Microwave-assisted synthesis of 1,3-disubstituted β-carbolines from β-(alkylideneamino)nitriles and gramine

Article abstract of DOI:10.1055/s-0031-1289675

Reaction of deprotonated α-(alkylidenamino)nitriles with gramine in the presence of tributylphosphine furnishes -substituted imines of tryptophane nitrile. Their subsequent intramolecular cyclization followed by dehydrocyanation and oxidation affords 1,3-

Full text of DOI:10.1055/s-0031-1289675

PAPER
747
Microwave-Assisted Synthesis of 1,3-Disubstituted b-Carbolines from
a-(Alkylideneamino)nitriles and Gramine
1
, 3-Disub
u
b
-C
a
l
rboline
i
s
en Letessier,a Heiner Detert,a Katharina Götz,b Till Opatz*a
a
Institute for Organic Chemistry, Johannes Gutenberg-University Mainz, Duesbergweg 10–14, 55099 Mainz, Germany
Fax +49(6131)3922338; E-mail: opatz@uni-mainz.de
b
Institute for Organic Chemistry, University of Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany
Received 28 November 2011; revised 14 December 2011
Dedicated to Heinz Kolshorn on the occasion of his retirement
ic conditions. Successive dehydrocyanation and oxidation
should in turn afford the desired b-carboline structure
(Scheme 1). The a-aminonitriles 1 required as starting
materials can be easily prepared via Strecker reaction of
an aldehyde with KCN and ammonia. They were con-
densed with a variety of aromatic and aliphatic aldehydes
2 (Table 1) to furnish the desired a-(alkylideneamino)ni-
triles 3 in moderate to high yields.
Abstract: Reaction of deprotonated a-(alkylidenamino)nitriles
with gramine in the presence of tributylphosphine furnishes a-sub-
stituted imines of tryptophane nitrile. Their subsequent intramolec-
ular cyclization followed by dehydrocyanation and oxidation
affords 1,3-disubstituted b-carbolines.
Key words: imines, a-aminonitriles, cyclization, alkaloids, b-car-
bolines
O
Carbolines form the core structure of many biologically
interesting alkaloids.1–5 In this compound class, the b-car-
boline system is by far the most prevalent isomer due to
its biogenetic connection with tryptophan. The construc-
tion of this nucleus is most frequently effected by two
well-established synthetic strategies based on either the
Pictet–Spengler reaction or the Bischler–Napieralski re-
action.6,7 Over the past two decades, several new method-
ologies have been developed, which mainly rely on
transition metal catalyzed reactions as the key steps for
the construction of this ubiquitous scaffold.8–18 Herein, we
describe a transition-metal-free and rapid access to 1,3-
disubstituted b-carbolines starting from a-(alkylidene-
amino)nitriles and gramine.
R2
H
CN
CN
2
R1
NH2
R1
N
R2
MgSO4, CH2Cl2
3
1
NMe2
CN
, Bu3P
N
R1
N
R2
H
MeCN, MW
140 °C, 60 min
HN
4
R1
1) TFA, MW, 60 °C
2) I2, r.t.
N
As part of our interest in alkaloids and related heterocy-
cles, we investigated the synthetic potential offered by
deprotonated aminonitrile derivatives.19 Their versatile
chemistry allowed us to access various classes of polysub-
stituted nitrogen heterocycles such as pyrrolidines,20,21
tetrahydroisoquinolines,22 polysubstituted pyrroles,23
indoles24 or 4-quinolones.25 Our strategy towards the b-
CH2Cl2
R2
N
H
5
Scheme 1 Synthesis of 1,3-disubstituted b-carbolines from a-amino-
nitriles
carboline core uses gramine as a readily accessible build- In the cases where aromatic aldehydes were used in the
ing block containing the indole nucleus. Remarkably, one condensation step, the reaction generally gave better re-
of the first synthetic applications of deprotonated Reissert sults when electron-withdrawing substituents were
compounds involved their reaction with gramine itself, re- present (e.g., Table 1, entry 7). Purification of the prod-
sulting in an efficient transfer of the 3-indolylmethyl ucts by silica gel column chromatography led to partial
group.26,27 It was demonstrated that this formal nucleo- hydrolysis even in the presence of triethylamine. To over-
philic substitution under liberation of dimethylamine in- come this drawback, the unreacted starting materials 1
volves an elimination–addition sequence.28–30 We studied and 2 were advantageously removed by bulb-to-bulb dis-
the ability of deprotonated a-(alkylideneamino)nitriles to tillation to afford the analytically pure a-(alkylidene-
effect a similar reaction with gramine since the resulting amino)nitriles 3a–h.
substitution products should be able to cyclize under acid-
The reactive 3-methyleneindolenine (6) is believed to be
involved in several biochemical transformations and can
be generated via different methodologies.31–35 Somei et al.
first reported a Bu3P-catalyzed nucleophilic substitution
of gramine derivatives with dialkyl malonates.29
SYNTHESIS 2012, 44, 747–754
Advanced online publication: 23.01.2012
DOI: 10.1055/s-0031-1289675; Art ID: T111311SS
x
x
.x
x
.2
0
1
2
© Georg Thieme Verlag Stuttgart · New York

748
J. Letessier et al.
PAPER
Table 1 Preparation of a-(Alkylideneamino)nitriles
CN
CN
O
H
MgSO4, CH2Cl2
+
R2
R1
N
R2
R1
NH2
1
2
3
Entry
Aminonitrile
R1
Aldehyde
R2
Product
3a
Yield (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1b
1b
1c
Me
2a
2b
2c
2d
2e
2f
2-naphthyl
4-BrC6H4
4-Me2NC6H4
2-thienyl
60
83
62
78
72
89
95
58
Me
3b
Me
3c
Me
3d
Me
3,4-(MeO)2C6H3
i-Pr
3e
c-C6H11
c-C6H11
Ph
3f
2g
2e
4-NCC6H4
3,4-(MeO)2C6H3
3g
3h
The reaction presumably involves the formation of elec- 4a could be isolated in 73% yield. The same reaction con-
trophile 6 via base-induced elimination of dimethylamine ditions were applied to the a-(alkylideneamino)nitriles
by treatment with Bu3P (Scheme 2). The phosphine reacts 3b–h. The more electron-rich starting materials 3 gave
with 6 obtained from gramine in a base-induced vinylo- lower conversions (Table 2, entries 5 and 8) and in the
gous elimination to give the zwitterion 7, which should be case of 4-[(dimethylamino)benzylidene]aminopropioni-
able to deprotonate both the CH-acidic pronucleophile 3 trile (3c), no reaction could be observed (Table 2, entry 3).
