Highly diastereoselective vinylogous Mukaiyama aldol reaction of α-keto phosphonates with 2-(trimethylsilyloxy)furan catalyzed by Cu(OTf)2

Article abstract of DOI:10.1039/c1ob05822c

The diastereospecific formation of δ-hydroxyalkylbutenolide phosphonate has been achieved via a vinylogous Mukaiyama aldol reaction. The reaction was performed using α-ketophosphonate 1 and 2-(trimethylsilyloxy) furan 2 mediated by Cu(OTf)₂ and 2,2,2-trifluoroethanol as additive in CH₂Cl₂. The reaction proceeds rapidly and affords the corresponding 5-(hydroxy(aryl)methyl) furan-2(5H)-one phosphonates 3 in high yields with good to excellent diastereoselectivities (d.r. up to >99:1). 5-(Hydroxy(alkyl)methyl)furan-2(5H)-one phosphonates could also be obtained with good diastereoselectivities.

Full text of DOI:10.1039/c1ob05822c

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PAPER
Highly diastereoselective vinylogous Mukaiyama aldol reaction of a-keto
phosphonates with 2-(trimethylsilyloxy)furan catalyzed by Cu(OTf)2†
Jipan Yu, Xiaona Zhao, Zhiwei Miao* and Ruyu Chen*
Received 25th May 2011, Accepted 24th June 2011
DOI: 10.1039/c1ob05822c
The diastereospecific formation of d-hydroxyalkylbutenolide phosphonate has been achieved via a
vinylogous Mukaiyama aldol reaction. The reaction was performed using a-ketophosphonate 1 and
2-(trimethylsilyloxy)furan 2 mediated by Cu(OTf)2 and 2,2,2-trifluoroethanol as additive in CH2Cl2.
The reaction proceeds rapidly and affords the corresponding 5-(hydroxy(aryl)methyl) furan-2(5H)-one
phosphonates 3 in high yields with good to excellent diastereoselectivities (d.r. up to >99 : 1).
5-(Hydroxy(alkyl)methyl)furan-2(5H)-one phosphonates could also be obtained with good
diastereoselectivities.
The pharmaceutical potential of these compounds has stimu-
lated the development of methodology for their preparation,
particularly in stereoselective enriched forms. Much effort has
been directed toward the stereoselective synthesis of a-hydroxy
Introduction
The catalytic coupling of trialkylsilyloxyfurans with aldehydes by
means of aldol reaction has emerged as a pre-eminent strategy
for butenolide synthesis.1 In 1974, Mukaiyama and co-workers
phosphonates that can fix the stereochemistry of the a-hydroxy-
substituted carbon.11 Recently, Zhao and co-workers reported the
organocatalytic enantioselective synthesis of both diastereomers
of a-hydroxy phosphinates through the asymmetric aldol reaction
of a-keto phosphinates.12 Rawal developed diastereoselective and
enantioselective synthesis of tertiary a-hydroxy phosphonates
through hydrogen-bond catalysis.13 However, the asymmetric
vinylogous Mukaiyama aldol reaction of a-keto phosphonates
has still not been decribed so far. Therefore, it is very desirable
to develop an asymmetric synthesis of d-hydroxyalkylbutenolide
phosphonates. As a part of our ongoing interest in preparing
chiral d-butenolide derivatives,14 we report herein a Cu(OTf)2
catalyzed diastereoselective vinylogous Mukaiyama aldol
reactions.
reported the Lewis acid-promoted condensation of trialkylsilyl
enol-ethers with carbonyl compounds to produce cross-aldol
products.2 The vinylogous Mukaiyama aldol reaction rapidly
provides 5-(hydroxy(aryl)methyl)furan-2(5H)-ones by addition of
the g-carbon of a dienolate on a carbonyl framework.3 The
corresponding vinylogous adducts were obtained as a mixture
of racemic stereoisomer and the stereochemical behavior of the
process began to be investigated over past years.4 In recent years,
the diastereoselective addition of variously substituted furan-
based silyloxy diene synthons to a variety of achiral aldehydes
and acetals using Lewis acids as catalysts has been reported.
