Synthesis of β-carbolines from 2-Acyl-1-benzenesulfonyl-3-iodo-1H-indoles

Article abstract of DOI:10.1055/s-2001-18715

2-Acyl-1-benzenesulfonyl-3-iodo-1H-indoles and 1-benzenesulfonyl-3-iodo-1H-indole-2-carbaldehyde give in satisfactory yields 1,3- and 3-substituted-β-carbolines, respectively, by combined palladium-catalyzed coupling with alk-1-ynes followed by 6-endo-dig

Full text of DOI:10.1055/s-2001-18715

PAPER
2477
Synthesis of -Carbolines from 2-Acyl-1-benzenesulfonyl-3-iodo-1H-indoles
S
ynthesis of -Car
i
boline
s
orgio Abbiati, Egle M. Beccalli, Alessandro Marchesini, Elisabetta Rossi*
Istituto di Chimica Organica, Facoltà di Farmacia, Università degli Studi di Milano, Via Venezian, 21 20133 Milano, Italy
Fax +39(2)58354476; E-mail: Elisabetta.Rossi@unimi.it
Received 13 July 2001; revised 11 September 2001
ene-4-sulfonic acid gave 2a in nearly quantitative yield,
Abstract: 2-Acyl-1-benzenesulfonyl-3-iodo-1H-indoles and 1-
compound 2a may be obtained from 1 in 83% yield over
two steps (Scheme 1).
benzenesulfonyl-3-iodo-1H-indole-2-carbaldehyde give in satisfac-
tory yields 1,3- and 3-substituted- -carbolines, respectively, by
combined palladium-catalyzed coupling with alk-1-ynes followed
by 6-endo-dig cycloamination reactions.
The 1-benzenesulfonyl-2-benzoyl-3-iodo-1H-indole (2b)
and the 1-benzenesulfonyl-3-iodo-1H-indole-2-carbalde-
hyde (2d)9 were obtained from the lithium derivative by
Key words: indoles, alkynes, 9H-pyrido[3,4-b]indoles, palladium,
annulation reactions
reaction with benzoic anhydride and ethyl formate respec-
tively, whereas the 1-benzenesulfonyl-2-furoyl-3-iodo-
1H-indole (2c) was formed, beside the ethyl 1-benzene-
sulfonyl-3-iodo-1H-indole-2-carboxylate (2g),8a,10 using
The 9H-pyrido[3,4-b]indole ( -carboline) nucleus occurs
in many natural alkaloids and several of these compounds
show significant biological activities. For instance, -car-
boline derivatives exhibit affinity for the benzodiazepine
receptor,1 antileukemic activity,2 antitumor3 and antibiot-
ic properties.3,4 Despite the fact that these properties have
spurred considerable synthetic efforts,5 the development
of new synthetic methods for the construction of -carbo-
line ring systems remains an attractive research area.
furoyl ethyl carbonate11 as electrophile (Scheme 1).
MeOH, ∆
pTSA, 96%
I
I
N
N
In connection with our ongoing interest in developing new
synthetic strategies for the construction of heterocyclic
rings involving alkyne derivatives,6 we focused our atten-
tion on the synthesis of 2-acyl-1-benzenesulfonyl-3-iodo-
1H-indoles and 1-benzenesulfonyl-3-iodo-1H-indole-2-
carbaldehyde. We envisaged that their 3-alkynyl-1-benze-
nesulfonylindole derivatives could represent useful build-
ing blocks for the synthesis of 1,3- and 3-substituted- -
carbolines, respectively, by sequential addition/elimina-
tion/cycloamination reactions.7
O
OAc
SO2Ph
2a 43%
SO2Ph
2f 42%
(MeCO)2O
I
I
I
R
LDA, THF
N2, - 60°C
E
Li
N
N
SO2Ph
N
O
SO2Ph
SO2Ph
2b, E=(PhCO)2O,
R=Ph, 79%
In this work we wish to report the full details of the results
we have obtained, as well as the scope and limitations of
this synthetic methodology. Our goal during this work
was to provide a clean, high yielding, general synthesis of
functionalized 9H-pyrido[3,4-b]indoles ( -carbolines).
1
2d, E=HCOOEt,
R=H, 65%
OCOOEt
O
O
The 2-acyl-1-benzenesulfonyl-3-iodo-1H-indoles 2a–c
and the 1-benzenesulfonyl-3-iodo-1H-indole-2-carbalde-
hyde (2d) were synthesized starting from the readily ac-
cessible 1-benzenesulfonyl-3-iodo-1H-indole (1),8 via
lithiation with LDA8 followed by electrophilic substitu-
tion with suitable electrophiles (Scheme 1, Table 1).
