First general approach to cyclohex-3-ene-1,1-bis(phosphonates) by Diels-Alder cycloaddition of tetraethyl vinylidenebis(phosphonate) to 1,3-dienes

Article abstract of DOI:10.1021/jo0205154

Tetraethyl vinylidenebis(phosphonate) (VBP) reacts smoothly with substituted 1,3-dienes at 90-110 °C without solvent to give the corresponding cyclohex-3-ene-1,1-bis(phosphonates) in good yields (60-85%). With nonsymmetrically substituted dienes, mixtures of regioisomers are obtained, the regioisomeric ratio being exclusively controlled by electronic effects. Danishefsky's diene allows tetraethyl 4-oxocyclohex-2-ene-1,1-bis(phosphonate) to be obtained in an 81% overall yield after the acid-catalyzed hydrolysis of the Diels-Alder cycloadduct. With 2,3-dimethoxy-1,3-butadiene, a mixture of regioisomeric dimethoxycyclohexene-1,1-bis(phosphonates) is formed by the VBP-catalyzed isomerization of the normal Diels-Alder cycloadduct. The mixture converges into tetraethyl 3,4-dimethoxycyclohex-2-ene-1,1-bis(phosphonate) at prolonged reaction times.

Full text of DOI:10.1021/jo0205154

F ir st Gen er a l Ap p r oa ch to Cycloh ex-3-en e-1,1-bis(p h osp h on a tes)
by Diels-Ald er Cycloa d d ition of Tetr a eth yl
Vin ylid en ebis(p h osp h on a te) to 1,3-Dien es
Renzo Ruzziconi,*,† Giacomo Ricci,† Antimo Gioiello,† He´le`ne Couthon-Gourve`s,‡ and
J ean-Philippe Gourve`s‡
Dipartimento di Chimica, Universita` di Perugia, Via Elce di Sotto, 8 I-06123 Perugia, Italy, and FRE
CNRS 2125 Chimie et Biologie des Substances Naturelles, Universite´ de la Bretagne Occidentale,
U.F.R. Sciences et Techniques, 6 av. Le Gorgeu, B.P. 809, 29285 Brest, France
ruzzchor@unipg.it
Received August 5, 2002
Tetraethyl vinylidenebis(phosphonate) (VBP) reacts smoothly with substituted 1,3-dienes at 90-
110 °C without solvent to give the corresponding cyclohex-3-ene-1,1-bis(phosphonates) in good yields
(60-85%). With nonsymmetrically substituted dienes, mixtures of regioisomers are obtained, the
regioisomeric ratio being exclusively controlled by electronic effects. Danishefsky’s diene allows
tetraethyl 4-oxocyclohex-2-ene-1,1-bis(phosphonate) to be obtained in an 81% overall yield after
the acid-catalyzed hydrolysis of the Diels-Alder cycloadduct. With 2,3-dimethoxy-1,3-butadiene, a
mixture of regioisomeric dimethoxycyclohexene-1,1-bis(phosphonates) is formed by the VBP-
catalyzed isomerization of the normal Diels-Alder cycloadduct. The mixture converges into
tetraethyl 3,4-dimethoxycyclohex-2-ene-1,1-bis(phosphonate) at prolonged reaction times.
In tr od u ction
attempting to provide more potent antiresorptive ana-
logues without significantly increasing the mineralization
defects formerly observed with the first-generation bis-
(phosphonates).6
Because of their physiological properties, gem-diphos-
phonic acid derivatives1 are now recognized as an im-
portant class of pharmacologically active molecules that
are likely to be effective therapeutic options in several
human pathologies,2 such as osteoporosis. They are also
effective in the treatment of cancer-related hypercalce-
mia,3 in the treatment of rheumatoid arthritis,4 and as
potent anti-inflammatory drugs.5 In this context, cyclo-
alkyl- and cycloalkenylbis(phosphonates) have become
increasingly important as an alternative strategy in
Whereas cycloalkylbis(phosphonate) esters can be eas-
ily prepared by the base-induced double alkylation of
tetraalkyl methanebis(phosphonate) with 1,ω-dibromoal-
kanes,7 an effective method for preparing the more
valuable cycloalkenylbis(phosphonates) is still lacking.
The Diels-Alder cycloaddition of vinylphosphonates to
1,3-dienes, which would seem to be the most obvious
synthetic approach to cyclohexenylbis(phosphonates), has
not been exploited, and the few reported examples are
limited to the synthesis of monophosphonate cyclo-
hexenes.8 As dienophiles, vinylphosphonates are much
less reactive than R,â-unsaturated carbonyl compounds
and nitriles,9,10 although their dienophilicity can be
substantially enhanced and good yields of cycloadducts
† Universita` di Perugia.
‡ Universite´ de la Bretagne Occidentale.
(1) (a) Geddes, A. D.; D’Souza, S. M.; Ebetino, F. H.; Ibbotson, K. J .
Bone and Mineral Research/ 8; Elsevier Science: New York, 1994. (b)
Papaploulos, S. E.; Lanoman, J . O.; Bijvoet, O. L. M.; Lowix, C. W. G.
M.; Valkema, R.; Pauwels, E. K. J .; Vermeij, P. Bone 1992, 13, S41-
S49.
(2) (a) Fleisch, H.; Senn, H.-J . In Bisphosphonates and Tumor-
Osteolysis; Brunner, K. W., Fleisch, H., Senn, H.-J ., Eds.; Recent
Results in Cancer Research; Springer-Verlag: New York, 1989; Vol.
11603. (b) See also: several authors in Bisphosphonate on Bones;
Bijvoet, O. L. M., Fleisch, H. A., Canfield, R. E., Russell, R. G. G., Eds.;
Elsevier Science Biomedical: Amsterdam, The Netherlands, 1995. (c)
Thuerlimann, B. Bisphosphonates in Clinical Oncology; Recent Results
in Cancer Research; Springer-Verlag: New York, 1998; Vol. 149. (d)
Ralston, S. H.; Baylink, D. J .; Bennett, S. T.; Brandi, M. L.; Econs, M.
