Efficient synthesis of maleimides and carbazoles via Zn(OTf) 2-catalyzed tandem annulations of Lsonitriles and allenic esters

Article abstract of DOI:10.1021/ol7018086

Lewis acid Zn(OTf)₂-catalyzed tandem annulations of isonitriles and allenic esters which lead to efficient and flexible syntheses of a range of biologically significant maleimides and carbazoles and related compounds are reported. A mechanistic rationale is proposed to account for the observed reactivity.

Full text of DOI:10.1021/ol7018086

ORGANIC
LETTERS
2007
Vol. 9, No. 20
4057-4060
Efficient Synthesis of Maleimides and
Carbazoles via Zn(OTf)2-Catalyzed
Tandem Annulations of Isonitriles and
Allenic Esters
Yuanzhen Li, Haixia Zou, Jianxian Gong, Jing Xiang, Tuoping Luo,§
Junmin Quan, Guoxin Wang,* and Zhen Yang*
Laboratory of Chemical Genomics, Shenzhen Graduate School, Key Laboratory of
Bioorganic Chemistry and Molecular Engineering of Ministry of Education and
Beijing National Laboratory for Molecular Science (BNLMS), College of Chemistry
and the State Key Laboratory of Natural and Biomimetic Drugs, School of
Pharmaceutical Science, Peking UniVersity, Beijing 100871, China
zyang@pku.edu.cn
Received July 27, 2007
ABSTRACT
Lewis acid Zn(OTf)2-catalyzed tandem annulations of isonitriles and allenic esters which lead to efficient and flexible syntheses of a range of
biologically significant maleimides and carbazoles and related compounds are reported. A mechanistic rationale is proposed to account for
the observed reactivity.
The maleimide and carbazole cores are privileged natural
product motifs1 that are endowed with a wide variety of
useful biological activities.2 Those compounds, both naturally
occurring and synthetic, are subjects of intensive investiga-
tions in recent years because they serve as important leads
in identifying novel molecular identities. For example,
pyrrolocarbazole 1 and its analogues are potent PARP-1
[poly(ADP-ribose) polymerase-1] inhibitors;3 disubstituted
maleimide 2 is a highly effective inhibitor of GSK3;4 and
compounds 3 represent a larger group of indolocarbazoles
with potent inhibitory effects on MLK1/3 (Figure 1).5
Clearly, high-throughput screenings of the biological pro-
files of these compounds and further studies on their detailed
Figure 1. Biologically active maleimides and carbazoles.
structure-activity relationships with regard to their interac-
tions with protein targets first demand the development of
§ Current address: Department of Chemistry and Chemical Biology,
Harvard University.
(3) (a) Dunn, D.; Husten, J.; Ator, M. A.; Chatterjee, S. Bioorg. Med.
Chem. Lett. 2007, 17, 542. (b) Tao, M.; Park, C. H.; Bihovsky, R.; Wells,
G. J.; Husten, J.; Ator, M. A.; Hudkins, R. L. Bioorg. Med. Chem. Lett.
2006, 16, 938. (c) Wells, G. J.; Bihovsky, R.; Hudkins, R. L.; Ator, M. A.;
Husten, J. Bioorg. Med. Chem. Lett. 2006, 16, 1151. (d) The NMR spectra
of our synthesized compound match fully with those provided by Cephalon
Inc.
(1) Sa´nchez, C.; Me´ndez, C.; Salas, J. A. Nat. Prod. Rep. 2006, 23, 1007.
(2) (a) Gribble, G. W.; Berthel, S. J. In Studies in Natural Products
Chemistry; Attaur-Rahman, Ed.; Elesvier Science Publishers: Dordrecht,
1993; Vol. 12. (b) Bailly, C. In Small Molecule DNA and RNA Binders;
Demeunynck, M., Bailly, C., Wilson, W., Eds.; Wiley-VCH: NY, 2003;
Vol. 2, p 538.
10.1021/ol7018086 CCC: $37.00
© 2007 American Chemical Society
Published on Web 08/29/2007

