One-Pot, Three-Component Approach to Diarylmethylphosphonates: A Direct Entry to Polycyclic Aromatic Systems

Article abstract of DOI:10.1021/acs.joc.9b00668

A new type of three-component reaction was developed consisting of aldehydes, electron-rich (hetero)arenes, and trialkyl phosphite, which provided facile access to a wide range of diarylmethylphosphonates under mild reaction conditions. Simple one- or two-step synthetic manipulation of the resulting compounds enabled us to reach several polycyclic (hetero)aromatic systems efficiently.

Full text of DOI:10.1021/acs.joc.9b00668

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Article
One-Pot, Three-Component Approach to Diarylmethylphosphonates:
A Direct Entry to Polycyclic Aromatic Systems
Sure Siva Prasad, Dileep Kumar Singh, and Ikyon Kim
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00668 • Publication Date (Web): 16 Apr 2019
Downloaded from http://pubs.acs.org on April 16, 2019
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One-Pot, Three-Component Approach to Diarylmethylphosphonates: A
Direct Entry to Polycyclic Aromatic Systems
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Sure Siva Prasad, Dileep Kumar Singh, and Ikyon Kim*
College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University
85 Songdogwahak-ro, Yeonsu-gu, Incheon, 21983, Republic of Korea
* Corresponding author. Tel.: +82 32 749 4515; fax: +82 32 749 4105; e-mail:
ikyonkim@yonsei.ac.kr
Table of Contents
Ar'H
P(OEt)3
Ar'
polycyclic
aromatics
ArCHO
Ar
PO(OEt)2
BF3-OEt2
- one-pot synthesis of diarylmethylphosphonates
- rapid access to polycyclic aromatic compounds
via post functionalization in one or two steps
Abstract: A new type of three-component reaction was developed consisting of aldehydes,
electron-rich (hetero)arenes, and trialkyl phosphite, which provided facile access to a wide
range of diarylmethylphosphonates under mild reaction conditions. Simple one- or two-step
synthetic manipulation of the resulting compounds enabled us to reach several polycyclic
(hetero)aromatic systems efficiently.
Keywords: Multicomponent reaction; Diarylmethylphosphonates; Friedel-Crafts reaction;
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Alkenes; Polycyclic heteroaromatics; Tandem reaction.
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Introduction
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Recently, we have reported a direct access to diarylacetonitriles 3 via one-pot, three-component
reaction of aldehydes 1, electron-rich (hetero)arenes, and TMSCN under the influence of BF3-
Et2O (Scheme 1a).1 Mechanistically, this reaction was presumed to occur via 2, which would
be formed by initial attack of TMSCN to aldehydes 1. Synthesis of 3 from 2 can be explained
by subsequent Friedel-Crafts type displacement of OR by (hetero)arenes with the help of Lewis
acid.2 As an extension of this protocol, we reasoned that other nucleophiles instead of TMSCN
could be employed to form a new type of three-component reaction. In this regard, trialkyl
phosphite was chosen in this reaction as a substitute for TMSCN. Indeed, this new combination
proceeded well to lead to various diarylmethylphosphonates 5 (Scheme 1b). To the best of our
knowledge, no one-pot synthesis of diarylmethylphosphonates from commercially available
materials has not been disclosed yet. They have been prepared by multiple steps and/or under
harsh reaction conditions.3 Due to the importance of a number of organophosphonate
compounds in agricultural and medicinal sciences as well as organic chemistry (Figure 1),4 we
hoped to investigate our findings in detail. Here we wish to report our preliminary results on
direct one-pot synthesis of diarylmethylphosphonates and application of this protocol to
polycyclic aromatic systems.
Scheme 1. Synthetic Plans for Three-Component Reactions
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(a) one-pot three-component approach to (ref 1)
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Ar'H
TMSCN
Ar'
OR
CN
(R = TMS or H)
ArCHO
Ar
CN
Ar
L.A.
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1
2
3
(b) new three-component reaction (this work)
Ar'H
P(OR)3
L.A.
Ar'
XO
ArCHO
Ar
PO(OR)2
Ar
PO(OR)2
L.A.
1
4
5
(X = H or Et)
Figure 1. Some Bioactive Organophosphonates
PO(OH)2
Ph
PO(OMe)2
O
(HO)2OP
MeO
OMe
CF3
anticancer agent
inhibitor of human
fosfomycin
(antibiotic)
prostatic acid phosphatase
N
N
PO(OH)2
NH2
N
N
O
HN
O
H
(HO)2OP
N
CO2H
(OH)2OP
O
N
adefovir
(antiviral)
perzinfotel
(NMDA antagonist)
glyphosate
(herbicide)
Results and discussion
After brief screening of several Lewis and Brønsted acids (Table 1), we were pleased to find
that reaction of 3,4-dimethoxybenzaldehyde (1a) with 1,3-dimethoxybenzene and triethyl
phosphite in the presence of BF3-OEt2 (1.0 equiv) at 80 °C gave rise to the desired product 5a
in 95% yield (entry 16).5 However, when the reaction was carried out at room temperature,
formation of intermediates 4a (47%) and 4a’ (40%) was only observed (entry 17). Treatment
of 4a or 4a’ with 1,3-dimethoxybenzene and BF3-OEt2 at 80 °C produced 5a in quantitative
yield.6 Although more catalyst loading resulted in a slight increase in chemical yield as well
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as shortening of the reaction time (entries 18-19), we decided to use 1.0 equiv of BF3-OEt2 for
subsequent reaction scope studies.
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Table 1. Reaction Optimizationa
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OMe
1,3-dimethoxybenzene
CHO
P(OEt)3
OMe
PO(OEt)2
MeO
catalyst
solvent, T (°C)
OMe
MeO
1a
5a
OMe
OH
OEt
+
Ar
PO(OEt)2 Ar
PO(OEt)2
4a'
4a
Ar = 3,4-(MeO)2C6H3
entry
1
2
3
4
5
6
7
8
catalyst (equiv)
Bi(OTf)3 (0.1)
Bi(OTf)3 (0.1)
Bi(OTf)3 (0.1)
Bi(OTf)3 (0.1)
Bi(OTf)3 (0.1)
Cu(OTf)2 (0.1)
Yb(OTf)3 (0.1)
Sc(OTf)3
solvent
DCE
DCE
temp (°C)
rt
time (h)
52
24
48
48
48
48
24
48
24
24
24
24
52
24
24
16
52
12
8
yield (%)b
NR
50
80
80
80
90
80
80
80
80
80
80
80
80
80
80
80
rt
80
80
80
80
80
80
80
DCE
52
54
54
20
38
34
NR
trace
trace
19
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
DCE
9
AgOTf (0.1)
Zn(OTf)2 (0.1)
FeCl3 (0.1)
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
FeCl3 (0.2)
BF3-OEt2 (0.2)
BF3-OEt2 (0.5)
BF3-OEt2 (0.5)
BF3-OEt2 (1.0)
BF3-OEt2 (1.0)
BF3-OEt2 (1.5)
BF3-OEt2 (2.0)
PTSA (0.2)
25
64
49
DCE
CH3NO2
DCE
95
c
DCE
DCE
DCE
-
96
97
NR
NR
15
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
48
48
48
48
48
TFA (0.2)
CH3SO3H (0.2)
TfOH (0.2)
45
77
TfOH (0.5)
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a
A mixture of 1a (100 mg, 0.6 mmol, 1 equiv), 1,3-dimethoxybenzene (1.2 equiv), P(OEt)3
(1.1 equiv), and catalyst in solvent (1 mL) was stirred at the temperature indicated in the Table.
b Isolated yield (%) c Only 4a (47%) and 4a’ (40%) were isolated.
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Other electron-rich arenes also successfully took part in these reactions to afford the
corresponding products in good to excellent yields (Table 2) Triphenyl phosphite and tributyl
phosphite were also employed to give 5i and 5j in good yields. While use of xylene and
mesitylene as arenes gave rise to 5k and 5l, respectively, only 4a’ was isolated in 62% yield in
case of toluene.