In 2005, Lera reported the simple diastereoselectivity of the
BF3·Et2O-catalyzed vinylogous Mukaiyama aldol reaction of 2-
(trimethylsilyloxy)furans with aldehydes.5 Ollevier and co-workers
developed an efficient diastereoselective vinylogous Mukaiyama
aldol reaction of 2-(trimethylsilyloxy)furans with various aromatic
aldehydes mediated by bismuth triflate. The reaction proceeded
rapidly and providing one major diastereoisomer with good
diastereoselectivity.4
Results and discussion
The reaction has been first explored with diethyl benzoylphospho-
nate 1a and 2-(trimethylsilyloxy)furan (TMSOF) 2 in Et2O at 0 ◦C
to examine the Lewis acid suitable for promoting the reaction. The
results revealed that there was no product 3a detected without the
aid of a Lewis acid (Table 1, entry 1). With iodine (20 mol%) as
catalyst only caused anomerization of a-ketophosphonate, and
no product 3a was observed (Table 1, entry 2). Other Lewis acids
tested (e.g., BF3·OEt2, FeCl3 and AlCl3) were able to promote the
addition (Table 1, entries 3–5). In the presence of Zn(OTf)2 or
Cu(OTf)2 (0.2 equiv) at 0 ◦C, the aromatic a-ketophosphonate 1a
led to 3a in good yield and excellent diastereoselectivity (Table 1,
a-Functionalized phosphonic acid derivatives have attracted
attention because of their widely used for pharmaceutical ap-
plications, such as anticancer6 and antivirus activities.7 They
have been found to display inhibitory activity towards several
important groups of enzymes, including renin,8 HIV protease,9
and various classes of protein tyrosine kinases and phosphatases.10
State Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai
University, Tianjin, 300071, China. E-mail: miaozhiwei@nankai.edu.cn;
Fax: +86 2350 2351; Tel: +86 2350 4783
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c1ob05822c
1
entries 6–7). In H and 31P NMR spectra, the diastereoisomer
ratio was measured. The X-ray crystal structure of 3a revealed the
figuration anti between C5 and C6 (Fig. 1).15 Since Cu(OTf)2 gave
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Table 1 Screening catalysts for the asymmetric vinylogous Makaiyama aldol reactiona
Entry
Lewis acid (equiv.)
Solvent
Time (h)
Yields (%)b
Dr (anti/syn)c
1
2
3
4
5
6
7
8
—
I2 (0.2)
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
CH2Cl2
toluene
THF
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
24
24
3
4
6
1
1
1
1
1
1
0.1
0.1
1
n.r.d
n.r.
36
77
79
66
69
78
94
77
81
86
88
—
—
BF3·Et2O (0.2)
84 : 16
50 : 50
86 : 14
90 : 10
94 : 6
95 : 5
84 : 16
80 : 20
92 : 8
95 : 5
95 : 5
—
FeCl3 (0.2)
AlCl3 (0.2)
Zn(OTf)2 (0.2)
Cu(OTf)2 (0.2)
Cu(OTf)2 (0.2)
Cu(OTf)2 (0.2)
Cu(OTf)2 (0.2)
Cu(OTf)2 (0.2)
Cu(OTf)2 (0.2)e
Cu(OTf)2 (0.05)e
Cu(OTf)2 (0.01)e
9
10
11
12
13
14
n.r.
a Unless otherwise noted all the reactions were performed with 1 mmol of 1a, 2.0 mmol TMSOF in 2 mL solvent at 0 ◦C. b After purification by
1
chromatography. c Diastereomeric ratio (Dr) values were determined by H and 31P NMR of unpurified products. d No reaction. e 1.2 Equiv of 2,2,2-
trifluoroethanol was added.
With further optimization of the reaction conditions, we found
that a lower catalyst loading (5 mol%) afforded the product with
the same diastereoselectivity and higher yield (Table 1, entry
13). When decreasing the amount of catalyst to 1 mol%, the
reaction did not proceed (Table 1, entry 14). Thus, the optimal
reaction conditions for this transformation were determined
to be 1.0 mmol of a-ketophosphonate 1, 2 equivalents of 2-
(trimethylsilyloxy)furan 2, 5 mol% of Cu(OTf)2 and 1.2 equivalent
of TFE as additive in CH2Cl2 as solvent at 0 ◦C.
Based on the above optimization efforts, the substrate scope
of this reaction was investigated (Table 2). A variety of aromatic
a-ketophosphonates were found to be suitable coupling partners
with TMSOF. Electron-donating and electron-withdrawing sub-
strates underwent reaction in isolated yields ranging from 56% to
89% and with good to excellent diastereoselectivities. Moreover,
variation in the electronic nature of the substituent position on
Fig. 1 The X-ray crystal structure of 3a.
the higher diastereoselectivity (d. r. = 94 : 6) compared with other
Lewis acids, it was used in further investigations.
the aromatic ring has apparently no influence on the efficiency
and diastereoselectivity of the reaction. Particularly, this process
was efficient for aliphatic a-ketophosphonates and afforded the
desired products with good diastereoselectivities in 46–71% yields
but with longer reaction time.
With the best Lewis acid Cu(OTf)2 being identified, we next
carried out the vinylogous Mukaiyama aldol reaction of 1a with 2
in different solvents to determine the best solvent for this reaction.
Among the various solvents tested, dichloromethane, toluene,
tetrahydrofuran and trichloromethane afforded good yields of
the expected product with moderate to good diastereoselectivities
(Table 1, entries 8–11). The most suitable solvent was found
to be dichloromethane. 5-(Hydroxy(phenyl)methyl)furan-2(5H)-
one phosphonate 3a was obtained in good yield and excellent
diastereoselectivity. In order to improve the reactivity and diastere-
oselectivity, the effect of additive was investigated. It was reported
that 2,2,2-trifluoroethanol (TFE) has the effect to improve the
reactivity and diastereoselectivity of the vinylogous Mukaiyama
aldol reaction.16 In our investigation, after screening the Lewis
acid, it was found that Cu(OTf)2 combined with TFE gave superior
results in terms of reactivity and diastereoselectivity (86% yield,
95 : 5 d.r., Table 1, entry 12).
The possible mechanistic pathway of the vinylogous
Mukaiyama aldol reaction of trimethylsilyloxyfuran and a-
ketophosphonate catalyzed by Cu(OTf)2 is illustrated in Fig. 2.
The reaction was proposed to proceed via the staggered acyclic
transition state.17 The Cu(OTf)2 occupied a coordination site
on the two oxygen atoms of a-ketophosphonate (TS I). It
is conceivable that interaction of a filled nonbonding orbital
on oxygen of the phosphoryl group with the p-orbital of the
carbon atom of the carbonyl group could occur. The molec-
ular models imply, assuming sp2-hybridization on oxygen of
the phosphonyl group, that overlap of the type postulated is
probable maximum when the P→O bond is perpendicular to
the plane composed of the aryl ring, carbon, and phosphorus.18
In fact, the anti-diastereoselectivity has to be attributed to the
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Table 2 The vinylogous Mukaiyama aldol reaction with a-ketophosphonates
Product
R1
R2
Time [h]
Yield (%)a
Dr (anti/syn)b
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
C6H5
C6H5
Et
0.1
0.2
0.2
0.1
0.1
0.1
0.1
0.1
0.2
0.2
0.1
20
88
74
77
84
70
64
77
89
89
56
66
71
46
55
95 : 5
Me
Me
Et
Me
Et
Me
Et
Me
Et
Et
Et
Me
Et
89 : 11
>99 : 1
>99 : 1
95 : 5
>99 : 1
88 : 12
>99 : 1
>99 : 1
>99 : 1
>99 : 1
95 : 5
p-ClC6H4
p-ClC6H4
o-CH3C6H4
m-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3OC6H4
p-CH3OC6H4
p-BrC6H4
Me
Et
Et
24
22
83 : 17
96 : 4
a After purification by chromatography. b Diastereomeric ratio determined from the crude product by 31P NMR.
duction. Further investigations on the enantioselective vinylogous
Mukaiyama aldol reaction are currently underway.
Experimental
General remarks
All reactions were carried out under an inert atmosphere and
in heat-dried glassware. Anhydrous CH2Cl2 were obtained by
standard method. Flash column chromatography was performed
on silica gel (particle size 10–40 mm, Ocean Chemical Factory
of Qingdao, China). 1H and 13C NMR spectra were recorded
1
on Brucker-400 (400 MHz for H, 100 MHz for 13C, 121 MHz
for 31P). Chemical shifts were reported in ppm downfield from
internal Si(CH3)4. The crystal structure was determined on a
Bruker SMART 1000 CCD diffractometer. Mass spectra were
recorded on a LCQ advantage spectrometer with ESI resource.
HR-MS were recorded on APEXII and ZAB-HS spectrometer.
Melting points were determined on a T-4 melting point apparatus
(uncorrected).
Fig. 2 The possible mechanistic pathway of the vinylogous Mukaiyama
aldol reaction.
steric effect caused by the coordination of Cu(OTf)2 and a-
ketophosphonate. Therefore, transition state I (TS I) is more
favorable by positioning the least steric hinder, leading preferably
to the anti-diastereoselectivity. 2,2,2-Trifluoroethanol could help
to remove the TMS group and increase the nucleophilic ability of
2-(trimethylsilyloxy)furan.
General procedure for the synthesis of dialkyl (2,5-dihydro-5-
oxofuran-2-yl)(hydroxy)methylphosphonate 3. A solution of a-
keto phosphonate 1 (1.0 mmol) in CH2Cl2 (2 mL) was cooled to
0 ◦C, 2-(trimethylsilyloxy)furan 2 (0.32 g, 2.0 mmol) and Cu(OTf)2
(0.018 g, 0.05 mmol) were added, subsequently added the TFE
(0.12 g, 1.2 mmol). The mixture was stirred for corresponding
time at 0 ◦C. The mixture was hydrolyzed with H2O (5 mL). The
aqueous phase was extracted with CH2Cl2 (3 ¥ 10 mL), and the
organic layers were dried with anhydrous MgSO4, filtered, and
concentrated in vacuo to yield the crude products 3, which were
purified by flash column chromatography on silica gel [petroleum
ether/ethyl acetate, 1 : 1 (v/v)] to provide pure products 3.