efficient and modular synthetic methods that would allow
for the creation of large libraries of these diverse molecular
structures.6 Although many documented synthetic protocols
are targeted on the preparation of these pharmaceutically in-
teresting heterocycles,7 they generally required lengthy steps
and lack the modularity that is essential for rapid library
construction.
Table 1. Syntheses of Compounds 6b-6ga
Herein, we report Lewis acid Zn(OTf)2-catalyzed cascade
processes8 initiated from isonitrile9 A and allenic ester10
B
that lead to rapid syntheses of substituted maleimides C and
carbazole derivatives D in a sequential manner under mild
conditions (Scheme 1).
Scheme 1. Zn(OTf)2-Catalyzed Isonitrile-Allenic Ester
Cascade Reaction Leading to Maleimide and Carbazole
The original impetus for this research came from an
earlier observation that maleimide 6 could be obtained
in 31% yield when isonitrile 4 reacted with allenic ester
511 in THF at 50 °C in the presence of 20 mol % of
Zn(OTf)2.12 We subsequently carried out a systematic opti-
mization and found that the yield of 6 could be eventually
improved to 83% by using a mixed solvent of THF and H2O
(10:1) with only a catalytic amount of Zn(OTf)2 (3 mol %)
(Scheme 2).
a Reagents and conditions: allene (0.6 mmol), isonitrile (0.5 mmol),
Zn(OTf)2 (5.5 mg, 0.015 mmol) in THF (8 mL) and H2O (0.8 mL) at 50
°C for 24 h. Isolated yield.
b
would then undergo a facile intramolecular cyclization to
afford imine H. With aromatization as a driving force, H
could undergo a facile[1,5]-H shift to give furan I.13
Oxidation of the R-position of the furan ring by molecular
oxygen14 and subsequent collapse of the resultant orthofor-
mate K in the presence of H2O would transform I into L,
which finally ring closes to yield the product M.15
Scheme 2. One-Pot Synthesis of Maleimide 6
To support the proposed mechanistic sequences, DFT
computational modeling was conducted on the step H f I,
and it was found that the [1,5]-H shift was significantly
To explore the scope of the above reaction, six additional
examples with both electron-withdrawing and electron-
donating groups on the phenyl ring were also tested, and
delightfully, all yielded analogous products in yields ranging
from 56% to 85% (Table 1).
A mechanistic proposal was advanced in Figure 2. We
envisaged that isonitrile E would act as a nucleophile to
attack the central, sp-hybrid carbon of allene F activated by
the Lewis acidic Zn(OTf)2, and the resultant intermediate G
(4) Coghlan, M. P.; Culbert, A. A.; Cross, D. A. E.; Corcoran, S. L.;
Yates, J. W.; Pearce, N. J.; Rausch, O. L.; Murphy, G. J.; Carter, P. S.;
Cox, L. R.; Mills, D.; Brown, M. J.; Halgh, D.; Ward, R. W.; Smith, D.
G.; Murray, K. J.; Reith, A. D.; Holder, J. C. Chem. Biol. 2000, 7, 793.
(5) Hudkins, R. L.; Johnson, N. W.; Angeles, T. S.; Gessner, G. W.;
Mallamo, J. P. J. Med. Chem. 2007, 50, 433.
Figure 2. Plausible mechanistic proposal.
(6) Hajduk, P. J.; Greer, J. Nat. ReV. Drug DiscoVery 2007, 6, 211.
4058
Org. Lett., Vol. 9, No. 20, 2007