Table 2. Synthesis of 5a-5la,b
Ar
ArH
P(OR)3
CHO
PO(OR)2
MeO
BF3-OEt2
DCE
MeO
OMe
OMe
5a-5l
80 °C, 16 h
1a
OMe
OMe
OMe
MeO
OMe
PO(OEt)2
PO(OEt)2
PO(OEt)2
MeO
MeO
MeO
OMe
OMe
OMe
5a (95%)
5b (91%)
5c (93%)
OMe
OMe
OMe
OMe
OMe
MeO
OMe
PO(OEt)2
MeO
OMe
PO(OEt)2
PO(OEt)2
MeO
MeO
MeO
OMe
OMe
OMe
5d (92%)
5e (88%)
5f (90%)
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OMe
OMe
OMe
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9
Br
OMe
Br
OMe
PO(OPh)2
PO(OEt)2
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PO(OEt)2
MeO
MeO
MeO
OMe
OMe
OMe
5i (62%)c
5g (78%)
5h (74%)
Me
OMe
Me
Me
Me
PO(OEt)2
OMe
PO(OBu)2
Me
PO(OEt)2
MeO
MeO
MeO
OMe
OMe
5j (74%)d
OMe
5k (54%)e
5l (68%)
a A mixture of 1a (100 mg, 0.6 mmol, 1 equiv), ArH (1.2 equiv), P(OEt)3 (1.1 equiv), and BF3-
OEt2 (1.0 equiv) in dry DCE (1 mL) was stirred at 80 °C for 16 h unless otherwise indicated. b
Isolated yield (%). c P(OPh)3 (1.1 equiv) was used. d P(OBu)3 (1.1 equiv) was used. e Xylene
(3.2 equiv) was used.
Reaction scope was further examined with different aldehydes as shown in Table 3. Various
aldehydes having alkoxy, hydroxyl, or amino group(s) at the o- and/or p-position reacted well
with 1,3-dimethoxybenzene and triethyl phosphite under optimized conditions to give the
corresponding diarylmethylphosphonates in good yields. Intriguingly, heteroaromatic
aldehydes such as 3-arylbenzofuran-2-carbaldehyde and 1-methyl-1H-indole-3-carbaldehyde
were also good substrates for this reaction to furnish 5u (89%) and 5v (87%), respectively.
When less reactive aldehydes such as p-tolualdehyde and trans-cinnamaldehyde were exposed
to the optimized reaction conditions with 1,3-dimethoxybenzene, respectively, 4a’-type
compounds (4a’-1 and 4a’-2) were obtained in 62 and 74% yields instead of the corresponding
diarylmethylphosphonates,7 implying the importance of resonance stabilization effect of the
reaction intermediate by alkoxy, hydroxyl, amino group(s) at the ortho- and(or) para-position(s)
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of aldehydes for successful three-component coupling reactions under these conditions.
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Table 3. Synthesis of 5m-5va,b
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OMe
1,3-dimethoxybenzene
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P(OEt)3
ArCHO
OMe
BF3-OEt2, DCE
80 °C, 16 h
1
Ar
PO(OEt)2
5m-5v
OMe
OMe
OMe
OMe
PO(OEt)2
OMe
PO(OEt)2
OMe
PO(OEt)2
O
Me
N
O
MeO
Me
5m (94%)
5n (90%)
5o (87%)
OMe
OMe
OMe
OMe
PO(OEt)2
OMe
PO(OEt)2
OMe
OMe
PO(OEt)2
MeO
MeO
MeO
HO
OMe
5p (91%)
5q (88%)
5r (66%)
OMe
OMe
OMe
MeO
OMe
PO(OEt)2
OMe
PO(OEt)2
OMe
PO(OEt)2
O
MeO
MeO
MeO
HO
OH
OMe
5s (71%)
5t (74%)
5u (89%)
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OMe
PO(OEt)2
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N
Me
5v (87%)
a
A mixture of 1 (100 mg, 1 equiv), 1,3-dimethoxybenzene (1.2 equiv), P(OEt)3 (1.1 equiv),
and BF3-OEt2 (1.0 equiv) in dry DCE (1 mL) was stirred at 80 °C for 16 h. b Isolated yield (%).
Heterocycles were successfully employed as nucleophiles in this process as well (Table 4).
Thus, indole, furan, thiophene, and benzofuran-containing diarylmethylphosphonates were
formed in good to excellent yields.
Table 4. Synthesis of 5w-5za,b
HetArH
HetAr
MeO
MeO
CHO
P(OEt)3
MeO
PO(OEt)2
BF3-OEt2, DCE
80 °C, 16 h
MeO
1a
5w-5z
Me
N
O
S
Br
PO(OEt)2
PO(OEt)2
PO(OEt)2
MeO
MeO
MeO
OMe
OMe
OMe
5w (93%)
5x (58%)c
5y (71%)
OMe
MeO
O
MeO
PO(OEt)2
MeO
OMe
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5z (87%)
a A mixture of 1a (100 mg, 0.6 mmol, 1 equiv), HetArH (1.2 equiv), P(OEt)3 (1.1 equiv), and
BF3-OEt2 (1.0 equiv) in dry DCE (1 mL) was stirred at 80 °C for 16 h. b Isolated yield (%). c
HetArH (2.1 equiv) was used.
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For elucidation of this reaction mechanism, a coupling reaction of 3,4-dimethoxybenzaldehyde
(1a) with 1,3-dimethoxybenzene in the presence of BF3-OEt2 was conducted to get
diarylcarbinol (Scheme 2). While no reaction was observed at room temperature, a complex
mixture of products was obtained at 80 °C, indicating that formation of diarylcarbinol is not a
first step in this reaction. On the other hand, when 1a was sequentially treated with triethyl
phosphite and 1,3-dimethoxybenzene under the influence of BF3-OEt2, the desired product 5a
was obtained in excellent yield. These results as well as observation of the reaction at rt led us
to conclude that the reaction occurs via 4a/4a’ intermediates.
Scheme 2. Control Experiments
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1,3-dimethoxybenzene
BF3-OEt2, DCE, rt, 48 h
OH OMe
MeO
MeO
CHO
CHO
MeO
MeO
(no reaction)
OMe
1a
1a
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1,3-dimethoxybenzene
BF3-OEt2, DCE
MeO
MeO
complex mixture
80 °C, 4 h
P(OEt)3
BF3-OEt2
MeO
PO(OEt)2
OX
MeO
MeO
CHO
DCE, 80 °C
MeO
4 h
1a
4a
(X = H)
4a'
(X = OEt)
OMe
MeO
OMe
OMe
PO(OEt)2
MeO
MeO
5a
These one-pot, three-component reactions were performed in gram scales to demonstrate the
feasibility of scale-up (Scheme 3). 5b and 5aa were synthesized in 92% and 94% yield,
respectively. With these two compounds in hand, Horner-Wadsworth-Emmons (HWE)
olefination reactions were carried out under mild conditions, leading to syntheses of triaryl-
substituted alkenes 6a-d as shown in Scheme 4.8 Our two-step sequence would be useful for
synthesis of diverse triarylethenes,9 important structural motifs in medicinal and material
sciences.10
Scheme 3. Gram-scale Synthesis of Diarylmethylphosphonates
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PO(OEt)2
P(OEt)3 (1.1 equiv)
BF3-OEt2 (1.0 equiv)
R
CHO
OMe
+
MeO
DCE, 80 °C, 16 h
MeO
OMe
R
R
R
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R = OMe (1 g, 6.02 mmol) R = OMe
R = H (1 g, 7.35 mmol) R = H
5b
5aa
(R = OMe): 2.45 g (92%)
(R = H): 2.51 g (94%)
Scheme 4. HWE Reactions of Diarylmethylphosphonates
Ar'
Ar'CHO (2 equiv)
PO(OEt)2
Ar
Ar
t-BuOK (2 equiv), THF
0 °C to rt, 14 h
Ar
Ar
5
6
OMe
Cl
Cl
OMe
OMe
MeO
OMe
MeO
OMe
MeO
OMe
OMe
OMe
OMe
6a (78%)
6b (83%)
6c (90%)
MeO
OMe
OMe
MeO
OMe
OMe
OMe
6d (85%)
Synthetic utility of this protocol was further demonstrated in Schemes 5-7. Triarylalkene 6c
was efficiently converted to polycyclic aromatic compounds11,12 7 and 8 by controlling the
amount of DDQ used for Scholl-type ring closure (Scheme 5).13,14 Under similar reaction
conditions, 6d underwent Scholl cyclization to give the fluorene derivative 9 in good yield.
