Convenient synthesis of α-diarylmethylphosphonates by HOTf catalyzed Friedel-Crafts arylation of α-aryl α-hydroxyphosphonates

Article abstract of DOI:10.1080/10426507.2017.1393424

We report a convenient catalytic Friedel-Crafts arylation of α-aryl α-hydroxyphosphonateswith various (hetero) aromatic compounds. HOTf (trifluoromethanesulfonic acid) is identified to be the best Br?nsted acid catalyst, and the desired α-diarylmethylphosphonates were obtained in up to 41–95% yield.

Full text of DOI:10.1080/10426507.2017.1393424

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Convenient Synthesis of α-
Diarylmethylphosphonates by HOTf
Catalyzed Friedel-Crafts Arylation of α-Aryl α-
hydroxyphosphonates
Long Chen, Yun-Xiang Zou, Xin-Yue Fang & Xu Yin
To cite this article: Long Chen, Yun-Xiang Zou, Xin-Yue Fang & Xu Yin (2017): Convenient
Synthesis of α-Diarylmethylphosphonates by HOTf Catalyzed Friedel-Crafts Arylation of α-
Aryl α-hydroxyphosphonates, Phosphorus, Sulfur, and Silicon and the Related Elements, DOI:
10.1080/10426507.2017.1393424
To link to this article: http://dx.doi.org/10.1080/10426507.2017.1393424
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Convenient Synthesis of -Diarylmethylphosphonates by HOTf Catalyzed Friedel-Crafts
Arylation of -Aryl -hydroxyphosphonates
Long Chena,*, Yun-Xiang Zoua, Xin-Yue Fanga and Xu Yina
a Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Sichuan
Industrial Institute of Antibiotics, Chengdu University, 168 Hua Guan Road, Chengdu 610052, P.
R. China
E-mail: harpshell@163.com
Convenient Synthesis of -Diarylmethylphosphonates by HOTf Catalyzed Friedel-Crafts
Arylation of -Aryl -hydroxyphosphonates
We report a convenient catalytic Friedel-Crafts arylation of -aryl -
hydroxyphosphonates with various (hetero)aromatic compounds. HOTf
(trifluoromethanesulfonic acid) is identified to be the best Brønsted acid catalyst,
and the desired -diarylmethylphosphonates were obtained in up to 41-95% yield.
Keywords: alcohols; Friedel-Crafts arylation; -Diarylmethylphosphonates;
homogeneous catalysis; -hydroxyphosphonates
Introduction
Organophosphonates and their derivatives are one of the most important families of heteroatom-
containing compounds, which not only have wide applications in the area of agricultural,1
pharmaceutical2 and material chemistry,3 but also have been regarded as ligands4 and reagents5 in
organic synthesis. Among them, -diarylmethylphosphonates often show particularly interesting
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properties in the field of drug chemistry6 and chemiluminescence materials (Figure 1).7 Besides,
they are essential precursors for introducing diarylethene moiety through the Horner-Wadsworth-
Emmons (HWE) reaction.
Figure 1. Important interesting molecules obtained from -diarylmethylphosphonates
Despite the ubiquitous application of -diarylmethylphosphonates, synthetic methods for
their preparation are limited. Classical methods involve Michaelis-Arbuzov or Michaelis-Becker
reactions,8 which often suffer from harsh reaction conditions and the unavailability of the starting
materials. As an alternative, the Walsh group developed an attractive method for accessing these
compounds via Pd-catalyzed -arylation of benzylic phosphonates.9 And recently, Anand and
co-workers10a reported a NHC catalyzed 1,6-hydrophosphonylation of p-quinone methides for
their synthesis.10 In spite of these achievements, it is necessary to develop other alternative and
cost-effective process to construct these compounds.
The Friedel-Crafts reaction11 of -aryl -hydroxyphosphonates and aromatic compounds,
possibly via a carbocationic intermediate (Scheme 1),12 would be an atom-economical
procedure13 for the synthesis of -diarylmethylphosphonates, as it only produces water as by-
product. The major advantages of this reaction include the easily available -aryl -
hydroxyphosphonates 114 and the rich diversity of product 3 by using various aromatic
compounds and varying the Ar1 and R group of 1. The Chakravarty group reported this reaction
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by using 1.0 equivalent of FeCl3 as an acid promoter.15 However, the substrate scope with respect
to both -aryl -hydroxyphosphonates and aromatic compounds was very limited. And to date,
no catalytic version of this reaction has been reported. To develop a catalytic version, the main
challenge consists in the difficulty in the formation of carbocationic intermediate I (Scheme 1)
for the Friedel-Crafts reaction step, which resulted from the net destabilizing effect of the strong
electron-withdrawing phosphoryl group of 1. Despite several achievements in the catalytic
Friedel-Crafts arylation of alcohols with an α-electron-withdrawing substitutent16 have been
made, all of them needed to use special alcohols that could generate reactive oxonium16e or
vinylogous iminium intermediate.17 Even so, Zhou and co-workers recently developed a highly
efficient catalytic Friedel-Crafts arylation of α-hydroxyesters or α-hydroxyketones that could not
form oxonium or vinylogous iminium intermediate.18a Inspired by this positive result, we
envisaged this reaction might be achieved by using suitable Lewis or Brønsted acids as catalyst
and adjusting reaction parameters such as solvent and reaction temperature. Herein, we are
pleased to find this arylation could proceed smoothly by using HOTf as Brønsted acid catalyst
and CH3NO2 as solvent, affording -diarylmethylphosphonates in good yields and
regioselectivities.
Scheme 1. Friedel-Crafts arylation of -aryl -hydroxyphosphonates
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Results and Discussion
To circumvent the destabilizing effect of phosphoryl group, we assumed introducing
para-methoxyphenyl, a carbocation stabilizing group, at the adjacent position of the
generated carbocation I. Therefore, the reaction of -hydroxyphosphonate 1a and 1,3-
dimethoxybenzene 2a was selected as the model reaction for condition optimization, and
typical results were presented in Table 1.
Inspired by the work of Chakravarty, we first examined FeCl3 as Lewis acid catalyst,
and found that the desired product 3a could be obtained only in 45% yield after 72 h when
20 mol% of FeCl3 was used (Table 1, entry 1). Then, the inexpensive and easily to handle
metal perchlorate hydrates,19 known as powerful Lewis acids were screened. FeIII-, CuII- and
AgI-derived perchlorate hydrates all could catalyze the reaction smoothly, and giving
product 3a in moderate yields (Table 1, entries 2-4). And we found that metal triflates20
could also mediate the reaction. For example, under the catalysis of Fe(OTf)3 and AgOTf,
product 3a was obtained in 75% and 24% yield, respectively (entries 5-6). Finally, different
Brønsted acids21 were investigated, and only HClO418 and HOTf could catalyze the Friedel-
Crafts reaction well, furnishing the corresponding product 3a in 75% and 82% yields,
respectively (entries 7-8).
Table 1. Condition optimization
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Cat.
Solvent
Time (h) Yield (%)b
Entrya
1
FeCl3
ClCH2CH2Cl
72
24
72
7
45
70
69
78
75
24
75
82
29
53
50
95
99
95
88
57
Fe(ClO4)3·6H2O ClCH2CH2Cl
Cu(ClO4)2·6H2O ClCH2CH2Cl
2
3
AgClO4·H2O
Fe(OTf)3
AgOTf
HClO4
HOTf
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
THF
4
24
96
10
3
5
6
7
8
HOTf
24
16
24
2.5
0.5
1.0
10
24
9
HOTf
Ethyl acetate
Acetone
10
11
12
13
14c
15c,d
16c,e
HOTf
HOTf
CH3CN
HOTf
CH3NO2
HOTf
HOTf
CH3NO2
CH3NO2
HOTf
CH3NO2
a On a 0.20 mmol scale. b Isolated yield. c 0.20 mmol of 1a and 0.40 mmol of 2a. d 10 mol%
of HOTf. e 40 oC.
