An improved synthesis of α-carbolines under microwave irradiation

Article abstract of DOI:10.1021/ol052552y

α-Carbolines are interesting core structures for designing DNA-interacting small molecules. However, these compounds are not commercially available and their synthetic methods are low yielding or time consuming. The shortest synthetic route, the modified Graebe-Ullmann reaction, has been optimized by using microwave heating in four different types of apparatus to give shorter reaction times and enhanced yields. Optimized conditions enabled the preparation of a small library of α-carbolines.

Full text of DOI:10.1021/ol052552y

ORGANIC
LETTERS
2006
Vol. 8, No. 3
415-418
An Improved Synthesis of
under Microwave Irradiation
r-Carbolines
Patricia Vera-Luque, Ramo´n Alajar´ın,* Julio Alvarez-Builla, and Juan J. Vaquero*
Departamento de Qu´ımica Orga´nica, UniVersidad de Alcala´,
28871-Alcala´ de Henares, Madrid, Spain
juanjose.Vaquero@uah.es; ramon.alajarin@uah.es
Received October 21, 2005
ABSTRACT
r
-Carbolines are interesting core structures for designing DNA-interacting small molecules. However, these compounds are not commercially
available and their synthetic methods are low yielding or time consuming. The shortest synthetic route, the modified Graebe Ullmann reaction,
has been optimized by using microwave heating in four different types of apparatus to give shorter reaction times and enhanced yields.
−
Optimized conditions enabled the preparation of a small library of
r-carbolines.
In recent years pyrido[2,3-b]indoles (R-carbolines) have
received renewed interest due to their biological activity as
antiviral and antitumor agents that function by the formation
of intercalation complexes with DNA or the inhibition of
topoisomerase II.1 Anxiolytic, antiinflammatory, and CNS-
stimulating activity has also been reported.2 Some natural
products contain this tricyclic core as grossularines and
cryptotackieine (Figure 1).3 R-Carbolines have also been
detected in the products from the pyrolysis of protein-
containing food products and cigarette smoke.4
Synthetic methods for R-carbolines can be divided into a
number of classes depending on the nature of the starting
material, the bonds formed, and the key reaction during the
(1) (a) Pogodaeva, N. N.; Shagun, V. A.; Semenov, A. A. Khim.-Fram.
Zh. 1985, 19, 1054-1056. (b) Peczyska-Czoch, W.; Pognan, F.; Kaczmarek,
L.; Boratynski, J. J. Med. Chem. 1994, 37, 3503-3510.
Figure 1. Pyrido[2,3-b]indole (R-carboline) and related natural
alkaloids.
(2) (a) Paolini, L. Sci. Rep. Ist. Super. Sanita 1961, 1, 86. (b) Okamoto,
T.; Akase, T.; Izumi, S.; Inaba, S.; Yamamoto, H. Japanese patent 7220196;
Chem. Abstr. 1972, 77, 152142. (c) Winters, J.; Di Mola, N. West German
patent 2442513; Chem. Abstr. 1975, 82, 156255.
(3) (a) Moquin-Patey, C.; Guyot, M. Tetrahedron 1989, 45, 3445-3450.
(b) Kim, J.-S.; Shin-ya, K.; Furihata, K.; Hayakawa, Y.; Seto, H.
Tetrahedron Lett. 1997, 38, 3431-3434. (c) Sharaf, M. H. M.; Schiff, P.
L., Jr.; Tackie, A. N.; Phoebe, C. H., Jr.; Martin, G. E. J. Heterocycl. Chem.
1996, 33, 239. (d) Cimanga, K.; De Bruyne, T.; Pieters, L.; Claeys, M.;
Vlietinck, A. Tetrahedron Lett. 1996, 37, 1703.
ring closing step. Most of the syntheses start from indoles,5
although triazoles have also been used as starting materials
in the modified Graebe-Ullmann reaction to give R-carbo-
(4) (a) Ioshida, D. Biochem. Biophys. Res. Commun. 1978, 83, 915. (b)
Ioshida, D.; Matsumoto, T. Cancer Lett. 1980, 10, 141.
10.1021/ol052552y CCC: $33.50
© 2006 American Chemical Society
Published on Web 01/13/2006

