Palladium-catalyzed, asymmetric Mizoroki-Heck reaction of benzylic electrophiles using phosphoramidites as chiral ligands

Article abstract of DOI:10.1021/ja304099j

We report herein the first examples of asymmetric Mizoroki-Heck reactions using benzyl electrophiles. A new phosphoramidite was identified to be an effective chiral ligand in the palladium-catalyzed reaction. The reaction is compatible with polar functional groups and can be readily scaled up. Several cyclic olefins worked well as olefin components. Thirty-one examples are included.

Full text of DOI:10.1021/ja304099j

Communication
pubs.acs.org/JACS
Palladium-Catalyzed, Asymmetric Mizoroki−Heck Reaction of
Benzylic Electrophiles Using Phosphoramidites as Chiral Ligands
Zhigang Yang and Jianrong (Steve) Zhou*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371
S
* Supporting Information
ABSTRACT: We report herein the first examples of
asymmetric Mizoroki−Heck reactions using benzyl elec-
trophiles. A new phosphoramidite was identified to be an
effective chiral ligand in the palladium−catalyzed reaction.
The reaction is compatible with polar functional groups
and can be readily scaled up. Several cyclic olefins worked
well as olefin components. Thirty-one examples are
included.
he Mizoroki−Heck reaction usually refers to Pd−
T
catalyzed C−C bond formation between olefins and
organic (pseudo)halides. Today, it has become a powerful tool
in synthesis and is commonly used in making of natural
products, drugs, and functional materials.1 In the past two
decades, asymmetric variants have also been extensively studied
and they have been employed in synthesis of many bioactive
natural products.2
Compared to aryl and vinyl electrophiles, the benzylic type is
less extensively studied in Heck reaction.3−5 The reactions of
benzyl electrophiles are often associated with slow oxidative
addition of unactivated benzyl electrophiles6 and slow olefin
insertion into the Pd−benzyl bond.7 In addition, benzyl
electrophiles often produce a mixture of Heck products due
to double bond migration. Herein, we report the first examples
of asymmetric Heck reaction of benzylic electrophiles. In the
presence of a phosphoramidite ligand 1, the reaction of benzyl
trifluoroacetate and 2,3-dihydrofuran gave 2-benzyl-2,5-dihy-
drofuran as major product in good yield and excellent
stereoselectivity (eq 1).8
Figure 1. Performance of phosphoramidite ligands in a model Heck
reaction (eq 1). The selectivity “s” refers to ratio of two olefinic
isomers.
chirality in the binaphthyl backbone as in (Sa)-2, (b)
introduction of methyl group on the binaphthyl skeleton (3),
(c) use of o-anisyl groups in the dialkylamine moiety (4), and
(d) use of a spiro−bisindane skeleton (5).
Later, we found that partial saturation of the binaphthyl
backbone of ligand 2 provided more encouraging results
(Figure 1). Ligand 6 gave 91% ee and 91% yield. Next, we
attempted to replace one of N-α-phenylethyl groups in 6. A
smaller benzyl (7) or a larger benzhydryl (8) did not lead to
better selectivity. Eventually, incorporation of a fluorenyl group
(1) gave satisfactory results with 94% ee and high olefins
selectivity between two isomers (75:1). Ligand (Sa)-1 contains
inverted axial chirality. It not only led to slightly lower ee, but
also inversion of configuration in the product. A similar trend
was also noticed when results from ligands 2 and (Sa)-2 were
compared. Thus, the diolates of the phosphoramidites are the
main structural element of the chiral ligands that contribute to
the asymmetric induction.
Initially, we tried many chiral monophosphines and
bisphosphines as ligands in the Pd-catalzyed model reaction
(eq 1), but they all failed to give any desired product. Probably,
phosphines can directly undergo nucleophilic subtitution with
reactive benzyl halides and esters. Later, we found that Feringa
ligand 2 gave promising results, 84% ee and 65:1 selectivity
between two olefinic isomers.9 The minor isomer from the
reaction was identified to be 5-benzyl-2,3-dihydrofuran. Figure
1 shows a sample of phosphoramidites that we have examined.