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Exposure of diarylmethylphosphonates 5 with potassium tert-butoxide in the presence of air15
afforded the corresponding diarylketones 10a-d in good yields (Scheme 6). As described in
Scheme 7, direct construction of phenanthrene skeletons (11a-c)16 from 5g, 5h, and 5y were
realized respectively by allowing Suzuki-Miyaura (SM) cross-coupling and HWE olefination
to occur in a one-pot manner. Notably, this type of tandem sequence for the synthesis of
phenanthrenes has not been reported, to the best of our knowledge.17
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Scheme 5. Scholl-type Cyclizations
OMe
OMe
OMe
OMe
OMe
OMe
BF3-OEt2 (10 equiv)
DDQ (1 equiv)
BF3-OEt2 (10 equiv)
DDQ (3 equiv)
6c
0 °C to rt, 20 min
(100%)
MeO
0 °C to rt, 4 h
(92%)
MeO
OMe
OMe
OMe
OMe
8
7
MeO
OMe
OMe
MeO
OMe
OMe
BF3-OEt2 (10 equiv)
DDQ (1 equiv)
0 °C to rt, 10 min
(90%)
MeO
OMe
MeO
OMe
OMe
OMe
OMe
OMe
6d
9
Scheme 6. Synthesis of Benzophenones
O
t-BuOK (5 equiv)
THF, rt, air, 14 h
PO(OEt)2
Ar
Ar
Ar
Ar
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O
O
OMe
O
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MeO
OMe
MeO
OMe
MeO
OMe
OMe
OMe
OMe
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10a (92%)
10b (90%)
10c (88%)
O
OMe
HO
OMe
OMe
10d (75%)
Scheme 7. One-pot Synthesis of Phenanthrenes via a Tandem SM-HWE Reaction
OHC
MeO
MeO
MeO
MeO
(HO)2B
PO(OEt)2
Br
PdCl2(dppf)-CH2Cl2
t-BuOK, dioxane
100 °C, 18 h
5
11a-c
5
11
yield (%)
78
MeO
MeO
5g
5h
11a
11b
OMe
MeO
MeO
70
MeO
OMe
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MeO
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MeO
5y
11c
73
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Conclusion
In conclusion, we have developed a modular one-pot approach to a wide range of
diarylmethylphosphonates from aldehydes, (hetero)arenes, and P(OEt)3 in the presence of BF3-
OEt2 in good to excellent yields under mild reaction conditions. Synthetic scope of this new
three-component reaction as well as mechanism study were investigated. Further elaboration
of the resulting compounds in various ways including HWE olefination/Scholl annulation and
tandem SM-HWE protocol permitted us to get rapid and facile access to polycyclic
(hetero)aromatic systems, which are highly valuable in material sciences.
Experimental Section
General Methods
Unless specified, all reagents and starting materials were purchased from commercial sources
and used as received without purification. “Concentrated” refers to the removal of volatile
solvents via distillation using a rotary evaporator. “Dried” refers to pouring onto, or passing
through, anhydrous magnesium sulfate followed by filtration. Flash chromatography was
performed using silica gel (230−400 mesh) with hexanes, ethyl acetate, and dichloromethane
as the eluents. All reactions were monitored by thin-layer chromatography on 0.25 mm silica
plates (F-254) visualizing with UV light. Melting points were measured using a capillary
melting point apparatus. H and 13C NMR spectra were recorded on 400 MHz NMR
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spectrometer and were described as chemical shifts, multiplicity (s, singlet; d, doublet; t, triplet;
q, quartet; m, multiplet), coupling constant in hertz (Hz), and number of protons. HRMS was
measured with electrospray ionization (ESI) and Q-TOF mass analyzer.
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General Procedure for the Synthesis of Diarylmethylphosphonates (5)
To a stirred solution of 3,4-dimethoxybenzaldehyde (100 mg, 0.6 mmol), various arenes (0.72
mmol, 1.2 equiv), and triethyl phosphite (113 µL, 0.66 mmol, 1.1 equiv) in dry DCE (1 mL)
was added BF3-OEt2 (76 µL, 0.6 mmol, 1.0 equiv) at 0 °C. After being stirred at 80 °C for 16
h, the reaction mixture was diluted with CH2Cl2 (20 mL), washed with aq. NaHCO3 (5 mL ×
2) and water (5 mL). All the organic layers were collected, dried over MgSO4, and concentrated
in vacuo to yield the crude product. Purification by flash chromatography on silica gel
(hexanes:EtOAc) afforded 5.
Diethyl
((2,4-dimethoxyphenyl)(3,4-dimethoxyphenyl)methyl)phosphonate
(5a).
Colorless viscous liquid (242 mg, 95%); Rf = 0.3 in 70% EtOAc
in hexane; 1H NMR (400 MHz, CDCl3) δ 7.80 (dd, J = 8.6, 1.8
Hz, 1H), 7.09 (s, 1H), 7.03 (d, J = 8.3 Hz, 1H), 6.76 (d, J = 8.3
Hz, 1H), 6.49 (dd, J = 8.6, 2.3 Hz, 1H), 6.41 (s, 1H), 4.93 (d, J
= 25.4 Hz, 1H), 4.02 – 3.91 (m, 2H), 3.87 – 3.79 (m, 8H), 3.77
OMe
OMe
PO(OEt)2
MeO
5a
OMe
(s, 3H), 3.77 (s, 3H), 1.12 (q, J = 7.2 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.8 (d, J
= 1.5 Hz, 1C), 157.6 (d, J = 10.1 Hz, 1C), 148.6 (s, 1C), 147.9 (d, J = 2.3 Hz, 1C), 130.6 (d, J
= 5.1 Hz, 1C), 129.8 (d, J = 4.6 Hz, 1C), 121.8 (d, J = 8.3 Hz, 1C), 118.2 (d, J = 3.1 Hz, 1C),
112.9 (d, J = 7.5 Hz, 1C), 111.0 (s, 1C), 104.4 (s, 1C), 98.8 (s, 1C), 62.5 (d, J = 7.2 Hz, 1C),
62.5 (d, J = 6.9 Hz, 1C), 55.9 (s, 1C), 55.7 (s, 1C), 55.7 (s, 1C), 55.4 (s, 1C), 40.6 (d, J = 140.2
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Hz, 1C), 16.4 (d, J = 2.2 Hz, 1C), 16.4 (d, J = 1.7 Hz, 1C); HRMS (ESI-QTOF) m/z [M+H]+
6
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calcd for C21H30O7P 425.1724, found 425.1730.
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4a and 4a’ were obtained when the reaction was conducted at room temperature.
Diethyl ((3,4-dimethoxyphenyl)(hydroxy)methyl)phosphonate (4a). Colorless solid (86 mg,
47%); mp: 100-102 °C; Rf = 0.1 in 100% EtOAc; 1H NMR (400
OH
PO(OEt)2
MHz, CDCl3) δ 7.07 (s, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.80 (d, J
MeO
= 8.2 Hz, 1H), 4.91 (dd, J = 10.1, 5.6 Hz, 1H), 4.64 (brs, 1H),
OMe
4a
4.12 – 3.89 (m, 4H), 3.84 (s, 3H), 3.84 (s, 3H), 1.21 (dt, J = 22.4,
7.0 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 148.8 (s, 2C), 129.2 (s, 1C), 119.7 (d, J = 7.1
Hz, 1C), 110.7 (d, J = 1.8 Hz, 1C), 110.4 (d, J = 5.1 Hz, 1C), 70.5 (d, J = 160.1 Hz, 1C), 63.3
(d, J = 7.1 Hz, 1C), 63.0 (d, J = 7.3 Hz, 1C), 55.9 (s, 2C), 16.5 (d, J = 3.4 Hz, 1C), 16.4 (d, J =
3.7 Hz, 1C); HRMS (ESI-QTOF) m/z [M+Na]+ calcd for C13H21 NaO6P 327.0968, found
327.0978.
