Ruthenium-catalyzed [2 + 2] cycloadditions of bicyclic alkenes with alkynyl phosphonates

Article abstract of DOI:10.1021/jo9010206

(Chemical Equation Presented) Ruthenium-catalyzed [2 + 2] cycloadditions of bicyclic alkenes with alkynyl phosphonates were investigated. The phosphonate moieties were found to be compatible with the Ru-catalyzed cycloadditions giving the corresponding cy

Full text of DOI:10.1021/jo9010206

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(via [2 þ 2 þ 1], [4 þ 2], [5 þ 2], [6 þ 2], and [4 þ 4] cyclo-
Ruthenium-Catalyzed [2 þ 2] Cycloadditions of
additions) that have been studied extensively,3-7 there are
relatively few studies on metal-catalyzed [2 þ 2] cycloaddi-
tions for the formation of 4-membered rings. Recently,
various aspects of transition-metal-catalyzed [2 þ 2] cyclo-
additions of an alkene and an alkyne for the synthesis of
cyclobutenes have been studied by us and others, including
development of novel catalysts, study of the intramolecular
variant of the reaction, investigation of the chemo- and
regioselectivity of unsymmetrical substrates, and asym-
metric induction studies with chiral auxiliaries on the alkyne
component.8-13
Bicyclic Alkenes with Alkynyl Phosphonates
Neil Cockburn, Elham Karimi, and William Tam*
Guelph-Waterloo Centre for Graduate Work in Chemistry and
Biochemistry, Department of Chemistry, University of
Guelph, Guelph, Ontario, Canada N1G 2W1
wtam@uoguelph.ca
Received May 15, 2009
We have previously investigated the Ru-catalyzed [2þ2]
cycloaddition of bicyclic alkenes with various heteroatom
functionalities (ynamide 2,8h,8n halide 3,8g,8r sulfide 4,8k
sulfone 58k) in the acetylenic position (Scheme 1). Alkynyl
halides 3 (X=Cl, Br, I) were found to be the most reactive,
proceeding at room temperature. Ynamides 2 (X = N-
(CO2Me)R0), alkynyl sulfides 4 (X = SAr, SR0), and sulfones
5 (X = SO2Ar, SO2R0) were less reactive than alkynyl halides
and required longer reaction time and higher temperature.
To the best of our knowledge, no examples of Ru-cata-
lyzed [2þ2] cycloaddition of alkynyl phosphonates are repor-
ted in the literature. The electron-deficient phosphonate
Ruthenium-catalyzed [2 þ 2] cycloadditions of bicyclic
alkenes with alkynyl phosphonates were investigated.
The phosphonate moieties were found to be compatible
with the Ru-catalyzed cycloadditions giving the corres-
ponding cyclobutene cycloadducts in low to excellent
yield (up to 96%). Alkynyl phosphonates showed lower
reactivity than other heteroatom-substituted alkynes
such as alkynyl halides, ynamides, alkynyl sulfides, and
alkynyl sulfones and required a higher reaction tempera-
ture and much longer reaction time.
(4) (a) Wender, P. A.; Jenkins, T. E. J. Am. Chem. Soc. 1989, 111, 6432.
(b) Jolly, R. S.; Luedtke, G.; Sheehan, D.; Livinghouse, T. J. Am. Chem. Soc.
1990, 112, 4965. (c) Wender, P. A.; Jenkins, T. E.; Suzuki, S. J. Am. Chem.
Soc. 1995, 117, 1843. (d) Murakami, M.; Ubukata, M.; Itami, K.; Ito, Y.
Angew. Chem., Int. Ed. 1998, 37, 2248. (e) Paik, S.-J.; Son, S. U.; Chung, Y.
K. Org. Lett. 1999, 1, 2045. (f) Hilt, G.; Smolko, K. I. Angew. Chem., Int. Ed.
€
2003, 42, 2795. (g) Hilt, G.; Luers, S.; Harms, K. J. Org. Chem. 2004, 69, 624.