Modifications of ligand 2, however, did not lead to improve-
ment. Examples of modifications include (a) inversion of axial
Some observations from condition optimization are worth
commenting. First, the amount of the olefin can be reduced to
Received: April 28, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja304099j | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
1.2 equiv and a similar result was observed. Second, the choice
of base was important. Li2CO3 proved to be the optimal to
deprotonate the palladium hydride and thus minimize olefin
isomerization in the immediate Heck product.10 Comparably
good results were also obtained when trialkylamine bases such
as triethylamine and Hunig base were used. Third, in terms of
̈
choice of solvents, many ethereal solvents worked well and gave
similarly good results (>90% conversion and 94% ee after 14 h
at 40 °C), including 2-methyltetrahydrofuran (2-MeTHF),
THF, dioxane, glyme, and diglyme. In less polar solvents such
as diethyl ether, TBME, and toluene, the turnover was lower.
DMSO and DMA inhibited the catalysis, probably due to
strong coordination of the solvents to the Pd−benzyl species.
After condition optimization, we have explored the scope of
benzylic electrophiles, using 2,3-dihydrofuran as model olefin
(Figure 2). A few observations are noteworthy. (a) The Pd/
Figure 3. Heck reaction of 2,5-dihydrofuran.
ones, are involved. This explains observed inhibition of catalysis
by strongly coordinating solvents and substrates. After olefin
insertion and β hydride elimination, the resulting Pd hydride
species should also be cationic.
We found that another electron-rich olefin, N-Boc-2,3-
pyrroline, also reacted well as olefin component (Figure 4).
Figure 4. Heck reaction of N-Boc-2,3-pyrroline.
Both electron-donating methoxy and electron-withdrawing
ester groups can be present on the benzyl electrophiles. The
Heck reaction of p-methoxybenzyl trifluoroacetate quickly
provided a key intermediate in asymmetric synthesis of
(+)-anisomycin, an antiprotozoal and antifungal antibiotic.11
In addition, this method can produce anisomycin analogues,
some of which showed antitumor activity.12
In reactions of cyclopentene, the desired products were also
obtained in high stereoselectivity and little double bond
migration was detected in the immediate Heck product (Figure
5). The reactions of cycloheptene, however, only led to ca. 60%
ee. Cyclohexene did not react, because in the twisted half-chair
conformation axial hydrogens hinder binding of either face of
the olefin to Pd.
Figure 2. Heck reaction of 2,3-dihydrofuran.
ligand 1 catalyst can tolerate sensitive groups such as aldehyde
and nitro groups. (b) Both electron-donating and electron-
withdrawing groups can be present on the aryl ring. (c) Ortho-
substituents can also be present. (d) When an o-vinyl group
was present in the benzyl ester, no insertion of the Pd−alkyl
intermediate into the vinyl group was observed. (e) Some
heteroaryl derivatives of thiophene and furan also worked well.
Pyridine-containing substrates inhibited the catalysis, due to
strong binding of pyridine nitrogen to the palladium center. (f)
1-Naphthylmethyl trifluoroacetate reacted much slower than
the benzyl ester. (g) Secondary electrophiles such as α-
phenylethyl and benzhydryl trifluoroacetates did not react. (h)
Benzyl electrophiles carrying other leaving groups, such as Br,
Cl, OTs, OMs, OCO2Et, OBz, and even OAc, did not react. In
all cases, <5% conversion was observed at 40 °C.
We have scaled up an asymmetric Heck reaction to 10 mmol
scale and the catalyst loading can be reduced to 2 mol % (eq 2).
The desired product was obtained in good yield and 94% ee.
We have examined other olefins in the new Heck reaction.
To our surprise, electron-deficient 2,5-dihydrofuran provided 2-
benzyl-2,5−dihydrofurans as major products (Figure 3).
Analysis of the reaction mixture at partial conversion revealed
that a fraction of 2,5-dihydrofuran isomerized to 2,3-
dihydrofuran. The latter is an electron-rich olefin and is
responsible for the formation of all isolated Heck products. In
classic Heck reactions involving cationic Pd−aryl species,
electron-rich olefins proved to be more reactive than electron-
deficient olefins. Thus, this observation suggested that in our
Heck reaction, cationic Pd−benzyl species, instead of neutral
Figure 5. Heck reaction of cyclopentene.
B
dx.doi.org/10.1021/ja304099j | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
J. Am. Chem. Soc. 2011, 133, 19020. (g) Higuchi, K.; Sawada, K.;
Nambu, H.; Shogaki, T.; Kita, Y. Org. Lett. 2003, 5, 3703.
(4) Ru-catalyzed benzylation of olefins using aliphatic and benzylic
alcohols: Lee, D.-H.; Kwon, K.-H.; Yi, C. S. Science 2011, 333, 1613.