lines by the direct or reverse approach.1b,6 The Fischer indole
reaction gives partially hydrogenated R-carbolines from
2-piperidone phenylhydrazones or cyclohexanone 2-pyridyl-
hydrazones.7
A number of syntheses from other diverse starting materi-
als have been reported. For example, 2(1H)-pyrazinones,
N-arylcarbodiimides, and 2-arylaminopyrimidines give R-car-
bolines through intramolecular Diels-Alder reactions.8
Finally, (o-pivaloylamino)phenyl-o′-fluoropyridines have also
been reported as starting materials in nucleophilic aryl-
fluorine displacement reactions.9
we decided to improve it by making use of microwave
technology.12
In this paper we wish to report the synthesis of the
R-carboline core through the modified Graebe-Ullman
reaction under microwave irradiation using four different
types of microwave ovens.13
Considering the modified Graebe-Ullman reaction as a
two-step process from commercially available starting ma-
terials, we first optimized the synthesis of pyridylbenzotri-
azole (1a) from benzotriazole (2a) and 2-chloro-6-meth-
ylpyridine (3a) as a model (Scheme 1).
As part of a wider project aimed at finding heteroaromatic
structures bearing a bridged nitrogen atom and having
selective DNA-intercalative properties as well as cyto-
toxic activities, we previously studied the synthesis, reactiv-
ity, and biological behavior of structures with a quino-
lizinium-type core.10 For instance, a number of com-
pounds derived from â- and γ-carbolines have been reported
by us.11 We have now turned our attention to the R-carboline
core.
Scheme 1. Microwave Synthesis of R-Carboline 4a
Most of the syntheses of R-carbolines are low yielding
and require several steps from starting materials that are not
commercially available. We therefore selected the modified
Graebe-Ullman reaction as the shortest route to access
R-carbolines. This approach is not particularly efficient so
(5) (a) Molina, P.; Fresneda, P. M. Synthesis 1989, 878-880. (b) Beccalli,
E. M.; Clerici, F.; Marchesini, A. Tetrahedron 2001, 57, 4787-4792. (c)
Erba, E.; Gelmi, M. L.; Pocar, D. Tetrahedron 2000, 56, 9991-9997. (d)
Ono, A.; Narasaka, K. Chem. Lett. 2001, 146-147. (e) Achab, S.; Guyot,
M.; Potier, P. Tetrahedron Lett. 1995, 36, 2615-2618. (f) Forbes, I. T.;
Johnson, C. N.; Thompson, M. J. Chem. Soc., Perkin. Trans. 1 1992, 275-
281.
Optimized results for this reaction are shown in Table 1.
The classical reaction was first optimized as a function of
(6) (a) Kaczmarek, L.; Peczynka-Czoch, W.; Osiadacz, J.; Mordarski,
M.; Sokalski, W. A.; Boratynski, J.; Marcinkovska, E.; Glazman-Kusnierc-
zyk, H.; Radzikowski, C. Bioorg. Med. Chem. Lett. 1999, 7, 22457-2464.
(b) Laurson, W.; Perkin, W. H.; Robinson, R. J. Chem. Soc. 1924, 125,
626. (c) Kaczmarek, L.; Balicki, R.; Nantka-Namirski, P.; Peczynska-Czoch,
W.; Mordarski, M. Arch. Pharm. (Weinheim, Ger.) 1988, 321, 463-467.
(b) Mehta, L. K.; Parrick, J.; Payne, F. J. Chem. Soc., Perkin. Trans. 1
1993, 1261-1267.
Table 1. Optimized Yields and Conditions for 1a
(7) (a) Okuda, S.; Robinson, M. M. J. Am. Chem. Soc. 1959, 81, 740.
(b) Yamazaki, T.; Matoba, K.; Imoto, S.; Terashima, M. Chem. Pharm.
Bull. 1976, 24, 3011.
(8) (a) Tahri, A.; Buysens, K. J.; Van der Eycken, E. V.; Vanderberghe,
D. M.; Hoornaert, G. J. Tetrahedron 1998, 54, 13211-13226. (b) Molina,
P.; Alajar´ın, M.; Vidal, A.; Sa´nchez-Aranda, P. J. Org. Chem. 1992, 57,
929-939. (c) Forbes, I. T.; Johnson, C. N.; Thompson, M. Synth. Commun.
1993, 23, 715-723.
power
(W)j
temp
(°C)
time
(min)
yield
(%)b,k
entry
methoda
1
2
3
4
5
6
7
8
9
10
11
12
13
14
thermal
Ac
155
nd
nd
nd
nd
nd
nd
nd
nd
30
10
15
10
10
10
10
10
10
10
15
7
70
40
36
49
41
10
36
dec
31
32
69
59
72
66
145
50
(9) Rocca, P.; Marsais, F.; Godard, A.; Queguiner, G. Tetrahedron 1993,
49, 49-64.
Ac
(10) Vaquero, J. J.; Alvarez-Builla, J. AdV. Nitrogen Heterocycl. 2000,
4, 159-250.
Bc
150
190
150
150
150
150
150
300
300
50
Bc
(11) (a) Molina, A.; Vaquero, J. J.; Garc´ıa-Nav´ıo, J. L.; Alvarez-Builla,
J.; de Pascual-Teresa, B.; Gago, F.; Rodrigo, M. M. J. Org. Chem. 1999,
64, 3907. (b) Fontana, A.; Benito, E. J.; Mart´ın, M. J.; Sa´nchez, N.; Alajar´ın,
R.; Vaquero, J. J.; Alvarez-Builla, J.; Lambel-Giraudet, S.; Leonce, S.;
Pierre´, A.; Caignard, D. Bioorg. Med. Chem. Lett. 2002, 12, 2611-
2614.
Bc,d
Bc,e
Bc,f
Bc,g
Bh
nd
(12) (a) Kappe, C. O.; Stadler, A. MicrowaVes in Organic and Medicinal
Chemistry; Wiley-VCH: Weinheim, Germany, 2005. (b) MicrowaVe
Assisted Organic Synthesis; Tierney, J. P., Lidstrom, P., Eds.; Blackwell
Publishing: Oxford, UK, 2005.
(13) (a) Domestic microwave A: Samsung M1719N.; Domestic micro-
wave B (inverter technology): Panasonic NN-F359WBE.; Focused micro-
wave C: Synthewave 402 from Prolabo; Focused microwave D: Explorer
from CEM. (b) Inverted technology replaces the conventional transformer
and capacitor of classic microwave ovens with an inverter circuit board,
which gives a constant power at every level, improving the efficiency of
the power supply. (c) Microwave digestion bomb model 4781 from Parr
Inc. CAUTION: domestic microwave apparatus are not safe when using
sealed reactors.
Cc
170
170
180
180
Cc
Di
10
10
Di
70
a A and B: domestic microwave ovens. C and D: focused microwave
ovens. See ref 13a. b Isolated yields. c Open vessel. d Adsorbed on silica
gel. e Disolved in ethanol. f Disolved in DMF. g Disolved in toluene. h 24
mL sealed vessel. See ref 13c. i 20 mL sealed vessel. j nd: not determined.
k dec: decomposition.
416
Org. Lett., Vol. 8, No. 3, 2006

