Synthesis of 1,2-dihydroisoquinolin-1-ylphosphonates via three-component reactions of 2-(2-formylphenyl)ethanone, amine, and diethyl phosphite

Article abstract of DOI:10.1016/j.tet.2008.12.038

Synthesis of 1,2-dihydroisoquinolin-1-ylphosphonates via CuI-catalyzed three-component tandem reactions of 2-(2-formylphenyl)ethanone, amine, and diethyl phosphite is described. The reactions proceed smoothly under mild conditions leading to the desired p

Full text of DOI:10.1016/j.tet.2008.12.038

Tetrahedron 65 (2009) 1294–1299
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Synthesis of 1,2-dihydroisoquinolin-1-ylphosphonates via three-component
reactions of 2-(2-formylphenyl)ethanone, amine, and diethyl phosphite
,b,
Shengqing Ye a, Haibo Zhou a, Jie Wu a
*
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:
Received 23 October 2008
Received in revised form 11 December 2008
Accepted 12 December 2008
Available online 24 December 2008
Synthesis of 1,2-dihydroisoquinolin-1-ylphosphonates via CuI-catalyzed three-component tandem re-
actions of 2-(2-formylphenyl)ethanone, amine, and diethyl phosphite is described. The reactions proceed
smoothly under mild conditions leading to the desired products in good yields.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
1,2-Dihydroisoquinolin-1-ylphosphonates
Copper iodide
2-(2-Formylphenyl)ethanone
Amine
Diethyl phosphite
1. Introduction
strategies used for the construction of small molecules, design and
synthesis of natural product-like compounds via tandem reactions
The prominence of 1,2-dihydroisoquinoline as a basic scaffold in
natural products and biologically active molecules1 has promoted
considerable efforts toward their synthesis.2–5 As part of a con-
tinuing effort in our laboratory for the expeditious synthesis of
biologically relevant heterocyclic compounds, we have developed
novel and efficient methods to construct the 1,2-dihydroisoquino-
line scaffold.4,5 Small library of 1,2-dihydroisoquinolines was gen-
erated meanwhile. Following biological screening showed that this
kind of compound was active as PTP1B (protein tyrosine phos-
have attracted much attention, and the development of tandem
reactions has been a fertile area in organic synthesis.9 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. The construction of 1,2-dihydroisoquinolin-1-ylphospho-
nate has been reported via AgOTf-catalyzed reaction of a-amino (2-
alkynylphenyl)methylphosphonate through 6-endo-cyclization.5a It
also could be generated via copper(I) iodide or silver triflate cata-
lyzed three-component reactions of 2-alkynylbenzaldehyde, amine,
and diethyl phosphite.5b–d We conceived that the desired 1,2-dihy-
droisoquinolin-1-ylphosphonate 4 could be obtained under suitable
conditions in an alternative route via three-component tandem re-
action of dicarbonyl compound 1, amine 2, and diethyl phosphite 3
(Scheme 1). In the reaction process, intermediated A would be
formed. Following tandem nucleophilic addition of phosphite to
imine and subsequent condensation of generated secondary amine
with ketone would give rise to the target compound 4 in the pres-
ence of suitable catalyst. Lewis acid-catalyzed addition of diethyl
phosphite to aldimine has been well known, which provides useful
phatase) inhibitor (IC50 4.6 mM). With a hope of finding more active
hits for our particular biological assay, it is highly desired to develop
novel methods to build up the new 1,2-dihydroisoquinoline-based
structures.
Organophosphorus compounds continue to receive widespread
attention due to their ubiquity in biological systems.6,7 Recent
studies have indicated that a lot of heterocycle analogues con-
taining phosphorus showed excellent bioactivities. For example,
phosphacoumarins showed good inhibitory activity against SHP-1.8
Prompted by these results, we envisioned that phosphorus in-
corporated 1,2-dihydroisoquinolines might be the choice for
methodology development and library construction. Among the
method for the preparation of a
-amino phosphonate.10 Moreover,
three-component synthesis starting from aldehyde, amine, and
diethyl phosphiteor triethylphosphite has been alsoreported byuse
of Lewis acids or Bronsted acid.11 For this kind of transformation, the
presence of Lewis acid or Bronsted acid promoted the reaction
* Corresponding author. Tel.: þ86 215 566 4619; fax: þ86 216 510 2412.
E-mail address: jie_wu@fudan.edu.cn (J. Wu).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.12.038

S. Ye et al. / Tetrahedron 65 (2009) 1294–1299
1295
Table 1
significantly. Based on these results, to verify the practicability of the
projected route as shown in Scheme 1, a set of experiments were
carried out using 2-(2-formylphenyl)ethanone 1a, p-anisidine 2a,
and diethyl phosphite 3 as model substrates, materials, which are
eithercommerciallyavailable orcanbe readilysynthesized(Table 1).