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1995, 117, 4720. (b) Wender, P. A.; Rieck, H.; Fuji, M. J. Am. Chem. Soc.
1998, 120, 10976. (c) Trost, B. M.; Shen, H. Angew. Chem., Int. Ed. 2001, 40,
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4550.
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2000, 122, 7815.
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Wender, P. A.; Nuss, J. M.; Smith, D. B.; Suarez-Sobrino, A.; Vagberg, J.;
Decosta, D.; Bordner, J. J. Org. Chem. 1997, 62, 4908.
While cycloaddition reactions can be carried out by using
heat, light, or Lewis acids,1 these promoters usually require
the presence of polar functional groups in the substrates.
Unactivated substrates require extreme conditions (high
temperature and high pressure) to promote reaction. Transi-
tion-metal catalysts provide a new opportunity to promote
cycloadditions of unactivated substrates and cycloadditions
that are theoretically forbidden or difficult to achieve. In this
way, transition-metal catalysts have shown themselves to be
a powerful method for the synthesis of rings and complex
molecular stuctures.2 Unlike many other metal-catalyzed
cycloadditions for the formation of 5- to 8-membered rings
(8) For our recent contibutions on metal-catalyzed cycloaddition reac-
tions of bicyclic alkenes, see: (a) Jordan, R. W.; Tam, W. Org. Lett. 2000, 2,
3031. (b) Jordan, R. W.; Tam, W. Org. Lett. 2001, 3, 2367. (c) Jordan, R. W.;
Tam, W. Tetrahedron Lett. 2002, 43, 6051. (d) Villeneuve, K.; Jordan, R. W.;
Tam, W. Synlett 2003, 2123. (e) Villeneuve, K.; Tam, W. Angew. Chem., Int.
Ed. 2004, 43, 610. (f) Jordan, R. W.; Khoury, P. K.; Goddard, J. D.; Tam, W.
J. Org. Chem. 2004, 69, 8467. (g) Villeneuve, K.; Riddell, N.; Jordan, R. W.;
Tsui, G. C.; Tam, W. Org. Lett. 2004, 6, 4543. (h) Riddell, N.; Villeneuve, K.;
Tam, W. Org. Lett. 2005, 7, 3681. (i) Burton, R. R.; Tam, W. Tetrahedron
Lett. 2006, 47, 7185. (j) Villeneuve, K.; Tam, W. Organometallics 2006, 25,
843. (k) Riddell, N.; Tam, W. J. Org. Chem. 2006, 71, 1934. (l) Liu, P.;
Jordan, R. W.; Goddard, J. D.; Tam, W. J. Org. Chem. 2006, 71, 3793. (m)
Jordan, R. W.; Villeneuve, K.; Tam, W. J. Org. Chem. 2006, 71, 5830. (n)
Villeneuve, K.; Riddell, N.; Tam, W. Tetrahedron 2006, 62, 3823. (o) Liu, P.;
Tam, W.; Goddard, J. D. Tetrahedron 2007, 63, 7659. (p) Burton, R. R.; Tam,
W. J. Org. Chem. 2007, 72, 7333. (q) Jordan, R. W.; Le Marquand, P.; Tam,
W. Eur. J. Org. Chem. 2008, 1, 80. (r) Allen, A.; Villeneuve, K.; Cockburn,
N.; Fatila, E.; Riddell, N.; Tam, W. Eur. J. Org. Chem. 2008, 24, 4178.
(9) Trost, B. M.; Yanai, M.; Hoogsteen, K. J. Am. Chem. Soc. 1993, 115,
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(1) (a)
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
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(2) (a) Lautens, M.; Klute, W.; Tam, W. Chem. Rev. 1996, 96, 49. (b)
Wender, P. A.; Love, J. A. Advances in Cycloaddition; JAI: Greenwich, 1999;
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(3) For recent reviews on transition metal-catalyzed [2 þ 2 þ 1] cycload-
ditions, see: (a) Pericas, M. A.; Balsells, J.; Castro, J.; Marchueta, I.;
Moyano, A.; Riera, A.; Vazquez, J.; Verdaguer, X. Pure Appl. Chem. 2002,
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5762 J. Org. Chem. 2009, 74, 5762–5765
Published on Web 07/02/2009
DOI: 10.1021/jo9010206
r
2009 American Chemical Society

Cockburn et al.