(5) Examples of Heck reaction of alkyl electrophiles: (a) Firmansjah,
L.; Fu, G. C. J. Am. Chem. Soc. 2007, 129, 11340. (b) Rauf, W.; Brown,
J. M. Angew. Chem., Int. Ed. 2008, 47, 4228. (c) Bloome, K. S.;
McMahen, R. L.; Alexanian, E. J. J. Am. Chem. Soc. 2011, 133, 20146.
(d) Lebedev, S. A.; Lopatina, V. S.; Petrov, E. S.; Beletskaya, I. P. J.
Organomet. Chem. 1988, 344, 253. (e) Affo, W.; Ohmiya, H.; Fujioka,
T.; Ikeda, Y.; Nakamura, T.; Yorimitsu, H.; Oshima, K.; Imamura, Y.;
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M. E.; Kreis, L. M.; Lauber, A.; Carreira, E. M. Angew. Chem., Int. Ed.
2011, 50, 11125.
(6) Narahashi, H.; Yamamoto, A.; Shimizu, I. Chem. Lett. 2004, 33,
348.
(7) Narahashi, H.; Shimizu, I.; Yamamoto, A. J. Organomet. Chem.
2008, 693, 283.
(8) Oxidative addition of benzyl trifluoroacetates to Pd(0)
complexes: Nagayama, K.; Shimizu, I.; Yamamoto, A. Bull. Chem.
Soc. Jpn. 1999, 72, 799.
(9) Reviews: (a) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346.
(b) Teichert, J. F.; Feringa, B. L. Angew. Chem., Int. Ed. 2010, 49, 2486.
(c) Jerphagnon, T.; Pizzuti, M. G.; Minnaard, A. J.; Feringa, B. L.
Chem. Soc. Rev. 2009, 38, 1039.
The absolute configuration of the product was assigned to be
(S), by comparison with reported values of optical rotation.13
This Heck product can be quickly transformed to adenophostin
A analogues, which can mimic inositol 1,4,5-trisphosphate to
stimulate Ca2+ release.14
In summary, we have realized the first examples of
asymmetric Heck reaction of benzylic electrophiles. Several
cyclic olefins can react efficiently as olefin components. The
ee’s of isolated Heck products were usually >90% and double
bond migration in the immediate Heck products was kept at
very low levels. The method is compatible with polar groups
such as aldehyde, ester, and nitro groups. We are currently
conducting mechanistic studies to understand the origin of the
stereoselectivity. Exploration of asymmetric Heck reactions
using other unconventional electrophiles is ongoing.
ASSOCIATED CONTENT
* Supporting Information
(10) A recent example of Pd-hydride catalyzed isomerization of
olefins: Gauthier, D.; Lindhardt, A. T.; Olsen, E. P. K.; Overgaard, J.;
Skrydstrup, T. J. Am. Chem. Soc. 2010, 132, 7998.
(11) (a) Detz, R. J.; Abiri, Z.; le Griel, R.; Hiemstra, H.; van
Maarseveen, J. H. Chem.Eur. J. 2011, 17, 5921. (b) Jegham, S.; Das,
B. C. Tetrahedron Lett. 1988, 29, 4419. (c) Schumacher, D. P.; Hall, S.
S. J. Am. Chem. Soc. 1982, 104, 6076.
■
S
Experimental procedures for synthesis of benzylic esters and
chiral phosphoramidite ligands and asymmetric Heck reactions;
characterization of new ligands and Heck products (NMR, MS,
and chiral HPLC analysis). This material is available free of
charge via the Internet at http://pubs.acs.org.
(12) Schwardt, O.; Veith, U.; Gaspard, C.; Jager, V. Synthesis 1999,
̈
1473.
AUTHOR INFORMATION
Corresponding Author
jrzhou@ntu.edu.sg
(13) (a) Wang, Y.; Zheng, K.; Hong, R. J. Am. Chem. Soc. 2012, 134,
4096. (b) Boisvert, L.; Beaumier, F.; Spino, C. Can. J. Chem. 2006, 84,
1290.
(14) Mochizuki, T.; Kondo, Y.; Abe, H.; Tovey, S. C.; Dedos, S. G.;
Taylor, C. W.; Paul, M.; Potter, B. V. L; Matsuda, A.; Shuto, S. J. Med.
Chem. 2006, 49, 5750.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Singapore National Research Foundation (NRF-
RF2008-10) and Nanyang Technological University for
financial support. We thank Johnson Matthey for a gift of
palladium salts.
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dx.doi.org/10.1021/ja304099j | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX