolidin-1-ylpent-2-enenitrile
(3e)
Brown oil. ¹H NMR (500 MHz,
DMSO-d
6): two inseparable isomers, δ = 1.14-1.24
(m, 3 H), 1.68-1.82 (m, 5 H), 2.50-2.70 (m, 2
H), 2.90-3.15 (m, 3 H), 7.45 (br s, 1 H), 7.53-7.59 (m,
1 H), 7.94 (d, J = 8.4
Hz, 1 H). MS (EI, 70 eV): m/z (%) = 305
(31), 235 (12), 165 (100), 110 (15). HRMS (EI): m/z calcd
for C15H16N3
³5ClO2:
305.0931; found: 305.0933.
5-Chloro-2-phenyl-1
H
-indole-3-carbonitrile
(
4a)
Pale
yellow solid, mp >260 ˚C. ¹H
NMR (500 MHz, DMSO-d
6): δ = 7.33
(dd, J = 8.6,
1.9 Hz, 1 H), 7.56-7.60 (m, 2 H), 7.62-7.68 (m,
3 H), 7.96-7.99 (m, 2 H), 12.80 (br s, 1 H). ¹³C NMR
(125 MHz, DMSO-d):²5 δ = 81.7,
114.8, 116.8, 118.0, 124.5, 127.2, 127.6, 129.4, 129.8, 130.8, 134.6,
146.6. MS (EI, 70 eV): m/z (%) = 252
(100), 217 (11), 190 (14). HRMS (EI): m/z calcd
for C15H9N2
³5Cl:
252.0454; found: 252.0449.
6-[(4-Methoxyphenyl)methyl]-7-methyl-2-[3-(methyl-amino)propyl]-3
H
,6
H
-pyrrolo[3,2-
e
]indole-1-carbonitrile
(
4d)
Pale
yellow crystals, mp 177 ˚C (dec., EtOH). ¹H
NMR (500 MHz, DMSO-d
6):²6 δ = 1.87-1.94
(m, 2 H), 2.32 (s, 3 H), 2.41 (s, 3 H), 2.58 (t, J = 7.0
Hz, 2 H), 2.93 (t, J = 7.4
Hz, 2 H), 3.67 (s, 3 H), 5.36 (s, 2 H), 6.55 (s, 1 H), 6.82-6.85
(m, 2 H), 6.89-6.93 (m, 2 H), 7.10 (d, J = 8.7
Hz, 1 H), 7.23 (d, J = 8.7
Hz, 1 H). ¹³C NMR (125 MHz, DMSO-d): δ = 13.0, 25.1,
28.6, 35.7, 45.9, 50.5, 55.5, 81.6, 97.7, 106.0, 106.9, 114.4, 118.3,
118.5, 119.1, 127.8, 129.6, 130.8, 132.4, 136.1, 147.1, 158.7. MS
(EI, 70 eV): m/z (%) = 386
(39), 355 (12), 121 (100). HRMS (EI): m/z calcd
for C24H26N4O: 386.2107; found:
386.2098.
5-Chloro-2-ethyl-1
H
-indole-3-carbonitrile
(
4e)
White
crystals, mp 176-182 ˚C. ¹H
NMR (500 MHz, DMSO-d
6): δ = 1.33
(t, J = 7.6
Hz, 3 H), 2.91 (t, J = 7.6
Hz, 2 H), 7.23 (dd, J = 8.6,
2.0 Hz, 1 H), 7.47 (d, J = 8.6
Hz, 1 H), 7.54 (d, J = 2.0
Hz, 1 H), 12.28 (br s, 1 H). ¹³C NMR (125
MHz, DMSO-d): δ = 13.1,
20.4, 81.7, 113.7, 115.7, 117.1, 122.8, 126.1, 128.3, 133.3, 152.8.
MS (EI, 70 eV):
m/z (%) = 204
(46), 189 (100). HRMS (EI): m/z calcd
for C11H9N2
³5Cl:
204.0454; found: 204.0463
2-(Dimethylamino)-1
H
-benzo[
g
]indole-3-carbonitrile (5)
²7
Yellow
solid. MS (EI, 70 eV): m/z (%) = 235
(100), 220 (54), 192 (24), 164 (8). HRMS (EI): m/z calcd
for C15H13N3: 235.1110; found:
325.1103.
5-Chloro-2-ethyl-1-hydroxy-1
H
-indole-3-carbonitrile
(
7e)
Colorless
crystals, mp 177-183 ˚C (hexane-EtOAc). ¹H NMR
(500 MHz, DMSO-d
6): δ = 1.32
(t, J = 7.6
Hz, 3 H), 2.93 (q, J = 7.6
Hz, 2 H),7.31 (dd, J = 8.7,
2.0 Hz, 1 H), 7.55 (dd, J = 8.7,
0.6 Hz, 1 H), 7.60 (dd, J = 2.0,
0.6 Hz, 1 H), 12.07 (s, 1 H). ¹³C NMR
(125 MHz, DMSO-d): δ = 13.1, 18.6,
77.4, 111.7, 115.7, 117.8, 123.7, 124.2, 127.2, 131.7, 149.5. MS
(EI, 70 eV): m/z (%) = 220
(100), 205 (46), 189 (46). HRMS (EI): m/z calcd
for C11H9N2
³5ClO:
220.0403; found: 220.0405.
One carbon resonance was not observed.
26N-H signals not visible.
27Compound 5 was isolated in insufficient quantities to obtain full analytical data.