I
I
CHO
OEt
O
N
N
N
O
O
O
SO2Ph
SO2Ph
2c 57%
2g 26%
In particular, the reaction of 1-benzenesulfonyl-3-iodo-2-
lithio-1H-indole (1) with acetic anhydride afforded, be-
side the 2-acetyl-1-benzenesulfonyl-3-iodo-1H-indole
(2a), the corresponding enol acetate 2f. Since the treat-
ment of compound 2f with methanol and catalytic tolu-
I
I
MnO2
N
N
CH2Cl2
N
N
OH
O
O
O
SO2Ph
SO2Ph
Synthesis 2001, No. 16, 30 11 2001. Article Identifier:
1437-210X,E;2001,0,16,2477,2483,ftx,en;Z07901SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881
2e 85%
Scheme 1

2478
G. Abbiati et al.
PAPER
Table 1 1-Benzenesulfonyl-3-iodo-1H-indoles 2a–f Prepared
Product
Mp (°C)
121
IR (KBr)
(cm–1)
1H NMR (200 MHz, CDCl3)
, J (Hz)
13C-APT NMR (50.3 MHz, CDCl3)
2a
1670, 1500
2.77 (s, 3 H, CH3), 7.34–7.57 (m, 6 Harom),
7.80 (m, 2 Harom), 8.02 (dd, 1 Harom, J = 8.0,
1.1)
32.1 (CH3), 73.1, 132.3, 136.0, 136.2, 140.2
(quat. Csp2, 2 C), 115.2, 123.4, 125.3, 127.3,
127.7, 129.2, 134.4 (Csp2H), 195.3 (C=O)
2b
2c
159–160
169
1649, 1570
7.47 (m, 2 Harom), 7.55–7.68 (m, 5 Harom), 7.73
(m, 2 Harom), 7.82–7.94 (m, 4 Harom), 8.04 (d,
1 Harom, J = 8.4)
72.5, 131.9, 135.5, 136.9, 137.1, 137.6 (quat.
C
sp2), 114.6, 123.0, 124.9, 127.3, 127.6,
128.8, 129.3, 130.1, 134.1, 134.3 (Csp2H),
189.1 (C=O)
1635, 1544
6.65 (dd, 1 Harom, J = 3.7, 1.8), 7.26 (dd, 1
Harom, J = 3.7, 0.7), 7.38–7.60 (m, 6 Harom),
7.75 (dd, 1 Harom, J = 1.8, 0.7), 7.95 (m, 1
Harom), 7.99 (m, 1 Harom), 8.08 (dd, 1 Harom, J
= 8.4, 0.7)
73.9, 131.9, 135.7, 136.8, 152.5 (quat. Csp2, 2
C overlap), 113.0, 114.8, 121.7, 123.2, 125.0,
127.6, 129.3, 134.4, 148.2 (Csp2H, 2C over-
lap), 175.5 (C=O)
2d
2e
183–184a
208–209
1761, 1482,
1438
7.45–7.65 (m, 6 Harom), 7.80 (m, 2 Harom), 8.23
(d, 1 Harom, J = 8.4), 10.43 (s, 1 H, CHO)
81.8, 132.3, 137.4, 137.8 (quat. Csp2, 2 C
overlap), 115.6, 124.9, 125.5, 126.9, 129.4,
130.0, 134.5 (Csp2H), 182.8 (C=O)
1638, 1526
3.30 (s, 3 H, CH3), 5.31 (s, 2 H, CH2), 7.40–
7.62 (m, 11 Harom), 8.10 (m, 3 Harom), 8.14 (m,
56.4 (CH3), 71.5 (CH2), 118.3, 126.8, 131.7,
135.3, 137.2, 137.4, 139.0 (quat. Csp2, 2 C
overlap), 110.8, 114.7, 122.8, 122.9, 123.8,
124.5, 124.8, 126.9, 127.8, 129.2, 134.3,
138.6 (Csp2H), 182.1 (C=O)
1 Harom
)
2f
164
1721, 1639
2.16 (s, 3 H, CH3), 5.29 (d, 1 H, =CH2, J =
1.8), 5.82 (d, 1 H, =CH2, J = 1.8), 7.36–7.55
(m, 6 Harom), 7.80 (m, 2 Harom), 8.18 (dd, 1
Harom, J = 8.0, 1.1)
21.4 (CH3), 111.4 (=CH2), 79.6, 132.2, 135.4,
136.6, 137.8, 144.4 (quat. Csp2), 115.6, 123.4,
124.9, 126.9, 127.2, 129.0, 134.1 (Csp2H),
168.3 (C=O)
2g
2h
136–137b
1726, 1598,
1580, 1545
1.49 (t, 3 H, CH3, J = 7.0), 4.55 (q, 2 H, CH2,
J = 7.0), 7.30–7.62 (m, 6 Harom), 8.02 (m, 3
14.1 (CH3), 62.8 (CH2), 73.5, 131.6, 133.6,
135.6, 137.5 (quat. Csp2), 114.8, 123.2, 124.8,
127.4, 127.5, 129.2, 134.2 (Csp2H), 161.8
(C=O)
Harom
)
88
3530, 1462,
1374
3.25 (s, 3 H, CH3), 4.43 (d, 1 H, J = 11.0, OH,
D2O exch.), 5.35, 5.42 (AB system, 2 H, CH2,
J = 11.0), 6.91 (dd, 1 H, CHOH, J = 1.4, 11),
7.05 (t, 1 Harom, J = 7.3), 7.10–7.59 (m, 11
56.3 (CH3), 67.3 (CH), 77.6 (CH2), 76.8,
116.5, 127.1, 131.6, 136.8, 137.1, 137.9,
140.4 (quat. Csp2), 110.2, 114.9, 115.3, 120.1,
120.5, 122.6, 123.0, 124.6, 126.4, 126.7,
128.9, 133.8 (Csp2H)
Harom), 8.07 (m, 1 Harom
)
a Lit.9 mp 189–191 °C.