Condition screening for three-component tandem reactions of 2-(2-for-
mylphenyl)ethanone 1a, p-anisidine 2a, and diethyl phosphite 3a
OEt
P
NH2
CHO
EtO
O
Lewis acid
(cat.)
O
PMP
Ph
+
+
HPO(OEt)2
N
R1
Ph
solvent
12 h
OMe
2a
3
4a
OEt
P
1a
EtO
O
CHO
R3
R2
O
R3 NH2
2
3
Entry
Lewis acid
Solvent
Temp
Yieldb (%)
N
R1
R1
N
+
R2
1
2
3
4
5
6
7
8
d
d
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
THF
rt
Trace
10
HPO(OEt)2
70 ꢀ
70 ꢀ
70 ꢀ
70 ꢀ
70 ꢀ
70 ꢀ
70 ꢀ
70 ꢀ
70 ꢀ
70 ꢀ
C
C
C
C
C
C
C
C
C
C
4
1
Nu
Cu(OTf)2 (10 mol %)
Dy(OTf)3 (10 mol %)
In(OTf)3 (10 mol %)
Bi(OTf)3 (10 mol %)
Zn(OTf)2 (10 mol %)
AgOTf (10 mol %)
Yb(OTf)3 (10 mol %)
PdCl2 (10 mol %)
CuI (10 mol %)
CuI (10 mol %)
CuI (10 mol %)
CuI (10 mol %)
CuI (5 mol %)
49
55
44
37
51
50
59
25
85
69
50
47
R3
O
R1
R2
A
9
10
11
12
13
14
15
Scheme 1. Projected route for three-component tandem reactions of dicarbonyl
compound 1, amine 2, and diethyl phosphite 3.
70 ꢀC
70 ꢀC
Toluene
CH3CN
ClCH2CH2Cl
70 ꢀ
70 ꢀ
C
C
56
2. Results and discussion
a
Reaction conditions: 2-(2-formylphenyl)ethanone 1a (0.30 mmol), p-anisidine
2a (1.1 equiv), diethyl phosphite (2.0 equiv), solvent (2.0 mL), 70 ꢀC, 4 Å molecular
sieves.
To identify suitable conditions for the proposed three-compo-
nent tandem reaction process, reaction screening involving a series
of metal catalysts was carried out. Results of this preliminary sur-
vey were shown in Table 1. Initially, only a trace amount of product
was detected in the absence of catalyst when the reaction was
performed at room temperature in 1,2-dichloroethane (Table 1,
entry 1). Product 4a (10% yield) was isolated when the reaction
temperature was increased to 70 ꢀC (Table 1, entry 2). Further
screening of Lewis acid catalysts revealed that the yield could be
dramatically improved when copper(I) iodide was utilized as the
catalyst, and the desired 1,2-dihydroisoquinolin-1-ylphosphonate
4a was obtained in 85% yield (Table 1, entry 11). Other Lewis acids
employed displayed inferior results (Table 1, entries 3–10). Solvent
screening revealed that dichloroethane was the best choice (Table
1, entries 12–14). Decreasing the amount of copper(I) catalyst di-
minished the yield (Table 1, entry 15).
b
Isolated yield based on 2-(2-formylphenyl)ethanone 1a.
3. Conclusions
In conclusion, we have described an efficient route for the
synthesis of 1,2-dihydroisoquinolin-1-ylphosphonates via CuI-
catalyzed three-component tandem reactions of 2-(2-for-
mylphenyl)ethanone, amine, and diethyl phosphite. The reactions
proceed smoothly under mild conditions leading to the desired
products in good yields. The efficiency of this method combined
with the operational simplicity of the present process makes it
potentially attractive for library construction. The focused library
generation and screening for biological activity of these small
molecules are under investigation in our laboratory.
With this promising result in hand, we started to investigate the
three-component reactions of 2-(2-formylphenyl)-ethanone 1,
amine 2, and diethyl phosphite 3 catalyzed by copper(I) iodide
under optimized reaction conditions [CuI (10 mol %), 1,2-di-
chloroethane, 70 ꢀC]. The results are shown in Table 2. From Table 2,
we rapidly noticed the broad field of application of the process and
the conditions were highly effective for the three-component
reactions. For all cases the desired products were furnished in
good to excellent yields. For instance, reaction of 2-(2-formyl-
phenyl)ethanone 1a, 4-methylbenzeneamine 2b, with diethyl
phosphite 3 under the standard conditions gave rise to the desired
product 4b in 82% yield (Table 2, entry 2). A 60% yield was obtained
when aniline 2c was utilized as a replacement (Table 2, entry 3).
