Efficient syntheses of 1H-isochromen-1-ylmethylphosphonates via regioselective 6-endo-dig addition to carbon-carbon triple bond catalyzed by Pd(OAc)2

Article abstract of DOI:10.1080/10426507.2011.604659

An efficient, regioselective, palladium-catalyzed intramolecular cycloisomerization of dialkyl [(2-(2-ethynyl)phenyl)(2-hydroxyl)ethyl] phosphonate 6 is reported. The reactions proceed through a 6-endo-dig cyclization to afford 1H-isochromen-1-ylmethylphosphonates 7 in good to excellent yields using palladium(II) acetate as the catalyst in tetrahydrofuran at room temperature. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426507.2011.604659

Phosphorus, Sulfur, and Silicon, 186:2357–2367, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2011.604659
EFFICIENT SYNTHESES OF 1H-ISOCHROMEN-1-
YLMETHYLPHOSPHONATES VIA REGIOSELECTIVE
6-ENDO-DIG ADDITION TO CARBON—CARBON TRIPLE
BOND CATALYZED BY Pd(OAc)2
Xiaona Zhao, Zhiwei Miao, and Ruyu Chen
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of
Elemento-Organic Chemistry, Nankai University, Tianjin,
People’s Republic of China
GRAPHICAL ABSTRACT
Abstract An efficient, regioselective, palladium-catalyzed intramolecular cycloisomerization
of dialkyl [(2-(2-ethynyl)phenyl)(2-hydroxyl)ethyl]phosphonate 6 is reported. The reactions
proceed through a 6-endo-dig cyclization to afford 1H-isochromen-1-ylmethylphosphonates 7
in good to excellent yields using palladium(II) acetate as the catalyst in tetrahydrofuran at
room temperature.
[Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements for the following free supplemental
resource: General Comments. Figures S1–S33.]
Keywords 1H-isochromen-1-ylmethylphosphonates; regioselective addition; 6-endo-dig; pal-
ladium(II) acetate
Received 3 June 2011; accepted 8 July 2011.
We thank the National Natural Science Foundation of China (21072102), the Committee of Science and
Technology of Tianjin (11JCYBJC04200), and the State Key Laboratory of Elemento-Organic Chemistry in
Nankai University for financial support.
Address correspondence to Zhiwei Miao, State Key Laboratory of Elemento-Organic Chemistry, Research
Institute of Elemento-Organic Chemistry, Nankai University, Tianjin, 300071, People’s Republic of China. E-mail:
miaozhiwei@nankai.edu.cn
2357

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X. ZHAO ET AL.
INTRODUCTION
Organophosphorus compounds have been given widespread attention in recent years
due to their ubiquity in biological systems and their potential to serve as novel pharmaceuti-
cals.1 Moreover, recent studies have indicated that heterocyclic analogues containing phos-
phorus showed interesting bioactivities.2 Isochromene derivatives are important and useful
skeletons in a wide variety of biologically active natural products and complex synthetic
molecules, as well as being useful and versatile synthetic intermediates.3 The development
of a simplified and efficient reaction protocol using palladium catalysts for the synthesis
of various heterocyclic scaffolds has attracted a great deal of attention in recent years.
Methods involving the annulation of acyclic substrates with suitably placed nucleophilic
and electrophilic functions are particularly attractive because they can regioselectively pro-
vide the heterocyclic ring with the desired substitution pattern under essentially neutral
conditions.4 Li and coworkers have developed a palladium-catalyzed protocol for the syn-
thesis of 1H-isochromenes.5 Larock has disclosed the iodocyclization of readily available
2-(1-alkynyl)benzylic alcohols to iodo-substituted isochromenes under mild conditions.6
Wu has reported the tandem cyclization–addition reaction of 2-alkynylbenzaldehyde with
diethyl phosphate catalyzed by AgOTf to afford 1H-isochromen-1-ylphosphonates at room
temperature in moderate yields.7 Gabriele has already reported several approaches to the
Pd(II)-catalyzed synthesis of heterocyclic derivatives starting from acetylenic substrates, by
a simple cycloisomerization approach4 as well as by carbonylative cyclization reactions.8
For the intramolecular cycloisomerization of readily available 2-alkynylbenzyl alcohols
1, there exist two possible pathways, namely, exo-dig or endo-dig cyclization to five- or
six-membered rings according to Baldwin’s rules (Scheme 1).9 We recently reported the
efficient syntheses of phosphonylated isochromenes by regioselective 6-endo-dig addition
to a carbon–carbon triple bond catalyzed by Pd(OAc)2.10 The new methodology reported in
this work is complementary to those previously reported procedures, Pd(OAc)2 catalyzed
the regioselective synthesis of 1H-isochromen-1-ylmethylphosphonates by the intramolec-
ular hydroaryloxylation of C≡C bonds.
