Gold-catalyzed one-pot cascade construction of highly functionalized pyrrolo[1,2-a]quinolin-1(2H)-ones

Article abstract of DOI:10.1021/jo901418m

(Chemical Equation Presented) An efficient protocol was developed for the synthesis of fused heterocyclic multiring compounds pyrrolo[1,2-a]quinolin-1(2H) -ones via a AuBr₃/AgSbF₆-catalyzed cascade transformation. Significantly, the

Full text of DOI:10.1021/jo901418m

pubs.acs.org/joc
Gold-Catalyzed One-Pot Cascade Construction of Highly Functionalized
Pyrrolo[1,2-a]quinolin-1(2H)-ones
Yu Zhou,† Enguang Feng,† Guannan Liu,† Deju Ye,† Jian Li,† Hualiang Jiang,†,‡ and
Hong Liu*,†
†The Center for Drug Discovery and Design, State Key Laboratory of Drug Research, Shanghai Institute of
Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai
201203, People’s Republic of China, and ‡School of Pharmacy, East China University of Science and
Technology, Shanghai, 200237, People’s Republic of China
hliu@mail.shcnc.ac.cn
Received July 4, 2009
An efficient protocol was developed for the synthesis of fused heterocyclic multiring compounds
pyrrolo[1,2-a]quinolin-1(2H)-ones via a AuBr3/AgSbF6-catalyzed cascade transformation. Signifi-
cantly, the strategy affords a straightforward and efficient approach to construction of tricyclic
lactam molecular architectures in which two new C-C bonds and one new C-N bond are formed in a
one-pot synthetic operation from simple starting materials. Moreover, a broad spectrum of
substrates can participate in the process effectively to produce the desired products in good yields
and with excellent regio- and chemoselectivities.
Introduction
alkyne functionality.2h Construction of complex fused hetero-
cyclic multiring architectures via an intermolecular union of
simple starting materials through a one-pot operation still
represents significant synthetic challenges. To our know-
ledge, the incorporation of less nucloephilic amides for
gold-promoted hydroamination/hydroarylation cascade re-
actions to build tricyclic lactams via one C-N bond and two
The development of catalytic cascade reactions for “one-
pot” synthesis of complex multiring molecular architectures
is fueled by its synthetic efficiency, atom economy, and high
selectivity.1 Recent years have witnessed tremendous growth
in the number of gold-catalyzed domino organic transfor-
mations.1b,2 Notably, gold-catalyzed inter- or intramolecu-
lar hydroamination of alkynes and inter- or intramolecular
hydroarylation of alkynes provide effective avenues for the
formation of complex heterocyclic structures.3 Despite sig-
nificant progress, several significant limitations remain to be
addressed, the vast majority of the reported cascade
sequences employed an intramolecular reaction with
starting materials containing multiple functional groups
strategically positioned along a chain, terminating with
(2) For selected examples of Au-catalyzed tandem processes, see: (a)
Dudnik, A. S.; Schwier, T.; Gevorgyan, V. Org. Lett. 2008, 10, 1465. (b) Jin,
T.; Yamamoto, Y. Org. Lett. 2008, 10, 3137. (c) Hsu, Y. C.; Datta, S.; Ting,
C. M.; Liu, R. S. Org. Lett. 2008, 10, 521. (d) Barluenga, J.; Riesgo, L.;
Vicente, R.; Lopez, L. A.; Tomas, M. J. Am. Chem. Soc. 2008, 130, 13528. (e)
Nieto-Oberhuber, C.; Perez-Galan, P.; Herrero-Gomez, E.; Lauterbach, T.;
Rodriguez, C.; Lopez, S.; Bour, C.; Rosellon, A.; Cardenas, D. J.; Echavarren,
A. M. J. Am. Chem. Soc. 2008, 130, 269. (f) Shi, M.; Wu, L.; Lu, J. M. J. Org.
Chem. 2008, 73, 8344. (g) Luo, T.; Schreiber, S. L. Angew. Chem., Int. Ed.
