Direct formation of cyclobutenylphosphonates from 1-alkynylphosphonates and Cp2ZrCl2/2EtMgCl/2CuCl

Article abstract of DOI:10.1016/j.tetlet.2008.11.108

Zirconacycles 2 prepared from 1-alkynylphosphonates 1, zirconocene dichloride, and 2 equiv of EtMgCl are smoothly converted into cyclobutenylphosphonates 3 when treated with two equiv of CuCl in 65-81% isolated yield. The reaction is specific and general

Full text of DOI:10.1016/j.tetlet.2008.11.108

Tetrahedron Letters 50 (2009) 867–869
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Tetrahedron Letters
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Direct formation of cyclobutenylphosphonates from 1-alkynylphosphonates
and Cp2ZrCl2/2EtMgCl/2CuCl
a,c,
Yulia Sinelnikove a,b, Abraham Rubinstein b, Morris Srebnik a, , Abed Al Aziz Al Quntar
*
*
a Department of Medicinal Chemistry and Natural Products. School of Pharmacy, Hebrew University, Jerusalem 91120, Israel
b Department of Pharmaceutics. School of Pharmacy, Hebrew University, Jerusalem 91120, Israel
c Department of Material Engineering, Faculty of Engineering, Al Quds University, Abu Deis, Palestiinian Authority
a r t i c l e i n f o
a b s t r a c t
Article history:
Zirconacycles 2 prepared from 1-alkynylphosphonates 1, zirconocene dichloride, and 2 equiv of EtMgCl
are smoothly converted into cyclobutenylphosphonates 3 when treated with two equiv of CuCl in 65–
81% isolated yield. The reaction is specific and general only for zirconacyclopentenyl phosphonates.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 6 November 2008
Revised 22 November 2008
Accepted 25 November 2008
Available online 30 November 2008
Keywords:
Alkynylphosphonates
Cyclization
Cyclobutenylphosphonates
Diethylzirconocene
Copper chloride
Cyclobutenes are a versatile group of compounds that are
both pharmacologically active1 and are also valuable synthetic
intermediates that undergo many useful transformations2
involving additions to the double bond (bromination,3 hydroge-
nation4 to the important cyclobutanes,5 epoxidations,6,7 halosel-
shown to possess pharmacological activity.28 Therefore, in our
opinion, juxtaposition of the cyclobutenyl and phosphonate
groups should lead to interesting compounds. In fact, cyclo-
butenylphosphonates would represent an essentially unexplored
class of compounds. Thus, Seyferth first reported the synthesis
of only the parent compound in 1971 by copper-induced
enylation,6
hydroboration,8
bromohydroxylation,6
halo-
selenylation9) polymerization,10 ring opening to dienes,11 and
ring contraction12 to name a growing list of reactions. Accord-
ingly, they have been prepared by various methods.13 Organo-
metallic routes include stannylcupration/epoxides14 and
ruthenium-catalysis/propargylic alcohols.15 Various zirconium-
mediated syntheses16 of cyclobutenes consist of reaction of
alkynyl halides with EtMgBr,17 cross-coupling of terminal al-
decomposition of
71% yield; but it could not be purified.29 In a related procedure,
-diazo b-ketophosphonates were converted into cyclobutenone
phosphonates.30 The parent compound was also prepared by
a-diazo cyclopropylmethylphosphonate in
a
treating
a
polymer-supported cyclic phenylsulfonylmethyl-
phosphonate with triethylamine.31 Darling and Subramanian
prepared two fused cyclobutenes by elimination of the corre-
sponding b-aminophosphonates.32
kynes and vinyl bromides,18 reaction of
c,c-dialkoxyallylic zirco-
nium species with acrylamide,19 migratory insertion of an
isocyanide into 1-zirconacyclopent-3-ynes,20 cyclodimerization
of alkynes,21 by double carbonylation,22 coupling of heteroaryl-
substituted alkynes,23 and coupling of 1,4-dicuprio-1,3-dienes,24
diiodination of zirconacyclopentenes followed by treatment with
n-BuLi,25 and from symmetrical 1,3-diynes via zirconacylopent-
enes.26 The zirconium-mediated methods are tedious at best.
Vinyl phosphonates are important chemically27 and have been
In this Letter, we describe the preparation of cyclo-
butenylphosphonates from Cp2ZrCl2/2EtMgCl/2CuCl. We had
previously reported the synthesis of the zirconacyclopentenyl
phosphonates 2 by the addition of alkynylphosphonates using
the reagent Cp2ZrEt2 prepared according to Takahashi and Negi-
shi.33 Various novel phosphonates were prepared by addition of
aldehydes, allyl bromide, and propargylbromide to the zircona-
cyclopentenyl phosphonates 2.34 However, when 2b, obtained
from 1-hexynylphosphonate and 2EtMgCl, was treated with
two equiv of CuCl, refluxed for 36 h, and worked up, cyclo-
butenylphosphonate 3b was obtained as the sole product in
78% yield (Eq. 1, Table 1).35
* Corresponding authors. Tel.: +972 2 675 7301; fax: +972 2 675 8201 (A.A.A.A.Q).
E-mail addresses: morris.srebnik@ekmd.huji.ac.il (M. Srebnik), abedalazi-
z@ekmd.huji.ac.il, abedalaziz@eng.alquds.edu (Abed Al Aziz Al Quntar).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.108