Scheme 1
RESULTS AND DISCUSSION
We started our investigation with diethyl 2-hydroxy-2-(2-(2-phenylethynyl)phenyl)
ethylphosphonate 6a, readily available using diethyl methylphosphonate 4 reacted with
o-alkynyl benzaldehyde 5 in the presence of n-BuLi in tetrahydrofuran (THF) at −78 ◦C.
This step generally gives yields of product above 80%.11 Treatment of 6a with palladium(II)
catalyst was selected as the prototypical case to screen the experimental conditions. The
results are summarized in Table 1.

SYNTHESES OF 1H-ISOCHROMEN-1-YLMETHYLPHOSPHONATES
2359
Table 1 Screening of the reactions of diethyl 2-hydroxy-2-(2-(2-phenylethynyl) phenyl)ethylphosphonate 6a
under different conditionsa
Entrya
Catalyst
Solvent
Yield (7a)f
1
2
3
Pd(OAc)2
CuI
Cu(OTf)2
Zn(OTf)2
Sc(OTf)3
AgOTf
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
DABCO
NaOCH3
DBU
THF
THF
THF
THF
THF
THF
THF
THF
Et2O
Toluene
CH2Cl2
CH3CN
THF
40
—
—
—
—
27
91
80
82
70
80
75
—
—
—
4
5
6b
7c
8d
9c
10c
11c
12c
13e
14e
15e
THF
THF
aUnless otherwise noted all the reactions were performed with 0.5 mmol of 6a and 10 mol% catalyst in 5 mL
solvent for 20 h at room temperature.
bReaction time is more than 72 h.
c20 mol% of Pd(OAc)2 was used.
d30 mol% of Pd(OAc)2 was used.
eThe amount of base was 1 equiv. of substrate 6a.
fIsolated yields.
We first carried out the reaction using palladium(II) acetate (10 mol%) as the catalyst
in THF at room temperature, the endo-dig cyclization product 7a was obtained in 40% as the
sole product (see Table 1, entry 1). Structural elucidation by 1H, 13C, 31P NMR, and mass
spectroscopy revealed this compound to be 1H-isochromen-1-ylmethylphosphonate 7a.
The transition-metal-catalyzed synthesis of various heterocycles via cyclization of alkynes
possessing a nucleophile in proximity to the triple bond is one of the most important
processes in organic synthesis.12 Further screening the reaction of substrates in the presence
of a variety of metal catalysts revealed that cyclizations were not observed in the presence
of other kinds of catalysts, such as CuI, Cu(OTf)2, Zn(OTf)2, and Sc(OTf)3 (see Table 1,
entries 2–5), and only starting material 6a was recovered. AgOTf can catalyze this reaction,
but the reaction time was long at 72 h (see Table 1, entry 6). Increasing the amount of
catalyst to 20 mol% gave a good result (91% yield, Table 1, entry 7). Further increasing
Pd(OAc)2 to 30 mol% resulted in the formation of 7a in 80% yield (see Table 1, entry 8).
Solvent screening showed that THF led to better results with respect to other sol-
vents tested, i.e., Et2O, toluene, CH2Cl2, and CH3CN (see Table 1, entries 9–12). Thus,

2360
X. ZHAO ET AL.
Table 2 Pd(OAc)2-catalyzed reactions of dialkyl 2-hydroxyl-2-(2-(2-phenylethynyl) phenyl)ethylphosphonate
6
Yield of 7
Entrya
Substrate 4
6
R2
R3
R4
(%)b
1
2
3
4
5
6
7
8
9
CH3(O)P(OC2H5)2
CH3(O)P(OCH3)2
C2H5(O)P(OC2H5)2
PhCH2(O)P(OC2H5)2
CH3(O)P(OC2H5)2
CH3(O)P(OCH3)2
CH3(O)P(OC2H5)2
CH3(O)P(OCH3)2
CH3(O)P(OC2H5)2
CH3(O)P(OCH3)2
CH3(O)P(OCH3)2
CH3(O)P(OC2H5)2
6a
6b
6c
6d
6e
6f
6g
6h
6i
H
H
CH3
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
7a
7b
7c
7d
7e
7f
7g
7h
7i
91
86
82
88
82
80
86
84
82
80
—
—
p-CH3C6H4
p-CH3C6H4
p-FC6H4
p-FC6H4
Ph
Ph
n-C3H7
n-C3H7
CH3
CH3
H
10
11c
12c
6j
6k
6l
H
H
H
7j
—
—
H
aUnless otherwise noted all the reactions were performed with 0.5 mmol of 5 and 20 mol% Pd(OAc)2 in 5 mL
THF at room temperature.
bIsolated yields.
cThe reaction was complicated and no desired product was isolated.
the selective synthesis of 6-endo-dig 1H-isochromen-1-ylmethyl phosphonate 7a from di-
ethyl (2-(2-ethynyl)phenyl) (2-hydroxyl)ethylphosphonate 6a was achieved through the
use of Pd(OAc)2 and THF as solvent, respectively. As it is known that the variables such
as base, metal cation, and solvent affect the selectivity.13 Several control experiments
were performed using 6a as the starting material. The nitrogen-containing basic catalysts,
such as 1,4-diazabicyclo[2.2.2]octane (DABCO), NaOCH3, and 1,8-diazabicyclo[5.4.0]-
7-undecene (DBU), proved to be ineffective under similar conditions (see Table 1, entries
13–15).
On the basis of the above optimization efforts, we next examined the scope and
limitations of the present Pd(OAc)2-catalyzed 6-endo-dig cyclization with a series of di-
alkyl 2-hydroxyl-2-(2-(2-phenylethynyl)phenyl)ethylphosphonate6. The application of this
methodology to the synthesis of a variety of 1H-isochromen-1-ylmethylphosphonates 7 is
summarized in Table 2. The reaction of o-alkynyl benzaldehyde 5 proceeded smoothly with
dialkyl methylphosphonate 4 in the presence of n-BuLi in THF at −78 ◦C and gave nearly
quantitative yields of dialkyl 2-hydroxyl-2-(2-(2-phenylethynyl) phenyl)ethylphosphonate
6. The structure of 6d was assigned on the basis of a detailed NMR analysis and firmly
established by an X-ray crystallographic study (see Figure 1).14
As can be seen, all the reactions of substrates bearing no further substituent at the
benzylic position (R3 = H) went to completion in the presence of catalytic amounts of

SYNTHESES OF 1H-ISOCHROMEN-1-YLMETHYLPHOSPHONATES
2361
Figure 1 ORTEP diagram of 6d.
Pd(OAc)2 in THF at room temperature within 24 h and the six-membered 1H-isochromen-
1-ylmethylphosphonates 7 were obtained in good to excellent yields (see Table 2, entries
1–8). When R2 was signed as methyl or phenyl group, the reactions were performed
very well, and the corresponding products were afforded in good yields (see Table 2,
entries 3 and 4). When R4 was replaced by 4-methylphenyl 6e, f or 4-fluorophenyl 6g,
h, the reaction remained acceptable and the desired products were isolated (see Table 2,
entries 5–8). The results indicated that the electron-donor group or electron-withdrawing
group attached on the aromatic ring of dialkyl 2-hydroxyl-2-(2-(2-phenylethynyl)phenyl)
ethylphosphonate 6 did not have a substantial influence on this cyclization reaction. Dialkyl
2-hydroxy-2-(2-(2-phenylethynyl) phenyl propylphosphonate 6i, j were synthesized when
o-alkynyl acetophenone 5 was employed as the starting material and reacted with dialkyl
methylphosphonate 4, the Pd(OAc)2-catalyzed 6-endo-dig cyclization proceeded smoothly
and the corresponding products were obtained (see Table 2, entries 9 and 10). When R4
was replaced by propyl group (6k, l), the reaction was complicated and no desired product
was isolated (see Table 2, entries 11 and 12).
The formation of 7a was followed by 31P NMR spectroscopy as shown in Figure 2.
The starting material diethyl 2-hydroxy-2-(2-(2-phenylethynyl)phenyl)ethyl phosphonate
6a in THF showed 31P NMR at 29.65 ppm. After Pd(OAc)2 (0.022 g, 20 mol%) was added
to the solution of 6a, one new single peak at 27.1 ppm appeared to be assigned as the
intermediate palladium ate complex 11 (see Scheme 2). Over time 31P NMR signals of the
starting material gradually disappeared and the signals of 7a (single peaks at 26.0 ppm)
increased. Pd(OAc)2 catalyzed the reaction via the formation of the intermediate 9, with an
active carbon–carbon triple bond. The reaction was almost complete after 20 h according
to the 31P NMR spectra (see Figure 2).
On the basis of all the results obtained, a plausible mechanism for Pd(OAc)2-catalyzed
cyclization reaction of 6 and 7 is outlined in Scheme 2.10 The coordination of the triple
bond of 6 to Pd(OAc)2 enhances the electrophilicity of the alkyne forming complex 9,
and the subsequent intramolecular nucleophilic attack of the oxygen atom on the electron-
deficient alkyne forms the palladious ate complex 10. Elimination of proton occurs to give

2362
X. ZHAO ET AL.
Figure 2 Time elapsed 31P NMR spectra for the synthesis of 7a (ppm).
complex 11 and AcOH, and protonolysis of 11 by AcOH gives the 6-endo-dig product 7
with regeneration of Pd(OAc)2.
CONCLUSION
In conclusion, we have described an efficient method for the efficient synthesis of 1H-
isochromen-1-ylmethylphosphonates via intramolecular 6-endo-dig cyclization of dialkyl
Scheme 2

SYNTHESES OF 1H-ISOCHROMEN-1-YLMETHYLPHOSPHONATES
2363
2-hydroxyl-2-(2-(2-phenylethynyl)phenyl)ethylphosphonate 6 catalyzed by Pd(OAc)2 in
THF at room temperature. The yields obtained were good to excellent in most cases, even
though the reaction did not take place in the presence of an alkyl substituent at the benzylic
position and the regioselectivity was always 100% favoring 6-endo-dig cyclization. Further
studies to elucidate the mechanism of this novel reaction and to extend the scope of its
synthetic utility are in progress in our laboratory.
EXPERIMENTAL
All melting points were determined on a Yanaco apparatus and were uncorrected.
NMR spectra were measured on a Varian AS 400 NMR instrument in CDCl3 and chemical
shifts were expressed as δ. Coupling constants (J) are given in Hz. Tetramethyl silane was
used as an internal standard for 1H NMR and 85% H3PO4 as an external standard for 31
P
NMR spectroscopy. Mass spectra were recorded on a Polaris-Q instrument of Thermofinni-
gan. X-ray analysis was performed on a Bruker SMART 1000 CCD diffractometer with
MoKα radiation (λ = 0.71073 Å). Column chromatograghy was performed using silica
gel H (10–40 µm, Haiyang Chemical Factory of Qingdao). High resolution mass spectra
(HRMS) were recorded on APEXII and ZAB-HS spectrometer (Varian Medical Systems,
Inc.). Selected 1H, 13C, and 31P spectra for 6 and 7a–7j can be found in the supplemental
materials (see Figures S 1–S 33).
General Procedure for the Synthesis of
Dialkyl(2-(2-Ethynyl)phenyl)(2-hydroxyl) Methylphosphonate 6
◦
To a cooled (−78 C) solution of dialkyl methylphosphonate (0.80 mmol) in THF
◦
(2.5 mL) was added n-BuLi in hexanes (0.80 mmol). After being stirred at −78 C for
15 min,◦the o-alkynyl benzaldehyde (0.80 mmol) in THF (1 mL) was added. After 60 min
at −78 C, aqueous NH4Cl was added, and the mixture was extracted with EtOAc. The
organic layer was washed with brine and dried over MgSO4. Purification by flash column
chromatography (CC) afforded 6 as a white solid.
General Procedure for the Synthesis of
1H-Isochromen-1-ylmethylphosphonates 7
Dialkyl 2-hydroxy-2-(2-(2-phenylethynyl)phenyl)ethylphosphonate (0.5 mmol) in
THF (5 mL) was stirred at room temperature for 10 min. Pd(OAc)2 (20 mol%) was added
to the mixture and the mixture was stirred for 20 h [thin layer chromatography (TLC; silica
gel) monitoring]. The resulted mixture was filtered through silica column and concentrated.
The residue was purified by flash CC [silica gel, AcOEt/petroleum ether (boiling point, bp,
60–90 ◦C) 1:3] to afford the product 7.
Diethyl (3-Phenyl-1H-isochromen-1-yl)methylphosphonate 7a
Yellow liquid; 31P NMR (121 MHz, CDCl3): δ 26.0; 1H NMR (400 MHz, CDCl3): δ
1.25 (t, JH-H = 6.9 Hz, 3H, P(OCH2CH3)2), 1.29 (t, JH-H = 6.9 Hz, 3H, P(OCH2CH3)2),
2.22–2.39 (m, 2H, H2CP(OCH2CH3)2), 4.06–4.18 (m, 4H, P(OCH2CH3)2), 5.88 (s, 1H,
HCCPh), 5.93 (m, 1H, HCCH2P), 7.06–7.71 (m, 9H, Ph); 13C NMR (100 MHz, CDCl3):
3
3
δ 14.4 (d, JC,P = 3.2 Hz, P(OCH2CH3)2), 14.5 (d, JC,P = 3.1 Hz, P(OCH2CH3)2) 31.3

2364
X. ZHAO ET AL.
(d, 1JC,P = 140.1 Hz, H2CP(OCH2CH3)2), 60.0 (d, 2JC,P = 6.3 Hz, P(OCH2CH3)2), 60.1
(d, 2JC,P = 6.6 Hz, P(OCH2CH3)2), 78.6 (d,2JC,P = 5.3 Hz, HCCH2P), 94.8 (s, HCCPh),
117.9, 119.7, 123.5, 126.0, 126.3, 126.7, 127.0, 132.3, 132.5, 134.1 (Ph), 152.6 (s, OCPh);
Ms-ESI: 359.32 ([M+H]+); HRMS calcd for C20H23O4P: 381.1218 [M+Na]+ found:
381.1226.
Dimethyl (3-Phenyl-1H-isochromen-1-yl)methylphosphonate 7b
Yellow liquid; 31P NMR (121 MHz, CDCl3): δ 28.7; 1H NMR (400 MHz, CDCl3): δ
2.28–2.47 (m, 2H, H2CP(OCH3)2), 3.79 (d, JP-H = 11.0 Hz, 3H, P(OCH3)2), 3.86 (d, JP-H
= 11.0 Hz, 3H, P(OCH3)2), 5.96 (s, 1H, HCCPh), 5.98–6.02 (m, 1H, HCCH2P), 7.15–7.78
1
(m, 9H, Ph);13C NMR (100 MHz, CDCl3): δ 32.4 (d, JP,C = 140.3 Hz, H2CP(OCH3)2),
2
2
2
52.6 (d, JP,C = 6.3 Hz, P(OCH3)2), 52.8 (d, JP,C = 6.3 Hz, P(OCH3)2), 80.4 (d, JP,C
= 5.0 Hz, HCCH2P), 96.6 (s, HCCPh), 120.0, 121.5, 125.6, 128.0, 128.3, 128.8, 129.1,
134.5, 136.0, 141.5 (Ph), 154.5 (s, OCPh); Ms-ESI: 331.19 ([M+H]+); HRMS calcd for
C18H19O4P: 353.0908 [M+Na]+, found: 353.0913.
Diethyl 1-(3-Phenyl-1H-isochromen-1-yl)ethylphosphonate 7c
Yellow liquid; 31P NMR (121 MHz, CDCl3): δ 30.1; 1H NMR (400 MHz, CDCl3): δ
0.88–0.94 (m, 3H, H3CCH), 1.38 (t, JH-H = 6.9 Hz, 3H, P(OCH2CH3)2), 1.42 (t, JH-H
=
6.9 Hz, 3H, P(OCH2CH3)2), 2.39–2.50 (m, 1H, HCP(OCH2CH3)2), 4.20–4.33 (m, 6H,
P(OCH2CH3)2), 5.92 (s, 1H, HCCPh), 6.18 (d, JH-H = 9.1 Hz, 1H, HCCHP), 7.13–7.19
3
(m, 9H, Ph); 13C NMR (100 MHz, CDCl3): δ 6.5 (s, H3CCH), 16.6 (d, JP,C = 5.9
1
2
Hz, P(OCH2CH3)2), 37.4 (d, JP,C = 142.0 Hz, HCP(OCH2CH3)2), 62.1 (d, JP,C = 7.3
2
2
Hz, P(OCH2CH3)2), 62.2 (d, JP,C = 6.92 Hz, P(OCH2CH3)2), 80.6 (d, JP,C = 5.1 Hz,
HCCHP(OCH2CH3)2), 96.4 (s, HCCPh), 119.8, 121.1, 125.4, 128.0, 128.2, 128.6, 129.0,
135.6, 136.2, 140.3 (Ph), 155.5 (s, OCPh); Ms-ESI: 373.48 ([M+H]+); HRMS calcd for
C21H25O4P: 395.1381 [M+Na]+, found: 395.1383.
Diethyl Phenyl(3-Phenyl-1H-isochromen-1-yl)methylphosphonate 7d
Yellow liquid; 31P NMR (121 MHz, CDCl3): δ 23.8; 1H NMR (400 MHz,
CDCl3): δ 0.90 (t, JH-H = 7.1 Hz, 3H, P(OCH2CH3)2), 1.38 (t, JH-H = 7.1 Hz, 3H,
P(OCH2CH3)2), 3.61–4.07 (m, 4H, P(OCH2CH3)2), 5.82 (s, 1H, HCCPh), 6.12–6.19 (m,
1H, HCP(OCH2CH3)2), 6.46 (d, JH-H = 7.6 Hz, 1H, HCCHP), 7.00–7.42 (m, 14H, Ph);
13C NMR (100 MHz, CDCl3): δ 16.1 (d, 3JP,C = 5.7 Hz, P(OCH2CH3)2), 16.3 (d, 3JP,C
=
=
1
2
6.5 Hz, P(OCH2CH3)2), 50.9 (d, JP,C = 137.9 Hz, HCP(OCH2CH3)2), 60.1 (d, JP,C
7.2 Hz, P(OCH2CH3)2), 63.1 (d, 2JP,C = 6.9 Hz, P(OCH2CH3)2), 85.1 (d, 2JP,C = 3.1 Hz,
HCCHP), 96.6 (s, HCCPh), 119.7, 122.9, 125.4, 127.9, 128.2, 128.2, 128.2, 128.6, 128.7,
130.4, 132.8, 135.1, 136.1, 140.3 (Ph), 154.5 (s, OCPh); Ms-ESI: 457.20 ([M+Na]+);
HRMS calcd for C26H27O4P: 457.1531 [M+Na]+, found: 457.1539.
Diethyl (3-p-tolyl-1H-isochromen-1-yl)methylphosphonate 7e
Yellow liquid; 31P NMR (121 MHz, CDCl3): δ 26.1; 1H NMR (400 MHz,
CDCl3): δ 1.26 (t, JH-H = 7.1 Hz, 3H, P(OCH2CH3)2), 1.30 (t, JH-H = 7.1 Hz, 3H,

SYNTHESES OF 1H-ISOCHROMEN-1-YLMETHYLPHOSPHONATES
2365
P(OCH2CH3)2), 2.27 (s, 3H, H3CPh), 2.28–2.36 (m, 2H, H2CP(OCH2CH3)2), 4.06–4.18
(m, 4H, P(OCH2CH3)2), 5.84 (s, 1H, HCCPh), 5.88–5.94 (m, 1H, HCCH2P), 7.05–7.60
3
(m, 8H, Ph); 13C NMR (100 MHz, CDCl3): δ 15.4 (d, JP,C = 5.3 Hz, P(OCH2CH3)2,),
3
15.5 (d, JP,C = 5.0 Hz, P(OCH2CH3)2), 20.2 (s, H3CPh), 32.3 (d,1JP,C = 140.0 Hz,
2
2
H2CP(OCH2CH3)2), 60.9 (d, JP,C = 6.3 Hz, P(OCH2CH3)2), 61.1 (d, JP,C = 6.5 Hz,
P(OCH2CH3)2), 79.4 (d, 2JP,C = 6.3 Hz, HCCHP), 95.7 (s, HCCPh), 118.7, 120.6, 126.9,
127.6, 127.7, 127.9, 132.1, 133.6, 134.1, 140.6 (Ph), 152.9 (s, OCPh); Ms-ESI: 373.48
([M+H]+); HRMS calcd for C21H25O4P: 395.138 [M+Na]+, found: 395.1383.
Dimethyl (3-p-tolyl-1H-isochromen-1-yl)methylphosphonate 7f
Yellow liquid; 31P NMR (121 MHz, CDCl3): δ 28.7; 1H NMR (400 MHz, CDCl3):
δ 2.26 (s, 3H, H3CPh), 2.29–2.38 (m, 2H, H2CP(OCH3)2), 3.70 (d, JP-H = 11.0 Hz, 3H,
P(OCH3)2), 3.77 (d, JP-H = 11.0 Hz, 3H, P(OCH3)2), 5.85 (s, 1H, HCCPh), 5.86–5.92 (m,
1H, HCCH2P), 7.05–7.46 (m, 8H, Ph), 13C NMR (100 MHz, CDCl3): δ 20.2 (s, H3CPh),
1
2
31.2 (d, JP,C = 140.0 Hz, H2CP(OCH3)2), 51.5 (d, JP,C = 6.1 Hz, P(OCH3)2), 51.7 (d,
2JP,C = 6.6 Hz, P(OCH3)2), 79.2 (d, JP,C = 4.8 Hz, HCCH2P), 95.9 (s, HCCPh), 118.8,
2
120.5, 126.9, 127.7, 127.8, 128.0, 132.1, 133.5, 134.2, 140.4 (Ph), 152.8 (s, OCPh); Ms-ESI:
345.20 ([M+H]+); HRMS calcd for C19H21O4P: 367.1068 [M+Na]+, found: 367.1070.
Diethyl (3-(4-Fluorophenyl)-1H-isochromen-1-yl)methyl phosphonate
7g
Yellow liquid; 31P NMR (121 MHz, CDCl3): δ 25.9; 1H NMR (400 MHz, CDCl3): δ
1.33 (t, JP-H = 13.0 Hz, 3H, P(OCH2CH3)2), 1.36 (t, JP-H = 13.0 Hz, 3H, P(OCH2CH3)2),
2.32–2.42 (m, 2H, H2CP(OCH2CH3)2), 4.13–4.23 (m, 4H, P(OCH2CH3)2), 5.90 (s, 1H,
3
HCCPh), 6.98–7.75 (m, 8H, Ph); 13C NMR (100 MHz, CDCl3): δ 16.4 (d, JP,C = 2.1
3
1
Hz, P(OCH2CH3)2), 16.5 (d, JP,C = 2.2 Hz, P(OCH2CH3)2), 33.7 (d, JP,C = 140.3
2
2
Hz, H2CP(OCH2CH3)2), 62.0 (d, JP,C = 5.8 Hz, P(OCH2CH3)2), 62.1 (d, JP,C = 6.1
2
Hz, P(OCH2CH3)2), 80.6 (d, JP,C = 4.4 Hz, HCCH2P), 95.7 (s, HCCPh), 115.1, 119.8,
121.6, 128.7, 129.0, 129.5, 132.3, 134.4, 141.7, 160.8 (Ph), 154.2 (OCPh); Ms-ESI: 399.13
([M+Na]+); HRMS calcd for C20H22FO4P: 399.1138 [M+Na]+, found: 399.1132.
Dimethyl (3-(4-Fluorophenyl)-1H-isochromen-1-yl)
methylphosphonate 7h
Yellow liquid; 31P NMR (121 MHz, CDCl3): δ 28.6; 1H NMR (400 MHz, CDCl3): δ
2.27–2.48 (m, 2H, H2CP(OCH3)2), 3.78 (d, JP-H = 11.0 Hz, 3H, P(OCH3)2), 3.84 (d, JP-H
=
11.0 Hz, 3H, P(OCH3)2), 5.91 (s, 1H, HCCPh), 5.95–6.01 (m, 1H, HCCH2P), 6.99–7.60
(m, 8H, Ph); 13C NMR (100 MHz, CDCl3): δ 32.3 (d, 1JP,C = 140.5 Hz, H2CP(OCH3)2),
52.6 (d, 2JP,C = 6.5 Hz, P(OCH3)2), 52.7 (d, 2JP,C = 6.8 Hz, P(OCH3)2), 80.3 (d, 1JP,C
=
4.8 Hz, HCCH2P), 95.9 (s, HCCPh), 151.1, 119.9, 121.5, 128.8, 129.1, 129.4, 132.2,
134.3, 141.5, 160.8 (Ph), 154.0 (s, OCPh); Ms-ESI: 371.07 ([M+Na]+); HRMS calcd for
C18H18FO4P: 371.0825 [M+Na]+, found: 371.0819.

2366
X. ZHAO ET AL.
Diethyl (1-Methyl-3-phenyl-1H-isochromen-1-yl)methylphosphonate 7i
Yellow liquid; 31P NMR (121 MHz, CDCl3): δ 24.6; 1H NMR (400 MHz, CDCl3): δ
1.12 (t, JH-H = 7.1 Hz, 3H, P(OCH2CH3)2), 1.21 (t, JH-H = 7.1 Hz, 3H, P(OCH2CH3)2),
1.84 (s, 3H, H3CCCH2P), 2.43–2.58 (m, 2H, CH2P(OCH2CH3)2), 3.88–4.07 (m, 4H,
P(OCH2CH3)2), 5.92 (s, 1H, HCCPh), 7.17–7.76 (m, 9H, Ph); 13C NMR (100 MHz,
CDCl3): δ 16.0 (d, 3JP,C = 5.3 Hz, P(OCH2CH3)2), 16.2 (d, 3JP,C = 5.3 Hz, P(OCH2CH3)2),
1
28.4 (d,3JP,C = 3.5 Hz, H3CCCH2P), 37.7 (d, JP,C = 143.0 Hz, H2CP(OCH2CH3)2),
61.5 (d,2JP,C = 6.2 Hz, P(OCH2CH3)2), 61.7 (d,2JP,C = 5.9 Hz, P(OCH2CH3)2), 87.9 (d,
2JP,C = 6.9 Hz, CCH2P), 96.5 (s, HCCPh), 119.8, 121.4, 125.3, 128.0, 128.2, 128.5, 128.8,
134.0, 136.3, 145.7 (Ph), 153.8 (s, OCPh); Ms-ESI: 373.35([M+H]+); HRMS calcd for
C21H25O4P: 395.1387 [M+Na]+, found: 395.1383.
Dimethyl (1-Methyl-3-phenyl-1H-isochromen-1-yl)methyl phosphonate
7j
Yellow liquid; 31P NMR (121 MHz, CDCl3): δ 27.2; 1H NMR (400 MHz, CDCl3):
1.74 (s, 3H, H3CCCH2P), 2.35–2.48 (m, 2H, H2CP(OCH3)2), 3.46 (d, JP-H = 11.0 Hz,
P(OCH3)2), 3.6 (d, JP-H = 11.0 Hz, P(OCH3)2), 5.87 (s, 1H, HCCPh), 7.05–7.71 (m, 9H,
Ph); 13C NMR (100 MHz, CDCl3): 27.1 (d,3JP,C = 7.0, H3CCCH2P), 35.7 (d, 1JP,C = 139.8
Hz, H2CP(OCH3)2), 51.2 (d,2JP,C = 6.5 Hz, P(OCH3)2), 51.4 (d, 2JP,C = 6.5 Hz, P(OCH3)2),
86.7 (d,2JP,C = 4.7 Hz, CCH2P), 95.7 (s, HCCPh), 118.9, 120.2, 124.4, 127.0, 127.2, 127.6,
127.9, 132.9, 135.2, 144.6 (Ph), 152.7 (s, HCCPh); Ms-ESI: 345.41 ([M+H]+); HRMS
calcd for C19H21O4P: 367.1064 [M+Na]+, found:367.1070.
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