Palladium-catalyzed sequential cyanation/N-addition/N-arylation in one-pot: Efficient synthesis of luotonin A and its derivatives

Article abstract of DOI:10.1021/ol901305q

Image Persented With the catalysis of palladium, a number of 2-bromo-N-(2-iodobenzyl)benzamides underwent sequential cyanation/N-addition/N- arylation leading to the efficient construction of isoindolo[1,2-b]quinazolin- 10(12H)-ones in a two-stage, one-po

Full text of DOI:10.1021/ol901305q

ORGANIC
LETTERS
2009
Vol. 11, No. 16
3582-3585
Palladium-Catalyzed Sequential
Cyanation/N-Addition/N-Arylation in
One-Pot: Efficient Synthesis of Luotonin
A and Its Derivatives
Yi Ju,‡ Feng Liu,† and Chaozhong Li*,†,‡
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, P. R. China, and Department of Chemistry, UniVersity of Science
and Technology of China, Hefei, Anhui 230026, P. R. China
clig@mail.sioc.ac.cn
Received June 11, 2009
ABSTRACT
With the catalysis of palladium, a number of 2-bromo-N-(2-iodobenzyl)benzamides underwent sequential cyanation/N-addition/N-arylation leading
to the efficient construction of isoindolo[1,2-b]quinazolin-10(12H)-ones in a two-stage, one-pot manner. This method also allowed the convenient
synthesis of luotonin A and its derivatives.
A number of alkaloids that incorporate the pyrroloquinazoline
chromophore have been isolated from natural sources and
display a wide range of biological activities.1 A typical
example is luotonin A (1), isolated from a Chinese medicinal
plant (Peganum nigellastrum) in 1997.2 Luotonin A is a
human DNA topoisomerase I poison and exhibits potent
cytotoxicity against P-388 cells.2,3 These important biological
activities have attracted considerable attention on the syn-
thesis of luotonin A and its derivatives.4,5 Although luotonin
A is not potent enough to be a drug candidate for cancer
chemotherapy, it serves as a good lead compound, and
modifications on the A, B, and E rings of luotonin A have
been reported.5b,6 More recently, Hecht and co-workers have
discovered that the water-soluble 14-azacamptothecin (2a),
a hybrid between luotonin A and the naturally occurring
antitumor agent camptothecin (2b), is nearly as potent as
camptothecin in stabilizing the covalent binary complex
formed between human topoisomerase I and DNA.7
† Chinese Academy of Sciences.
‡ University of Science and Technology of China.
(1) For a review, see: Mhaske, S. B.; Argade, N. P. Tetrahedron 2006,
62, 9787.
The anticancer activity of luotonin A and 14-azacamp-
tothecin encourages the further identification of more potent
analogues. Hence, methods for the efficient, general, and
rapid assembly of the luotonin A skeleton are certainly highly
desirable. Curran et al. nicely introduced the synthesis of
luotonin A and analogues by cascade radical annulations of
(2) Ma, Z.-Z.; Hano, Y.; Nomura, T.; Chen, Y.-J. Heterocycles 1997,
46, 541.
(3) Cagir, A.; Jones, S. H.; Gao, R.; Eisenhauer, B. M.; Hecht, S. M.
J. Am. Chem. Soc. 2003, 125, 13628
(4) For a review on the synthesis of luotonin A, see: Ma, Z.; Hano, Y.;
Nomura, T. Heterocycles 2005, 65, 2203
.
.
10.1021/ol901305q CCC: $40.75
Published on Web 07/28/2009
 2009 American Chemical Society