Conclusions
In conclusion, we have developed an efficient and highly di-
astereoselective synthesis of d-hydroxyalkylbutenolide phospho-
nates from the vinylogous Mukaiyama aldol reaction of a-
ketophosphonate and 2-(trimethylsilyloxy)furan catalyzed by
Cu(OTf)2 with TFE as additive. A wide range of stereoselective
novel functionalized tertiary a-hydroxy phosphonates were ob-
tained in high yields with good to excellent diastereoselectivities
(up to 99 : 1 d.r.). A plausible transition state has been proposed
to explain the origin of the activation and the asymmetric in-
Diethyl hydroxy(5-oxo-2,5-dihydrofuran-2-yl)(phenyl)methyl-
phosphonate (3a). White solid; mp 104–106 ◦C; 31P-NMR
(121 MHz, CDCl3): d 18.64, 18.80; 1H-NMR (400 MHz, CDCl3):
3
3
d 1.25 (td, JH–H = 7.0 Hz, JP–H = 5.0 Hz, 6H, (POCH2CH3)2),
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3
3.93–4.15 (m, 4H, P(OCH2CH3)2), 5.60 (d, JH–H = 5.6 Hz, 1H,
(121 MHz, CDCl3): d 20.75, 22.24; 1H-NMR (400 MHz, CDCl3):
d 2.63 (s, 3H, CH3), 3.55 (d, 3JP–H = 10.5 Hz, 3H, P(OCH3)2), 3.78
3
HC CHCH), 6.07 (d, JH–H = 5.6 Hz, 1H, HC CHCH), 7.31
3
3
3
(t, JH–H = 7.2 Hz, 1H, Ph), 7.36 (t, JH–H = 7.4 Hz, 2H, Ph),
(d, JP–H = 10.5 Hz, 3H, P(OCH3)2), 5.93 (s, 1H, HC CHCH),
3
3
3
7.62 (d, JH–H = 7.6 Hz, 2H, Ph), 7.66 (t, JH–H = 5.7 Hz, 1H,
6.18 (d, JH–H = 5.6 Hz, 1H, HC CHCH), 7.18–7.26 (m, 3H,
HC CHCH); 13C-NMR (100 MHz, CDCl3): d 16.32 (t, JC,P
=
Ph), 7.66 (d, JH–H = 5.9 Hz, 1H, Ph), 7.70 (d, JH–H = 5.6 Hz,
1H, HC CHCH); 13C-NMR (100 MHz, CDCl3): d 23.11, 54.38
(d, 2JC,P = 7.7 Hz, P(OCH3)2), 54.63 (d, 2JC,P = 7.7 Hz, P(OCH3)2),
79.53 (d, 1JC,P = 161.1 Hz, HCP(OCH3)2), 85.50 (d, 2JC,P = 14.4 Hz,
HC CHCH), 122.68, 125.70, 128.10 (d, 3JC,P = 3.5 Hz), 128.44,
128.82, 130.94, 133.30, 154.16, 173.15; ESI-MS: 312.7 ([M+H]+);
HRMS calcd for C14H17O6P: 335.0655 (M+Na)+, found: 335.0660.
3
3
3
5.0 Hz, P(OCH2CH3)2), 64.23 (d, 2JC,P = 7.8 Hz, P(OCH2CH3)2),
64.44 (d, 2JC,P = 7.5 Hz, P(OCH2CH3)2), 76.45 (d, 1JC,P = 162.5 Hz,
2
CP(OCH2CH3)2), 85.00 (d, JC,P = 10.0 Hz, HC CHCH),
123.00, 126.12 (d, 3JC,P = 4.2 Hz), 128.19 (d, 4JC,P = 1.7 Hz), 128.23
2
3
(d, JC,P = 9.2 Hz), 135.58, 153.65 (d, JC,P = 4.7 Hz), 172.60;
ESI-MS: 349.0 ([M+Na]+); HRMS calcd for C15H19O6P: 349.0811
(M+Na)+, found: 349.0819.
Diethyl hydroxy(5-oxo-2,5-dihydrofuran-2-yl)(m-tolyl)methyl-
phosphonate (3f). White solid; mp 48–51 ◦C; 31P-NMR
(121 MHz, CDCl3): d 18.67; 1H-NMR (400 MHz, CDCl3): d
Dimethyl hydroxy(5-oxo-2,5-dihydrofuran-2-yl)(phenyl)methyl-
phosphonate (3b). White solid; mp 131–134 ◦C; 31P-NMR
(121 MHz, CDCl3): d 20.15, 20.81; 1H-NMR (400 MHz, CDCl3):
d 3.67 (d, 3JP–H = 10.5 Hz, 3H, P(OCH3)2), 3.77 (d, 3JP–H = 10.5 Hz,
3H, P(OCH3)2), 5.61 (d, 3JH–H = 6.0 Hz, 1H, HC CHCH), 6.11
3
3
1.22 (t, JH–H = 7.1 Hz, 3H, P(OCH2CH3)2), 1.28 (t, JH–H
=
7.1 Hz, 3H, P(OCH2CH3)2), 2.37 (s, 3H, CH3), 3.84–4.16 (m,
3
4H, P(OCH2CH3)2), 5.62 (d, JH–H = 5.6 Hz, 1H, HC CHCH),
3
4
3
3
(dd, JH–H = 6.0 Hz, JH–H = 1.6 Hz, 1H, HC CHCH), 7.32–
7.41 (m, 3H, Ph), 7.62–7.69 (m, 3H, Ph, HC CHCH); 13C-NMR
(100 MHz, CDCl3): d 54.56 (d, 2JC,P = 7.8 Hz, P(OCH3)2), 54.83 (d,
2JC,P = 7.3 Hz, P(OCH3)2), 76.72 (d, 1JC,P = 162.2 Hz, CP(OCH3)2),
6.12 (dd, JH–H = 5.6 Hz, JH–H = 1.8 Hz, 1H, HC CHCH),
3
3
7.13 (d, JH–H = 7.4 Hz, 1H, Ph), 7.26 (d, JH–H = 15.2 Hz, 1H,
3
3
Ph), 7.42 (d, JH–H = 11.1 Hz, 2H, Ph), 7.69 (d, JH–H = 5.6 Hz,
1H, HC CHCH); 13C-NMR (100 MHz, CDCl3): d 16.30 (d,
84.79 (d, 2JC,P = 9.6 Hz, HC CHCH), 123.10, 126.02 (d, 3JC,P
=
3JC,P = 5.5 Hz, P(OCH2CH3)2), 21.63, 64.25 (d, JC,P = 7.7 Hz,
2
4.4 Hz), 128.35 (d, 2JC,P = 8.4 Hz), 128.45 (d, 4JC,P = 2.2 Hz), 135.20,
2
P(OCH2CH3)2), 64.46 (d, JC,P = 7.3 Hz, P(OCH2CH3)2), 76.46
153.50 (d, JC,P = 4.9 Hz), 172.48; ESI-MS: 321.0 ([M+Na]+);
3
1
2
(d, JC,P = 161.5 Hz, CP(OCH2CH3)2), 85.12 (d, JC,P = 10.6 Hz,
HRMS calcd for C13H15O6P: 321.0498 (M+Na)+, found: 321.0507.
HC CHCH), 122.96, 123.17(d, 3JC,P = 3.9 Hz), 126.66 (d, 3JC,P
=
4
4
4.4 Hz), 128.08 (d, JC,P = 1.2 Hz), 129.02 (d, JC,P = 1.6 Hz),
135.48, 137.85, 153.66 (d, 3JC,P = 4.1 Hz), 172.63; ESI-MS: 340.7
([M+H]+); HRMS calcd for C16H21O6P: 363.0968 (M+Na)+,
found: 363.0962.
Dimethyl hydroxy(5-oxo-2,5-dihydrofuran-2-yl)(p-chlorophenyl)-
methylphosphonate (3c). White solid; mp 123–126 ◦C; 31P-NMR
(121 MHz, CDCl3): d 20.76; 1H-NMR (400 MHz, CDCl3): d 3.52
(d, 3JP–H = 10.6 Hz, 3H, P(OCH3)2), 3.94 (d, 3JP–H = 10.6 Hz, 3H,
3
P(OCH3)2), 5.74 (t, JH–H = 2.0 Hz, 1H, HC CHCH), 6.18 (d,
Dimethyl hydroxy(5-oxo-2,5-dihydrofuran-2-yl)(p-tolyl)meth-
ylphosphonate (3g). White solid; mp 127–130 ◦C; 31P-NMR
(121 MHz, CDCl3): d 20.99, 21.26; 1H-NMR (400 MHz, CDCl3):
3
3JH–H = 5.8 Hz, 1H, HC CHCH), 6.85 (d, JH–H = 5.8 Hz, 1H,
HC CHCH), 7.43 (d, 3JH–H = 8.5 Hz, 2H, Ph), 7.63 (dd, 3JH–H
=
8.7 Hz, JP–H = 2.0 Hz, 2H, Ph); 13C-NMR (100 MHz, CDCl3):
4
3
d 2.34 (s, 3H, CH3), 3.67 (d, JP–H = 10.4 Hz, 3H, P(OCH3)2),
2
2
d 54.46 (d, JC,P = 7.5 Hz, P(OCH3)2), 54.69 (d, JC,P = 6.6 Hz,
3.77 (d, 3H, 3JP–H = 10.5 Hz, P(OCH3)2), 5.58 (d, 3JH–H = 5.6 Hz,
1
P(OCH3)2), 75.68 (d, JC,P = 159.8 Hz, CP(OCH3)2), 85.56 (d,
3
1H, HC CHCH), 6.11 (dd, JH–H = 5.7 Hz, 1H, HC CHCH),
2JC,P = 3.9 Hz, HC CHCH), 123.96, 126.77 (d, JC,P = 4.3 Hz),
3
7.19 (d, 3JH–H = 7.8 Hz, 2H, Ph), 7.50 (d, 3JH–H = 8.1 Hz, 2H, Ph),
129.14, 133.55, 134.82 (d, 4JC,P = 3.1 Hz), 151.86 (d, 2JC,P = 9.9 Hz),
172.15; ESI-MS: 354.9 ([M+Na]+); HRMS calcd for C13H14ClO6P:
355.0109 (M+Na)+, found: 355.0116.
7.65 (d, 3JH–H = 5.7 Hz, 1H, HC CHCH); 13C-NMR (100 MHz,
2
CDCl3): d 21.06, 54.54 (d, JC,P = 7.7 Hz, P(OCH3)2), 54.81 (d,
2JC,P = 7.4 Hz, P(OCH3)2), 76.65 (d, 1JC,P = 162.5 Hz, CP(OCH3)2),
84.73 (d, 2JC,P = 9.4 Hz, HC CHCH), 122.96, 125.93 (d, 3JC,P
4.1 Hz), 129.05, 132.07, 138.24 (d, JC,P = 2.1 Hz), 153.65 (d,
3JC,P = 5.4 Hz), 172.56; ESI-MS: 312.7 ([M+H]+); HRMS calcd
for C14H17O6P: 335.0655 (M+Na)+, found: 335.0662.
=
Diethyl hydroxy(5-oxo-2,5-dihydrofuran-2-yl)(p-chlorophenyl)-
methylphosphonate (3d). White solid; mp 77–80 ◦C; 31P-NMR
(121 MHz, CDCl3): d 18.54; 1H-NMR (400 MHz, CDCl3): d
4
3
1.28 (q, JH–H = 7.5 Hz, 6H, P(OCH2CH3)2), 3.98–4.19 (m, 4H,
P(OCH2CH3)2), 5.56 (d, 3JH–H = 5.5 Hz, 1H, HC CHCH), 6.11
Diethyl hydroxy(5-oxo-2,5-dihydrofuran-2-yl)(p-tolyl)methyl-
phosphonate (3h). White solid; mp 87–89 ◦C; 31P-NMR
(121 MHz, CDCl3): d 18.86; 1H-NMR (400 MHz, CDCl3): d
3
4
(dd, JH–H = 5.8 Hz, JH–H = 1.0 Hz, 1H, HC CHCH), 7.34 (d,
3JH–H = 8.5 Hz, 2H, Ph), 7.57 (dd, 3JH–H = 8.7 Hz, 4JP–H = 1.8 Hz,
2H, Ph), 7.64 (d, JH–H = 5.8 Hz, 1H, HC CHCH); 13C-NMR
3
3
1.26 (t, JH–H = 7.1 Hz, 6H, P(OCH2CH3)2), 2.33 (s, 3H, CH3),
3
(100 MHz, CDCl3): d 16.31 (d, JC,P = 5.6 Hz, P(OCH2CH3)2),
3
3.92–4.16 (m, 4H, P(OCH2CH3)2), 5.58 (t, JH–H = 6.2 Hz, 1H,
16.39 (d, 3JC,P = 5.6 Hz, P(OCH2CH3)2), 64.41 (d, 2JC,P = 7.6 Hz,
3
3
HC CHCH), 6.12 (dd, JH–H = 9.9 Hz, JH–H = 4.6 Hz, 1H,
2
P(OCH2CH3)2), 64.58 (d, JC,P = 7.6 Hz, P(OCH2CH3)2), 76.80
3
3
HC CHCH), 7.18 (d, JH–H = 7.8 Hz, 2H, Ph), 7.50 (d, JH–H
=
1
2
(d, JC,P = 161.7 Hz, CP(OCH2CH3)2), 84.60 (d, JC,P = 9.2 Hz,
3
7.8 Hz, 2H, Ph), 7.66 (t, JH–H = 6.2 Hz, 1H, HC CHCH);
HC CHCH), 123.29, 127.63 (d, 3JC,P = 3.9 Hz), 128.38 (d, 4JC,P
=
13C-NMR (100 MHz, CDCl3): d 16.31 (d, JC,P = 2.5 Hz,
3
1.1 Hz), 134.04, 134.36 (d, 3JC,P = 2.5 Hz), 153.28 (d, 2JC,P = 5.0 Hz),
172.32; ESI-MS: 383.0 ([M+Na]+); HRMS calcd for C15H18ClO6P:
383.0422 (M+Na)+, found: 383.0415.
3
P(OCH2CH3)2), 16.37 (d, JC,P = 2.5 Hz, P(OCH2CH3)2), 21.07,
64.12 (d, 2JC,P = 7.6 Hz, P(OCH2CH3)2), 64.38 (d, 2JC,P = 7.6 Hz,
1
P(OCH2CH3)2), 76.40 (d, JC,P = 161.2 Hz, CP(OCH2CH3)2),
2
Dimethyl hydroxy(5-oxo-2,5-dihydrofuran-2-yl)(o-tolyl)methyl-
phosphonate (3e). White solid; mp 89–91 ◦C; 31P-NMR
85.10 (d, JC,P = 10.4 Hz, HC CHCH), 123.01, 125.94 (d,
4JC,P = 4.3 Hz), 128.97 (d, JC,P = 5.6 Hz), 132.42, 138.07 (d,
3
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3
4JC,P = 2.0 Hz), 153.55 (d, 3JC,P = 4.6 Hz), 172.51; ESI-MS: 340.7
([M+H]+); HRMS calcd for C16H21O6P: 363.0968 (M+Na)+,
found: 363.0962.
153.10 (d, JC,P = 4.3 Hz), 171.86; ESI-MS: 286.8 ([M+Na]+);
HRMS calcd for C10H17O6P: 287.0655 (M+Na)+, found:
287.0649.