energetically favorable.16 Furthermore, employment of the
d6-dimethyl deuterated allene substrate led to the correspond-
ing product in which one deuterium was lost from these
positions. It merits a note that direct condensation processes
of allenes and isonitriles are very rare in the literature.17 The
Lewis acid catalyzed cascades involving these versatile
substrates we uncovered here should therefore have useful
synthetic and mechanistic implications.
to excellent yields (Table 2), and the structure of 9 was
confirmed by X-ray crystallography.
To generate biologically more robust pyrrolo- and indolo-
carbazoles, indole-fused allenic esters VII (n ) 1-3) were
also made (Table 3) and then subjected to Zn(OTf)2-mediated
Table 3. Syntheses of Compounds 1 and 19-26a
We next directed our attention to delineating the scope
and generality of this new synthetic methodology. The facile
formation of 6 suggested that our method might be especially
useful for making a novel type of cycloalkylaryl-disubstituted
maleimide III7i-k such as structures C, which may undergo
a direct aminolysis to afford IV by treatment of III with
NH3 with regard to its easily cleavable 4-nitrophenylamine
group. We further envisioned that the formed maleimides
III should undergo photoinduced in situ 6π-electrocyclic ring
closure,18 followed by oxidative aromatization, to yield
products V, which could then be readily converted into
type-D structures VI upon aminolysis (Table 2).
Table 2. Syntheses of Compounds 7-18a
a Reagents and conditions: (a) allene (0.6 mmol), isonitrile (0.5 mmol),
Zn(OTf)2 (5.5 mg, 0.015 mmol) in THF (8 mL) and H2O (0.8 mL) at 50
°C for 24 h; (b) VIII in a saturated solution of NH3 in MeOH (8 mL) at 25
°C for 2 h; (c) IX (0.5 mmol) and I2 (635 mg, 2.5 mmol) in PhH (100 mL)
b
under hV at 25 °C for 1.5 h. Isolated yield.
maleimide formation (VIII), aminolysis (IX), and photoin-
duced oxidative 6π-electrocyclization (X) to give their
corresponding products 19-21, 22-24, 1, and 25 and 26,
(7) For selected references, see: (a) Joyce, R. P.; Gainor, J. A.; Weinreb,
S. M. J. Org. Chem. 1987, 52, 1177. (b) Davis, P. D.; Bit, R. A.; Hurst, S.
A. Tetrahedron Lett. 1990, 31, 2353. (c) Davis, P. D.; Hill, C. H.; Lawton,
G.; Nixon, J. S.; Wilkinson, S. E.; Hurst, S. A.; Keech, E.; Turner, S. E. J.
Med. Chem. 1992, 35, 177. (d) Porter, B.; Ross, B. C. J. Org. Chem. 1992,
57, 2105. (e) Wood, J. L.; Stoltz, B. M.; Dietrich, H.-J.; Pflum, D. A.;
Petsch, D. T. J. Am. Chem. Soc. 1997, 119, 9641. (f) Hudkins, P. L.;
Johnson, N. W. J. Heterocycl. Chem. 2001, 38, 591. (g) Trost, B. M.;
Krische, M. J.; Berl, V.; Grenzer, E. M. Org. Lett. 2002, 4, 2005. (h) Kuethe,
J. T.; Wong, A.; Davies, I. W. Org. Lett. 2003, 5, 3721. (i) Stewart, S. G.;
Polomska, M. E.; Lee, R. W. Tetrahedron Lett. 2007, 48, 2241. (j) Wang,
J.; Soundarajan, N.; Liu, N.; Zimmermann, K.; Naidu, B. N. Tetrahedron
Lett. 2005, 46, 907. (k) Dubernet, M.; Caubert, V.; Guillard, J.; Viaud-
Massuard, M.-C. Tetrahedron 2005, 61, 4585.
a Reagents and conditions: see Supporting Information for details on
the syntheses of 7-18. bIsolated yield. cStructure was confirmed by X-ray
study.
(8) For a recent review on tandem catalysis, see: Wasilke, J.-C.; Obrey,
S. J.; Baker, R. T.; Bazan, G. C. Chem. ReV. 2005, 105, 1001.
(9) For leading reference, see: Do¨mling, A. Chem. ReV. 2006, 106, 17.
(10) For leading reference, see: Ma, S. Chem. ReV. 2005, 105, 2829.
(11) Marshall, J. A.; Wolf, M. A.; Wallace, E. M. J. Org. Chem. 1997,
62, 367.
To that end, allenic esters I (n ) 1-3) were prepared,
and their reactivities under the above-mentioned conditions
were examined. To our delight, they all afforded the
corresponding products 7-12 and 13-18 smoothly in good
Org. Lett., Vol. 9, No. 20, 2007
4059