and gramine itself. Since the phosphine addition is revers- Furthermore, the condensation product of an enolizable
ible, 7 and its protonated form 8 may act as a reservoir for aliphatic aldehyde 3f did not react, presumably because of
methyleneindolenine 6, which is ultimately trapped by the formation of the corresponding enamine (Table 2, en-
1,4-addition of the deprotonated a-(alkylideneamino)ni- try 6). Products 4g and 4h could not be isolated due to
trile to furnish compounds 9. The direct reaction of phos- their high reactivity. Attempts to purify these two inter-
phonium salt 8 with the nucleophile might be an mediates by chromatography led to partial cyclization and
alternative pathway.36 Attempts to replace tributylphos- the crude mixtures were directly submitted to the follow-
phine by nitrogen bases such as Hünig’s base or a combi- ing transformation without purification (Table 2, entries 7
nation of DBU and Ph3P were unsuccessful.28 A brief and 8). However, recrystallization of 4h from petroleum
study of the reaction conditions was performed and ether–chloroform afforded crystals suitable for X-ray
showed that the best results can be obtained at 140 °C in structural analysis.37
acetonitrile under microwave irradiation for one hour with
a substoichiometric amount of Bu3P (0.4 equiv) and a
Imines 4 can undergo a Pictet–Spengler type cyclization
to the indole core under acidic conditions.7 Several pa-
slight excess of gramine (1.05 equiv). Under these condi-
rameters of the cyclization step were investigated such as
tions, the expected b-indolyl-a-(alkylideneamino)nitrile
the nature of the acid, the solvent, and the reaction temper-
ature. With acetic acid or p-TsOH, no cyclization could be
observed. AlCl3 gave better results and the formation of
+
Me2N
Bu3P
the desired product could be effected. However, the con-
version was incomplete and traces of starting material
were still detectable even after prolonged reaction times.
PBu3
base
– HNMe2
N
N
N
TFA gave promising results since conversion was com-
plete while partial decomposition was observed when the
reaction was performed at 140 °C in xylene. In contrast,
carrying out the process in dichloromethane at 60 °C in a
sealed vial under microwave irradiation resulted in a mix-
ture of the desired tetrahydro-b-carboline intermediate
and the fully aromatic b-carboline.
–
H
7
6
–
+ NuH – Nu
NuH
+
– H
– Bu3P
+
Bu3P
Nu
–
+ Nu
While partial dehydrocyanation followed by dehydroge-
nation/aromatization proceeded already during the acid-
induced cyclization, the mixture could be converted to the
expected b-carboline by treatment with iodine. In this
manner, all previously synthesized b-indolyl-a-(alkyli-
– Bu3P
N
N
H
H
8
9
Scheme 2 Possible mechanism for the Bu3P-catalyzed nucleophilic
substitution of gramine with a-(alkylideneamino)nitriles
Synthesis 2012, 44, 747–754
© Thieme Stuttgart · New York

PAPER
1,3-Disubstituted b-Carbolines
749
Table 2 Coupling of a-(Alkylideneamino)nitriles with Gramine
NMe2
CN
, Bu3P
N
H
CN
R1
N
R2
R1
N
R2
MeCN, MW
140 °C, 60 min
3
HN
4
Entry
R1
R2
a-(Alkylideneamino)nitrile
Product
4a
Yield (%)
1
2
3
4
5
6
7
8
Me
2-naphthyl
4-BrC6H4
3a
3b
3c
3d
3e
3f
73a
89a
Me
4b
b
Me
4-Me2NC6H4
2-thienyl
4c
–
Me
4d
62a
56a
Me
3,4-(MeO)2C6H3
i-Pr
4e
b
c-C6H11
c-C6H11
Ph
4f
–
c,d
4-NCC6H4
3g
3h
4g
–
c,d
3,4-(MeO)2C6H3
4h
–
a Isolated yields after purification by column chromatography.
b No reaction.
c Product could not be isolated.
d The crude mixture was used without purification.
deneamino)nitriles were converted to compounds 5 in In summary, we have demonstrated the application of
moderate to good yields (Table 3). Cyclization proceeds deprotonated a-(alkylideneamino)nitriles for the synthe-
within 10 minutes at 60 °C in dichloromethane under mi- sis of 1,3-disubstituted b-carbolines by means of a substi-
crowave irradiation. Finally, elemental iodine is added to tution/cyclization strategy. This method involves only
the reaction mixture in order to complete the conversion. easily accessible and inexpensive reagents and gives the
Crystals of carboline 5e suitable for X-ray diffraction best results for 3-alkyl-1-aryl-substituted products. At-
were obtained by recrystallization from petroleum ether– tempts to establish a 1,3-dialkyl substitution pattern have
dichloromethane (Figure 1).
so far met with little success.
Table 3 Acid-Induced Ring Closure and Aromatization of b-Indolyl-a-(alkylideneamino)nitriles to b-Carbolines
R1
CN
1) TFA, MW, 60 °C
2) I2, r.t.
R1
N
R2
N
CH2Cl2
R2
N
HN
H
4
5
Entry
R1
R2
b-Indolyl-a-(alkylideneamino)nitrile
Product
5a
Yield (%)
75a
1
2
3
4
5
6
Me
2-naphthyl
4-BrC6H4
2-thienyl
4a
4b
4d
4e
4g
4h
Me
5b
81a
Me
5d
72a
Me
3,4-(MeO)2C6H3
4-NCC6H4
5e
47a
c-C6H11
Ph
5g
21b
3,4-(MeO)2C6H3
5h
8b
a Isolated yields after purification on column chromatography.
b Over two steps.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 747–754

750
J. Letessier et al.
PAPER
FD-MS: m/z (%) = 236.2 (100, [C10H9BrN2]+), 237.2 (12), 238.2
(98), 239.2 (11).
ESI-HRMS: m/z calcd for C10H10BrN2 [M + H]+: 237.0027; found:
237.0026.
Anal. Calcd for C10H9BrN2: C, 50.66; H, 3.83; N, 11.82. Found: C,
50.41; H, 4.05; N, 11.68.
2-{(E)-[4-(Dimethylamino)benzylidene]amino}propanenitrile
(3c)
Yellow solid (4.79 g, 62%); mp 63–64 °C; Rf = 0.24 (PE–EtOAc,
4:1).
Figure 1 Crystal structure of the b-carboline 5e
IR (neat, ATR): 2983 (w), 2936 (w), 2856 (w), 2244 (w), 1525 (vs),
1484 (s), 1365 (s), 1229 (m), 1303 (w), 1229 (w), 1176 (m), 942
(w), 825 (s), 810 cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 8.33 (s, 1 H, CHN), 7.64 (d,
3JHH = 8.9 Hz, 2 H, 2¢-CH), 6.71 (d, 3JHH = 8.9 Hz, 2 H, 3¢-CH), 4.58
(qd, 3JHH = 7.1 Hz, 4JHH = 1.2 Hz, 1 H, 2-CH), 3.03 (s, 6 H, NCH3),
1.65 (d, 3JHH = 7.1 Hz, 3 H, 3-CH3).
13C NMR (75 MHz, CDCl3): d = 162.2 (d, CHN), 152.6 (s, 4¢-C),
130.2 (d, 2¢-C), 122.8 (s, 1¢-C), 119.4 (s, CN), 111.5 (d, 3¢-CH), 53.1
(d, 2-CH), 40.1 (q, NCH3), 21.4 (q, 3-CH3).
