cis-vinylphosphonates and 1,3-butadienylphosphonates by zirconation of 1-alkynylphosphonates

Article abstract of DOI:10.1021/ol0157454

(equation presented) Addition of "zirconocene" to 1-alkynylphosphonates gives three-membered zirconacylces that can be hydrolyzed to cis-vinylphosphonates or further reacted with alkynes/hydrolysis to give substituted (Z,E)- and (E,E)-1,3-butadienylphosph

Full text of DOI:10.1021/ol0157454

ORGANIC
LETTERS
2001
Vol. 3, No. 9
1379-1381
cis-Vinylphosphonates and
1,3-Butadienylphosphonates by
Zirconation of 1-Alkynylphosphonates
Abed Al Aziz Quntar† and Morris Srebnik*
Department of Medicinal Chemistry and Natural Products, School of Pharmacy,
Hebrew UniVersity in Jerusalem, Jerusalem 91120, Israel
msrebni@md2.huji.ac.il
Received February 21, 2001
ABSTRACT
Addition of “zirconocene” to 1-alkynylphosphonates gives three-membered zirconacylces that can be hydrolyzed to cis-vinylphosphonates or
further reacted with alkynes/hydrolysis to give substituted (Z,E)- and (E,E)-1,3-butadienylphosphonates.
Although 1-alkynylphosphonates have been known since
1957 and their synthesis was developed in the 1960s,1
addition reactions of organometallics remain relatively
unexplored and include syn addition of organocuprates to
1-alkynylphosphonates to give 2,2-disubstituted vinylphos-
phonates,2 reaction of R-stannylated phosphonates with
aldehydes to give E/Z mixtures of 1,2-disubstituted vinyl-
phosphontaes,3 anti hydrotelluration of 1-alkynylphos-
phonates,4 Heck reactions using aryldiazonium salts,5 R-lithi-
ation of â-oxy or â-thio vinylphosphontes,6 NaH-catalyzed
olefination of benzenesulfinylmethylphosphonates,7 and ad-
dition of sodium organyl chalcogenolates to 1-alkynylphos-
phonates.8 These reactions provide access to 1-alkenylphos-
phonates that are very useful compounds for organic
transformations9 and for the synthesis of biologically active
compounds.10 We have recently started to investigate the
addition of organometallic reagents to 1-alkynylphosphon-
ates. Thus, we have discovered that the hydroboration of
1-alkynylphosphonates can be controlled to place boron on
either C1 or C2 of the triple bond by proper use of base,
(8) Braga, A. L.; Alves, E. F.; Silveira, C. C.; Andrade de, L. H.
Tetrahedron Lett. 2000, 41, 161.
(9) For a recent review, see: (a) Minami I, T.; Motoyoshiya, J. Synthesis
1992, 333. Selected recent reactions of vinylphosphonates include the
following. Aziridination: (b) Kim, D. Y.; Rhie, D. Y. Tetrahedron 1997,
53, 13603. Epoxidation: (c) Cristau, H.-J.; Mbianda, X. Y.; Geze, A.; Beziat,
Y.; Gasc, M.-B. J. Organomet. Chem. 1998, 571, 189. Organocuprate
addition: (d) Afarinkia, K.; Binch, H. M.; Modi, C. Tetrahedron Lett. 1998,
39, 7419. C-glycosylation, (e) Junker, H.-D.; Fessner, W.-D. Tetrahedron
Lett. 1998, 39, 269.
† Affiliated with the David R. Bloom Center for Pharmaceutics at the
Hebrew University in Jerusalem.
(1) Iorga, B.; Eymery, F.; Carmichael, D.; Savignac, P. Eur. J. Org.
Chem. 2000, 3103.
(2) (a) Cristau, H.-J.; Mbianda, X. Y.; Beziat, Y.; Gasc, M.-B. J.
Organomet. Chem. 1997, 529, 301. (b) Gil, J. M.; Oh, D. Y. J. Org. Chem.
