A versatile palladium-mediated three-component reaction for the one-pot synthesis of stereodefined 3-arylidene-(or 3-alkenylidene-)tetrahydrofurans

Article abstract of DOI:10.1021/jo0012997

A one-pot reaction between equimolecular amounts of various propargyl alcohols Michael acceptors, and unsaturated halides (or triflates) in the presence of a palladium(0) catalyst provides a simple and flexible entry into highly substituted 3-arylidene-(or 3-alkenylidene-)tetrahydrofurans. The efficiency of this palladium-mediated three-component reaction has been shown to be strongly influenced by the nature of the catalyst system, and in this regard, a palladium(0) catalyst generated in situ by reduction of PdCl₂(PPh₃)₂ with n-butyllithium has been found particularly effective.

Full text of DOI:10.1021/jo0012997

J . Org. Chem. 2001, 66, 175-179
175
A Ver sa tile P a lla d iu m -Med ia ted Th r ee-Com p on en t Rea ction for
th e On e-P ot Syn th esis of Ster eod efin ed 3-Ar ylid en e-(or
3-Alk en ylid en e-)tetr a h yd r ofu r a n s
Marilyn Bottex,† Marcello Cavicchioli,† Benoˆıt Hartmann,‡ Nuno Monteiro,† and
Genevie`ve Balme*,†
Laboratoire de Chimie Organique 1, CNRS UMR 5622, Universite´ Claude Bernard, Lyon I, CPE,
43 Bd du 11 Novembre 1918, 69622 Villeurbanne Ce´dex, France, and Aventis Cropscience
14/ 20 rue Pierre Baizet, 69623 Lyon, France
balme@univ-lyon1.fr
Received August 28, 2000
A one-pot reaction between equimolecular amounts of various propargyl alcohols, Michael acceptors,
and unsaturated halides (or triflates) in the presence of a palladium(0) catalyst provides a simple
and flexible entry into highly substituted 3-arylidene-(or 3-alkenylidene-)tetrahydrofurans. The
efficiency of this palladium-mediated three-component reaction has been shown to be strongly
influenced by the nature of the catalyst system, and in this regard, a palladium(0) catalyst generated
in situ by reduction of PdCl2(PPh3)2 with n-butyllithium has been found particularly effective.
In tr od u ction
materials.6 In this area, methodologies based on pal-
ladium-catalyzed cascade reactions are of particular
importance owing to the diversity of bond-forming pro-
cesses available, the mildness of reaction conditions, the
high levels of chemo-, regio-, and stereoselectivities, and
the excellent functional group tolerance.7
Five-membered oxygen heterocycles are important
synthetic targets due to their occurrence in numerous
natural products,1 their wide range of biological activi-
ties,2 and their utility as versatile intermediates.3 This
important class of heterocyclic products has therefore
stimulated the development of new synthetic methodolo-
gies.4 During the past few years, in addition to radical
chemistry, transition metal-mediated synthesis has
emerged as one of the most powerful tools for the
construction of these subunits.5 Over the same period,
multicomponent condensations have gained considerable
interest in the field of heterocycle synthesis due to their
potential of generating molecular diversity in a single
synthetic step from simple, readily available, starting
As part of our ongoing program in heterocyclic syn-
thesis, we recently undertook the development of mul-
ticomponent condensation reactions based on palladium-
mediated cyclization processes devised in our laboratory
and aimed at the preparation of highly functionalized
tetrahydrofurans.8 The underlying goal of this study was
to devise a methodology that would ultimately be utiliz-
able in a combinatorial way. With this aim, we recently
succeeded in developing a one-pot three-component con-
densation that combines three readily available and
inexpensive materials: an allylic alcohol, an activated
olefin, and an unsaturated halide to yield 4-benzyltet-
rahydrofuran-3,3-dicarboxylates (Scheme 1). The meth-
odology consisted in an oxygen nucleophile initiated
Michael addition followed by a carbopalladation reaction.9
Unfortunately, this approach suffered from several draw-
backs that impaired its combinatorial potential. Of
* To whom correspondence should be addressed: FAX: Int + (0)4-
72-43-12-14.
† Universite´ Claude Bernard, Lyon I.
‡ Aventis Cropscience.
(1) Polyether Antibiotics: Naturally Occurring Acid Ionophores;
Westley, J . W., Ed.; Marcel Dekker: New York, 1982. Doblem, M.
Ionophores and their structures; Wiley-Interscience, New York, 1981.
Erickson, K. L. In Marine Natural Products; Scheuer, P. J ., Ed.;
Academic Press: New York, 1983; Vol. 5, Chapter 4, p 131. Moody, C.
J .; Davies, M. In Studies in Natural Product Chemistry; Ata-ur-
Rahman, Ed.; Elsevier: Amsterdam, 1992; Vol. 10, p 201.
(2) Gottlieb, O. R. In New Natural Products and Plant Drugs with
Pharmacological, Biological, or Therapeutical Activity; Springer-Ver-
lag: Berlin-Heidelberg, 1987; p 227.
(3) Dean, F. M.; Sargent, M. V. In Comprehensive Heterocyclic
Chemistry; Katrizky, A. R., Rees, C. W., Eds.; Pergamon: 1984; Vol.
4.
(4) For reviews on the synthesis of tetrahydrofurans, see: Boivin,
T. L. B. Tetrahedron 1987, 43, 3309. Semple, J . E.; J oullie, M. M.
Heterocycles 1980, 14, 1825. Bartlett, P. A. Tetrahedron 1980, 36, 2.
Harmange, J . C.; Figade`re, B. Tetrahedron Asymmetry 1993, 1711.
Postema, M. H. D. Tetrahedron 1992, 48, 8545
(5) Trost, B. M.; Bonk, P. J . J . Am. Chem. Soc. 1985, 107, 8277.
Trost, B. M.; King, S. A. Tetrahedron Lett. 1986, 27, 5971. Trost, B.
M.; King, S. A.; Schmidt, T. J . Am. Chem. Soc. 1989, 111, 5902. J ones,
M. D.; Kemmit, R. D. W. J . Chem. Soc., Chem. Commun. 1986, 1201.
Trost, B. M.; King, S. A. J . Am. Chem. Soc. 1990, 112, 408. van der
Louw, J .; van der Baan, J . L.; Sticker, H.; Out, G. J . J .; de Kanter, F.
J . J .; Bickelhaupt, F.; Klumpp, G. W. Tetrahedron 1992, 45, 9877.
Klumpp, G. W.; van der Baan, J . L.; van der Heide, T. A. J .; van der
Louw, J . Synlett 1995, 1. Delgado, A.; Liebaria, A.; Camps, F.; Moreto,
M. Tetrahedron Lett. 1994, 35, 1763.
(6) Ugi, I.; Do¨mling, A.; Ho¨rl, W. Multicomponent Reactions in
Organic Chemistry. Endeavour 1994, 18, 115. Armstrong, R. W.;
Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc. Chem.
Res. 1996, 29, 123. Tietze, L. F. Chem. Rev. 1996, 96, 115.
(7) Negishi, E. I. Pure Appl. Chem. 1992, 64, 323. Overman, L. E.;
Abelman, M. M.; Kucera, D. J .; Tran, V. D.; Ricca, D. J . Pure Appl.
Chem. 1992, 64, 1813. Hok T. L. Tandem Organic Reactions; Wiley-
Interscience: New York, 1992. Tietze, L. F.; Beifuss, U. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 131. Bunce, R. A. Tetrahedron 1995, 13103.
Tsuji, J . Palladium Reagents and Catalysts; Innovations in Organic
Chemistry; Wiley: Chichester, 1995. Tetrahedron Symposium-in-Print
1996, 52, vol. 35. Bra¨se, S.; de Meijere, A. In Metal-Catalyzed Cross-
coupling Reactions; Diederich, F., Stang, P. J ., Eds.; Wiley-VCH:
Weinheim, 1998; p 99.
(8) Cavicchioli, M.; Sixdenier, E.; Derrey, A.; Bouyssi, D., Balme,
G. Tetrahedron Lett. 1997, 38, 1763.
(9) Two-component reactions based on a similar strategy have since
been reported by us, see: (a) Marat, X.; Monteiro, N.; Balme, G. Synlett
1997, 845. (b) Clique, B.; Monteiro, N.; Balme, G. Tetrahedron Lett.
1999, 40, 1301. (c) Woods, M.; Monteiro, N.; Balme, G. Eur. J . Org.
Chem. 2000, 1711. (d) Monteiro, N.; Balme, G. J . Org. Chem. 2000,
65, 3223.
10.1021/jo0012997 CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/14/2000

176 J . Org. Chem., Vol. 66, No. 1, 2001
Bottex et al.
Sch em e 1. Retr osyn th etic An a lysis of Eth yl
4-Ben zyltetr a h yd r ofu r a n -3,3-d ica r boxyla tes
byproduct undoubtedly arose from another palladium-
mediated reaction recently reported by us, which involves
a palladium hydride species as an electrophilic partner
rather than the phenylpalladium iodide needed in the
three-component condensation reaction.9a Minimizing
this competitive two-component cyclization process proved
less problematic than expected. In a first set of experi-
ments, a range of phosphine ligands such as triphen-
ylphosphine, tris-furylphosphine, tris-(p-fluoro)phenylphos-
phine, dppb, and dppf were screened.11 It emerged that
the nature of the catalytic system had a negligible effect
on the final product distribution. Nevertheless, these
experiments showed that the PPh3 ligand was much more
effective in terms of yields and reaction times. Turning
our attention to possible solvent effects, it was found that
the use of DMSO completely inhibited the formation of
the side product.12 Thus, effecting the reaction in a 1/1
mixture of THF/DMSO in the presence of 5 mol % of a
Pd0/(PPh3) catalyst produced 4a within 1 h as the sole
product in 55% yield. Another significant improvement
came later from the utilization of a palladium complex
generated by reduction of PdCl2(PPh3)2 with n-BuLi. By
using 5 mol % of this catalyst, the reaction took place at
room temperature in less than 15 min, leading to the
exclusive formation of 4a in up to 89% isolated yield. The
amount of catalyst could be considerably decreased (1 mol
%) without significant loss in the yield (70% yield), albeit
a prolonged reaction time was needed (3 h).
particular importance was the reluctance of secondary
and tertiary alcohols to participate in the reaction, thus
restricting the choice to the simple allyl alcohol. Another
important limitation was the necessity of using impracti-
cal slow addition techniques in order to avoid undesirable
competitive reactions. Excess reagents were also needed
to bring the reactions to completion, rendering the
isolation of the products tedious and time-consuming.10
Ideally, a practical procedure would consist of simply
mixing equal amounts of each of the three partners and
treating them with a catalytic quantity of a palladium
complex at room temperature. To this end, it was decided
to substitute allylic alcohols for their propargylic ana-
logues because of their high reactivity generally observed
in similar carbocyclization reactions.9 This would produce
a new class of valuable stereodefined arylidenetetrahy-
drofurans (eq 1). Another advantage of this alternative
would be that a greater diversity in structure may be
produced if disubstituted acetylenic substrates were
involved in the process. The results of this study are
reported below.
With this model study in hand, we sought to investi-
gate various combinations of unsaturated halides, pro-
pargylic alcohols, and activated olefins. The generality
of the methodology was firmly demonstrated by the
variety of tetrahydrofurans that could be produced. The
results are summarized in Table 1. Almost all aryl iodides
gave satisfactory results (entries 1-6, 9-21), particularly
those having electron-donating substituents. The pres-
ence of an ester in the aromatic ring was tolerated in
the reaction (entry 3). Some limitations were nevertheless
encountered with other unsaturated compounds. Indeed,
phenyl bromide, 2-bromopropene, and phenyl triflate led
to the formation of complex mixtures of unidentified
products. However, â-bromostyrene (1g) and cyclohexenyl
triflate (1h ) took part in the coupling process in satisfac-
tory yields (entries 7 and 8). As vinylic triflates can be
easily prepared from the corresponding ketones, their use
in the present reaction would greatly expand the range
of accessible products. Varying the activated olefin
component, it was observed that a variety of aryliden-
emalonates, having electron-withdrawing or electron-
donating substituents, participated well in the three-
component reaction (entries 9-15, and 21). The reaction
also proceeded with Michael acceptors bearing alkyl
chains (entry 16). In marked contrast with what was
observed with allylic alcohols, the present reaction
showed wide structural flexibility with respect to the
propargylic alcohol component. Although requiring more
elevated temperatures in some cases in order to proceed
Resu lts a n d Discu ssion
The first assays to determine the viability of propar-
gylic nucleophiles participating in the cascade Michael
addition-carbocyclization process were carried out by
using conditions slightly different from those previously
used in reactions involving allylic alcohols. As mentioned
above, one important feature of the new procedure is that
stoichiometric amounts of each of the three partners are
reacted simultaneously. THF as solvent was also pre-
ferred to DMSO for practical reasons. Thus, treatment
of propargyl alcohol (2a ) with 1 equiv of n-BuLi in THF
was followed by addition of diethyl benzylidenemalonate
(3a ) and phenyl iodide (1a ). Upon heating the reaction
mixture (up to 50 °C) in the presence of 5 mol % of a
Pd0/(dppe) catalyst,11 we observed the formation of two
cyclic products identified as the desired arylidenetet-
rahydrofuran 4a and the 3-methylenetetrahydrofuran 5a
(2:1 mixtures as shown by NMR analysis). The undesired
(11) The Pd0 catalysts were preformed by reaction of palladium
acetate with 2 equiv of monodentate phosphine (alternatively 1 equiv
of bidentate phosphine) per palladium followed by addition of 1-hexene
as reducing agent. Dppe ) 1,2-bis(diphenylphosphino)ethane; dppb )
1,4-bis(diphenylphosphino)butane; dppf ) 1, 1′-bis(diphenylphosphino)-
ferrocene.
(12) Accordingly, the two-component condensation was attempted
in DMSO under the conditions previously described for this reaction
(see ref 9a), but failed to produce the expected 3-methylenetetrahy-
drofuran.
(10) In a typical procedure, the alkoxide was generated by treatment
of allyl alcohol (2 equiv) with n-BuLi at 0 °C and added via a syringe
pump to a heated (50 °C) solution of the Michael acceptor (1 equiv),
the aryl iodide (1.5 equiv), and the catalyst. The reaction did only
proceed in DMSO.

3-Arylidene-(or 3-Alkenylidene-)tetrahydrofurans
J . Org. Chem., Vol. 66, No. 1, 2001 177
Ta ble 1. Syn th esis of Tetr a h yd r ofu r a n s fr om Un sa tu r a ted Ha lid es (or tr ifla tes), P r op a r gyl Alcoh ols, a n d Ben zylid en e
(or a lk ylid en e) Ma lon a tesa

178 J . Org. Chem., Vol. 66, No. 1, 2001
Bottex et al.
Ta ble 1. (Con tin u ed )
a
b
All reactions were performed on a 1 mmol scale using equimolar amounts of each component. Yields refer to pure isolated products.
c Mixture of diastereomers. Ratios are indicated in brackets. Not isolated as a pure product (see text). Yield determined by 1H NMR
d
analysis.
Sch em e 2
Stimulated by these interesting results, we briefly
revisited the reaction of allylic alcohols using our new
protocol. We were pleased to find that allyl alcohol
reacted at room temperature with equimolar amounts of
1a and 3a to yield the expected tetrahydrofuran 8 in 50%
isolated yield (eq 2). However, the reaction proceeded
slowly (24 h), and nonnegligible amounts of side-products
were also formed. Since purification problems still re-
mained, this study was not pursued.
efficiently, secondary alcohols furnished the correspond-
ing tetrahydrofurans in reasonable yields. In those cases,
essentially 1:1 mixtures of the cis and trans diastereo-
mers were obtained (entries 17, 19-21). 2-Methyl-3-
butyn-2-ol (2c) also underwent cyclization but yielded an
inseparable 2.5:1 mixture of the expected tetrahydrofuran
and the corresponding and previously reported9a 3-meth-
ylenetetrahydrofuran (entry 18).
Con clu sion
The present three-component reaction makes an in-
teresting and valuable complement to our recently de-
scribed tetrahydrofuran synthesis involving allyl alcohol.
The methodology is extremely practical and versatile in
that a range of readily available propargylic alcohols,
unsaturated halides or triflates, and activated olefins can
be reacted without using slow addition techniques. Es-
sentially no side reaction was observed under the opti-
mized procedure, rendering the isolation of the products
very easy. With such features, the protocol described in
this paper holds promise for the preparation of tetrahy-
drofuran libraries. Future work will focus on the reactiv-
ity of olefins bearing electron-withdrawing groups other
than esters as an additional element of diversity. Exten-
sion of our methodology to the preparation of other
heteroatom-containing cyclic compounds is already un-
derway.
To further explore the scope and generality of the
reaction, we next examined the behavior of disubstituted
acetylenic alcohols. As an example, reaction of 1a with
2-butyn-1-ol and dimethyl (4-nitro)benzylidenemalonate
proceeded smoothly at 40 °C leading after 7 h to the
formation of two inseparable isomeric heterocycles. These
were identified as the tetrahydrofuran 6 and the dihy-
1
dropyran 7 (4:1 ratio; 57% combined yield) by using H,
13C, HMBC, and NOESY NMR experiments.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were carried out under a
nitrogen atmosphere using standard syringe, cannula, and
septa techniques. Commercial reagents were used as pur-
chased: Aryl halides were commercially available except for
5-iodo-1,2,3-trimethoxybenzene13a and4-iodo-1,2-(methylenedioxy)-
benzene.13b Noncommercial propargylic alcohols were synthe-
sized by standard propargyl anion chemistry,14 and Michael
acceptors were prepared from the corresponding aldehydes
applying conventional Knoevenagel condensations (catalytic
The structure of compound 6 again suggests a con-
certed 5-exo cyclization process that consists of an in-
tramolecular nucleophilic attack of the enolate interme-
diate onto the tethered unsaturation activated by the
organopalladium species (Scheme 2).8 The dihydropyran
7 would therefore result from a competitive 6-endo
cyclization process.
(13) (a) Bowden, B. F.; Read, R. W.; Taylor, W. C. Aust. J . Chem.
1981, 34, 799. (b) Pearson, W. H.; Postich, M. J . J . Org. Chem. 1994,
59, 5662.
(14) Feldman, K. S.; Bruendl, M. M.; Schildknegt, K.; Bohnstedt,
A. C. J . Org. Chem. 1996, 61, 5440.

3-Arylidene-(or 3-Alkenylidene-)tetrahydrofurans
J . Org. Chem., Vol. 66, No. 1, 2001 179
piperidine, catalytic HOAc, toluene, reflux).15 Tetrahydrofuran
and dimethyl sulfoxide were distilled over calcium hydride.
Thin-layer chromatography was carried out on Merck silica
60/F-254 aluminum-backed plates. Flash chromatography was
performed using Merck silica gel 60 (40-63 µm). Melting
points are uncorrected. NMR spectra were recorded in CDCl3.
Chemical shifts (δ) are quoted in parts per million. J values
are given in hertz.
