Multicatalytic synthesis of 1,2-dihydroisoquinolin-1-ylphosphonates via a tandem four-component reaction

Article abstract of DOI:10.1016/j.tetlet.2009.05.106

A tandem four-component reaction of 2-bromobenzaldehyde, alkyne, amine, and diethyl phosphite catalyzed by the combination of palladium and copper salts provides a facile and efficient route to 1,2-dihydroisoquinolin-1-ylphosphonate. A cascade Sonogashira

Full text of DOI:10.1016/j.tetlet.2009.05.106

Tetrahedron Letters 50 (2009) 4616–4618
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Multicatalytic synthesis of 1,2-dihydroisoquinolin-1-ylphosphonates
via a tandem four-component reaction
Haibo Zhou a, Hanpeng Jin a, Shengqing Ye a, Xiaodan He 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
Article history:
A tandem four-component reaction of 2-bromobenzaldehyde, alkyne, amine, and diethyl phosphite cat-
alyzed by the combination of palladium and copper salts provides a facile and efficient route to 1,2-dihy-
Received 16 April 2009
Revised 16 May 2009
Accepted 27 May 2009
Available online 2 June 2009
droisoquinolin-1-ylphosphonate.
A
cascade Sonogashira-intramolecular cyclization-nucleophilic
addition may be involved in the reaction process.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
2-Bromobenzaldehyde
Diethyl phosphite
1,2-Dihydroiso-quinolin-1-ylphosphonate
Four-component reaction
Multicatalysis
Tandem C–C bond formations are powerful methods for molec-
ular complexity generation from relatively simple starting materi-
als in a convergent way.1–3 These transformations are usually
operated in one pot without the need for intermediate workups
or purifications. In particular, the development of tandem reactions
for the efficient construction of small molecules is an important
goal in combinatorial chemistry from the viewpoints of operational
simplicity and assembly efficiency. Recently, the multicatalytic
processes have attracted growing interest in the filed of tandem
reactions.4,5 One or more catalysts are involved in the reaction
and promote two or more distinct chemical transformations in a
single flask. We have also developed multicatalytic system for
the generation of 1,2-dihydroisoquinolines.6 For instance, silver
triflate and proline catalysis were found highly effective in the
three-component reactions of 2-alkynylbenzaldehydes, amines,
and ketones.6a The combination of Mg(ClO4)2/Cu(OTf)2 shows high
efficiency as well in the one-pot reaction of 2-alkynylbenzaldehy-
des, amines, zinc, and allylic bromide or benzyl bromide. As part of
a continuing effort in our laboratory toward developing highly effi-
cient strategies for accessing privileged organic architectures,7 we
became interested in exploring the new multicatalytic processes to
facilitate the natural product-like compounds generation.
this scaffold show remarkable biological activities.8 Effort for devel-
opment of new 1,2-dihydroisoquinoline-based structures and novel
methods for their construction continues to be given.9–11 Recently,
we also have developed efficient methods for 1,2-dihydroisoquino-
line synthesis via tandem reactions.6,7g,11 Among the compounds
constructed, the 1,2-dihydroisoquinolin-1-ylphosphonates showed
promising activity as PTP1B (protein tyrosine phosphatase) inhibi-
tor in the subsequent biological assays. With expectation to search
for better inhibitor, we need to develop efficient and rapid synthe-
ses and evaluations of analogous structures. Since the multicatalyt-
ic processes offer the potential to significantly advance the field of
synthesis, herein we would like to disclose our recent efforts for the
synthesis of 1,2-dihydroisoquinolin-1-ylphosphonates via
a
multicatalytic system in a four-component reaction starting from
2-bromobenzaldehyde, alkyne, amine, and diethyl phosphite.
Encouraged by the advancement of Sonogashira coupling reac-
tion12,13 as well as the intramolecular electrophilic cyclization,14,15
we conceived that during the reaction process, 2-alkynylbenzalde-
hyde would be formed via coupling reaction of 2-bromobenzalde-
hyde with alkyne in the presence of palladium catalyst. Following
condensation with amine would generate the o-alkynylarylaldi-
mine, which then undergo the intramolecular electrophilic cycliza-
tion in the presence of suitable Lewis acid. Subsequent nucleophilic
addition of diethyl phosphite would afford the desired 1,2-dihy-
droisoquinolin-1-ylphosphonates. To verify the practicability of
this projected route, we started to investigate the possibility for
multicatalytic one-pot four-component reaction of 2-bromobenz-
aldehyde, alkyne, amine, and diethyl phosphite.
The importance of 1,2-dihydroisoquinolines has been recog-
nized since many natural products and pharmaceuticals containing
* Corresponding author. Tel.: +86 21 5566 4619; fax: +86 21 6510 2412.
E-mail address: jie_wu@fudan.edu.cn (J. Wu).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.106