time and temperature. Power and time were optimized for
the domestic ovens. Experiments performed with a micro-
wave digestion bomb (entry 10), organic solvents (DMF,
EtOH, and toluene; entries 8, 7, and 9, respectively), dry
media (silica gel; entry 6), and even a 2-fold excess of 3 all
gave poor results.13c Both thermal and microwave reactions
were carried out without solvent (neat media). For the
focused instruments, power, time, and temperature were
modified. In each case, the best reagents ratio was the
stequiometric one. As expected, domestic ovens gave lower
yields than the focused systems. However, domestic ovens
with inverter technology gave better results than domestic
ones without this implement.13b The yield for each optimiza-
tion experiment was determined by reverse-phase HPLC and,
for the best experiment, the yield refers to product isolated
by chromatography.
Table 2. Synthesized Pyridylbenzotriazoles 1
After optimization, the level of formation of 1 using a
focused apparatus (method D) was as efficient as that in the
classical thermal reaction, but the microwave reaction was
three times faster. We selected method D instead of method
C since it works on sealed reactors and allows a better control
of parameters on up to 24 reactors individually. The
optimized conditions were applied to prepare a small array
of N-substituted benzotriazoles. Commercially available
benzotriazoles 2 and azine building blocks 3 were reacted
(Table 2). Symmetrically substituted benzotriazoles 2 were
selected to avoid the formation of isomeric products 1.
Yields and structures for compounds 1a-l are given in
Table 2. The crude product was purified by column chro-
matography and isolated 1 gave satisfactory elemental
analyses. 2-Chloro-substituted azines 3 gave better yields
than 2-bromo- or 2-methylthio-substituted ones (entries 1,
2, 5, 6, 9, and 10), probably due to differences in the dipole
moments. Both electron-donating and electron-withdrawing
substituents in 2 led to lower yields than with benzotriazole
(2a) itself (entries 2, 5, 9; 1, 6, 10; 3, 7, 12; and
4, 8, 13).
Table 3. Optimized Yields and Conditions for 4a
H4P2O7
entry (mmol) methoda
power
(W)
temp
(°C)
time
(min)
yield
(%)b
1
2
3
4
5
6
7
16
16
8
thermal
Bc
Bc
Bc
De
De
De
150-200 120
32
47
21
22d
54
43
44
150
150
150
150
150
150
nd
nd
2
2
16
16
16
16
nd
2
170
170
185
0.5
0.25
0.5
a See ref 13; b Isolated yields; c Open vessels; d Yield for the sequential
process; e 20 mL sealed vessels.
Org. Lett., Vol. 8, No. 3, 2006
417