Table 1. Optimization of the Synthesis of 5a from 3a
Table 2. Pd(OAc)2-Catalyzed Cyanation of Iodide 4a
entrya
ligandb
base
time (h)
yield (%)c
entrya
ligandb
PPh3
BINAP
DPEphos
dppf
PPh3
dppb
dppe
dppf
additive
solvent
yield (%)c
1
2
3
4
5
6
7
8
PPh3
BINAP
DPEphos
dppe
dppp
dppb
dppf
dppf
dppf
dppf
dppf
none
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K3PO4
K3PO4
none
24
24
24
24
24
24
2
2
2
2
24
trace
4
27
6
11
10
76
91
94
96
0
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
-
-
-
-
-
THF
THF
THF
THF
THF
THF
THF
THF
THF
dioxane
0
0
0
0
trace
16
24
19
60
86
9
9
10
DPEphos
DPEphos
10d
11
12
-
a Reaction conditions: 4a (1 mmol), Pd(OAc)2 (0.05 mmol), ligand (0.1
mmol), KCN (1.2 mmol), additive (0.1 mmol), solvent (4 mL), reflux, 24 h.
b See Table 1. c Isolated yield based on 4a.
K3PO4
24
0
a Reaction conditions: 3a (0.2 mmol), Pd(OAc)2 (0.02 mmol), ligand
(0.04 mmol), base (0.4 mmol), dioxane (2 mL), reflux. b BINAP: 2,2′-
bis(diphenylphosphino)-1,1′-binaphthyl. DPEphos: bis[(2-diphenylphos-
phino)phenyl]ether. dppe: 1,2-bis(diphenylphosphino)ethane. dppp: 1,3-
bis(diphenylphosphino)propane. dppb: 1,4-bis(diphenylphosphino)butane.
dppf: 1,1′-bis(diphenylphosphino)ferrocene. c Isolated yield based on 3a.
d 5 mol % of Pd(OAc)2 and 10 mol % of dppf were used.
undergo further transition-metal-catalyzed intramolecular
N-arylation with an aryl halide to allow the one-step
generation of the pyrroloquinazolinone skeleton (the C and
D rings of luotonin A). To explore this possibility, 2-bromo-
N-(2-cyanobenzyl)benzamide (3a) was used as the model
substrate, which could be synthesized in 55% yield by the
cyanation of N-(2-iodobenzyl)-2-bromobenzamide (4a) with
KCN under the catalysis of Pd(PPh3)4/CuI according to the
literature method9 (also vide infra). A typical experimental
procedure10 for the Sonogashira coupling was initially
applied to the cyclization of 3a: 10 mol % of Pd(OAc)2, 20
mol % of PPh3, and 200 mol % of Cs2CO3 in refluxing
dioxane. After 24 h, the expected product 5a was observed
in only a trace amount, while most of the starting material
remained unchanged (entry 1, Table 1). Switching PPh3 to
a bidentate phosphine ligand resulted in an increased yield
of 5a (entries 2-7, Table 1). To our delight, with the use of
1,1′-bis(diphenylphosphino)ferrocene (dppf) as the ligand,
5a was obtained in 76% yield within a much shorter period
of time (entry 7, Table 1). We next examined the bases.
K2CO3 or K3PO4 showed a better performance than Cs2CO3
(entries 7-9, Table 1). Finally, the combination of K3PO4
(200 mol %), Pd(OAc)2 (5 mol %), and dppf (10 mol %)
allowed the formation of 5a in almost quantitative yield
(entry 10, Table 1). As a comparison, no reaction occurred
isonitriles, featuring the one-step construction of the B and
C rings.5b However, their method required the use of highly
toxic bis(trimethyltin) as the initiator. Other methods typically
suffered from either the low efficiency or the lack of
generality.4-7 Herein we report that the palladium-catalyzed
sequential cyanation/N-addition/N-arylation of N-((2-bro-
moquinolin-3-yl)methyl)-2-bromobenzamides allows the con-
venient and rapid assembly of the luotonin A skeleton in a
one-pot procedure.
We recently reported the TMSOTf/Et3N-triggered in-
tramolecular formal [4 + 2] cycloaddition of nitriles with
R,ꢀ-unsaturated amides or ꢀ-ketoamides leading to the
synthesis of luotonin A derivatives with a saturated E ring.8
However, analogues with an aromatic E ring cannot be
accessed by this method. We envisioned that the intramo-
lecular nucleophilic N-addition of an amide to a Ct N bond
would generate the imidamide intermediate, which might
(5) For the latest examples of the synthesis of luotonin A, see: (a)
Bowman, W. R.; Cloonan, M. O.; Fletcher, A. J.; Stein, T. Org. Biomol.
Chem. 2005, 3, 1460. (b) Tangirala, R.; Antony, S.; Agama, K.; Pommier,
Y.; Curran, D. P. Synlett 2005, 2843. (c) Servais, A.; Azzouz, M.; Lopes,
D.; Courillon, C.; Malacria, M. Angew. Chem., Int. Ed. 2007, 46, 576. (d)
Zhou, H.-B.; Liu, G.-S.; Yao, Z.-J. J. Org. Chem. 2007, 72, 6270.
(6) (a) Ma, Z.; Hano, Y.; Nomura, T.; Chen, Y. Bioorg. Med. Chem.
Lett. 2004, 14, 1193. (b) Cagir, A.; Jones, S. H.; Eisenhauer, B. M.; Gao,
R.; Hecht, S. M. Bioorg. Med. Chem. Lett. 2004, 14, 2051. (c) Cagir, A.;
Eisenhauer, B. M.; Gao, R.; Thomas, S. J.; Hecht, S. M. Bioorg. Med. Chem.
2004, 12, 6287. (d) Lee, E. S.; Park, J. G.; Kim, S. I.; Jahng, Y. Heterocycles
2006, 68, 151.
(9) Anderson, B. A.; Bell, E. C.; Ginah, F. O.; Harn, N. K.; Pagh, L. M.;
Wepsiec, J. P. J. Org. Chem. 1998, 63, 8224.
(10) Chen, Q.; Li, C. Organometallics 2007, 26, 223.
(11) For reviews on palladium-catalyzed N-arylation, see: (a) Muci,
A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131. (b) Hartwig,
J. F. In Handbook of Organopalladium Chemistry for Organic Synthesis;
Negichi, E.-i., Ed.; Wiley: New York, 2002; Vol. 1, p 1051. (c) Littke,
A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176. (d) Prim, D.;
Campagne, J. M.; Joseph, D.; Andrioletti, B. Tetrahedron 2002, 58, 2041.
(e) Yang, B. Y.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125. (f)
Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res.
1998, 31, 805. (g) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046.
(h) Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852.
(7) (a) Cheng, K.; Rahier, N. J.; Eisenhauer, B. M.; Thomas, S. J.; Gao,
R.; Hecht, S. M. J. Am. Chem. Soc. 2005, 127, 838. (b) Rahier, N. J.; Cheng,
K.; Gao, R.; Eisenhauer, B. M.; Hecht, S. M. Org. Lett. 2005, 7, 835. (c)
Elban, M. A.; Sun, W.; Eisenhauer, B. M.; Gao, R.; Hecht, S. M. Org.
Lett. 2006, 8, 3513.
(8) Liu, F.; Li, C. J. Org. Chem. 2009, 74, ASAP (DOI: 10.1021/
jo900907h).
Org. Lett., Vol. 11, No. 16, 2009
3583