J .; Eisman, J . A.; Fleisch, H.; J ohnson, M. L.; Langdahl, B. L.; van
Leeuwen, H.; Seeman, E.; Uitterlinden, A. G.; Spector, T. D.; Young,
M. F. Calcif. Tissue Int. 2000, 67, 481-500. Martin, M. B.; Grimley,
J . S.; Lewis, J . C.; Heath, H. T., III; Bailey, B. N.; Kendrick, H.;
Yardley, V.; Caldera, A.; Lira, R.; Urbina, J . A.; Moreno, S. N. J .;
Docampo, R.; Croft, S. L.; Oldfield, E. J . Med. Chem. 2001, 44, 909-
916.
(5) Nugent, R. A.; Schlachter, S. T.; Murphy, M.; Dunn, C. J .; Staite,
N. D.; Galinet, L. A.; Shields, S. K.; Wu, H.; Aspar, D. G.; Richard, K.
A. J . Med. Chem. 1994, 34, 4449. Schlachter, S. T.; Galinet, L. A.;
Shields, S. K.; Aspar, D. G.; Dunn, C. J .; Staite, N. D.; Nugent, R. A.
Bioorg. Med. Chem. Lett. 1998, 8, 1093-1096.
(6) Ebetino, F. H.; Dansereau, S. M. In Bisphosphonate Antiresorp-
tive Structure-Activity Relationships; Bijvoet, O. L. M., Fleisch, H. A.,
Canfield, R. E., Russell, R. G. G., Eds.; Elsevier Science Biomedical:
Amsterdam, The Netherlands, 1995; Chapter 9.
(7) (a) Ebetino, F. H.; Degenhardt, C. R.; J amieson, L. A.; Burdsall,
D. C. Heterocycles 1990, 30, 855-862. (b) Couthon, H.; Gourve`s, J .-P.;
Guervenou, J .; Corbel, B.; Sturtz, G. Synth. Commun. 1999, 29, 4251-
4260. (c) Guervenou, J .; Couthon-Gourve`s, H.; Gourve`s, J .-P.; Corbel,
B. Synth. Commun. 2002, 32, 1543-1548.
(3) Pecherstorfer, M.; Herrmann, Z.; Body, J .-J .; Manegolg, C.;
Degardin, M.; Clemens, M. R.; Thurlimann, B.; Tubiana-Hulin, M.;
Steinhauer, E. U. J . Clin. Oncol. 1996, 14, 268-76.
(4) Russell, R. G. G.; Rogers, M. J . Br. J . Rheumatol. 1997, 36
(Suppl. 1), 10-14.
(8) Daniewski, W. M.; Griffin, C. E. J . Org. Chem. 1966, 31, 3236-
3241.
(9) McClure, C. K.; Hansen, K. B. Tetrahedron Lett. 1996, 37, 2149-
2152.
10.1021/jo0205154 CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/07/2003
736
J . Org. Chem. 2003, 68, 736-742

Cyclohex-3-ene-1,1-bis(phosphonates)
can be obtained in the presence of Lewis acids9,11 or by
introduction of a second electron-withdrawing substitu-
ent around the carbon-carbon double bond.10 Data
concerning the use of tetraalkyl vinylidene-1,1-bis(pho-
sphonates) as dienophiles in Diels-Alder cycloaddition
are anything but encouraging. Accordingly, the introduc-
tion of a second dialkyl phosphonyl group in the R
position of dialkyl vinylphosphonate causes a drop in the
reactivity of the resulting bis(phosphonate) dienophile
even with electron-rich dienes. As a matter of fact, the
reaction of tetraethyl vinylidenebis(phosphonate) (VBP)
with N-buta-1,3-dienylsuccinimide was reported to give
only 10% of the expected pseudo-ortho cycloadduct after
10 days in refluxing acetonitrile.12 Although 1,3-dipolar
cycloadditions of VBP to diazoketones were formerly
exploited in the synthesis of the pharmacologically
important pyrazoline bis(phosphonates),13 to our knowl-
edge, the above example is the sole report in the
literature that deals with Diels-Alder reactions of 1,3-
dienes involving VBP as a dienophile.
the reaction with isoprene (4a ), a 4.6:1 mixture of two
inseparable isomeric cycloadducts was obtained in 79%
yield. Among the other 13C NMR signals, the triplet at δ
116.7 (J ) 5.6 Hz) and the singlet at δ 133.3, attributed
to the H- and CH3-substituted olefinic carbons, respec-
tively, allowed the structure of 4-methylcyclohex-3-ene-
1,1-bis(phosphonate) to be assigned to the main regio-
isomer (4b; Chart 1). Conversely, the triplet at δ 129.6
(J ) 5.6 Hz) and the singlet at δ 120.6, attributed to the
CH3- and H-substituted olefinic carbons, respectively, are
compatible with the structure of 3-methylcyclohex-3-ene-
1,1-bis(phosphonate) assigned to the minor regioisomer
(4c).
As expected, the electron-releasing effect of the methyl
group at C(2) of isoprene governs the regioselectivity of
the cycloaddition process, orienting the attack of C(1) at
the very electrophilic methylenic carbon of the VBP. The
broad triplet of a relatively low J value (5.6 Hz), while
stating the near magnetic equivalence of the two phos-
phorus atoms toward C(3), suggests a stable half-chair
conformation for both the regioisomers 4b and 4c with a
P-C-C-C(3) dihedral angle of about 120°.15 In such
way, the 1,3-diaxial interactions of the bulky phospho-
nate groups would be minimized.
The importance of cycloalkenyl-1,1-bis(phosphonates)
as valuable precursors in the synthesis of biologically
active molecules and the lack of information about these
kinds of processes induced us to reinvestigate the reaction
of VBP with a variety of 1,3-dienes under quite different
conditions (eq 1). Here, we report the results of this
research.