All reactions were carried out under dry argon or nitrogen unless
otherwise indicated. Commercially available reagents were used
without further purification unless otherwise indicated; solvents
and gases were dried by standard procedures.38 Yields refer to chro-
matographically and spectroscopically pure compounds, unless oth-
erwise stated. The microwave-accelerated reactions were
performed in a Discover monomode apparatus (CEM) using air
cooling. 1H and 13C NMR spectra were recorded on Bruker AC 300
(300 MHz), Bruker AV 400 (400 MHz), and Bruker ARX 400 (400
MHz) spectrometers in CDCl3 or DMSO-d6. Chemical shifts are
referenced to the residual solvent signal (CDCl3: dH = 7.26 ppm,
dC = 77.16 ppm, DMSO-d6: dH = 2.50 ppm, dC = 39.52 ppm) and are
expressed as d values in ppm.39 Melting points were determined on
a Büchi HWS SG 200 instrument. IR spectra were recorded on a
Jasco 4100 FTIR (ATR) spectrometer. FD-MS spectra were record-
ed on a MAT 95 (Finnigan) spectrometer. HRMS (ESI) spectra
were obtained with a Q-TOF-Ultima III with LockSpray interface
(Waters-Micromass). Elemental analyses were carried out on a Var-
io EL Cube (Elementar). Petroleum ether (PE) used had a boiling
point range of 40–70 °C. TLC was performed on aluminum sheets
coated with silica gel (0.2 mm, ALUGRAM SIL G/UV, Macherey-
Nagel). Aminonitriles 1a, 1b, and 1c as well as 2-[(E)-(naphthalen-
2-ylmethylidene)amino]propanenitrile (3a) were synthesized ac-
cording to known literature procedures in 62%, 65%, 25%, and 60%
yield, respectively.40–45
FD-MS: m/z (%) = 201.4 (100, [C12H15N3]+), 202.4 (11).
ESI-HRMS: m/z calcd for C12H16N3 [M + H]+: 202.1344; found:
202.1333.
2-[(E)-(Thiophen-2-ylmethylidene)amino]propanenitrile (3d)
Orange oil (4.92 g, 78%); Rf = 0.26 (PE–EtOAc, 9:1).
IR (neat, ATR): 3087 (w), 2989 (w), 2872 (w), 1627 (vs), 1428 (s),
1376 (w), 1335 (w), 1308 (w), 1238 (m), 1220 (m), 1111 (s), 1083
(m), 1044 (s), 961 (w), 921 (w), 859 (w), 838 (w), 713 cm–1 (vs).
1H NMR (400 MHz, CDCl3): d = 8.61 (s, 1 H, CHN), 7.49 (d,
3JHH = 5.0 Hz, 1 H, 5¢-CH), 7.44 (dd, 3JHH = 3.6 Hz, 4JHH = 0.9 Hz,
3
3
1 H, 3¢-CH), 7.11 (dd, JHH = 5.0 Hz, JHH = 3.6 Hz, 1 H, 4¢-CH),
3
4
4.67 (qd, JHH = 7.2 Hz, JHH = 1.5 Hz, 1 H, 2-CH), 1.65 (d,
3JHH = 7.2 Hz, 3 H, 3-CH3).
13C NMR (75 MHz, CDCl3): d = 157.8 (d, CHN), 141.1 (s, 2¢-C),
132.9 (d, 5¢-CH), 130.9 (d, 4¢-CH), 128.0 (d, 3¢-CH), 118.8 (s, CN),
53.0 (d, 2-CH), 21.4 (q, 3-CH3).
FD-MS: m/z (%) = 164.2 (100, [C8H8N2S]+), 165.3 (7), 166.3 (5).
ESI-HRMS: m/z calcd for C8H9N2S [M + H]+: 165.0486; found:
Condensation of a-Aminonitriles 1 with Aldehydes 2 to
a-(Alkylideneamino)nitriles 3a–h; General Procedure
The aldehyde 2 (1 equiv, 38.4 mmol) was dissolved in CH2Cl2 (40
mL). To this solution were added MgSO4 (3.0 equiv, 115.2 mmol),
the a-aminonitrile 1 (1.30 equiv, 42.2 mmol), and AcOH (catalytic
amount, 5 drops). After stirring overnight under N2 at r.t., the
MgSO4 was filtered off, and the organic layer was washed with aq
sat. NaHCO3 (20 mL) and dried (MgSO4). The solvent was evapo-
rated in vacuo. Traces of unreacted starting material were removed
by bulb-to-bulb distillation in vacuo and the product was used with-
out further purification (Table 1).
165.0502.
Anal. Calcd for C8H8N2S: C, 58.51; H, 4.91; N, 17.04; S, 19.52.
Found: C, 58.06; H, 5.05; N, 16.96; S, 19.63.
2-[(E)-(3,4-Dimethoxybenzylidene)amino]propanenitrile (3e)
Orange oil (6.03 g, 72%); Rf = 0.29 (PE–EtOAc, 7:3).
IR (neat, ATR): 2938 (w), 2838 (w), 1680 (w), 1639 (m), 1598 (s),
1585 (s), 1510 (vs), 1462 (s), 1420 (m), 1263 (vs), 1236 (s), 1160
(m), 1137 (s), 1020 (vs), 861 (w), 811 (w), 753 cm–1 (w).
2-[(E)-(4-Bromobenzylidene)amino]propanenitrile (3b)
White solid (7.55 g, 83%); mp 40–41 °C; Rf = 0.21 (PE–EtOAc,
9:1).
1H NMR (400 MHz, CDCl3): d = 8.39 (d, 4JHH = 1.5 Hz, 1 H, CHN),
IR (neat, ATR): 2982 (w), 1910 (w), 1698 (w), 1645 (s), 1587 (s),
1567 (m), 1484 (m), 1376 (m), 1312 (m), 1275 (w), 1222 (w), 1112
(m), 1065 (s), 1009 (s), 980 (m), 926 (m), 860 (m), 821 (vs), 812
(vs), 708 cm–1 (w).
4
3
7.43 (d, JHH = 1.9 Hz, 1 H, 2¢-CH), 7.22 (dd, JHH = 8.2 Hz,
4JHH = 1.9 Hz, 1 H, 6¢-CH), 6.91 (d, 3JHH = 8.2 Hz, 1 H, 5¢-CH), 4.64
(qd, 3JHH = 7.1 Hz, 4JHH = 1.5 Hz, 1 H, 2-CH), 3.94 (s, 3 H, OCH3),
3.93 (s, 3 H, OCH3), 1.65 (d, 3JHH = 7.1 Hz, 3 H, 3-CH).