Diethyl ((3,4-dimethoxyphenyl)(ethoxy)methyl)phosphonate (4a’). Colorless liquid (80 mg,
40%); Rf = 0.2 in 100% EtOAc; 1H NMR (400 MHz, CDCl3) δ
OEt
PO(OEt)2
6.98 (s, 1H), 6.90 (d, J = 8.1 Hz, 1H), 6.79 (d, J = 8.2 Hz, 1H),
MeO
4.49 (d, J = 15.6 Hz, 1H), 4.09 – 3.85 (m, 4H), 3.83 (s, 3H), 3.81
4a'
OMe
(s, 3H), 3.57 – 3.36 (m, 2H), 1.21 (t, J = 7.0 Hz, 3H), 1.15 (t, J =
7.0 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 149.0 (d, J = 3.0 Hz, 1C), 148.9 (d, J = 2.4
Hz, 1C),127.4 (d, J = 1.5 Hz, 1C), 120.6 (d, J = 7.1 Hz, 1C), 110.7 (d, J = 4.8 Hz, 1C), 110.6
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(dd, J = 2.2 Hz, 1C), 78.5 (d, J = 169.6 Hz, 1C), 66.2 (d, J = 14.3 Hz, 1C), 63.1 (d, J = 6.9 Hz,
1C), 62.7 (d, J = 6.8 Hz, 1C), 55.8 (s, 1C ), 55.8 (s, 1C ), 16.5 (d, J = 5.7 Hz, 1C), 16.3 (d, J =
5.9 Hz, 1C), 15.15 (s, 1C); HRMS (ESI-QTOF) m/z [M+Na]+ calcd for C15H25NaO6P 355.1281,
found 355.1293.
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Diethyl (ethoxy(p-tolyl)methyl)phosphonate (4a’-1). Colorless liquid (148 mg, 62%); Rf =
0.4 in 70% EtOAc in hexane; 1H NMR (400 MHz, CDCl3) δ 7.34
OEt
(d, J = 6.8 Hz, 2H), 7.16 (d, J = 7.4 Hz, 2H), 4.59 (d, J = 15.8
PO(OEt)2
Hz, 1H), 4.15 – 3.93 (m, 4H), 3.64 – 3.40 (m, 2H), 2.34 (s, 3H),
Me
4a'-1
1.32 – 1.15 (m, 9H); 13C{1H} NMR (100 MHz) δ 137.7 (d, J =
3.4 Hz, 1C), 131.8 (d, J = 1.9 Hz, 1C), 128.8 (d, J = 2.4 Hz, 2C), 127.7 (d, J = 6.0 Hz, 2C),
78.2 (d, J = 168.0 Hz, 1C), 66.0 (d, J = 14.2 Hz, 1C), 62.8 (d, J = 7.0 Hz, 1C), 62.6 (d, J = 7.0
Hz, 1C), 20.9 (s, 1C), 16.2 (d, J = 6.0 Hz, 1C), 16.1 (d, J = 6.0 Hz, 1C); 14.9 (s, 1C); HRMS
(ESI-QTOF) m/z [M+Na]+ calcd for C14H23NaO4P 309.1226, found 309.1213.
Diethyl (E)-(1-ethoxy-3-phenylallyl)phosphonate (4a’-2). Colorless liquid (167 mg, 74%);
Rf = 0.4 in 80% EtOAc in hexane; 1H NMR (400 MHz, CDCl3)
OEt
δ 7.42 (d, J = 7.4 Hz, 2H), 7.33 (t, J = 7.4 Hz, 2H), 7.28 (dd, J =
Ph
PO(OEt)2
4a'-2
8.5, 5.3 Hz, 1H), 6.72 (dd, J = 15.9, 4.3 Hz, 1H), 6.25 (ddd, J =
15.9, 7.1, 5.2 Hz, 1H), 4.29 (dd, J = 16.4, 7.2 Hz, 1H), 4.26 – 4.14 (m, 4H), 3.77– 3.69 (m,
1H), 3.65 – 3.55 (m, 1H), 1.33 (t, J = 7.1 Hz, 6H), 1.26 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (100
MHz) δ 136.2 (d, J = 2.7 Hz, 1C), 133.9 (d, J = 13.5 Hz, 1C), 128.7 (s, 2C), 128.1 (s, 1C),
126.8 (d, J = 1.5 Hz, 2C), 123.1 (d, J = 4.1 Hz, 1C), 77.3 (d, J = 168.0 Hz, 1C), 66.6 (d, J =
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12.0 Hz, 1C), 63.2 (d, J = 6.9 Hz, 1C), 62.9 (d, J = 6.9 Hz, 1C), 16.6 (t, J = 4.1 Hz, , 2C ), 15.3
(s, 1C); HRMS (ESI-QTOF) m/z [M+H]+ calcd for C15H24O4P 299.1407, found 299.1406.
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Subjection of 4a or 4a’ to 1,3-dimethoxybenzene and BF3-OEt2 at 80 °C gave rise to 5a in
quantitative yield, respectively.
OMe
MeO
(EtO)2OP
1.2 eq
OMe
(EtO)2OP
MeO
OH
OMe
BF3-Et2O (50 mol%)
DCE, 80 °C, 2 h
OMe
MeO
OMe
4a
5a
OMe
MeO
(EtO)2OP
1.2 eq
OMe
(EtO)2OP
MeO
OEt
OMe
BF3-Et2O (50 mol%)
DCE, 80 °C, 6 h
OMe
MeO
OMe
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5a
Diethyl (bis(3,4-dimethoxyphenyl)methyl)phosphonate (5b). Colorless viscous liquid (231
1
mg, 91%); Rf = 0.3 in 70% EtOAc in hexane; H NMR (400
MHz, CDCl3) δ 7.06 (s, 2H), 7.01 (d, J = 8.3 Hz, 2H), 6.78 (d, J
= 8.3 Hz, 2H), 4.28 (d, J = 25.3 Hz, 1H), 4.02 – 3.90 (m, 2H),
3.87 – 3.73 (m, 14H), 1.11 (t, J = 7.0 Hz, 6H); 13C{1H} NMR
(100 MHz, CDCl3) δ 148.7 (s, 2C), 148.1 (d, J = 2.0 Hz, 2C),
OMe
OMe
PO(OEt)2
MeO
5b
OMe
129.4 (d, J = 5.0 Hz, 2C), 121.6 (d, J = 8.6 Hz, 2C), 112.6 (d, J = 7.7 Hz, 2C), 111.1 (s, 2C),
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62.7 (d, J = 7.2 Hz, 2C), 55.8 (s, 2C), 55.8 (s, 2C), 50.0 (d, J = 137.9 Hz, 1C), 16.4 (d, J = 5.9
Hz, 2C); HRMS (ESI-QTOF) m/z [M+Na]+ calcd for C21H29NaO7P 447.1543, found 447.1556.
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Diethyl ((3,4-dimethoxyphenyl)(4-methoxyphenyl)methyl)phosphonate (5c). Colorless
viscous liquid (219 mg, 93%); Rf = 0.3 in 60% EtOAc in hexane;
OMe
1H NMR (400 MHz, CDCl3) δ 7.40 (dd, J = 8.6, 1.6 Hz, 2H),
7.07 (s, 1H), 7.01 (dd, J = 8.3, 1.8 Hz, 1H), 6.86 – 6.79 (m, 2H),
PO(OEt)2
6.77 (d, J = 8.3 Hz, 1H), 4.29 (d, J = 25.3 Hz, 1H), 4.02 – 3.88
MeO
5c
OMe
(m, 2H), 3.87 – 3.75 (m, 8H), 3.73 (s, 3H), 1.20 – 1.01 (m, 6H);
13C{1H} NMR (100 MHz, CDCl3) δ 158.6 (d, J = 2.1 Hz, 1C), 148.7 (s, 1C), 148.0 (d, J = 1.7
Hz, 1C), 130.3 (d, J = 7.8 Hz, 2C), 129.6 (d, J = 5.0 Hz, 1C), 129.1 (d, J = 5.2 Hz, 1C), 121.6
(d, J = 8.6 Hz, 1C), 113.9 (d, J = 1.0 Hz, 2C), 112.6 (d, J = 7.9 Hz, 1C), 111.1 (s, 1C), 62.6 (d,
J = 7.1 Hz, 2C), 55.8 (s, 1C), 55.8 (s, 1C), 55.2 (s, 1C), 49.7 (d, J = 138.0, 1C), 16.3 (d, J = 6.3
Hz, 2C); HRMS (ESI-QTOF) m/z [M+H]+ calcd for C20H28O6P 395.1618, found 395.1627.