1999, 64, 2950.
(3) Mimouni, N.; About-Jaudet, E.; Collignon, N.; Savignac, Ph. Synth.
Commun. 1991, 21, 2341.
(4) Jang, W. B.; Oh, D. Y.; Lee, C.-W. Tetrahedron Lett. 2000, 41, 5103.
(5) Brunner, H.; Le Cousturier de Courcy, N.; Geneˆt, J.-P. Synlett 2000,
210.
(6) Kouno. R.; Okauchi, T.; Nakamura, M.; Ichikawa, J.; Minami, T. J.
Org. Chem. 1998, 63, 6239.
(10) As intermediates in drugs or biological investigative compounds:
(a) Harnden, M. R.; Parkin, A.; Parratt, M. J.; Perkins, R. M. J. Med. Chem.
1993, 36, 1343. (b) Smeyers, Y. G.; Romero-Sanchez, F. J.; Hernandez-
Laguna, A.; Fernandez-Ibanez, N.; Galvez-Ruano, E.; Arias-Perez, S. J.
Pharm. Sci. 1987, 76, 753. (c) Megati, S.; Phadtare, S.; Zemlicka, J. J.
Org. Chem. 1992, 57, 2320. (d) Lazrek, H. B.; Rochdi, A.; Khaider, H.;
Barascut, J. L.; Imbach, J. L.; Balzarini, J.; Witvrouw, M.; Pannecouque,
C.; De Clerq, E. Tetrahedron 1998, 54, 3807. (e) Smith, P. W.; Chamiec,
A. J.; Chung-G.; Cobley, K. N.; Duncan, K.; Howes, P. D.; Whittington,
A. R.; Wood, M. R. J. Antibiot. Tokyo 1995, 4 8, 73. Agrochemicals: (e)
Chance, L. H.; Moreau, J. P. U.S. Patent 3910886, 1975.
(7) Shen, Y.; Jiang, G.-F. Synthesis 2000, 99.
10.1021/ol0157454 CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/21/2001

catalyst, and reaction time. Another very useful reaction of
triple bonds that has not been applied to 1-alkynylphosphon-
ates is the addition of zirconocene. Hydrolysis of the
zirconacycles would provide cis-vinylphosphonates, and
subsequent insertion reactions of the three-membered zir-
conacycles with various electrophiles would provide access
to functionalized vinylphosphonates.11 In the context of this
paper, we explored the insertion of alkynes to provide
substituted 1,3-butadienylphosphonates.
cis-Vinyphosphonates are useful intermediates in organic
transformations.9a Reduction of 1-alkynylphosphonates with
hydrogen under various conditions has been reported. Gener-
ally, mixtures of cis- and trans-vinylphosphonates are
obtained.12 When diethyl butynylphosphonate13 was treated
with Cp2ZrCl2/2n-BuLi,11 and hydrolyzed, GCMS analysis
indicated complete conversion. cis-Diethyl 1-butenylphos-
phonate was obtained as a single isomer in 76% isolated
yield (eq 1).14
constants of vinylphosphonates obtained by reaction of
1-alkynylphosphonates with “zirconocene” followed by hy-
drolysis.
A further utilization of the three-membered zirconacycles,
2, in this work was the investigation of alkyne insertion. This
would lead to 1,3-butadienylphosphonates. The latter are
interesting compounds that undergo a variety of reactions
including 1,3-additions,15 cycloaddition with CH2N2,16 and
[2 + 2] cycloadditions.17 They have been prepared by
isomerization of 1-alkynylphosphonates in the presence of
palladium salts,18 by Knoevenagel reaction,17 by reaction of
unsaturated cyanophosphonates with N-tosylsulfonylimines,19
and by procedures similar to the preparation of vinylphos-
phonates.9a
When zirconacycles 2 (R ) C4H9CH2) were treated with
a different alkyne (both terminal and internal alkynes were
used), and the reaction mixture was hydrolyzed, two isomeric
products were detected by GCMS, 6 and 7, and isolated by
silica gel chromatography (eq 2). Presumably, they arise from
The reaction is general, isolated yields are excellent, and
only the cis-vinylphosphonates, 3, are obtained (Table 1).
zirconocyles 5 and 4. Other possible isomeric 1,3-butadi-
enylphosphonates were not isolated, apparently due to
unfavorable steric interactions between the R′ groups of the
incoming alkyne, the phosphonate, and C4H9CH2 groups of
the zirconacycle.
