Lewis acid-catalyzed reactions of N′-(2-alkynylbenzylidene)hydrazides with diethyl phosphite

Article abstract of DOI:10.1016/j.tetlet.2009.05.013

Lewis acid catalyst-tuned reactions of N′-(2-alkynylbenzylidene)hydrazides with diethyl phosphite are described. Isoquinolin-1-ylphosphonate is generated when copper triflate is utilized as catalyst, while 2-amino-1,2-dihydroisoquinolin-1-ylphosphonate is

Full text of DOI:10.1016/j.tetlet.2009.05.013

Tetrahedron Letters 50 (2009) 4279–4282
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Tetrahedron Letters
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Lewis acid-catalyzed reactions of N0-(2-alkynylbenzylidene)hydrazides
with diethyl phosphite
Xingxin Yu a, Qiuping Ding a, Zhiyuan Chen a, Jie Wu a,b,
*
a Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Lewis acid catalyst-tuned reactions of N0-(2-alkynylbenzylidene)hydrazides with diethyl phosphite are
described. Isoquinolin-1-ylphosphonate is generated when copper triflate is utilized as catalyst, while
2-amino-1,2-dihydroisoquinolin-1-ylphosphonate is obtained in the presence of palladium acetate.
Ó 2009 Elsevier Ltd. All rights reserved.
Article history:
Received 3 April 2009
Revised 2 May 2009
Accepted 8 May 2009
Available online 12 May 2009
Keywords:
N0-(2-Alkynylbenzylidene)hydrazide
Copper triflate
Diethyl phosphite
Palladium acetate
Isoquinolines, including 1,2-dihydroisoquinolines are common
structural motifs in many natural products and pharmaceuticals
that exhibit remarkable biological activities.1 Thus, many efforts
have been given for the development of new methods for their
constructions.2–4 Recently, we have focused on the methodology
development for the expeditious synthesis of biologically relevant
heterocyclic compounds.4,5 For example, 1,2-dihydroisoquinolines
could be generated via three-component tandem reactions6,7 of 2-
alkynylbenzaldehyde, amine, and various nucleophiles.4 Screening
in a PTP1B (protein tyrosine phosphatase) inhibition assay led to
Recently, it was reported that in the presence of Lewis acid or
electrophiles, isoquinoline-N-oxide could be formed starting from
2-alkynylbenzaldoxime A.5a,5c,8 Prompted by these results, we
envisaged that N0-(2-alkynylbenzylidene)hydrazide might undergo
similar transformation catalyzed by suitable Lewis acid. It is well-
known that Lewis acid-catalyzed cyclization of alkynes possessing
a nucleophile in proximity to the triple bond is an important pro-
cess in organic synthesis, which can construct various heterocycles
efficiently.9,10 We conceived that for reaction of N0-(2-alkynylben-
zylidene)hydrazide with nucleophile, in the presence of Lewis acid
the intermediate isoquinolinium would be generated,11 which then
underwent nucleophilic attack to give rise to the corresponding 2-
amino-1,2-dihydroisoquinolines. Thus, initial studies were per-
formed by using N0-(2-alkynylbenzylidene)hydrazide 1a and
diethyl phosphite 2 as model substrates, catalyzed by various Le-
wis acids (Scheme 1).
the identification of a hit with a promising IC50 value of 4.6 lM.
The discovery of promising lead compounds and their moderate
activity warranted the development of efficient and rapid syntheses
and evaluations of analogous structures in the search for better
inhibitors. Thus, subsequently therelated heterocycles were synthe-
sized via tandem reactions starting from 2-alkynylbenzaldoxime A
or 2-(2-(alkynyl)benzylidene)malonate B.5a,b Meanwhile, the struc-
turally similar N0-(2-alkynylbenzylidene)hydrazides C were utilized
as substrates as well to investigate the possibility for reactions with
nucleophiles (Fig. 1). Herein, we disclosed our recent efforts for
Lewis acid-catalyzed reactions of N0-(2-alkynylbenzylidene)hydra-
zides with diethyl phosphite, which led to different outcomes under
different conditions: isoquinolin-1-ylphosphonate was generated
when copper triflate was utilized as catalyst, while 2-amino-1,2-
dihydroisoquinolin-1-ylphosphonate was obtained when the
reaction was catalyzed by palladium acetate.
Firstly, the reaction was carried out in the presence of 10 mol %
of Lewis acid in dichloroethane at room temperature. For most cat-
alysts employed [such as Zn(OTf)2, Yb(OTf)3, Dy(OTf)3, In(OTf)3,
Bi(OTf)3, and AgOTf], no desired product was isolated and only
H
CO2R3
OH
R2
N
N
N
R3
R1
R1
R1
CO2R3
R2
R2
B
A
C
* Corresponding author. Tel.: +86 21 5566 4619; fax: +86 21 6510 2412.
E-mail address: jie_wu@fudan.edu.cn (J. Wu).
Figure 1. Structures of 2-alkynylbenzaldoxime A, 2-(2-(alkynyl)benzylidene)mal-
onate B, and N0-(2-alkynylbenzylidene)hydrazide C.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.013

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X. Yu et al. / Tetrahedron Letters 50 (2009) 4279–4282
H
N
Lewis acid
(10 mol %)
solvent, temp.
N
Ts
O
+
HPO(OEt)2
Ph
1a
OEt
P
OEt
O
OEt
P
OEt
NHTs
N
N
N
N
Ts
Ph
Ph
Ph
5a
3a
4a
Lewis acids: Cu(OTf)2, CuI, Pd(OAc)2, PdCl2, Zn(OTf)2
Yb(OTf)3, Dy(OTf)3, Bi(OTf)3, In(OTf)3, AgOTf
Solvent: THF, CH2Cl2, toluene, MeCN, (CH2Cl)2, MeNO2
Temp.: rt, 70 ºC
Figure 2. ORTEP diagram of 2-amino-1,2-dihydroiso-quinoline 4a.
Scheme 1. Reaction of N0-(2-alkynylbenzylidene)hydrazide 1a and diethyl phos-
phite 2 catalyzed by various Lewis acids.
proceeded smoothly in dichloroethane at 70 °C to afford the
desired 2-amino-1,2-dihydroisoquinoline 4a in 45% yield. Further
solvent screening revealed that the yield could be increased to
62% when toluene was utilized as a replacement. The structure
of 4a was verified by 1H and 13C NMR, mass spectroscopy, as well
as X-ray diffraction analysis (Fig. 2, also see Supplementary data).
intermediate isoquinolinium 5a was generated. Elevating the
reaction temperature to 70 °C could not improve the result. Grati-
fyingly, in the presence of Pd(OAc)2 (10 mol %), this reaction
Table 1
Copper triflate- or palladium acetate-catalyzed reactions of N0-(2-alkynylbenzylidene)hydrazides 1 with diethyl phosphite 2a
H
N
OEt
OEt
P OEt
R3
O
O
P
OEt
N
R1
A
NHR3
B
1
R2
N
N
R1
R1
+
R2
R2
HPO(OEt)2
2
3
4
Method A: Cu(OTf)2, (CH2Cl)2, 70 οC
Method B: Pd(OAc)2, toluene, 70 οC
Entry
Compound 1
Product 3
Product 4
OEt
O
OEt
OEt
NHTs
H
N
P
OEt
O
P
N
Ts
N
1
N
Ph
Ph
Ph
Method A: 3a,
1a
Method B: 4a, 62%
71%
OEt
OEt
O
H
N
O
P
OEt
F
P
OEt
NHTs
N
Ts
F
F
N
2
3
4
N
Ph
Ph
Ph
Method A: 3b,
1b
Method B: 4b, 53%
54%
OEt
O
OEt
O
H
N
P
OEt
N
P
OEt
N
Ts
NHTs
N
PMP
PMP
PMP
Method B: 4c, 55%
Method A: 3c,
1c
74%
OEt
OEt
OEt
O
H
N
O
P
F
P
OEt
NHTs
N
Ts
F
N
F
N
PMP
PMP
PMP
Method B: 4d, 50%
Method A: 3d,
1d
50%
(continued on next page)

X. Yu et al. / Tetrahedron Letters 50 (2009) 4279–4282
4281
Table 1 (continued)
Entry
Compound 1
Product 3
Product 4
OEt
O
OEt
OEt
NHSO2Ph
H
N
P
OEt
N
O
P
N
SO2Ph
5
6
7
N
Ph
Ph
Ph
Method A: 3a,
1e
Method B: 4e, 60%
72%
OEt
O
OEt
O
H
N
P
OEt
N
P
OEt
NHSO2Ph
N
SO2Ph
N
PMP
PMP
PMP
Method B: 4f, 57%
Method A: 3c,
1f
67%
OEt
O
OEt
O
H
N
P
OEt
F
P
OEt
N
SO2Ph
F
F
F
F
NHSO2Ph
N
N
Ph
Ph
Ph
Method A: 3b,
1g
Method B: 4g, 70%
72%
OEt
O
OEt
O
H
N
P
OEt
F
P
OEt
N
SO2Ph
NHSO2Ph
N
N
8
PMP
PMP
PMP
Method B: 4h, 64%
Method A: 3d,
1h
75%
a
Isolated yield based on N0-(2-alkynylbenzylidene)hydrazides 1.
Interestingly, a different product 3a with 71% yield was obtained
when copper triflate was employed as a catalyst (DCE, 70 °C).
Under this condition, other solvents displayed inferior results. This
result is reasonable since in the presence of copper catalyst the
amino group attached on the nitrogen of 2-amino-1,2-dihydroiso-
quinoline 4a is easily released. To test this idea, reaction of 2-ami-
no-1,2-dihydro-isoquinoline 4a in dichloroethane at 70 °C
catalyzed by copper triflate was performed. As expected, isoquino-
lin-1-ylphosphonate 3a was generated. We also examined other
nucleophiles (such as phenyl acetylene, methanol, and diethyl mal-
onate) in the reaction of N0-(2-alkynylbenzylidene)hydrazide 1a.
However, no nucleophilic addition adducts were detected and only
intermediate 5a was isolated.
With this preliminary result in hand, we started to investigate the
scope of these metal-tuned reactions of N0-(2-alkynylbenzylid-
ene)hydrazides under palladium acetate- or copper triflate-cata-
lyzed conditions [Pd(OAc)2 (10 mol %), toluene, 70 °C; Cu(OTf)2,
DCE, 70 °C], and the results are shown in Table 1. The N0-(2-alkynylb-
enzylidene)hydrazides could be easily synthesized via condensation
of 2-alkynylbenzaldehyde with hydrazine.12 From Table 1, it was
found that for allcases, this metal-tunedreactions of N0-(2-alkynylb-
enzylidene)hydrazides with diethyl phosphite furnished the
similar yields were observed (Table 1, entry 3). However, the reac-
tion was complicated and no desired products were generated when
the phenyl group was changed to aliphatic groups (such as butyl and
cyclopropyl group, data not shown in Table 1). Compound 1e was
also suitable substrate in this process, which reacted with diethyl
phosphite 2 under the copper- or palladium-catalyzed conditions
leading to the corresponding product 3a or 4e in 72% and 60% yield,
respectively (Table 1, entry 5). Reactions of other substrates 1f–h
with phosphite also proceeded smoothly, which gave rise to the
desired product in good yield (Table 1, entries 6–8).
In conclusion, we have described copper triflate- or palladium
acetate-catalyzed reactions of N0-(2-alkynylbenzylidene)hydrazides
with diethyl phosphite, thus offering an unprecedented and straight-
forward route for the synthesis of isoquinolin-1-ylphosphonate or
2-amino-1,2-dihydroisoquinolin-1-ylphosphonate. Application of
N0-(2-alkynylbenzylidene)hydrazides in other transformations is
under investigation in our laboratory, and the results will be reported
in due course.
Acknowledgments
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.
corresponding isoquinolin-1-ylphosphonate
3 or 2-amino-1,2-
dihydroisoquinoline 4 in good yields. For example, reaction of
fluoro-substituted N0-(2-alkynylbenzylidene)hydrazide 1b with
diethylphosphitecatalyzedbycoppertriflategaverisetothedesired
product 3b in 54% yield, while 53% yield of product 4b was generated
when Pd(OAc)2 was used as catalyst (Table 1, entry 2). When the
phenyl group attached on the triple bond in N0-(2-alkynylbenzylid-
ene)hydrazide 1 was replaced by 4-methoxyphenyl group, the
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.05.013.

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X. Yu et al. / Tetrahedron Letters 50 (2009) 4279–4282
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