1H NMR (400 MHz, CDCl3): d = 8.45 (d, 4JHH = 1.6 Hz, 1 H, CHN),
13C NMR (75 MHz, CDCl3): d = 161.8 (d, CHN), 152.2 (s, 4¢-C),
149.4 (s, 3¢-C), 128.0 (s, 1¢-C), 124.1 (d, 6¢-CH), 118.9 (s, CN),
110.4 (d, 5¢-CH), 108.9 (2¢-CH), 56.0 (2 signals, q, OCH3), 53.0 (d,
2-CH), 21.2 (q, 3-CH3).
7.66 (d, 3JHH = 8.5 Hz, 2 H, 2¢-CH), 7.59 (d, 3JHH = 8.5 Hz, 2 H, 3¢-
3
4
CH), 4.68 (qd, JHH = 7.2 Hz, JHH = 1.6 Hz, 1 H, 2-CH), 1.72 (d,
3JHH = 7.2 Hz, 3 H, 3-CH3).
13C NMR (75 MHz, CDCl3): d = 161.4 (d, CHN), 134.0 (s, 1-C),
132.4 (d, 3¢-CH), 130.4 (d, 2¢-CH), 126.7 (s, 4¢-C), 118.7 (s, CN),
53.4 (d, 2-CH), 21.3 (q, 3-CH3).
FD-MS: m/z (%) = 218.4 (100, [C12H14N2O2]+), 219.4 (11).
Synthesis 2012, 44, 747–754
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1,3-Disubstituted b-Carbolines
751
ESI-HRMS: m/z calcd for C12H15N2O2 [M + H]+: 219.1134; found:
219.1133.
7.82 (m, 3 H, 4-CHnaphthyl, 5-CHnaphthyl, 8-CHnaphthyl), 7.74 (d,
3JHH = 8.0 Hz, 1 H, 4-CHindolyl), 7.55 (mc, 2 H, 6-CHnaphthyl, 7-
CHnaphthyl), 7.28 (d, 3JHH = 8.0 Hz, 1 H, 7-CHindolyl), 7.16–7.12 (m, 2
H, 2-CHindolyl, 5-CHindolyl), 7.08 (mc, 1 H, 6-CHindolyl), 3.46 (d,
2JHH = 14.4 Hz, 1 H, 3-CH2), 3.38 (d, 2JHH = 14.4 Hz, 1 H, 3-CH2),
1.82 (s, 3 H, CH3).
4-((E)-{[Cyano(cyclohexyl)methyl]imino}methyl)benzonitrile
(3g)
Yellow oil (9.16 g, 95%); Rf = 0.24 (PE–EtOAc, 9:1).
IR (neat, ATR): 2928 (vs), 2853 (s), 2228 (s), 1643 (s), 1412 (m),
1377 (w), 1321 (w), 1284 (w), 1221 (w), 1015 (w), 892 (w), 836
cm–1 (s).
1H NMR (400 MHz, CDCl3): d = 8.49 (d, 4JHH = 1.7 Hz, 1 H, CHN),
7.89 (d, 3JHH = 8.4 Hz, 2 H, 2¢-CH), 7.73 (d, 3JHH = 8.4 Hz, 2 H, 3¢-
CH), 4.58 (dd, 3JHH = 5.5 Hz, 4JHH = 1.7 Hz, 1 H, 2-CH), 1.92–1.69
(m, 6 H, cyclohexyl), 1.30–1.19 (m, 5 H, cyclohexyl).
13C NMR (75 MHz, CDCl3): d = 161.0 (d, CHN), 139.0 (s, 1¢-C),
132.9 (d, 3¢-CH), 129.4 (d, 2¢-CH), 118.6 (s, CN), 117.0 (s, CN),
115.2 (s, 4¢-C), 64.6 (d, 2-CH), 42.1 (d, 3-CH), 30.0 (t, cyclohexyl),
28.9 (t, cyclohexyl), 26.2 (t, cyclohexyl), 26.1 (t, cyclohexyl), 25.9
(t, cyclohexyl).
13C NMR, HMBC, HSQC (100.6 MHz, 400 MHz, CDCl3): d =
160.2 (d, CHN), 136.1 (s, C-7aindolyl), 135.3 (s, C-4anaphthyl), 133.3 (s,
C-8anaphthyl), 133.1 (s, C-2naphthyl), 131.5 (d, C-1naphthyl), 129.1 (d, C-
4naphthyl), 128.8 (d, C-5naphthyl), 128.2 (s, C-3aindolyl), 128.2 (d, C-
8
2
indolyl), 127.9 (d, C-6naphthyl), 126.9 (d, C-7naphthyl), 124.6 (d, C-
indolhyl), 124.1 (d, C-3naphthyl), 122.3 (d, C-5indolyl), 120.8 (s, CN),
119.9 (d, C-4indolyl), 119.8 (d, C-6indolyl), 111.3 (d, C-7indolyl), 109.7
(s, C-3indolyl), 65.8 (s, C-2), 37.7 (t, 3-CH2), 28.1 (q, CH3).
ESI-MS (+): m/z = 338.18 [M + H]+, 360.17 [M + Na]+.
ESI-HRMS: m/z calcd for C23H19N3 + Na [M + Na]+: 360.1477;
found: 360.1481.
Anal. Calcd for C23H13N2: C, 81.87; H, 5.68; N, 12.45. Found: C,
81.51; H, 5.90; N, 12.12.
FD-MS: m/z (%) = 251.4 (100, [C16H17N3]+), 252.4 (24).
ESI-HRMS: m/z calcd for C16H18N3 [M + H]+: 252.1501; found:
252.1503.
2-[(E)-(4-Bromobenzylidene)amino]-3-(1H-indol-3-yl)-2-meth-
ylpropanenitrile (4b)
White solid (117 mg, 89%); mp 117–118 °C; Rf = 0.24 (PE–EtOAc,
9:1).
[(E)-(3,4-dimethoxybenzylidene)amino](phenyl)acetonitrile
(3h)
Yellow solid (6.24 g, 58%); mp 91–92 °C; Rf = 0.13 (PE–EtOAc,
4:1).
IR (neat, ATR): 3413 (br), 1645 (m), 1588 (m), 1487 (s), 1456 (s),
1235 (m), 1094 (w), 1067 (s), 1009 (s), 907 (s), 819 (s), 775 cm–1
(m).
1H NMR (400 MHz, CDCl3): d = 8.21 (s, 1 H, CHN), 8.13 (s, 1 H,
NH), 7.62 (d, 3JHH = 7.9 Hz, 1 H), 7.55 (mc, 4 H, 2¢-CH and 3¢-CH),
7.30 (d, 3JHH = 7.9 Hz, 1 H), 7.15–7.11 (m, 2 H), 7.03 (t, 3JHH = 7.5
Hz, 1 H), 3.39 (d, 2JHH = 14.4 Hz, 1 H, 3-CH2), 3.31 (d, 3JHH = 14.4
Hz, 1 H, 3-CH2), 1.75 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 158.9 (d, CHN), 136.0 (s), 134.2
(s), 132.1 (d), 130.1 (d), 128.0 (s), 126.1 (s), 124.5 (d), 122.3 (d),
120.4 (s), 119.8 (d), 119.7 (d), 111.2 (d), 109.5 (s), 65.7 (s), 37.5 (t),
27.8 (q).