b Lit.8a,10 mp 128–130 °C.
Finally, the (1-benzenesulfonyl-3-iodo-1H-indol-2-yl)(1- be correlated to the steric hindrance exerted by the bulky
methoxymethyl-1H-indol-3-yl)methanone (2e) was ob- indolyl substituent bonded at C-2.
tained by active manganese dioxide oxidation of the cor-
responding alcohol, prepared by reaction of the lithium
The subsequent treatment of 3 with ammonia in methanol
leads to the formation of the -carbolines 4a–k through
sequential addition/elimination/cycloamination reactions
(Scheme 2 and Tables 2– 5).
derivative of 1 with 1-methoxymethyl-1H-indole-3-
carbaldehyde12 (Scheme 1).
The 3-iodo-indoles 2a–d undergo palladium-catalyzed
As depicted in Scheme 2, when the reaction was per-
formed with 3-alkynyl-indoles 3a–g, the N-benzenesulfo-
nyl group was lost during the cyclization step and the
coupling with alk-1-ynes13 at room temperature to afford
the 2-acyl-3-alkynyl-1-benzenesulfonyl-1H-indoles 3a–h
and the 3-alkynyl-1-benzenesulfonyl-1H-indole-2-carbal-
corresponding -carbolines 4a–g are the sole reaction
dehydes 3i–j. Surprisingly, the reaction of 2e with pheny-
products. Whereas, when the reaction was performed with
3-alkynyl-indoles 3i–j, both N-benzenesulfonyl and N-
unsubstituted- -carbolines, 4h–j and 4i–k respectively,
lacetylene failed to give the target 3-alkynyl derivative
and, even heating the reaction mixture at 60 °C, the start-
ing material was recovered in quantitative yield. Very
were isolated after chromatographic purification of the
likely the behavior of 2e in cross-coupling reactions can
crude reaction mixture. Moreover, compounds 4h and 4j
were recovered unchanged even when heated at 120 °C in
Synthesis 2001, No. 16, 2477–2483 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of -Carbolines
-Carbolines 4a–k Prepared
2479
R1
Table 3
I
Product
Yield (%)
80
Mp (°C)
147–149
R1
H
R
R
Pd(OAc)2, DPPF,
TEA, DMF, rt
N
Ph
O
N
4a
SO2Ph
N
O
SO2Ph
3a-j
N
H
2a-d
C5H11
R1
N
4b
4c
54
68
84–86
NH3
N
H
3a-g
N
MeOH
N
H
R
HO
4a-g
169–171
N
N
H
R1
R1
Ph
NH3
N
3i-j
N
N
4d
4e
MeOH
73
68
105–107
137–139
N
N
H
N
H
Ph
SO2Ph
4h,j
4i,k
HO
N
N
H
NH3
Ph
3h
3k
MeOH
C5H11
Scheme 2
N
4f
55
76
151–153
164–166
N
H
O
Table 2 1-Benzenesulfonyl-3-alkynyl-1H-indoles 3a–k Prepared
HO
Product
3a
R
R1
Yield (%)
Mp (°C)
152–154
157–159
4g
N
Me
Me
Ph
82
86
N
H
O
3b
C5H11
OH
Ph
3c
Me
Ph
83
75
111–112
139–141
165–167a
N
4h
30
N
SO2Ph
3d
Ph
Ph
OH
3e
Ph
64
93–95
N
4i
4j
53
66
251–253b
177–180
N
H
HO
3f
C5H11
82
92
105–106
66–69
O
O
O
N
HO
CH3
CH3
N
3g
SO2Ph
HO
3h
3i
SiMe3
53
85
65–66
4k
27
248–251
N
H
H
Ph
141–143a
N
H
HO
CH3
CH3
a Lit.5d mp 167–170 °C.
b Lit.14 mp 253–254 °C.