Ullmann reaction (Scheme 1), to compare the efficiency of
the best monomode instrument versus the best multi-
mode one and the thermal reaction for the next reaction step.
First, the amount of pyrophosphoric acid (mmol), power, and
time were optimized in the multimode apparatus B (Table
3). Method B, using a smaller amount of acid, does not
improve yield (entry 3). In addition, the one-pot sequen-
tial process was attempted by using optimized conditions
for both steps, but lower yields were obtained (entry 4, Table
3).
Table 4. Synthesized R-Carbolines 4
The yield for 4a was improved and the time was reduced
in comparison to the thermal reaction. The amount of acid
(mmole) was kept constant and the power, temperature, and
time were optimized in the monomode instrument D. Power
was set to 150 W and the yield and time were further
improved. For method D, shorter times or higher tempera-
tures do not improve yields (entries 6 and 7). Thus, both
monomode and multimode microwave ovens give 4a
more efficiently and more rapidly than thermal heating.
These conditions were subsequently applied to 4b-i (Table
4).
Compounds bearing chloro-substituents either gave lower
yields (4i, entry 8) or failed to react (1j-l, Table 2, entries
10-13).
In summary, we have shown that the synthesis of R-car-
bolines from benzotriazoles and azines bearing a leaving
group at the C2 position, through the modified Graebe-
Ullmann reaction, can be performed more efficiently and
more rapidly using microwave irradiation. The increases in
the yields and the lowering of the reaction times are more
marked when a monomode microwave instrument is
used.
Acknowledgment. The authors are grateful to the Min-
isterio de Ciencia y Tecnolog´ıa (Plan Nacional de Investi-
gacio´n Cient´ıfica, Desarrollo e Innovacio´n Tecnolo´gica,
BQU2002-03578) for financial support and a fellowship
(P.V.). We also acknowledge M. J. Dom´ınguez and
M. P. Mat´ıa (Planta Piloto de Qu´ımica Fina, Universidad de
Alcala´) for the use of the monomode microwave instru-
ment.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds (1 and 4).
This material is available free of charge via the Internet at
http://pubs.acs.org.
Microwave systems B and D were selected for the
optimization of the second step, the modified Graebe-
OL052552Y
418
Org. Lett., Vol. 8, No. 3, 2006