Diethyl ((3,4-dimethoxyphenyl)(2,3,4-trimethoxyphenyl)methyl)phosphonate (5d). Light
yellow viscous liquid (252 mg, 92%); Rf = 0.3 in 60% EtOAc in
OMe
OMe
hexane; 1H NMR (400 MHz, CDCl3) δ 7.61 (dd, J = 8.7, 1.8 Hz,
OMe
1H), 7.11 (s, 1H), 7.04 (d, J = 8.3 Hz, 1H), 6.77 (d, J = 8.3 Hz,
PO(OEt)2
1H), 6.68 (d, J = 8.8 Hz, 1H), 4.89 (d, J = 25.1 Hz, 1H), 4.02–
MeO
5d
OMe
3.92 (m, 2H), 3.88 – 3.77 (m, 17H), 1.12 (dd, J = 15.5, 7.2 Hz,
6H); 13C{1H} NMR (100 MHz, CDCl3) δ 152.9 (d, J = 1.5 Hz, 1C), 151.6 (d, J = 10.6 Hz, 1C),
148.7 (s, 1C), 148.1 (s, 1C), 142.2 (s, 1C), 129.8 (d, J = 5.0 Hz, 1C), 124.4 (d, J = 5.3 Hz, 1C),
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107.4 (d, J = 2.1 Hz, 1C), 62.6 (t, J = 7.2 Hz, 2C), 61.3 (s, 1C), 60.8 (s, 1C), 55.9 (s, 1C), 55.9
(s, 1C), 55.9 (s, 1C), 41.5 (d, J = 140.5 Hz, 1C), 16.5 (d, J = 3.8 Hz, 1C), 16.4 (d, J = 3.7 Hz,
1C); HRMS (ESI-QTOF) m/z [M+H]+ calcd for C22H32O8P 455.1829, found 455.1849.
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Diethyl ((3,4-dimethoxyphenyl)(2,4,6-trimethoxyphenyl)methyl)phosphonate (5e). White
solid (241 mg, 88%); mp: 110-112 °C; Rf = 0.3 in 70% EtOAc in hexane; 1H NMR (400 MHz,
OMe
CDCl3) δ 7.19 (s, 1H), 6.94 (d, J = 8.3 Hz, 1H), 6.70 (d, J = 8.3
Hz, 1H), 6.11 (s, 2H), 5.12 (d, J = 28.3 Hz, 1H), 4.01 – 3.85 (m,
MeO
OMe
4H), 3.82 (s, 3H), 3.78 (s, 3H), 3.77 (s, 6H), 3.76 (s, 3H), 1.14
(dt, J = 17.8, 7.1 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ
160.4 (d, J = 2.0 Hz, 1C), 158.8 (s, 1C), 148.1 (d, J = 1.2 Hz,
PO(OEt)2
MeO
5e
OMe
2C), 147.5 (d, J = 2.0 Hz, 1C), 129.8 (d, J = 3.9 Hz, 1C), 121.8 (d, J = 8.6 Hz, 1C), 113.2 (d, J
= 6.7 Hz, 1C), 110.6 (s, 1C), 107.5 (d, J = 4.0 Hz, 1C), 91.0 (s, 1C), 61.9 (d, J = 6.9 Hz, 1C),
61.8 (d, J = 7.1 Hz, 1C), 55.7 (s, 3C), 55.7 (s, 1C), 55.3 (s, 1C), 55.4 (s, 1C), 39.4 (d, J = 143.3
Hz, 1C), 16.4 (d, J = 6.0 Hz, 1C), 16.3 (d, J = 6.1 Hz, 1C); HRMS (ESI-QTOF) m/z [M+Na]+
calcd for C22H31NaO8P 477.1649, found 477.1666.
Diethyl
((3,4-dimethoxyphenyl)(2,4,5-trimethoxyphenyl)methyl)phosphonate
(5f).
Colorless viscous liquid (246 mg, 90%); Rf = 0.4 in 100% EtOAc; 1H NMR (400 MHz, CDCl3)
OMe
δ 7.52 (d, J = 1.1 Hz, 1H), 7.07 (s, 1H), 7.02 (d, J = 8.3 Hz, 1H),
MeO
6.74 (d, J = 8.3 Hz, 1H), 6.47 (s, 1H), 4.92 (d, J = 25.2 Hz, 1H),
OMe
4.00 – 3.89 (m, 2H), 3.88 – 3.80 (m, 11H), 3.79 (s, 3H), 3.75 (s,
PO(OEt)2
20
MeO
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3H), 1.10 (q, J = 7.1 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 151.0 (d, J = 11.0 Hz, 1C),
148.5 (s, 2C), 147.9 (d, J = 2.2 Hz, 1C), 142.9 (d, J = 1.5 Hz, 1C), 129.6 (d, J = 4.7 Hz, 1C),
121.6 (d, J = 8.3 Hz, 1C), 117.1 (d, J = 3.4 Hz, 1C), 113.7 (d, J = 4.8 Hz, 1C), 112.7 (d, J = 7.6
Hz, 1C), 111.0 (d, J = 1.1 Hz, 1C), 97.8 (s, 1C), 62.5 (d, J = 6.9 Hz, 2C), 56.9 (s, 1C), 56.5 (s,
1C), 56.0 (s, 1C), 55.8 (s, 1C), 55.8 (s, 1C), 40.7 (d, J = 140.3, 1C), 16.4 (d, J = 3.1 Hz, 1C),
16.3 (d, J = 3.1 Hz, 1C); HRMS (ESI-QTOF) m/z [M+H]+ calcd for C22H32O8P 455.1829,
found 455.1836.
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Diethyl ((2-bromo-4-methoxyphenyl)(3,4-dimethoxyphenyl)methyl)phosphonate (5g).
Light yellow viscous liquid (221 mg, 78%); Rf = 0.3 in 70% EtOAc in hexane; 1H NMR (400
OMe
MHz, CDCl3) δ 7.96 (dd, J = 8.8, 1.7 Hz, 1H), 7.12 – 7.08 (m,
2H), 7.05 (d, J = 8.3 Hz, 1H), 6.88 (dd, J = 8.8, 2.6 Hz, 1H), 6.78
Br
(d, J = 8.2 Hz, 1H), 4.95 (d, J = 25.7 Hz, 1H), 4.05 – 3.85 (m,
PO(OEt)2
MeO
7H), 3.83 (s, 3H), 3.76 (s, 3H), 1.14 (td, J = 7.0, 3.8 Hz, 6H);
13C{1H} NMR (100 MHz, CDCl3) δ 159.0 (d, J = 1.4 Hz, 1C),
5g
OMe
148.8 (s, 1C), 148.2 (d, J = 2.2 Hz, 1C), 131.2 (d, J = 4.8 Hz, 1C), 128.8 (dd, J = 9.1, 2.3 Hz,
1C), 125.6 (d, J = 13.6 Hz, 1C), 121.9 (d, J = 8.3 Hz, 1C), 118.4 (s, 2C), 113.8 (d, J = 1.8 Hz,
1C), 112.8 (d, J = 7.6 Hz, 1C), 111.1 (s, 1C), 62.8 (d, J = 7.3 Hz, 1C), 62.7 (d, J = 7.4 Hz, 1C),
55.9 (s, 1C), 55.9 (s, 1C), 55.6 (s, 1C), 47.7 (d, J = 140.2 Hz, 1C), 16.4 (d, J = 2.7 Hz, 1C),
16.3 (d, J = 2.8 Hz, 1C); HRMS (ESI-QTOF) m/z [M+H]+ calcd for C20H2781BrO6P 475.0703,
found 475.0701.
Diethyl((2-bromo-4,6-dimethoxyphenyl)(3,4-dimethoxyphenyl)methyl)phosphonate(5h).
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Light yellow viscous liquid (224 mg, 74%); Rf = 0.2 in 100%
EtOAc; 1H NMR (400 MHz, CDCl3) δ 7.19 (s, 1H), 6.99 (d, J =
8.3 Hz, 1H), 6.73 (d, J = 8.3 Hz, 2H), 6.42 (d, J = 2.0 Hz, 1H),
5.14 (d, J = 28.2 Hz, 1H), 4.03 – 3.88 (m, 4H), 3.83 (s, 3H), 3.81
(s, 3H), 3.79 (s, 3H), 3.75 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H), 1.14
OMe
Br
OMe
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PO(OEt)2
MeO
5h
OMe
(t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.9 (d, J = 1.1 Hz, 1C), 159.5 (d, J
= 4.2 Hz, 1C), 148.3 (s, 1C), 147.8 (s, 1C), 128.6 (d, J = 4.3 Hz, 1C), 126.8 (d, J = 12.4 Hz,
1C), 121.9 (d, J = 8.6 Hz, 1C), 119.5 (d, J = 3.3 Hz, 1C), 113.1 (d, J = 6.9 Hz, 1C), 110.7 (s,
1C), 109.7 (s, 1C), 99.2 (s, 1C), 62.2 (d, J = 6.7 Hz, 1C), 62.1 (d, J = 6.9 Hz, 1C), 55.8 (s, 2C),
55.7 (s, 1C), 55.6 (s, 1C), 47.8 (d, J = 143.5 Hz, 1C), 16.5 (d, J = 6.0 Hz, 1C), 16.40 (d, J = 6.0
Hz, 1C); HRMS (ESI-QTOF) m/z [M+Na]+ calcd for C21H28BrNaO7P 525.0648, found
525.0668.