Results are listed in Tables 2 and 3.With terminal alkynes,
6 was the major isomer in all cases, apparently due to steric
considerations. With an internal alkyne (Table 2, entry e),
Table 1. Synthesis of 3 and Selected NMR Data
J (Hz)
entry
R
yield,a %
J P-H2
J P-C3
a
b
c
d
e
C4H9
C5H11
ClC3H6
Ph
79
76
63
76
78
53.1
53.1
52.5
51.5
52.6
8
8
8.3
8.8
8.1
TBDMSOC3H6
a Isolated yields. GCMS conversion was >99%, except for entry e, 85%.
Table 2. Synthesis of 6 and Selected NMR Data
J (Hz)
The stereochemistry of the 3 was determined from the
coupling constants obtained from the NMR data where both
the 3JP-H2 coupling constant (∼50 Hz) and the small 3JP-C3
(∼8 Hz) indicates that H2 is trans to phosphonate group
and that the R group is cis. Table 1 shows select coupling
entry
R′′
R′
yielda%
J H4-H5
J P-H2
J P-C3
a
b
c
d
e
H
H
H
H
C4H9
C5H11
Ph
C3H6Cl
C2H5
68
60
73
57
<3%b
15.4
15.7
16.2
15.9
48.8
48.9
48.9
54.0
5.4
5.6
6.5
6.6
C2H5
(11) (a) Negishi, E.; Takahashi, T. Acc. Chem. Res. 1994, 27, 124. (b)
Negishi, E. In ComprehensiVe Organic Synthesis; Paquette, L. A., Ed.;
Pergamon Press: New York, 1991; Vol. 5, p 1163.
a Isolated yield GCMS conversion for combined 6 and 7 was >99%.
b Not isolated.
(12) (a) L’vova, S. D.; Kozlov, Yu. P.; Gunar, V. I. J. Gen. Chem. USSR
(Engl. Transl.) 1977, 47, 1153; Zh. Obshch. Khim. 1977, 47, 1251. (b)
Rudinskas, A. J.; Hullar, T. L. J. Org. Chem. 1976, 41, 2411. (c) Cristau,
H.-J.; Gase, M.-B.; Mbianda, X. Y. J. Organomet. Chem. 1994, 474, C14.
(d) Cristau, H.-J.; Mbianda, X. Y.; Beziat, Y.; Gase, M.-B. J. Organomet.
Chem. 1997, 529, 301. (e) Blackburn, G. M.; Forster, A. R.; Guo, M.-J.;
taylor, G. E. J. Chem. Soc., Perkin Trans. 1 1979, 44, 865. In one example,
hydrogenation of di-n-butyl 3-hydroxy-1-propynylphosphonate, the use of
Pd/BaSO4 provided the desired cis-olefin in 95% yield: (f) Machida, Y.;
Saito, I. J. Org. Chem. 1979, 44, 856.
compound 7e was essentially the only product isolated (Table
3), 6e being obtained in less than 3%. The structures of
compounds 6 were determined by NMR spectroscopy. The
doublet of triplets in the double bond region 6.5-6.2 ppm
indicates that the alkyne coupling occurred on C1. Also, the
1380
Org. Lett., Vol. 3, No. 9, 2001

3
coupling constants JH4-H5 (15-16 Hz) indicate that the
hydrogens are trans. Thus compounds 6 have a Z,E config-
uration for the double bonds.