Anilines with electron-withdrawing groups attached on the aro-
matic ring were also employed in the reaction of 1a, and the similar
yields were observed (Table 2, entries 4 and 5). We also examined
aliphatic amine in this reaction. However, no desired product was
isolated when benzyl amine was used as substrate in the reaction of
2-(2-formylphenyl)ethanone 1a with diethyl phosphite 3 (data not
shown in Table 2). Other 2-(2-formylphenyl)ethanones were tested
in the three-component tandem reactions. For example, when the
phenyl group attached on the carbonyl unit was replaced by p-
methoxyphenyl or cyclopropyl group, similar yield was isolated
(Table 2, entries 6–10). The reactions also worked well when fluoro-
substituted 2-(2-formylphenyl)ethanone 1d was utilized in the
reactions.
4. Experimental section
4.1. General
All reactions were performed in reaction tubes under nitrogen
atmosphere. Flash column chromatography was performed using
silica gel (60-Å pore size, 32–63
mm, standard grade). Analytical
thin-layer chromatography was performed using glass plates pre-
coated with 0.25 mm 230–400 mesh silica gel impregnated with
a fluorescent indicator (254 nm). Thin layer chromatography plates
were visualized by exposure to ultraviolet light. Organic solutions
were concentrated on rotary evaporators at w20 Torr (house vac-
uum) at 25–35 ꢀC. Commercial reagents and solvents were used as
received. Nuclear magnetic resonance (NMR) spectra are recorded
in parts per million from internal tetramethylsilane on the
d scale.
4.2. General procedure for three-component reactions of
2-(2-formylphenyl)ethanone, amine, and diethyl phosphite
Diethyl phosphite 3 (0.6 mmol, 2.0 equiv) was added to a mix-
ture of 2-(2-formylphenyl)ethanone
amine 2 (0.33 mmol, 1.1 equiv), CuI (0.03 mmol, 10 mol %), and
molecular sieves (150 mg) in DCE (2.0 mL). The mixture was then
stirred at 70 ꢀC. After completion of reaction as indicated by TLC,
1 (0.30 mmol, 1.0 equiv),

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S. Ye et al. / Tetrahedron 65 (2009) 1294–1299
Table 2
CuI-catalyzed three-component tandem reactions of 2-(2-formylphenyl)ethanone 1, amine 2, and diethyl phosphite 3a
OEt
P
EtO
CHO
O
O
NH2
CuI (10 mol %)
R3
R2
R3
R1
N
+
+
HPO(OEt)2
R1
R2
DCE, 4Å MS
70 °C
1
2
3
4
Entry
1
Substrate 1
R3
Product 4
Yieldb (%)
85 (12 h)
OEt
P
EtO
CHO
O
O
PMP
Ph
4-OMe
N
Ph
1a
4a
OEt
P
EtO
CHO
O
O
C6H4-p-Me
2
3
4-Me
82 (12 h)
N
Ph
Ph
4b
1a
OEt
EtO
CHO
O
N
P
O
Ph
Ph
H
60 (14 h)
Ph
1a
4c
OEt
P
EtO
O
CHO
O
C6H4-3-NO2
Ph
N
4
5
6
3-NO2
64 (24 h)
66 (16 h)
75 (18 h)
Ph
1a
4d
OEt
P
EtO
CHO
O
O
C6H4-p-F
4-F
N
Ph
Ph
1a
4e
OEt
EtO
CHO
O
P
O
Ph
H
N
PMP
PMP
1b
4f
OEt
P
EtO
EtO
CHO
O
O
C6H4-p-Me
7
8
4-Me
65 (24 h)
N
PMP
PMP
1b
4g
OEt
P
CHO
O
O
C6H4-p-F
4-F
77 (18 h)
N
PMP
PMP
1b
4h
OEt
P
EtO
CHO
O
O
Ph
N
9
H
56 (24 h)
1c
4i

S. Ye et al. / Tetrahedron 65 (2009) 1294–1299
1297
Table 2 (continued )
Entry
Substrate 1
R3
Product 4
Yieldb (%)
OEt
EtO
CHO
O
P
O
C6H4-p-F
N
10
11
12
4-F
61 (24 h)
1c
4j
OEt
EtO
CHO
O
P
O
F
Ph
Ph
H
47 (24 h)
N
Ph
F
1d
4k
OEt
P
CHO
EtO
O
O
F
C6H4-p-F
4-F
70 (20 h)
N
Ph
Ph
F
F
Ph
1d
4l
OEt
EtO
CHO
O
P
O
F
C6H4-p-Me
13
4-Me
75 (20 h)
N
Ph
1d
4m
a
Reaction conditions: 2-(2-formylphenyl)ethanone 1 (0.30 mmol), amine 2 (1.1 equiv), diethyl phosphite (2.0 equiv), 1,2-dichloroethane (2.0 mL), 70 ꢀC.
Isolated yield based on 2-(2-formylphenyl)ethanone 1. PMP: p-methoxyphenyl.
b
the solvent was evaporated and the residue was quenched with
7.55 (d, J¼7.4 Hz, 2H), 7.68 (d, J¼8.3 Hz, 1H), 7.93 (s, 1H); 13C NMR
1
water (10 mL), extracted with EtOAc (2ꢁ10 mL), dried by anhydrate
Na2SO4. Evaporation of the solvent followed by purification on
silica gel provided the corresponding product 4.