IR (neat, ATR): 3011 (w), 2838 (w), 1645 (m), 1598 (m), 1515 (s),
1454 (m), 1330 (m), 1264 (vs), 1242 (vs), 1164 (s), 1119 (vs), 1020
(vs), 910 (w), 858 (m), 816 (m), 754 (vs), 699 cm–1 (vs).
1H NMR (400 MHz, CDCl3): d = 8.52 (d, 4JHH = 1.5 Hz, 1 H, CHN),
3
4
7.49–7.39 (m, 6 H), 7.29 (dd, JHH = 8.2 Hz, JHH = 1.9 Hz, 1 H),
6.91 (d, 3JHH = 8.2 Hz, 1 H), 5.76 d, 4JHH = 1.5 Hz, 1 H), 3.94 (s, 3
H, OCH3), 3.93 (s, 3 H, OCH3).
13C NMR (75 MHz, CDCl3): d = 163.1 (d, CHN), 152.7 (s), 149.8
(s), 135.3 (s), 129.5 (d), 129.4 (d), 128.3 (s), 127.8 (d), 124.8 (d),
117.6 (s), 110.8 (d), 109.5 (d), 62.0 (d), 56.3 (2 signals, q, OCH3).
FD-MS: m/z (%) = 280.4 (100, [C17H16N2O2]+), 281.4 (10).
ESI-HRMS: m/z calcd for C17H17N2O2 [M + H]+: 281.1290; found:
FD-MS: m/z (%) = 365.4 (84, [C19H16BrN3]+), 336.5 (18), 367.4
(100), 368.4 (15).
ESI-HRMS: m/z calcd for C19H17BrN3 [M + H]+: 366.0606; found:
366.0604.
281.1293.
Coupling of Gramine with a-(Alkylideneamino)nitriles 3a–h to
Imines 4a–h; General Procedure
3-(1H-Indol-3-yl)-2-methyl-2-[(E)-(thiophen-2-ylmeth-
ylidene)amino]propanenitrile (4d)
Yellow solid (65 mg, 62%); mp 169–170 °C; Rf = 0.20 (PE–EtOAc,
The a-(alkylideneamino)nitrile 3 (1.0 equiv, 0.36 mmol) and
gramine (1.05 equiv, 0.38 mmol) were dissolved in MeCN (3 mL)
in a microwave reaction tube and Bu3P (0.40 equiv, 0.14 mmol) was
added. The tube was sealed and irradiated (300 W) at 140 °C for 1
h. The tube content was diluted with CH2Cl2 (20 mL) and washed
with sat. aq NaHCO3 (3 × 10 mL) and brine (10 mL). The organic
layer was then dried (MgSO4), filtered, and the solvent was evapo-
rated in vacuo. The crude product was purified by silica gel column
chromatography using the same eluent as that used for TLC
(Table 2).
4:1).
IR (neat, ATR): 3354 (br), 1632 (s), 1454 (w), 1428 (m), 1355 (w),
1340 (w), 1263 (w), 1220 (m), 1097 (m), 1045 (m), 1006 (w), 949
(m), 858 (w), 839 (w), 754 (w), 733 (vs), 709 cm–1 (vs).
1H NMR, COSY, HMBC (400 MHz, 100.6 MHz, CDCl3): d = 8.38
(d, 4JHH = 0.8 Hz, 1 H, CHN), 8.11 (s, 1 H, NH), 7.68 (d, 3JHH = 7.8
Hz, 1 H, 4-CHindolyl), 7.46 (dt, 3JHH = 5.0 Hz, 4JHH = 0.8 Hz, 1 H, 5¢-
3
CHthienyl), 7.31 (d, JHH = 8.1 Hz, 1 H, 7-CHindolyl), 7.26 (dd,
4
3JHH = 3.7 Hz, 4JHH = 1.1 Hz, 1 H, 3¢-CHthienyl), 7.16 (d, JHH = 2.5
3-(1H-Indol-3-yl)-2-methyl-2-[(E)-(naphthalen-2-ylmeth-
ylidene)amino]propanenitrile (4a)
Yellow solid (88 mg, 73%); mp 74–76 °C; Rf = 0.21 (PE–EtOAc,
9:1).
Hz, 1 H, 2-CHindolyl), 7.14–7.12 (m, 1 H, 6-CHindolyl), 7.08–7.03 (m,
2 H, 5-CHindolyl, 4¢-CHthienyl), 3.37 (d, 2JHH = 14.4 Hz, 1 H, 3-CH2),
3.29 (d, 2JHH = 14.4 Hz, 1 H, 3-CH2), 1.73 (s, 3 H, 1-CH3).
13C NMR, HMBC, HSQC (100.6 MHz, 400 MHz, CDCl3): d =
153.3 (d, CHN), 141.3 (s, 2¢-Cthienyl), 135.9 (s, 7a-Cindolyl), 132.3 (d,
3¢-CHthienyl), 130.2 (d, 5¢-CHthienyl), 128.0 (s, 3a-Cindolyl), 127.6 (d, 4¢-
CHthienyl), 124.5 (d, 2-CHindolyl), 122.1 (d, 6-CHindolyl), 120.4 (s, 1-
CN), 119.8 (d, 4-CHindolyl), 119.8 (d, 5-CHindolyl), 111.1 (d, 7-
CHindolyl), 109.5 (s, 3-Cindolyl), 65.2 (s, 2-C), 37.5 (t, 3-CH2), 27.8 (q,
1-CH3).
IR (neat, ATR): 3417 (br), 1637 (m), 1455 (w), 1339 (w), 1268 (w),
1233 (w), 1093 (w), 1010 (w), 972 (w), 859 (w), 819 (m), 768 (w),
740 (vs), 669 cm–1 (w).
1H NMR, COSY, HMBC (400 MHz, 100.6 MHz, CDCl3): d = 8.49
3
(s, 1 H, CHN), 8.12 (s, 1 H, 1-NH), 8.05 (dd, JHH = 8.6 Hz,
4JHH = 1.5 Hz, 1H, 3-CHnaphthyl), 7.96 (s, 1 H, 1-CHnaphthyl), 7.92–
© Thieme Stuttgart · New York
Synthesis 2012, 44, 747–754

752
J. Letessier et al.
PAPER
FD-MS: m/z (%) = 293.3 (100, [C17H15N3S]+), 294.3 (18), 295.3
ESI-MS (+): m/z = 309.1 [M + H]+, 617.3 [2 M + H]+.
(5).
ESI-HRMS: m/z calcd for C22H17N2 [M + H]+: 309.1392; found:
309.1382.
ESI-HRMS: m/z calcd for C17H15N3 + Na [M + Na]+: 316.0884;
found: 316.0891.
1-(4-Bromophenyl)-3-methyl-9H-b-carboline (5b)
White solid (30 mg, 81%); mp 160–162 °C; Rf = 0.45 (PE–EtOAc,
7:3).