Table 3. Synthesis of 7 and Selected NMR Data
J (Hz)
In a similar manner the structures of compounds 7 were
determined. The doublet in the region 5.3-5.5 ppm corre-
sponds to the hydrogen on the C1. This indicates that the
entry
R′′
R′
yield,a % J H4-H5
J P-C3
J P-C4
a
b
c
d
e
H
H
H
H
C4H9
C5H11
Ph
C3H6Cl
C2H5
15
19
11
20
83
15.9
15.8
17.2
15.9
5.6
5.6
5.7
6.4
6.5
28
3
alkyne coupling occurred on C2. Also, the large JP-C4
27.8
26.7
26.6
23
3
coupling constants (23-28 Hz) and the relatively small JP-C3
coupling constant (5.6-6.5 Hz) indicate that the stereochem-
istry of the C1-C2 double bond is E in compounds 7. In
addition, the multiplet (H4-H5) in the region 6.3-5.9 ppm
corresponds to two vinylic hydrogens with a coupling
C2H5
a Isolated yields. GCMS conversion for combined 6 and 7 was >99%.
3
constant JHH (15.8-17.2 Hz) indicative of the E configu-
ration. Thus compounds 7 are the E,E isomers (Table 3).
3
large JP-H2 coupling constant (∼50 Hz) and the relatively
3
small JP-C3 coupling constant (5-6 Hz) indicate that the
Acknowledgment. The authors thank the Israeli Science
Foundation and MECC for support of this work.
stereochemistry of the C1-C2 double bond is Z. The
(13) All 1-alkynylphosphonates were prepared by reaction of the
corresponding lithium acetylide with diethyl chlorophosphates: (a) Poss,
A. J.; Belter, R. K. J. Org. Chem. 1987, 52, 4810. (b) Acheson, R. M.;
Ansell, P. J J. Chem. Soc., Perkin Trans. 1 1987, 1275. (c) Knierzinger,
A.; Grieder, A.; Scho¨nholzer, P. HelV. Chim. Acta 1991, 74, 517. (d) Ruder,
S. M.; Norwood, B. K. Tetrahedron Lett. 1994, 35, 3473. (e) Saalfrank, R.
W.; Welch, A.; Haubner, M.; Bauer, U. Liebigs Ann. 1996, 171. (f) Gil, J.
M.; Sung, J. W.; Park, C. P.’ Oh, D. Y. Synth. Commun. 1997, 27, 3171.
(14) To 1 mmol (0.292 g) of zirconocene dichloride dissolved in 5 mL
of dry THF was added 2 mmol (1.25 mL of n-BuLi 1.6 M in hexane)
dropwise at -78 °C. The mixture was stirred for 3 h, then 0.9 mmol of
1-alkynylphosphonate was added, and the mixture was slowly warmed to
25 °C and stirred overnight. The mixture was worked up with dilute aqueous
HCl, and the vinylphosphonate was extracted in ether and separated on a
silica gel column (80% petroleum ether: 20% ethyl acetate).
Supporting Information Available: Experimental pro-
cedures and full NMR data This material is available free
of charge via the Internet at http://pubs.acs.org.
OL0157454
(16) Minami, T.; Tokomasu, S.; Mimasu, R.; Hirao, I. Chem. Lett. 1985,
1099.
(17) Okauchi, T.; Kakiuchi, T.; Kitamura, N.; Utsunomiya, T.; Ichikawa,
J.; Minami, T. J. Org. Chem. 1997, 62, 8419.
(18) Ma, C. L.; Lu, X. Y.; Ma, Y. X. Main Group Metal Chem. 1995,
18, 391.
(19) Shen, Y.; Jiang, G.-F.; Sun, J. J. Chem. Soc., Perkin Trans. 1 1999,
3495.
(15) Martin, S. F.; Garrison, P. J. Synthesis 1982, 394.
Org. Lett., Vol. 3, No. 9, 2001
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