Using the same criterion, the structure of 2-methyl-
cyclohex-3-ene-1,1-bis(phosphonate) (5b) was assigned to
the major regioisomer of the two obtained from the
reaction of VBP with piperylene in a 3:1 molar ratio and
in 60% yield. Interestingly, here the 13C NMR signal
attributed to C(3) appears as a doublet at δ 130.9 (3J PC(3)
) 10.2 Hz) and that of C(5) as a double-doublet at δ 22.1
(3J PC(5) ) 11.0 and 4.0 Hz), suggesting a quasi-chair
conformation for 5b with calculated dihedral angles P1-
C-C-C(3) and P2-C-C-C(3) of 100 and 130°, respec-
tively (Chart 1). Most probably, such a conformation
allows the steric interaction of the two phosphonate
groups at C(1) with the methyl group at C(2) to be
minimized. The singlet at δ 18.4, assigned to the methyl
carbon at C(2), suggests that it adopts a pseudoequatorial
Resu lts a n d Discu ssion
A mixture of VBP and diene was reacted in a sealed
steel reactor at a suitable temperature for varying times,
depending on the nature of the diene. The crude oil was
evaporated at reduced pressure to remove the excess
diene, and the products were isolated, when possible, by
column chromatography. Yields, regioisomeric ratios, and
the conditions relative to the reaction of each diene are
reported in Table 1.
position. In fact, according to the Karplus equation,15
a
substantial coupling between the carbon of a pseudoaxial
methyl group and the vicinal phosphorus in the anti
position would be expected. Similar effects are also
observed in the minor regioisomer to which the structure
of 5-methylcyclohex-3-ene-1,1-bis(phosphonate) (5c) was
assigned on the basis of its characteristic 13C NMR
signals.16 Once again, the regioselectivity of the cycload-
dition process is determined by the electron-releasing
effect of the methyl group of piperylene, which favors the
attack of C(1) at the methylenic carbon of the VBP with
the predominant formation of the thermodynamically
less-stable cycloadduct.
Quantitative analysis of the regioisomeric mixture was
performed by gas-liquid chromatography (GLC) and
confirmed by 31P NMR. Because of the relatively large
3
values of the J PC coupling constants and their strong
dependence on the P-C-C-C dihedral angle,10,14 13C
NMR turned out to be a valuable tool for the structural
determination of the regioisomers obtained in the reac-
tions involving nonsymmetrically substituted dienes. In
Analogous considerations were made to identify the
two regioisomeric products obtained in nearly equimolar
amounts, in 77% yield, from the reaction of 1-vinylcyclo-
hexene (6a ) with VBP. Chromatography of the crude
(10) Defacqz, N.; Touillaux, R.; Tinant, B.; Declercq, J .-P.; Peeters,
D.; Marchand-Brynaert, J . J . Chem. Soc., Perkin Trans. 2 1997, 1965-
1968.
(11) Maffei, M.; Buono, G. New J . Chem. 1988, 12, 923-930.
(12) Defacqz, N.; Touillaux, R.; Marchand-Brynaert, J . J . Chem.
Res., Miniprint 1998, 2273-2286.
(13) Dunn, C. J .; Nugent, R. A. U.S. Patent WO 9,012,017 A1;
Application WO 1990-US1106; Chem. Abstr. 1991, 114, 122364q.
Nugent, R. A.; Murphy, M.; Schlachter, S. T.; Dunn, C. J .; Smith, R.
J .; Staite, N. D.; Galinet, L. A.; Shields, S. K.; Aspar, D. G.; Richard,
K. A.; Rohloff, N. A. J . Med. Chem. 1993, 36, 134-139
(14) Grossmann, G.; Lang, R.; Ohms, G.; Scheller, D. Magn. Reson.
Chem. 1990, 28, 500-504.
(15) The value was determined by applying the semiempirical
3
equation J PC ) 7.23 - 5.41 cos φ + 6.29 cos 2φ derived by Grossmann
for diethyl cycloalkylphosphonates. For the sake of comparison, the
3
calculated J PC values of 7.4, 0.9, and 19.0 Hz for the dihedral angles
of 0, 90, and 180°, respectively, are reported.14
(16) The doublets at δ 122.2 (3J PC(3) ) 10.8 Hz) and 26.7 (3J PC(5)
)
11.9 Hz) attributed to C(3) and C(5), respectively, would suggest a
quasi-chair conformation for this regioisomer with the methyl group
taking on an equatorial position.
J . Org. Chem, Vol. 68, No. 3, 2003 737

Ruzziconi et al.
TABLE 1. Diels-Ald er Cycloa d d ition P r od u cts fr om VBP a n d 1,3-Dien es
a
Calculated with respect to VBP after purification by column chromatography on neutral Al2O3 (eluent 9:1 petroleum ether and diethyl
ether/EtOH). Determined by GLC and 31P NMR. c Calculated with respect to VBP after the acid-catalyzed hydrolysis of 8b in EtOH.
b
reaction mixture allowed a small amount of the minor
regioisomer to be isolated to which the structure of
tetraethyl 3,5,6,7,8,8a-hexahydronaphthalene-1,1(2H)-
bis(phosphonate) (6c) was assigned on the basis of the
following 13C NMR signals: the tight double-doublet at
δ 138.0 (J ) 6.8 and 3.4 Hz) assigned to the olefinic C(4a)
and the singlet at δ 118.7 attributed to C(4) (Chart 2).
The main regioisomer was identified in the regioiso-
meric mixture as 3,5,6,7,8,8a-hexahydronaphthalene-2,2-
(1H)-bis(phosphonate) (6b) by the presence of two dou-
blets at δ 115.1 (J ) 11.5 Hz) and δ 33.7 (J ) 12.6 Hz)
attributed to C(4) and C(8a), respectively.
The fact that the two regioisomers form in near-
equimolar amounts supports the above statements about
the important role of electronic effects on the regioselec-
tivity of the cycloaddition process. Hence, the electron-
releasing ability of the alkyl substitution at C(1) of 6a ,
which would increase the coefficient on C(2) in the
HOMO of the diene, is counterbalanced to nearly the
same extent by the electron-releasing effect of the alkyl
738 J . Org. Chem., Vol. 68, No. 3, 2003

Cyclohex-3-ene-1,1-bis(phosphonates)
CHART 1
CHART 3
In agreement with the latter considerations, the reac-
tion of Danishefsky’s diene 8a with VBP gave exclusively
the bis(phosphonate) adduct 8b that was easily converted
into the R,â-unsaturated cyclohexenone bis(phosphonate)
(8c) in 81% overall yield by simple acid-catalyzed hy-
drolysis in refluxing ethanol.
More intriguing results were obtained from the reac-
tion of VBP with 2,3-dimethoxy-1,3-butadiene. After 18
h at 100 °C, the expected Diels-Alder cycloadduct 3,4-
dimethoxycyclohex-3-ene-1,1-bis(phosphonate) (9b) turned
out to be the main reaction product. However, it was
accompanied by two minor isomeric species formed in
nearly equimolar amounts (see Table 1).17 At a longer
reaction time (96 h), the amount of one isomer increased
at the expense of both the adduct 9b and the other
isomer; after 240 h, it was the sole reaction product. Two
characterizing triplets of its 13C NMR spectrum at δ 158.4
(J ) 11.3 Hz) and at δ 90.4 (J ) 10.4 Hz) attributed to
methoxy- and hydrogen-substituted olefinic carbons,
respectively, and a doublet at δ 24.1 (J ) 9.0 Hz) assigned
to methoxy-substituted sp3 carbon allowed the product
to be identified as tetraethyl 3,4-dimethoxycyclohex-2-
ene-1,1-bis(phosphonate) (9c; Chart 3).
CHART 2
The second regioisomer was unequivocally identified
as tetraethyl 4,5-dimethoxycyclohex-3-ene-1,1-bis(phos-
phonate) (9d ) by the doublet at δ 93.0 (J ) 12.6 Hz) and
the singlet at δ 154 and attributed to the hydrogen- and
OCH3-substituted olefinic carbons, respectively, in the
spectrum of a 1:1 mixture with 9c. In full agreement with
these structural assignments, the absorption of the
methoxy-bearing C(4) of 9c appears as a singlet at δ 73.3,
whereas the methoxy-substituted carbon C(5) in 9d
resonates as a clean doublet at δ 72.7 (J ) 14.5 Hz), as
3
expected for a J PC coupling with only the equatorial
phosphorus atom.
A plausible explanation of this unexpected outcome
could be found in the VBP-promoted isomerization of the
previously formed cycloadduct 9b. Accordingly, when a
1:0.7:0.7 mixture of 9b, 9c, and 9d was heated to 100 °C
for 96 h in the presence of an equimolar amount of VBP,
the isomer 9c was recovered in 95% yield as the only
product. In contrast, under the same conditions, the
composition of the above mixture remained unchanged
either in the absence of VBP or in the presence of the
starting diene. Most probably, because of the marked
ability of the two phosphonate groups to stabilize a
negative charge on the R carbon, VBP turns out to be an
efficient hydride-trapping species which transforms itself
into a relatively stable ethanide-1,1-bis(phosphonate)
(EBP-; Scheme 1).
substitution at C(2) in 6a , enhancing the coefficient on
the vinylic carbon of CH2.
In the same way, the structure of tetraethyl 3,9,10,-
10a-tetrahydrophenanthrene-2,2(1H)-bis(phosphonate) (7b)
and that of tetraethyl 3,9,10,10a-tetrahydrophenanthrene-
1,1(2H)-bis(phosphonate) (7c) were assigned to the two
regioisomers obtained in 74% overall yield from a reaction
of VBP with 1-vinyl-3,4-dihydronaphthalene (7a ). Once
again, the regioisomeric distribution (93:7 7b/7c) is in
good agreement with the prediction on the basis of the
electronic effects of the substituents at C(1) and C(2) in
the HOMO of 7a (Chart 2). An aryl group at C(2) is
expected to enhance the coefficient on C(1) of a 1,2-
disubstituted 1,3-diene substantially more than an alkyl
substituent at C(1) does on C(4). Thus, the attack at the
methylenic carbon of the VBP by C(2) of 7a is expected
to be the preferred outcome of the cycloaddition process,
leading to the preferential formation of the adduct 7b,
as was really observed.
(17) A pure sample of 9b was obtained from the reaction of 9a with
VBP performed at 80 °C for 6 h, after chromatography on Al2O3, and
identified on the basis of its spectroscopic and analytical characteristics
(see Experimental Section).
J . Org. Chem, Vol. 68, No. 3, 2003 739

Ruzziconi et al.
methanol, followed by TsOH-catalyzed elimination of methanol
in refluxing toluene according to Degenhardt and Burdsall’s
protocol.21
SCHEME 1
Sta n d a r d P r oced u r e for th e Syn th esis of Cycloh ex-
en yl-1,1-bis(p h osp h on a tes). A 2-mL steel reactor equipped
with a Teflon gasket and filled with a mixture of VBP (4.0
mmol) and diene (1.1-10 equiv; see Table 1) was sealed with
a steel cap fixed with six screws and immersed in an oil bath
kept at the suitable temperature (see Table 1) for a certain
time depending on the nature of the diene. After cooling, the
reactor was opened and the crude oil was evaporated at a
reduced pressure to remove any excess diene. Chromatography
of the residue on neutral Al2O3 (activity grade V according to
Brockman; eluent hexanes and 9:1 diethyl ether/ethanol)
allowed pure or unresolvable regioisomeric mixtures of cyclo-
alkenylbis(phosphonates) to be collected.
Tetr a eth yl cycloh ex-3-en e-1,1-bis(p h osp h on a te) (1b;
1.0 g, 70%): 1H NMR δ 5.79-5.59 (br AB system, J ) 10.6
Hz, 2H), 4.25-4.10 (m, 8H), 2.55 (br t, J ) 16.2 Hz, 2H), 2.24-
2.05 (m, 4H), 1.39-1.26 (m, 12H); 13C NMR (100 MHz) δ 126.5,
123.0 (t, J ) 5.5 Hz), 62.8 (quint, J ) 3.3 Hz), 62.5 (quint, J
) 3.3 Hz), 39.9 (t, J ) 133.4 Hz), 25.6 (t, J ) 4.4 Hz), 24.0 (t,
J ) 4.9 Hz), 21.8 (t, J ) 7.5 Hz), 16.4; 31P NMR δ 27.8; IR
(film) νmax 3027 (w), 2982-2860 (s), 1662 (w), 1246 (s), 1026
(s) cm-1; MS (70 eV) m/z (%) 354 (M+, 11), 308 (18), 217 (100),
189 (19), 161 (23), 79 (13). Anal. Calcd for C14H28O6P2: C,
47.46; H, 7.97. Found: C, 47.31; H, 8.01.