respectively, in good yields, indicating that the methodology
is quite general in assembling structurally diverse hetero-
cycles (Table 3). Moreover, the approach provided a concise
total synthesis of PARP-1 inhibitor 1 that has an IC50 as low
as 36 nM.3
In an initial effort to investigate kinase inhibition of these
synthesized compounds, we set out to profile five representa-
tive structures against a panel of kinases covering the entire
human kinome.19
In summary, we have developed Lewis acid Zn(OTf)2-
catalyzed tandem annulations of isonitriles and allenic esters
that enable efficient and flexible syntheses of a range of
structurally interesting and biologically active maleimides
and carbazoles and related molecules. The substrates em-
ployed in these processes are readily available; the reaction
conditions are exceptionally mild; and the generated com-
pounds are amenable for further structural modifications. This
method is therefore of considerable value in combinatorial
chemistry, diversity-oriented synthesis, drug discovery, and
natural products synthesis. Efforts along this line are currently
underway in our laboratories.
We have chosen 6e′, 6b′, 11, 12, and 16 which represent
the key scaffolds of the synthesized maleimides. As shown
in Figure 3, these five compounds demonstrated distinct
Acknowledgment. This work was supported by grants
from the National Science Foundation of China (20325208,
20225318, 20521202). The kinase selectivity profiling data
shown in Figure 3 were kindly provided to us by Pfizer
Research Technology Center at Carbridge, MA, U.S.A. We
also thank Dr. David Zhigang Wang of Columbia University
Chemistry Department for useful discussions.
Supporting Information Available: Experimental, com-
putational (including coordinates), and X-ray structural
details. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL7018086
(15) An alternative mechanism involving [4+2] cycloaddition of singlet
oxygen to furan I was ruled out because the operation of this reaction
requires neither light nor sensitizer. (For a leading reference, see: Vassi-
likogiannajis, G.; Margaros, I.; Montagnon, T.; Stratakis, M. Chem.-Eur.
J. 2005, 11, 5899.) Another pathway involving nucleophilic addition of
H2O to a Lewis acid activated furan ring is also unlikely as the use of
H2O18 does not lead to the incorporation of the oxygen atom in the product
(see Supporting Information for details).
Figure 3. Biological profiles of five representative compounds
against a panel of kinases.
(16) The estimated activation free energy is 28.8 kcal/mol and is much
lower than the diene system (see Supporting Information for details).
inhibition profiles against the panel when tested at the 10
µM level, with compound 12 being weakly responsive,
compound 16 being moderately active, and compound 6b′
being the most potent yet less selective. Compounds 6e′ and
11 predominantly hit one kinase, and compound 6b′ inhibits
one kinase strongly (at about 90% inhibition) but four other
kinases at medium levels. The hitmap compiled in Figure 3
overall suggests that their biological profiles are quite
different.
(17) In one system we were aware of, the reaction terminated at structure
H: Avetisyan, E. A.; Gambaryan, N. P. Russ. Chem. Bull. 1974, 8, 1904.
(18) Greshock, T. J.; Funk, R. L. J. Am. Chem. Soc. 2006, 128, 4946.
(19) The kinase selectivity profiling data were collected at Pfizer Research
Technology Center at Carbridge, MA, U.S.A.
(12) Xia, Q.; Ganem, B. Org. Lett. 2002, 4, 1631.
(13) Nair, V.; Vinod, A. U. Chem. Commun. 2000, 1019.
(14) Ma, S.; Wu, B.; Shi, Z. J. Org. Chem. 2004, 69, 1429.
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