3j
70
68
143–144
178–179
3k
H
O
ammonia and methanol for 24 h. These results clearly
point out that the deprotection of N-1 precedes the forma-
tion of -carboline nucleus. Finally, 3-alkynylindole 3h
failed to give the target -carboline derivative and the
a Lit.5d mp 156–157 °C.
Synthesis 2001, No. 16, 2477–2483 ISSN 0039-7881 © Thieme Stuttgart · New York

2480
G. Abbiati et al.
PAPER
Table 4 Spectral Data of 1-Benzenesulfonyl-3-alkynyl-1H-indoles 3a–k
Product
IR (KBr)
1H NMR (200 MHz, CDCl3)
, J (Hz)
13C-APT NMR (50.3 MHz, CDCl3)
C=O (cm–1)
3a
1690
1695
1690
1650
1650
2.87 (s, 3 H, CH3), 7.38–7.62 (m, 10 Harom), 7.78
(m, 1 Harom), 7.98 (m, 2 Harom), 8.11 (d, 1 Harom, J =
8.4)
31.2 (CH3), 79.7, 98.7 (Csp), 109.8, 122.4, 129.7,
136.82, 137.89, 140.63 (quat. Csp2), 115.4, 121.8,
124.8, 127.4, 127.9, 128.6, 129.1, 129.2, 131.8,
134.1 (Csp2H), 193.0 (C=O)
3b
3c
3d
3e
0.94 (t, 3 H, CH3CH2, J = 7.3), 1.42 (m, 4 H, CH2),
1.66 (m, 2 H, CH2), 2.51 (t, 2 H, CH2, J = 7.0), 2.79
(s, 3 H, CH3CO), 7.28–7.67 (m, 6 Harom), 7.95 (m, 2
Harom), 8.07 (d, 1 Harom, J = 8.4)
14.0 (CH3CH2), 19.8, 22.2, 28.3, 31.1 (CH2), 31.2
(CH3CO), 70.9, 100.7 (Csp), 110.9, 130.2, 136.8,
137.9, 140.3 (quat. Csp2), 115.4, 121.7, 124.6,
127.4, 127.7, 129.0, 134.0 (Csp2H), 193.1 (C=O)
1.70 (m, 8 H, CH2), 2.05 (m, 2 H, CH2), 2.38 (br s,
1 H, D2O exch.), 2.80 (s, CH3), 7.29–7.66 (m, 6
23.4, 25.2, 39.9 (CH2), 31.4 (CH3), 69.3 (C–OH),
74.4, 102.7 (Csp), 109.4, 129.7, 136.6, 137.7, 140.7
(quat. Csp2), 115.3, 121.6, 124.8, 127.4, 127.8,
129.1, 134.2 (Csp2H), 193.2 (C=O)
Harom), 7.95 (m, 2 Harom), 8.08 (m, 1 Harom
)
7.14–7.33 (m, 4 Harom), 7.37–7.72 (m, 9 Harom),
7.76–7.82 (m, 1 Harom), 8.30–8.18 (m, 5 Harom
79.4, 98.0 (Csp), 109.6, 122.5, 129.5, 136.1, 137.4,
137.9, 138.7 (quat. Csp2), 114.9, 121.5, 124.7,
127.3, 127.7, 128.3, 128.7, 128.8, 129.3, 130.3,
131.6, 133.9, 134.3 (Csp2H), 187.9 (C=O)
)
1.05 (m, 10 H, CH2), 1.98 (br s, 1 H, OH, D2O
exch.), 7.33–7.70 (m, 9 Harom), 8.00–8.15 (m, 5
23.3, 25.0, 39.7 (CH2), 69.2 (COH), 74.3, 101.6
(Csp), 108.6, 129.3, 135.9, 137.3, 138.0, 138.7 3
(quat. Csp2), 114.7, 121.4, 124.5, 127.2, 127.8,
128.7, 129.2, 130.3, 133.9, 134.3 (Csp2H), 188.0
(C=O)
Harom
)
3f
1655
0.89 (t, 3 H, CH3CH2, J = 7.3), 1.34 (m, 4 H, CH2),
1.49 (m, 2 H, CH2), 2.36 (t, 2 H, CH2, J = 7.0), 6.64
(dd, 1 Harom, J = 1.8, 3.7), 7.28–7.75 (m, 8 Harom),
13.9 (CH3CH2), 19.6, 22.2, 28.2, 30.9 (CH2), 70.2,
99.6 (Csp), 111.0, 130.1, 136.0, 137.1, 137.4, 152.9
(quat. Csp2), 112.7, 114.9, 121.5, 124.5, 127.3,
127.6, 129.1, 134.2, 147.8 (Csp2H, 2 C overlap),
174.6 (C=O)
8.06 (m, 3 Harom
)
3g
3h
3i
1650
1650
1670
1670
1655
1.49 (s, 6 H, CH3), 1.90 (br s, OH, D2O exch.), 6.67
(dd, 1 Harom, J = 1.8, 3.6), 7.33–7.77 (m, 8 Harom),
31.3 (CH3), 71.9 (COH), 65.5, 102.8 (Csp), 109.8,
129.4, 136.0, 137.3, 137.6, 152.7 (quat. Csp2),
112.9, 114.9, 121.5, 121.9, 124.7, 127.6, 129.2,
134.4 (Csp2H, 2 + 2 C overlap), 174.2 (C=O)
8.08 (m, 3 Harom
)
0.14 (s, 9 H, CH3), 6.65 (dd, 1 Harom, J = 1.5, 3.7),
7.32–7.77 (m, 8 Harom), 8.10 (m, 3 Harom
–0.14 (CH3), 94.1, 104.1 (Csp), 109.6, 129.5, 135.9,
137.7, 138.2, 152.7 (quat. Csp2), 112.8, 114.7,
121.6, 122.0, 124.5, 127.4, 127.8, 129.2, 134.3,
148.0 (Csp2H), 174.2 (C=O)
)