2-[(E)-(3,4-Dimethoxybenzylidene)amino]-3-(1H-indol-3-yl)-2-
methylpropanenitrile (4e)
Light yellow oil (70 mg, 56%); Rf = 0.37 (PE–EtOAc, 3:2).
IR (neat, ATR): 3240 (br), 1623 (m), 1496 (m), 1467 (m), 1445 (m),
1375 (w), 1319 (m), 1237 (s), 1147 (m), 1069 (w), 1053 (w), 1008
(m), 911 (w), 874 (w), 835 (m), 749 cm–1 (vs).
1H NMR, COSY (400 MHz, 100.6 MHz, CDCl3): d = 8.52 (s, 1 H,
9-NH), 8.11 (d, 3JHH = 7.9 Hz, 1 H, 5-CH), 7.78 (s, 1 H, 4-CH), 7.76
(d, 3JHH = 8.4 Hz, 2 H, 2¢-CH), 7.60 (d, 3JHH = 8.4 Hz, 2 H, 3¢-CH),
7.53 (pseudo t, 3JHH = 8 Hz, 1 H, 7-CH), 7.44 (d, 3JHH = 8.2 Hz, 1 H,
8-CH), 7.29 (d, 3JHH = 7.7 Hz, 1 H, 6-CH), 2.77 (s, 3 H, CH3).
13C NMR (100.6 MHz, 400 MHz, CDCl3): d = 148.5 (s, 3-C), 141.1
(s, 8a-C), 141.0 (s, 1-C), 138.0 (s, 9a-C), 132.6 (d, 3¢-CH), 132.1 (s,
1¢-C), 131.5 (s, 4¢-C), 130.1 (d, 2¢-CH), 128.9 (d, 7-CH), 123.2 (s,
4a-C), 122.2 (d, 5-CH), 122.1 (s, 4b-C), 120.5 (d, 6-CH), 113.4 (d,
4-CH), 111.8 (d, 8-CH), 24.8 (q, CH3).
IR (neat, ATR): 2938 (w), 2838 (w), 1680 (w), 1640 (m), 1585 (m),
1510 (vs), 1462 (m), 1420 (m), 1389 (m), 1264 (vs), 1236 (s), 1160
(m), 1138 (s), 1020 (s), 917 (w), 811 cm–1 (w).
1H NMR (400 MHz, CDCl3): d = 8.23 (s, 1 H, CHN), 8.13 (s, 1 H,
NH), 7.65 (d, 3JHH = 7.9 Hz, 1 H), 7.38 (d, 4JHH = 1.8 Hz, 1 H), 7.31
(d, 3JHH = 8.2 Hz, 1 H), 7.16–7.12 (m, 3 H), 7.04 (t, 3JHH = 7.5 Hz,
1 H), 6.87 (d, 3JHH = 8.2 Hz, 1 H), 3.94 (s, 3 H, OCH3), 3.92 (s, 3 H,
2
OCH3), 3.39 (d, JHH = 14.4 Hz, 1 H, 3-CH2), 3.29 (d, 2JHH = 14.4
Hz, 1 H, 3-CH2), 1.72 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 159.2 (d, CHN), 151.8 (s), 149.2
(s), 135.8 (s), 128.3 (s), 127.9 (s), 124.2 (d), 123.8 (d), 122.0 (d),
120.6 (s), 119.5 (d, 2 signals), 111.0 (d), 110.4 (d), 109.5 (s), 109.2
(s), 65.2 (s, 2-C), 55.9 (2 signals, q, OCH3), 37.4 (t, 3-CH2), 27.7
(CH3).
FD-MS: m/z (%) = 347.4 (100, [C21H21N3O2]+), 348.4 (23).
ESI-HRMS: m/z calcd for C21H22N3O2 [M + H]+: 348.1712; found:
FD-MS: m/z (%) = 336.2 (42), 338.2 (100, [C18H13BrN2]+).
ESI-HRMS: m/z calcd for C18H14BrN2 [M + H]+: 337.0340; found:
337.0342.
348.1705.
3-Methyl-1-(thiophen-2-yl)-9H-b-carboline (5d)
Yellow solid (21 mg, 72%); mp 198–199 °C; Rf = 0.32 (PE–EtOAc,
4:1).
Cyclization of Indolyl-a-(alkylideneamino)nitriles 4a–h to
b-Carbolines 5a–h; General Procedure
IR (neat, ATR): 3343 (br), 1622 (m), 1557 (m), 1493 (m), 1436 (s),
1373 (w), 1323 (w), 1235 (s), 1143 (w), 1020 (m), 910 (w), 852 (w),
841 (s), 791 (s), 737 (vs), 708 cm–1 (vs).
The b-indolyl-a-(alkylideneamino)nitrile 4 (1.0 equiv, 0.11 mmol)
was dissolved in anhyd CH2Cl2 (3 mL) in a microwave reaction tube
containing molecular sieves (3 Å). TFA (0.5 equiv, 53 mmol) was
added and the reaction mixture was heated to 60 °C for 10 min un-
der microwave irradiation (300 W, CAUTION! Evolution of
HCN). The reaction mixture was cooled, I2 (1.0 equiv, 0.11 mmol)
was added and the mixture was stirred at r.t. for further 30 min. The
resulting solution was filtered, washed with aq sat. NaHCO3 (10
mL), brine (10 mL), dried (MgSO4), and the solvent was evaporated
in vacuo. The crude b-carboline 5 was then purified by silica gel
column chromatography using the same eluent as that used for TLC
(Table 3).
1H NMR, COSY, HMBC (400 MHz, 100.6 MHz, DMSO-d6): d =
11.33 (s, 1 H, 9-NH), 8.19 (d, 3JHH = 7.8 Hz, 1 H, 5-CH), 8.06 (dd,
3JHH = 3.4 Hz, 3JHH = 0.9 Hz, 1 H, 3¢-CHthienyl), 7.91 (s, 1 H, 4-CH),
3
7.72–7.65 (m, 2 H, 8-CH, 5¢-CHthienyl), 7.55 (ddd, JHH = 8.2 Hz,
3JHH = 7.1 Hz, 4JHH = 1.1 Hz, 1 H, 7-CH), 7.32 (dd, 3JHH = 5.1 Hz,
3JHH = 3.4 Hz, 1 H, 4¢-CHthienyl), 7.24 (mc, 1 H, 6-CH), 2.63 (s, 3 H,
CH3).
13C NMR, HMBC, HSQC (100.6 MHz, 400 MHz, DMSO-d6): d =
145.9 (s, 3-C), 143.7 (s, 1-C), 141.7 (s, 8a-C), 135.4 (s, 2¢-Cthienyl),
130.9 (s, 4a-C), 129.4 (s, 9a-C), 128.4 (d, 7-CH), 128.4 (d,
4¢-CHthienyl), 127.9 (d, 5¢-CHthienyl), 125.5 (d, 3¢-CHthienyl), 121.6 (d,
5-CH), 120.6 (s, 4b-C), 119.7 (d, 6-CH), 112.7 (d, 4-CH), 112.5 (d,
8-CH), 23.9 (q, CH3).
