Molecules 2003, 8, 480-487
molecules
ISSN 1420-3049
http://www.mdpi.org
Second Eurasian Meeting on Heterocyclic Chemistry
“Heterocycles in Organic and Combinatorial Chemistry“
Synthesis of New Polyfused Heterocycles of Biological
Importance by Means of Pd(0) Catalysis
Gy. Hajós a,*, Zs. Riedl a, G. Timári a,&, P. Mátyus b, B. U. W. Maes c and G. L. F. Lemière c
a
b
c
&
Institute of Chemistry, Chemical Research Center, Hungarian Academy of Sciences, Pusztaszeri út
59, H-1025 Budapest, Hungary.
Institute of Organic Chemistry, Semmelweis University, H-1092 Budapest, Hőgyes E. u. 7.,
Hungary.
Department of Chemistry, University of Antwerp (RUCA), Groenenborgerlaan 171, B-2020,
Antwerpen, Belgium.
Present address: CHINOIN Pharmaceutical Works Co. Ltd, H-1325 Budapest, PO Box 110, Hungary.
* Author to whom correspondence should be addressed. E-mail: [email protected]
Received: 13 May 2003; in revised form: 20 May 2003 / Accepted: 21 May 2003 / Published: 30 June
2003
Abstract: A general synthetic methodology employing heteroaryl-aryl Suzuki coupling is
reviewed, by which 15 heteroaromatic ring systems of biological interest have been
prepared.
Keywords: Suzuki-coupling, indole alkaloids, total synthesis, pyridazine, intercalation
Introduction
Our ongoing interest in polyfused heteroaromatics as potential intercalating agents [1] and reverse
transcriptase inhibitors [2] prompted us to elaborate new and economical reaction paths to such ring
systems. In the course of these efforts we found [1,3] that the palladium(0)-catalyzed cross-coupling
reaction may provide valuable biaryl compounds suitable to further ring closure reactions yielding the
481
Molecules 2003, 8
desired polycycles. In this paper we review our activity in this field during the last five years and show
that15 different polycyclic systems have been synthesized by this methodology.
The general concept of the syntheses discussed here is depicted by the retrosynthetic analysis
shown in Figure 1. This figure reveals that if the reaction partners participating in the Suzuki-reaction
(by cross-coupling of the X and boronic acid functions) bear appropriate substituents F1 and F2 suitable
for reactions to form new ring moieties, novel polycycles can be obtained. A large variety of
combinations of the functional groups F1 and F2 is available, e.g. a condensation reaction (if F1 = NH2
and F2 = CH=O groups), insertion reaction (if F1 = a nitrene N-atom and F2 = a H atom) or
nucleophilic substitution reaction (if F1 = NH2 and F2 = a halogen atom) can be carried out.
Figure 1. Retrosynthetic analysis of polyfused ring systems employing the Suzuki crosscoupling reaction
C
B
A
F1 F2
B
A
F2
F1
A
X
+
(OH)2B
B
X = halogen, OTf
F1 and F2: -NH2 + carbonyl group; or a nitrene + CH bond
Results and Discussion
By application of the synthetic principle outlined in the Introduction above, new straightforward
syntheses for three analogous compounds isolated from Cryptolepis Sanguinolenta have been
elaborated. These reactions are depicted in Schemes 1-3.
Thus, Cryptosanguinolentine (Scheme 1) was obtained from 3-bromoquinoline in 5 steps: the
Suzuki-coupling to a phenylquinoline was followed by deprotection of the amino moiety and
formation of an azide, which at higher temperature (via formation of a nitrene) underwent ring closure
to the product in good yield [4].
482
Molecules 2003, 8
Scheme 1.
N
o
mp 132 C
N
CH3
Cryptosanguinolentine
(OH) 2B
Br
ButCONH
NHCOtBu
N
N
151-2 oC (90%)
H
1) H2SO4
2) HNO2
3) NaN3
N
80%
product
N3
N
93%
N
o
78 C (80%)
o
>250 C (75%)
Cryptotackieine was synthesized starting from 3-bromoquinoline-N-oxide in 4 steps (Scheme 2) [4].