7.25–7.60 (m, 10 Harom), 7.85 (m, 3 Harom), 8.30 (d,
1 Harom, J = 8.4), 10.55 (s, 1 H, CH=O).
80.3, 100.0 (Csp), 116.1, 122.4, 129.5, 137.1, 137.8
(quat. Csp2, 2 C overlap), 115.6, 122.5, 125.1, 127.0,
128.5, 129.4, 129.7 132.2, 132.6, 134.4 (Csp2H),
181.3 (CH=O)
3j
1.69 (s, 6 H, CH3), 2.90 (br s, 1 H, OH, D2O exch.),
7.33–7.87 (m, 8 Harom), 8.23 (d, 1 Harom, J = 8.4),
10.47 (s, 1 H, CH=O)
31.3 (CH3), 73.0 (COH), 65.8, 105.1 (Csp), 115.6,
137.2, 137.5, 137.6 (quat. Csp2, 2C overlap), 115.5,
122.4, 125.1, 126.9, 129.4, 129.8, 134.5 (Csp2H),
181.6 (CH=O)
3k
3.31 (s, 1 H, CH), 6.65 (dd, 1 Harom, J = 1.8, 3.7),
7.33 (dd, 1 Harom, J = 0.7, 3.7), 7.37–7.68 (m, 5
Harom), 7.71 (m, 1 Harom), 7.76 (dd, 1 Harom, J = 0.7,
73.4, 85.5 (Csp), 108.3, 129.6, 135.7, 137.2, 138.8,
152.7 (quat. Csp2), 112.9, 114.8, 121.4, 121.9,
124.8, 127.5, 127.7, 129.3, 134.4, 148.3 (Csp2H),
174.2 (C=O)
1.8), 8.02–8.13 (m, 3 Harom
)
1-benzenesulfonyl-3-ethynyl-2-furoyl-1H-indole
was isolated as the main reaction product.
(3k) In summary, we have shown that the combined palladi-
um-catalyzed coupling of readily available 3-iodo-2-
acylindoles 2 with alk-1-ynes followed by 6-endo-dig an-
The reaction mechanism probably involves the intermedi-
acy of an imine that undergoes a regioselective 6-endo-dig
cyclization to give 4.15
nulation reactions in the presence of ammonia led in sat-
isfactory yields to functionalized 9H-pyrido[3,4-
b]indoles.
Synthesis 2001, No. 16, 2477–2483 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of -Carbolines
2481
Table 5 Spectral Data of -Carbolines 4a–k
Product
IR (KBr)
cm–1
1H NMR (200 MHz, CDCl3)
, J (Hz)
13C-APT NMR (50.3 MHz, CDCl3)
4a
3428, 1624,
1600, 1565
2.86 (s, 3 H, CH3), 7.28–7.56 (m, 6 Harom), 8.08–
8.18 (m, 3 Harom), 8.23 (s, 1 Harom), 8.41 (br s, 1 H,
D2O exch.)
20.5 (CH3), 122.5, 129.5, 133.9, 140.6, 140.9,
141.4, 147.8 (quat. Csp2), 109.7, 111.7, 120.2,
121.8, 127.0, 127.6, 128.3, 128.7 (Csp2H)
4b
3432, 1626,
1566, 1501
0.94 (t, 3 H, CH3CH2, J = 7.3), 1.40 (m, 4 H, CH2),
1.83 (m, 2 H, CH2), 2.80 (s, 3 H, CH3), 2.96 (t, 2 H,
CH2, J = 7.0), 7.27 (dt, 1 Harom, J = 1.5, 6.3), 7.50
(m, 2 Harom), 7.68 (s, 1 Harom), 8.11 (d, 1 Harom, J =
8.0), 8.65 (br s, 1 H, D2O exch.)