JOCNote
SCHEME 1. Previous Studies on Heteroatom-Substituted
Alkynes in the Ru-Catalyzed [2 þ 2]
SCHEME 2. Synthesis of Alkynyl Phosphonates from Terminal
Alkynes
TABLE 1. Optimization of Ru-Catalyzed [2 þ 2] Cycoladditions of
Norbornadiene 1a with 1-Phenylethynyl phosphonate 12a
group allows for the scope of the reaction to be expanded to a
new category of heteroatom substituents with phosphorus
functionality that is stable toward further oxidation.
Formation of 1-cyclobutenyl phosphonates has pre-
viously been reported in the literature; however, these syn-
thetic methods have limited scope and cannot be applied
with our substrates.14 Ruder and Norwood observed ther-
mal [2 þ 2] cycloaddition between an alkynyl phosphonate
and enamine, though the temperatures necessary to promote
the cycloaddition caused spontaneous electrocyclic ring-
opening of the adduct, and no cyclobutene was isolated.14d
In this paper, we report the first example of Ru-catalyzed
[2 þ 2] cycloadditions of alkynyl phosphonates with bicyclic
alkenes to form 1-cyclobutnenyl phosphonates.
entry
solvent
T (°C)
time (h)
yielda (%)
1
2
3
4
5
6
THF
THF
THF
Et3N
dioxane
neat
60
80
100
100
100
100
24
144
240
240
240
240
0b
27c
66
0b
60
71
aThe yield of the isolated cycloadducts after column chromatogra-
phy. bOnly the starting alkyne was recovered. cThe reaction did not go to
completion, and some starting alkyne was recovered.
Vinyl phosphonates have been found to be important
biomolecules in metabolic processes, as anticancer and anti-
viral drugs, as well as antibacterial and antifungal com-
pounds.15 The phosphonate group can also be modified by
established procedures to a wide variety of other phosphorus
groups including phosphines.16,17 The possible phosphine
derivatives of the cycloadduct products could find applica-
tion in the growing field of phosphine-olefin ligands.18
To begin this study, the alkynyl phosphonates had to be
synthesized. There are various methods in the literature for
the formation of alkynyl phosphonates.19 It was found that
the procedure developed by Oh and co-workers was the
simplest and most applicable.19c The original procedure
involved deprotonating various terminal alkynes 10 with
n-BuLi and subsequent trapping of the anion formed with
chlorophosphates 11 to generate the desired alkynyl phos-
phonates 12. However, it was found that unreacted n-BuLi
was adding to 11 to form butyl phosphonate 13, which had
an Rf value very similar to that of 12 and was difficult to
remove by flash chromatography. Therefore, the procedure
was modified, and LDA was employed in place of n-BuLi to
eliminate any nucleophilic addition side reactions
(Scheme 2).
The reaction conditions of the Ru-catalyzed [2 þ 2] cy-
cloadditions were first optimized with alkynyl phospho-
nate 12a and norbornadiene 1a as the model reaction
(Table 1). It was found that the alkynyl phosphonate 12a
was compatible with ruthenium-catalyzed [2 þ 2] cycloaddi-
tion to produce the expected cyclobutene adduct 14a. While
the reaction did proceed, higher temperatures and longer
reaction times were needed relative to the other alkyne
substrates previously studied in this mode of reaction.8 No
reaction was observed when the reaction was carried out in
THF at 60 °C, and the reaction did not go to completion at
80 °C for 144 h (entries 1 and 2). When the reaction was
carried out in THF at 100 °C for 240 h, the desired cyclo-
butene cycloadduct 14a was obtained in 66% yield (entry 3).