H. Zhou et al. / Tetrahedron Letters 50 (2009) 4616–4618
4617
Table 2
At the outset, our studies commenced with the reaction of 2-
bromobenzaldehyde 1a, phenyl acetylene 2a, p-anisidine 3a, and
diethyl phosphite 4 (Table 1). Initially, the reaction occurred in
the presence of different palladium catalyst and copper(I) iodide.
We reasoned that the presence of palladium and copper catalyst
would facilitate both the Sonogashira coupling reaction and cycli-
zation-nucleophilic addition process. However, only trace amount
of desired 1,2-dihydroisoquinoline 5a was detected when the reac-
tion was catalyzed by PdCl2 (5 mol %) and CuI (5 mol %) in the pres-
ence of Et3N as base in THF at 60 °C (Table 1, entry 1). Most of the
product generated was the Sonogashira coupling adduct 2-alkynyl-
benzaldehyde. Similar results were observed when other palla-
dium catalysts (such as Pd(PhCN)2Cl2, Pd(PPh3)2Cl2, Pd(OAc)2,
and Pd(dppf)Cl2) were employed in the reaction (Table 1, entries
2–5). We conceived that the palladium catalyst might be deacti-
vated in the subsequent transformation. Thus, different Lewis acids
were screened, including AgOTf, Sc(OTf)3, Cu(OTf)2, In(OTf)3, or
Zn(OTf)2 (Table 1, entries 6–10). To our delight, 60% yield of prod-
uct 5a was generated when Cu(OTf)2 was used as co-catalyst in the
above reaction (Table 1, entry 7). Solvent screening identified THF
was the best choice (Table 1, entries 11–14). Finally, we found that
the yield could be increased to 80% in the presence of molecular
sieves (Table 1, entry 15). Decreasing the reaction temperature
diminished the product yield with prolonged reaction time (data
not shown in Table 1). Screening the ratio of catalysts revealed that
the reaction occurred efficiently as well catalyzed by the combina-
tion of Pd(PPh3)2Cl2 (2 mol %), CuI (1 mol %), and Cu(OTf)2
(10 mol %) (Table 1, entry 16).
Multicatalytic one-pot four-component reaction of 2-bromobenzaldehyde 1, alkyne 2,
amine 3, and diethyl phosphite 416
2 mol %
PdCl2(PPh3)2
1
10 mol %
Cu(OTf)2
CHO
R2
EtO
R1
O
N
EtO
P
2
O
H
2
Br
+
R3
R2
1
R1
cyclization-
addition
Sonogashira
R3
NH2
P
OEt
OEt
THF, 4A MS, 50~60 ºC
5
3
4
Entry
1
Substrate 1
CHO
Br
R2
R3
Yielda (%)
C6H5 (2a)
4-MeOC6H4 (3a)
80 (5a)
1a
2
3
4
5
6
7
8
9
10
1a
1a
1a
1a
1a
1a
1a
1a
1a
C6H5 (2a)
C6H5 (2a)
C6H5 (2a)
C6H5 (2a)
Cyclopropyl (2b)
Cyclopropyl (2b)
4-MeOC6H4 (2c)
4-MeOC6H4 (2c)
4-MeOC6H4 (2c)
4-MeC6H4 (3b)
3,5-Me2C6H3 (3c)
C6H5 (3d)
4-FC6H4 (3e)
4-MeOC6H4 (3a)
C6H5 (3d)
4-MeC6H4 (3b)
C6H5 (3d)
4-FC6H4 (3e)
63 (5b)
50 (5c)
50 (5d)
60 (5e)
42 (5f)
40 (5g)
62 (5h)
70 (5i)
64 (5j)
F
CHO
Br
11
C6H5 (2a)
4-MeOC6H4 (3a)
55 (5k)
1b
12
13
1b
1b
C6H5 (2a)
Cyclopropyl (2b)
4-MeC6H4 (3b)
4-MeOC6H4 (3a)
44 (5l)
42 (5m)
CHO
Br
Having demonstrated the viability of this catalytic strategy we
next investigated the scope of the transformation under the opti-
mized conditions [PdCl2(PPh3)2 (2 mol %), CuI (1 mol %), Cu(OTf)2
(10 mol %), Et3N, 4A molecular sieves, THF, 50–60 °C]. The results
are summarized in Table 2. For all cases, this four-component tan-
dem reaction proceeded smoothly, leading to the corresponding
products 5 in moderate to good yields. For instance, reaction of
2-bromobenzaldehyde 1a with phenyl acetylene 2a, p-toluidine
3b, and diethyl phosphite 4 under the standard conditions gave
O
O
14
C6H5 (2a)
C6H5 (2a)
4-MeOC6H4 (3a)
4-MeC6H4 (3b)
52 (5n)
50 (5o)
1c
15
1c
a
Isolated yield based on 2-bromobenzaldehyde 1.
rise to the desired product 5b in 63% yield (Table 2, entry 2). When
3,5-dimethylaniline 3c was utilized as a replacement, the desired
product 5c could be afforded in 50% yield (Table 2, entry 3). Similar
yield was obtained when aniline 3d was utilized as a coupling part-
ner (Table 2, entry 4, 50% yield). When aniline with electron-with-
drawing group attached on the aromatic ring (such as 4-
fluoroaniline 3e) was employed in the reaction, the expected prod-
uct 5e was afforded in 60% yield (Table 2, entry 5). Other alkynes
were used in the multi-component reactions of 2-bromobenzalde-
hyde 1a as well. Moderate yields were observed when ethynylcy-
clopropane 2b reacted with 2-bromobenzaldehyde 1a, aniline 3a
or 3d with diethyl phosphite 4 (Table 2, entries 6 and 7). Higher
yields were displayed when 4-methoxyphenyl acetylene 2c was
utilized in the reaction of 2-bromobenzaldehyde 1a (Table 2, en-
tries 8–10). We also tested other substrates, such as 2-bromo-5-
fluorobenzaldehyde 1b and 6-bromopiperonal 1c in this multicat-
alytic system. As expected, the four-component reactions worked
well to give rise to the corresponding product 5 in reasonable
yields (Table 2, entries 11–15).
Table 1
Initial studies for the multicatalytic one-pot four-component reaction
CHO
Ph
EtO
O
N
[Pd] (cat.), CuI (cat.)
Lewis acid (cat.)
EtO
P
2a
Br
+
PMP
Ph
1a
O
P
Et3N, Solvent
50-60 ºC
NH2
H
OEt
OEt
5a
MeO
4
3a
Entry [Pd] (5 mol %)/CuI (5 mol %) Lewis acid (10 mol %) Solvent
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15b
16c
PdCl2/CuI
None
None
None
None
None
AgOTf
Cu(OTf)2
In(OTf)3
Zn(OTf)2
Sc(OTf)3
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
DCE
Trace
Trace
Trace
Trace
Trace
43
60
20
21
28
Pd(PhCN)2Cl2/CuI
Pd(PPh3)2Cl2/CuI
Pd(OAc)2/CuI
Pd(dppf)Cl2/CuI
Pd(PPh3)2Cl2/CuI
Pd(PPh3)2Cl2/CuI
Pd(PPh3)2Cl2/CuI
Pd(PPh3)2Cl2/CuI
Pd(PPh3)2Cl2/CuI
Pd(PPh3)2Cl2/CuI
Pd(PPh3)2Cl2/CuI
Pd(PPh3)2Cl2/CuI
Pd(PPh3)2Cl2/CuI
Pd(PPh3)2Cl2/CuI
Pd(PPh3)2Cl2/CuI
In conclusion, we have described an efficient route for genera-
tion of 1,2-dihydroisoquinolin-1-ylphosphonate via
a tandem
four-component reaction of 2-bromobenzaldehyde, alkyne, amine,
and diethyl phosphite under multicatalytic conditions. We believe
that the operational simplicity of the present process combined
with the efficiency of this method will make it potentially attrac-
tive for further library construction.
33
Toluene 42
DMF
EtOH
THF
28
45
80
80
THF
Acknowledgments
a
b
c
Isolated yield based on 2-bromobenzaldehyde 1.
In the presence of molecular sieves.
[Pd] (2 mol %), CuI (1 mol %), in the presence of molecular sieves.
Financial support from National Natural Science Foundation of
China (20772018), Shanghai Pujiang Program, and Program for

4618
H. Zhou et al. / Tetrahedron Letters 50 (2009) 4616–4618
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16. General procedure for the multicatalytic one-pot four-component reaction of 2-
bromobenzaldehyde 1, alkyne 2, amine 3, and diethyl phosphite 4: A mixture of 2-
bromobenzaldehyde 1 (0.5 mmol), alkyne 2 (1.0 mmol, 2.0 equiv), Pd(PPh3)2Cl2
(2 mol %), CuI (1 mol %), and Et3N (1.5 mmol, 3.0 equiv) in THF was stirred at
50 °C. After consumption of 2-bromobenzaldehyde 1 as indicated by TLC,
amine
3 (0.5 mmol, 1.0 equiv), diethyl phosphite 4 (0.6 mmol, 1.2 equiv),
Cu(OTf)2 (10 mol %), and 4A molecular sieves (100 mg) were added. After
completion of the reaction, the mixture was quenched with water (10 mL) and
extracted with EtOAc (2 Â 10 mL). Evaporation of the solvent followed by
purification of the residue on silica gel afforded pure 1,2-dihydroisoquinolin-1-
ylphosphonate 5. Selected example: diethyl 2-(4-methoxyphenyl)-3-phenyl-
1,2-dihydroiso-quinolin-1-ylphosphonate (5a), 80% yield. yellow liquid. 1H
NMR (400 MHz, CDCl3) d 1.20–1.25 (m, 6H), 3.65 (s, 3H), 3.90–4.12 (m, 4H),
5.33 (d, J = 19.0 Hz, 1H), 6.44 (s, 1H), 6.63 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 8.8 Hz,
2H), 7.06–7.28 (m, 7H), 7.57 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) d
16.5, 55.3, 62.5, 62.6, 64.9, 111.1, 113.9, 124.1, 124.5, 125.0, 126.4, 127.3,
127.5, 127.8, 127.9, 128.2, 133.3, 137.5, 141.5, 142.6, 155.4; 31P NMR
(161 MHz, CDCl3) d 21.25; HRMS calcd for C26H28NO4P: 449.1756, found:
449.1752.
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