14.1 (CH3CH2), 20.2 (CH3), 22.7, 30.7, 31.8, 38.3
(CH2), 122.1, 129.5, 133.2, 140.8, 151.5 (quat. Csp2
2 C overlap), 111.0, 111.6, 119.8, 121.8 , 128.1
(Csp2H)
,
4c
4d
4e
4f
3392, 3232,
1624, 1570,
1501
1.55–2.15 (m, 10 H, CH2), 2.83 (s, 3 H, CH3), 5.20
(br s, 1 H, D2O exch.), 7.25 (m, 1 Harom), 7.54 (m, 2
Harom), 7.86 (s, 1 Harom), 8.14 (d, 1 Harom, J = 7.7),
8.23 (br s, 1 H, D2O exch.)
20.2 (CH3), 23.1, 25.1, 39.7 (CH2), 72.6 (COH),
122.2, 129.9, 133.6, 139.1, 140.9, 155.8 (quat.
Csp2), 107.3, 111.6, 120.1, 121.8, 129.1 (Csp2H)
3430, 1622,
1558, 1519,
1491
7.30–7.70 (m, 9 Harom), 8.08–8.28 (m, 5 Harom), 8.41
(s, 1 Harom), 8.51 (br s, 1 H, D2O exch.)
122.4, 131.2, 132.9, 139.0, 140.6, 140.9, 142.2,
148.1 (quat. Csp2), 110.3, 111.7, 120.4, 121.8,
126.9, 127.8, 128.3, 128.5, 128.7, 128.8, 129.9
(Csp2H)
3400, 1626,
1563, 1495
1.55–2.15 (m, 10 H, CH2), 5.20 (br s, 1 H, D2O
exch.), 7.33 (m, 1 Harom), 7.58 (m, 5 Harom), 8.05 (m,
3 Harom), 8.19 (d, 1 Harom, J = 7.7), 8.52 (br s, 1 H,
D2O exch.)
22.6, 25.9, 39.5 (CH2), 72.9 (COH), 112.8, 122.1,
131.6, 132.6, 138.4, 141.2, 156.4 (quat. Csp2),
108.5, 111.6, 120.3, 121.8, 128.2, 128.7, 128.9,
129.2 (Csp2H)
3400, 1628,
1577, 1554
0.94 (t, 3 H, CH3CH2, J = 7.3), 1.40 (m, 4 H, CH2),
1.88 (m, 2 H, CH2), 3.00 (t, 2 H, CH2, J = 7.0), 6.67
(dd, 1 Harom, J = 1.8, 3.7), 7.25 (m, 2 Harom), 7.58 (m,
2 Harom), 7.73 (m, 2 Harom), 8.13 (d, 1 Harom, J = 7.7),
9.22 (br s, 1 H, D2O exch.)
14.1 (CH3CH2), 22.7, 30.2, 31.7, 38.8 (CH2), 121.4,
130.0, 132.5, 140.9 , 151.9, 154.9 (quat. Csp2, 2 C
overlap), 111.6, 112.2, 112.3, 119.8, 121.7, 128.4,
128.9, 131.0 (Csp2H)
4g
4h
3435, 1626,
1579, 1555
1.71 (s, 6 H, CH3), 5.30 (br s, 1 H, D2O exch.), 6.69
(dd, 1 Harom, J = 1.8, 3.3), 7.34 (m, 2 Harom), 7.59 (m,
2 Harom), 7.74 (m, 1 Harom), 7.92 (s, 1 Harom), 8.17 (d,
1 Harom, J = 8.1), 9.32 (br s, 1 H, D2O exch.)
31.3 (CH3), 71.8 (COH), 121.4, 130.4, 130.7,
132.0, 141.3, 154.5, 155.8 (quat. Csp2), 108.1,
108.9, 111.7, 112.4, 120.2, 121.8, 128.8, 142.9
(Csp2H)
1615, 1594,
1582, 1555
7.34–7.57 (m, 7 Harom), 7.68 (dt, 1 Harom
,
124.8, 133.9, 134.0, 137.6, 139.4, 139.5, 152.4
(quat. Csp2), 110.9, 115.4, 121.6, 124.5, 126.7,
127.0, 128.8, 128.9, 129.4, 130.2, 134.3, 136.9
(Csp2H)
J = 1.1, 7.3), 7.91 (m, 2 Harom), 8.08 (m, 3 Harom),
8.24 (d, 1 Harom, J = 0.7), 8.41 (d, 1 Harom, J = 8.4),
9.72 (d, 1 Harom, J = 0.7)
4i
4j
3434, 1629,
1600, 1577,
1553
7.30–7.58 (m, 6 Harom), 8.12 (m, 2 Harom), 8.22 (d, 1
Harom, J = 8.0), 8.41 (s, 1 Harom), 8.60 (br s, 1 H, D2O
exch.), 9.01 (d, 1 Harom, J = 1.1)
121.9, 130.3, 135.3, 140.5, 141.1, 148.1 (quat.