Next, solvent effects were evaluated in the presence of 20 mol% HOTf. We found that the
solvent had a great effect on reaction outcome. For instance, the use of tetrahydrofuran (THF) as
solvent led to deep decrease in reaction yield (entry 9), and only moderate yields were obtained
in ethyl acetate and acetone. To our delight, excellent yields could be achieved when CH3CN and
CH3NO2 were used (entries 12-13). And CH3NO2 was found to be the best solvent in terms of
reaction yield and time, which gave 3a in 99% yield within 0.5 h (entry 13). It should be noted
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that 3a could still be achieved in 95% yield even if reducing the amount of 2a to from 3.0 to 2.0
equivalents (entry 14).
Finally, we attempted to decrease the catalyst loading to 10 mol%, and found lower
yields (88%) along with longer period (10 h) was observed (entry 15). In addition, only 57%
o
yield was obtained when reducing the reaction temperature to 40 C, as the reaction could
not proceed completely even if extending the reaction time to 24 h (entry 16). The
evaluation of substrate scope was then carried out in CH3NO2 at 60 °C, using 20 mol % of
HOTf as the catalyst.
Firstly, we examined a variety of (hetero)aromatic compounds (Scheme 2), and found
activated arenes such as 1,3-dimethoxybenzene, anisole, methyl(phenyl)sulfane and 1,4-
dimethoxybenzene all could work well to afford the corresponding products 3a-3d in good
to high yields. It was worth mentioning that excellent regioselectivities were achieved for
3b-3c, as only one isomer was observed from the crude 1H and 31P NMR spectrum of 3b-3c.
Mesitylene, 1,3,5-trimethoxybenzene, 4-(tert-butyl)phenol and 2,6-dimethylphenol were
also effective, and the desired products 3e-3h could be obtained in moderate to good yields.
Noticeably, unactivated arenes such as toluene, tert-butylbenzene, naphthalene and 1-
methylnaphthalene could be also compatible,22 but 50 mol% of HOTf should be used. When
tert-butylbenzene and 1-methylnaphthalene were used, the corresponding products 3j and 3l
were isolated in 50% and 85% yield with only one regioisomer detected. However, as
anticipated, the reaction of 1a with toluene and naphthalene gave products 3i and 3k with a
mixture of two regioisomers (probably para/ortho 90:10 and / 75/25, respectively) as
confirmed by 1H and 31P NMR spectrum of 3i and 3k.
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Scheme 2. The substrate scope of different (hetero)aromatics
In addition to arenes, (hetero)aromatic compounds were also suitable substrates for this
Friedel-Crafts arylation. For examples, N-methyl indole, N-methyl pyrrole, 2-
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methylthiophene and benzofuran all performed well, furnishing the expected products 3m-
3p in reasonable yields. Generally, 2-methylthiophene and benzofuran showed higher
reactivity than N-methyl indole and N-methyl pyrrole as much higher yields and shorter
reaction time were observed for 3o-3p than that of 3m-3n. In case of N-methyl indole and
N-methyl pyrrole, undesired reactions occurred along with some side-products detected,
which finally resulted in lower yields for 3m-3n. Other (hetero)arenes such as furan, N-
unprotected indole and indoline were also tried, but no desired product was detected.
The 1,3-dimethoxybenzene was then selected to evaluate the scope of -aryl -
hydroxyphosphonates (Scheme 3). -Hydroxyphosphonates with methyl, isopropyl and n-
butyl as the ester functionality could also give the corresponding products 3q-3s in good
yields. As expected, the electronic and steric effects of substituents on -
hydroxyphosphonates 1 had a great effect on reaction outcome. For example, -
hydroxyphosphonates bearing ethoxy and methylthio at the para-position of the phenyl ring
afforded the desired products 3t-3u in good yields (80-88%), while -hydroxyphosphonate
with a simple methyl at the para-position of the phenyl ring was much less reactive and only
50% yield was obtained for 3w. And almost no reaction occurred when phenyl substituted
-hydroxyphosphonate was used, even increasing the reaction temperature or the catalyst
loading.
The steric effect lied in the fact that the methoxy group at the ortho-position of the
phenyl ring slowed down the reaction rate significantly, and the corresponding product 3x
was obtained in only 53% yield after 24 h. -Hydroxyphosphonates with 2,4-
dimethoxyphenyl or 2,4-dimethylphenyl worked well to afford the desired products 3y and
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3z in good yields. Moreover, -hydroxyphosphonates with 3,4,5-trimethoxyphenyl or 3,5-
dimethyl-4-hydroxylphenyl were also viable substrates for the reaction, furnishing products
3za and 3zb in 80% and 85% yield, respectively.
Scheme 3. The substrate scope of -aryl -hydroxyphosphonates
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Conclusions
In summary, we have developed a metal-free catalytic Friedel-Crafts arylation of -aryl
-hydroxyphosphonates with various (hetero)aromatic compounds, which provides a facile
method for the synthesis of -diarylmethylphosphonates. The cheap and easily available
Brønsted acid HOTf was identified as a powerful acid catalyst to promote the reaction,
affording the desired -diarylmethylphosphonates in good to excellent yields. The
exploration of potential applications of the obtained -diarylmethylphosphonates and the
development of new efficient acid catalysts to enlarge the substrate scope is under
investigation in our laboratory.
Experimental
General information: Reactions were monitored by thin layer chromatography using UV
light to visualize the reaction course. Purification of reaction products was carried out by
flash chromatography on silica gel. Chemical yields refer to pure isolated substances. 1H and
13C NMR spectra were obtained using a Bruker DPX-400 spectrometer. The 31P NMR
spectra were recorded at 162 MHz with 85% H3PO4 as external standard. All reactions were
run under an atmosphere of air. Anhydrous CH3NO2 was prepared by first drying with
anhydrous Na2SO4 and then distilling under reduced pressure. Commercially available
HOTf (trifluoromethanesulfonic acid) was used as received. -Hydroxyphosphonates 1 were
prepared according to the literature report.14 Compounds 3b6, 3f15, 3k15 are known products.
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1
The Supplemental Materials contains H, 13C and 31P NMR spectra of the products 3
(Figures S 1 – S 83).
General procedure for the Friedel-Crafts arylation of -aryl -hydroxyphosphonates
The reaction was carried out under an air atmosphere. To a 5 mL vial were added α-
hydroxyphosphontes 1 (0.3 mmol), (hetero)arenes 2 (0.6 mmol, 2.0 equivs) and anhydrous
CH3NO2 (1 mL). After adding HOTf (9.0 mg, 20 mol%) which was prepared as a solution in
o
CH3NO2, the reaction mixture was stirred at 60 C till almost full conversion of 1 by TLC
analysis. The reaction mixture was then directly subjected to column chromatography using
methylene dichloride/ethyl acetate (v/v) as the eluent to afford the desired product 3.