Diphenyl
((2,4-dimethoxyphenyl)(3,4-
OMe
dimethoxyphenyl)methyl)phosphonate(5i). Colorlessviscous
OMe
PO(OPh)2
1
liquid (191 mg, 61%); Rf = 0.4 in 70% EtOAc in hexane; H
NMR (400 MHz, CDCl3) δ 7.89 (dd, J = 8.5, 1.7 Hz, 1H), 7.20
(t, J = 7.4 Hz, 4H), 7.17 – 7.11 (m, 2H), 7.08 (t, J = 7.4 Hz, 2H),
MeO
5i
OMe
6.88 (d, J = 8.1 Hz, 4H), 6.79 (d, J = 8.3 Hz, 1H), 6.52 (dd, J = 8.5, 2.2 Hz, 1H), 6.43 (s, 1H),
5.33 (d, J = 26.0 Hz, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 3.79 (s, 3H), 3.75 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 160.3 (d, J = 1.6 Hz, 1C), 157.7 (d, J = 11.0 Hz, 1C), 150.8 (d, J = 3.0
Hz, 1C), 150.7 (d, J = 3.0 Hz, 1C), 148.9 (s, 1C), 148.3 (d, J = 2.6 Hz, 1C), 130.8 (d, J = 5.4
Hz, 1C), 129.5 (d, J = 3.3 Hz, 4C), 128.6 (d, J = 4.6 Hz, 1C), 124.9 (s, 2C), 122.2 (d, J = 9.1
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Hz, 1C), 120.7 (dd, J = 4.3, 2.3 Hz, 4C), 117.1 (d, J = 2.9 Hz, 1C), 113.1 (d, J = 7.8 Hz, 1C),
111.3 (s, 1C), 104.6 (s, 1C), 98.9 (s, 1C), 55.9 (s, 2C), 55.7 (s, 1C), 55.5 (s, 1C), 41.0 (d, J =
141.0, 1C); HRMS (ESI-QTOF) m/z [M+H]+ calcd for C25H38O7P 481.2350, found 481.2350.
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Dibutyl
((2,4-dimethoxyphenyl)(3,4-dimethoxyphenyl)methyl)phosphonate
(5j).
Colorless liquid (242 mg, 84%); Rf = 0.4 in 50% EtOAc in
hexane; 1H NMR (400 MHz, CDCl3) δ 7.82 (dd, J = 8.5, 1.6 Hz,
1H), 7.11 (s, 1H), 7.04 (d, J = 8.3 Hz, 1H), 6.77 (d, J = 8.3 Hz,
1H), 6.50 (dd, J = 8.5, 2.3 Hz, 1H), 6.42 (s, 1H), 4.94 (d, J = 25.4
Hz, 1H), 3.96 – 3.88 (m, 2H), 3.87 (s, 3H), 3.83 (s, 3H), 3.78 (s,
OMe
OMe
PO(OBu)2
MeO
5j
OMe
6H), 3.78 – 3.70 (m, 2H), 1.43 (dt, J = 15.3, 7.8 Hz, 4H), 1.23 (dp, J = 14.1, 7.2 Hz, 4H), 0.82
(td, J = 7.4, 3.6 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.9 (d, J = 1.8 Hz, 1C), 157.7
(d, J = 10.2 Hz, 1C), 148.7 (s, 1C), 148.0 (d, J = 1.5 Hz, 1C), 130.7 (d, J = 5.3 Hz, 1C), 130.1
(d, J = 4.5 Hz, 1C), 121.9 (d, J = 8.4 Hz, 1C), 118.4 (d, J = 3.1 Hz, 1C), 113.1 (d, J = 7.5 Hz,
1C), 111.2 (s, 1C), 104.5 (s, 1C), 98.8 (s, 1C), 66.3 (d, J = 7.1 Hz, 1C), 66.2 (d, J = 7.3 Hz,
1C), 55.9 (s, 2C), 55.8 (s, 1C), 55.5 (s, 1C), 40.3 (d, J = 140.4 Hz, 1C), 32.6 (d, J = 3.3 Hz,
1C), 32.6 (d, J = 3.3 Hz, 1C), 18.8 (s, 1C), 18.7 (s, 1C), 13.7 (s, 2C); HRMS (ESI-QTOF) m/z
[M+H]+ calcd for C25H37O7P 481.2350, found 481.2350.
Diethyl ((3,4-dimethoxyphenyl)(2,4-dimethylphenyl)methyl)phosphonate (5k). Colorless
1
liquid (127 mg, 54%); Rf = 0.3 in 50% EtOAc in hexane; H
Me
NMR (400 MHz, CDCl3) δ 7.79 (d, J = 7.9 Hz, 1H), 7.05 (s,
Me
1H), 7.02 (d, J = 8.3 Hz, 1H), 6.96 (d, J = 7.4 Hz, 2H), 6.76 (d,
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J = 8.3 Hz, 1H), 4.56 (d, J = 26.1 Hz, 1H), 4.01 – 3.92 (m, 2H), 3.84 (s, 3H), 3.83 – 3.75 (m,
5H), 2.29 (s, 3H), 2.27 (s, 3H), 1.16 (t, J = 7.1 Hz, 3H), 1.11 (t, J = 7.3 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 148.8 (d, J = 1.3 Hz, 1C), 148.1 (d, J = 2.5 Hz, 1C), 136.7 (d, J = 1.3 Hz,
1C), 136.2 (s, 1C), 136.1 (s, 1C), 132.5 (d, J = 3.7 Hz, 1C), 131.5 (s, 1C), 129.2 (d, J = 5.4 Hz,
1C), 126.9 (d, J = 1.4 Hz, 1C), 122.1 (d, J = 8.4 Hz, 1C), 113.1 (d, J = 7.2 Hz, 1C), 111.1 (s,
1C), 62.7 (d, J = 7.2 Hz, 1C), 62.5 (d, J = 7.2 Hz, 1C), 55.9 (s, 1C), 55.9 (s, 1C), 45.8 (d, J =
139.1 Hz, 1C), 21.0 (s, 1C), 20.0 (s, 1C), 16.4 (d, J = 7.0 Hz, 1C), 16.3 (d, J = 6.1 Hz, 1C);
HRMS (ESI-QTOF) m/z [M+H]+ calcd for C21H30O5P 393.1825, found 393.1802.
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Diethyl ((3,4-dimethoxyphenyl)(mesityl)methyl)phosphonate (5l). Colorless liquid (127 mg,
68%); Rf = 0.3 in 50% EtOAc in hexane; 1H NMR (400 MHz,
Me
CDCl3) δ 7.03 (s, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.88 (s, 1H),
Me
Me
6.75 (d, J = 8.2 Hz, 2H), 5.02 (d, J = 30.9 Hz, 1H), 4.27 – 4.05
(m, 2H), 3.89 – 3.81 (m, 4H), 3.79 (s, 3H), 3.49 – 3.32 (m, 1H),
2.45 (s, 3H), 2.24 (s, 3H), 2.08 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H),
PO(OEt)2
MeO
5l
OMe
1.00 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 148.6 (s, 1C), 147.4 (s, 1C), 139.5
(d, J = 4.4 Hz, 1C), 137.8 (d, J = 7.7 Hz, 1C), 136.6 (d, J = 3.2 Hz, 1C), 131.1 (d, J = 1 3.0 Hz,
1C), 131.0 (d, J = 6.3 Hz , 1C), 129.9 (d, J = 1.1 Hz, 1C), 129.0 (d, J = 1.7 Hz, 1C), 121.4 (d,
J = 11.2 Hz, 1C), 112.6 (d, J = 10.7 Hz, 1C), 111.04 (s, 1C), 62.9 (d, J = 6.8 Hz, 1C), 61.5 (d,
J = 7.5 Hz, 1C), 55.9 (s, 1C), 55.9 (s, 1C), 44.3 (d, J = 141.0 Hz, 1C), 21.8 (s, 1C), 21.6 (s,
1C), 20.9 (s, 1C), 16.6 (d, J = 6.0 Hz, 1C), 16.3 (d, J = 5.7 Hz, 1C); HRMS (ESI-QTOF) m/z
[M+H]+ calcd for C22H32O5P 407.1982, found 407.1980.