Tet r a et h yl 3,4-d im et h ylcycloh ex-3-en e-1,1-b is(p h os-
p h on a te) (2b; 0.98 g, 64%): 1H NMR δ 4.2 (m, 8H), 2.42 (t, J
) 16.0 Hz, 2H), 2.2-1.8 (m, 4H), 1.62 (s, 6H), 1.3 (m, 12H);
13C NMR δ 125.2, 121.3 (t, J ) 5.5 Hz), 62.5, 62.1, 40.9 (t, J )
133.2 Hz), 31.3 (t, J ) 4.3 Hz), 28.2 (t, J ) 7.6 Hz), 24.5 (t, J
) 4.5 Hz), 18.7, 18.5, 16.2; 31P NMR δ 27.98; IR (film) νmax
2983-2864 (s), 1634 (w), 1243 (s), 1029 (s) cm-1; MS (70 eV)
m/z (%) 382 (M+, 5), 245 (100), 217 (13), 189 (13), 107 (9), 91
(6). Anal. Calcd for C16H32O6P2: C, 50.26; H, 8.44. Found: C,
50.12; H, 8.49.
In this case, the hydride abstraction from each isomer
of the above mixture generates an allylic carbocation (10
or 11) whose positive charge is further stabilized by one
R-methoxy group. The process, which probably generates
a tight ion pair, would be reversible, allowing 9b and 9d
to converge into the thermodynamically more stable 9c
through the ion pair 10 where the positive charge could
take advantage of an additional stabilizing effect by the
oxygen of the adjacent phosphonate group (10a ).
Tet r a et h yl b icyclo[2.2.2]oct -5-en e-2,2-b is(p h osp h o-
1
n a te) (3b; 1.0 g, 73%): H NMR δ 6.36 (br tdd, J ) 7.0, 2.7,
and 1.2 Hz, 1H), 6.17 (t, J ) 7.0 Hz, 1H), 4.1 (m, 8H), 3.02 (br
s, 1H), 2.62 (br s, 1H), 2.6-2.1 (m, 3H), 1.9-1.5 (m, 3H), 1.3
(m, 12H); 13C NMR δ 134.8 (dd, J ) 14.2 and 2.1 Hz), 130.6,
61.9 (m), 44.8 (dd, J ) 133.2 and 127.8 Hz) 32.0 (t, J ) 2.8
Hz), 28.8, 23.9 (dd, J ) 13.8 and 4.1 Hz), 21.7, 15.9, 15.8; 31P
NMR δ 28.21 (d, J ) 7.4 Hz), 27.98 (d, J ) 7.4 Hz); IR (film)
νmax 3049 (w), 2980 (s), 2941-2872 (m), 1651 (w), 1444 (m),
1392 (m), 1244 (s), 1032 (vs), 969 (s), 804 (m) cm-1; MS (70
eV) m/z (%) 380 (M+, 5), 379 (9), 301 (100), 273 (18), 243 (29),
189 (18), 171 (13), 105 (15). Anal. Calcd for C16H30O6P2: C,
50.52; H, 7.95. Found: C, 50.62; H, 7.91.
Exp er im en ta l Section
If not specified otherwise, 1H NMR and 13C NMR spectra
were recorded at 200 and 50 MHz, respectively, in a CDCl3
solution using tetramethylsilane as an internal standard. 31P
NMR spectra were recorded at 81 MHz in a CDCl3 solution
using 85% H3PO4 as an external standard. IR spectra of neat
samples were taken in the 4000-625-cm-1 range. Gas-
chromatographic analyses were performed using 30-m × 0.32-
mm capillary columns loaded with two different stationary
phases: HP-5 MS (5% phenylmethylpolysiloxane) and HP-35
MS (35% phenylmethylpolysiloxane) at 70-310 °C. Mass
spectra were obtained at 70 eV.
R ea gen t s. 1,3-Butadiene, isoprene, piperylene, 2,3-di-
methyl-1,3-butadiene, 2,3-dimethoxy-1,3-butadiene, 1-meth-
oxy-3-(trimethylsilyloxy)-1,3-butadiene (Danishefsky’s diene),
and 1,3-cyclohexadiene of the highest grade of purity were used
as purchased. 1-Vinylcyclohexene was prepared by the distil-
lation of 1-vinylcyclohexanol in the presence of KHSO4.18 3,4-
Dihydro-1-vinylnaphthalene was prepared by the addition of
vinylmagnesium bromide to 1-tetralone, followed by the
CuSO4-promoted dehydration of the resulting vinylcarbinol in
refluxing benzene.19 VBP was prepared in 82% yield by the
condensation of tetraethyl methylenebis(phosphonate)20 with
formaldehyde in the presence of diethylamine in refluxing
Tetr a eth yl 4-Meth yl- a n d 3-Meth ylcycloh ex-3-en e-1,1-
bis(p h osp h on a te) (4b a n d 4c; 1.2 g, 79% Over a ll Yield ).
4b: 1H NMR δ 5.29 (br s), 4.1 (m, 8H), 2.51 (br t, J ) 16.1 Hz,
2H), 2.2-2.0 (m, 4H), 1.64 (br s, 2.5H), 1.3 (m, 12H); 13C NMR
δ 133.3, 116.7 (t, J ) 5.6), 62.4, 62.2, 39.3 (t, J ) 133.3 Hz),
26.5 (t, J ) 7.7 Hz), 25.8 (t, J ) 4.0 Hz), 24.4 (t, J ) 4.4 Hz),
23.5, 16.2; 31P NMR δ 28.06; MS (70 eV) m/z (%) 368 (M+, 5),
1
231 (100), 203 (11), 175 (14), 93 (9). 4c: H NMR (character-
izing signals in the 82:18 mixture of 4b and 4c) δ 5.43 (br s),
1.63 (br s); 13C NMR δ 129.6 (t, J ) 5.6 Hz), 120.6, 63.4, 61.7,
40.6 (t, J ) 133.5 Hz), 39.8 (t, J ) 4.3 Hz), 23.7 (t, J ) 4.7
Hz), 23.3 (t, J ) 7.5 Hz), 22.0, 16.2; 31P NMR δ 27.97; MS (70
eV) m/z (%) 368 (M+, 17), 231 (100), 203 (16), 175 (15), 93 (10);
IR (82:18 mixture of 4b and 4c; film) νmax 3059 (w), 2981-
2909 (s), 1652 (w), 1444 (m), 1246 (s), 1028 (s), 966 (s) cm-1
.
Anal. Calcd for C15H30O6P2 (82:18 mixture of 4b and 4c): C,
48.91; H, 8.21. Found: C, 48.69; H, 8.22.
Tetr a eth yl 2-Meth yl- a n d 5-Meth ylcycloh ex-3-en e-1,1-
bis(p h osp h on a te) (5b a n d 5c; 0.88 g, 60% Over a ll Yield ).
