The high stereoselective synthesis of β-alkynyl-enol phosphates

Article abstract of DOI:10.1081/SCC-100000538

A high stereoselective synthesis for β-alkynyl-enol phosphates from β-alkynyl ketone and dialkyl phosphite, via Atherton-Todd reaction, was reported. NaH as base gave a nearly pure Z-isomer.

Full text of DOI:10.1081/SCC-100000538

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THE HIGH STEREOSELECTIVE SYNTHESIS OF β-
ALKYNYL-ENOL PHOSPHATES
Yixiang Ding a & Xiaogen Huang a
a Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences , 354 Fenglin
Road, Shanghai, 200032, People's Republic of China
Published online: 09 Nov 2006.
To cite this article: Yixiang Ding & Xiaogen Huang (2001) THE HIGH STEREOSELECTIVE SYNTHESIS OF β-ALKYNYL-ENOL
PHOSPHATES, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 31:3, 449-454, DOI: 10.1081/SCC-100000538
To link to this article: http://dx.doi.org/10.1081/SCC-100000538
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SYNTHETIC COMMUNICATIONS, 31(3), 449–454 (2001)
THE HIGH STEREOSELECTIVE
SYNTHESIS OF β-ALKYNYL-ENOL
PHOSPHATES
Yixiang Ding∗ and Xiaogen Huang
Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, 354 Fenglin Road, Shanghai 200032,
People’s Republic of China
ABSTRACT
A high stereoselective synthesis for β-alkynyl-enol phos-
phates from β-alkynyl ketone and dialkyl phosphite, via Atherton–
Todd reaction, was reported. NaH as base gave a nearly pure
Z-isomer.
Enol phosphates are a class of important organic compounds. For example,
phosphenol pyruvate (PEP) is a well-known high-energy species that plays a vi-
tal role in a number of biological processes. Further efforts have been made in
the preparation of bioactive enol phosphates. As a pesticide, they are very potent,
with a wide field of application. Recently, Raushel (1) described the bioactivity
of alkynyl phosphate as a mechanism-based inactivation of bacterial phospho-
triesterase. Widlauski (2) reported the synthesis of enol phosphates with leav-
ing groups at the 1-position that should have substantial utility in the design of
∗Corresponding author.
449
Copyright ꢀ 2001 by Marcel Dekker, Inc.
www.dekker.com
C

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DING AND HUANG
phosphatase or phosphodiesterase inhibitors. Enol phosphates are also key inter-
mediates in certain organic synthesis (3–8).
Now we report a high stereoselective synthesis for β-alkynyl-enol phos-
phates via Atherton–Todd reaction, which are a kind of new compound. β-
alkynyl-enol phosphates would undergo hydrolytic reaction to give a reactive al-
lenyl ketones. Such a molecular structure would be valuable for the design of
mechanism-based inactivators of phosphatase. At the same time, they are useful
intermediates for the preparation of enynes.
Because of the base-catalyzed “propargylic rearrangements,” the enolate
anion of β-alkynyl ketone can be obtained from allenyl ketone or β-alkynyl
ketone. This anion then reacted with dialkyl phosphorochloride, intermediate of
Atherton–Todd reaction, to give the β-alkynyl-enol phosphates. We prepared a
number of different compounds as shown in Table 1. All of the products formed
Z-isomer in a high stereoselective manner using NaH as bases.
O
O
O
O
NaH
R
R
R
R
1
OP(O)(OR')2
OP(O)(OR')2
NaH, (R'O)2PHO
R
R
CCl4, THF, −15°C
2Z
2E
Table 1. The Preparation of β-Alkynyl-enol Phosphates
Entry
2a
R
Rꢁ
Et
Z/E
Yield %
62
>95/5
2b
2c
Et
Et
>95/5
>95/5
65
69
CH3O
Cl
O
2d
2e
Et
>95/5
>95/5
61
74
O
Me
2f
Me
Me
>95/5
>95/5
75
62
CH3O
O
2g
O