Csp2), 111.7, 111.8, 120.3, 121.8, 127.0, 127.9,
128.7, 128.8, 133.1 (Csp2H)
3434, 1618,
1581, 1562
1.65 (s, 6 H, CH3), 4.85 (br s, 1 H, D2O exch.),
7.35–7.57 (m, 4 Harom), 7.67 (dt, 1 Harom, J = 1.1,
7.3), 7.90 (m, 3 Harom), 8.03 (dq, 1 Harom, J = 0.7,
1.5, 7.7), 8.38 (dd, 1 Harom, J = 0.7, 8.4), 9.53 (d, 1
Harom, J = 1.1)
31.3 (CH3), 72.3 (COH), 124.5, 133.8, 134.0,
137.5, 139.5, 160.9 (quat. Csp2), 109.2, 115.2,
121.7, 124.4, 126.6, 129.4, 130.3 134.3, 134.9
(Csp2H)
4k
3246, 2964,
1629, 1557,
1501
1.71 (s, 6 H, CH3), 4.70 (br s, 1 H, D2O exch.), 7.31
(m, 1 Harom), 7.54 (m, 2 Harom), 8.04 (s, 1 Harom),
8.16 (d, 1 Harom, J = 7.7), 8.75 (br s, 1 H, D2O
31.3 (CH3), 72.3 (COH), 121.6, 130.6, 135.0,
141.3, 155.9 (quat. Csp2), 109.2, 111.7, 120.2,
121.8, 128.8, 131.0 (Csp2H)
exch.), 8.81 (s, 1 Harom
)
Merck silica gel 60 F254 thin-layer plates were employed for TLC.
Merck silica gel (230–400 mesh) was used for flash column chro-
matography. Melting points, measured with a Stuart Scientific
SMP3 apparatus, are uncorrected. IR spectra were recorded on a
FT-IR Perkin Elmer Spectrum One spectrophotometer in KBr pel-
lets. 1H NMR and 13C NMR spectra were recorded in CDCl3, with
a Varian-Gemini 200 spectrometer. All starting materials, catalysts,
ligands, bases, and solvents (anhyd solvents included) if not already
stated, are commercially available and were used as purchased,
without further purification. All new compounds gave satisfactory
microanalyses: C 0.35; H 0.15; N 0.25.
Synthesis 2001, No. 16, 2477–2483 ISSN 0039-7881 © Thieme Stuttgart · New York

2482
G. Abbiati et al.
PAPER
2-Acetyl-1-benzenesulfonyl-3-iodo-1H-indole (2a) and 2-(1-
Acetylethen-1-yl)-1-benzenesulfonyl-3-iodo-1H-indole (2f)
To a N2 flushed solution of 1 (1.92 g, 5 mmol) in anhyd THF (20
mL) was added a 2.0 M solution of LDA (3 mL, 6 mmol) in heptane/
THF/ethylbenzene at –60 °C. The reaction mixture was then
warmed to –40 °C and Ac2O was added (0.66 mL, 7 mmol). The
mixture was reacted at r.t. for 1 h, poured into 4.5% HCl (30 mL)
and extracted with CH2Cl2 (2 40 mL). The combined organic
phases were dried (Na2SO4), filtered and evaporated to dryness. The
crude product was purified by flash chromatography (eluent: hex-
ane–CH2Cl2, from 6:1 to 1:1) to afford progressively compounds 2a
and 2f.
(1-Benzenesulfonyl-3-iodo-1H-indol-2-yl)-(1-methoxymethyl-
1H-indol-3-yl)methanone (2e)
A mixture of 2h (573 mg, 1 mmol), CH2Cl2 (20 mL) and active
MnO2 (2.5 g) was stirred at r.t. for 12 h. The reaction mixture was
then filtered through a Celite pad and evaporated to dryness. The
crude product was purified by flash chromatography over silica gel.
Elution with hexane–CH2Cl2 (from 3:1 to 1:3) afforded pure 2e. For
data see Scheme 1 and Table 1.
2-Acyl-3-alkynyl-1-benzenesulfonyl-1H-indoles 3a–j
To a N2 flushed solution of 3-iodoindoles 2a–d (1.0 mmol) in anhyd
DMF (4 mL) were added the appropriate alk-1-yne (1.2 mmol),
Et3N (2.77 mL, 20 mmol), CuI (3.81 mg, 0.02 mmol), and tet-
rakis(triphenylphosphine)palladium(0) (46.22 mg, 0.04 mmol). The
reaction mixture was stirred at r.t. for 24 h, poured into 0.1 M HCl
(150 mL) and extracted with EtOAc (2 70 mL). The combined or-
ganic layers were dried (Na2SO4) and evaporated to dryness. The
crude was purified by flash chromatography over silica gel (eluent:
hexane–EtOAc mixtures) to furnish pure 3a–j. For data see
Scheme 2 and Tables 2, 4.