2007, 46, 8250. (h) Yang, T.; Campbell, L.; Dixon, D. J. J. Am. Chem. Soc.
2007, 129, 12070. (i) Yan, B.; Liu, Y. Org. Lett. 2007, 9, 4323. (j) Kirsch, S. F.;
Binder, J. T.; Crone, B.; Duschek, A.; Haug, T. T.; LiNbert, C.; Menz, H.
Angew. Chem., Int. Ed. 2007, 46, 2310. (k) Toullec, P. Y.; Genin, E.; Leseurre,
L.; Gentt, J.-P.; Michelet, V. Angew. Chem., Int. Ed. 2006, 45, 7427. (l)
Zhang, J.; Schmalz, H.-G. Angew. Chem., Int. Ed. 2006, 45, 6704. (m)
Barluenga, J.; Dieguez, A.; Fernandez, A.; Rodriguez, F.; Fananas, F. J.
Angew. Chem., Int. Ed. 2006, 45, 2091. (n) Nieto-Oberhuber, C.; Lopez, S.;
Jimenez-Nunez, E.; Echavarren, A. M. Chem.;Eur. J. 2006, 12, 5916. (o)
Nguyen, R.-V.; Yao, X.; Li, C.-J. Org. Lett. 2006, 8, 2397. (p) Buzas, A.;
Istrate, F.; Gagosz, F. Org. Lett. 2006, 8, 1957. (q) Yao, X.; Li, C.-J. Org.
Lett. 2006, 8, 1953. (r) Jung, H. H.; Floreancig, P. E. Org. Lett. 2006, 8, 1949.
(s) Gorin, D. J.; DubN, P.; Toste, F. D. J. Am. Chem. Soc. 2006, 128, 14480.
*To whom correspondence and requests for reprints should be addressed.
Phone: +86-21-50807042. Fax: +86-21-50807088.
(1) (a) Verma, A. K.; Kesharwani, T.; Singh, J.; Tandon, V.; Larock, R.
C. Angew. Chem., Int. Ed. 2009, 48, 1138. (b) Liu, X. Y.; Che, C. M. Angew.
Chem., Int. Ed. 2008, 47, 3805. For recent reviews, see: (c) de Meijere, A.; von
Zezschwitz, P.; Brase, S. Acc. Chem. Res. 2005, 38, 413. (d) Wasilke, J. C.; Obrey,
S. J.; Baker, R. T.; Bazan, G. C. Chem. Rev. 2005, 105, 1001. (e) Ajamian, A.;
Gleason, J. L. Angew. Chem., Int. Ed. 2004, 43, 3754. (f) Lee, J. M.; Na, Y.; Han,
H.; Chang, S. Chem. Soc. Rev. 2004, 33, 302. (g) Tietze, L. F. Chem. Rev. 1996,
96, 115.
7344 J. Org. Chem. 2009, 74, 7344–7348
Published on Web 09/01/2009
DOI: 10.1021/jo901418m
r
2009 American Chemical Society

Zhou et al.
JOCArticle
SCHEME 1. Synthesis of Diversely Substituted Pyrrolo[1,2-
a]quinolin-1(2H)-ones
TABLE 1. Optimization of the Reaction Conditions for the Synthesis of
3a,7-Dimethyl-5-phenyl-3,3a-dihydropyrrolo[1,2-a]quinolin-1(2H)-onea
C-C bonds formation in one synthetic operation has not
been disclosed. In our effort to develop new methods for
synthesizing biologically active heterocycles using transition
metal catalysts,4 we herein report an unprecedented gold-
catalyzed hydroamination/hydroarylation cascade process
for the construction of fused tricyclic architectures pyrrolo-
[1,2-a]quinolin-1(2H)-ones (Scheme 1), of which analogues
are widely distributed in a large collection of biologically
interesting natural products and synthetic molecules.1b,5
entry
Au source
Ag source solvent yield (%)
1
2
3
4
5
6
7
8
9
AuCl3
AuBr3
AuCl(PPh3)
[Au{P(t-Bu)2(o-biphenyl)}]Cl
[Au{P(t-Bu)2(o-biphenyl)}]SbF6
toluene 30 (70b)
toluene 55 (81b)
toluene 17 (70b)
toluene 10 (55b)
toluene 15 (75b)
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
Ag2CO3
toluene
CH2Cl2
DMF
45
0
0
0
0
0
0
30
66
0
AuBr3
AuBr3
AuBr3
NMP
10 AuBr3
dioxane
C2H5OH
CH3CN
DCE
xylene
toluene
11 AuBr3
12 AuBr3
13 AuBr3
14 AuBr3
15 AuBr3
16 AuBr3
17 AuBr3
18 AuBr3
19 AuBr3
20 AuBr3
21 AuBr3
22 AuBr3
23 AuBr3
24 AuBr3
Results and Discussion
To identify optimal reaction conditions for the gold-
catalyzed tandem synthesis of pyrrolo[1,2-a]quinolinones,
various Au(III), Au(I), and Ag(I) catalysts were screened for
a model reaction of N-p-tolylpent-4-ynamide (1A) with
phenylacetylene (2a) in toluene in a sealed tube under argon.
As depicted in Table 1, different gold salts such as AuCl3,
AuBr3, AuCl(PPh3), [Au{P(t-Bu)2(o-biphenyl)}]Cl, and
[Au{P(t-Bu)2(o-biphenyl)}]SbF6 were probed at 120 °C in
toluene, but the desired products were obtained only in low
yields (Table 1, entries 1-5). However, upon activation of
these gold complexes with AgSbF6, the yields were increased
significantly under otherwise the same reaction conditions
(Table 1, entries 1-5). The AuBr3/AgSbF6 catalytic system
seemed slightly better than other gold salts and AgSbF6. In
the absence of gold salts, the reaction resulted in a dramatic
decrease in the yield of 3Aa (entry 6). These results indicated
that both Au source and AgSbF6 played a crucial role in this
tandem cyclization. Subsequently, we screened different sol-
vents, which indicates that CH2Cl2, DMF, NMP, dioxane,
AgOCOCF3 toluene
AgBF4 toluene
AgSO2CF3 toluene
0
30
0
Ag2O
toluene
toluene
toluene
toluene
toluene
toluene
0
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
80c
78d
60e
75f
80g
a1A (0.1 mmol), 2a (0.4 mmol), Au salts (3 mol %)/Ag salts (5 mol %),
Ar protection. bReaction performed in the presence of 5 mol % of
AgSbF6. cReaction performed without Ar protection. d1A (0.1 mmol),
e
2a (0.15 mmol), AuBr3 (3 mol %)/AgSbF6 (5 mol %). The reaction
temperature was below 100 °C. fThe reaction temperature was 140 °C.
gThe reaction time was prolonged to 10 h.
C2H5OH, and CH3CN are not effective solvents (Table 1,
entries 7-12). Nevertheless, treatment of the mixture of 1A
and 2a with the presence of AuBr3/AgSbF6 in ClCH2CH2Cl
and xylene provided the desired product in 30% and 66%
yields, respectively (Table 1, entries 13 and 14). It was also
found that the reaction solvent plays an important role in this
transformation. Furthermore, variations of Ag salts were
also probed in the cascade process (Table 1, entries 15-19),
and the results revealed that the product 3Aa was only
obtained in 30% yield after 4 h at 120 °C by using 5 mol %
of AgBF4 in the presence of 3 mol % of AuBr3. Some
protonic acids other than Ag salts, such as TFA and TsOH,
were also investigated as a cocatalyst, but no good results
were obtained (data were not shown). The yield of 3Aa was
not significantly affected without Ar protection (Table 1,
entry 20). It is well-known that the formation of two new
carbon-carbon and one new carbon-nitrogen bonds to
make two rings in a one-pot reaction is particularly challeng-
ing because the region- and chemoselectivity must be well-
controlled to avoid formation of intractable mixture of
regioisomeric homo- and heterocoupled compounds. How-
ever, the current transformation does not require a large
excess of either reagent or careful control of reagent addi-
tion. As a consequence, a comparable efficiency was
(3) For some interesting examples of gold-catalyzed reaction involving
hydroamination or hydroarylation, see: (a) Liu, X. Y.; Ding, P.; Huang, J. S.;
Che, C. M. Org. Lett. 2007, 9, 2645. (b) Hashmi, A. S. K.; Blanco, M. C.;
ꢀ
Kurpejovic, E.; Frey, W.; Bats, J. W. Adv. Synth. Catal. 2006, 348, 709. (c)
Hashmi, A. S. K.; Blanco, M. C. Eur. J. Org. Chem. 2006, 4340. (d) Hashmi,
A. S. K.; Haufe, P.; Schmid, C.; Nass, A. R.; Frey, W. Chem.;Eur. J. 2006,
ꢀ
12, 5376. (e) Gorin, D. J.; Dube, P.; Toste, F. D. J. Am. Chem. Soc. 2006, 128,
ꢀ ꢀ
14480. (f) Marion, N.; Dıez-Gonzalez, S.; de Fremont, P.; Noble, A. R.;
´
Nolan, S. P. Angew. Chem., Int. Ed. 2006, 45, 3647. (g) Nevado, C.;
Echavarren, A. M. Chem.;Eur. J. 2005, 11, 3155. (h) Luo, Y.; Li, Z.; Li,
C. J. Org. Lett. 2005, 7, 2675. (i) Shi, Z.; He, C. J. Org. Chem. 2004, 69, 3669.
(j) Mizushima, E.; Hayashi, T.; Tanaka, M. Org. Lett. 2003, 5, 3349. (k)
Reetz, M. T.; Sommer, K. Eur. J. Org. Chem. 2003, 3485.
(4) (a) Ye, D.; Wang, J.; Zhang, X.; Zhou, Y.; Ding, X.; Feng, E.; Sun, H.;
Liu, G.; Jiang, H.; Liu, H. Green Chem. 2009, 11, 1201. (b) Feng, E.; Huang,
H.; Zhou, Y.; Ye, D.; Jiang, H.; Liu, H. J. Org. Chem. 2009, 74, 2846. (c) Li,
Z.; Sun, H.; Jiang, H.; Liu, H. Org. Lett. 2008, 10, 3263. (d) Li, Z.; Huang, H.;
Sun, H.; Jiang, H.; Liu, H. J. Comb. Chem. 2008, 10, 484.
(5) (a) Weinreb, S. M. Chem. Rev. 2006, 106, 2531. (b) Maier, T.; Graedler,
U.; Baer, T.; Vennemann, M. PCT Int. Appl. WO 2005002579. (c) Wei, L. L.;
Hsung, R. P.; Sklenicka, H. M.; Gerasyuto, A. I. Angew. Chem., Int. Ed. 2001, 40,
1516. (d) Pearson, W. H.; Fang, W. K. J. Org. Chem. 2000, 65, 7158. (e) Ding, Q.;
Chichak, K.; Lown, J. W. Curr. Med. Chem. 1999, 6, 1. (f) Edwards, J. P.;
Higuchi, R.; Jones, T. PCT Int. Appl. WO 9749709; (g) Faulkner, D. J. Nat.
Prod. Rep. 1996, 13, 75. (h) St. Clair-Black, D.; Kumar, N. Org. Prep. Proced.
Int. 1991, 23, 67. (i) Anderson, W. K.; Heider, A. R.; Raju, N.; Yucht, J. A. J. Med.
Chem. 1988, 31, 2097. (j) Eggler, J. F.; Johnson, M. R.; Melvin, L. S. Eur. Pat.
Appl. EP 90516.
J. Org. Chem. Vol. 74, No. 19, 2009 7345

Zhou et al.
JOCArticle
a
TABLE 2. Tandem Synthesis of Diversely Substituted Pyrrolo[1,2-a]quinolin-1(2H)-ones Catalyzed via AuBr3/AgSbF6
a1A (0.1 mmol), 2 (0.4 mmol), AuBr3 (3 mol %)/AgSbF6 (5 mol %), toluene (2 mL), Ar protection. bThe reaction time was prolonged from 4 to 6 h to
complete substrate conversion.
achieved even with 1.5 equiv of 2a (Table 1, entry 21 and
Table 3, entry 7) without homocoupled product.6 On the
other hand, the reaction temperature was found to be an
important factor for this tandem transformation. For exam-
ple, compound 3Aa was obtained in 60% yield when the
temperature was reduced to 100 °C (Table 1, entry 22),
whereas increasing reaction temperature to 140 °C resulted
in a decreased yield (Table 1, entry 23). In addition, longer
reaction time (10 h) did not improve the yield in this tandem
process (Table 1, entry 24).
Under our optimized reaction conditions (0.1 mmol of 1A,
0.4 mmol of 2a, 3 mol % of AuBr3/5 mol % of AgSbF6,7 2
mL of toluene, Ar protection, 120 °C, 4 h), we examined the
substrate scope of this tandem cyclization reaction. A variety
of aromatic alkynes can participate in the process to afford
products 3Aa-3Ai in moderate to good yields (52-81%)
(Table 2, entries 1-9), and a relatively longer reaction time
was needed to complete substrate conversion in the cases of
p-t-Bu- and p-Ph-substituted phenylacetylenes, presumably
due to the steric effect (Table 2, entries 5 and 9). However,
limitation of the reaction was also realized. No desired
products 3Aj and 3Al were obtained under the optimized
condition when 2-ethynylpyridine and 1-octyne, respec-
tively, were used (Table 2, entries 10 and 12); and only a
trace amount of 3Ak was observed for ethynylcyclopropane,
presumably due to charge effects (Table 2, entry 11).
We further probed the substrate scope in variation of N-
aryl-4-ynamides. As shown in Table 3, N-aryl-4-ynamides
with substituents bearing steric and electronic properties are
tolerant of the cascade reactions. (Table 3, entries 1-27).
Relatively higher yields were obtained in the case of treat-
ment of p-COOEt-substituted N-aryl-4-ynamides with dif-
ferent aromatic alkynes (Table 3, entries 6-9).
A catalytic cycle for the above transformation, which is
similar to the gold-catalyzed tandem reactions reported by
Che and Li,1b,8 is shown in Scheme 2. The terminal alkyne
moiety of 1 is first activated by the AuBr3/AgSbF6 catalyst
system to generate intermediate A, which then converts to
enamine intermediate B via intramolecular hydroamination.
Attack of enamine B by alkynes 2 in the presence of AuBr3/
AgSbF6 generates a propargylamine C. Finally, the propar-
gylamine is also activated by gold-/silver-salt catalyst to
generate D, which undergoes intramolecular hydroarylation
to yield the final product 3.
(6) The byproducts of this reaction were also investigated by treatment of
N-p-tolylpent-4-ynamide (1A) with phenylacetylene (2a) in toluene in a
sealed tube at 120 °C for 4 h, and only intermediate propargylamine 4Aa
was obtained. (see the Supporting Information, Table S1). Characterization
data for 4Aa: 1H NMR (CDCl3, 400 MHz) δ 7.39 (m, 2H), 7.33 (m, 3H), 7.29
(d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 2.81 (m, 1H), 2.61 (m, 2H), 2.36
(s, 3H), 2.22 (m, 1H), 1.55 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 174.4,
137.6, 133.6, 131.5, 129.7, 128.5, 128.4, 128.0, 122.4, 90.8, 84.3, 59.8, 36.3,
30.5, 27.8, 21.2; LRMS (EI) m/z 289 (Mþ); HRMS (EI) m/z calcd C20H19NO
(Mþ) 289.1467, found 289.1464.
(7) The amount of AuBr3/AgSbF6 catalyst was also optimized in this
cascade reaction, and these results showed that 3 mol % of AuBr3 and 5 mol
% of AgSbF6 is the optimum reaction condition. In addtion, increasing the
amount of AgSbF6 can accelerate this transformation. (see the Supporting
Information, Table S2).
(8) Zhang, Y. H.; Donahue, J. P.; Li, C. J. Org. Lett. 2007, 9, 627.
7346 J. Org. Chem. Vol. 74, No. 19, 2009

Zhou et al.
JOCArticle
a
TABLE 3. Tandem Synthesis of a Broad Spectrum of Pyrrolo[1,2-a]quinolin-1(2H)-ones Catalyzed by AuBr3/AgSbF6
a1 (0.1 mmol), 2 (0.4 mmol), AuBr3 (3 mol %)/AgSbF6 (5 mol %), toluene (2 mL), Ar protection. b1 (0.1 mmol), 2 (0.15 mmol), AuBr3 (3 mol %)/
AgSbF6 (5 mol %), toluene (2 mL).
J. Org. Chem. Vol. 74, No. 19, 2009 7347

Zhou et al.
JOCArticle
SCHEME 2. A Plausible Mechanism
Experimental Section
General Procedure for the Gold-Catalyzed Tandem Reaction
for the Synthesis of Pyrrolo[1,2-a]quinolin-1(2H)-ones (Com-
pound 3Aa, for Example). To a solution of 0.1 mmol of
N-p-tolylpent-4-ynamide and 0.4 mmol of phenylethyne in 2 mL
of toluene was added 0.003 mmol of AuBr3 and 0.005 mmol of
AgSbF6. The reaction tube was sealed under Ar protection and
the mixture was stirred under argon in a sealed tube and at
120 °C for 4 h. After the starting materials were completely
consumed, the solvent was removed under reduced pressure,
and the residue was purified by a flash column chromatography
(petroleum ether/ethyl acetate = 4/1, v/v, as an eluent) to yield
the desired product 3Aa in 81% yield. The characterization data
obtained are as follows: 1H NMR (CDCl3, 300 MHz) δ 8.07 (d,
J = 8.1 Hz, 1H), 7.39 (m, 3H), 7.32 (m, 2H), 7.13 (d, J = 8.1 Hz,
1H), 6.87 (s, 1H), 5.82 (s, 1H), 2.64 (m, 1H), 2.50 (m, 1H), 2.23 (s,
3H), 2.20 (m, 2H), 1.29 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ
173.2, 138.8, 135.5, 133.7, 131.8, 130.9, 129.0, 128.9, 128.3,
127.7, 126.8, 126.3, 121.4, 60.6, 32.4, 29.9, 24.0, 21.1; LRMS
(EI) m/z 289 (Mþ); HRMS (EI) m/z calcd for C20H19NO (Mþ)
289.1467, found 289.1466.
Conclusion
In summary, we have developed an efficient method for
the synthesis of fused heterocyclic building blocks pyrrolo-
[1,2-a]quinolin-1(2H)-ones via a AuBr3/AgSbF6-catalyzed
tandem reaction in good yields and with excellent regio-
and chemoselectivities. Significantly, the strategy affords a
straightforward and efficient construction of tricyclic lactam
molecular architectures in which several carbon-carbon and
carbon-nitrogen bonds are formed in a one-pot reaction
from simple starting materials. It is our expectation that the
biologically interesting compound can be found from the
pool of these products. Further investigation of this powerful
cascade reaction and its application to our medicinal chem-
istry program will be reported in the future.
Acknowledgment. We gratefully acknowledge financial
support from the National Natural Science Foundation
of China (Grants 20721003 and 20872153), International
Collaboration Projects (Grants 2007DFB30370 and
20720102040), the 863 Hi-Tech Program of China (Grants
2006AA020602), and the Shanghai Postdoctoral Science
Foundation (Grant 09R21418000).
Supporting Information Available: Part of the experimental
details, general information, and 1H and 13C NMR spectra for
all products. This material is available free of charge via the
Internet at http://pubs.acs.org.
7348 J. Org. Chem. Vol. 74, No. 19, 2009