In contrast to the previous reaction, the final ring closure was accomplished by a condensation reaction
of the amino moiety and the oxo function of the carbostyryl ring. The third related compound,
Quindoline, was prepared from 2,3-dibromoquinoline via a selective cross-coupling of the 2-bromo
atom to an amine followed by deprotection and intramolecular nucleophilic substitution. (Scheme 3)
[5].
Scheme 2.
N
N
CH3
mp 104 C
o
Cryptotackieine
Br
Br
1) TsCl/K2CO3
2) MeI
N
O
N
yield: 81%
CH3
t
N
O
NHCO Bu
CH3
o
179 C (85%)
N
O
O
NH2
CH3
o
174 C (quant)
65%
product
483
Molecules 2003, 8
Scheme 3.
Br
pivHN
Br
+
N
Br
Pd(0)
(HO) 2B
NHpiv
N
o
104 C (54%)
Br
H+/H2O
H
pyridiniumhydrochloride
NH2
N
N
N
Qindoline
solid (85%)
250 oC (66%)
Our ring closure methodology has also been successfully applied in the area of indole-fused ring
systems. Thus, we have reported recently that the alkaloid Furostifoline can conveniently be
synthesized by our protocol as outlined in Scheme 4 [6]. In this case the cross-coupling was carried out
by the reaction of a heterocyclic boronic acid and o-bromonitrobenzole and, then the nitro group was
transformed to a nitrene to yield the tetracyclic end product.
Scheme 4.
CH3
N
O
H
Furostifoline
CH3
CH3
CH3
OH
O
Br
O
CH(OEt)2
Br
Br
CH3
CH3
O
Br
O
NO2
B(OH)2
product
42%
72%
NO2
The continuation of our studies with 3-substituted arylisoquinolines [1] also led to the synthesis of
a novel indole-fused ring. We found that o-azidophenylisoquinoline-N-oxide, obtained from the
corresponding diazonium salt by an aza transfer reaction, undergoes ring closure at position 4 in the
isoquinoline ring and, after a spontaneous deoxygenation, yields the indolo[3,2-c]isoquinoline skeleton
as shown in Scheme 5 [7].
484
Molecules 2003, 8
Scheme 5.
N
N2
N
43%
N3
O
O
H
H
N
N
43%
N
N
O
As summarized in Scheme 6, a new synthetic pathway to the indazolo[3,2-a]-β-carboline ring
system has been elaborated. In this case the cross-coupling reaction was carried out with β-carboline1-triflate to yield a protected amine, which was transformed similar to some related cases to the new
pentacyclic ring system [8].
Scheme 6.
1.(CF3SO2)2O
N H
N
NHPiv
N
H
2. Pd(0),
O
B(OH)2
H2SO4
HNO2
N
NH2
N
H
NHPiv
N
H
N
N2 A
N
H
o
132 C (96%)
NaN3
NaOAc
66%
N
H
N N
∆
N
N3
58%
N
H
Our most recent investigation with halopyridazines revealed that some iodo and chloro derivatives
of 2-alkylpyridazin-3-ones are suitable starting compounds for cross-coupling reactions. Thus, Scheme
7 shows that the starting 5-iodo derivative can be converted in 5 reaction steps to pyridazino[4,5-b]indoles [9] in good yield
485
Molecules 2003, 8
Scheme 7.
X
X
B(OH)2
I
N
NHCOBu-t
N
N
Me
t-BuOC
O
N
NH
X
1) H2SO4
2) NaNO2/ HCl
3) NaN3/ NaOAc
Me
O
X
N
N
N3
N
.
N
N
Me
H
O
Me
O
Halomethoxypyridaziones also proved to be suitable derivatives for ring closure reactions as
shown by Scheme 8. Suzuki coupling of the chlorine atom with appropriately substituted
phenylboronic acid and subsequent ring closure – i.e. intramolecular nucleophilic substitution – gave
rise to new pyridazoquinolinones [10]. In the case of the N-benzyl substituted derivative preparation of
the unsubstituted pyridazinoquinolinone could also be accomplished
Scheme 8.