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Diethyl ((2,4-dimethoxyphenyl)(4-methoxyphenyl)methyl)phosphonate (5m). Colorless
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viscous liquid (223 mg, 94%); Rf = 0.3 in 50% EtOAc in hexane;
OMe
1H NMR (400 MHz, CDCl3) δ 7.82 (dd, J = 8.5, 1.3 Hz, 1H),
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OMe
7.42 (d, J = 7.2 Hz, 2H), 6.81 (d, J = 8.5 Hz, 2H), 6.50 (dd, J =
PO(OEt)2
8.5, 2.1 Hz, 1H), 6.41 (s, 1H), 4.94 (d, J = 25.4 Hz, 1H), 4.03 –
MeO
5m
3.80 (m, 4H), 3.78 (s, 3H), 3.77 (s, 3H), 3.75 (s, 3H), 1.12 (td, J
= 7.0, 3.5 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.8 (s, 1C), 158.5 (d, J = 2.2 Hz,
1C), 157.6 (d, J = 10.5 Hz, 1C), 130.7 (s, 1C), 130.6 (s, 1C), 130.6 (s, 2C), 129.4 (d, J = 4.9
Hz, 1C), 118.4 (d, J = 2.9 Hz, 1C), 113.8 (s, 1C), 104.3 (s, 1C), 98.8 (s, 1C), 62.5 (d, J = 7.1
Hz, 1C), 62.4 (d, J = 7.0 Hz, 1C), 55.7 (s, 1C), 55.4 (s, 1C), 55.3 (s, 1C), 40.0 (d, J = 140.5,
1C), 16.4 (s, 1C), 16.3 (s, 1C); HRMS (ESI-QTOF) m/z [M+K]+ calcd for C20H27KO6P
433.1177, found 433.1169.
Diethyl
(benzo[d][1,3]dioxol-5-yl(2,4-dimethoxyphenyl)methyl)phosphonate
(5n).
Colorless viscous liquid (245 mg, 90%); Rf = 0.4 in 50% EtOAc
in hexane; 1H NMR (400 MHz, CDCl3) δ 7.80 (dd, J = 8.5, 1.7
Hz, 1H), 7.01 (s, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.70 (d, J = 8.0
Hz, 1H), 6.50 (dd, J = 8.5, 2.3 Hz, 1H), 6.41 (s, 1H), 5.89 (s,
2H), 4.90 (d, J = 25.4 Hz, 1H), 4.05 – 3.81 (m, 4H), 3.78 (s, 3H),
OMe
OMe
PO(OEt)2
5n
O
O
3.77 (s, 3H), 1.14 (dt, J = 17.0, 7.1 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.9 (d, J =
1.4 Hz, 1C), 157.7 (d, J = 10.3 Hz, 1C), 147.6 (s, 1C), 146.5 (d, J = 2.3 Hz, 1C), 131.1 (d, J =
4.8 Hz, 1C), 130.6 (d, J = 5.3 Hz, 1C), 122.9 (d, J = 8.4 Hz, 1C), 118.2 (d, J = 2.9 Hz, 1C),
110.2 (d, J = 7.5 Hz, 1C), 108.2 (d, J = 1.4 Hz, 1C), 104.4 (d, J = 1.4 Hz, 1C), 101.0 (s, 1C),
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98.8 (s, 1C), 62.7 (d, J = 7.1 Hz, 1C), 62.5 (d, J = 7.1 Hz, 1C), 55.80 (s, 1C), 55.42 (s, 1C),
40.8 (d, J = 140.9, 1C), 16.4 (d, J = 3.0 Hz, 1C), 16.4 (d, J = 3.0 Hz, 1C); HRMS (ESI-QTOF)
m/z [M+Na]+ calcd for C20H25NaO7P 431.1230, found 431.1236.
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Diethyl ((2,4-dimethoxyphenyl)(4-(dimethylamino)phenyl)methyl)phosphonate (5o).
Light yellow viscous liquid (237 mg, 87%); Rf = 0.4 in 50%
OMe
1
EtOAc in hexane; H NMR (400 MHz, CDCl3) δ 7.81 (d, J =
OMe
PO(OEt)2
5o
8.4 Hz, 1H), 7.36 (d, J = 8.2 Hz, 2H), 6.65 (d, J = 8.4 Hz, 2H),
6.49 (dd, J = 8.5, 1.9 Hz, 1H), 6.40 (s, 1H), 4.91 (d, J = 25.4 Hz,
1H), 4.03 – 3.90 (m, 2H), 3.85 (dt, J = 15.9, 7.9 Hz, 2H), 3.77
Me
N
Me
(s, 6H), 2.89 (s, 6H), 1.13 (q, J = 7.0 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.7 (d, J
= 1.5 Hz, 1C), 157.7 (d, J = 10.4 Hz, 1C), 149.6 (s, 1C), 130.7 (d, J = 5.2 Hz, 1C), 130.3 (d, J
= 7.7 Hz, 2C), 125.1 (d, J = 5.3 Hz, 1C), 118.8 (d, J = 2.8 Hz, 1C), 112.7 (d, J = 1.0 Hz, 2C),
104.3 (s, 1C), 98.8 (s, 1C), 62.5 (s, 1C), 62.4 (s, 1C), 55.8 (s, 1C), 55.4 (s, 1C), 40.8 (d, J =
140.0, 1C), 40.7 (s, 2C), 16.5 (d, J = 2.7 Hz, 1C), 16.4 (d, J = 2.7 Hz, 1C); HRMS (ESI-QTOF)
m/z [M+Na]+ calcd for C21H30NNaO5P 430.1754, found 430.1748.
Diethyl ((2,4-dimethoxyphenyl)(3,4,5-trimethoxyphenyl)methyl)phosphonate (5p).
Colorless viscous liquid (210 mg, 91%); Rf = 0.3 in 50% EtOAc
in hexane; 1H NMR (400 MHz, CDCl3) δ 7.78 (dd, J = 8.5, 1.8
Hz, 1H), 6.77 (s, 2H), 6.50 (dd, J = 8.6, 2.2 Hz, 1H), 6.43 (s,
1H), 4.92 (d, J = 25.4 Hz, 1H), 4.03 – 3.84 (m, 4H), 3.82 (s, 6H),
OMe
OMe
MeO
MeO
PO(OEt)2
5p
OMe
3.79 (s, 3H), 3.78 (s, 6H), 1.13 (dt, J = 17.4, 7.1 Hz, 6H); 13C{1H}
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NMR (100 MHz, CDCl3) δ 159.9 (d, J = 1.5 Hz, 1C), 157.7 (s, 1C), 157.6 (s, 1C), 152.9 (d, J
= 1.3 Hz, 2C), 136.9 (d, J = 2.5 Hz, 1C), 132.9 (d, J = 4.4 Hz, 1C), 130.6 (d, J = 5.1 Hz, 1C),
117.8 (d, J = 3.4 Hz, 1C), 106.8 (d, J = 8.2 Hz, 1C), 104.4 (d, J = 1.6 Hz, 1C), 98.8 (s, 1C),
62.7 (s, 1C), 62.6 (s, 1C), 60.8 (d, J = 2.0 Hz, 1C), 56.1 (s, 2C), 55.8 (s, 1C), 55.4 (s, 1C), 41.1
(d, J = 140.2, 1C), 16.4 (d, J = 2.0 Hz, 1C), 16.4 (d, J = 1.8 Hz, 1C); HRMS (ESI-QTOF) m/z
[M+Na]+ calcd for C22H31NaO8P 477.1649, found 477.1652.