Table 3. Synthesis of Isoindolo[1,2-b]quinazolin-10(12H)-ones
Table 4. Synthesis of Luotonin A and Its Derivatives
a Isolated yield based on 4. b See text.
a Isolated yield based on 6. b See text.
without the ligand dppf or the base (entries 11 and 12, Table
1). To the best of our knowledge, this is the first example of
N-arylation of imidamides under palladium catalysis.11,12
As can be seen above, both the cyanation of aryl iodide
4a and the intramolecular N-arylation of bromide 3a were
carried out under palladium catalysis. It would be ideal that
these two steps could be operated in a one-pot procedure.
To achieve this goal, the cyanation step had to be performed
in a higher efficiency under the catalysis of Pd(OAc)2.13,14
Thus, iodide 4a was chosen as the model for the optimization
of reaction conditions (Table 2). Initially we switched the
Pd(PPh3)4/CuI catalyst system to the Pd(OAc)2/PPh3/CuI
combination. However, no reaction occurred (entry 1, Table
2). Changing PPh3 to a diphosphine ligand did not help
(entries 2-4, Table 2). On the other hand, when the
cocatalyst CuI was removed out of the catalyst system, the
formation of the product 3a could be observed in variable
amounts, depending on the types of ligands used (entries
5-9, Table 2). Among the diphosphine ligands screened,
bis[(2-diphenylphosphino)phenyl]ether (DPEphos) offered
the best result (entry 9, Table 2). When the reaction of 4a
(14) For examples of the Pd(OAc)2-catalyzed cyanation of aryl halides,
see: (a) Schareina, T.; Zapf, A.; Magerlein, W.; Muller, N.; Beller, M.
Tetrahedron Lett. 2007, 48, 1087. (b) Weissman, S. A.; Zewge, D.; Chen,
C. J. Org. Chem. 2005, 70, 1508. (c) Schareina, T.; Zapf, A.; Beller, M. J.
Organomet. Chem. 2004, 689, 4576. (d) Schareina, T.; Zapf, A.; Beller,
M. Chem. Commun. 2004, 1388. (e) Sundermeier, M.; Zapf, A.; Beller, M.
Angew. Chem., Int. Ed. 2003, 42, 1661. (f) Sundermeier, M.; Zapf, A.;
Mutyala, S.; Baumann, W.; Sans, J.; Weiss, S.; Beller, M. Chem.-Eur. J.
2003, 9, 1828. (g) Sundermeier, M.; Zapf, A.; Beller, M.; Sans, J.
Tetrahedron Lett. 2001, 42, 6707.
(12) For Pd- or Cu-catalyzed N-arylation of amidines, see: (a) Brain,
C. T.; Brunton, S. A. Tetrahedron Lett. 2002, 43, 1893. (b) Brain, C. T.;
Steer, J. T. J. Org. Chem. 2003, 68, 6814. (c) Brasche, G.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2008, 47, 1932. (d) Liu, X.; Fu, H.; Jiang, Y.; Zhao,
Y. Angew. Chem., Int. Ed. 2009, 48, 348. (e) Deng, X.; McAllister, H.;
Mani, N. S. J. Org. Chem. 2009, 74, ASAP (DOI: 10.1021/jo900912h)
.
(13) For reviews on the cyanation of aryl halides, see: (a) Ellis, G. P.;
Romney-Alexander, T. M. Chem. ReV. 1987, 87, 779. (b) Sundermeier,
M.; Zapf, A.; Beller, M. Eur. J. Inorg. Chem. 2003, 3513
.
3584
Org. Lett., Vol. 11, No. 16, 2009