The enol acetate 2f (935 mg, 2 mmol) was then converted to the cor-
responding ketone 1a by heating in MeOH (30 mL) with a catalytic
amount (50 mg) of p-TSA for 1 h. The mixture was evaporated to
dryness, washed with H2O (30 mL) and extracted with CH2Cl2 (2
25 mL). The combined organic layers were dried (Na2SO4) and the
solvent was evaporated under reduced pressure. The crude product
was purified by flash chromatography over silica gel (eluent: hex-
ane–CH2Cl2, 1:1) to yield pure 2a. For data see Scheme 1 and
Table 1.
9H-Pyrido[3,4-b]indoles 4a–k
A solution of the appropriate 3-alkynyl-1-(phenylsulfonyl)indoles 3
(1.0 mmol) in anhyd NH3 and MeOH (NH3/MeOH, 2 M solution,
10 mL) was heated at 90 °C in a sealed tube for 20 h. The solvent
was then evaporated under reduced pressure. The residue, purified
by flash chromatography (hexane–EtOAc mixtures) afforded pure
4. For data see Scheme 2 and Tables 3, 5.
1-Benzenesulfonyl-2-benzoyl-3-iodo-1H-indole (2b), 1-
Benzenesulfonyl-2-furoyl-3-iodo-1H-indole (2c) and Ethyl 1-
benzenesulfonyl-3-iodo-1H-indole-2-carboxylate (2g)
To a N2 flushed solution of 1 (1.15 g, 3 mmol) in anhyd THF (20
mL) was added a 2.0 M solution of LDA (3 mL, 6 mmol) in heptane/
THF/ethylbenzene at –60 °C. After 10 min at –60 °C, a solution of
benzoic anhydride (1.51 g, 6 mmol) or mixed anhydride (0.92 g, 5
mmol) in THF (3 mL) was added. The mixture was allowed to warm
to r.t. (1 h), evaporated to dryness, washed with H2O (50 mL) and
extracted with CH2Cl2 (2 40 mL). The combined organic layers
were dried (Na2SO4) and the solvent was evaporated under reduced
pressure. The crude product was purified by flash chromatography
over silica gel (eluent: hexane–CH2Cl2 mixtures) to give pure 2b
when the reaction was performed with benzoic anhydride, 2c and 2g
when the reaction was performed with mixed anhydride. For data
see Scheme 1 and Table 1.
1-Benzenesulfonyl-3-ethynyl-2-furoyl-1H-indole (3k)
A solution of 3h (447 mg, 1.0 mmol) in anhyd NH3 and MeOH
(NH3/MeOH, 2 M solution, 10 mL) was heated at 90 °C in a sealed
tube for 20 h. The solvent was then evaporated under reduced pres-
sure. The residue, purified by flash chromatography (hexane–
EtOAc, 9:1), afforded pure 3k. For data see Scheme 2 and
Tables 2, 4.
References
1-Benzenesulfonyl-3-iodo-1H-indole-2-carbaldehyde (2d)
To a N2 flushed solution of 1 (0.77 mg, 2 mmol) in anhyd THF (10
mL) was added a 2.0 M solution of LDA (2 mL, 4 mmol) in heptane/
THF/ethylbenzene at –60 °C. The mixture was then allowed to
warm to r.t (1.5 h), cooled again to –60 °C and treated with ethyl
formate (0.5 mL, 8.1 mmol). After stirring for 1 h at a temperature
ranging from –60 to –30 °C, the solution was poured into 1 N HCl
(50 mL) and extracted with CH2Cl2 (2 40 mL). The combined or-
ganic layers were dried (Na2SO4) and the solvent evaporated under
reduced pressure. The crude product obtained was purified by flash
chromatography over silica gel (eluent: hexane–CH2Cl2 (from 3:1
to 0:1) to afford pure 2d. For data see Scheme 1 and Table 1.
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To a N2 flushed solution of 1 (0.77 mg, 2 mmol) in anhyd THF (10
mL) was added a 2.0 M solution of LDA (1.3 mL, 2.6 mmol) in hep-
tane/THF/ethylbenzene at –60 °C. The mixture was then allowed to
warm to –40 °C (10 min), cooled again to –60 °C and treated with
1-methoxymethyl-1H-indole-3-carbaldehyde (380 mg, 2 mmol).
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ness, washed with aq NH4Cl solution (50 mL) and extracted with
CH2Cl2 (2 40 mL). The combined organic layers were dried
(Na2SO4) and the solvent was evaporated under reduced pressure.
The crude product obtained was purified by flash chromatography
over silica gel (eluent: hexane–CH2Cl2 (from 2:1 to 1:1) to give pure
2h. For data see Scheme 1 and Table 1.
Synthesis 2001, No. 16, 2477–2483 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
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Synthesis 2001, No. 16, 2477–2483 ISSN 0039-7881 © Thieme Stuttgart · New York