A novel double olefination. Highly stereoselective synthesis of trifluoromethylated 1,3-butadienylphosphonates

Article abstract of DOI:10.1021/jo981381q

The bisphosphoryl-stabilized carbanion (2), generated from tetraethyl ethyl-1,1-bisphosphonate (1) and n-butyllithium in tetrahydrofuran (THF), was acylated by the addition of trifluoroacetic anhydride to give trifluoroacylated bisphosphonate (3). Without isolation, 3 was reacted with [(diethylphosphinoyl)methyl]lithium, and elimination of phosphonic acid anion afforded 4. Treatment of 4 with LDA gave phosphoryl-stabilized carbanion 5, which in the reaction medium was able to react with aldehyde to give substituted trifluromethylated 1,3-butadienylphosphonates in 66-88% yields with the 1E,3E isomer exclusively or predominately. Thus, the double- olefination methodology provides a simple and convenient synthesis of the title compounds. The first example of crystallization of diethyl 1-methyl-2- trifluoromethyl-4-(4'-nitrophenyl)-1,3-butadienylphosphonate with 1,4- dinitrobenzene was obtained by a cocrystallization method. Hence, the configuration of the products could be ascertained on the basis of the crystal structure. A possible mechanism for the explanation of stereochemical results is proposed.

Full text of DOI:10.1021/jo981381q

9396
J . Org. Chem. 1998, 63, 9396-9398
A Novel Dou ble Olefin a tion . High ly Ster eoselective Syn th esis of
Tr iflu or om eth yla ted 1,3-Bu ta d ien ylp h osp h on a tes
Yanchang Shen,* Ping Li, J iahong Ni, and J ie Sun
Shanghai Institute of Organic Chemistry, Academia Sinica, 354 Fenglin Lu, Shanghai 200032, China
Received J uly 15, 1998
The bisphosphoryl-stabilized carbanion (2), generated from tetraethyl ethyl-1,1-bisphosphonate (1)
and n-butyllithium in tetrahydrofuran (THF), was acylated by the addition of trifluoroacetic
anhydride to give trifluoroacylated bisphosphonate (3). Without isolation, 3 was reacted with
[(diethylphosphinoyl)methyl]lithium, and elimination of phosphonic acid anion afforded 4. Treat-
ment of 4 with LDA gave phosphoryl-stabilized carbanion 5, which in the reaction medium was
able to react with aldehyde to give substituted trifluromethylated 1,3-butadienylphosphonates in
66-88% yields with the 1E,3E isomer exclusively or predominately. Thus, the double-olefination
methodology provides a simple and convenient synthesis of the title compounds. The first example
of crystallization of diethyl 1-methyl-2-trifluoromethyl-4-(4′-nitrophenyl)-1,3-butadienylphosphonate
with 1,4-dinitrobenzene was obtained by a cocrystallization method. Hence, the configuration of
the products could be ascertained on the basis of the crystal structure. A possible mechanism for
the explanation of stereochemical results is proposed.
In tr od u ction
methodology for their operational simplicity and efficient
entry to complex compounds by including two or more
transformations in a single operation to increase the
complexity of substrate starting from commercially avail-
able relatively simple precusors.6 In our laboratory,
sequential transformations of phosphonates have been
developed as a general synthetic approach for perfluo-
roalkylated R-fluoro-R,â-unsaturated esters,7 perfluoro-
alkylated 4-cyanoalka-1,4-dienes,8 perfluoroalkylated R,â-
unsaturated nitriles,9 and tetrasubstituted perfluoroalkyl-
ated (Z)-R,â-unsaturated esters,10 which would be difficult
to prepare otherwise.
Recently, a double-olefination methodology has been
found for the preparation of allenes in a one-pot reaction.1
Vinylphosphonium salts are conveniently obtained from
the reaction of carbonyl compounds with titanium-
substituted ylide species and can be converted to allenes
by deprotonation and condensation with aldehydes.1a
Allenes can also be synthesized by condensation of a
phosphorus methylide, Ti(IV) halide alkoxide and aro-
matic aldehydes in one-pot procedure.1b This methodol-
ogy is simple and convenient. However, only aldehydes
bearing an R-proton were able to afford 1,3-dienes rather
than allenes.1b
Resu lts a n d Discu ssion
In our continuing investigation of the synthetic ap-
plication of seqential transformation of phosphonates in
organic synthesis,7-10 herein we report a novel double
olefination via seqential transformation of phosphonates
and its application to the synthesis of trifluoromethylated
1,3-butadienylphosphonates with 1E,3E isomers exclu-
sively or predominately.