(14) (a) Ueda, T.; Inukai, K.; Muramatsu, H. Bull. Chem. Soc. Jpn. 1969,
42, 1684. (b) Darling, S. D.; Subramanian, N. Tetrahedron Lett. 1975, 16,
3279. (c) Facklam, T.; Hoffmann, K. -L.; Regitz, M. Chem. Ber. 1987, 120,
1397. (d) Ruder, S. M.; Norwood, B, C. Tetrahedron Lett. 1994, 35, 3473. (e)
Liu, X. -L.; Sheng, S. -R.; Zhou, W.; Wang, Q. -Y.; Zhang, X. -L.; Gong, B.
Synth. Commun. 2007, 37, 119.
(15) (a) Smeyers, Y.; Sanchez, F.; Laguna, A.; Ibanez, N.; Ruano, E.;
Perez, S. J. Pharm. Sci. 1987, 76, 753. (b) Megati, S.; Phadtare, S.; Zemlicka,
J. J. Org. Chem. 1992, 57, 2320. (c) Harnden, M. R.; Parkin, A.; Parratt, M.
J.; Perkins, R. M J. Med. Chem. 1993, 36, 1343. (d) Smith, P.; Chamiec, A.;
Chung, G.; Cobley, K.; Duncan, K.; Howes, P.; Whittington, A.; Wood, M.
J. Antibiot. Tokyo 1995, 48, 73. (e) Lazrek, H.; Rochdi, A.; Khaider, H.;
Barascut, J.; Imbach, J.; Balzarini, J.; Witvrouw, M.; Pannecouque, C.; De
Clerq, E. Tetrahedron 1998, 54, 3807. (f) Holstein, S.; Cermak, D.; Wiemer,
D.; Lewis, K.; Hohl, R. Bioorg. Med. Chem. 1998, 6, 687.
(16) For the reduction of phosphonates, see: (a) Horner, L.; Hoffmann,
H.; Beck, P. Chem. Ber. 1958, 91, 1583. (b) Fritsche, H.; Hasserodt, U.;
Korte, F.; Friese, G.; Adrian, K.; Arenz, H. J. Chem. Ber. 1965, 98, 1681. (c)
Keglevich, G.; Gaumont, A.-C.; Denis, J.-M. Heteroatom Chem. 2001, 12,
161.
(17) For the functionalization of primary phosphines, see: (a) Mann, F.
G.; Millar, I. T. J. Chem. Soc. 1952, 3039. (b) Issleib, K.; Hausler, S. Chem.
Ber. 1961, 94, 113. (c) Welcher, R. P.; Day, N. E. J. Org. Chem. 1962, 27,
1824.
€
(18) (a) Laporte, C.; Bohler, C.; Schonberg, H.; Grutzmacher, H. J.
Organomet. Chem. 2002, 641, 227. (b) Maire, P.; Deblon, S.; Breher, F.;
€
€
(19) (a) Aguiar, A. M.; Chattha, M. S. J. Org. Chem. 1971, 36, 2719. (b)
ꢀ
Diziere, R.; Savignac, P. Tetrahedron Lett. 1996, 37, 1783. (c) Gil, J. M.;
€
€
€
€
Geier, J.; Bohler, C.; Ruegger, H.; Schonberg, H.; Grutzmacher, H. Chem.;
Eur. J. 2004, 10, 4198. (c) Shintani, R.; Duan, W.-L.; Okamoto, K.; Hayashi,
T. Tetrahedron: Asymmetry 2005, 16, 3400. (d) Shi, W.; Luo, Y.; Luo, X.;
Chao, L.; Zhang, H.; Wang, J.; Lei, A. J. Am. Chem. Soc. 2008, 130, 14713.
Sung, J. W.; Park, C. P.; Oh, D. Y. Synth. Commun. 1997, 27 3171. (d) Iorga,
B.; Eymery, F.; Carmichael, D.; Savignac, P. Eur. J. Org. Chem. 2000, 3103.
(e) Lera, M.; Hayes, C. J. Org. Lett. 2000, 2, 3873. (f) Lahrache, H.; Robin, S.;
Rousseau, G. Tetrahedron Lett. 2005, 46 1635. (g) Yatsumonji, Y; Ogata, A.;
Tsubouchi, A.; Takeda, T. Tetrahedron Lett. 2008, 49, 2265. (h) Konno, T.;
Morigaki, A.; Ninomiya, K.; Miyabe, T.; Ishihara, T. Synthesis 2008, 4, 564.
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(e) Defieber, C.; Grutzmacher, H.; Carreira, E. M. Angew. Chem., Int. Ed.
2008, 47, 4482.
J. Org. Chem. Vol. 74, No. 15, 2009 5763

Cockburn et al.
JOCNote
TABLE 2. Ru-Catalyzed [2 þ 2] Cycloadditions of Norbornadiene with
unsubstituted alkyl chain (entry 4) and differed by only 2%
in yield between the bare and protected alcohol groups.
Examining the reactions with aromatic substrates (12h-m,
entries 8-13) illustrates similar trends as observed in previous
studies. Again, steric hindrance reduced reactivity of the
alkyne when comparing the substitution of a methyl group
in either the ortho or para positions on the ring (entries 8 and 9).
With the methyl group far from the reaction site in the para
position, an 83% yield was achieved, whereas the methyl group
ortho to the reaction site reduced the yield to a mere 8%.
Substrates with electron-donating groups on the benzene ring
(R=p-MeO-C6H4, m-NH2-C6H4, entries 10 and 11) did not
work as well as those with an electron-withdrawing group
(R=m-F-C6H4, entry 12). Though all three moieties produced
the desired cycloadducts in good yields, substrates with
an electron-withdrawing group gave better yields. This is
especially evident when considering the electron-rich 3-thio-
phene moiety 12m (entry 13) which had a reduced yield of
only 65%.
In order to investigate the scope of the Ru-catalyzed [2 þ 2]
cycloaddition of alkynyl phosphonates, cycloadditions of
alkynyl phosphonate 12a with various bicyclic alkenes were
carried out, and the results are shown in Table 3. Though
higher yields were observed with THF as solvent (Table 1,
entry 3) compared to dioxane (entry 5), solvent loss of THF
was experienced due to the elevated reaction temperatures.
Therefore, dioxane was employed for this series of reactions.
With the exception of 1h (entry 8), all alkenes studied (1b-g,
entries 1-7) underwent Ru-catalyzed [2 þ 2] cycloaddition
to produce, in a stereoselective manner, only the exo cyclo-
adduct. In addition, when one of the homoconjugated olefins
was substituted with methyl esters (1c and d, entries 3 and 4)
the reaction was chemoselective, with cycloaddition occur-
ring only on the less substituted double bonds.
Alkynyl Phosphonates 3b-l
entry
alkyne
R1
R
yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
12a
12b
12c
12d
12e
12f
12g
12h
12i
Et
Me
Ph
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Ph
Ph
Ph
n-Bu
Cy
CH2OH
CH2OTBS
o-Tol
p-Tol
p-MeO-C6H4
m-NH2-C6H4
m-F-C6H4
3-thiophene
71
44
97
68
0b
69
67
8c
83
80
78
89
65
12j
12k
12l
12m
aThe yield of the isolated cycloadducts after column chromatogra-
phy. bOnly the starting alkyne was recovered. cThe reaction did not go to
completion, and some starting alkyne was recovered.