Gen er a l P r oced u r e for th e On e-P ot Th r ee-Com p on en t
Rea ction . A stirred suspension of PdCl2(PPh3)2 (35 mg, 0.05
mmol) in DMSO (3 mL) was treated with n-BuLi (2.0 M in
hexanes, 50 µL, 0.1 mmol) at room temperature, affording a
dark-red homogeneous solution. In a separate flask, n-BuLi
(2.0 M in hexanes, 500 µL, 1 mmol) was added dropwise to an
ice-cooled solution of the propargylic alcohol (1 mmol) in THF
(3 mL), and the solution was allowed to reach room temper-
ature (15 min). The Michael acceptor (1 mmol), the unsatur-
ated halide (1 mmol), and the palladium catalyst solution were
then successively added to the reaction mixture. The advance-
ment of the reaction was monitored by GC (following the
disappearance of the Michael acceptor). The reaction was
quenched with a saturated aqueous solution of ammonium
chloride, and the mixture was extracted with ethyl acetate.
The organic layer was dried (Na2SO4) and concentrated in
vacuo. The residue was purified by chromatography on silica
gel (eluent: ethyl acetate/petroleum ether). Melting points,
NMR, and analytical data of selected exemples are as follows
(see the Supporting Information for all other examples).
J ) 10.7 and 7.1, 1H), 3.83 (s, 3H), 3.71 (dq, J ) 10.7 and 7.1,
1H), 1.30 (t, J ) 7.0, 3H), 0.75 (t, J ) 7.0, 3H). 13C NMR
(CDCl3, 50 MHz) δ 168.3, 167.9, 159.7, 147.5, 147.3, 138.3,
137.8, 130.1, 129.6, 126.0, 121.1, 120.5, 114.3, 113.2, 107.9,
107.6, 100.1, 84.6, 70.3, 69.5, 62.1, 61.5, 55.3, 14.1, 13.7. Anal.
Calcd for C25H26O8: C, 66.07; H, 5.77. Found C, 65.82; H, 6.00.
Meth yl 4-ben zylid en e-2-(4-n itr o)p h en yl-tetr a h yd r ofu -
r a n -3,3-d ica r boxyla te (4o): solid; mp 141-143 °C; 1H NMR
(CDCl3, 300 MHz) δ 8.20 (d, J ) 8.8, 2H), 7.68 (d, J ) 8.8,
2H), 7.46-7.29 (M, 5H), 6.85 (s, 1H), 5.84 (s, 1H), 5.13 (dd, J
) 13.6 and 2.2, 1H), 4.84 (dd, J ) 13.6 and 2.7, 1H), 3.92 (s,
3H), 3.28 (s, 3H). 13C NMR (CDCl3, 50 MHz) δ 168.5, 167.9,
147.9, 144.4, 136.9, 136.0, 128.7, 128.6, 128.0, 127.7, 126.5,
123.2, 83.8, 70.7, 69.9, 53.4, 52.5. Anal. Calcd for C21H19O7: C,
63.47; H, 4.82; N, 3.53. Found C, 63.72; H, 4.61; N, 3.62.
Eth yl 4-ben zylid en e-2-isop r op yl-tetr a h yd r ofu r a n -3,3-
d ica r boxyla te (4p ): oil; 1H NMR (CDCl3, 300 MHz) δ 7.38-
7.14 (M, 5H), 6.60 (s, 1H), 4.85 (dd, J ) 13.8 and 2.2, 1H),
4.63 (dd, J ) 13.8 and 2.6, 1H), 4.36-4.14 (M, 4H), 1.83 (m,
1H), 1.34 (d, J ) 7.1, 3H), 1.25 (d, J ) 7.1, 3H), 1.05 (t, J )