(18) Robins, P. A.; Walker, J . J . Chem. Soc. 1952, 642-649. Miller,
P. C.; Gaspar, P. P. J . Org. Chem. 1991, 56, 5101-5107.
(19) Minuti, L.; Selvaggi, R.; Taticchi, A.; Scheeren, H. W. Synth.
Commun. 1992, 22, 1535-1540.
(20) Hormi, O. E. O.; Pajunen, E. O.; A° vall, A.-K. C.; Pennanen, P.;
Na¨sman, J . H.; Sundell, M. Synth. Commun. 1990, 2, 1865-1867.
(21) Degenhardt, C. R.; Burdsall, D. C. J . Org. Chem. 1986, 51,
3488-3490.
740 J . Org. Chem., Vol. 68, No. 3, 2003

Cyclohex-3-ene-1,1-bis(phosphonates)
5b: 1H NMR δ 5.67 (br d, J ) 10.1 Hz, 1H), 5.40 (br d, J )
10.1 Hz, 1H), 4.3-4.0 (m, 8H), 3.0-1.8 (m, 5H), 1.3 (m, 15H);
13C NMR δ 130.9 (d, J ) 10.2 Hz), 124.7, 63.2-61.3 (m), 45.6
(dd, J ) 132.5 and 129.3 Hz), 32.1 (t, J ) 3.9 Hz), 26.0 (t, J )
5.2 Hz), 22.1 (dd, J ) 11.0 and 4.0 Hz), 18.4, 16.3 (m); 31P NMR
δ 28.26 (d, J ) 9.2 Hz), 26.09 (d, J ) 9.2 Hz); MS (70 eV) m/z
(%) 368 (M+, 4), 322 (12), 231 (100), 203 (10), 175 (12), 93 (13).
5c: 1H NMR (characterizing absorption in the 3:1 mixture of
5b and 5c) δ 5.57 (s, 2H), 1.01 (d, J ) 6.8 Hz, 3H); 13C NMR
δ 132.9, 122.2 (d, J ) 10.8 Hz), 62.5-61.3 (m), 40.6 (dd, J )
134.7 and 131.5 Hz), 32.7 (t, J ) 4.2 Hz), 26.7 (d, J ) 11.9
Hz), 25.5 (t, J ) 4.0 Hz), 21.4, 16.3; 31P NMR δ 28.20 (d, J )
6.0 Hz), 27.29 (d, J ) 6.0 Hz); MS (70 eV) m/z (%) 368 (M+, 2),
322 (19), 231 (100), 203 (14), 175 (16), 93 (15); IR (3:1 mixture
of 5b and 5c; film) νmax 3028 (w), 2980-2908 (s), 1661 (w),
1246 (s), 1047 (s), 1027 (s), 964 (s) cm-1. Anal. Calcd for
Tetr a eth yl 2-m eth oxy-4-(tr im eth ylsilyloxy)cycloh ex-
3-en e-1,1-bis(p h osp h on a te) (8b): H NMR δ 5.28 (dd, J )
1
3.7 and 1.8 Hz, 1H), 4.54 (ddd, J ) 12.9, 11.3, and 4.1 Hz,
1H), 4.4-4.1 (m, 8H), 3.35 (s, 3H), 2.8-2.2 (m, 4H), 1.27-1.2
(m, 12H), 0.29 (s, 9H); 13C NMR δ 153.6, 102.3 (t, J ) 5.6 Hz),
76.5 (d, J ) 6.4 Hz), 63.3-61.5 (m), 56.6, 48.9 (dd, J ) 132.8
and 125.9 Hz), 28.1 (t, J ) 8.1 Hz), 25.3 (t, J ) 5.3 Hz), 16.6,
16.5, 0.4; 31P NMR δ 25.1 (d, J ) 1.5 Hz), 24.2 (d, J ) 1.5 Hz);
IR (film) νmax 2981-2823 (m), 1669 (m), 1623 (m), 1254 (s),
1217 (s), 1030 (s), 848 (s) cm-1; MS (70 eV) m/z (%), 472 (M+,
1), 457 (3), 373 (8), 335 (68), 303 (100), 247 (21), 196 (16), 157
(19), 141 (10), 73 (16).
Tetr a eth yl 4-Oxocycloh ex-2-en e-1,1-bis(p h osp h on a te)
(8c). A solution of crude 8b (2.0 g) and p-toluenesulfonic acid
(50 mg) in ethanol (50 mL) was refluxed for 1 h. Solid NaHCO3
(0.1 g) was added, and the solvent was evaporated. Chroma-
tography of the residual oil on neutral aluminum oxide (eluent
9:1 diethyl ether/EtOH) allowed pure 8c (1.2 g, 81% overall
yield with respect to VBP) to be collected: 1H NMR δ 6.94 (dt,
J ) 10.3 and 6.3 Hz, 1H), 6.18 (dt, J ) 10.3 and 4.1 Hz, 1H),
4.2 (m, 8H), 2.8-2.4 (m, 4H), 1.34 (td, J ) 7.0 and 1.3 Hz,
12H); 13C NMR δ 197.3, 142.3 (t, J ) 9.8 Hz), 131.7 (t, J )
10.8 Hz), 64.2 (m), 63.8 (m), 46.1 (t, J ) 131.1 Hz), 34.0 (t, J
) 5.5 Hz), 25.1 (t, J ) 3.9 Hz), 16.7; 31P NMR δ 21.36; IR (film)
C
15H30O6P2 (3:1 mixture of 5b and 5c): C, 48.91; H, 8.21.
Found: C, 48.79; H, 8.16.
Tetr aeth yl 3,5,6,7,8,8a-Hexah ydr on aph th alen e-2,2(1H)-
a n d -1,1(2H)-bis(p h osp h on a te) (6b a n d 6c; 1.3 g, 77%
Over a ll Yield ). 6b: 1H NMR (characteristic signals in a 1:1
mixture of 6b and 6c) δ 5.27 (br s), 4.1 (m, 8H), 3.0-1.5 (m,
13H), 1.3 (m, 12H); 13C NMR δ 140.0, 115.1 (d, J ) 11.5 Hz),
62.0 (d, J ) 7.4 Hz), 61.5 (d, J ) 7.4 Hz), 40.4 (dd, J ) 134.3
and 131.3 Hz), 34.6, 33.7 (d, J ) 12.6 Hz), 32.5 (t, J ) 4.0 Hz),
27.2, 27.1, 26.1, 25.9, 16.3; 31P NMR δ 28.33 (d, J ) 8.0 Hz),
27.40 (d, J ) 8.0 Hz); IR (1:1 mixture of 6b and 6c; film) νmax
3053 (w), 2982 (s), 2929 (s), 2855 (m), 1654 (w), 1444 (m), 1245
(s), 1028 (vs), 967 (s), 732 (m) cm-1; MS (70 eV) m/z (%) 408
(M+, 3), 362 (2), 301 (3), 271 (100), 243 (11), 215 (13), 133 (7),
91 (14). Anal. Calcd for C18H34O6P2 (1:1 mixture of 6b and
6c): C, 52.94; H, 8.39. Found: C, 53.08; H, 8.40. Chromatog-
raphy of the above mixture on Al2O3 (eluent 95:5 (v/v) diethyl
ether/EtOH) was allowed to isolate pure 6c (91 mg). 6c: 1H
NMR δ 5.42 (br s, 1H), 4.2 (m, 8H), 2.7-1.4 (m, 13H), 1.3 (m,
12H); 13C NMR δ 138.0 (dd, J ) 6.8 and 3.4 Hz), 118.7, 63.0
(dd, J ) 38 and 7.0 Hz), 62.2 (dd, J ) 25.2 and 7.3 Hz), 46.7
(dd, J ) 131.7 and 127.9 Hz), 39.9, 36.9, 30.8, 27.7, 27.2, 25.5
(t, J ) 5.6 Hz), 22.3 (dd, J ) 9.4 and 6.9 Hz), 16.4; 31P NMR
δ 28.36 (d, J ) 8.3 Hz), 26.74 (d, J ) 8.3 Hz); IR (film) νmax
3049 (w), 2982 (s), 2930 (s), 2855 (m), 1443 (m), 1244 (s), 1029
(s), 965 (s), 732 (m) cm-1; MS (70 eV) m/z (%) 408 (M+, 15),
301 (5), 271 (100), 243 (9), 215 (9), 133 (8), 91 (13). Anal. Calcd
for C18H34O6P2: C, 52.94; H, 8.39. Found: C, 52.75; H, 8.34.
ν
max 3060 (w), 2985 (s), 2934 (m), 1684 (s), 1446 (m), 1389 (m),
1250 (s), 1022 (vs), 973 (s), 775 (s) cm-1; MS (70 eV) m/z (%)
368 (M+, 11), 339 (43), 311 (26), 283 (25), 255 (46), 231 (100),
203 (28), 175 (49), 65 (27). Anal. Calcd for C14H26O7P2: C,
45.66; H, 7.12. Found: C, 45.59; H, 7.17.
Tetr a eth yl 3,4-Dim eth oxycycloh ex-3-en e-1,1-bis(p h o-
sp h on a te) (9b). A mixture of VBP (1.2 g, 4.0 mmol) and 9a
(1.4 g, 12 mmol) was heated at 80 °C for 6 h. After cooling,
most of the unreacted diene was evaporated at a reduced
pressure, and the residue was chromatographed on Al2O3
(eluent 9:1 (v/v) diethyl ether/EtOH) to collect 9b (75 mg). The
product was contaminated by traces of two isomeric products:
1H NMR δ 4.2 (m, 8H), 3.62 (s, 3H), 3.60 (s, 3H), 2.61 (br t, J
) 15.8 Hz, 2H), 2.4-2.0 (m, 4H), 1.36 (t, J ) 7.0 Hz, 12H); 13
C
NMR δ 138.3, 134.7 (t, J ) 7.3 Hz), 62.6 (m), 57.6, 56.6, 41.0
(t, J ) 133.4 Hz), 26.6, 24.6 (t, J ) 4.3 Hz), 22.9 (t, J ) 8.8
Hz), 16.2; 31P NMR δ 27.05; IR (film) νmax 2981 (s), 2934 (s),
2833 (m), 1652 (w), 1444 (m), 1391 (m), 1245 (s), 1025 (vs),
968 (s) cm-1; MS (70 eV) m/z (%) 414 (M+, 7), 276 (100), 233
(6), 205 (17), 139 (12), 109 (5). Anal. Calcd for C16H32O8P2: C,
46.38; H, 7.78. Found: C, 46.47; H, 7.71.
Tetr a m eth yl 3,9,10,10a -Tetr a h yd r op h en a n th r en e-2,2-
(1H)- a n d -1,1(2H)-bis(p h osp h on a te) (7b a n d 7c; 1.3 g,
74% Over a ll Yield ). Pure 7b (90 mg) was obtained by
chromatography of the above mixture on Al2O3 (eluent 95:5
(v/v) diethyl ether/EtOH). 7b: 1H NMR (400 MHz) δ 7.6 (m,
1H), 7.1 (m, 3H), 6.22 (br s, 1H), 4.2 (m, 8H), 3.0-2.6 (m, 4H),
2.7-2.4 (m, 2H), 2.1-1.7 (m, 3H), 1.3-1.2 (m, 12H); 13C NMR
(100 MHz) δ 136.4, 136.0 (d, J ) 1.6 Hz), 133.7, 129.2, 126.7,
125.9, 123.1, 116.1 (d, J ) 10.6 Hz), 63.3 (d, J ) 7.1 Hz), 62.6
(d, J ) 7.1 Hz), 62.5 (d, J ) 7.1 Hz), 40.1 (dd, J ) 135.3 and
132.0 Hz), 32.6 (t, J ) 4.9 Hz), 32.3 (d, J ) 12.6 Hz), 30.6,
29.6, 27.2 (t, J ) 4.4 Hz), 16.4; 31P NMR δ 28.17 (d, J ) 8.1
Tetr a eth yl 3,4-Dim eth oxycycloh ex-2-en e-1,1-bis(p h o-
sp h on a te) (9c). A mixture of VBP (1.2 g, 4.0 mmol) and 9a
(1.4 g, 12.2 mmol) was heated at 100 °C for 18 h. After cooling,
most of the unreacted diene was evaporated at a reduced
pressure, and the residue was passed through a short column
of Al2O3 (eluent 9:1 (v/v) diethyl ether/EtOH). GLC and 31P
NMR analyses of the collected oil (1.3 g) showed the presence
of 9b and two other isomeric products in a 1.7:1:1 molar ratio.