Unlike our previous studies with other alkynes in which Et3N
was shown to be a good solvent in the ruthenium-catalyzed
[2þ2] cycloadditions, no reaction was observed when Et3N
was used as solvent in the reactions with alkynyl phos-
phonate 12a (entry 4). The best yield was observed when
the reaction was carried out using 5 mol % of catalyst,
Cp*RuCl(COD) (COD=1,5-cyclooctadiene, Cp*=1,2,3,-
4,5-pentamethylcyclopentadiene), at 100 °C over 240 h in
excess norbornadiene as solvent. The exo [2 þ 2] cycloadduct
14a was formed as the only stereoisomer.20
Considering the reactivity of different alkenes toward
alkynyl phosphonates in the ruthenium-catalyzed [2 þ 2]
cycloaddition reaction, similar trends are observed as with
previous reports. The loss of homoconjugation in comparing
norbornadiene 1a (entry 1) and norbornene 1b (entry 2) did
not greatly affect the yield of the reaction, though the yield
was moderately improved as was observed with alkynyl
sulfones.8k The addition of two methyl ester groups on
norbornadiene (entry 3) increased the yield of the reaction,
while replacing the one carbon bridge with an oxygen (entry
4) in that same molecule greatly reduced the yield. The large
decrease in yields is attributed to the decomposition of the
alkene reaction partner which was not stable at the elevated
temperatures required to promote reaction. As previously
observed,8p addition of a benzene ring to the bicyclic struc-
ture (entry 5) reduced the reactivity substantially. In contrast
to 1d, however, the substitution of an oxygen into the bridge
greatly improved the yield of the reaction (entry 6). Investi-
gations into the enhanced reactivity of oxabenzonorbornene
1f in various reactions are currently underway in our labora-
tory. Extending the aromatic system (entry 7) reduced the
yield of the reaction as did adding a t-BuO group on the
bridge (entry 8), which can be attributed to decomposition of
the alkene component as was observed with 1d. 7-t-BuO-
norbornadiene 1h was also found to be inert in the Ru-
catalyzed [2 þ 2] cycloadditions with alkynyl sulfides.8k
In conclusion, we have demonstrated the first examples of
ruthenium-catalyzed [2 þ 2] cycloadditions between bicyclic
After the optimal conditions were determined, the effect of
the alkynyl phosphonate on the cycloaddition was studied,
and the results are given in Table 2. First, different groups on
the phosphonate moiety, R1 (12a-c, entries 1-3), were
investigated. While dimethyl phosphonate (R1=Me, entry
2) gave the lowest yield (44%) in the cycloaddition, diphenyl
phosphonate (R1=Ph, entry 3) was found to give the highest
yield (97%) among the three phenylethynyl phosphonates
(12a-c) tested. The effect of different groups (R) at the
acetylenic position was studied (alkynes 12d-m), and the
results are shown in Table 2, entries 4-13.
In general, the reaction was found to proceed slower with
aliphatic groups compared to aromatic groups with little
exception. As with previous studies, the primary alkyl group
(R=n-Bu, entry 4) produced a higher yield than the sterically
hindered secondary alkyl group (R=Cy, entry 5), which
produced no adduct. Interestingly, while previous studies
demonstrated that propargylic alcohols stabilize coordina-
tion to the catalyst through hydrogen bonding to the chlorine
ligand of the active catalyst, [Cp*RuCl],8o such increased
reactivity was not observed in the reaction of 12f (entry 6) as
compared to its TBS-protected analogue 12g (entry 7).
Both substrates demonstrated similar reactivity to an
(20) For the determination of the exo and endo stereochemistry of [2 þ 2]
cycloadducts, see our previous work in ref 8. Also, no cycloaddition with the
COD ligand was observed, as this type of Ru-catalyzed [2 þ 2] cycloaddition
was known to occur only on strained bicyclic alkenes; see refs 8 and 10.
5764 J. Org. Chem. Vol. 74, No. 15, 2009

Cockburn et al.
JOCNote
phosphonates with various bicyclic alkenes proceeds in a
chemo- and stereoselective manner, producing the desired
cyclobutene adducts in moderate to good yields. Further
investigation into the use of other phosphorus-containing
alkynes (phosphonite, phosphine oxide, chiral alkynyl phos-
phonates) in Ru-catalyzed [2 þ 2] cycloadditions, along with
the functionalization and application of the cycloadduct as
an olefin-phosphorus ligand are currently in progress in our
laboratory.
TABLE 3. Ru-Catalyzed [2 þ 2] Cycoladditions of Various Bicyclic
Alkenes 1b-h and Alkynyl Phosphonate 12a
Experimental Section
A representative procedure of the ruthenium-catalyzed [2 þ 2]
cycloaddition and characterization of a cycloadduct is described
here. For the synthesis of alkynyl phosphonates and details of
other adducts, see the Supporting Information.
General Procedure for Ruthenium-Catalyzed [2 þ 2] Cycload-
ditions with Norbornadiene. A mixture of norbornadiene
(0.4 mL, 3.94 mmol) and alkynyl phosphonate (1 equiv) was
prepared in an oven-dried screw-cap vial. The vial was purged
with nitrogen and taken into the drybox where 5-10 mol % of
Cp*RuCl(COD) was weighed out and added and the vial sealed.
The reaction mixture was stirred outside the glovebox at 100 °C
for 10 days. The crude product was purified by flash chroma-
tography to yield the corresponding cycloadduct (ethyl acetate/
hexanes mixture).
Cycloadduct 14a (Table 1, Entry 6). The above general
procedure was followed using alkynyl phosphonate 12a (39.8
mg, 0.167 mmol) and Cp*RuCl(COD) (7.5 mg, 0.02 mmol). The
crude product was purified by column chromatography
(EtOAc/hexanes 6:4) to provide cycloadduct 14a (39.3 mg,
0.119 mmol, 71%) as a yellow oil: Rf 0.34 (EtOAc/hexanes
1:1); IR (CH2Cl2, NaCl) 3058 (m), 2977 (s), 2939 (s), 1491 (m),
1447 (m), 1390 (w), 1243 (s), 1024 (s), 962 (s), 779 (m) cm-1; 1H
NMR (CDCl3, 400 MHz) δ 7.90 (dd, 2H, J=7.9, 1.6 Hz), 7.41-
7.35 (m, 3H), 6.19 (br s, 2H), 4.19-4.06 (m, 4H), 2.78 (t, 1H, J=
4.6 Hz), 2.71 (s, 2H), 2.52 (d, 1H, J=3.5 Hz), 1.47 (d, 1H, J=9.2
Hz), 1.36 (d, 1H, J=9.2 Hz), 1.32 (td, 6H, J=7.0, 1.0 Hz) ; 13
C
NMR (APT, CDCl3, 100 MHz) δ 161.3 (d, J=8.4 Hz), 136.1,
135.3, 132.5 (d, J =1.1 Hz), 129.7, 128.51 (d, J = 180.5 Hz),
128.46, 127.9, 61.55 (d, J=3.4 Hz), 61.50 (d, J=3.4 Hz), 45.2,
44.9, 43.3, 39.6, 39.2, 38.9, 16.4 (d, J=3.8 Hz), 16.3 (d, J=3.8
Hz); 31P NMR (CDCl3, 160 MHz) δ 10.74; HRMS (CI) calcd for
C19H23O3P m/z 330.1385, found m/z 330.1389.
aThe yield of the isolated cycloadducts after column chromatogra-
phy. bDecomposition of the alkene was evident by TLC of the crude
mixture. cOnly the starting alkyne was recovered
Acknowledgment. This work was supported by Merck
Frosst Centre for Therapeutic Research, Natural Sciences
and Engineering Research Council of Canada (NSERC),
and Boehringer Ingelheim (Canada) Ltd. N.C. thanks the
Ontario Government for a postgraduate scholarship (OGS).
alkenes and alkynyl phosphonates. We found the alkynyl
phosphonate moiety bearing diethyl, dimethyl and diphenyl
groups to be compatible with Ru-catalyzed [2 þ 2] cyclo-
additions, though with lower reactivity than other hetero-
atom functionalities previously reported.8 Finally, it was
found that Ru-catalyzed [2 þ 2] cycloaddition of alkynyl
Supporting Information Available: Detailed experimental
procedures and compound characterization data of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 15, 2009 5765