Dimethyl hydroxy(5-oxo-2,5-dihydrofuran-2-yl)(p◦-methoxyphe-
nyl)methylphosphonate (3i). White solid; mp 82–84 C; 31P-NMR
(121 MHz, CDCl3): d 21.15, 21.26; 1H-NMR (400 MHz, CDCl3):
d 3.71 (d, 3JP–H = 10.3 Hz, 3H, P(OCH3)2), 3.77 (d, 3JP–H = 10.4 Hz,
3H, P(OCH3)2), 3.80 (s, 3H, OCH3), 5.54 (d, 3JH–H = 5.5 Hz, 1H,
HC CHCH), 6.07 (dd, 3JH–H = 5.4 Hz, 1H, HC CHCH), 6.89
Dimethyl 1-(2,5-dihydro-5-oxofuran-2-yl)-1-hydroxypropylpho-
sphonate (3m). Colorless oil; 31P-NMR (121 MHz, CDCl3): d
24.53, 24.59; 1H-NMR (400 MHz, CDCl3): d 1.08 (t, 3H, 3JH–H
7.4 Hz, CH2CH3), 1.86–2.02 (m, 2H, CH2CH3), 3.85 (t, 6H, 3JP–H
=
=
10.5 Hz, P(OCH2CH3)2), 5.28 (td, 3JH–H = 7.4 Hz, 3JH–H = 1.8 Hz,
1H, HC CHCH), 6.20 (dd, 3JH–H = 5.8 Hz, 3JH–H = 1.9 Hz, 1H,
3
3
(d, JH–H = 7.9 Hz, 2H, Ph), 7.53 (d, JH–H = 8.3 Hz, 2H, Ph),
3
3
HC CHCH), 7.65 (dd, JH–H = 5.8 Hz, JH–H = 1.2 Hz, 1H,
7.61 (d, 3JH–H = 5.5 Hz, 1H, HC CHCH); 13C-NMR (100 MHz,
HC CHCH); 13C-NMR (100 MHz, CDCl3): d 7.14 (d, JC,P
=
3
2
2
CDCl3): d 54.51 (d, JC,P = 7.5 Hz, P(OCH3)2), 54.83 (d, JC,P
=
3.1 Hz, CCH2CH3), 26.26 (d, 2JC,P = 2.0 Hz, CCH2CH3), 52.70 (d,
7.3 Hz, P(OCH3)2), 72.15, 76.48 (d, 1JC,P = 162.7 Hz, CP(OCH3)2),
84.77 (d, 2JC,P = 9.9 Hz, HC CHCH), 113.70, 123.02, 127.38 (d,
3JC,P = 3.8 Hz), 152.82, 153.62 (d, 3JC,P = 5.2 Hz), 159.57, 172.51;
ESI-MS: 328.6 ([M+H]+); HRMS calcd for C14H17O7P: 351.0600
(M+Na)+, found: 351.0604.
2JC,P = 7.6 Hz, P(OCH3)2), 53.35 (d, JC,P = 7.4 Hz, P(OCH3)2),
2
1
2
75.00 (d, JC,P = 162.1 Hz, CP(OCH2CH3)2), 82.60 (d, JC,P
=
11.8 Hz, HC CHCH), 121.62, 152.77 (d, 3JC,P = 3.2 Hz), 171.70;
ESI-MS: 272.6 ([M+Na]+); HRMS calcd for C9H15O6P: 273.0498
(M+Na)+, found: 274.0506.
Diethyl hydroxy(5-oxo-2,5-dihydrofuran-2-yl)(p-methoxyphen-
yl)methylphosphonate (3j). White solid; mp 72–75 ◦C; 31P-NMR
(121 MHz, CDCl3): d 18.97; 1H-NMR (400 MHz, CDCl3): d 1.23–
1.30 (m, 6H, P(OCH2CH3)2), 3.81 (s, 3H, OCH3), 3.91–4.18 (m,
Diethyl 1-(2,5-dihydro-5-oxofuran-2-yl)-1-hydroxypropylphos-
phonate (3n). Colorless oil; 31P-NMR (121 MHz, CDCl3): d
20.80, 22.26; 1H-NMR (400 MHz, CDCl3): d 1.03 (t, 3H, 3JH–H
=
3
7.5 Hz, CH2CH3), 1.29 (t, 6H, JH–H = 7.0 Hz, P(OCH2CH3)2),
1.81–1.95 (m, 2H, CH2CH3), 4.11–4.20 (m, 4H, P(OCH2CH3)2),
5.23 (d, 3JH–H = 6.5 Hz, 1H, HC CHCH), 6.11 (d, 3JH–H = 5.0 Hz,
1H, HC CHCH), 7.63 (d, 3JH–H = 5.8 Hz, 1H, HC CHCH); 13C-
NMR (100 MHz, CDCl3): d 7.26 (d, 3JC,P = 2.6 Hz, CCH2CH3),
15.40 (d, 3JC,P = 2.7 Hz, P(OCH2CH3)2), 15.45 (d, 3JC,P = 2.9 Hz,
3
4H, P(OCH2CH3)2), 5.57 (d, JH–H = 4.6 Hz, 1H, HC CHCH),
3
3
6.10 (dd, JH—H = 4.6 Hz, 1H, HC CHCH), 7.18 (d, JH–H
=
3
5.6 Hz, 2H, Ph), 7.50 (d, JH–H = 7.8 Hz, 2H, Ph), 7.66 (d,
3JH–H = 6.0 Hz, 1H, HC CHCH); 13C-NMR (100 MHz, CDCl3):
2
d 16.32, 55.17, 64.10 (d, JC,P = 7.6 Hz, P(OCH2CH3)2), 64.36
2
1
(d, JC,P = 7.4 Hz, P(OCH2CH3)2), 76.23 (d, JC,P = 162.1 Hz,
CP(OCH2CH3)2), 84.99 (d, 2JC,P = 10.1 Hz, HC CHCH), 113.56,
122.94, 127.27, 127.44 (d, 3JC,P = 4.0 Hz), 153.62 (d, 3JC,P = 4.8 Hz),
2
P(OCH2CH3)2), 26.40 (d, JC,P = 1.1 Hz, CCH2CH3), 62.37
2
2
(d, JC,P = 7.6 Hz, P(OCH2CH3)2), 62.84 (d, JC,P = 7.3 Hz,
P(OCH2CH3)2), 74.53 (d, 1JC,P = 162.0 Hz, CP(OCH2CH3)2), 82.71
(d, 2JC,P = 12.6 Hz, HC CHCH), 121.48, 153.02 (d, 3JC,P = 2.2 Hz),
171.83; ESI-MS: 300.6 ([M+Na]+); HRMS calcd for C11H19O6P:
301.0811 (M+Na)+, found: 301.0818.
159.47 (d, JC,P = 1.2 Hz), 172.49; ESI-MS: 356.7 ([M+H]+);
4
HRMS calcd for C16H21O6P: 379.0917 (M+Na)+, found:
379.0925.
Diethyl hydroxy(5-oxo-2,5-dihydrofuran-2-yl)(p-bromophenyl)-
methylphosphonate (3k). White solid; mp 119–122 ◦C; 31P-NMR
(121 MHz, CDCl3): d 18.18; 1H-NMR (400 MHz, CDCl3): d 1.25–
1.33 (m, 6H, P(OCH2CH3)2), 4.08–4.16 (m, 4H, P(OCH2CH3)2),
Acknowledgements
We thank the National Natural Science Foundation of China
(21072102), the Committee of Science and Technology of Tian-
jin (11JCYBJC04200) and State Key Laboratory of Elemento-
Organic Chemistry in Nankai University for financial support.
3
3
5.56 (d, JH–H = 3.6 Hz, 1H, HC CHCH), 6.05 (d, JH–H
=
5.6 Hz, 1H, HC CHCH), 7.48 (m, 3H, Ph, HC CHCH),
3
7.60 (d, JH–H = 6.0 Hz, 2H, Ph); 13C-NMR (100 MHz, CDCl3):
3
2
d 16.32 (t, JC,P = 5.6 Hz, P(OCH2CH3)2), 64.44 (d, JC,P
=
7.7 Hz, P(OCH2CH3)2), 64.58 (d, 2JC,P = 7.7 Hz, P(OCH2CH3)2),
1
2
Notes and references
76.23 (d, JC,P = 161.7 Hz, CP(OCH2CH3)2), 84.61 (d, JC,P
=
9.8 Hz, HC CHCH), 121.54, 123.27, 127.98 (d, 3JC,P = 4.1 Hz),
131.30 (d, 3JC,P = 1.8 Hz), 134.78, 152.91, 173.74; ESI-MS: 404.7
([M+H]+); HRMS calcd for C15H18BrO6P: 426.9916 (M+Na)+,
found: 426.9919.
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´
´
5 C. S. Lo´pez, R. Alvarez, B. Vaz, O. N. Faza and A. R. de Lera, J. Org.
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P(OCH2CH3)2), 1.39 (d, JP–H = 15.1 Hz, CCH3), 4.12–4.18 (m,
3
4H, P(OCH2CH3)2), 4.65 (s, 1H, OH), 5.16 (d, JH–H = 5.6 Hz,
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1H, HC CHCH), 6.13 (d, JH–H = 4.5 Hz, 1H, HC CHCH),
7.64 (d, 3JH–H = 5.0 Hz, 1H, HC CHCH); 13C-NMR (100 MHz,
CDCl3): d 15.43 (d, 3JC,P = 5.2 Hz, P(OCH2CH3)2), 18.15 (d, 2JC,P
=
2
1.8 Hz, CCH3), 62.61 (d, JC,P = 7.5 Hz, P(OCH2CH3)2), 62.89
2
1
(d, JC,P = 7.3 Hz, P(OCH2CH3)2), 71.48 (d, JC,P = 166.3 Hz,
CP(OCH2CH3)2), 83.78 (d, 2JC,P = 11.0 Hz, HC CHCH), 121.65,
9 B. Stowasser, K.-H. Budt, J.-Q. Li, A. Peyman and D. Ruppert,
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6726 | Org. Biomol. Chem., 2011, 9, 6721–6726
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The Royal Society of Chemistry 2011
©