Silver triflate and palladium acetate Co-catalyzed reaction of N -(2-alkynylbenzylidene)hydrazide with N -allyl ynamide

Article abstract of DOI:10.1021/ol301023m

A silver triflate and palladium acetate co-catalyzed reaction of N′-(2-alkynylbenzylidene)hydrazide with N-allyl ynamide is described, which generates 2-amino-H-pyrazolo[5,1-a]isoquinolines in good to excellent yield. The transformation proceeds with high efficiency through 6-endo cyclization, [3 + 2] cycloaddition, 3,3-sigmatropic rearrangement, and aromatization.

Full text of DOI:10.1021/ol301023m

ORGANIC
LETTERS
2012
Vol. 14, No. 11
2790–2793
Silver Triflate and Palladium Acetate
Co-catalyzed Reaction of
N0-(2-Alkynylbenzylidene)hydrazide with
N-Allyl Ynamide
Ping Huang,† Zhiyuan Chen,*,† Qin Yang,‡ and Yiyuan Peng*,†,‡
Key Laboratory of Functional Small Organic Molecules, Ministry of Education and
College of Chemistry & Chemical Engineering, and Jiangxi’s Key Laboratory of Green
Chemistry and College of Life Science, Jiangxi Normal University, 99 Ziyang Road,
Nanchang, Jiangxi 330022, China
yiyuanpeng@yahoo.com; zchenjx@yahoo.cn
Received April 19, 2012
ABSTRACT
A silver triflate and palladium acetate co-catalyzed reaction of N0-(2-alkynylbenzylidene)hydrazide with N-allyl ynamide is described, which
generates 2-amino-H-pyrazolo[5,1-a]isoquinolines in good to excellent yield. The transformation proceeds with high efficiency through 6-endo
cyclization, [3 þ 2] cycloaddition, 3,3-sigmatropic rearrangement, and aromatization.
The isoquinoline skeleton has been widely known as a
privileged framework in naturally occurring alkaloids and
biologically active molecules.1 Moreover, as an important
member of the family, fused isoquinoline has attracted
much attention because of its remarkable biological
activities.2 For example, lamellarin D, containing a highly
substituted pyrroloisoquinoline core, is found to be a potent
inhibitor of human topoisomerase I2c and was recently
realized to act on mitochondria to induce apoptosis.2d
Therefore, there has been considerable interest concerning
the synthesis of these compounds.3,4 Recently, Wu and co-
workers have developed a small library of H-pyrazolo[5,1-a]-
isoquinolines via tandem reactions starting from N0-(2-
alkynylbenzylidene)hydrazide with various nucleophiles.4
Some hits were discovered with promising inhibitory activ-
ities versus targets suchasCDC25B, TC-PTP, orPTP1B.4a
† Key Laboratory of Functional Small Organic Molecules.
‡ Jiangxi's Key Laboratory of Green Chemistry and College of Life
Science.
(1) For selected examples, see: (a) Bentley, K. W. The Isoquinoline
Alkaloids; Harwood Academic: Sydney, 1998; Vol. 1. (b) Trotter, B. W.;
Nanda, K. K.; Kett, N. R.; Regan, C. P.; Lynch, J. J.; Stump, G. L.; Kiss,
L.; Wang, J.; Spencer, R. H.; Kane, S. A.; White, R. B.; Zhang, R.;
Anderson, K. D.; Liverton, N. J.; McIntyre, C. J.; Beshore, D. C.;
Hartman, G. D.; Dinsmore, C. J. J. Med. Chem. 2006, 49, 6954. (c)
Ikedou, K. Takeuchi, M. Ogino, Y. Banno, H. Tawada Yamane, T. PCT
Int. Appl. WO 2002062764 A1, 2002, 600 pp. (d) Kaneda, T.; Takeuchi, Y.;
Matsui, H.; Shimizu, K.; Urakawa, N.; Nakajyo, S. J. Pharmacol. Sci. 2005,
98, 275. (e) Marchand, C.; Antony, S.; Kohn, K. W.; Cushman, M.;
Ioanoviciu, A.; Staker, B. L.; Burgin, A. B.; Stewart, L.; Pommier, Y.
Mol. Cancer Ther. 2006, 5, 287.
(2) (a) Su, S.; Porco, J. A., Jr. J. Am. Chem. Soc. 2007, 129, 7744. (b)
Bailly, C. Curr. Med. Chem. Anti-Cancer Agents 2004, 4, 363. (c) Marco,
E.; Laine, W.; Tardy, C.; Lansiaux, A.; Iwao, M.; Ishibashi, F.; Bailly,
C.; Gago, F. J. Med. Chem. 2005, 48, 3796. (d) Kluza, J.; Gallego, M.-A.;
Loyens, A.; Beauvillain, J. -C.; Fernandez; Sousa-Faro, J.-M.; Cuevas,
C.; Marchetti, P.; Bailly, C. Cancer Res. 2006, 66, 3177.
(3) For selected examples, see: (a) Roy, S.; Roy, S.; Neuenswander,
B.; Hill, D.; Larock, R. C. J. Comb. Chem. 2009, 11, 1061. (b) Obika, S.;
Kono, H.; Yasui, Y.; Yanada, R.; Takemoto, Y. J. Org. Chem. 2007, 72,
4462. (c) Yanada, S.; Obika, S.; Kono, H.; Takemoto, Y. Angew. Chem.,
Int. Ed. 2006, 45, 3822. (d) Asao, N.; Iso, K.; Yudha, S. S. Org. Lett.
2006, 8, 4149. (e) Asao, N.; Yudha, S. S.; Nogami, T.; Yamamoto, Y.
Angew. Chem., Int. Ed. 2005, 44, 5526.
(4) (a) Chen, Z.; Wu, J. Org. Lett. 2010, 12, 4856. (b) Chen, Z.; Yu, X.;
Wu, J. Chem. Commun. 2010, 46, 6356. (c) Chen, Z.; Pan, X.; Wu, J.
Synlett 2011, 964. (d) Li, S.; Wu, J. Org. Lett. 2011, 13, 712. (e) Ye, S.;
Yang, X.; Wu, J. Chem. Commun. 2010, 46, 5238. (f) Yu, X.; Ye, S.; Wu,
J. Adv. Synth. Catal. 2010, 352, 2050. (g) Yu, X.; Chen, Z.; Yang, X.; Wu,
J. J. Comb. Chem. 2010, 12, 374. (h) Chen, Z.; Yang, X.; Wu, J. Chem.
Commun. 2009, 3469. (i) Chen, Z.; Ding, Q.; Yu, X.; Wu, J. Adv. Synth.
Catal. 2009, 351, 1692. (j) Chen, Z.; Su, M.; Yu, X.; Wu, J. Org. Biomol.
Chem. 2009, 7, 4641.
r
10.1021/ol301023m
Published on Web 05/22/2012
2012 American Chemical Society

Witha goalof finding betterleadantitumor compounds by
biological evaluations of analogous structures, the develop-
ment of efficient and novel methods for rapid syntheses of
H-pyrazolo-[5,1-a]isoquinolines is still of urgent importance.
As versatile and useful building blocks, ynamides have
been widely applied in synthetic organic chemistry.5 For
example, Witulski6 and Tanaka7 independently reported
expedient synthesis of functionalized conjugated arenes
through a transition-metal catalyzed [2 þ 2 þ 2] cycloaddi-
tionof conjugated ynamides withdiynes. Hsung reporteda
palladium-catalyzed transformation of N-allyl-N-sulfonyl
ynamides to amidines.8 The reaction was featured as a
palladium-catalyzed N-to-C allyl transfer to form a key
intermediate ketenimine via ynamidoꢀpalladiumꢀπ-allyl
complexes.
Recently, ketenimine chemistry, which involves a copper-
(I)-catalyzed azideꢀalkyne cycloaddition for the generation
of various heterocycles, has been an attractive area.9 We have
disclosed two efficient approaches for the rapid access of
polysubstituted indoles and 1,2-dihydroisoquinolin-3(4H)-
imines, based on the ketenimine chemistry.10 Additionally,
the ketenimine species could also be applied in the reaction of
N0-(2-alkynylbenzylidene)hydrazide.4d Prompted by the ad-
vancement mentioned above, we conceived that ynamides,
which could be regarded as a potential ketenimine species,
would be involved in the reaction of N0-(2-alkynylbenzy-
lidene)hydrazide to form H-pyrazolo[5,1-a]isoquinoline de-
rivatives. Herein, we disclose our recent efforts for this
transformation.
Since a palladium catalyst is crucial for the generation of
the ketenimine intermediate and silver triflate has been
demonstrated to be an effective catalyst for the cyclization
of N0-(2-alkynylbenzylidene)hydrazide,4 a multicatalytic
process is proposed. To identify the practicability of the
protocol, initial experiments focused on the reaction of
N0-(2-alkynylbenzylidene)hydrazide 1a and N-allyl-N-to-
syl ynamide 2a in the presence of silver triflate (5 mol %)
and a palladium catalyst in dichloroethane.
At first, Pd(PPh3)4 was used as the catalyst and K2CO3
was employed as the base. To our delight, the desired
product 3a was isolated in 49% yield after 12 h at room
temperature under N2 atmosphere (Table 1, entry 1). The
structure of 3a was confirmed by X-ray diffraction analysis
Table 1. Optimization of Reaction Conditions
entry
[Pd]
ligand base
K2CO3 DCE
solvent
yielda (%)
1
2
3
4
5
6
7
8
9
Pd(PPh3)4
Pd2(dba)3
Pd(OAc)2
49
Cs2CO3 DCE
37
PPh3 K2CO3 DCE
45
Pd(PPh3)2Cl2 PPh3 K2CO3 DCE
46
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PPh3 K2CO3 THF
PPh3 K2CO3 THF
X-Phos K2CO3 THF
PCy3 K2CO3 THF
S-Phos K2CO3 THF
PPh3 Cs2CO3 THF
PPh3 Na2CO3 THF
PPh3 NaOAc THF
63
53b
36
trace
trace
81
10 Pd(OAc)2
11 Pd(OAc)2
12 Pd(OAc)2
13 Pd(OAc)2
14 Pd(OAc)2
15 Pd(OAc)2
16 Pd(OAc)2
17 Pd(OAc)2
18 Pd(OAc)2
19 Pd(OAc)2
20 Pd(OAc)2
21 Pd(OAc)2
22 Pd(OAc)2
24 Pd(OAc)2
45
50
PPh3 Et3N
PPh3 K3PO4 THF
PPh3 Cs2CO3 DCE/Toluene
THF
13
66
90
PPh3 Cs2CO3 DCE/1,4-dioxane 82
PPh3 Cs2CO3 DCE/DCM
PPh3 Cs2CO3 DCE/CH3CN
PPh3 Cs2CO3 DCE/DMF
PPh3 Cs2CO3 DCE/CHCl3
PPh3 Cs2CO3 DCE/Toluene
PPh3 Cs2CO3 DCE/Toluene
PPh3 Cs2CO3 DCE/Toluene
76
50
73
76
81c
72d
53e
a Isolated yield based on N0-(2-alkynylbenzylidene)hydrazide 1a.
b
4 A MS as additive. c Pd(OAc)2 (5 mol %). d The reaction was carried
˚
out at 60 °C. e The reaction was carried out at 90 °C.
(see the Supporting Information). A palladium(II) cata-
lyst, such as Pd(OAc)2 or Pd(PPh3)2Cl2, could also be
used as the cocatalyst. Considering the catalyst’s stability
and the ease of controlment, we chose the easily handled
Pd(OAc)2 and PPh3 system as a replacement of Pd(PPh3)4
in the subsequent investigation (Table 1, entries 2ꢀ4). The
product yield of 3a could be improved to 63% when the
reaction was carried out in THF (Table 1, entry 5).
Interestingly, the ligand effectwasfoundtobe crucial for
product generation, and PPh3 was proven to be most
suitable toward the other phosphine ligands such as X-Phos,
PCy3, and S-Phos (Table 1, entries 7ꢀ9). The reaction was
tested with various bases as well, which showed the best
result (81% yield) was generated in Cs2CO3 (Table 1, entry 10).