7.0, 6H). 13C NMR (CDCl3, 50 MHz) δ 168.8, 168.4, 140.5,
136.4, 128.6, 128.5, 127.4, 124.1, 89.4, 70.0, 67.2, 61.8, 61.5,
30.5, 20.0, 19.9, 14.1. Anal. Calcd for C20H26O5: C, 69.30; H,
7.56. Found C, 68.98; H, 7.96.
Eth yl 4-ben zyliden e-2-ph en yl-5-(2,3,4-tr im eth oxy)ph en -
yl-tetr a h yd r ofu r a n -3,3-d ica r boxyla te (4s): An oil contain-
ing a 1:1 mixture of diastereomers: 1H NMR (CDCl3, 300 MHz)
δ 7.55-6.75 (M, 24H), 6.56 (d, J ) 8.8, 1H), 6.51 (s, 1H), 6.45
(d, J ) 8.8, 1H), 6.31 (s, 1H), 5.96 (s, 1H), 5.83 (s, 3H), 4.40
(m, 4H), 3.98-3.68 (M, 20H), 3.49 (m, 2H), 1.40 (t, J ) 7.0,
3H), 1.33 (t, J ) 7.0, 3H), 0.83 (t, J ) 7.0, 3H), 0.80 (t, J )
7.0, 3H).13C NMR (CDCl3, 50 MHz) δ 168.9, 168.8, 168.7, 168.5,
154.2, 153.5, 152.9, 142.8, 141.7, 140.9, 139.3, 137.4, 137.2,
135.9, 135.5, 129.1, 128.9, 128.7, 128.3, 128.1, 128.0, 127.8,
127.5, 127.4, 127.1, 126.9, 125.3, 125.2, 123.6, 123.2, 107.7,
106.6, 83.8, 81.1, 77.3, 75.9, 70.9, 70.7, 62.0, 61.9, 61.6, 61.5,
61.3, 61.0, 60.9, 60.7, 56.2, 55.9, 14.2, 14.1, 13.5, 13.4. Anal.
Calcd for C32H34O5 (mixture of isomers): C, 70.31; H, 6.27.
Found C, 69.83; H, 6.66.
Eth yl 4-ben zylid en e-2-p h en yl-tetr a h yd r ofu r a n -3,3-d i-
1
ca r boxyla te (4a ): solid; mp 95-97 °C; H NMR (CDCl3, 300
MHz) δ 7.22-7.32 (M, 10H), 6.88 (s, 1H), 5.79 (s, 1H), 5.11
(dd, J ) 13.6 and 2.2, 1H), 4.81 (dd, J ) 13.6 and 2.6, 1H),
4.35 (q, J ) 7.0, 2H), 3.84 (m, 1H), 3.54 (m, 1H), 1.35 (t, J )
7.0, 3H), 0.81 (t, J ) 7.0, 3H). 13C NMR (CDCl3, 50 MHz) δ
168.3, 167.9, 138.0, 137.3, 136.5, 128.6, 128.3, 128.0, 127.7,
126.9, 126.1, 84.8, 70.4, 69.7, 62.0, 61.4, 14.1, 13.5. Anal. Calcd
for C23H24O5: C, 72.61; H, 6.36. Found C, 72.52; H, 6.32.
Eth yl 4-cin n a m ylid en e-2-p h en yl-tetr a h yd r ofu r a n -3,3-
d ica r boxyla te (4g): solid; mp 92-94 °C; 1H NMR (CDCl3, 300
MHz) δ 7.27-7.50 (M, 10H), 6.73-6.58 (m, 3H), 5.77 (s, 1H),
5.12 (d, J ) 13.7, 1H), 4.74 (d, J ) 13.7, 1H), 4.37 (m, 2H),
3.83 (m, 1H), 3.53 (m, 1H), 1.34 (t, J ) 7.2, 3H), 0.81 (t, J )
7.2, 3H). 13C NMR (CDCl3, 50 MHz) δ 168.4, 168.2, 138.4,
138.0, 137.6, 137.2, 135.3, 129.1, 128.7, 128.4, 128.3, 127.2,
127.0, 125.1, 124.7, 85.8, 70.1, 69.2, 62.4, 61.8, 14.5, 13.8. Anal.
Calcd for C25H24O5: C, 73.87; H, 6.45. Found C, 73.29; H, 6.57.