The reaction sequence is shown in Scheme 1. The
bisphosphoryl-stabilized carbanion 2, generated from the
corresponding bisphosphonate and n-butyllithium in
tetrahydrofuran (THF), was acylated by the addition of
trifluoroacetic anhydride to give trifluoroacylated phos-
phonate 3. Without isolation, 3 was attacked by [(dieth-
ylphosphinoyl)methyl]lithium, and elimination of phos-
phonic acid anion afforded 4. Treatment of 4 with LDA
gave phosphoryl-stabilized carbanion 5, which in the
reaction medium was reacted with aldehydes to give
substituted trifluoromethylated 1,3-butadienylphospho-
nates in 66-88% yields with 1E,3E isomers exclusively
or predominately. The results are summarized in Table
1.
Functionalized vinylphosphonates have attracted much
interest in synthetic chemistry, and the synthetic ap-
plications have been widely investigated in the last two
decades.2 It has been reported in recent years that
vinylphosphonates and 1,3-dienylphosphonates bearing
an ene moiety are useful intermediates that have been
used in the synthesis of bicyclic compounds and of
cadalane and valerenic acid sesquiterpenoids.3 However,
the synthetic methodologies are the classic Knoevenagel
condensation mediated by titanium compounds3b and the
palladium-catalyzed coupling reaction.4 Furthermore,
the method for the preparation of fluorinated analogues
is limited.5 Therefore, to develop an effective method for
their preparation would be valuable. Sequential trans-
formations have emerged in recent years as a powerful
(1) (a) Reynolds, K. A.; Dopico, P. G.; Brody, M. S.; Finn, M. G. J .
Org. Chem. 1997, 62, 2564. (b) Reynolds, K. A.; Dopics, P. G.;
Sundermann, M. J .; Hughes, K. A.; Finn, M. G. J . Org. Chem. 1993,
58, 1298.
(2) Minami, T.; Motoyoshiya, J . Synthesis 1992, 333.
(3) (a) Minami, T.; Utsunomiya, T.; Nakamura, S.; Okubo, M.;
Kitamura, N.; Okada, Y.; Ichikawa, J . J . Org. Chem. 1994, 59, 671.
(b) Okauchi, T.; Kakiuchi, T.; Kitamura, N.; Utsunomiya, T.; Ichikawa,
J .; Minami, T. J . Org. Chem. 1997, 62, 8419.
(6) (a) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993,
32, 131. (b) Padwa. A.; Curtis, E. A.; Sandanayaka, V. P. J . Org. Chem.
1996, 61, 73. (c) Tietze, L. F. Chem. Rev. 1996, 96, 115. (d) Parsons, P.
J .; Penkett, C. S.; Shell, A. J . Chem. Rev. 1996, 96, 195.
(7) Shen, Y.; Ni, J . J . Org. Chem. 1997, 62, 7260.
(4) (a) Huang, X.; Zhang C,; Lu, X. Synthesis 1995, 769. (b)
Akermark, B.; Nystrom, J .-E.; Rein, T.; Backvall, J .-E. Tetrahedron
Lett. 1984, 25, 5719
(8) Shen, Y.; Ni, J . J . Chem. Res., Synop. 1997, 358.
(5) Blackburn, G. M.; Parratt, M. J . J . Chem. Soc., Perkin Trans. 1
1986, 1417.
(9) Shen, Y.; Ni, J . J . Fluorine Chem. 1997, 86, 173.
(10) Shen, Y.; Ni, J . J . Fluorine Chem. 1998, 89, 141.
10.1021/jo981381q CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/18/1998

A Novel Double Olefination
Sch em e 1
J . Org. Chem., Vol. 63, No. 25, 1998 9397
Sch em e 2
making step results in a racemic adduct, for which two
pairs of enantiomeric conformers are possible for the
olefination step to occur (Scheme 2). The reactive size
of groups is PO3Et2 > CF3 > CH3 > CH2PO3Et2.11 Since
the 7a /7c pair involves syn-periplanar (eclipsed) orienta-
tion of two pairs of “small”/“large” substituents (CH2PO3-
Et2/PO3Et2, CF3/CH3), those conformers should be favored
relative to the 7b/7d pair, which contains unfavorable
“large”/“large” (CF3/PO3Et2) nonbond interactions. There-
fore, the stereoselectivity of olefination in our case is a
function of the conformational equilibrium of the adduct.