Diethyl ((2,4-dimethoxyphenyl)(4-methoxyphenyl)methyl)phosphonate (3a): 112
1
mg, 95% yield, white solid; Mp: 50-52 oC; H NMR (400 MHz, CDCl3):  = 7.82 (dd, J =
8.6 Hz, 1.2 Hz, 1H), 7.43-7.41 (m, 2H), 6.82-6.79 (m, 2H), 6.50 (dd, J = 8.4 Hz, 2.4 Hz,
1H), 6.41 (s, 1H), 4.94 (d, J = 25.2 Hz, 1H), 4.00-3.93 (m, 2H), 3.88-3.79 (m, 2H), 3.78 (s,
13
3H), 3.77 (s, 3H), 3.75 (s, 3H), 1.13 (t, J = 7.2 Hz, 3H), 1.12 (t, J = 7.2 Hz, 3H); C NMR
(100 MHz, CDCl3):  = 159.6 (d, J = 1.0 Hz), 158.2 (d, J = 2.0 Hz), 157.4 (d, J = 11.0 Hz),
130.4 (d, J = 5.0 Hz), 130.3 (d, J = 2.0 Hz), 129.2 (d, J = 4.0 Hz), 118.1 (d, J = 3.0 Hz),
113.6, 104.1, 98.5, 62.3 (d, J = 7.0 Hz), 62.2 (d, J = 7.0 Hz), 55.5 (d, J = 2.0 Hz), 55.1 (d, J
31
= 2.0 Hz), 55.0 (d, J = 2.0 Hz), 40.1 (d, J = 140.0 Hz), 16.13, 16.07; P NMR (162 MHz,
CDCl3): δ = 26.8; IR (neat): 3060, 2923, 2838, 1607, 1503, 1206, 1023, 962, 608 cm-1;
HRMS (ESI): Exact mass calcd for C20H28O6P [M+H]+: 395.1618, Found: 395.1617.
Diethyl (bis(4-methoxyphenyl)methyl)phosphonate (3b)6: 87 mg, 80% yield, white
o
1
solid; Mp: 53-55 C; H NMR (400 MHz, CDCl3):  = 7.42-7.40 (m, 4H), 6.84-6.82 (m,
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4H), 4.32 (d, J = 25.2 Hz, 1H), 4.01-3.93 (m, 2H), 3.85-3.78 (m, 2H), 3.75 (s, 6H), 1.12 (t, J
13
= 7.2 Hz, 6H); C NMR (100 MHz, CDCl3):  = 158.5 (d, J = 2.0 Hz), 130.3 (d, J = 8.0
Hz), 129.1 (d, J = 5.0 Hz), 113.8, 62.5, 62.4, 55.09, 55.07, 49.3 (d, J = 139.0 Hz), 16.2, 16.2;
31P NMR (162 MHz, CDCl3): δ = 25.7.
Diethyl ((4-methoxyphenyl)(4-(methylthio)phenyl)methyl)phosphonate (3c): 99 mg,
87% yield, white solid; Mp: 46-48 oC; 1H NMR (400 MHz, CDCl3):  = 7.42-7.38 (m, 4H),
7.17-7.15 (m, 2H), 6.82-6.80 (m, 2H), 4.36 (d, J = 25.2 Hz, 1H), 4.00-3.90 (m, 2H), 3.87-
13
3.75 (m, 2H), 3.72 (s, 3H), 2.39 (s, 3H), 1.10 (dt, J = 4.8 Hz, 2.0 Hz, 6H); C NMR (100
MHz, CDCl3):  = 158.5 (d, J = 2.0 Hz), 136.9 (d, J = 3.0 Hz), 133.8 (d, J = 5.0 Hz), 130.2
(d, J = 8.0 Hz), 129.6 (d, J = 8.0 Hz), 128.6 (d, J = 5.0 Hz), 126.4, 113.8, 62.4 (d, J = 7.0
Hz), 62.3 (d, J = 8.0 Hz), 54.96, 54.95, 49.5 (d, J = 138.0 Hz), 16.1 (d, J = 6.0 Hz), 15.5; 31P
NMR (162 MHz, CDCl3): δ = 25.2; IR (neat): 2981, 2957, 1510, 1242, 1024, 960, 741 cm-1;
HRMS (ESI): Exact mass calcd for C19H26O4PS [M+H]+: 381.1284, Found: 381.1283.
Diethyl ((2,5-dimethoxyphenyl)(4-methoxyphenyl)methyl)phosphonate (3d): 96 mg,
81% yield, colorless oil; 1H NMR (400 MHz, CDCl3):  = 7.53-7.52 (m, 1H), 7.45-7.43 (m,
2H), 6.81-6.70 (m, 4H), 5.02 (d, J = 24.8 Hz, 1H), 4.01-3.90 (m, 2H), 3.88-3.80 (m, 2H),
13
3.76 (s, 3H), 3.73 (s, 3H), 3.72 (s, 3H), 1.12 (td, J = 6.8 Hz, 1.6 Hz, 6H); C NMR (100
MHz, CDCl3):  = 158.4 (d, J = 2.0 Hz), 153.4 (d, J = 2.0 Hz), 150.9 (d, J = 10.0 Hz), 130.6
(d, J = 7.0 Hz), 128.8 (d, J = 5.0 Hz), 126.9 (d, J = 3.0 Hz), 115.9 (d, J = 5.0 Hz), 113.7,
112.9, 112.0, 62.4 (d, J = 2.0 Hz), 62.3 (d, J = 3.0 Hz), 56.4 (d, J = 2.0 Hz), 55.6 (d, J = 3.0
Hz), 55.1 (d, J = 3.0 Hz), 40.9 (d, J = 141.0 Hz), 16.23, 16.19; 31P NMR (162 MHz, CDCl3):
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δ = 26.3; IR (neat): 3468, 2986, 2835, 1609, 1498, 1234, 1097, 956, 794 cm-1; HRMS (ESI):
Exact mass calcd for C20H28O6P [M+H]+: 395.1618, Found: 395.1615.
Diethyl ((4-methoxyphenyl)(2,4,6-trimethoxyphenyl)methyl)phosphonate (3e): 114
mg, 90% yield, colorless oil; 1H NMR (400 MHz, CDCl3):  = 7.40 (dd, J = 8.8 Hz, 2.0 Hz,
2H), 6.75 (d, J = 8.8 Hz, 2H), 6.11 (s, 2H), 5.13 (d, J = 28.0 Hz, 1H), 4.00-3.83 (m, 4H),
3.76 (s, 6H), 3.75 (s, 3H), 3.71 (s, 3H), 1.18-1.11 (m, 6H); 13C NMR (100 MHz, CDCl3):  =
160.3 (d, J = 1.0 Hz), 158.8, 157.9 (d, J = 2.0 Hz), 130.5 (d, J = 8.0 Hz), 129.3 (d, J = 8.0
Hz), 113.2, 107.6 (d, J = 4.0 Hz), 90.9, 61.7 (d, J = 7.0 Hz), 61.6 (d, J = 7.0 Hz), 55.6, 55.1
31
(d, J = 2.0 Hz), 55.0 (d, J = 2.0 Hz), 39.0 (d, J = 143.0 Hz), 16.3, 16.2 (d, J = 7.0 Hz); P
NMR (162 MHz, CDCl3): δ = 27.5; IR (neat): 3450, 2978, 2935, 2838, 1605, 1510, 1245,
1026, 950, 748, 633 cm-1; HRMS (ESI): Exact mass calcd for C21H30O7P [M+H]+: 425.1724,
Found: 425.1723.
Diethyl (mesityl(4-methoxyphenyl)methyl)phosphonate (3f)15: 100 mg, 89% yield,
1
white solid; Mp: 90-92 oC; H NMR (400 MHz, CDCl3):  = 7.33 (d, J = 8.8 Hz, 2H), 6.89
(s, 1H), 6.79 (d, J = 8.8 Hz, 2H), 6.75 (s, 1H), 5.02 (d, J = 30.8 Hz, 1H), 4.26-4.08 (m, 2H),
3.90-3.80 (m, 1H), 3.76 (s, 3H), 3.48-3.38 (m, 1H), 2.46 (s, 3H), 2.24 (s, 3H), 2.06 (s, 3H),
13
1.33 (t, J = 7.2 Hz, 3H), 1.01 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3):  = 157.7,
139.3 (d, J = 4.0 Hz), 137.6 (d, J = 7.0 Hz), 136.4 (d, J = 4.0 Hz), 131.0, 131.0, 129.7 (d, J =
11.0 Hz), 129.3 (d, J = 1.0 Hz), 128.8, 113.4, 62.7 (d, J = 7.0 Hz), 61.3 (d, J = 7.0 Hz), 55.1,
43.8 (d, J = 140.0 Hz), 21.4 (d, J = 25.0 Hz), 20.7, 16.3 (d, J = 6.0 Hz), 16.1 (d, J = 6.0 Hz);
31P NMR (162 MHz, CDCl3): δ = 26.5.
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Diethyl ((4-(tert-butyl)-2-hydroxyphenyl)(4-methoxyphenyl)methyl)phosphonate
(3g): 77 mg, 63% yield, white solid; Mp: 148-150 oC; 1H NMR (400 MHz, CDCl3):  = 8.86
(brs 1H), 7.44-7.42 (m, 2H), 7.19-7.17 (m, 1H), 7.07 (s, 1H), 6.93-6.91 (m, 1H), 6.88-6.86
(m, 2H), 4.59 (d, J = 26.8 Hz, 1H), 4.06-3.97 (m, 2H), 3.92-3.81 (m, 2H), 3.79 (s, 3H), 1.21
(s, 9H), 1.17 (t, J = 7.2 Hz, 3H), 1.10 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):  =
158.6 (d, J = 2.0 Hz), 152.6 (d, J = 6.0 Hz), 143.4, 130.7 (d, J = 8.0 Hz), 128.0 (d, J = 8.0
Hz), 127.4 (d, J = 5.0 Hz), 125.8 (d, J = 3.0 Hz), 122.5 (d, J = 6.0 Hz), 118.7 (d, J = 2.0 Hz),
113.9, 63.6 (d, J = 8.0 Hz), 63.2 (d, J = 7.0 Hz), 55.2 (d, J = 2.0 Hz), 47.1 (d, J = 136.0 Hz),
34.0, 31.4, 16.2 (d, J = 5.0 Hz), 16.0 (d, J = 6.0 Hz); 31P NMR (162 MHz, CDCl3): δ = 28.8;
IR (neat): 3330, 3111, 2963, 2860, 1549, 1248, 1186, 1018, 959, 826, 749 cm-1; HRMS
(ESI): Exact mass calcd for C22H32O5P [M+H]+: 407.1982, Found: 407.1979.
Diethyl
((4-hydroxy-3,5-dimethylphenyl)(4-methoxyphenyl)methyl)phosphonate
(3h): 98 mg, 86% yield, colorless oil; 1H NMR (400 MHz, CDCl3):  = 7.41 (dd, J = 6.8 Hz,
1.6 Hz, 2H), 7.06 (s, 2H), 6.82 (d, J = 8.8 Hz, 2H), 6.20 (brs, 1H), 4.26 (d, J = 25.2 Hz, 1H),
4.03-3.92 (m, 2H), 3.89-3.77 (m, 2H), 3.74 (s, 3H), 2.17 (s, 6H), 1.16-1.11 (m, 6H); 13C
NMR (100 MHz, CDCl3):  = 158.4 (d, J = 2.0 Hz), 151.8 (d, J = 2.0 Hz), 130.3 (d, J 8.0
Hz), 129.2 (d, J = 5.0 Hz), 129.2 (d, J = 2.0 Hz), 127.7 (d, J = 5.0 Hz), 123.8, 113.8, 62.54,
31
62.47, 55.1 (d, J = 2.0 Hz), 49.3 (d, J = 138.0 Hz), 16.1; P NMR (162 MHz, CDCl3): δ =
26.0; IR (neat): 3243, 2984, 2911, 1608, 1390, 1249, 1022, 960, 746 cm-1; HRMS (ESI):
Exact mass calcd for C20H28O5P [M+H]+: 379.1669, Found: 379.1670.
Diethyl ((4-methoxyphenyl)(p-tolyl)methyl)phosphonate (3i): a regioisomer mixture
1
with a ratio of 9:1. 58 mg, 56% yield, colorless oil; H NMR (400 MHz, CDCl3):  = 7.44-
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7.37 (m, 4H), 7.12-7.10 (m, 2H), 6.85-6.83 (m, 2H), 4.34 (d, J = 25.2 Hz, 1H), 4.02-3.92 (m,
13
2H), 3.87-3.79 (m, 2H), 3.77 (s, 3H), 2.30 (s, 3H), 1.13 (t, J = 7.2 Hz, 6H); C NMR (100
MHz, CDCl3):  = 158.5 (d, J = 2.0 Hz), 136.6 (d, J = 2.0 Hz), 134.1 (d, J = 4.0 Hz), 130.4
(d, J = 8.0 Hz), 129.2, 129.1 (d, J = 12.0 Hz), 129.0, 113.9 (d, J = 1.0 Hz), 62.6 (d, J = 1.0
Hz), 62.5 (d, J = 2.0 Hz), 55.2, 49.8 (d, J = 138.0 Hz), 21.0, 16.3 (d, J = 2.0 Hz), 16.2 (d, J =
31
1.0 Hz); P NMR (162 MHz, CDCl3): δ = 25.6; IR (neat): 3060, 2921, 2854, 1500, 1250,
1040, 965, 709 cm-1; HRMS (ESI): Exact mass calcd for C19H26O4P [M+H]+: 349.1563,
Found: 349.1561.
Diethyl ((4-(tert-butyl)phenyl)(4-methoxyphenyl)methyl)phosphonate (3j): 59 mg,
50% yield, colorless oil; 1H NMR (400 MHz, CDCl3):  = 7.46-7.40 (m, 4H), 7.32-7.30 (m,
2H), 6.86-6.84 (m, 2H), 4.35 (d, J = 25.2 Hz, 1H), 4.02-3.92 (m, 2H), 3.86-3.79 (m, 2H),
3.77 (s, 3H), 1.28 (s, 9H), 1.14-1.09 (m, 6H); 13C NMR (100 MHz, CDCl3):  = 158.6 (d, J
= 2.0 Hz), 149.8 (d, J = 3.0 Hz), 133.9 (d, J = 5.0 Hz), 130.5 (d, J = 8.0 Hz), 129.1 (d, J =
5.0 Hz), 128.9 (d, J = 8.0 Hz), 125.4 (d, J = 1.0 Hz), 113.9, 62.6, 62.5 (d, J = 7.0 Hz), 55.2,
49.9 (d, J = 138.0 Hz), 34.4, 31.3, 16.3, 16.2 (d, J = 7.0 Hz); 31P NMR (162 MHz, CDCl3): δ
= 25.7; IR (neat): 3100, 2921, 2854, 1440, 1250, 1052, 960, 751 cm-1; HRMS (ESI): Exact
mass calcd for C22H32O4P [M+H]+: 391.232, Found: 391.2027.
Diethyl
((4-methoxyphenyl)(naphthalen-1-yl)methyl)phosphonate
(3k)15:
a
1
regioisomer mixture with a ratio of 3:1. 92 mg, 80% yield, colorless oil; H NMR (400
MHz, CDCl3):  = 8.25-8.23 (m, 1H), 8.08-8.06 (m, 1H), 7.84-7.77 (m, 3H), 7.54-7.50 (m,
1H) (belonging to the major isomer), 7.48-7.43 (m, 4H), 6.82 (d, J = 8.4 Hz, 2H), 5.24 (d, J
= 26.4 Hz, 1H), 4.60-3.94 (m, 2H), 3.88-3.80 (m, 2H), 3.77 (s, 1H) (belonging to the minor
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isomer), 3.73 (s, 3H) (belonging to the major isomer), 1.18 (t, J = 7.2 Hz, 3H) (belonging to
the major isomer), 1.14 (t, J = 7.2 Hz, 1H) (belonging to the minor isomer), 1.11 (t, J = 6.8
Hz, 3H) (belonging to the minor isomer), 1.04 (t, J = 7.2 Hz, 3H) (belonging to the major
isomer).
Diethyl ((4-methoxyphenyl)(4-methylnaphthalen-1-yl)methyl)phosphonate (3l): 101
mg, 85% yield, colorless oil; 1H NMR (400 MHz, CDCl3):  = 8.18-8.16 (m, 1H), 8.09-8.07
(m, 1H), 8.02-7.99 (m, 1H), 7.50-7.45 (m, 4H), 7.38 (d, J = 7.6 Hz, 1H), 6.82 (d, J = 8.8 Hz,
2H), 5.23 (d, J = 26.4 Hz, 1H), 4.04-3.95 (m, 2H), 3.88-3.80 (m, 2H), 3.72 (s, 3H), 2.68 (s,
13
3H), 1.18 (t, J = 7.2 Hz, 3H), 1.07 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3):  =
158.5 (d, J = 2.0 Hz), 133.8 (d, J = 1.0 Hz), 133.2, 131.5 (d, J = 12.0 Hz), 131.0 (d, J = 2.0
Hz), 130.5 (d, J = 8.0 Hz), 128.6 (d, J = 7.0 Hz), 127.0 (d, J = 7.0 Hz), 126.1 (d, J = 1.0 Hz),
125.8, 125.2, 124.9, 123.6, 113.8 (d, J = 2.0 Hz), 62.54, 62.47, 55.0, 44.9 (d, J = 139.0 Hz),
19. 4, 16.3 (d, J = 6.0 Hz), 16.1 (d, J = 6.0 Hz); 31P NMR (162 MHz, CDCl3): δ = 26.3; IR
(neat): 3474, 2980, 2837, 1462, 1247, 1051, 751, 610 cm-1; HRMS (ESI): Exact mass calcd
for C23H28O4P [M+H]+: 399.1720, Found: 399.1719.
Diethyl ((4-methoxyphenyl)(1-methyl-1H-indol-3-yl)methyl)phosphonate (3m): 62
mg, 53% yield, brown oil; 1H NMR (400 MHz, CDCl3):  = 7.50 (s, 1H), 7.49-7.41 (m, 3H),
7.28-7.25 (m, 1H), 7.19-7.16 (m, 1H), 7.05-7.02 (m, 1H), 6.83-6.80 (m, 2H), 4.67 (d, J =
24.0 Hz, 1H), 4.04-3.86 (m, 3H), 3.78 (s, 3H), 3.76-3.72 (m, 1H), 3.74 (s, 3H), 1.16-1.10 (m,
13
6H); C NMR (100 MHz, CDCl3):  = 158.5 (d, J = 3.0 Hz), 136.6, 130.3 (d, J = 7.0 Hz),
129.1 (d, J = 6.0 Hz), 128.3 (d, J = 5.0 Hz), 127.5 (d, J = 12.0 Hz), 121.6, 118.9, (d, J = 21.0
Hz), 113.7 (d, J = 2.0 Hz), 109.6 (d, J = 7.0 Hz), 109.1, 62.7 (d, J = 7.0 Hz), 62.4 (d, J = 7.0
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31
Hz), 55.1 (d, J = 2.0 Hz), 40.8 (d, J = 139.0 Hz), 32.8 (d, J = 2.0 Hz), 16.3; P NMR (162
MHz, CDCl3): δ = 26.3; IR (neat): 3250, 2960, 2854, 1600, 1240, 1025, 960, 790 cm-1;
HRMS (ESI): Exact mass calcd for C21H27NO4P [M+H]+: 388.1672, Found: 388.1670.
Diethyl ((4-methoxyphenyl)(1-methyl-1H-pyrrol-2-yl)methyl)phosphonate (3n): 41
1
mg, 41% yield, brown oil; H NMR (400 MHz, CDCl3):  = 7.29-7.26 (m, 2H), 6.84-6.82
(m, 2H), 6.58-6.57 (m, 1H), 6.53 (t, J = 6.0 Hz, 1H), 6.09 (t, J = 8.0 Hz, 1H), 4.38 (d, J =
28.0 Hz, 1H), 4.08-4.02 (m, 1H), 4.00-3.89 (m, 2H), 3.82-3.80 (m, 1H), 3.77 (s, 3H), 3.38 (s,
3H), 1.20-1.14 (m, 6H); 13C NMR (100 MHz, CDCl3):  = 158.6 (d, J = 3.0 Hz), 130.4 (d, J
= 6.0 Hz), 127.3 (d, J = 6.0 Hz), 126.6, 122.2, 113.8 (d, J = 2.0 Hz), 109.5 (d, J = 4.0 Hz),
106.7, 62.9 (d, J = 7.0 Hz), 62.6 (d, J = 7.0 Hz), 55.2, 42.1 (d, J = 142.0 Hz), 33.7, 16.3,
31
16.2 (d, J = 4.0 Hz); P NMR (162 MHz, CDCl3): δ = 24.2; IR (neat): 3200, 2850, 1510,
1253, 1095, 755, 697, 650 cm-1; HRMS (ESI): Exact mass calcd for C17H25NO4P [M+H]+:
338.1516, Found: 338.1511.
Diethyl ((4-methoxyphenyl)(5-methylthiophen-2-yl)methyl)phosphonate (3o): 91
1
mg, 86% yield, brown oil; H NMR (400 MHz, CDCl3):  = 7.42-7.40 (m, 2H), 6.97-6.96
(m, 1H), 6.86-6.84 (m, 2H), 6.59-6.58 (m, 1H), 4.51 (d, J = 24.0 Hz, 1H), 4.08-3.93 (m, 3H),
3.82-3.74 (m, 1H), 3.77 (s, 3H), 2.40 (s, 3H), 1.21 (t, J = 8.0 Hz, 3H), 1.11 (t, J = 8.0 Hz,
3H); 13C NMR (100 MHz, CDCl3):  = 158.8 (d, J = 3.0 Hz), 139.3 (d, J = 3.0 Hz), 136.7 (d,
J = 4.0 Hz), 130.3 (d, J = 7.0 Hz), 128.55 (d, J = 3.0 Hz), 126.64 (d, J = 8.0 Hz), 124.9 (d, J
= 2.0 Hz), 113.9 (d, J = 1.0 Hz), 62.9 (d, J = 8.0 Hz), 62.7 (d, J = 8.0 Hz), 55.2, 45.5 (d, J =
140.0 Hz), 16.3, 16.2 (d, J = 6.0 Hz), 15.2; 31P NMR (162 MHz, CDCl3): δ = 23.6; IR (neat):
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2928, 1713, 1475, 1253, 878, 739, 696 cm-1; HRMS (ESI): Exact mass calcd for
C17H24O4PS [M+H]+: 355.1127, Found: 355.1125.
Diethyl (benzofuran-3-yl(4-methoxyphenyl)methyl)phosphonate (3p): 102 mg, 91%
yield, colorless oil; 1H NMR (400 MHz, CDCl3):  = 7.54-7.52 (m, 1H), 7.45-7.40 (m, 3H),
7.24-7.16 (m, 2H), 6.93-6.92 (m, 1H), 6.89-6.87 (m, 2H), 4.62 (d, J = 25.6 Hz, 1H), 4.14-
3.95 (m, 3H), 3.86-3.79 (m, 1H), 3.76 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H), 1.14 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3):  = 159.0 (d, J = 3.0 Hz), 154.5, 153.1, 130.4 (d, J = 6.0
Hz), 128.3 (d, J = 2.0 Hz), 125.6 (d, J = 6.0 Hz), 123.8, 122.6, 120.7, 113.9 (d, J = 2.0 Hz),
110.8, 105.3 (d, J = 5.0 Hz), 63.0 (d, J = 7.0 Hz), 62.8 (d, J = 7.0 Hz), 55.0, 44.6 (d, J =
31
140.0 Hz), 16.2, 16.1 (d, J = 7.0 Hz); P NMR (162 MHz, CDCl3): δ = 21.8; IR (neat):
3200, 2950, 1513, 1480, 1253, 1095, 755 cm-1; HRMS (ESI): Exact mass calcd for
C20H24O5P [M+H]+: 375.1356, Found: 375.1354.
Dimethyl ((2,4-dimethoxyphenyl)(4-methoxyphenyl)methyl)phosphonate (3q): 77
mg, 70% yield, white solid; Mp: 98-100 oC; 1H NMR (400 MHz, CDCl3):  = 7.80 (dd, J =
8.4 Hz, 1.6 Hz, 1H), 7.42-7.41 (m, 2H), 6.83-6.81 (m, 2H), 6.51 (dd, J = 7.2 Hz, 2.4 Hz,
1H), 6.42 (s, 1H), 4.97 (d, J = 25.6 Hz, 1H), 3.78 (s, 6H), 3.76 (s, 3H), 3.56 (dd, J = 10.4 Hz,
13
7.6 Hz, 6H); C NMR (100 MHz, CDCl3):  = 159.8, 158.4 (d, J = 3.0 Hz), 157.4 (d, J =
11.0 Hz), 130.5 (d, J = 2.0 Hz), 130.4, 129.0 (d, J = 5.0 Hz), 117.9 (d, J = 3.0 Hz), 113.8,
104.3, 98.7, 55.6 (d, J = 2.0 Hz), 55.2 (d, J = 2.0 Hz), 55.1 (d, J = 2.0 Hz), 53.2, 39.8 (d, J =
140.0 Hz); 31P NMR (162 MHz, CDCl3): δ = 29.1; IR (neat): 2949, 2922, 2847, 1608, 1457,
1246, 1022, 797, 608 cm-1; HRMS (ESI): Exact mass calcd for C18H24O6P [M+H]+:
367.1305, Found: 367.1302.
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Diisopropyl ((2,4-dimethoxyphenyl)(4-methoxyphenyl)methyl)phosphonate (3r): 90
mg, 71% yield, colorless oil; 1H NMR (400 MHz, CDCl3):  = 7.85 (dd, J = 8.6 Hz, 1.6 Hz,
1H), 7.44-7.41 (m, 2H), 6.79-6.77 (m, 2H), 6.48 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 6.39 (s, 1H),
4.87 (d, J = 25.6 Hz, 1H), 4.53-4.44 (m, 2H), 3.75 (s, 3H), 3.74 (s, 3H), 3.72 (s, 3H), 1.22-
13
1.19 (m, 6H), 0.93-0.91 (m, 6H); C NMR (100 MHz, CDCl3):  = 159.6 (d, J = 2.0 Hz),
158.2 (d, J = 2.0 Hz), 157.5 (d, J = 11.0 Hz), 130.5 (d, J = 8.0 Hz), 130.4 (d, J = 6.0 Hz),
129.7 (d, J = 5.0 Hz), 118.6 (d, J = 3.0 Hz), 113.5 (d, J = 1.0 Hz), 104.0, 98.5, 70.7 (d, J =
8.0 Hz), 70.6 (d, J = 7.0 Hz), 55.5, 55.1 (d, J = 11.0 Hz), 40.5 (d, J = 142.0 Hz), 24.1 (d, J =
3.0 Hz), 23.3, 23.2 (d, J = 6.0 Hz); 31P NMR (162 MHz, CDCl3): δ = 25.1; IR (neat): 2980,
2922, 2847, 1600, 1436, 1250, 1022, 797, 608 cm-1; HRMS (ESI): Exact mass calcd for
C22H32O6P [M+H]+: 423.1931, Found: 423.1929.
Dibutyl ((2,4-dimethoxyphenyl)(4-methoxyphenyl)methyl)phosphonate (3s): 109
1
mg, 81% yield, white solid; Mp: 58-60 oC; H NMR (400 MHz, CDCl3):  = 7.82 (dd, J =
8.6 Hz, 1.6 Hz, 1H), 7.42-7.40 (m, 2H), 6.79-6.77 (m, 2H), 6.48 (dd, J = 8.4 Hz, 2.4 Hz,
1H), 6.39 (s, 1H), 4.94 (d, J = 25.2 Hz, 1H), 3.92-3.84 (m, 2H), 3.81-3.77 (m, 2H), 3.74 (s,
3H), 3.73 (s, 3H), 3.71 (s, 3H), 1.46-1.38 (m, 4H), 1.26-1.16 (m, 4H), 0.80 (td, J = 8.0 Hz,
2.8 Hz, 6H); 13C NMR (100 MHz, CDCl3):  = 159.6 (d, J = 2.0 Hz), 158.2 (d, J = 2.0 Hz),
157.4 (d, J = 10.0 Hz), 130.39, 130.38 (d, J = 8.0 Hz), 129.3 (d, J = 5.0 Hz), 118.2 (d, J =
3.0 Hz), 113.5, 104.1, 98.5, 65.9 (d, J = 7.0 Hz), 65.8 (d, J = 7.0 Hz), 55.4, 55.1 (d, J = 2.0
Hz), 55.0 (d, J = 1.0 Hz), 40.0 (d, J = 140.0 Hz), 32.3 (d, J = 2.0 Hz), 32.2 (d, J = 2.0 Hz),
31
18.4 (d, J = 3.0 Hz), 13.4; P NMR (162 MHz, CDCl3): δ = 26.7; IR (neat): 2956, 2905,
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2870, 1583, 1239, 1025, 976, 609 cm-1; HRMS (ESI): Exact mass calcd for C24H36O6P
[M+H]+: 451.2244, Found: 451.2242.
Diethyl ((2,4-dimethoxyphenyl)(4-ethoxyphenyl)methyl)phosphonate (3t): 108 mg,
88% yield, colorless oil; 1H NMR (400 MHz, CDCl3):  = 7.80 (dd, J = 8.6 Hz, 1.6 Hz, 1H),
7.39 (dd, J = 11.0 Hz, 5.0 Hz, 2H), 6.77 (d, J = 8.4 Hz, 2H), 6.48 (dd, J = 8.4 Hz, 2.4 Hz,
1H), 6.40-6.39 (m, 1H), 4.92 (d, J = 25.2 Hz, 1H), 3.98-3.91 (m, 4H), 3.86-3.77 (m, 2H),
13
3.74 (s, 3H), 3.73 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H), 1.10 (td, J = 7.2 Hz, 2.4 Hz, 6H); C
NMR (100 MHz, CDCl3):  = 159.6 (d, J = 2.0 Hz), 157.6 (d, J = 2.0 Hz), 157.4 (d, J = 11.0
Hz), 130.39, 130.38 (d, J = 8.0 Hz), 129.0 (d, J = 5.0 Hz), 118.1 (d, J = 3.0 Hz), 114.1,
104.1 (d, J = 1.0 Hz), 98.5, 63.1, 62.3, 62.2 (d, J = 7.0 Hz), 55.5 (d, J = 2.0 Hz), 55.1 (d, J =
31
2.0 Hz), 40.1 (d, J = 140.0 Hz), 16.13, 16.08, 14.7; P NMR (162 MHz, CDCl3): δ = 26.8;
IR (neat): 2960, 2900, 2874, 1600, 1240, 1025, 976, 609 cm-1; HRMS (ESI): Exact mass
calcd for C21H30O6P [M+H]+: 409.1774, Found: 409.1773.
Diethyl ((2,4-dimethoxyphenyl)(4-(methylthio)phenyl)methyl)phosphonate (3u): 98
1
mg, 80% yield, white solid; Mp: 80-82 oC; H NMR (400 MHz, CDCl3):  = 7.81 (dd, J =
8.8 Hz, 2.0 Hz, 1H), 7.43-7.40 (m, 2H), 7.16-7.14 (m, 2H), 6.49 (dd, J = 8.4 Hz, 2.4 Hz,
1H), 6.41-6.40 (m, 1H), 4.94 (d, J = 25.6 Hz, 1H), 4.00-3.94 (m, 2H), 3.88-3.81 (m, 2H),
3.76 (s, 3H), 3.75 (s, 3H), 2.41 (s, 3H), 1.15-1.10 (m, 6H); 13C NMR (100 MHz, CDCl3):  =
159.7 (d, J = 1.0 Hz), 157.4 (d, J = 11.0 Hz), 136.5 (d, J = 3.0 Hz), 134.2 (d, J = 4.0 Hz),
130.4 (d, J = 5.0 Hz), 129.8 (d, J = 8.0 Hz), 126.4 (d, J = 1.0 Hz), 117.7 (d, J = 4.0 Hz),
104.1 (d, J = 1.0 Hz), 98.5, 62.4 (d, J = 7.0 Hz), 62.2 (d, J = 7.0 Hz), 55.5 (d, J = 2.0 Hz),
55.1 (d, J = 2.0 Hz), 40.5 (d, J = 140.0 Hz), 16.1 (d, J = 6.0 Hz), 15.7; 31P NMR (162 MHz,
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CDCl3): δ = 26.3; IR (neat): 2962, 2921, 2851, 1610, 1584, 1408, 1236, 1045, 965, 633 cm-
1; HRMS (ESI): Exact mass calcd for C20H28O5PS [M+H]+: 411.1390, Found: 411.1388.
Diethyl
((2,4-dimethoxyphenyl)(4-(dimethylamino)phenyl)methyl)phosphonate
1
(3v): 68 mg, 56% yield, brown oil; H NMR (400 MHz, CDCl3):  = 7.82 (dd, J = 8.6 Hz,
2.0 Hz, 1H), 7.36 (dd, J = 8.8 Hz, 2.0 Hz, 2H), 6.65 (d, J = 8.8 Hz, 2H), 6.49 (dd, J = 8.8
Hz, 2.4 Hz, 1H), 6.40 (s, 1H), 4.91 (d, J = 25.2 Hz, 1H), 4.01-3.92 (m, 2H), 3.89-3.78 (m,
2H), 3.76 (s, 6H), 2.88 (s, 6H), 1.15-1.10 (m, 6H); 13C NMR (100 MHz, CDCl3):  = 159.5
(d, J = 1.0 Hz), 157.5 (d, J = 10.0 Hz), 149.3, 130.5 (d, J = 5.0 Hz), 130.0 (d, J = 8.0 Hz),
125.0, 118.6 (d, J = 3.0 Hz), 112.5, 104.1, 98.6, 62.24, 62.17, 55.6, 55.2, 40.5, 40.0 (d, J =
31
140.0 Hz), 16.23 (d, J = 2.0 Hz), 16.18 (d, J = 3.0 Hz); P NMR (162 MHz, CDCl3): δ =
27.2; IR (neat): 3301, 2920, 2854, 1585, 1408, 1240, 1045, 965, 609 cm-1; HRMS (ESI):
Exact mass calcd for C21H31NO5P [M+H]+: 408.1934, Found: 408.1931.
Diethyl ((2,4-dimethoxyphenyl)(p-tolyl)methyl)phosphonate (3w): 57 mg, 50% yield,
1
colorless oil; H NMR (400 MHz, CDCl3):  = 7.83-7.81 (m, 1H), 7.40-7.38 (m, 2H), 7.08-
7.06 (m, 2H), 6.51-6.48 (m, 1H), 6.41-6.40 (m, 1H), 5.00-4.94 (d, J = 25.6 Hz, 1H), 4.01-
3.92 (m, 2H), 3.88-3.80 (m, 2H), 3.77 (s, 3H), 3.76 (s, 3H), 2.28 (s, 3H), 1.15-1.10 (m, 6H);
13C NMR (100 MHz, CDCl3):  = 159.7, 157.5 (d, J = 11.0 Hz), 136.2 (d, J = 2.0 Hz), 134.2
(d, J = 5.0 Hz), 130.6 (d, J = 5.0 Hz), 129.3 (d, J = 7.0 Hz), 128.9, 118.0 (d, J = 3.0 Hz),
104.2, 98.6, 62.4 (d, J = 7.0 Hz), 62.2 (d, J = 7.0 Hz), 55.5, 55.2, 40.6 (d, J = 140.0 Hz),
20.9, 16.2, 16.1; 31P NMR (162 MHz, CDCl3): δ = 27.3; IR (neat): 3440, 3030, 2965, 2850,
1506, 1450, 1232, 1049, 938, 614 cm-1; HRMS (ESI): Exact mass calcd for C20H28O5P
[M+H]+: 379.1669, Found: 379.1664.
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Diethyl ((2,4-dimethoxyphenyl)(2-methoxyphenyl)methyl)phosphonate (3x): 63 mg,
53% yield, white solid; Mp: 66-68 oC; 1H NMR (400 MHz, CDCl3):  = 7.79 (dt, J = 7.6 Hz,
2.0 Hz, 1H), 7.72 (dd, J = 8.6 Hz, 2.0 Hz, 1H), 7.19-7.15 (m, 1H), 6.93-6.89 (m, 1H), 6.83-
6.81 (m, 1H), 6.46 (dd, J = 8.6 Hz, 2.4 Hz, 1H), 6.41-6.40 (m, 1H), 5.62 (d, J = 24.8 Hz,
1H), 4.00-3.89 (m, 2H), 3.88-3.82 (m, 2H), 3.80 (s, 3H), 3.78 (s, 3H), 3.75 (s, 3H), 1.15-1.09
13
(m, 6H); C NMR (100 MHz, CDCl3):  = 159.6 (d, J = 2.0 Hz), 158.0 (d, J = 10.0 Hz),
157.0 (d, J = 9.0 Hz), 131.0 (d, J = 5.0 Hz), 130.5 (d, J = 5.0 Hz), 127.8 (d, J = 2.0 Hz),
126.1 (d, J = 4.0 Hz), 120.5 (d, J = 2.0 Hz), 118.2 (d, J = 4.0 Hz), 110.9, 104.2 (d, J = 1.0
Hz), 98.8, 62.3, 62.2 (d, J = 7.0 Hz), 55.84 (d, J = 2.0 Hz), 55.77 (d, J = 2.0 Hz), 55.2 (d, J =
31
2.0 Hz), 32.8 (d, J = 141.0 Hz), 16.2, 16.1 (d, J = 6.0 Hz); P NMR (162 MHz, CDCl3): δ
27.1; IR (neat): 3831, 2924, 2852, 1607, 1438, 1241, 1020, 955, 751, 622 cm-1; HRMS
(ESI): Exact mass calcd for C20H28O6P [M+H]+: 395.1618, Found: 395.1615.
Diethyl (bis(2,4-dimethoxyphenyl)methyl)phosphonate (3y): 108 mg, 85% yield,
colorless oil; 1H NMR (400 MHz, CDCl3):  = 7.68 (dd, J = 8.6 Hz, 2.0 Hz, 2H), 6.43 (dd, J
= 8.4 Hz, 2.4 Hz, 2H), 6.38 (s, 2H), 5.49 (d, J = 25.2 Hz, 1H), 4.00-3.89 (m, 2H), 3.87-3.78
(m, 2H), 3.75 (s, 6H), 3.73 (s, 6H), 1.11 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3): 
= 159.4 (d, J = 2.0 Hz), 157.8 (d, J = 10.0 Hz), 130.8 (d, J = 5.0 Hz), 118.3 (d, J = 3.0 Hz),
31
104.0 (d, J = 1.0 Hz), 98.6, 62.1, 62.0, 55.7, 55.1, 32.1 (d, J = 142.0 Hz), 16.13, 16.07; P
NMR (162 MHz, CDCl3): δ = 27.4; IR (neat): 3830, 2924, 2854, 1607, 1440, 1260, 1045,
955, 761, 649 cm-1; HRMS (ESI): Exact mass calcd for C21H30O7P [M+H]+: 425.1724,
Found: 425.1722.
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Diethyl ((2,4-dimethoxyphenyl)(2,4-dimethylphenyl)methyl)phosphonate (3z): 76
1
mg, 65% yield, brown oil; H NMR (400 MHz, CDCl3):  = 7.79-7.77 (m, 1H), 7.67-7.64
(m, 1H), 6.97-6.95 (m, 1H), 6.93 (s, 1H), 6.49-6.46 (m, 1H), 6.40-6.39 (m, 1H), 5.12 (d, J =
25.6 Hz, 1H), 4.01-3.91 (m, 2H), 3.89-3.80 (m, 2H), 3.78 (s, 3H), 3.76 (s, 3H), 2.36 (s, 3H),
2.24 (s, 3H), 1.14 (t, J = 7.2 Hz, 3H), 1.11 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
 = 159.6 (d, J = 2.0 Hz), 157.5 (d, J = 10.0 Hz), 136.6 (d, J = 11.0 Hz), 136.1 (d, J = 2.0
Hz), 132.6 (d, J = 5.0 Hz), 130.9 (d, J = 5.0 Hz), 129.4 (d, J = 5.0 Hz), 126.6 (d, J = 2.0 Hz),
118.1 (d, J = 3.0 Hz), 104.2 (d, J = 2.0 Hz), 98.4, 62.4, 63.2 (d, J = 8.0 Hz), 55.4, 55.2, 36.8
31
(d, J = 141.0 Hz), 20.9, 19.6, 16.3, 16.2 (d, J = 7.0 Hz); P NMR (162 MHz, CDCl3): δ =
27.5; IR (neat): 3500, 3029, 2960, 2850, 1500, 1450, 1240, 1051, 940, 621 cm-1; HRMS
(ESI): Exact mass calcd for C21H30O5P [M+H]+: 393.1825, Found: 393.1820.
Diethyl ((2,4-dimethoxyphenyl)(3,4,5-trimethoxyphenyl)methyl)phosphonate (3za):
94 mg, 80% yield, white solid; Mp: 74-76 oC; 1H NMR (400 MHz, CDCl3):  = 7.75 (dd, J =
8.4 Hz, 2.0 Hz, 1H), 6.74-6.73 (m, 2H), 6.44 (dd, J = 8.6 Hz, 2.4 Hz, 1H), 6.40-6.39 (m,
1H), 4.89 (d, J = 25.6 Hz, 1H), 3.99-3.82 (m, 4H), 3.78 (s, 6H), 3.75 (s, 3H), 3.74 (s, 3H),
3.73 (s, 3H), 1.11 (t, J = 7.2 Hz, 3H), 1.07 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
 = 159.7 (d, J = 1.0 Hz), 157.4 (d, J = 10.0 Hz), 152.6 (d, J = 1.0 Hz), 136.6 (d, J = 2.0 Hz),
132.7 (d, J = 4.0 Hz), 130.3 (d, J = 5.0 Hz), 117.4 (d, J = 43.0 Hz), 106.5 (d, J = 8.0 Hz),
104.2, 98.5, 62.4 (d, J = 7.0 Hz), 62.2 (d, J = 7.0 Hz), 60.5, 55.8 (d, J = 1.0 Hz), 55.5 (d, J =
31
2.0 Hz), 55.0 (d, J = 2.0 Hz), 40.8 (d, J = 140.0 Hz), 16.11, 16.07; P NMR (162 MHz,
CDCl3): δ = 26.3; IR (neat): 3436, 3029, 2965, 2852, 1606, 1454, 1232, 1051, 938, 614 cm-
1; HRMS (ESI): Exact mass calcd for C22H32O8P [M+H]+: 455.1829, Found: 455.1827.
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Diethyl
((2,4-dimethoxyphenyl)(4-hydroxy-3,5-
dimethylphenyl)methyl)phosphonate (3zb): 116 mg, 85% yield, brown oil; 1H NMR (400
MHz, CDCl3):  = 7.79-7.76 (m, 1H), 7.06 (s, 2H), 6.50-6.47 (m, 1H), 6.41-6.40 (m, 1H),
5.73 (brs, 1H), 4.89 (d, J = 25.2 Hz, 1H), 4.00-3.93 (m, 2H), 3.88-3.81 (m, 2H), 3.76 (s, 6H),
2.14 (s, 6H), 1.14 (t, J = 7.2 Hz, 3H), 1.11 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
 = 159.6 (d, J = 1.0 Hz), 157.4 (d, J = 10.0 Hz), 151.6 (d, J = 2.0 Hz), 130.6 (d, J = 5.0 Hz),
129.4 (d, J = 8.0 Hz), 127.7 (d, J = 5.0 Hz), 123.4 (d, J = 2.0 Hz), 118.1 (d, J = 3.0 Hz),
104.2 (d, J = 2.0 Hz), 98.6, 62.4 (d, J = 7.0 Hz), 62.3 (d, J = 7.0 Hz), 55.18, 55.17, 40.0 (d, J
= 140.0 Hz), 16.1; 31P NMR (162 MHz, CDCl3): δ = 27.0; IR (neat): 3600, 3030, 2950,
2850, 1600, 1420, 1250, 1049, 940, 621 cm-1; HRMS (ESI): Exact mass calcd for C21H30O6P
[M+H]+: 409.1775, Found: 409.1772.
Funding
The financial support from Chengdu University New Faculty Start-up Funding (No.
2081916045) and the Open Project Program of Antibiotics Research and Re-evaluation Key
Laboratory of Sichuan Province (No. ARRLKF16-03) is highly appreciated.
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22. We also tried arenes with electronic-withdrawing group such as bromobenzene,
chlorobenzene and the simple benzene and found most of -hydroxyphosphonate 1a
underwent the retro-Pudovik reaction under the strong acid conditions. Meanwhile, due to
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the low nucleophilicity of these arenes, the Friedel-Crafts arylation between 1a and these
arenes could hardly proceed, which resulted in no desired arylated product detected.
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