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Diethyl (bis(2,4-dimethoxyphenyl)methyl)phosphonate (5q). Colorless viscous liquid (225
1
mg, 88%); Rf = 0.3 in 70% EtOAc in hexane; H NMR (400
OMe
MHz, CDCl3) δ 7.67 (dd, J = 8.5, 1.7 Hz, 2H), 6.42 (dd, J = 8.5,
2.0 Hz, 2H), 6.37 (s, 2H), 5.48 (d, J = 25.1 Hz, 1H), 3.93 (tt, J =
OMe
PO(OEt)2
16.9, 7.0 Hz, 2H), 3.86 – 3.79 (m, 2H), 3.74 (s, 6H), 3.70 (s, 6H),
MeO
OMe
13
1.09 (t, J = 7.1 Hz, 6H); C{1H} NMR (100 MHz, CDCl3) δ
5q
159.6 (d, J = 1.6 Hz, 2C), 157.9 (d, J = 9.7 Hz, 2C), 130.9 (d, J = 5.2 Hz, 2C), 118.5 (d, J = 3.4
Hz, 2C), 104.2 (d, J = 1.4 Hz, 2C), 98.7 (s, 2C), 62.2 (s, 1C), 62.1 (s, 1C), 55.8 (s, 2C), 55.2
(s, 2C), 32.2 (d, J = 142.2, 1C), 16.3 (s, 1C), 16.2 (s, 1C); HRMS (ESI-QTOF) m/z [M+H]+
calcd for C21H30O7P 425.1724, found 425.1735.
Diethyl ((2,4-dimethoxyphenyl)(4-hydroxyphenyl)methyl)phosphonate (5r). Brown solid
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(205 mg, 66%); mp: 90-92°C; Rf = 0.3 in 100% EtOAc; H
OMe
NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.5 Hz, 1H), 7.27 – 7.19
OMe
(m, 2H), 6.65 (d, J = 8.0 Hz, 2H), 6.50 (d, J = 8.4 Hz, 1H), 6.41
PO(OEt)2
(s, 1H), 4.94 (d, J = 25.6 Hz, 1H), 3.94 (ddd, J = 23.0, 12.8, 5.5
HO
5r
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Hz, 4H), 3.78 (s, 3H), 3.75 (s, 3H), 1.13 (t, J = 6.0 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3)
δ 159.9 (d, J = 1.3 Hz, 1C), 157.7 (d, J = 10.7 Hz, 1C), 156.1 (d, J = 2.7 Hz, 1C), 130.6 (s, 1C),
130.6 (s, 1C), 130.5 (s, 2C), 127.1 (d, J = 5.4 Hz, 1C), 117.9 (d, J = 2.9 Hz, 1C), 115.8 (d, J =
1.3 Hz, 1C), 104.3 (s, 1C), 98.8 (s, 1C), 63.0 (d, J = 7.3 Hz, 1C), 60.8 (d, J = 7.0 Hz, 1C), 55.7
(s, 1C), 55.4 (s, 1C), 40.0 (d, J = 140.8, 1C), 16.4 (s, 1C), 16.3 (s, 1C); HRMS (ESI-QTOF)
m/z [M+H]+ calcd for C19H26O6P 381.1462, found 381.1469.
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Diethyl ((2,4-dimethoxyphenyl)(4-hydroxy-3-methoxyphenyl)methyl)phosphonate (5s).
OMe
Ivory liquid (191 mg, 71%); Rf = 0.3 in 100% EtOAc; 1H NMR
(400 MHz, CDCl3) δ 7.80 (dd, J = 8.5, 1.8 Hz, 1H), 7.08 (s, 1H),
OMe
6.94 (d, J = 8.2 Hz, 1H), 6.78 (d, J = 8.2 Hz, 1H), 6.49 (dd, J =
PO(OEt)2
HO
8.5, 2.4 Hz, 1H), 6.41 (s, 1H), 6.17 (s, 1H), 4.92 (d, J = 25.5 Hz,
5s
OMe
1H), 4.01 – 3.92 (m, 2H), 3.87 – 3.80 (m, 5H), 3.77 (s, 6H), 1.12
(dd, J = 15.8, 7.1 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.8 (d, J = 1.5 Hz, 1C), 157.6
(d, J = 10.1 Hz, 1C), 146.5 (d, J = 1.3 Hz, 1C), 144.8 (d, J = 2.3 Hz, 1C), 130.5 (d, J = 5.3 Hz,
1C), 128.8 (d, J = 4.8 Hz, 1C), 122.5 (d, J = 8.5 Hz, 1C), 118.2 (d, J = 3.1 Hz, 1C), 114.4 (s,
1C), 112.4 (d, J = 7.4 Hz, 1C), 104.4 (d, J = 1.1 Hz, 1C), 98.8 (s, 1C), 62.6 (d, J = 7.0 Hz, 1C),
62.5 (d, J = 7.0 Hz, 1C), 55.9 (s, 1C), 55.7 (s, 1C), 55.3 (s, 1C), 40.6 (d, J = 140.4 Hz, 1C),
16.4 (d, J = 1.1 Hz, 1C),16.3 (s, 1C); HRMS (ESI-QTOF) m/z [M+H]+ calcd for C20H28O7P
411.1567, found 411.1583.
Diethyl
((2,4-dimethoxyphenyl)(3-hydroxy-4-
OMe
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methoxyphenyl)methyl)phosphonate (5t). White solid (199 mg, 74%); mp: 147-149 °C; Rf
= 0.3 in 100% EtOAc; 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.3 Hz, 1H), 7.12 (s, 1H),
7.01 (d, J = 8.0 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.47 (d, J = 8.1 Hz, 1H), 6.41 (s, 1H), 6.15
– 5.89 (m, 1H), 4.91 (d, J = 25.4 Hz, 1H), 4.04 – 3.92 (m, 2H), 3.91 – 3.83 (m, 2H), 3.81 (s,
3H), 3.76 (s, 6H), 1.13 (dt, J = 13.8, 7.0 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.8
(s, 1C), 157.6 (d, J = 10.5 Hz, 1C), 145.8 (d, J = 2.3 Hz, 1C), 145.5 (d, J = 4.2 Hz, 1C), 130.7
(d, J = 5.2 Hz, 1C), 130.5 (d, J = 4.4 Hz, 1C), 121.1 (d, J = 7.9 Hz, 1C), 118.3 (d, J = 3.3 Hz,
1C), 116.2 (d, J = 7.8 Hz, 1C), 110.7 (s, 1C), 104.4 (d, J = 1.2 Hz, 1C), 98.8 (s, 1C), 62.7 (s,
1C), 62.5 (d, J = 7.2 Hz, 1C), 55.9 (s, 1C), 55.8 (s, 1C), 55.4 (s, 1C), 40.5 (d, J = 140.7 Hz,
1C), 16.4 (d, J = 2.2 Hz, 1C), 16.3 (d, J = 2.1 Hz, 1C); HRMS (ESI-QTOF) m/z [M+H]+ calcd
for C20H28O7P 411.1567, found 411.1586.
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Diethyl
((5,6-dimethoxy-3-(4-methoxyphenyl)benzofuran-2-yl)(2,4-
dimethoxyphenyl)methyl)phosphonate (5u). Colorless liquid (178 mg, 89%); Rf = 0.4 in
100% EtOAc; 1H NMR (400 MHz, CDCl3) δ 8.06 (dd, J =
OMe
MeO
8.6, 2.1 Hz, 1H), 7.43 (d, J = 8.6 Hz, 2H), 7.15 (s, 1H), 7.03
(d, J = 8.6 Hz, 2H), 6.90 (s, 1H), 6.55 (dd, J = 8.6, 2.2 Hz,
1H), 6.42 (s, 1H), 5.42 (d, J = 26.3 Hz, 1H), 4.03 – 3.86 (m,
10H), 3.85 (s, 3H), 3.79 (s, 3H), 3.70 (s, 3H), 1.11 (t, J = 7.1
OMe
PO(OEt)2
O
MeO
MeO
5u
Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.3 (d, J = 2.2 Hz, 1C), 158.9 (s, 1C), 157.4
(d, J = 7.8 Hz, 1C), 149.2 (s, 1C), 147.8 (s, 1C), 147.4 (d, J = 12.5 Hz, 1C), 146.6 (s, 1C), 132.1
(d, J = 4.4 Hz, 1C), 130.5 (s, 2C), 124.8 (d, J = 2.0 Hz, 1C), 120.5 (d, J = 1.4 Hz, 1C), 118.8
(d, J = 10.2 Hz, 1C), 115.1 (d, J = 3.9 Hz, 1C), 114.2 (s, 2C), 104.7 (d, J = 2.1 Hz, 1C), 101.2
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