with DPEphos as the ligand was performed at a higher
temperature (dioxane, reflux), 3a was achieved in 86%
isolated yield (entry 10, Table 2).
the substrates. We were pleased to find that the desired
cyanation occurred chemoselectively in all the cases screened.
Further N-addition/N-arylation also proceeded smoothly,
furnishing the cyclized products in a one-pot procedure.
Luotonin A was thus achieved in 75% yield via Method A.
The luotonin A derivatives 7b-7e bearing a substituent in
either the A or E ring were also synthesized in satisfactory
yields from the corresponding dibromides via Method A or
B. Again the N-alkenylation was also successful as shown
in the reaction of 6f.
We next tried to operate the two reactions in a two-stage,
one-pot manner. The following two methods were designed
for this purpose. In Method A, the cyanation of the iodide
substrate was performed first under the optimized conditions
(5 mol % of Pd(OAc)2, 10 mol % of DPEphos, dioxane,
reflux, 24 h). The second ligand dppf (10 mol %) and the
base K2CO3 (200 mol %) were then directly added into the
resulting mixture, and the solution was refluxed for another
2 h. In Method B, the same procedure as Method A was
followed except that, in the second stage, a second portion
of 5 mol % of Pd(OAc)2 was introduced into the reaction
mixture along with the addition of dppf and K2CO3. To our
satisfaction, the final product 5a was obtained in 91% isolated
yield via Method A. Apparently, the presence of DPEphos
did not show a significant influence on the N-arylation in
the second step.
We then set out to explore the scope and limitation of the
above two methods. As can be seen in Table 3, the expected
cyclization products 5 were achieved in good to excellent
yields directly from the iodides 4. Functional groups such
as -OR, -COMe, and -CO2Et were well tolerated (entries
2, 3, and 5, Table 3). The sequential cyanation/N-addition/
N-alkenylation also proceeded smoothly as evidenced by the
reactions of 4f and 4g. With the use of Method A, satisfactory
results could be obtained in most cases, indicating the high
efficiency of the Pd-based catalyst system. The only excep-
tion was observed in the reaction of 4b with a 1,3-dioxolane
moiety, in which the product 5b was isolated in only 45%
yield via Method A due to the incomplete N-arylation.
However, when Method B was applied, 5b was obtained in
71% yield.
In conclusion, we have successfully developed a novel
strategy for the convenient and efficient preparation of
pyrroloquinazolinones via palladium-catalyzed sequential
cyanation/intramolecular N-addition/intramolecular N-ary-
lation processes in a one-pot, two-stage manner. This method
has then been applied to the synthesis of luotonin A starting
from the simple amide 6a, featuring the one-step construction
of the C and D rings. Furthermore, the modifications of both
the A and E rings of luotonin A are made easy by this
strategy in view of the ready access to the corresponding
substituted 2-bromobenzoic acids and (2-bromoquinolin-3-
yl)methanamines as well as their fast assembly into the amide
substrates. This chemistry should find important application
in the further identification of luotonin A analogues with
more potent anticancer activity.
Acknowledgment. This project was supported by the
National Natural Science Foundation of China (Grant Nos.
20672136, 20702060, and 20832006) and by the Shanghai
Municipal Committee of Science and Technology (Grant No.
07XD14038).
Supporting Information Available: Experimental pro-
cedures for the synthesis of 1, 5, and 7 and characterizations
of 1 and 3-7. This material is available free of charge via
the Internet at http://pubs.acs.org.
The above methods were then applied to the synthesis of
luotonin A and its derivatives (Table 4). Instead of the use
of aryl iodides in 4, 2-bromoquinolines 6, which were easily
accessible via conventional methods,7b,c were now used as
OL901305Q
Org. Lett., Vol. 11, No. 16, 2009
3585