868
Y. Sinelnikove et al. / Tetrahedron Letters 50 (2009) 867–869
Table 1
Table 3
Diethyl 2-alkylcyclobut-1-enylphosphonate 3 from diethyl alkynylphosphonate
Attempted cylization of disubstituted alkynes other than phosphonates
R2
R1
Entry
R
31P (ppm)
Yield (isolated)a (%)
3a
3b
3c
3d
3e
3f
n-C3H7
n-C4H9
n-C5H11
n-C8H17
n-C12H25
Phenyl
PhCH2OCH2CH2
(PhCH2O)CHCH2CH2CH2CH3
10.70
10.75
10.67
11.01
12.78
10.29
10.35
9.57
75
78
73
81
76
70
65
65
Entry
R1
R2
Yielda
a
b
c
n-Bu
n-Bu
Ph
SiMe3
Sn(n-Bu)3
Ph
<2%
<2%
7%
3g
3h
d
Ethyl
Ethyl
5%
a
a
After silical gel chromatography.
Estimated by GCMS.
P(O)(OEt)2
Cp2ZrCl2
2 EtMgCl, THF
P(O)(OEt)2
2 CuCl
P(O)(OEt)2
ZrCp2
2b
1b
ð1Þ
3b 78 %
This is very different from another reagent system we devel-
oped consisting of Cp2ZrCl2/2EtMgBr/2AlCl3 which provided meth-
ylcyclopropylphosphonates from 1-alkynylphosphonates (Eq. 2).36
Thus, the products of cyclization obtainable from zirco-
nacylopentenylphosphonates are very sensitive to the metal in
the transmetallation step.
after copper chloride and copper iodide (entry c) gave the lowest
yields. On the other hand, when other metal chlorides such as
TiCl4, CoCl2, SnCl2 SbCl3, ZnCl2, CeCl3, and BaCl2 were used (Table
2, g–n), only the ethylated product was obtained, and no trace of
cyclobutenylphosphonates 3 were detected. The reaction has limi-
tations. Bulky substituted alkynylphosphonates, that is t-buty-
lethynylphosphonate, did not afford the corresponding
zirconacyclopentenylphosphonate, 2, but rather the zirco-
nacyclopropenylphosphonate which gave cis-t-butylvinylphospho-
nate after hydrolysis. Alkylhalide side chains are also not
compatible. Thus, diethyl 5-chloro-1-pentynylphosphonate could
not be converted to the corresponding cyclobutenylphosphonate.
An intractable reaction mixture was obtained presumably due to
various copper-induced coupling reactions.
We briefly investigated other disubstituted alkynes (Table 3).
None gave satisfactory results. The reason for this is unclear but
not surprising. In the past, we have noticed that the phosphono
group enhances the stability of zirconacycles. For instance, zirco-
nacyclopropenylphosphonates do not dimerize and do not require
stabilization by adding phosphine ligands.37 Be that as it may, the
present method of preparing 2-substituted cycobutenylphospho-
nates is general, conceptually simple, and is far superior to any
methodology, whether organometallic or other, reported to date.
H
H
O
P
Cp2ZrCl2/2 EtMgCl/ 2 AlCl3
OEt
OEt
R
R
P(O)(OEt)2
ð2Þ
After addition of 2 equiv of CuCl to zirconacyclopentenyl phos-