(CDCl3, 100 MHz)
d
16.4, 16.5, 62.8, 62.9, 63.4 (d, JCP¼162.0 Hz),
113.9, 116.4, 116.6, 124.8, 125.8, 127.1, 127.2, 127.5, 127.8, 128.4, 128.6,
128.7, 129.0, 132.4, 136.3, 140.7, 148.3, 148.5. IR (KBr): nmax/cmꢂ1
3063, 2914, 1608, 1527, 1445. HRMS calcd for C25H25N2O5P:
464.1501, found: 464.1505.
4.2.1. Diethyl-2-(4-methoxyphenyl)-3-phenyl-1,2-dihydroiso-
quinolin-1-ylphosphonate (4a)5b
Yield: 85%. 1H NMR (400 MHz, CDCl3)
d
1.18–1.24 (m, 6H), 3.64
4.2.5. Diethyl-2-(4-fluorophenyl)-3-phenyl-1,2-dihydroisoquinolin-
(s, 3H), 3.91–4.12 (m, 4H), 5.33 (d, J¼19 Hz, 1H), 6.44 (s, 1H), 6.62 (d,
1-ylphosphonate (4e)5b
J¼8.8 Hz, 2H), 7.04 (d, J¼8.8 Hz, 2H), 7.08–7.26 (m, 7H), 7.57 (d,
Yield: 66%. 1H NMR (400 MHz, CDCl3)
d 1.21–1.23 (m, 6H), 3.90–
J¼6.8 Hz, 2H); 13C NMR (CDCl3, 100 MHz)
d
16.4, 16.5, 55.3, 62.5,
4.09 (m, 4H), 5.34 (d, J¼19 Hz, 1H), 6.48 (s, 1H), 6.78 (t, J¼8.8 Hz,
62.6, 64.9 (d, 1JCP¼163.0 Hz), 111.1, 113.9, 124.1, 124.5, 125.0, 126.4,
2H), 7.04–7.07 (m, 2H), 7.07 (d, J¼7.8 Hz, 1H), 7.15–7.28 (m, 6H), 7.56
127.3, 127.5, 127.8, 127.9, 128.2, 133.3, 137.5, 141.5, 142.6, 155.4.
(d, J¼7.3 Hz, 2H); 13C NMR (CDCl3, 100 MHz)
d 16.4, 16.5, 62.5, 62.6,
1
2
64.5 (d, JCP¼163.0 Hz), 111.8, 115.1 (d, JCF¼23.0 Hz), 124.3, 124.4,
125.2, 126.6, 127.2, 127.7, 128.0, 128.3, 133.0, 137.1, 142.1, 143.9, 158.5
(d, 1JCF¼241.0 Hz).
4.2.2. Diethyl-3-phenyl-2-p-tolyl-1,2-dihydroisoquinolin-1-
ylphosphonate (4b)5b
Yield: 82%. 1H NMR (400 MHz, CDCl3)
d 1.17–1.23 (m, 6H), 2.16 (s,
3H), 3.92–4.08 (m, 4H), 5.40 (d, J¼19 Hz, 1H), 6.48 (s, 1H), 6.88 (d,
4.2.6. Diethyl-3-(4-methoxyphenyl)-2-phenyl-1,2-
J¼7.8 Hz, 2H), 6.97 (d, J¼7.8 Hz, 2H), 7.09–7.25 (m, 7H), 7.58 (d,
dihydroisoquinolin-1-ylphosphonate (4f)
J¼7.8 Hz, 2H); 13C NMR (CDCl3, 100 MHz)
d
16.4, 16.5, 20.5, 62.5,
Yield: 75%. 1H NMR (400 MHz, CDCl3)
d 1.18–1.23 (m, 6H), 3.75
62.6, 64.4 (d, 1JCP¼163.0 Hz), 111.7, 122.7, 124.1, 125.3, 126.4, 127.2,
(s, 3H), 3.93–4.10 (m, 4H), 5.43 (d, J¼19 Hz, 1H), 6.42 (s, 1H), 6.77 (d,
127.6, 127.8, 128.1, 128.2, 129.1, 131.8, 133.1, 137.4, 142.2, 145.4.
J¼8.8 Hz, 2H), 6.85 (t, J¼6.8 Hz, 1H), 7.06–7.18 (m, 7H), 7.23 (d,
J¼6.8 Hz, 1H), 7.50 (d, J¼8.3 Hz, 2H); 13C NMR (100 MHz, CDCl3)
1
4.2.3. Diethyl-2,3-diphenyl-1,2-dihydroisoquinolin-1-
d
16.4, 16.5, 55.1, 62.6, 62.7, 64.2 (d, JCP¼163.0 Hz), 110.9, 113.7,
ylphosphonate (4c)5b
122.2, 122.8, 124.1, 125.5, 126.2, 127.2, 128.2, 128.5, 128.9, 129.8,
133.3, 141.8, 147.8, 159.4; IR (KBr): nmax/cmꢂ1 3063, 2976, 1598,
1506, 1491, 1450. MS (ESI) m/z 450 (MþþH); HRMS calcd for
C26H28NO4P (MþþH): 450.1837, found: 450.1837.
Yield: 60%. 1H NMR (400 MHz, CDCl3)
d 1.18–1.24 (m, 6H), 3.93–
4.10 (m, 4H), 5.45 (d, J¼19 Hz,1H), 6.51(s,1H), 6.85 (m,1H), 7.06–7.27
(m, 11H), 7.58 (d, J¼7.3 Hz, 2H); 13C NMR (CDCl3, 100 MHz)
d 16.4,
1
16.5, 62.5, 62.7, 64.2 (d, JCP¼162.0 Hz), 112.2, 122.3, 122.6, 124.3,
125.6,126.5,127.2,127.6,127.9,128.2,128.5,133.0,137.3,142.0,147.6.
4.2.7. Diethyl-3-(4-methoxyphenyl)-2-p-tolyl-1,2-dihydro-
isoquinolin-1-ylphosphonate (4g)
4.2.4. Diethyl-2-(3-nitrophenyl)-3-phenyl-1,2-dihydroisoquinolin-
Yield: 65%. 1H NMR (400 MHz, CDCl3)
d 1.19–1.23 (m, 6H), 2.17 (s,
1-ylphosphonate (4d)
3H), 3.74 (s, 3H), 3.91–4.11 (m, 4H), 5.38 (d, J¼19 Hz, 1H), 6.39 (s,
1H), 6.76 (d, J¼8.3 Hz, 2H), 6.89 (d, J¼8.3 Hz, 2H), 6.97 (d, J¼7.8 Hz,
2H), 7.07–7.25 (m, 4H), 7.50 (d, J¼8.3 Hz, 2H); 13C NMR (100 MHz,
Yield: 64%. 1H NMR (400 MHz, CDCl3)
d
1.20–1.29 (m, 6H), 3.97–
4.12 (m, 4H), 5.44 (d, J¼19 Hz, 1H), 6.58 (s, 1H), 7.17–7.33 (m, 9H),

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S. Ye et al. / Tetrahedron 65 (2009) 1294–1299
1
CDCl3)
d
16.4, 16.5, 20.6, 55.1, 62.5, 62.6, 64.5 (d, JCP¼163.0 Hz),
4.2.13. Diethyl-7-fluoro-3-phenyl-2-p-tolyl-1,2-dihydroisoquinolin-
110.4,113.6,122.8,123.9, 125.2, 126.1,127.2, 128.1,128.9,129.1,129.9,
131.8, 133.4, 141.9, 145.5, 159.4; IR (KBr): nmax/cmꢂ1 3022, 2980,
1608, 1510. MS (ESI) m/z 464 (MþþH); HRMS calcd for C27H30NO4P
(MþþH): 464.1991, found: 464.2001.
1-ylphosphonate (4m)
Yield: 75%. 1H NMR (400 MHz, CDCl3)
d 1.20–1.25 (m, 6H), 2.17
(s, 3H), 3.96–4.12 (m, 4H), 5.34 (d, J¼19 Hz, 1H), 6.46 (s, 1H), 6.83 (d,
J¼8.3 Hz, 1H), 6.89 (d, J¼7.8 Hz, 2H), 6.92–6.98 (m, 3H), 7.12–7.25
(m, 4H), 7.57 (d, J¼7.8 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 16.4,
1
4.2.8. Diethyl-2-(4-fluorophenyl)-3-(4-methoxyphenyl)-1,2-
16.5, 20.6, 62.7, 62.8, 64.2 (d, JCP¼164.0 Hz), 110.8, 114.3 (d,
2
dihydroisoquinolin-1-ylphosphonate (4h)
2JCF¼23.0 Hz), 115.1 (d, JCF¼22.0 Hz), 122.7, 125.5, 127.3, 127.5,
Yield: 77%. 1H NMR (400 MHz, CDCl3)
d
1.91–1.25 (m, 6H), 3.75
127.9, 128.2, 129.2, 129.4, 132.2, 137.2, 141.7, 145.3, 161.5 (d,
1JCF¼245.0 Hz); IR (KBr): nmax/cmꢂ1 3053, 2976, 1609, 1516, 1501,
1450. MS (ESI) m/z 452 (MþþH); HRMS calcd for C26H27FNO3P
(MþþH): 452.1791, found: 452.1810.
(s, 3H), 3.92–4.13 (m, 4H), 5.31 (d, J¼19 Hz, 1H), 6.39 (s, 1H), 6.76–
6.80 (m, 4H), 7.03–7.26 (m, 6H), 7.48 (d, J¼7.8 Hz, 2H); 13C NMR
(100 MHz, CDCl3)
d 16.4, 16.5, 55.1, 62.6, 62.7, 64.6 (d,
1JCP¼163.0 Hz), 110.5, 113.7, 115.2 (d, JCF¼23.0 Hz), 124.1, 124.4,
125.1, 126.3, 127.2, 128.3, 129.0, 129.5, 133.2, 141.8, 144.1, 158.5 (d,
1JCF¼241.0 Hz), 159.5; IR (KBr): nmax/cmꢂ1 3053, 2986, 1613, 1506,
1445. MS (ESI) m/z 468 (MþþH); HRMS calcd for C26H27FNO4P
(MþþH): 468.1740, found: 468.1748.
2
Acknowledgements
Financial support from National Natural Science Foundation of
China (20772018), Program for New Century Excellent Talents in
University (NCET-07-0208), and Shanghai Pujiang Program is
gratefully acknowledged.
4.2.9. Diethyl-3-cyclopropyl-2-phenyl-1,2-dihydroisoquinolin-1-
ylphosphonate (4i)
Yield: 56%. 1H NMR (400 MHz, CDCl3)
d 0.68–0.84 (m, 4H), 1.22–
References and notes
1.30 (m, 6H), 1.41–4.48 (m, 1H), 3.89–4.11 (m, 4H), 5.23 (d, J¼18 Hz,
1H), 5.83 (s, 1H), 6.97 (d, J¼7.3 Hz, 1H), 7.00–7.07 (m, 3H), 7.16 (t,
1. For selected examples, see: (a) Bentley, K. W. The Isoquinoline Alkaloids; Har-
wood Academic: Amsterdam, 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) Ramesh, P.; Reddy, N. S.; Venkateswarlu, Y. J. Nat. Prod. 1999, 62, 780; (d) Oi,
S.; Ikedou, K.; Takeuchi, K.; Ogino, M.; Banno, Y.; Tawada, H.; Yamane, T. PCT Int.
Appl. (WO 2002062764 A1) 2002, 600 pp; (e) Kaneda, T.; Takeuchi, Y.; Matsui,
H.; Shimizu, K.; Urakawa, N.; Nakajyo, S. J. Pharm. Sci. 2005, 98, 275; (f) Mikami,
Y.; Yokoyama, K.; Tabeta, H.; Nakagaki, K.; Arai, T. J. Pharm. Dyn. 1981, 4, 282; (g)
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; (h) Pettit,
G. R.; Gaddamidi, V.; Herald, D. L.; Singh, S. B.; Cragg, G. M.; Schmidt, J. M.;
Boettner, F. E.; Williams, M.; Sagawa, Y. J. Nat. Prod. 1986, 49, 995.
2. (a) Obika, S.; Kono, H.; Yasui, Y.; Yanada, R.; Takemoto, Y. J. Org. Chem. 2007, 72,
4462 and references cited therein; (b) Asao, N.; Yudha, S. S.; Nogami, T.;
Yamamoto, Y. Angew. Chem., Int. Ed. 2005, 44, 5526; (c) Yanada, R.; 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) Mori, S.; Uerdingen, M.; Krause, N.;
Morokuma, K. Angew. Chem., Int. Ed. 2005, 44, 4715; (f) Asao, N.; Chan, C. S.;
Takahashi, K.; Yamamoto, Y. Tetrahedron 2005, 61, 11322; (g) Ohtaka, M.;
Nakamura, H.; Yamamoto, Y. Tetrahedron Lett. 2004, 45, 7339; (h) Witulski, B.;
Alayrac, C.; Tevzadze-Saeftel, L. Angew. Chem., Int. Ed. 2003, 42, 4257; (i) Yavari,
I.; Ghazanfarpour-Darjani, M.; Sabbaghan, M.; Hossaini, Z. Tetrahedron Lett.
2007, 48, 3749; (j) Shaabani, A.; Soleimani, E.; Khavasi, H. R. Tetrahedron Lett.
2007, 48, 4743; (k) Wang, G.-W.; Li, J.-X. Org. Biomol. Chem. 2006, 4, 4063; (l)
Diaz, J. L.; Miguel, M.; Lavilla, R. J. Org. Chem. 2004, 69, 3550.
J¼7.3 Hz,1H),7.26–7.34(m, 4H);13CNMR(100 MHz,CDCl3)
d8.2,10.3,
14.1, 16.4, 16.5, 62.7, 62.8, 64.5 (d, 1JCP¼161.0 Hz), 104.9, 123.0, 123.2,
123.4,124.0,125.4,127.0,128.1,128.7,133.2,145.7,147.3;IR(KBr):nmax
/
cmꢂ1 3058, 2986, 1619,1593,1485. MS (ESI) m/z 384 (MþþH); HRMS
calcd for C22H26NO3P (MþþH): 384.1729, found: 384.1728.
4.2.10. Diethyl-3-cyclopropyl-2-(4-fluorophenyl)-1,2-
dihydroisoquinolin-1-ylphosphonate (4j)
Yield: 61%. 1H NMR (400 MHz, CDCl3)
d 0.66–0.70 (m, 2H), 0.77–
0.81 (m, 2H),1.22–1.26 (m, 6H),1.32–1.39 (m,1H), 3.94–4.12 (m, 4H),
5.11 (d, J¼18 Hz,1H), 5.78 (s,1H), 6.94–6.98 (m, 4H), 7.06 (t, J¼7.3 Hz,
1H), 7.17 (t, J¼7.3 Hz, 1H), 7.29–7.32 (m, 2H); 13C NMR (100 MHz,
CDCl3)
d
7.7, 10.4, 14.0, 16.4, 16.5, 62.7, 62.8, 64.8 (d, 1JCP¼162.0 Hz),
104.2, 115.3 (d, 2JCF¼22.0 Hz), 123.1, 123.6, 125.4, 125.5, 125.6, 127.0,
1
128.2, 133.2, 143.4, 145.7, 159.2 (d, JCF¼241.0 Hz); IR (KBr): nmax
/
cmꢂ1 3068, 2986,1634,1501. MS (ESI) m/z 402 (MþþH); HRMS calcd
for C22H25FNO3P (MþþH): 402.1634, found: 402.1627.
4.2.11. Diethyl-7-fluoro-2,3-diphenyl-1,2-dihydroisoquinolin-1-
ylphosphonate (4k)
Yield: 47%. 1H NMR (400 MHz, CDCl3)
d 1.23–1.26 (m, 6H),
3. (a) Huang, Q.; Larock, R. C. J. Org. Chem. 2003, 68, 980; (b) Dai, G.; Larock, R. C.
J. Org. Chem. 2003, 68, 920; (c) Dai, G.; Larock, R. C. J. Org. Chem. 2002, 67, 7042;
(d) Huang, Q.; Hunter, J. A.; Larock, R. C. J. Org. Chem. 2002, 67, 3437; (e) Roesch,
K. R.; Larock, R. C. J. Org. Chem. 2002, 67, 86; (f) Roesch, K. R.; Zhang, H.; Larock,
R. C. J. Org. Chem. 2001, 66, 8042; (g) Roesch, K. R.; Larock, R. C. Org. Lett. 1999, 1,
553.
4. (a) Ding, Q.; Wu, J. Org. Lett. 2007, 9, 4959; (b) Gao, K.; Wu, J. J. Org. Chem. 2007,
72, 8611; (c) Ding, Q.; Wu, J. Adv. Synth. Catal. 2008, 350, 1850; (d) Ding, Q.; Yu,
X.; Wu, J. Tetrahedron Lett. 2008, 49, 2752; (e) Ding, Q.; Wang, Z.; Wu, J.
Tetrahedron Lett. 2009, 50, 198.
3.97–4.10 (m, 4H), 5.90 (d, J¼19 Hz, 1H), 6.49 (s, 1H), 6.85–6.88
(m, 2H), 6.96 (t, J¼8.8 Hz, 1H), 7.05–7.12 (m, 4H), 7.15–7.26 (m,
4H), 7.57 (d, J¼7.8 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 16.4, 16.5,
1
2
62.7, 62.8, 63.9 (d, JCP¼164.0 Hz), 111.3, 114.3 (d, JCF¼23.0 Hz),
2
115.2 (d, JCF¼22.0 Hz), 122.5, 122.6, 125.6, 127.5, 127.6, 128.0,
1
128.3, 128.6, 129.4, 137.0, 141.5, 147.6, 161.5 (d, JCF¼245.0 Hz); IR
(KBr): nmax/cmꢂ1 3058, 2981, 1603, 1491, 1450. MS (ESI) m/z 438
(MþþH); HRMS calcd for C25H25FNO3P (MþþH): 438.1634, found:
438.1640.
5. (a) Ding, Q.; Ye, Y.; Fan, R.; Wu, J. J. Org. Chem. 2007, 72, 5439; (b) Sun, W.; Ding,
Q.; Sun, X.; Fan, R.; Wu, J. J. Comb. Chem. 2007, 9, 690; (c) Ye, Y.; Ding, Q.; Wu, J.
Tetrahedron 2008, 64, 1378; (d) Ding, Q.; Wang, B.; Wu, J. Tetrahedron 2007, 63,
12166.
6. (a) Westheimer, F. H. Science 1987, 235, 1173; (b) Seto, H.; Kuzuyama, T. Nat.
Prod. Rep. 1999, 16, 589.
4.2.12. Diethyl-7-fluoro-2-(4-fluorophenyl)-3-phenyl-1,2-
dihydroisoquinolin-1-ylphosphonate (4l)
7. For examples of phosphorus compounds as pharmaceuticals, see: (a) Kafarski,
P.; LeJczak, B. Curr. Med. Chem.: Anti-Cancer Agents 2001, 1, 301; (b) Colvin, O. M.
Curr. Pharm. Des. 1999, 5, 555; (c) Zon, G. Prog. Med. Chem. 1982, 19, 205; (d)
Stec, W. J. Organophosphorus Chem. 1982, 13, 145; (e) Mader, M. M.; Bartlett, P. A.
Chem. Rev. 1997, 97, 1281; (f) Kafarski, P.; Lejczak, B. Phosphorus, Sulfur Silicon
Relat. Elem. 1991, 63, 193.
Yield: 70%. 1H NMR (400 MHz, CDCl3)
d 1.21–1.26 (m, 6H), 4.00–
4.10 (m, 4H), 5.29 (d, J¼19 Hz, 1H), 6.46 (s, 1H), 6.77–6.81 (m, 2H),
6.85 (d, J¼8.8 Hz, 1H), 6.97 (t, J¼8.3 Hz,1H), 7.03–7.07 (m, 2H), 7.15–
7.26 (m, 4H), 7.55 (d, J¼6.8 Hz, 2H); 13C NMR (100 MHz, CDCl3)
1
8. Li, X. S.; Zhang, D. W.; Pang, H.; Shen, F.; Fu, H.; Jiang, Y. Y.; Zhao, Y. F. Org. Lett.
2005, 7, 4919.
d
16.4, 16.5, 62.7, 62.8, 64.3 (d, JCP¼165.0 Hz), 110.9, 114.3 (d,
2JCF¼23.0 Hz), 115.2 (d, 2JCF¼22.0 Hz), 115.3 (d, 2JCF¼22.0 Hz), 124.3,
9. For selected examples, see: (a) Denmark, S. E.; Thorarensen, A. Chem. Rev. 1996,
96, 137; (b) Porco, J. A., Jr.; Schoenen, F. J.; Stout, T. J.; Clardy, J.; Schreiber, S. L.
J. Am. Chem. Soc. 1990, 112, 7410; (c) Molander, G. A.; Harris, C. R. J. Am. Chem.
Soc. 1996, 118, 4059; (d) Chen, C.; Layton, M. E.; Sheehan, S. M.; Shair, M. D.
J. Am. Chem. Soc. 2000, 122, 7424; (e) Shi, F.; Li, X.; Xia, Y.; Zhang, L.; Yu, Z.-X.
J. Am. Chem. Soc. 2007, 129, 15503.
125.6, 127.2, 127.6, 128.1, 128.3, 129.3, 136.8, 141.5, 143.8, 158.6 (d,
1JCF¼241.0 Hz), 161.6 (d, JCF¼247.0 Hz); IR (KBr): nmax/cmꢂ1 3053,
1
2986, 1593, 1501, 1445. MS (ESI) m/z 456 (MþþH); HRMS calcd for
C25H24F2NO3P (MþþH): 456.1540, found: 456.1546.

S. Ye et al. / Tetrahedron 65 (2009) 1294–1299
1299
10. For selected examples, see: (a) Laschat, S.; Kunz, H. Synthesis 1992, 90; (b)
Yadav, J. S.; Reddy, B. V. S.; Raj, K. S.; Reddy, K. B.; Prasad, A. R. Synthesis 2001,
2277.
11. For selected examples, see: (a) Heydari, A.; Javidan, A.; Shaffie, M. Tetrahedron
Lett. 2001, 42, 8071; (b) Saidi, M. R.; Azizi, N. Synlett 2002, 1347; (c) Ranu, B. C.;
Hajra, A.; Jana, U. Org. Lett. 1999, 1, 1141; (d) Qian, C.; Huang, T. J. Org. Chem.
1998, 63, 4125; (e) Manabe, K.; Kobayashi, S. Chem. Commun. 2000, 669; (f) Lee,
S.; Park, J. H.; Kang, J.; Lee, J. K. Chem. Commun. 2001, 1698; (g) Chandrasekhar,
S.; Prakash, S. J.; Jagadeshwar, V.; Narsihmulu, C. Tetrahedron Lett. 2001, 42,
5561; (h) Yadav, J. S.; Reddy, B. V. S.; Madan, C. Synlett 2001, 1131; (i) Kaboudin,
B.; Nazari, R. Tetrahedron Lett. 2001, 42, 8211; (j) Joly, G. D.; Jacobsen, E. N. J. Am.
Chem. Soc. 2004, 126, 4102; (k) Akiyama, T.; Sanada, M.; Fuchibe, K. Synlett 2003,
1463; (l) Wu, J.; Sun, W.; Sun, X.; Xia, H.-G. Green Chem. 2006, 8, 365; (m) Wu, J.;
Sun, W.; Xia, H.-G.; Sun, X. Org. Biomol. Chem. 2006, 4, 1663.