3-Methyl-1-(naphthalen-2-yl)-9H-b-carboline (5a)
Pale yellow solid (25 mg, 75%); mp 157–159 °C; Rf = 0.17 (PE–
EtOAc, 9:1).
ESI-HRMS: m/z calcd for C16H13N2S [M + H]+: 265.0799; found:
265.0792.
IR (neat, ATR): 1623 (m), 1561 (m), 1497 (m), 1450 (m), 1319 (w),
1273 (w), 1240 (s), 1145 (w), 1049 (w), 893 (w), 859 (m), 815 (m),
739 (vs), 685 cm–1 (w).
Anal. Calcd for C16H12N2S: C, 72.70; H, 4.58; N, 10.60. Found: C,
72.63; H, 4.60; N, 10.22.
1H NMR, COSY, HMBC (400 MHz, 100.6 MHz, DMSO-d6): d =
11.51 (s, 1 H, 9-NH), 8.56 (s, 1 H, 1-CHnaphthyl), 8.23 (d, 3JHH = 7.6
3
4
Hz, 1 H, 5-CH), 8.18 (dd, JHH = 8.6 Hz, JHH = 1.4 Hz, 1 H, 3-
CHnaphthyl), 8.13–8.11 (m, 2 H, 4- CHnaphthyl, 6-CHnaphthyl), 8.04–8.01
(m, 1 H, 7-CHnaphthyl), 7.99 (s, 1 H, 4-CH), 7.59–7.64 (m, 3 H, 8-CH,
1-(3,4-Dimethoxyphenyl)-3-methyl-9H-b-carboline (5e)
Yellow solid (16 mg, 47%); mp 191–192 °C; Rf = 0.16 (PE–EtOAc,
3:2).
3
5-CHnaphthyl, 8-CHnaphthyl), 7.54 (t, JHH = 7.6 Hz, 1 H, 7-CH), 7.24
IR (neat, ATR): 3328 (br), 2833 (w), 1623 (m), 1559 (m), 1513 (vs),
1439 (s), 1380 (m), 1343 (m), 1317 (s), 1273 (w), 1245 (vs), 1136
(s), 1025 (s), 854 (m), 811 (w), 741 cm–1 (ws).
(ddd, 3JHH = 8.2 Hz, 3JHH = 7.1 Hz, 4JHH = 1.1 Hz, 1 H, 6-CH), 2.72
(s, 3 H, CH3).
13C NMR, HMBC, HSQC (100.6 MHz, 400 MHz, DMSO-d6): d =
146.3 (s, 3-C), 141.4 (s, 8a-C), 140.9 (s, 1-C), 135.8 (s, 2-Cnaphthyl),
132.9 (s, 8a-Cnaphthyl), 132.8 (s, 4a-Cnaphthyl), 131.8 (s, 9a-C), 130.4
(s, 4a-C), 128.7 (d, 4-CH), 128.1 (d, 7-CH), 128.1 (d, 6-CHnaphthyl),
127.6 (d, 1-CHnaphthyl), 127.4 (d, 7-CHnaphthyl), 126.6 (d, 3-CHnaphthyl),
126.4 (d, 5-CHnaphthyl), 126.3 (d, 8-CHnaphthyl), 121.6 (d, 5-CH),
120.8 (s, 4b-C), 119.3 (d, 6-CH), 112.6 (d, 4-CHnaphthyl), 112.3 (d, 8-
CH), 24.1 (q, CH3).
1H NMR, COSY, HMBC (400 MHz, 100.6 MHz, DMSO-d6): d =
11.30 (s, 1 H, 9-NH), 8.18 (d, 3JHH = 7.9 Hz, 1 H, 5-CH), 7.89 (s, 1
3
H, 4-CH), 7.59 (d, JHH = 8.2 Hz, 1 H, 8-CH), 7.57–7.54 (m, 2 H,
3
4
6¢-CH, 2¢-CH), 7.50 (ddd, JHH = 8.2 Hz, 3JHH = 7.0 Hz, JHH = 1.8
Hz, 1 H, 7-CH), 7.21 (ddd, 3JHH = 7.9 Hz, 3JHH = 7.0 Hz, 4JHH = 1.0
Hz, 1 H, 6-CH), 7.16 (d, 3JHH = 8.8 Hz, 1 H, 5¢-CH), 3.88 (s, 3 H,
OCH3), 3.86 (s, 3 H, OCH3), 2.65 (s, 3 H, CH3).
Synthesis 2012, 44, 747–754
© Thieme Stuttgart · New York

PAPER
1,3-Disubstituted b-Carbolines
753
13C NMR, HMBC, HSQC (100.6 MHz, 400 MHz, DMSO-d6): d =
149.2 (s, 3¢-C), 148.8 (s, 4¢-C), 146.0 (s, 3-C), 141.4 (s, 8a-C), 141.2
(s, 1-C), 131.3 (s, 9a-C), 131.2 (s, 1¢-C), 130.1 (s, 4a-C), 127.9 (d,
7-CH), 121.5 (d, 5-CH), 120.9 (d, 6¢-CH), 120.8 (s, 4b-C), 119.2 (d,
6-CH), 112.4 (d, 8-CH), 112.0 (d, 4-CH), 111.8 (d, 5¢-CH), 111.8
(d, 2¢-CH), 55.7 (q, OCH3), 55.5 (q, OCH3), 24.1 (q, CH3).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
The authors are grateful to H. Kolshorn for helpful discussions and
NMR spectroscopy, to Dr. N. Hanold for mass spectrometry, and to
Dr. D. Schollmeyer for X-ray crystallography.
ESI-HRMS: m/z calcd for C20H19N2O2 [M + H]+: 319.1447; found:
319.1454.
4-(3-Cyclohexyl-9H-b-carbolin-1-yl)benzonitrile (5g)
Pale yellow solid (2 steps, 26 mg, 21%); mp 178–180 °C; Rf = 0.35
(PE–EtOAc, 4:1).
References
(1) Husson, H.-P. In The Alkaloids: Chemistry and
Pharmacology, Vol. 26; Brossi, A., Ed.; Academic Press:
New York, 1985, 1–51.
(2) Love, B. Top. Heterocycl. Chem. 2006, 2, 93.
(3) Love, B. E. Org. Prep. Proced. Int. 1996, 28, 1.
(4) Rao, K. V.; Cullen, W. P. Antibiot. Annu. 1959-1960, 950.
(5) Torreilles, J.; Guérin, M.-C.; Previero, A. Biochimie 1985,
67, 929.
(6) Bischler, A.; Napieralski, B. Ber. Dtsch. Chem. Ges. 1893,
26, 1903.
(7) Pictet, A.; Spengler, T. Ber. Dtsch. Chem. Ges. 1911, 44,
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(8) Dassonneville, B.; Witulski, B.; Detert, H. Eur. J. Org.
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(9) Nissen, F.; Detert, H. Eur. J. Org. Chem. 2011, 2845.