B(OH)2
CHO
O
R
N
N
O
R
OCH3
Pd(PPh3)4
Na2CO3
DME / H2O
a: R = Me (84 %)
b: R = Bn (74 %)
Cl
N
OCH3
CHO
N
O
O
R
NH4OH
N3
CH3OH
N
2
4
N
5
HN
6
1
7
10
9
8
AlCl3
toluene
R = Bn
93 %
N
N
Biological tests on selected polycyclic derivatives revealed that some of these heterocyclic
derivatives behave valuable reverse transcriptase inhibitory [1] and intercalating [8, 11] properties.
Conclusions
Straightforward syntheses of 15 different polyfused hetercycles (Scheme 9) have been elaborated
by a general ring closure principle including Suzuki-coupling. Extension of these investigations to
novel ring systems is in progress.
486
Molecules 2003, 8
Scheme 9.
N
N
N
N
N
R
R
N
NH
O
N
N
N
NH
A
A
R
N
N N
N N
N R
N
N
NH
O
N
H
O
R
N
N
O
R
N
N
N
R
N
O
N
R
N
O
N
O
O
N
O
HN
N
O
N
O
Acknowledgments
Financial support from the National Research Fund OTKA T 33105 and MediChem 1/047 NKFP as
well as EU fund QLK2-CT-2002-90436 is gratefully acknowledged.
References
1.
2.
3.
4.
Timári, G.; Soós, T.; Hajós, Gy.; Messmer, A.; Nacsa, J.; Molnár, J. Synthesis of Novel
Ellipticine Analogues and Their Inhibition of Moloney Leukemia Reverse Transcriptase. Bioorg.
Med. Chem. Lett., 1996, 6, 2831-2836.
Hajós, Gy.; Riedl, Zs.; Molnár, J.; Szabó, D. Non-nucleoside reverse transcriptase inhibitors.
Drugs of the Future. 2000, 25, 47-62.
Timári, G.; Hajós, Gy.; Riedl, Zs.; Béres, M.; Soós T.; Messmer, A. Synthesis of Polyfused
Heteroaromatics by Palladium-catalysed Cross-coupling Reaction. Molecules, 1996, 1, 1-5.
Timári, G.; Soós, T.; Hajós, Gy. A Convenient Synthesis of Two New Indoloquinoline Alkaloids.
Synlett, 1997, 1067-68.
Molecules 2003, 8
5.
487
Csányi, D.; Timári, G.; Hajós, Gy. An alternative synthesis of quindoline and one of its closely
related derivative. Synth. Commun., 1999, 29, 3959-3969.
6. Soós, T.; Timári, G.; Hajós, Gy. A New and Concise Synthesis of Furostifoline. Tetrahedron
Lett., 1999, 40, 8607 – 8609.
7. Béres, M.; Timári, G.; Hajós, Gy. Straightforward synthesis of 11H-indolo[3,2-c]isoquinoline and
benzofuro[3,2-c]isoquinoline by ring transformation Tetrahedron Lett., 2002, 43, 6035-6038.
8. Csányi, D.; Hajós, Gy.; Riedl, Zs.; Timári, G.; Bajor, Z.; Cochard, F.; Sapi, J.; Laronze, J. –Y.
Synthesis of two New Heteroaromatic ß-Carboline-fused Pentacycles. Observation of a New
Intercalating Agent. Bioorg. Med. Chem. Lett., 2000, 10, 1767-1769.
9. Krajsovszky, G.; Mátyus, P.; Riedl, Zs., Csányi, D.; Hajós, Gy. New Synthetic Approach to
Pyridazino[4,5-b]indoles by Pd(0)-Catalyzed Cross-Coupling Reaction. Heterocycles, 2001, 55,
1105 – 11.
10. Riedl, Zs.; Maes, B. U. W.; Monsieurs, K.; Lemiere, G. L. F.; Mátyus, P.; Hajós, Gy. Synthesis of
pyridazino [4,5-c] isoquinolinones by Suzuki cross-coupling reaction. Tetrahedron, 2002, 58,
5645-5650.
11. Sharples, D.; Molnár, J.; Szabó, D.; Hajós, Gy., Riedl, Zs.; Csányi, D. Ellipticine Analogues and
Related Compounds as Inhibitors of Reverse Transciptase and as Inhibitors of the Efflux Pump. Arch.
Pharm., 2001, 331, 269-74.
© 2003 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes.