Synthesis of β-carbolines using microwave-assisted aza-Wittig methodology in ionic liquids

Article abstract of DOI:10.1016/j.tetlet.2012.03.049

The improved preparation of 1-substituted-β-carbolines is reported using microwave-assisted aza-Wittig/electrocyclic ring-closure reaction with ionic liquids as solvent. In all cases an unprecedented N-methoxymethyl group (MOM) deprotection is observed.

Full text of DOI:10.1016/j.tetlet.2012.03.049

Tetrahedron Letters 53 (2012) 2618–2621
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Tetrahedron Letters
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Synthesis of b-carbolines using microwave-assisted aza-Wittig methodology
in ionic liquids
⇑
Pilar M. Fresneda , Jose Antonio Blázquez
Departamento de Química Orgánica, Facultad de Química, Universidad de Murcia, Campus de Espinardo, E-30100 Murcia, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The improved preparation of 1-substituted-b-carbolines is reported using microwave-assisted aza-Wit-
tig/electrocyclic ring-closure reaction with ionic liquids as solvent. In all cases an unprecedented N-
methoxymethyl group (MOM) deprotection is observed.
Received 12 January 2012
Revised 8 March 2012
Accepted 13 March 2012
Available online 21 March 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
b-Carbolines
Iminophosphoranes
Aza-Wittig reaction
Microwave irradiation
Ionic liquids
The b-carboline core is of great interest because it is present in
numerous natural and synthetic compounds and has important
pharmacological properties.1 Moreover, the 1-substituted b-carbo-
line alkaloids have antimalarial,2 antitumoral,3 anti-Alzheimer,4
anti-HIV,5 antitrypanosomal, and antileishmanial6 properties, they
also act as regulators of the dioxin receptor (AhR).7 Over the years,
many synthetic methods have been described for the preparation
of 1-substituted b-carbolines, however most of the reported meth-
ods involve cyclization and oxidation as separate steps.8 Recently,
based on the domino approach using a bifunctional catalyst Pd/C/
K-10 combined with microwave irradiation,9 via Heck aza Michael
methodology,10 or by intramolecular palladium-catalyzed enolate
arylation of 2-iodoindole derivatives have been developed.11
In the course of our studies directed toward the synthesis of
nitrogen heterocyclic compounds based on the heterocyclization
process of 2-aza-1,3,5-hexatriene systems, generated by Stauding-
er reaction of 1,3-diene azides with triphenylphosphine and the
subsequent aza-Wittig reaction with carbonyl compounds or hete-
rocumulenes, we have developed the tandem aza-Wittig/electro-
cyclic ring-closure strategy for the synthesis of fused pyridines.12
This methodology has been successfully applied for the synthesis
of natural b-carbolines such as eudistomins, lavendamycin, fasca-
plysin, nitramarin, and xestomanzamine A.13 However, when tolu-
ene or o-xylene is used as the solvent, rather long reaction times at
high temperatures are required to successfully obtain the carboline
core; and milder synthetic methods would be preferable. Since the
microwave radiation14 acts as an alternative heating source and
provides an efficient procedure to accelerate organic transforma-
tions. Ionic liquids are an environmentally benign reaction med-
ium, due to their polar nature and special properties such as a
wide liquid range, good solvating ability, high thermal stability,
low vapor pressure, and easy recyclability.15 We decided to com-
bine the advantages of microwave and ionic liquids to ascertain
their combined influence on the preparation of 1-substituted b-
carboline (pyrido[3,4-b]indole) using the aza-Wittig/electrocyclic
ring-closure reaction.
First, iminophosphorane 1,16 which is easily prepared from 3-
formyl-N-methoxymethylindole by sequential treatment with
ethyl azidoacetate and triphenylphosphine, and aromatic alde-
hydes Ar-CHO 2, were used in a series of experiments involving dif-
ferent combinations of heating modes and ionic liquids: (a)
conventional heating, (b) microwave irradiation, (c) conventional
heating/ionic liquid, and (d) microwave irradiation/ionic liquid.