Eth yl 4-(cycloh ex-1-en ylid en e)-2-p h en yl-tetr a h yd r o-
fu r a n -3,3-d ica r boxyla te (4h ): solid; mp 84-86 °C; 1H NMR
(CDCl3, 300 MHz) δ 7.44-7.26 (M, 5H), 6.25 (s, 1H), 5.70 (br
s, 1H), 5.67 (s, 1H), 5.03 (d, J ) 13.4, 1H), 4.66 (d, J ) 13.4,
1H), 4.30 (q, J ) 7.0, 2H), 3.78 (m, 1H), 3.46 (m, 1H), 2.14 (m,
4H), 1.60 (m, 4H), 1.30 (t, J ) 7.0, 3H), 0.75 (t, J ) 7.0, 3H).
13C NMR (CDCl3, 50 MHz) δ 168.6, 168.2, 137.5, 135.1, 134.0,
130.8, 128.9, 128.1, 127.9, 126.8, 84.6, 70.2, 69.5, 61.8, 61.2,
27.9, 25.9, 22.8, 21.8, 14.1, 13.4. Anal. Calcd for C23H28O5: C,
71.85; H, 7.34. Found C, 71.85; H, 7.43.
E t h yl 4-(1-p h en yl-et h ylid en e)-2-(4-n it r o)p h en yl-t et -
r a h yd r ofu r a n -3,3-d ica r boxyla te (6) a n d eth yl 4-m eth yl-
2-(4-n itr o)p h en yl-5-p h en yl-3,6-d ih yd r o-2H-p yr a n -3,3-d i-
ca r boxyla te (7): isolated as an inseparable mixture, in a ratio
1
of 4:1. Data for 6: H NMR (CDCl3, 300 MHz) δ 8.18 (d, J )
8.8, 2H), 7.68 (d, J ) 8.8, 2H), 7.40-7.15 (M, 5H), 5.83 (s, 1H),
4.43 (s, 1H), 3.93 (s, 3H), 3.26 (s, 3H), 2.04 (s, 3H).13C NMR
(CDCl3, 75 MHz) δ 169.6, 168.1, 147.7, 144.6, 142.9, 136.4,
132.5, 128.5, 127.8, 127.1, 122.9, 85.9, 72.0, 68.6, 53.3, 52.3,
22.0. Data for 7: 1H NMR (CDCl3, 300 MHz) δ 8.19 (d, J )
8.8, 2H), 7.55 (d, J ) 8.8, 2H), 7.40-7.15 (M, 5H), 5.49 (s, 1H),
4.53 (m, 2H), 3.83 (s, 3H), 3.56 (s, 3H), 1.67 (s, 3H). 13C NMR
(CDCl3, 75 MHz) δ 167.5, 147.4, 146.3, 137.3, 135.7, 128.6,
127.7, 125.8, 122.8, 79.4, 70.8, 64.3, 52.8, 17.4. HRMS m/z calcd
for C22H21NO7 (mixture of isomers) 411.1318, found 411.1319.
Ackn owledgm en t. We gratefully acknowledge Aven-
tis Cropscience and the Centre National de la Recherche
Scientifique for their generous support of this work.
Eth yl 4-(3-m eth oxy)ben zylid en e-2-(3,4-d ioxym eth yl-
en e)ph en yl-tetr a h yd r ofu r a n -3,3-d ica r boxyla te (4k): solid;
mp 88-90 °C; 1H NMR (CDCl3, 300 MHz) δ 7.35-6.75 (M,
8H), 5.93 (s, 2H), 5.68 (s, 1H), 5.07 (dd, J ) 13.7 and 2.2, 1H),
4.77 (dd, J ) 13.7 and 2.7, 1H), 4.35 (q, J ) 7.1, 2H), 3.91 (dq,
Su p p or tin g In for m a tion Ava ila ble: Complementary
characterization for compounds 4 including copies of 1H NMR
spectra for 4b-f, 4i-j, 4l-n , 4q (two isomers), and 4r . This
material is available free of charge via the Internet at
http://pubs.acs.org.
(15) Horning, O. C. Organic Syntheses; Wiley: New York, 1955;
Collect. Vol. III, p 377. See also ref 9d.
J O0012997