Other inorganic bases, including Na2CO3, NaOAc, K3PO4,
and K2CO3, were proven to be reactive while the organic
base was inefficient (Table 1, entries 10ꢀ14). The reaction
was explored in various solvents as well. Good result was
obtained when DCE/toluene was used as the reaction
medium, the desired product 3a could be isolated in
90% yield, while no obvious improvement was achieved
in other solvents (Table 1, entries 15ꢀ20). Further screening
revealed that attempts to reduce the amount of palladium
(5) For reviews on ynamides, see: (a) Zificsak, C.; Mulder, J.; Hsung,
R.; Rameshkumar, C.; Wei, L. Tetrahedron 2001, 57, 7575. (b) Katritzky,
A. R.; Jiang, R.; Singh, S. K. Heterocycles 2004, 63, 1455. (c) Mulder, J. A.;
Kurtz, K. C. M.; Hsung, R. P. Synlett 2003, 1379. (d) Evano, G.; Coste, A.;
Jouvin, K. Angew. Chem., Int. Ed. 2010,49, 2840. (e) DeKorver, K. A.; Li, H.;
Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P. Chem. Rev. 2010,
110, 5064.
(6) (a) Witulski, B.; Stengel, T. Angew. Chem., Int. Ed. 1999, 38, 2426.
(b) Witulski, B.; Alayrac, C. Angew. Chem., Int. Ed. 2002, 41, 3281.
(7) (a) Tanaka, K.; Takeishi, K.; Noguchi, K. J. Am. Chem. Soc.
2006, 128, 4586. (b) Tanaka, K.; Takeishi, K. Synthesis 2007, 2920.
(8) (a) Zhang, Y.; DeKorver, K. A.; Lohse, A. G.; Zhang, Y. S.;
Huang, J.; Hsung, R. P. Org. Lett. 2009, 11, 899. (b) DeKorver, K. A.;
Hsung, R. P.; Lohse, A. G.; Zhang, Y. Org. Lett. 2010, 12, 1840.
(9) For reviews on ketenimines, see: (a) Kim, S. H; Park, S. H.; Choi,
J. H.; Chang, S. Chem. Asian J. 2011, 6, 2618. (b) Lu, P.; Wang, Y. G.
Synlett. 2010, 165. (c) Yoo, E. J.; Chang, S. Curr. Org. Chem. 2009, 13,
1766.
(10) (a) Chen, Z.; Zheng, D.; Wu, J. Org. Lett. 2011, 13, 848. (b)
Chen, Z.; Ye, C.; Gao, L.; Wu, J. Chem. Commun. 2011, 47, 5623.
Org. Lett., Vol. 14, No. 11, 2012
2791

catalyst loading or increasing the reaction temperature were
ineffective and led to a lower yield (Table 1, entries 21ꢀ24).
With the optimized conditions in hand, we next investi-
gated the reaction scope with various N0-(2-alkynylbenzy-
lidene)hydrazides 1 and N-allyl-N-sulfonyl ynamides 2,
and the results are summarized in Table 2. To assess the
impact of the structural and functional motifs on the
reaction of N-allyl-N-tosylsulfonyl ynamide 2a, we tested
a range of N0-(2-alkynylbenzylidene)hydrazide 1. For all
cases, compounds 1 reacted with ynamide 2a leading to the
corresponding 2-amino-H-pyrazolo[5,1-a]isoquinolines 3
in moderate to excellent yields. Moreover, it was found
that substrates with electron-donating groups on the R1
position were less reactive to some extent than those with
the electron-withdrawing groups when the R2 group was
phenyl. For example, reaction of 5-methyl- or 4,5-di-
methoxy-substituted N0-(2-phenylbenzylidene)hydrazide
with compound 2a gave rise to the desired product 3 in
66% or 63% yield, respectively (Table 2, entries 2 and 3).
While forthe 5-Cl- or4-F-substituted substrate1dor 1ethe
corresponding yield was 80% or 85%, respectively
(Table 2, entries 4 and 5). It is noteworthy that the hetero-
cyclic substrate 1f could also be well tolerated in the
reaction, leading to the desired product 3f in 85% yield
(Table 2, entry 6).
However, when the R2 group attachedon the triple bond
was an alkyl group, the corresproding product could be
isolated only in moderate yield. This might be due to the
lower stability of the substrates under the reaction condi-
tions (Table 2, entries 7ꢀ10). We next examined the
reactivity of N-allyl-N-sulfonyl ynamide 2 with substitu-
ents on the triple bond moiety. As expected, the corre-
sponding products were obtained in good yields whenever
the N-allyl-N-sulfonyl ynamides 2 were attached with an
electron-donating or electron-withdrawn group (Table 2,
entries 10ꢀ20). Interestingly, the terminal alkyne 2e could
also be reactive under the standard reaction conditions,
leading to the corresponding product 3q in an acceptable
yield (Table 2, entry 20). A good yield (74%) was obtained
when N-allyl-N-4-bromobenzenesulfonyl ynamide 2f was
employed in the transformation (Table 2, entry 21).
Next, we devoted our efforts to the reaction of N0-(2-
alkynylbenzylidene)hydrazide 1 with N-30-methyl allyl yna-
mide 2 under the standard reaction conditions (Table 3).
Good results were obtained as well, and two isomers ranging
from a ratio of 5:3 to 3:1 were isolated. For example, the
reaction proceeded smoothly when N-30-methyl allyl-N-tosyl
ynamide 2g, 2c, or 2d was used in the reaction of N0-(2-
alkynylbenzylidene)hydrazide 1a, giving rising to a total yield
of 82%, 85%, or 80%, respectively, while for the reaction of
N0-(2-alkynylbenzylidene) hydrazide 1e with N-30-methyl
allyl-N-tosyl ynamide 2g the corresponding product yield
was 88%, with a molecular ration of 2:1. The structure of the
two isomers 4 and 40 were confirmed by X-ray diffraction
analysis as well (also see the Supporting Information).
Surprisingly, for the reaction of N-methyl-N-tosyl yna-
mide 2j or N-benzyl-N-tosyl ynamide 2k with compound
1a, no reaction was detected under the standard reaction
conditions (Scheme 1). Prolonging the reaction time or
Table 2. Generation of 2-Amino-H-pyrazolo[5,1-a]-
isoquinolines 3 via Silver Triflate and Palladium Acetate Co-
catalyzed Reaction of N0-(2-Alkynylbenzylidene)hydrazide 1
with N-Allyl Ynamide 2
entry
R1, R2 (1)
R3, R4 (2)
yielda (%)
1
2
3
4
5
6
7
8
9
H, Ph (1a)
5-Me, Ph (1b)
4,5-dimethoxy, Ph (1c) (2a)
Ph, Ts (2a)
90 (3a)
66 (3b)
63 (3c)
80 (3d)
88 (3e)
85 (3f)
51 (3g)
40 (3h)
64 (3i)
46 (3j)
84 (3k)
85 (3l)
88 (3m)
74 (3n)
68 (3o)
71 (3p)
85 (3q)
87 (3r)
92 (3s)
61 (3t)
(2a)
5-Cl, Ph (1d)
4-F, Ph (1e)
(2a)
(2a)
4,5-benzothio, Ph(1f) (2a)
H, Bu (1g)
(2a)
5-Me, Bu (1h)
4-F, Bu (1i)
(2a)
(2a)
10 4-F, cyclopropyl (1j)
11 (1a)
(2a)
Bu, Ts (2b)
PMP, Ts (2c)
4-Cl-Ph, Ts(2d)
(2b)
12 (1a)
13 (1a)
14 (1b)
15 (1b)
(2c)
16 (1b)
(2d)
17 (1e)
(2b)
18 (1e)
(2c)
19 (1e)
(2d)
20 (1e)
H, Ts (2e)
21 (1a)
4-Cl-Ph, 4-Br-PhSO2(2f) 74 (3u)
a Isolated yield based on N0-(2-alkynylbenzylidene)hydrazide 1.