When iminophosphorane 1 reacted in an aza-Wittig/electrocy-
clic cyclization fashion with 4-methoxybenzaldehyde 2a and 4-
chlorobenzaldehyde 2b in dry toluene by heating in a sealed tube
at 160 °C for 48 h, N-methoxymethyl-b-carbolines 4a and 4b were
obtained in yields of 77% and 65%, respectively. However, when the
reaction mixture was irradiated with a single-mode microwave,
using a pre-selected maximum temperature of 200 °C, (200 W
maximum power), in a sealed vessel and using dry toluene as the
solvent, compounds 4a and 4b were obtained after a shorter reac-
tion time of 8 h, in yields of 87% and 83%, respectively (Scheme 1),
(Table 1).
⇑
Corresponding author. Tel.: +34 868887484; fax: +34 868884148.
E-mail address: fresneda@um.es (P.M. Fresneda).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.049

P. M. Fresneda, J. A. Blázquez / Tetrahedron Letters 53 (2012) 2618–2621
2619
Table 2
CO2Et
Microwave-assisted synthesis of 1-substituted-b-carbolines 5 in [bmim][BF4]a
N=PPh3
CO2Et
CO2Et
N
N=PPh3
2 R-CHO or
N
O
3 R-COCH(OH)2
N
N
H
1
X
O
X= R
1
5
X= COR
a), b), c)
d)
2 R-CHO or
3
R-COCH(OH)2
2
Ar-CHO
5
R-CHO 2a–d
R-COCH(OH)2 3a–c
Time (min)
Yield (%)
5a
5b
5c
5d
5e
5f
4-MeOC6H4
4-Cl C6H4
C6H5
15
20
20
20
15
15
25
79
70
73
65
88
90
76
CO2Et
CO2Et
N
C6H5-(CH2)2
N
C6H5
4-MeOC6H4
N-MOM-indol-3-yl
N
5g
N
Ar
H
X
a
0.19 mmol of 1 and 0.19 mmol of 2 or 3 were used, 1 mL, [bmim][BF4], MW,
O
power = 1 W, T = 200 °C.
5
X= R
4
X= COR
Scheme 1. Synthesis of 1-substituted-b-carbolines 4 and 5 via aza-Wittig/electro-
cyclic ring-closure reaction. Reagents and conditions: (a) toluene, sealed tube,
160 °C, 48 h; (b) toluene, MW, 200 W, 200 °C, 8 h; (c) (i) [bmim][BF4], 160 °C, 2 h.
(ii) [bmim][PF6], 160 °C, 2.5 h; (d) [bmim][BF4], MW, 1 W, 200 °C, 15 min.
200 °C, (1 W maximum power), in a sealed vessel and [bmim][BF4]
as the solvent, unexpectedly b-carbolines 5a and 5b with the
N-methoxymethyl group cleaved were obtained in 79% and
70% yields, respectively after shorter reaction times of 15–
20 min.20
Table 1
Synthesis of 1-substituted-b-carboline
4 via aza-Wittig/electrocyclic ring-closure
Although several reagents, including HCO2H-reflux,21 CF3SO3H/
MeOH/HC(OCH3)3, nitromethane/100 °C,22 HCl (EtOH, THF, and
dioxane)23 and HCl-dioxane/MW,24 have been used for deprotec-
tion of the N-MOM group, however their use in conjunction with
ionic liquids and microwave energy has not been reported in the
literature.
reaction from iminophoshorane 1 and aldehyde 2
CO2Et
CO2Et
2 Ar-CHO
N=PPh3
N
N
To establish the generality and viability of this method, the
same conditions were successfully applied to several R-CHO 2
aldehydes, benzaldehyde 2c, 3-phenylpropanal 2d, and RCO-
CH(OH)2 3, aryl/heteroaryl glyoxals,21d,25 phenylglyoxal 3a, 4-
methoxyphenylglyoxal 3b, 2-(N-methoxymethyl-3-indolyl)glyoxal
3c, to give the corresponding aryl/aroyl 1-substituted-9H-pyr-
ido[3,4-b]indoles 5e–5g in yields ranging from 65% to 90% and in
shorter reaction times of 15–25 min (Scheme 1), (Table 2).26
In summary, we have developed a useful and an efficient meth-
od for the preparation of aryl/aroyl 1-substituted-9H-pyrido[3,4-
b]indoles through the tandem aza-Wittig/electrocyclic ring-closure
reaction using microwave irradiation in combination with an ionic
liquid [bmim][BF4] as the solvent. In addition, we describe here, for
the first time a pyridoannulation process involving the simulta-
neous deprotection of N-methoxymethyl group using ionic li-
quid/microwave-assisted irradiation with good yields (65–90%)
and short reaction times (15–25 min). The advantage of this meth-
od is that it uses microwave radiation and a non-contaminating,
reusable solvent [bmim][BF4], in addition, the fact that the starting
material is readily accessible, it is easily manipulated, and the few
steps necessary mean that the method is suitable for preparing
new b-carbolines.
N
Ar
O
O
1
4
4
ArCHO
Heata yield (%)
MWb yield (%)
Heat+ILc yield (%)
4a
4b
4-MeOC6H4
4-Cl C6H4
77
65
87
83
85/30
84/25
a
b
c
1.0 mmol of 1 and 1.2 of 2 were used, toluene, sealed tube, 160 °C, 48 h.
0.19 mmol of 1 and 0.19 mmol of 2 were used toluene, MW, 200 W, 200 °C, 8 h.
(i) 1 mL, [bmim][BF4], 160 °C, 2 h/(ii) 1 mL, [bmim][PF6], 160 °C, 2.5 h.
In order to explore the reaction in ionic liquids, and based
on a recent study on the thermal stability of a variety of ionic
liquid/solvent combinations under high-temperature microwave
conditions,17 we selected 1-butyl-3-methylimidazolium tetrafluo-
roborate [bmim][BF4] (290 °C) and 1-butyl-3-methylimidazolium
hexafluorophosphate [bmim][PF6] (276 °C).18 The best yields for
4a and 4b (85–86%) were obtained when the reaction was
performed in [bmim][BF4] as the solvent and heating at 160 °C
for 2–2.5 h. However, when [bmim][PF6] was used under the same
conditions, 4a and 4b showed yields of 30% and 25%, respec-
tively.19 Consequently we decided to use only [bmim][BF4] as the
solvent for the next experiment based on microwave irradiation/
ionic liquid. When the reaction mixture was irradiated with a single-
mode microwave, using a pre-selected maximum temperature of
Acknowledgments
We thank the Seneca Foundation (Comunidad Autónoma de la
Región de Murcia), for financial support. We would also like to
thank the University of Murcia for financial support to J.A.B. (Mas-
ter’ Grant).

2620
P. M. Fresneda, J. A. Blázquez / Tetrahedron Letters 53 (2012) 2618–2621
chromatographed on a silica gel column using EtOAc/CH2Cl2/n-hexane (2:3:6)
References and notes
as the eluent to give 4a (85% and 30%) or 4b (84% and 25%) yields.
Ethyl N-methoxymethyl-1-(4-methoxyphenyl)-9H-pyrido[3,4-b]indole-3-
carboxylate (4a). Yield 85%, 62 mg, white prisms, mp 167–168 °C (CH2Cl2/n-
hexane, 4:1). 1H NMR (400 MHz, CDCl3, 25 °C): d = 1.47 (t, J = 7.2 Hz, 3H), 2.94
(s, 3H), 3.90 (s, 3H), 4.52 (q, J = 7.2 Hz, 2H), 5.29 (s, 2H), 7.05 (dd, J = 8.8, 2.4 Hz,
2H), 7.40 (td, J = 7.4, 1.2 Hz, 1H), 7.58–7.65 (m, 4 H), 8.22 (d, J = 7.6 Hz, 1H),
8.83 (s, 1H). 13C NMR (100 MHz, CDCl3, 25 °C): d = 14.5, 55.4, 61.6, 74.6, 111.3,
113.9, 116.3, 121.6, 122.1, 129.1, 130.8, 131.1, 131.6, 136.2, 138.5, 142.5, 144.3,
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160.2, 166.1. IR (nujol):
t
= 1707, 1610, 1456, 1241 cmÀ1. MS (EI): m/z (%): 390
(54), [M]+, 345 (6), [MÀCH2OCH3]+, 283 (7), [MÀPhOCH3]+. Anal. Calcd for
C
23H22N2O4: C, 70.75; H, 5.68, N, 7.17. Found: C, 70.67; H, 5.75; N, 7.23.
