AgOTf-catalyzed tandem reaction of N′-(2-alkynylbenzylidene)hydrazide with alkyne

Article abstract of DOI:10.1039/b904498a

AgOTf-catalyzed tandem reactions of N′-(2-alkynylbenzylidene) hydrazides with various alkynes under mild conditions are described, which generate fused 1,2-dihydroisoquinolines in good to excellent yields.

Full text of DOI:10.1039/b904498a

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AgOTf-catalyzed tandem reaction of N0-(2-alkynylbenzylidene)hydrazide
with alkynew
Zhiyuan Chen,a Xiaodi Yangc and Jie Wu*ab
Received (in Cambridge, UK) 5th March 2009, Accepted 14th April 2009
First published as an Advance Article on the web 7th May 2009
DOI: 10.1039/b904498a
AgOTf-catalyzed tandem reactions of N0-(2-alkynylbenzylidene)-
hydrazides with various alkynes under mild conditions are
described, which generate fused 1,2-dihydroisoquinolines in good
to excellent yields.
block in tandem reactions for the construction of heterocycles.
Prompted by the results, we envisioned that N0-(2-alkynyl-
benzylidene)hydrazide might have similar functionality for
further elaboration due to the structural similarity with
2-alkynylbenzaldehyde. Recently, we have discovered that
N0-(2-alkynylbenzylidene)hydrazide 1 can be converted to
isoquinolinium-2-yl amide A in the presence of Lewis acids
or electrophiles.7 Based on this result, we conceived that
a nucleophilic addition might occur in the presence of
nucleophiles. To identify the practicability of this proposed
route, we started to investigate the possibility for one-pot
tandem cyclization–nucleophilic addition of N0-(2-alkynyl-
benzylidene)hydrazide 1.
The starting material N0-(2-alkynylbenzylidene)hydrazide
was easily accessible via condensation of 2-alkynylbenzaldehyde
with hydrazine. The reaction was initially studied with
N0-(2-alkynylbenzylidene)hydrazide 1a and phenylacetylene
2a (Scheme 1). As described above, in the presence of Lewis
acid, N0-(2-alkynylbenzylidene)hydrazide could be transferred
to the intermediate A via electrophilic cyclization. Indeed, after
screening various Lewis acids, the intermediate could be
isolated and AgOTf (10 mol%) was demonstrated as the best
choice when this reaction was performed in dichloroethane.
Encouraged by this result, the AgOTf-catalyzed one-pot
reaction of N0-(2-alkynylbenzylidene)hydrazide 1a with
phenylacetylene 2a in the presence of base was performed.
Surprisingly, no further transformation was observed when
NaOAc was used as the base. Gratifyingly, the formation of a
product was detected when potassium phosphate was
employed as the base. Further screening revealed that DBU
was the most efficient base for the transformation (59% yield).
However, structural identification revealed that the product
generated was compound 3a, instead of the desired product
4a. Since AgOTf is one of the most popular reagents for
inducing transformations, which take advantage of its affinity
As
a privileged fragment, the 1,2-dihydroisoquinoline
(including isoquinoline) core is found in many natural
products and pharmaceuticals that exhibit remarkable biological
activities.1 Recently, the method development and small
library generation of 1,2-dihydroisoquinolines were established
by us and others.2–4 For instance, Yamamoto and Takemoto
described that functionalized 1,2-dihydroisoquinoline skeletons
could be generated through the direct addition of various
carbon pronucleophiles to ortho-alkynylaryl aldimines
catalyzed by Lewis acids.3a,c Larock and co-workers reported
the transition-metal catalyzed cyclization of ortho-alkynylaryl
aldimines for the synthesis of isoquinoline derivatives.4 We
also developed 1,2-dihydroisoquinoline synthesis via tandem
reactions starting from 2-alkynylbenzaldehyde, amine, and
various nucleophiles.2 Screening in a HCT-116 inhibition
assay led to the identification of a hit with a promising IC50
value of 0.18 mM. With a hope for finding better lead
anti-tumor compounds by evaluations of analogous structures,
we need to develop an efficient method for rapid syntheses of
new 1,2-dihydroisoquinoline-based structures. Herein, we
disclose our recent efforts for the generation of fused
1,2-dihydroisoquinolines via tandem reactions of N0-(2-alkynyl-
benzylidene)hydrazides with various alkynes. This transformation
is highly effective under mild conditions, which probably
proceeds through 6-endo cyclization, alkyne addition, 5-endo
cyclization and aromatization.
Among the strategies used for preparation of small
molecules, utilizing tandem reactions for design and synthesis
of natural product-like compounds has attracted much
attention, and the development of tandem reactions has been
a fertile area in organic synthesis.5,6 In our previous reports,2
we found that 2-alkynylbenzaldehyde was a versatile building
a Department of Chemistry, Fudan University, 220 Handan Road,
Shanghai 200433, China. E-mail: jie_wu@fudan.edu.cn;
Fax: 86 21 6510 2412; Tel: 86 21 5566 4619
b State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China
c Laboratory of Advanced Materials, Fudan University,
220 Handan Road, Shanghai 200433, China
w Electronic supplementary information (ESI) available: 1: General
experimental methods (S2). 2: General experimental procedure and
characterization data (S2–S9). 3: H and 13C spectra of compounds 3
(S10–S41). CCDC 722722. For ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/b904498a
1
Scheme 1 One-pot tandem reaction of N0-(2-alkynylbenzylidene)-
hydrazide 1a with phenylacetylene 2a.
ꢀc
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Chem. Commun., 2009, 3469–3471 | 3469

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and 13C NMR, mass spectroscopy, as well as X-ray diffraction
analysis (Fig. 1).z Excellent yield was observed when
4-methoxyphenyl acetylene 2b was used as a replacement in
the reaction (Table 1, entry 5). When R3 was changed to
n-butyl or cyclopropyl group, the reactions also occurred
smoothly to generate the corresponding products in good
yields (Table 1, entries 6, 7). Interestingly, it was found
that a hydroxy group as substituent in the substrate 2e
was well tolerated under these conditions and the fused
Table 1 AgOTf-catalyzed tandem reaction of N0-(2-alkynylbenzyli-
dene)hydrazide 1 with alkynes
Scheme 2 Possible mechanism of the one-pot tandem reaction of
N0-(2-alkynylbenzylidene)hydrazide 1 with alkyne 2.
for halogen and carbon–carbon unsaturated bonds, we
reasoned that initially the triple bond coordinated to the silver
salt, and subsequently the nitrogen atom of N0-(2-alkynyl-
benzylidene)hydrazide
1 attack on the triple bond via
6-endo-cyclization afforded isoquinolinium intermediate A
(Scheme 2). Following nucleophilic addition of alkyne to the
isoquinolinium intermediate A afforded the corresponding
product B, which then underwent the intramolecular 5-endo
cyclization leading to the intermediate C. Finally, aromatization
occurred to generate the unexpected product 3. With this
promising result in hand, we subsequently screened different
solvents in the reaction. We realized that the combination of
dichloroethane (DCE) and CCl4 gave rise to the best result
and the product was generated in 80% yield.
Having demonstrated the viability of this catalytic strategy
we next investigated the scope of the transformation under the
preliminary optimized conditions [AgOTf (10 mol%), DBU,
DCE–CCl4, rt]. The results are summarized in Table 1. To
assess the impact of the structural and functional motifs on
the reaction we tested a range of linking units between
N0-(2-alkynylbenzylidene)hydrazides and alkynes. For all
cases, N0-(2-alkynylbenzylidene)hydrazide
1 reacted with
alkyne 2 leading to the corresponding fused 1,2-dihydro-
isoquinoline 3 in good to excellent yields. For instance,
reaction of N0-(2-alkynylbenzylidene)hydrazide 1a with
4-methoxyphenyl acetylene 2b under the standard conditions
gave rise to the desired product 3b in 74% yield (Table 1, entry 2).
A
similar yield was isolated when substrate 1b was
employed in the reaction of 4-methoxyphenylacetylene 2b
(70% yield, Table 1, entry 3). When N0-(2-alkynylbenzylidene)-
hydrazide 1c was utilized in the reaction, we rapidly noticed
the broad field of application of the process and its remarkable
functional group compatibility on alkynes (Table 1, entries 4–8).
All the expected products were generated under our standard
experimental conditions, whatever the nature of the substituents.
For example, almost quantitative yield of product 3d was
generated when phenylacetylene 2a was involved as a partner
(Table 1, entry 4). The structure of 3d was also verified by 1H
a Isolated yield based on N0-(2-alkynylbenzylidene)hydrazide 1.
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Fig. 1 X-Ray ORTEP illustration of fused 1,2-dihydroisoquinoline
3d (30% probability ellipsoids).
1,2-dihydroisoquinoline 3h could be isolated in 64% yield
(Table 1, entry 8). The conditions have also proven to
be useful for other N0-(2-alkynylbenzylidene)hydrazide
substrates. As expected, the substrates 1e–1i are suitable
partners in this process and the desired 1,2-dihydroisoquino-
lines were generated in good yields (Table 1, entries 11–16).
In conclusion, we have described an efficient tandem
reaction of N0-(2-alkynylbenzylidene)hydrazide with alkynes
catalyzed by silver triflate, which generated the highly
functionalized fused 1,2-dihydroisoquinolines in good to
excellent yields. Small library construction as well as biological
screening of these small molecules is ongoing, and the results
will be reported in due course.
Financial support from National Natural Science
Foundation of China (20772018), Shanghai Pujiang Program,
and Program for New Century Excellent Talents in University
(NCET-07-0208) is gratefully acknowledged.
Notes and references
z Crystal data and structure refinement for compound 3d. Empirical
formula: C21H20N2, Mr = 300, monoclinic, space group Pca21, a =
11.8040(2), b = 13.1961(3), c = 23.5991(4) A, V = 3675.96(12) A3,
Z = 8, Dc = 1.239 Mg mꢁ3, T = 296(2) K, Reflections collected/
unique: 19108/10218 (Rint = 0.0251), Final R indices [I 4 2s(I)]:
R1 = 0.0911, wR2 = 0.2659; R indices (all data): R1 = 0.1410,
wR2 = 0.3158.
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Chem. Commun., 2009, 3469–3471 | 3471