phonates 2 at room temperature, the reaction was refluxed for
36 h. It was quenched with dilute aqueous HCl. The reaction can
be followed by 31P NMR and GC/MS. The cyclobut-1-enylphospho-
nate products 3 were extracted with ethyl acetate and isolated by
silica gel column chromatography in good yield (65–81%). This effi-
cient inter-molecular cyclization reaction is tolerant to alkyl (3a–
e), phenyl (3f), and benzyloxy (3g–h), groups. The addition of
two equivalents of anhydrous CuCl was essential in order to reach
the maximum yield.
The reaction did not proceed either under CuCl catalytic condi-
tions or at room temperature. Other copper-containing compounds
were investigated, and the yields were varied. Thiophene-2-car-
bonyloxy copper(I) (Table 2, entry b) afforded the highest yields
Acknowledgments
The study was supported by a research grant from the Hebrew
University. Morris Srebnik and Abraham Rubinstein are affiliated
with the David R. Bloom Center of Pharmacy.
Table 2
Effect of various metal complexes on cyclization of zirconacyclopentenyl phospho-
nates 2
References and notes
Entry
Metal complex
Yield of 3d (%)
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35. Procedure for the synthesis of 3b: To 0.306 g (1.05 mmol) of zirconocene
dichloride dissolved in 6 ml of dry THF at ꢀ78° C was added 1.05 ml of 2 M
EtMgBr (2.1 mmol) dropwise in a 25 ml round-bottomed flask. After stirring for
5 min at ꢀ78 °C, 1 mmol of alkynylphosphonate was added and the reaction
was gradually warmed to 25 °C, and stirred for 2 h. Then, 0.20 g (2 mmol) of
CuCl was added under N2. After stirring at reflux for 36 h, the reaction was
quenched with dilute aqueous HCl. The oily product was extracted with Et2O
(2 ꢁ 10 ml), separated on silica gel column (70% petroleum ether: 30% ethyl
acetate). 1H NMR (300 MHz):
d 0.91 (t, 3H, JHH = 4.2 Hz), 1.31 (t, 6H,
JHH = 4.2 Hz), 1.28–1.38 (overlap m, 2H), 1.43 (m, 2H), 2.35 (br t, 2H,
JHH = 4.8 Hz), 2.54 (br s, 4H), 4.04–4.10 (m, 4H). 31P NMR (121.4 MHZ): d
3
10.75; 13C NMR (75.5 MHz): d 13.81, 16.39 (d, JPC = 3.7 Hz), 22.52, 27.18 (d,
3
2
2JPC = 5.1 Hz), 29.15, 30.41, 31.04 (d, JPC = 19.3 Hz), 61.31 (d, JPC = 3.7 Hz),
1
2
127.19 (d, JPC = 109.1 Hz), 168.53 (d, JPC = 4.2 Hz); MS(EI):m/z (%) 246 (6.5),
231 (8.8), 217 (48.0), 204 (83.4), 189 (28.2), 176 (24.7), 161 (82.2), 148 (62.0),
129 (8.9), 107 (56.1), 93 (50.8), 79 (100), 65 (62.7), 53 (20.1); Anal. Calcd for
C12H23O3P: C, 58.52; H, 9.41; P, 12.58. Found: C, 58.69; H, 9.47; P, 12.44.
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