Ethyl N-methoxymethyl-1-(4-chlorophenyl)-9H-pyrido[3,4-b]indole-3-
carboxylate (4b). Yield 84%, 62 mg, white prisms, mp 189–191 °C, (CH2Cl2/n-
hexane, 4:1). 1H NMR (400 MHz, CDCl3, 25 °C): d = 1.48 (t, J = 7.2 Hz, 3H), 2.97
(s, 3H), 4.53 (q, J = 7.2 Hz, 2H), 5.24 (s, 2H), 7.42 (t, J = 7.2 Hz, 1H), 7.51 (d,
J = 8.4 Hz, 2H), 7.59 (d, J = 8.0 Hz, 1H), 7.64–7.67 (m, 3H), 8.24 (d, J = 7.6 Hz,
1H), 8.86 (s, 1H). 13C NMR (100 MHz, CDCl3, 25 °C): d = 14.5, 55.4, 61.8, 74.7,
111.2, 116.8, 121.0, 121.9, 122.0, 128.7, 129.9, 130.9, 131.1, 135.1, 135.8, 137.6
138.7, 142.7, 143.1, 165.9. IR (nujol):
t
= 1712, 1458, 1376, 1083 cmÀ1. MS (EI):
m/z (%): 396 (16), [M+2]+, 394 (42), [M]+, 323 (37), [MÀCOOEt]+. Anal. Calcd for
C
22H19ClN2O4: C, 66.92; H, 4.85; Cl, 8.98; N, 7.09. Found: C, 66.89; H, 4.93; Cl,
8.92; N, 7.17.
20. General procedure in ionic liquid/microwave irradiation. Preparation of ethyl 1-
substituted-9H-pyrido[3,4-b]indole-3
carboxylate
(5).
A
mixture
of
or
iminophosphorane (100 mg, 0.19 mmol) and aryl/alkylaldehyde
1
2
arylglyoxal 3 (0.19 mmol) was dissolved in [bmim][BF4] (1 mL), contained in
sealed tube. The reaction mixture was irradiated with single-mode
a
a
microwave (1 W, 200 °C) under nitrogen for 15–20 min. After cooling, the
mixture was extracted with ethyl acetate (10 Â 5 mL) and dried over
anhydrous Na2SO4. To the residual material was added dichloromethane
(10 mL) and active carbon, filtrated over celite, and concentrated to dryness to
give [bmim][BF4], which was re-used. The filtrate was concentrated under
reduced pressure and the residue was chromatographed on a silica gel column
using ethyl acetate/dichloromethane/n-hexane (2:3:6) as the eluent to give 5
in 65–90% yield.
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Ethyl 1-(4-methoxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate (5a). Yield 79%,
51 mg, white prisms, mp 222–224 °C, (CH2Cl2/n-hexane, 4:1). 1H NMR
(400 MHz, CDCl3, 25 °C): d = 1.48 (t, J = 7.2 Hz, 3H), 3.83 (s, 3H), 4.53 (q,
J = 7.2 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 7.37 (td, 1H), 7.57–7.59 (m, 2H),7.85 (d,
J = 8.8 Hz, 2H), 8.21 (d, J = 8 Hz, 1H), 8.80 (s, 1H), 8.99 (br s, 1H). 13C NMR
(100 MHz, CDCl3, 25 °C): d = 14.5, 55.0, 61.1, 111.5, 114.1, 115.9, 120.6, 121.5,
121.8, 128.3, 129.2, 129.3, 130.0, 134.5, 138.1, 140.1, 142.3, 160.0, 166.0. IR
11. Solé, D.; Bennasar, M.-L.; Jiménez, I. Org. Biomol. Chem. 2011, 9, 4535–4544.
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Fresneda, P. J. Chem. Soc., Perkin Trans. 1 1988, 1819–1822; (c) Molina, P.;
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(nujol):
t
= 3252, 1703, 1458 cmÀ1. MS (EI): m/z (%): 346 (54), [M]+, 345 (6),
283 (7), [MÀPhOCH3]+, 273 (100), [MÀCOOEt]+. Anal. Calcd for C21H18N2O3: C,
72.82; H, 5.24; N, 7.09. Found: C 72.74, H 5.30, N 7.02.