The latter mixture was divided into three portions (0.4 g each);
one portion was heated at 100 °C without added reagents for
240 h. To the second and third portions were added respec-
tively 9a (0.11 g, 0.96 mmol) and VBP (0.29 g, 0.96 mmol),
and the resulting mixtures were heated once again at 100 °C
for 240 h. GC-MS and 31P NMR analyses of the former two
mixtures did not show any change in their composition,
whereas those containing VBP showed the presence of one
isomer of 9b slightly contaminated (less than 2%) by a third
isomeric species. A pure sample of the above product, obtained
by chromatography of the mixture on Al2O3, using 95:5 (v/v)
diethyl ether/EtOH as the eluent, exhibited the following
spectroscopic and analytical characteristics compatible with
the structure of 9c: 1H NMR δ 4.84 (dd, J ) 6.9 and 4.9 Hz,
1H), 4.2 (m, 8H), 3.63 (br s, 1H), 3.62 (s, 3H), 3.39 (s, 3H),
2.5-1.8 (m, 4H), 1.3 (m, 12H); 13C NMR δ 158.4 (d, J ) 11.3
Hz), 90.5 (t, J ) 10.4 Hz), 73.3, 63.4 (d, J ) 7.0 Hz), 63.0 (d,
J ) 7.0 Hz), 62.8 (m), 56.9, 54.4, 43.4 (dd, J ) 135.8 and 135.5
Hz), 24.1 (d, J ) 9.0 Hz), 19.7 (t, J ) 3.7 Hz), 16.2; 31P NMR
Hz), 27.22 (d, J ) 8.1 Hz); MS (70 eV) m/z (%) 411 (M+
-
OC2H5, 1), 347 (1), 319 (100), 291 (6), 261 (9), 179 (10). Anal.
Calcd for C22H34O6P2: C, 57.89; H, 7.51. Found: C, 57.97; H,
7.49. 7c: 1H NMR (400 MHz; characterizing peaks in the 85:
15 mixture of 7b and 7c) δ 6.40 (br s, 1H); 13C NMR (100 MHz)
δ 136.1, 135.0, 133.5 (d, J ) 11.1 Hz), 128.9, 126.5, 125.6,
123.8, 119.9, 63.5 (d, J ) 7.0 Hz), 62.6 (d, J ) 7.0 Hz), 62.0 (d,
J ) 7.3 Hz), 61.3 (d, J ) 7.5 Hz), 46.0 (dd, J ) 133.0 and 129.0
Hz), 38.4 (t, J ) 3.4 Hz), 30.9, 26.4 (d, J ) 4.2 Hz), 26.2, (t, J
) 5.5 Hz), 23.1 (dd, J ) 12.5 and 3.2 Hz), 16.4; 31P NMR δ
28.29 (d, J ) 11.2 Hz), 26.30 (d, J ) 11.2 Hz); MS (70 eV) m/z
(%) 456 (M+, 29), 319 (100), 301 (16), 261 (14), 179 (32), 141
(8); IR (85:15 mixture of 7b and 7c; film) νmax 3050 (w), 2982-
2821 (s), 1652 (w), 1246 (s), 1026 (s) cm-1. Anal. Calcd for
C
22H34O6P2 (85:15 mixture of 7a and 7b): C, 57.89; H, 7.51.
Found: C, 57.74; H, 7.57.
J . Org. Chem, Vol. 68, No. 3, 2003 741

Ruzziconi et al.
δ 24.65 (d, J ) 9.1 Hz), 23.67 (d, J ) 9.1 Hz); IR (film) νmax
3064 (w), 2980 (s), 2933 (s), 1655 (s), 1444 (m), 1391 (m), 1247
(s), 1021 (vs), 966 (s) cm-1; MS (70 eV) m/z (%) 414 (M+, 5),
276 (100), 245 (10), 189 (16), 161 (19), 109 (14). Anal. Calcd
for C16H32O8P2: C, 46.38; H, 7.78. Found: C, 46.54; H, 7.81.
Tetr a eth yl 4,5-Dim eth oxycycloh ex-3-en e-1,1-bis(p h o-
sp h on a te) (9d ). A mixture of VBP (1.2 g, 4.0 mmol) and 9a
(1.4 g, 12.2 mmol) was heated at 100 °C for 120 h. After cooling,
most of the unreacted diene was evaporated at a reduced
pressure, and the residue was passed through a short column
of Al2O3 (eluent 9:1 (v/v) diethyl ether/EtOH). GLC and 31P
NMR analyses of the collected oil (1.1 g) showed the presence
of 9c and a second isomeric product in an 8:2 molar ratio. In
the mixture, the latter was identified as 9d on the basis of
the following spectral characteristics: 1H NMR δ 4.64 br s,
1H), 4.15 (m, 8H), 3.65 (br s, 1H), 3.56 (s, 4H), 3.46 (s, 3H),
2.8-1.8 (m, 4H), 1.3 (m, 12H); 13C NMR δ 154.1, 93.0 (d, J )
12.6 Hz), 72.8 (d, J ) 14.5 Hz), 62.7-62.4 (m), 56.9, 54.1, 40.7
(t, J ) 131.9 Hz), 30.0 (t, J ) 4.7 Hz), 24.8, 16.2; 31P NMR δ
26.78 (d, J ) 6.5 Hz), 26.56 (d, J ) 6.5 Hz); IR (8:2 mixture of
9c and 9d ; film) νmax 3076 (w), 2982 (s), 2935 (s), 2826 (w),
1654 (w), 1445 (m), 1247 (s), 1026 (vs), 969 (s) cm-1; MS (70
eV) m/z (%) 414 (M+, 2), 276 (100), 245 (90), 217 (18), 189 (40),
109 (23). Anal. Calcd for C16H32O8P2 (8:2 mixture of 9c and
9d ): C, 46.38; H, 7.78. Found: C, 46.42; H, 7.82.
Ack n ow led gm en t. Thanks are expressed to the
Universita` di Perugia, Ministero dell’Istruzione, Uni-
versita` e Ricerca (MIUR), and the French Ministry of
Research and Technology for financial support.
Su p p or tin g In for m a tion Ava ila ble: 1H, 13C, and 31P
NMR spectra of all the reported products. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O0205154
742 J . Org. Chem., Vol. 68, No. 3, 2003