Synthesis of 1H-isochromen-1-ylphosphonates via AgOTf-catalyzed reaction of 2-alkynylbenzaldehyde with diethyl phosphite

Article abstract of DOI:10.1016/j.tetlet.2008.05.009

Tandem cyclization-addition reaction of 2-alkynylbenzaldehyde with diethyl phosphite catalyzed by AgOTf at room temperature was developed, which afforded the desired 1H-isochromen-1-ylphosphonates in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2008.05.009

Tetrahedron Letters 49 (2008) 4390–4393
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Tetrahedron Letters
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Synthesis of 1H-isochromen-1-ylphosphonates via AgOTf-catalyzed reaction
of 2-alkynylbenzaldehyde with diethyl phosphite
Xingxin Yu a, Qiuping Ding a, Weizi Wang 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:
Tandem cyclization–addition reaction of 2-alkynylbenzaldehyde with diethyl phosphite catalyzed by
AgOTf at room temperature was developed, which afforded the desired 1H-isochromen-1-ylphospho-
nates in moderate to good yields.
Received 18 January 2008
Revised 29 April 2008
Accepted 5 May 2008
Available online 9 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
2-Alkynylbenzaldehyde
Diethyl phosphate
1H-Isochromen-1-ylphosphonate
Silver triflate
Due to their ubiquity in biological systems1 and their potential
to serve as pharmaceuticals,2 considerable attention has been paid
to organophosphorus compounds. Moreover, recent studies have
indicated that many heterocycle analogues containing phosphorus
showed interesting bioactivities. For instance, phosphacoumarins
showed good inhibitory activity against SHP-1.3 Meanwhile, as a
privileged fragment, 1H-isochromene is a ubiquitous subunit in
many natural products with remarkable biological activity.4
Because of the importance of organophosphorus compound and
1H-isochromene, our continuous interest in natural product-like
compounds5 led us to devote our efforts for the development of
efficient methods for the synthesis of phosphorus-contained 1H-
isochromene molecules, with a hope of finding more active hits
or leads for our particular biological assays.6 Herein, we would like
to disclose our preliminary results for the synthesis of 1H-isochro-
men-1-ylphosphonates via AgOTf-catalyzed reaction of 2-alkynyl-
benzaldehyde with diethyl phosphite.
Significant research has been reported utilizing cyclization and
cycloisomerization of o-alkynylbenzaldehydes and related sub-
strates.7–11 For instance, Yamamoto and others have reported
numerous approaches starting from 2-alkynylbenzaldehyde to af-
ford putative metal-‘ate’ dipolar intermediates that may be reacted
further to afford a variety of structures.7 We also found that o-alky-
nylbenzaldehyde could be utilized in multi-component reactions
for the construction of 1,2-dihydroisoquinoline scaffold.5a,e
Prompted by these results, we envisioned that the scaffold of
1H-isochromen-1-ylphosphonate 3 might be generated via tandem
cyclization–addition reaction of 2-alkynylbenzaldehyde 1 with
diethyl phosphite 2 under suitable conditions in the presence of
metal catalysis (Scheme 1). Retro-synthetically, the cyclization
involving metal catalysis is believed to proceed via the formation
of the metal-complex, which renders the electrophilicity of the al-
kyne moiety. This triggers intermolecular attack of the nucleophile,
which gives rise to the cyclic vinyl metal species that upon proton-
olysis will yield the desired 1H-isochromen-1-ylphosphonate 3 and
the metal-cation, which can then enter again the catalytic cycle.
To verify the practicability of the projected route as shown in
Scheme 1, the reaction was initially studied with 2-alkynylbenzal-
dehyde 1a, which was selected as suitable substrate for reaction
development (Table 1). This compound could be easily accessed
via palladium-catalyzed Sonogashira coupling reactions of 2-bro-
mobenzaldehyde with phenylacetylene.10e At the outset, various
Lewis acids were screened and the results are shown in Table 1.
No reaction occurred when copper(I) iodide was employed as
OH
OR3
OR3
O
P
OR3
OR3
O
OR3
OR3
O
P
P
H
2
O
R1
R1
R2
R2
O
R1
A
3
M
R2
1
M
* Corresponding author. Tel.: +86 21 5566 4619; fax: +86 21 6510 2412.
E-mail address: jie_wu@fudan.edu.cn (J. Wu).
Scheme 1.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.009

X. Yu et al. / Tetrahedron Letters 49 (2008) 4390–4393
4391
Table 1
catalyst for the reaction of 2-alkynylbenzaldehyde 1a with diethyl
phosphite at room temperature in 1,2-dichloroethane (Table 1, en-
try 1). To our delight, we observed the formation of desired 1H-iso-
chromen-1-ylphosphonate 3a when the catalyst was replaced by
copper(II) triflate, albeit in low yield (29%, Table 1, entry 2). Further
investigation revealed that this result could be dramatically im-
proved when silver triflate was utilized in the reaction, and the
corresponding product was afforded in 82% yield (Table 1, entry
3). It is well-known that silver(I) salts have mild Lewis acidity
and have been used as catalysts in organic synthesis. Among these
salts, AgOTf is one of the most popular reagents for inducing trans-
formations, which take advantage of its affinity for halogen and
sulfur functional groups, and carbon–carbon unsaturated bonds
rather than oxygen functional groups.11 Following an extensive
investigation, we observed that the yields were inferior when other
Lewis acids [PdCl2, Yb(OTf)3, Zn(OTf)2, In(OTf)3, Dy(OTf)3, FeCl3]
were employed in the reaction (Table 1, entries 4–9). These results
indicated that AgOTf was the most efficient catalyst for this kind of
transformation. Solvent screening demonstrated that 1,2-dichloro-
ethane was the solvent of choice. Other solvents such as THF, tol-
uene, MeCN gave unsatisfactory results (Table 1, entries 10–15).
Similar yield was observed when the catalytic amount of AgOTf
was reduced to 5 mol % (Table 1, entry 16). However, prolonged
reaction time was necessary for completion of the reaction.
Screening conditions for reaction of alkynylbenzaldehyde 1a with diethyl phosphite 2
O
O
OEt
OEt
O
Lewis acid
P
O
P
H
OEt (10 mol %)
+
solvent, r.t.
OEt
H
Ph
Ph
1a
3a
2
Entry
Lewis acid
CuI (10 mol %)
Solvent
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
THF
Toluene
DMF
DMSO
MeCN
Acetone
(CH2Cl)2
—
Cu(OTf)2 (10 mol %)
AgOTf (10 mol %)
PdCl2 (10 mol %)
Zn(OTf)2 (10 mol %)
Yb(OTf)3 (10 mol %)
Dy(OTf)3 (10 mol %)
FeCl3 (10 mol %)
In(OTf)3 (10 mol %)
AgOTf (10 mol %)
AgOTf (10 mol %)
AgOTf (10 mol %)
AgOTf (10 mol %)
AgOTf (10 mol %)
AgOTf (10 mol %)
AgOTf (5 mol %)
29
82
20
—
—
—
—
—
66
79
—
—
—
14
80
a
Isolated yield based on 2-alkynylbenzaldehydes 1a.
Table 2
AgOTf-catalyzed tandem addition–cyclization reaction of alkynylbenzaldehydes 1 with diethyl phosphite 212,a
O
O
OEt
OEt
O
P
O
AgOTf (10 mol %)
(CH2Cl)2, r.t.
H
OEt
OEt
R1
+
P
R1
H
R2
R2
1
3
2
2-Alkynylbenzaldehyde
Product
Yieldb (%)
82 (12 h)
O
O
O
OEt
OEt
O
P
P
H
1a
3a
Ph
Ph
O
H
OEt
OEt
O
1b
C6H4p-OMe
3b
75 (12 h)
44 (12 h)
45 (5 h)
C6H4
p
-OMe
O
O
OEt
OEt
O
P
P
F
H
1c
F
F
3c
Ph
Ph
O
O
OEt
OEt
O
F
H
1d
-OMe
3d
C6H4p-OMe
C6H4
p
O
OEt
OEt
O
P
MeO
MeO
MeO
MeO
H
O
1e
3e
88 (4 h)
Ph
OMe
Ph
OMe
(continued on next page)

4392
X. Yu et al. / Tetrahedron Letters 49 (2008) 4390–4393
Table 2 (continued)
2-Alkynylbenzaldehyde
Product
Yieldb (%)
74 (7 h)
O
O
OEt
OEt
O
P
MeO
H
MeO
MeO
1f
C6H4p-OMe
3f
MeO
C6H4p-OMe
OMe
OMe
O
O
OEt
P
O
O
OEt
O
H
1g
Ph
3g
87 (7 h)
O
O
Ph
O
O
O
OEt
OEt
O
P
P
H
H
c
1h
3h
-F
—
—
(12 h)
(12 h)
C6H4
p
C6H4p-F
O
O
OEt
OEt
O
c
1i
3i
Bu
Bu
O
OEt
OEt
O
P
H
c
1j
3j
—
(12 h)
a
b
c
Reaction conditions: alkynylbenzaldehydes 1 (0.20 mmol), diethyl phosphite 2 (0.24 mmol), AgOTf (10 mol %), DCE (2.0 mL), rt.
Isolated yield based on 2-alkynylbenzaldehydes 1.
The reaction was complicated and no desired product was isolated.
To test the effectiveness of the silver(I) triflate catalytic system,
O
O
OEt
OEt
O
HPO(OEt)2
AgOTf (10 mol %)
2
O
P
a range of o-alkynylbenzaldehydes 1 were examined using the pre-
liminary optimized reaction conditions (1,2-dichloroethane as the
solvent, 10 mol % of AgOTf, room temperature, overnight), and the
results are summarized in Table 2. Complete conversion and mod-
erate to good isolated yields were observed for most cases utilized.
For instance, 75% yield of 1H-isochromen-1-ylphosphonate 3b was
obtained for the reaction of 2-alkynylbenzaldehyde 1b with diethyl
phosphite. Inferior results were displayed when substrates with
electron-withdrawing groups attached on the aromatic ring of
2-alkynylbenzaldehyde were employed. The results indicated that
the electron-withdrawing group attached on the aromatic ring of
2-alkynylbenzaldehyde might presumably decrease the nucleophi-
licity of oxygen in carbonyl group, since intermediate A would be
formed during the reaction process. For example, 44% or 45% yield
of product 3c or 3d was generated, respectively when fluoro-
substituted 2-alkynylbenzaldehydes 1c and 1d were employed in
the reaction. 2-Alkynylbenzaldehyde 1e reacted with diethyl phos-
phite leading to the corresponding product 3e in 88% yield. A sim-
ilar yield (87%) was observed when substrate 1g was utilized in the
reaction. In this kind of transformation, the R2 group attached on
the triple bond is crucial. When R2 was replaced by 4-fluorophenyl
(1h), butyl (1i), or cyclopropyl group (1j), the reaction was compli-
cated and no desired product was isolated. Although the mecha-
nism for this messy outcome is not clear, we reasoned that it
might be due to the instability of the corresponding product since
compounds 3a–g were also unstable and easy to be deteriorated at
room temperature. Interestingly, reaction of substrate 1k under
H
O
OH
OH
(CH2Cl)2, r.t.
12 h, 71% yield
1k
4
3k (not observed)
Scheme 2.
silver-catalyzed conditions proceeded well to afford acetal product
4 in 71% yield and the desired product 3k was not detected at all
(Scheme 2). In this transformation, diethyl phosphite did not
involve and only intramolecular addition occurred.
In summary, we have described AgOTf-catalyzed tandem addi-
tion–cyclization reaction of 2-alkynylbenzaldehyde with diethyl
phosphite, which provide a facile and efficient protocol to facilitate
the concise synthesis of 1H-isochromen-1-ylphosphonate deriva-
tives. We also observed the intramolecular addition of substrate
1k to generate acetal compound 4. Introducing enantioselectivity
in the scaffold and screening for biological activity of these small
molecules are under investigation in our laboratory, and the results
will be reported in due course.
Acknowledgments
We thank Dr. Renhua Fan for his invaluable advice during the
course of this research. Financial support from National Natural
Science Foundation of China (20772018), Shanghai Pujiang

X. Yu et al. / Tetrahedron Letters 49 (2008) 4390–4393
4393
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.
Program, and Program for New Century Excellent Talents in
University (NCET-07-0208) is gratefully acknowledged.
12. General procedure for AgOTf-catalyzed tandem addition–cyclization reaction of
alkynylbenzaldehydes
1with
diethyl
phosphite
2:
A
mixture
of
References and notes
alkynylbenzaldehydes 1 (0.20 mmol), diethyl phosphite 2 (0.24 mmol), and
AgOTf (0.02 mmol, 10 mol %) in 1,2-dichloroethane (2.0 mL) was stirred at
room temperature under nitrogen atmosphere overnight. After completion of
the reaction as indicated by TLC, the reaction mixture was quenched with
water (10 mL) and extracted with EtOAc (2 Â 10 mL). The extracts were
evaporated in vacuo, followed by purification on silica gel affording the
product 1H-isochromen-1-ylphosphonates 3. Compound 3a: 1H NMR
(400 MHz, CDCl3): 1.12 (t, J = 6.8 Hz, 3H), 1.27 (t, J = 6.8 Hz, 3H), 3.82–3.96
(m, 2H), 4.05–4.12 (m, 2H), 5.75 (d, J = 12.2 Hz, 1H), 6.32 (s, 1H), 7.05 (d,
J = 7.3 Hz, 1H), 7.16 (t, J = 6.8 Hz, 1H), 7.22 (d, J = 8.3 Hz, 2H), 7.30–7.38 (m, 3H),
7.73 (d, J = 7.3 Hz, 2H), 13C NMR (100 MHz, CDCl3) d 16.2, 16.3, 62.6, 63.2, 63.3,
74.4 (d, JCP = 159.2 Hz), 100.4, 123.9, 124.1, 125.1, 125.7, 125.8, 126.7, 128.1,
128.8, 130.9, 131.0, 133.7, 151.7; 31P NMR (161 MHz, CDCl3) d 17.93. MS (ESI):
m/z 343 (M+ÀH); HRMS calcd for C19H21O4P (M+ÀH): 343.1099, found:
343.1117. Compound 3b: 1H NMR (400 MHz, CDCl3): 1.14 (t, J = 7.1 Hz,
3H),1.29 (t, J = 6.8 Hz, 3H), 3.82 (s, 3H), 4.09–4.11 (m, 4H), 5.73 (d,
J = 12.2 Hz, 1H), 6.21 (s, 1H), 6.91 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 7.3 Hz, 1H),
7.15 (d, J = 6.4 Hz, 1H), 7.20–7.24 (m, 2H), 7.68 (d, J = 9.3 Hz, 2H); 13C NMR
(100 MHz, CDCl3) d 16.3, 16.4, 55.2, 62.5 63.2, 74.6 (d, JCP = 158.3 Hz), 99.0,
113.6, 123.8, 123.9, 125.7, 125.8, 126.4, 126.5, 126.7, 128.8, 131.4, 151.8,
160.3; 31P NMR (161 MHz, CDCl3) d 18.10. MS (ESI): m/z 375 (M++H); HRMS
calcd for C20H23O5P (M++H): 375.1361, found: 375.1378. Compound 3c: 1H
NMR (400 MHz, CDCl3): 1.19 (t, J = 7.4 Hz, 3H), 1.31 (t, J = 6.8 Hz, 3H), 3.95–
4.03 (m, 2H), 4.09–4.15 (m, 2H), 5.70 (d, J = 13.2 Hz, 1H), 6.30 (s, 1H), 6.95–7.05
(m, 3H), 7.34–7.40 (m, 3H), 7.72 (d, J = 6.8 Hz, 2H), 13C NMR (100 MHz, CDCl3) d
16.3, 16.4, 62.8, 63.3, 74.2 (d, JCP = 161.1 Hz), 99.7, 113.3 (d, J = 20.4 Hz), 115.6
(d, J = 20.7 Hz), 125.1, 125.5 (d, J = 7.6 Hz), 126.3 (d, J = 7.6 Hz), 127.3, 128.3,
128.9, 133.6, 151.3, 161.5 (d, J = 246.0 Hz); 31P NMR (161 MHz, CDCl3) d 17.25.
MS (ESI): m/z 363 (M++H); HRMS calcd for C19H20FO4P (M++H): 363.1161,
found: 363.1179. Compound 3d: 1H NMR (400 MHz, CDCl3): 1.18 (t, J = 6.6 Hz,
3H), 1.30 (t, J = 6.6 Hz, 3H), 3.83 (s, 3H), 3.92–4.15 (m, 4H), 5.68 (d, J = 13.2 Hz,
1H), 6.19 (s, 1H), 6.90 (d, J = 7.2 Hz, 2H), 6.92–7.00 (m, 3H), 7.66 (d, J = 8.8 Hz,
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2H); 13C NMR (100 MHz, CDCl3)
d 16.4, 16.5, 55.3, 62.8, 63.3, 74.3 (d,
JCP = 159.2 Hz), 98.2, 113.2 (d, J = 22.9 Hz), 113.7, 115.6 (d, J = 21.9 Hz), 125.1,
126.0 (d, J = 7.8 Hz), 126.3, 126.7, 127.7, 151.3, 160.3, 161.3 (d, J = 246.9 Hz);
31P NMR (161 MHz, CDCl3) d 17.47. MS (ESI): m/z 393 (M++H); HRMS calcd for
C
20H22FO5P (M++H): 393.1267, found: 393.1291. Compound 3e: 1H NMR
(400 MHz, CDCl3): 1.14 (t, J = 6.8 Hz, 3H), 1.35 (t, J = 6.8 Hz, 3H), 3.87 (s, 3H),
3.89 (s, 3H), 3.92 (s, 3H), 3.92–4.17 (m, 4H), 5.67 (d, J = 11.7 Hz, 1H), 6.55 (s,
1H), 6.66 (s, 1H), 7.31–7.38 (m, 3H), 7.74 (d, J = 7.3 Hz, 2H), 13C NMR (100 MHz,
CDCl3) d 16.2, 16.3, 29.5, 30.1, 56.0, 60.8, 61.2, 61.6, 62.5, 63.2, 74.1 (d,
JCP = 158.3 Hz), 94.9, 105.6, 118.0, 119.7, 124.9, 128.1, 128.4, 134.0, 142.2,
147.9, 150.0, 152.3; 31P NMR (161 MHz, CDCl3) d 19.10. MS (ESI): m/z 457
(M++Na); HRMS calcd for C22H27O7P (M++Na): 457.1392, found: 375.1410.
Compound 3f: 1H NMR (400 MHz, CDCl3): 1.15 (t, J = 7.2 Hz, 3H),1.33 (t,
J = 7.2 Hz, 3H), 3.84 (s, 3H), 3.87 (s, 3H), 3.87 (s, 3H), 3.91 (s, 3H), 3.92–4.15 (m,
4H), 5.65 (d,J = 11.6 Hz, 1H), 6.42 (s, 1H), 6.65 (d, J = 1.6 Hz,1H), 6.90 (d,
J = 8.8 Hz, 2H), 7.69 (d, J = 8.8 Hz, 2H), 13C NMR (100 MHz, CDCl3) d 16.4, 16.5,
55.2, 56.1, 60.9, 61.3, 62.6, 63.3, 73.3, 74.2 (d, JCP = 158.3 Hz), 105.7,
113.6,118.4, 119.5, 126.5, 126.8, 142.2, 147.8, 150.1, 152.0, 160.0;31P NMR
(161 MHz, CDCl3) d 18.14.MS (ESI): m/z 465 (M++H); HRMS calcd for C23H29O8P
(M++H): 465.1678, found: 465.1679. Compound 3g: 1H NMR (400 MHz, CDCl3):
1.18 (t, J = 7.2 Hz, 3H),1.31 (t, J = 7.2 Hz, 3H), 3.99–4.13 (m, 4H), 5.64
(d,J = 11.2 Hz, 1H), 5.94 (dd, J = 5.9 Hz, J = 1.5 Hz, 2H), 6.23 (s, 1H), 6.58 (s,
1H), 6.77 (s, 1H), 7.32– 7.37 (m, 3H), 7.71 (d, J = 6.8 Hz, 2H), 13C NMR (100 MHz,
CDCl3) d 16.3, 16.4, 29.6, 30.2, 61.7, 62.6, 63.3, 74.5 (d, JCP = 159.2 Hz), 100.7,
101.1, 104.9, 106.9, 117.4, 125.0, 125.6, 128.3, 128.7, 133.7, 146.4, 148.0, 150.5;
31P NMR (161 MHz, CDCl3) d 18.44. MS (ESI): m/z 411 (M++Na); HRMS calcd for
10. (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.
11. (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,
C
20H21O6P (M++Na): 411.0973, found: 411.0991. Compound 4: 1H NMR
(400 MHz, CDCl3) d 2.51–2.53 (m, 2H), 3.73–3.76 (m, 1H), 4.60–4.62 (m, 1H),
5.77 (s, 1H), 6.00 (s, 1H), 6.97 (d, J = 7.3 Hz, 1H), 7.17–7.26 (m, 3H); 13C NMR
(100 MHz, CDCl3) d 34.4, 63.5, 97.5, 102.9, 123.5, 125.7, 125.9, 126.6, 129.1,
130.4, 150.4. MS (ESI): m/z 175 (M++H); HRMS calcd for C11H10O2 (M++H):
175.0759, found: 175.0757.