Ethyl 1-(4-methoxybenzoyl)-9H-pyrido[3,4-b]indole-3-carboxylate (5f). Yield
90%, 63 mg, yellow prisms, mp 211 °C (d), (CH2Cl2/n-hexane, 4:1). 1H NMR
(400 MHz, CDCl3, 25 °C): d = 1.54 (t, J = 7.2 Hz, 3H), 3.93 (s, 3H) 4.54 (q,
J = 7.2 Hz, 2H), 7.05 (d, J = 8.8 H, 2H) 7.38–7.42 (m, 1H), 7.60–7.65 (m, 2H), 8.24
(d, J = 7.6 Hz, 1H), 8.83 (d, J = 8.8 Hz, 2H), 9.02 (s, 1H), 10.72 (br s, 1H). 13C NMR
(100 MHz, CDCl3, 25 °C): d = 14.5, 55.6, 61.7, 112.4, 120.3, 121.3, 121.6, 122.1,
129.7, 129.8, 132.0, 134.6, 136.2, 136.5, 138.3, 141.3, 163.7, 165.8, 191.6. IR
(nujol):
t
= 3420,1707, 1596 cmÀ1. MS (EI): m/z (%): 374 (66), [M]+, 315 (58),
[MÀEt]+, 301 (41), [MÀCOOEt]+. Anal. Calcd for C22H18N2O4: C, 70.58; H, 4.85;
N, 7.48. Found: C, 70.50; H, 4.93; N, 7.39.
Ethyl 1-[(1H-indole-3-yl)carbonyl]-9H-pyrido[3,4-b]indole-3-carboxylate (5g).
Yield 76%, 55 mg, yellow prisms, after chromatographed on
a silica gel
column using ethyl acetate/n-hexane/aqueous NH3 (3.5:6:0.5) as the eluent,
and recrystallization from CH2Cl2/n-hexane (4:1), mp 159–161 °C. 1H NMR
(400 MHz, [D6]acetone, 25 °C): d = 1.53 (t, J = 7.2 Hz, 3H), 4.51 (q, J = 7.2 Hz,
2H), 7.25–7.35 (m, 2H), 7.43 (t, J = 7.5 Hz, 1H), 7.58–7.68 (m, 1H), 7.69 (t,
J = 7.5 Hz, 1H), 8.02 (d, J = 8.1 Hz, 1H), 8.45 (d, J = 7.8 Hz, 1H), 8.68 (dd, J = 2.16,
7.7 Hz, 1H), 9.10 (s, 1H), 10.02 (s, 1H), 11.33 (br s, 1H), 11.82 (br s, 1H). 13C
NMR (100 MHz, [D6]acetone, 25 °C): d = 13.5, 60.5, 111.3, 112.8, 116.8, 119.0,
120.6, 120.7, 121.5, 121.8, 121.9, 122.6, 127.6, 128.8, 131.4, 131.5, 135.5, 135.8,
136.5, 138.7, 141.8, 165.0, 186.6. IR (nujol):
t
= 3385, 1697, 1603 cmÀ1. MS
(EI): m/z (%): 383 (87), [M]+, 315 (4), [MÀEt]+, 301 (37), [MÀCOOEt]+. Anal.
Calcd for C23H17N3O3: C, 72.05; H, 4.47; N, 10.96. Found: C, 72.16; H, 4.54; N,
10.88.
21. (a) Moody, C. J.; Ward, J. G. J. Chem. Soc., Perkin Trans. 1 1984, 2895; (b) Molina,
P.; Fresneda, P. M.; García-Zafra, S.; Almendros, P. Tetrahedron Lett. 1994, 35,
8851–8854; (c) Molina, P.; Fresneda, P. M.; García-Zafra, S. Tetrahedron Lett.
1995, 36, 3581–3582; (d) Fresneda, P. M.; Castañeda, M.; Blug, M.; Molina, P.
Synlett 2007, 324–326.
22. (a) Choshi, T.; Kuwada, T.; Fukui, M.; Matsuya, Y.; Sugino, E.; Hibino, S. Chem.
Pharm. Bull. 2000, 48, 108–113; (b) Kuwada, T.; Fukui, M.; Hirayama, M.;
Nobuhiro, J.; Choshi, T.; Hibino, S. Heterocycles 2002, 58, 325–332; (c) Omura,
K.; Choshi, T.; Watanabe, S.; Satoh, Y.; Nobuhiro, J.; Hibino, S. Chem. Pharm. Bull.
2008, 56, 237–238.
23. (a) Meyers, A. I.; Highsmith, T. K.; Buonora, P. T. J. Org. Chem. 1991, 56, 2960–
2964; (b) Zhang, H.; Larock, R. C. J. Org. Chem. 2002, 67, 9318–9330; (c) Putey,
A.; Popowcyz, F.; Do, Q.-T.; Bernard, P.; Talapatra, S. K.; Kozielski, F.; Galmarini,
C. M.; Benoit, J. J. Med. Chem. 2009, 52, 5916–5925; (d) Tohyama, S.; Choshi, T.;
Matsumoto, K.; Yamabuki, A.; Hieda, Y.; Nobuhiro, J.; Hibino, S. Heterocycles
2010, 82, 397–416.
18. Fredlake, C. P.; Crostwaite, J. M.; Gert, D. G.; Aki, S. N. V. K.; Brennecke, J. F. J.
Chem. Eng. Data 2004, 49, 954–964.
19. General procedure in ionic liquids. Preparation of ethyl N-methoxymethyl-1-
substituted-9H-pyrido[3,4-b]indole-3
carboxylate
(4).
A
mixture
of
iminophosphorane 1 (100 mg, 0.19 mmol) and 4-methoxybenzaldehyde 2a,
or 4-chlorobenzaldehyde 2b (0.19 mmol) was dissolved in [bmim][BF4] or
[bmim][PF6] (1 mL), dried previously during 4 h at 80 °C, under nitrogen. The
solution was stirred at 160 °C during 2 h. After cooling, the mixture was
extracted with EtOAc (10 Â 5 mL) and dried over anhydrous Na2SO4. The
solvent was concentrated to dryness under reduced pressure. The residue was

P. M. Fresneda, J. A. Blázquez / Tetrahedron Letters 53 (2012) 2618–2621
2621
24. Attenni, B.; Hernando, J. I. M.; Malancona, S.; Narjes, F.; Ontoria, J. M.; Rowley,
M. GB Patent WO2005/02319A1, 2005.
NMR spectra (Bruker Avance 300 MHz and 400 MHz) were determined using
tetramethylsilane as an internal standard. The proton (1H NMR) and carbon
25. (a) Fodor, G.; Kovacs, O. J. Am. Chem. Soc. 1949, 71, 1045–1048; (b) Douglas, K.
T.; Demircioglu, H. J. Chem. Soc., Perkin Trans. 2 1985, 1951–1956; (c) Molina, P.;
Fresneda, P. M.; Sanz, M. A.; Foce-Foces, M. C.; de Arellano, M. C. R. Tetrahedron
1998, 54, 9623–9638; (d) Turbiak, J.; Kampf, W.; Showalter, H. D. H.
Tetrahedron Lett. 2010, 51, 1326–1328.
(
13C NMR) signals were assigned by DEPT or two-dimensional NMR
experiments. Mass spectra were recorded with Agilent 5973 (EI) mass
spectrometers. Elemental analyses were performed with a Carlo Erba EA-
1108 elemental analyzer. Microwave irradiation was carried out with a single-
mode microwave CEM Discover Focused Synthesizer with standard IR
temperature sensor. Ethyl-2-[(triphenylphosphoranylideneamino]-3-[(N-
methoxymethyl) indole-3-yl]acrylate was prepared according to our
previously described method.16 Arylglyoxals were prepared according to the
published procedure.21d,25
26. General Methods: All reactions were carried out under N2 and the solvent was
dried by standard procedures. Column chromatography purification was
performed using silica gel (60 Å, 70–200 lm, SDS) as stationary phase. All
melting points were determined on a hot-plate melting point apparatus and
are uncorrected. IR spectra were recorded with a Nicolet 380 FT-IR instrument.