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β-ALKYNYL-ENOL PHOSPHATES
451
Table 2. Effect of Bases to the Ratio of Z and E of 2a
Entry
Reaction Condition
Yield %
Z/E
1
2
3
4
NaH/−15◦C
BuLi/−78◦C
62
52
54
71
>95/5
66/34
67/33
34/66
LDA/−78◦C
LDA/HMPA/−78◦C
The effect of bases on the stereochemistry of the reaction was studied. The
results are shown in Table 2. We found that the ratio of geometrical isomers
2aZ and 2aE is closely related to the used bases. The smaller base NaH gave
nearly pure Z-isomer. The Z/E were determined by NMR analysis of the reaction
mixture. The E and Z configurations of enol phosphates were determined using the
Tobey–Pascual substituent shielding constants method (9). The calculated values
are close to the observed values.
EXPERIMENTS
All melting points were uncorrected. IR spectra were measured with a Shi-
1
madzu IR-440 spectrometer. H NMR spectra were Recorded at FX-90Q using
TMSasinternalstandardandCCl4 assolvent. 31PNMRwererecordedon300MHz
at 161.97 MHz using CDCl3 as solvent and 85% of H3PO4 as external standard.
Mass spectra were taken on a Finnigan GC-MS-4021 spectrometer. Elemental
– –
analyses were performed on a Rapid CHN O S analyzer.
All allenyl aryl ketones were prepared according to the literature procedures
(10,11) by the Jones oxidation of corresponding arylbutynol that were obtained by
treatment of arylaldehyde with 3-bromo-propyne in the presence of Zn. All known
1
precursor compounds (GC purity >95%) were characterized by H NMR and
physical constants in agreement with the literature (10–12), 1b is a new compound.
Diethyl phosphite (purity >99%) was purchased from FLUKA company and was
distilled prior to use. CCl4 was distilled prior to use. THF was treated with sodium
and benzophenone. 1b: Jonse oxidation yield 80%, m.p. 55–56◦C. 1H NMR: δ 7.93
(m, 2H), 6.93 (m, 2H), 6.46 (t, J = 6.5 Hz, 1H), 5.25 (d, J = 6.5 Hz, 2H), 3.86
(s, 3H). MS (m/z, %): 174 (M, 5.33), 107 (3.86), 92 (10.63), 77 (9.26), 63 (8.03).
IR (KBr, cm−1): 1957, 1923, 1644, 1592, 1233. Anal. calcd. for C11H10OH2: C,
75.83; H, 5.79. Found: C, 76.00; H, 5.68.
General Procedure
A multinecked round-bottom flask was charged with NaH (1.0 mmol) and
anhydrous THF (5 mL). The mixture was stirred under a nitrogen atmosphere

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DING AND HUANG
and cooled to −10◦C. A solution of allenyl ketone (1.0 mmol) in THF was added
slowly. After the mixture had been stirred for 0.5 h, diethyl phosphite (1.2 mmol)
in CCl4 was added dropwise. After stirring for about 1.5 h, the reaction mixture
was neutralized with acetic acid and diluted with ether. The solution was washed
with water, dried, and concentrated in vacuum to give an oil. The ratios of isomers
were determined by NMR spectroscopy. The pure product was obtained after
chromatography on silica gel using petroleum ether and ethyl acetate as eluent.
1
1-Phenyl-1-buten-3-ynyl Diethyl Phosphate (2aZ). Deep red oil. H
==
NMR: δ 7.25–7.68 (m, 5H, Ph), 5.60 (t, JHH = JPH = 2.4 Hz, 1H, HC C), 4.12
(m, 4H, 2CH2), 3.17 (m, 1H, C CH), 1.25 (t, J = 7Hz, 6H, 2CH3). 31P NMR:
≡
δ-6.596. MS (m/z, %): 280 (M, 34.23), 253 (2.80), 225 (3.92), 154 (2.56), 126
(100), 105 (18.70), 77 (16.43). IR (neat film, cm−1): 1623, 1448, 1274, 1166, 1034.
Anal. calcd. for C14H17O4P: C, 59.99; H, 6.13. Found: C, 60.18, H, 6.02.
1
1-Phenyl-1-buten-3-ynyl Diethyl Phosphate (2aE). Deep red oil. H
==
NMR: δ 7.24–7.90 (m, 5H, Ph), 5.82 (t, JHH = JPH = 2.6Hz, 1H, HC C), 4.10
(m, 4H, 2CH2), 3.10 (m, 1H, C CH), 1.25 (m, 6H, 2CH3). 31P NMR: δ −6.207.
≡
MS (m/z, %): 280 (M, 34.77), 253 (1.89), 225 (2.34), 155 (9.47), 126 (100.00),
105 (20.08), 77 (20.07). IR (neat film, cm−1): 1614, 1496, 1276, 1166, 1031. Anal.
calcd. for C14H17O4P: C, 59.99, H, 6.13. Found: C, 59.81, H, 6.27.
1-(4-Methoxyl-phenyl)-1-buten-3-ynyl Diethyl Phosphate (2bZ). Deep
1
red oil. H NMR: δ 6.72–7.45(m, 4H, Ph), 5.48 (t, JHH = JPH = 2.4Hz, 1H,
==
≡
HC C), 4.11 (m, 4H, 2CH2), 3.75 (s, 3H, CH3O), 3.15 (m, 1H, C CH), 1.24
(t, J = 6Hz, 6H, 2CH3). 31P NMR: δ −6.562. MS (m/z, %): 310 (M, 16.48), 184
(2.69), 156 (100.00), 145 (5.00), 135 (12.46), 113 (3.52), 77 (4.18). IR (neat film,
cm−1): 2100, 1606, 1531, 1256, 1031. Anal. calcd. for C15H19O5P: C, 58.05; H,
6.18. Found: C, 58.34; H, 6.40.
1-(4-Chlorophenyl)-1-buten-3-ynyl Diethyl Phosphate (2cZ). Deep red
1
oil. H NMR: δ 7.50–7.95 (m, 4H, Ph), 5.92 (dd, J = 2.5Hz, J = 2.3Hz, 1H,
HC C), 4.43 (m, 4H, 2CH2), 3.53 (m, 1H, C CH),1.55 (m, 6H, 2CH3). 31P NMR:
δ −6.525. MS (m/z, %): 314 (M, 9.13), 286 (2.26), 258 (2.90), 160 (100.00), 139
(16.67), 126 (5.55), 99 (3.99). IR (neat film, cm−1): 1619, 1492, 1272, 1052, 1001.
Anal. calcd. for C14H16ClO4P: C, 53.24; H, 5.13. Found: C, 53.51; H, 5.20.
==
≡
1-(3,4-Methylenedioxyphenyl)-1-buten-3-ynylDiethylPhosphate(2dZ).
Deep red oil. 1H NMR: δ 6.77–7.30 (m, 3H, Ph), 6.00 (s, 2H, OCH2O), 5.58 (t,
==
≡
J = J = 2.4Hz, 1H, HC C), 4.24 (m, 4H, 2CH2), 3.28 (m, 1H, C CH), 1.35
(t, J = 6Hz, 6H, 2CH3). 31P NMR: δ −6.544. MS (m/z, %): 324 (M, 36.4), 268
(3.22), 188 (5.56), 170 (100.00), 149 (14.57), 121 (7.96), 91 (6.06). IR (neat film,