(10) Nissen, F.; Richard, V.; Alayrac, C.; Witulski, B. Chem.
Commun. 2011, 47, 6656.
IR (neat, ATR): 3344 (br), 2923 (vs), 2852 (s), 2222 (s), 1734 (w),
1624 (m), 1561 (w), 1492 (w), 1467 (m), 1445 (s), 1377 (w), 1318
(w), 1234 (m), 1151 (w), 852 (m), 830 (w), 734 cm–1 (s).
1H NMR, COSY, HMBC (400 MHz, 100.6 MHz, CDCl3): d = 8.44
3
(s, 1 H, 9-NH), 8.14 (d, JHH = 8.4 Hz, 1 H, 5-CH), 8.12 (d,
3JHH = 8.5 Hz, 2 H, 2¢-CH), 7.85 (s, 1 H, 4-CH), 7.81 (d, 3JHH = 8.5
Hz, 2 H, 3¢-CH), 7.55 (ddd, 3JHH = 8.1 Hz, 3JHH = 7.0 Hz, 4JHH = 1.1
3
Hz, 1 H, 7-CH), 7.49 (d, JHH = 8.1 Hz, 1 H, 8-CH), 7.31 (ddd,
3
4
3JHH = 8.1 Hz, JHH = 7.0 Hz, JHH = 1.1 Hz 1 H, 6-CH), 2.97 (tt,
3JHHcis = 11.9 Hz, JHHtrans = 3.4 Hz, 1 H, 1¢-CHcyclohexyl), 2.15–
1.26 (m, 10 H, cycohexyl).
3
13C NMR, HMBC, HSQC (100.6 MHz, 400 MHz, CDCl3): d =
157.3 (s, 3-C), 143.7 (s, 8a-C), 141.0 (s, 1-C), 139.0 (s, 1¢-C), 132.9
(d, 3¢-CH), 132.4 (s, 9a-C), 131.8 (s, 4a-C), 129.0 (d, 2¢-CH), 128.8
(s, 7-C), 122.0 (s, 4b-C), 121.9 (d, 5-CH), 120.5 (d, 6-CH), 119.0 (s,
CN), 111.9 (s, 4¢-C), 111.7 (d, 8-CH), 111.5 (d, 4-CH), 46.5 (cyclo-
hexyl), 33.9 (cyclohexyl), 26.9 (cyclohexyl), 26.4 (cyclohexyl).
(11) Nissen, F.; Schollmeyer, D.; Detert, H. Acta Crystallogr.,
Sect. E 2011, 67, o1497.
ESI-HRMS: m/z calcd for C24H22N3 [M + H]+: 352.1817; found:
352.1817.
(12) Shi, Z.; Cui, Y.; Jiao, N. Org. Lett. 2010, 12, 2908.
(13) Ding, S.; Shi, Z.; Jiao, N. Org. Lett. 2010, 12, 1540.
(14) Zhang, H.; Larock, R. C. J. Org. Chem. 2002, 67, 9318.
(15) Wagner, F. F.; Comins, D. L. Org. Lett. 2006, 8, 3549.
(16) Hostyn, S.; Maes, B. U. W.; Van Baelen, G.; Gulevskaya,
A.; Meyers, C.; Smits, K. Tetrahedron 2006, 62, 4676.
(17) Verniest, G.; England, D.; De Kimpe, N.; Padwa, A.
Tetrahedron 2010, 66, 1496.
1-(3,4-Dimethoxyphenyl)-3-phenyl-9H-b-carboline (5h)
Yellow solid (2 steps, 11 mg, 8%); mp 185–186 °C; Rf = 0.19 (PE–
EtOAc, 4:1).
IR (neat, ATR): 3337 (br), 1623 (w), 1510 (s), 1436 (m), 1315 (w),
1251 (m), 1225 (m), 1137 (m), 1022 (m), 907 (w), 864 (w), 813 (w),
742 (vs), 694 cm–1 (s).
(18) Rocca, P.; Marsais, F.; Godard, A.; Queguiner, G.
Tetrahedron 1993, 49, 3325.
(19) Opatz, T. Synthesis 2009, 1941.
1H NMR, COSY, HMBC (400 MHz, 100.6 MHz, CDCl3): d = 8.53
(s, 1 H, NH), 8.36 (s, 1 H, 4-CH), 8.23–8.20 (m, 3 H, 5-CH, 2¢-CH),
(20) Meyer, N.; Werner, F.; Opatz, T. Synthesis 2005, 945.
(21) Meyer, N.; Opatz, T. Eur. J. Org. Chem. 2006, 3997.
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3911.
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4
7.68 (d, JHH = 1.9 Hz, 1 H, 2¢¢-CH), 7.61–7.50 (m, 5 H, 7-CH, 8-
3
CH, 3¢-CH, 6¢¢-CH), 7.39 (t, JHH = 7.3 Hz, 1 H, 4¢-CH), 7.32 (t,
3JHH = 7.0 Hz, 1 H, 6-CH), 7.06 (d, 3JHH = 8.2 Hz, 1 H, 5¢¢-CH), 4.02
(s, 3 H, OCH3), 3.98 (s, 3 H, OCH3).
13C NMR, HMBC, HSQC (100.6 MHz, 400 MHz, CDCl3): d =
149.9 (s, 3¢¢-C), 149.8 (s, 4¢¢-C), 147.9 (s, 3-C), 142.2 (s, 1-C), 140.9
(s, 8a-C), 140.7 (1¢-C), 132.8 (s, 9a-C), 131.9 (s, 1¢¢-C), 131.1 (s, 4a-
C), 128.8 (d, 3¢-CH), 128.6 (d, 7-CH), 127.9 (d, 4¢-CH), 127.0 (d,
2¢-CH), 122.5 (s, 4b-C), 121.9 (d, 5-CH), 120.4 (2 signals, 6-CH
and 6¢¢-CH), 111.9 (d, 2¢¢-CH), 111.8 (d, 8-CH), 111.3 (d, 5¢¢-CH),
110.2 (d, 4-CH), 56.3 (q, OCH3), 56.2 (q, OCH3).
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ESI-HRMS: m/z calcd for C25H21N2O2 [M + H]+: 381.1598; found:
381.1600.
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X-ray Crystal Structure of 5e46
X-ray crystallographic analysis was performed on a Turbo-CAD 4
instrument with Mo-Ka radiation (graphite monochromator) at 193
K. Crystal structure solution and refinement were performed using
the SIR-97 and SHELXL-97 program, respectively.47
3(C20H18N2O2), 2(CH2Cl2) M = 1124.94 g·mol–1, monoclinic, space
group: P21/c, unit cell dimensions: a = 21.6175(11) Å, b =
11.3492(6) Å, c = 23.3515(11) Å, b = 95.691(2)°, V = 5700.8(5) Å3,
z = 4, dcalc = 1.311 g·cm–3, R1 = 0.0480, wR2 = 0.1365.
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© Thieme Stuttgart · New York