Palladium-catalyzed regiocontrolled and stereoselective alkylations of bis(trifluoroethyl) malonates with dienyl alcohols

Article abstract of DOI:10.1016/S1268-7731(03)00074-2

The triethylborane-promoted and palladium-catalyzed reactions of 2, 4-dienyl alcohols or the corresponding isomeric divinyl alcohols with bis(trifluoroethyl) malonates provide an improved method for the regio- and stereoselective dienylation of malonates.

Full text of DOI:10.1016/S1268-7731(03)00074-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7075–7079
Palladium-catalyzed regiocontrolled and stereoselective
alkylations of bis(trifluoroethyl) malonates with dienyl alcoholsꢀ
James M. Takacs,* Xun-tian Jiang and Alexei P. Leonov
Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588-0304, USA
Received 18 April 2003; revised 13 July 2003; accepted 15 July 2003
Abstract—The triethylborane-promoted and palladium-catalyzed reactions of 2,4-dienyl alcohols or the corresponding isomeric
divinyl alcohols with bis(trifluoroethyl) malonates provide an improved method for the regio- and stereoselective dienylation of
malonates. The phosphine ligand is an important control element in the reaction. Combinations of Pd(OAc)2 with BIPHEP or
BINAP give dienylated malonates in good yield and higher isomeric purity than the traditional combination of Pd(OAc)2 and
Ph3P affords in the catalyzed reactions of dienyl acetates.
© 2003 Elsevier Ltd. All rights reserved.
Methods for the stereoselective preparation of substi-
tuted 1,3-dienes are of interest due to their presence
within the structures of natural products and their use
as substrates for cycloaddition reactions and a variety
of metal-catalyzed reactions. We are particularly inter-
ested in the latter topic,1 and consequently, seek simple,
practical methods for introducing the 1,3-diene moiety
with good regio- and stereochemical control. Toward
this end, we have developed and refined several dienyl-
ation methods.2–4
plicated by the fact that the diene substrate presents
three potential sites for alkylation. Considering even a
relatively simple diene, for example, the 5-substituted-
2,4-dienyl acetate illustrated in Figure 1, alkylation at
any of the three sites can potentially give rise to two or
more stereoisomers. In the example illustrated, eight
isomers are possible from the dienylation reaction. For
our purposes, we are particularly interested in obtaining
the product of alkylation at the a-position with good
control of diene geometry (i.e. (E,E)-1).
Transition metal catalyzed alkylations of malonates
and related pronucleophiles by dienyl acetates and car-
bonates represents a rather simple and direct method
for dienylation, and as such, these methodologies have
been quite extensively investigated. The reaction is com-
Improving the regiocontrol and stereoselectivity of
metal-catalyzed dienylations has been recognized as an
important goal, and a number of mechanistic and syn-
thetic studies have been reported. Most studies focus on
one or more of the following factors, the effect of
substituents on the diene substrate and its substitution
pattern,5–9 the nature of the nucleophile and its counte-
rion,10 or the choice of metal and ligand. Catalysts
systems derived from tungsten,9 molybdenum,11 and
iridium12 tend to give predominantly the product of
internal alkylation, that is, addition to the g-position
illustrated in Figure 1 and afford a divinyl alcohol,
rather than conjugated diene, as the major product.
Dienylations catalyzed by palladium are strongly influ-
enced by the nature of the ligand.13,14 Those modified
by PPh3 generally give a mixture of products with the
predominant one derived from addition to the a-posi-
tion. For example, the palladium-catalyzed dienylation
of diethyl methylmalonate (2) by 2,4-hexadienyl acetate
(3) proceeds in high yield, but affords a mixture of
products 4 (70%) and 5 (30%) resulting from competing
Figure 1. The problems of regio- and stereochemical control
in malonate dienylations.
ꢀ Supplementary data associated with this article can be found at
doi:10.1016/S1268-7731(03)00074-2
* Corresponding author. Tel.: +1-402-472-6232; fax: +1-402-472-9402;
e-mail: jtakacs1@unl.edu
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S1268-7731(03)00074-2

7076
J. M. Takacs et al. / Tetrahedron Letters 44 (2003) 7075–7079
substitution at the a- and g-positions (Scheme 1). Con-
trol over the alkene geometry in the diene derived from
each mode is usually good (>95% E). The alkylation is
reversible at elevated temperature with palladium cata-
lysts that use PBu3 as the ligand. Dienylation under
these conditions increases the percentage of 4, but
suffers from the erosion of its stereoisomeric purity.
The product mixture typically contains only 70–90% of
the (E,E)-isomer of 4.13
phine ligand (THF, 25°C, 12 h) affords dienylated
products in good yield (Scheme 2).
A broad range of ligands have been examined in palla-
dium-catalyzed allylation reactions, and the choice of
ligand has been shown to substantially influence the
regio- and stereochemical outcome of the addition.20–22
A variety of phosphine ligands were screened in the
dienylation reaction illustrated in Scheme 2. In each
case, the reaction was found to be highly regioselective
for substitution at the a-position, but inevitably formed
a mixture of stereoisomers. As summarized in Table 1,†
the isomer ratio is strongly dependent on the ligand
Table 1. The influence of ligands on the yield and
stereoselectivity for the formation of 8 under the condi-
tions of Scheme 2a
Entry
Ligandb
(E,E)-8 (%)
8% (%)
8¦ (%)
1
2
3
4
PPh3
dppe
dppp
dppb
57
47
56
55
54
46
92
88
13
13
15
18
17
20
4
6
15
11
13
10
6
Scheme 1. Results typical of those obtained for the palla-
dium-catalyzed alkylation of malonates by dienyl acetates.
5
dppf
Recently, Tamaru and co-workers reported the Et3B-
promoted reaction of allyl alcohols in palladium-cata-
lyzed allylations of active methylene compounds,15 and
other pronucleophiles.16–18 Their report included one
promising malonate dienylation reaction, and we there-
fore decided to further explore the scope of the reac-
tion. Our study led to the development of an alternative
malonate substrate and a modified catalyst system that
provides an improved method for the regio- and
stereoselective dienylations of malonates. Via this new
procedure, dienylated malonates are obtained in higher
isomeric purity than typically observed for palladium-
catalyzed reactions of dienyl acetates.
6
XANTPHOS
BIPHEP
rac-BINAP
7c
8c
4
6
6
a The reported yields were determined by analysis of the 1H NMR
spectrum of the crude reaction mixture. See the representative
procedure† for the experimental details.
b 1 equiv. of ligand was employed, except in the case of Ph3P where
2 equiv. were added.
c The isolated product is obtained in 89% yield and is 93% the
(E,E)-isomer using BIPHEP and in 80% yield (92% (E,E)) using
BINAP.
† Representative procedure: To a nitrogen blanketed solution (ca.
25°C) of bis(trifluoroethyl) methylmalonate (100 mg, 0.36 mmol)
and 2,4-hexadien-1-ol (7) (35 mg, 0.36 mmol) in THF (1 mL) was
added NaH (9.4 mg, 0.39 mmol). The resulting mixture was stirred
until the NaH was consumed (ca. 15 min). In a separate flask, a
mixture of Pd(OAc)2 (8.0 mg, 0.036 mmol) and either rac-BINAP
(23.5 mg, 0.036 mmol) or BIPHEP (18.6 mg, 0.036 mmol) was
stirred in THF (2 mL, 10 min). (Note: An orange precipitate
typically forms in the case of BINAP, and occasionally, a precipi-
tate forms with BIPHEP.) The substrate mixture was added to the
Pd(OAc)2 mixture, followed by the addition of Et3B (1 M in
hexanes, 0.43 mL, 0.43 mmol). (It should be noted that this
addition order was found to be important for successful reaction).
The resulting homogeneous mixture was stirred overnight (ca 12 h,
25°C). Afterwards, the mixture was concentrated via rotovap and
filtered through a plug of silica. (Yields reported for the stereoiso-
mers in Table 1 are determined by analysis of the 1H NMR
spectrum at this stage.) In preparative experiments (vide infra), the
residue was purified by chromatography on silica (1% ether in
hexane) to afford compound 8 (115 mg (89%) in the case of
BIPHEP and 103 mg (80%) in the case of BINAP): 1H NMR (500
MHz, CDCl3, major isomer): l 6.02–6.07 (m, 1H), 5.93–5.99 (m,
1H), 5.58–5.65 (m, 1H), 5.34–5.52 (m, 1H), 4.44–4.50 (m, 4H), 2.65
(d, 7.2 Hz, 2H), 1.66 (d, 7.1 Hz, 3H), 1.47 (s, 3H); 13C NMR (125
MHz, CDCl3): l 169.6, 135.7, 130.8, 129.5, 122.7, 122.5 (q, 275.3
Hz), 60.9 (q, 36.7 Hz), 54.0, 38.8, 19.6, 17.9; IR (neat): 2978, 2331,
1731, 1452, 1378, 1021, 968, 852, 747 cm−1; MS (m/z): 362 (M+),
234, 107, 81 (100); HRMS calcd for C14H16F6O4 (M+) 362.0963,
found 362.0946.
Bis(trifluoroethyl) malonates are more acidic than the
corresponding diethyl malonates, and as a consequence,
exhibit subtle differences in their alkylation chemistry.
For example, as carbon nucleophiles, bis(trifluoroethyl)
malonates participate more readily than the corre-
sponding diethyl derivatives in Mitsunobu alkylation
reactions.19 We decided to explore their use in dienyla-
tion reactions and find that treating a mixture of the
sodium salt of bis(trifluoroethyl) methylmalonate (6)
with an equivalent of 2,4-hexadien-1-ol (7), 1.2 equiv.
of triethylborane, 0.1 equiv. of Pd(OAc)2 and a phos-
Scheme 2. The Et3B-promoted and palladium-catalyzed reac-
tion of bis(trifluoroethyl) malonate 6 with 2,4-hexadien-1-ol
(7).

J. M. Takacs et al. / Tetrahedron Letters 44 (2003) 7075–7079
7077
The ligand–metal–ligand angle (bite angle) of bidentate
ligands23 has been found to play an important role in
controlling regio- and stereoselectivity in palladium-cat-
alyzed allylations. For example, van Leeuween and
co-workers found that the percentage of (E)-isomer
obtained from allylation increased for the ligands dppe,
dppp, dppb, dppf and sixantphos, a series of chelating
ligands that span the range of bite angles from ca. 85°
to 109°.24 A similar series was examined in the dienyla-
tion reaction (i.e. Table 1, entries 2–5 and entry 6
(xantphos)), but we do not see a similar correlation
with the yield of (E,E)-8. Nonetheless, two of the
ligands screened, BIPHEP (2,2%-bis(diphenylphos-
phino)-1,1%-biphenyl)25 and BINAP (entries 7 and 8),
proved superior to the others.
The data in Table 1 are based on NMR analysis of the
crude reaction mixture. Figure 2 shows the relevant
regions of the 1H NMR spectra. Figure 2A shows peaks
due to (E,E)-8 (Ha) and its (Z)-isomers 8% (Ha%) and 8¦
(Ha¦) and is obtained on the crude product prepared
using BIPHEP. For comparison, Figure 2B shows the
less favorable mixture obtained using Ph3P (2 equiv.)
under otherwise identical conditions, and Figure 2C
shows the reaction mixture obtained under the Ph3P
conditions when the diethyl methylmalonate anion (2)
is used in place of the bis(trifluoroethyl) derivative 6.
The latter spectrum shows the regioisomeric divinyl
product 5 is present in substantial amount, while in
comparison that isomer is not observed with the
bis(trifluoroethyl) derivative 6.
Table 2 illustrates dienylation with a range of sub-
strates. In most cases the reaction was examined with
both BIPHEP and BINAP. Typically, the differences
are small. Since no new tetrahedral stereocenters are
generated in the course of the dienylation, the racemate
is employed in cases where BINAP is used. Both dienyl
alcohols and divinyl alcohol can be used as substrates
in the reaction (e.g. entries 1 and 2). In a number of
cases (e.g. entries 3, 4, and 6), products containing
trisubstituted double bonds formed with good to excel-
lent control of stereochemistry. In other examples (e.g.
entries 5 and 7) the level of control is only moderate.
Aryl substituted dienols also show good regioselectivity
in the reaction (entries 7–11).7,9
Attempted monoalkylation of the parent bis(tri-
fluoroethyl) malonate (9) gave mostly the doubly alkyl-
ated product 10. The double dienylation can be pre-
paratively useful as illustrated by the reaction of 9 with
2 equiv. of dienol 7 (Scheme 3).
Figure 2. Comparing the isomer distribution obtained under
the conditions described in Scheme 2 and Table 1, regions of
the crude 1H NMR spectra showing peaks due to (E,E)-8
(Ha), its (Z)-isomers 8% (Ha%) and 8 (Ha¦), and due to (E,E)-4
(Ha) and its stereoisomers (Ha%, Ha¦) and 5 (Hb).
used. For example, PPh3 (entry 1) gives a relatively
modest level of stereoselectivity, just 3:1 favoring the
(E,E)-8 isomer over (Z)-isomers.
Scheme 3. The double dienylation of bis(trifluoroethyl) mal-
onate 9.

7078
J. M. Takacs et al. / Tetrahedron Letters 44 (2003) 7075–7079
Table 2. A survey of Et3B-promoted, palladium-catalyzed alkylation of bis(trifluoroethyl)malonates with dienyl and divinyl
alcohols
In summary, Tamaru recently reported the Et3B-pro-
moted and palladium-catalyzed alkylation of malonates
by allyl alcohols. Inspired by their work, we examined
dienylations by dienyl and divinyl alcohols, and find
bis(trifluoroethyl) malonate derivatives and palladium
catalysts modified by BIPHEP or BINAP afford dienyl-
ated malonates with high regioselectivity and good-to-
excellent stereoselectivity.
Acknowledgements
Support from the NIH under grant GM34927 is grate-
fully acknowledged. The NMR spectrometers used for
these studies were purchased with shared instrument
grant funds (NIH SIG-1-510-RR-06307) and (NSF
CHE-0091975).

J. M. Takacs et al. / Tetrahedron Letters 44 (2003) 7075–7079
7079
References
14. Andersson, P. G.; Backvall, J. E. J. Org. Chem. 1991, 56,
5349–5353.
1. Takacs, J. M.; Vayalakkada, S.; Mehrman, S. J.; Kings-
bury, C. L. Tetrahedron Lett. 2002, 43, 8417–8420.
2. Takacs, J. M.; Jaber, M. R.; Clement, F.; Walters, C. J.
Org. Chem. 1998, 63, 6757–6760.
15. Tamaru, Y.; Horino, Y.; Araki, M.; Tanaka, S.; Kimura,
M. Tetrahedron Lett. 2000, 41, 5705–5709.
16. Horino, Y.; Naito, M.; Kimura, M.; Tanaka, S.; Tamaru,
Y. Tetrahedron Lett. 2001, 42, 3113–3116.
3. Takacs, J. M.; Jaber, M. R.; Swanson, B. J.; Mehrman,
S. J. Tetrahedron: Asymmetry 1998, 9, 4313–
4324. 4.Takacs, J. M.; Weidner, J. J. J. Org. Chem. 1994,
59, 6480–6483.
5. Shimizu, I.; Matsumoto, Y.; Nishikawa, M.; Kawahara,
T.; Satake, A.; Yamamoto, A. Chem. Lett. 1998, 983–
984.
6. Kang, S.-K.; Park, D.-C.; Jeon, J.-H.; Rho, H.-S.; Yu,
C.-M. Tetrahedron Lett. 1994, 35, 2357–2360.
7. Trost, B. M.; Urch, C. J.; Hung, M. H. Tetrahedron Lett.
1986, 27, 4949–4952.
8. Trost, B. M.; Lautens, M.; Hung, M. H.; Carmichael, C.
S. J. Am. Chem. Soc. 1984, 106, 7641–7643.
9. Trost, B. M.; Hung, M. H. J. Am. Chem. Soc. 1984, 106,
6837–6839.
17. Kimura, M.; Horino, Y.; Mukai, R.; Tanaka, S.;
Tamaru, Y. J. Am. Chem. Soc. 2001, 123, 10401–10402.
18. Kimura, M.; Futamata, M.; Shibata, K.; Tamaru, Y.
Chem. Commun. 2003, 234–235.
19. Takacs, J. M.; Xu, Z.; Jiang, X.-t.; Leonov, A. P.;
Theriot, G. C. Org. Lett. 2002, 4, 3843–3845.
20. Ogasawara, M.; Takizawa, K.-i.; Hayashi, T.
Organometallics 2002, 21, 4853–4861.
21. Ross, J.; Chen, W.; Xu, L.; Xiao, J. Organometallics
2001, 20, 138–142.
22. van Haaren, R. J.; Druijven, C. J. M.; van Strijdonck, G.
P. F.; Oevering, H.; Reek, J. N. H.; Kamer, P. C. J.; van
Leeuwen, P. W. N. M. J. Chem. Soc., Dalton Trans. 2000,
10, 1549–1554.
23. van Leeuwen, P. W. N. M.; Kamer, P. C. J.; Reek, J. N.
H.; Dierkes, P. Chem. Rev. 2000, 100, 2741–2769.
24. van Haaren, R. J.; Oevering, H.; Coussens, B. B.; van
Strijdonck, G. P. F.; Reek, J. N. H.; Kamer, P. C. J.; van
Leeuwen, P. W. N. M. Eur. J. Inorg. Chem. 1999, 1237–
1241.
10. Trost, B. M.; Bunt, R. C. J. Am. Chem. Soc. 1998, 120,
70–79.
11. Trost, B. M.; Hildbrand, S.; Dogra, K. J. Am. Chem.
Soc. 1999, 121, 10416–10417.
12. Takeuchi, R.; Tanabe, K. Angew. Chem., Int. Ed. 2000,
39, 1975–1978.
13. Nilsson, Y. I. M.; Andersson, P. G.; Backvall, J. E. J.
Am. Chem. Soc. 1993, 115, 6609–6613.
25. Ogasawara, M.; Yoshida, K.; Hayashi, T. Organometal-
lics 2000, 19, 1567–1571.