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β-ALKYNYL-ENOL PHOSPHATES
453
cm−1): 1606, 1492, 1446, 1257, 1037, 949. Anal. calcd. for C15H17O6P: C, 55.55;
H, 5.29, C. 55.33; H, 5.27.
1
1-Phenyl-1-buten-3-ynyl Dimethyl Phosphate (2eZ). Deep red oil. H
==
NMR: δ 7.20–7.65 (m, 5H, Ph), 5.63 (dd, J = 1.8Hz, J = 3.2Hz, 1H, HC C),
3.25 (m, 1H, C CH), 3.75 (d, J = 12Hz, 6H, 2CH3). 31P NMR: δ −4.1834. MS
≡
(m/z, %): 252 (M, 31.99), 235 (1.90), 203 (1.88), 126 (100.00), 109 (15.47), 105
(10.83), 77 (20.30). IR (neat film, cm−1): 1625, 1448, 1284, 1187, 1049, 909. Anal.
calcd. for C12H13O4P: C, 57.14; H, 5.21. Found: C, 56.88; H, 5.40.
1-(4-Methoxyl-phenyl)-1-buten-3-ynyl Dimethyl Phosphate (2fZ).
1
Deep red oil. H NMR: δ 6.85–7.58 (d, 2H, Ph), 5.64 (dd, J = 2.4Hz, J =
==
2.2Hz, 1H, HC C), 3.90 (d, J = 6Hz, 6H, 2CH3), 3.80 (s, 3H, CH3O), 3.3 (m,
1H, C CH). 31P NMR: δ −4.1439. MS (m/z, %): 282 (M, 99.59), 203 (0.50),
≡
156 (100.00), 141 (21.78), 127 (5.82), 109 (17.85), 92 (6.86). IR (neat film, cm−1):
1606, 1513, 1284, 1182, 1048, 911. Anal. calcd. for C13H15O5P: C, 55.32; H, 5.37.
Found: C, 55.31; H, 5.40.
1-(3,4-Methylenedioxyphenyl)-1-buten-3-ynyl Dimethyl Phosphate
(2gZ). Deep red solid. m.p. 81–82◦C. 1H NMR: δ 6.48–7.03 (m, 3H, Ph), 5.74
==
(s, 2H, OCH2O), 5.34 (dd, J = 1.8Hz, J = 3.2Hz, 1H, HC C), 3.70 (d, J = 4Hz,
6H, 2CH3), 3.27 (m, 1H, C CH). 31P NMR: δ − 4.1270. MS (m/z, %): 296 (M,
≡
32.24), 184 (3.32), 170 (100.00), 149 (6.56), 109 (14.39), 101 (3.57), 79 (8.79),
IR (KBr, cm−1): 1604, 1491, 1446, 1286, 1256, 1256, 1010. Anal. calcd. for
C13H13O6P: C, 52.71; H, 4.43. Found: C, 52.97; H, 4.52.
ACKNOWLEDGMENT
The project was supported by the National Science Foundation of China.
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Received in Japan March 21, 2000

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