PMP = 4-MeO-Ph.
elevating the temperature only resulted in decomposion of
the starting materials. These results strongly indicated the
crucial importance of the allyl group in the starting
ynamide.
Table 3. Generation of 2-Amino-H-pyrazolo[5,1-a]-
isoquinolines 4 via Silver Triflate and Palladium Acetate Co-
catalyzed Reaction of N0-(2-Alkynylbenzylidene) Hydrazide 1
with N-Substituted Allyl Ynamide 2
entry
R1 (1)
H (1a)
R3 (2)
yield of 4 (%)a ratio (4/40)a
1
2
3
4
Ph (2g)
PMP (2c)
4-Cl-Ph (2d) 80 (4c þ 4c0)
82 (4a þ 4a0)
85 (4b þ 4b0)
2:1
5:3
3:1
2:1
(1a)
(1a)
4-F, Ph (1e) Ph (2g)
88 (4d þ 4d0)
a Isolated yield based on N0-(2-alkynylbenzylidene) hydrazide 1.
PMP = 4-MeO-Ph.
2792
Org. Lett., Vol. 14, No. 11, 2012

Scheme 1. Mechanistic Investigation for the Silver(I) and
Palladium(II) Co-catalyzed Reaction of N0-(2-
Alkynylbenzylidene) hydrazide 1 with Ynamide 2
Scheme 2. Plausible Mechanism for the Reaction of N0-(2-
Alkynylbenzylidene)hydrazide 1 with N-Allyl Ynamide 2
On the basis of the above observation, and prompted by
the advancement of the ynamide chemistry,5,8 weproposed
a plausible mechanism for this cascade cyclization (Scheme 2).
We envisioned that in the presence of a Pd(0) catalyst, the
reactive ketenimine c would be derived from N-allyl-N-
tosyl ynamide 2 via a ynamido-Pd-π-allyl complex b and
the subsequent allyl migration from N to C atom. Mean-
while, isoquinolinium-2-yl amide a would be formed via
silver-catalyzed 6-endo-cyclization of N0-(2-alkynylben-
zylidene)hydrazide 1.4 The intermolecular [3 þ 2]
cyclization reaction would occur to generate the key inter-
mediate d. Subsequently, an intramolecular [3,3]-sigma-
tropic rearrangement would be involved in the reaction to
produce the intermediate e, which would then undergo the
release of tosyl group and subsequent aromatization to
furnish the 2-amino-H-pyrazolo[5,1-a]isoquinoline 3 or 4.
It is noticeable that for the alkyl substituted allyl ynamide
(R5 = Me), the chemoselective of the two isomers c and c0
could be easily formed due to the substitutent hindrance in
the reactive ketenimine complex during the process of the
allyl migration from N to C atom. The key intermediate c,
in which had less substitutent hindrance between R3 and
R5 groups, would be formed in a major portion as com-
pared with another intermediate c0.
co-catalyzed by silver triflate and palladium acetate, affording
2-amino-H-pyrazolo[5,1-a]isoquinolines in good yields. The
transformation proceeds with high efficiency through 6-endo
cyclization, [3 þ 2] cycloaddition, 3,3-sigmatropic rearrange-
ment, and aromatization. Additionally, the reaction condition
is mild, which is attractive for further library construction.
Acknowledgment. Financial support from National
Natural Science Foudation of China (No. 20962010 and
21162012), Jiangxi Educational Committee (GJJ10386),
and Foundation for Young People (Yang Qin) of Jiangxi
Normal University is gratefully acknowledged. Z.C.
acknowledges financial support from the Jiangxi Provincial
Education Department (GJJ12192).
Supporting Information Available. Experimental pro-
cedure, characterization data, 1H and 13C NMR spectra
of compounds 3 and 4, X-ray data for compounds 3a, 4a0,
and 4c (CIF). This material is available free of charge via
the Internet at http://pubs.acs.org.
In conclusion, we have developed an efficient reaction of
N0-(2-alkynylbenzylidene)hydrazide with N-allyl ynamide
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 11, 2012
2793