Each of those intermediates decomposes via a syn
elimination, affording 4-(E) or 4-(Z). In our case, forma-
tion of 7a /7c will be favored over 7b/7d , and the E isomer
was obtained exclusively.
Ta ble 1. P r ep a r a tion of Su bstitu ted
Tr iflu or om eth yla ted 1,3-Dien ylp h osp h on a tes
compd
R
yieldsa (%)
1E,3E:1E,3Zb
6a
6b
6c
6d
6e
6f
6g
6h
6i
c-C3H5
2-furyl
73
81
72
83
67
80
88
66
77
71
100:0
100:0
100:0
100:0
100:0
98:2
95:5
95:5
90:10
90:10
4-NO2C6H4
2-CF3C6H4
(E)-C6H4CHdCH
4-CH3OC6H4
4-CH3C6H4
4-ClC6H4
4-FC6H4
C6H5
6j
a
b
Isolated yields. The ratios of 1E,3E and 1E,3Z isomers were
estimated on the basis of NMR data.
For the assignment of the configuration of products,
we did the X-ray crystallographic analysis of 6c. As is
known, the derivatives of phosphonates usually are oils
and hard to crystallize. Fortunately, to the best of our
knowledge, the first example of crystallization of phos-
phonate (6c) was successfully obtained by a cocrystalli-
zation method. The crystal of diethyl 1-methyl-2-(tri-
fluoromethyl)-4-(4′-nitrophenyl)-1,3-butadien-ylphosphonate
was grown with 1,4-dinitrobenzene from n-pentane. The
crystal structure of 6c shows that the methyl group is
cis with respect to the trifluoromethyl group (1E) and the
H group is trans with respect to the H group (3E). Hence,
the configuration of products could be ascertained on the
basis of the crystal structure.
The stereochemical results may be rationalized as
follows: The mechanism of first olefination for the for-
mation of trifluoromethylated R,â-unsaturated bisphos-
phonate is analoguous to that of bisphosphonate reported
in the literature11,12 and is outlined in Scheme 2.
The stereoselectivity of the reaction is determined by
the condensation step. The reaction is initiated by
nucleophilic attack of nucleophile on the carbon-oxygen
double bond of the carbonyl group, and the C-C bond
The mechanism of the second olefination for the
fomation of the title compounds is analoguous to that of
the Horner-Waldsworth-Emmons reaction13 and is
outlined in Scheme 3.
Each of those intermediates decomposes via a syn
elimination, affording 6-(1E,3E) or 6-(1E,3Z). Like the
former explanation, 8a will be favored over 8b, and the
E isomer was obtained exclusively or predominately (see
Table 1).
In conclusion, the double-olefination methodology has
been applied to the synthesis of substituted trifluorom-
ethylated 1,3-butadienylphosphonate, giving 1E,3E iso-
mers exclusively or predominately in a one-pot reaction.
This methodology provides a simple and convenient
synthesis of the title compounds from readily available
starting materials. The crystal of diethyl 1-methyl-2-
(trifluoromethyl)-4-(4′-nitrophenyl)-1,3-butadienylphos-
phonate with 1,4-dinitrobenzene was obtained by a
cocrystallization method for the assignment of the con-
figuration of the products. The title compounds would
be expected to be useful intermediates for the synthesis
of fluorine containing biologically active compounds. This
double-olefination methodology can also be extended to
(11) Gedye, R. N.; Westaway, K. C.; Arora, P.; Bisson, R.; Khalil, A.
H. Can. J . Chem. 1977, 55, 1218. It has been reported in this paper
that space-filling models indicate that the steric hindrance between
the CH3 group and the CO2CH3 group is larger than that between the
CH2PO(OEt)2 group and the CO2CH3 group.
(12) Perlikowska, W.; Mphahlele, M. J .; Modro, T. A. J . Chem. Soc.,
Perkin Trans. 2 1997, 967.
(13) Tasi, H.-J .; Thenappan, A.; Burton, D. J . J . Org. Chem. 1994,
59, 7085.

9398 J . Org. Chem., Vol. 63, No. 25, 1998
Shen et al.
(3 mmol) and diethyl methylphosphonate (3 mmol) in tetrahy-
drofuran (20 mL) for 30 min at -78 °C.
Sch em e 3
Gen er a l P r oced u r e for th e P r ep a r a tion of Tr iflu o-
r om eth yla ted 1,3-Bu ta d ien ylp h osp h on a tes 6. n-Butyl-
lithium (3.3 mmol in 2.5 mL hexane) was added dropwise over
10 min to a stirred solution of tetraethyl ethyl-1,1-bisphos-
phonate(3 mmol) in absolute THF (20 mL) at -78° C under
nitrogen. The mixture was stirred at -78 °C for 0.5 h, and
trifluoroacetic anhydride (3 mmol) was added to it in one
portion. Stirring was continued at -78 °C for 1 h, after which
time [(diethylphosphinoyl)methyl]lithium (3 mmol) was added
dropwise to the mixture, which was stirred for another 1 h.
Then LDA and aldehyde were added in turn to the mixture,
which was stirred for 1 h and allowed to warm to room
temperature. After the mixture was stirred for 3 h and the
aldehyde disappeared (showed by TLC), the reaction mixture
was poured into water (10 mL), and the water layer was
extracted with dichloromethane (4 × 20 mL). The combined
organic layer was washed with water (2 × 10 mL) and dried
over Na2SO4. Evaporation of the solvent gave a residue, which
was purified by column chromatography, eluting with petro-
leum ether (60-90 °C)-ethyl acetate (9:1) to give the product
6.
Diet h yl 1-m et h yl-2-(t r iflu or om et h yl)-4-cyclop r op yl-
1,3-bu ta d ien yl p h osp h on a te (6a ): yield 73%; bp 130 °C/0.8
mmHg; 1E,3E:1E,3Z ) 100:0; IR (neat) 1630, 1250, 1130, 950
cm-1; H NMR (CDCl3/TMS) δ 6.68(d, 1H, J ) 15.8 Hz), 5.49
1
the synthesis of other functionalized fluorinated dienes
and now is being pursued.
(dd, 1H, J )15.6, 6.7 Hz), 4.13-4.00 (m, 4H), 2.06 (dq, 3H, J
) 15.4, 2.2 Hz), 1.52-1.42 (m, 1H), 1.31 (t, 6H, J ) 7.1 Hz),
0.79 (dt, 2H, J ) 8.1, 4.5 Hz), 0.49 (dt, 2H, J ) 9, 4.5 Hz); 19
F
NMR(CDCl3/CFCl3) δ -56.2 (s, 3F); MS 313 (M+ + 1, 9), 312
(M+, 40), 283 (40), 256 (100), 241 (41), 215 (51). Anal. Calcd
for C13H20F3O3P: C, 50.00; H, 6.46. Found: C, 50.05; H, 6.49.
Exp er im en ta l Section
Gen er a l Meth od s. Analytical samples were purified by
Kugelrohr distillation with the oven temperature (ot) given.
The published 19F NMR spectra were recalculated using a
standard chemical shift of reference δ(F) (CF3COOH) -76.5
ppm with respect to δ(F) (CFCl3) 0.00 ppm. MS were obtained
using ionization and are reported as m/e (relative intensity).
All reactions were performed in oven-dried glassware under
an atmosphere of dry nitrogen. Solvents were evaporated
under reduced pressure with a rotary evaporator, and the
residue was chromatographed on a silica gel column.
Ma ter ia ls. All solvents were purified before use. THF was
purified by distillation from sodium benzophenone ketyl.
Tetraethyl ethyl-1,1-bisphosphonates (1) were prepared ac-
cording to the known procedure.14 [(Diethylphosphinoyl)-
methyl]lithium was prepared by the reaction of n-butyllithium
Ack n ow led gm en t. We thank the National Natural
Science Foundation of China, the Laboratory of Orga-
nometallic Chemistry, and Academia Sinica for financial
support.
Su p p or tin g In for m a tion Ava ila ble: Characterization
and analytical data of compounds 6b-j and X-ray structure
report including ORTEP diagram and tables of crystallo-
graphic data, atomic coordinates and thermal parameters, and
bond length and angles for 6c (22 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
(14) Teulade, M. P..; Savignic, P. J . Organomet. Chem. 1986, 304,
283.
J O981381Q