Highly versatile Pd-thioether-phosphite catalytic systems for asymmetric allylic alkylation, amination, and etherification reactions

Article abstract of DOI:10.1021/ol500758y

A Pd-furanoside thioether-phosphite catalytic system that can create new C-C, C-N, and C-O bonds in several substrate types using a wide range of nucleophiles in high yields and enantioselectivities has been identified. Of particular note are the excellent enantioselectivities obtained in the etherification of linear and cyclic substrates. The potential application of the new Pd-thioether-phosphite catalytic systems was also demonstrated by the synthesis of the chiral carbo- and heterocycles.

Full text of DOI:10.1021/ol500758y

Letter
pubs.acs.org/OrgLett
Highly Versatile Pd−Thioether−Phosphite Catalytic Systems for
Asymmetric Allylic Alkylation, Amination, and Etherification
Reactions
Merce Coll, Oscar Pamies,* and Montserrat Dieguez*
̀
̀
́
Departament de Química Física i Inorgan
̀
ica, Universitat Rovira i Virgili, C/Marcel·lí Domingo, s/n, 43007 Tarragona, Spain
S
* Supporting Information
ABSTRACT: A Pd−furanoside thioether−phosphite catalytic
system that can create new C−C, C−N, and C−O bonds in
several substrate types using a wide range of nucleophiles in
high yields and enantioselectivities has been identified. Of
particular note are the excellent enantioselectivities obtained in
the etherification of linear and cyclic substrates. The potential
application of the new Pd−thioether−phosphite catalytic
systems was also demonstrated by the synthesis of the chiral
carbo- and heterocycles.
n recent decades, the growing demand for enantiomerically
pure compounds for preparing technologically interesting
capacity of the phosphite moiety increases activities, and the
adaptability of phosphite groups enables the catalyst to
appropriately tune its chiral pocket to accommodate substrates
with different steric requirements.4 Nevertheless, the success of
phosphite-containing ligands is restricted to the allylic
alkylation using dimethyl malonate as a nucleophile.4 More
research is needed to expand the range of nucleophiles with the
aim to synthesize more complex organic compounds. In this
respect, the use of functionalized malonates,3c β-diketones,3c
and alkyl alcohols5 have hardly been reported. In this context, a
small number of catalysts have been efficiently used in the
allylic substitution of a broad range of substrates. Substantial
improvements are therefore needed in terms of enantioselec-
tivity, chemical yield, and substrate versatility if they are to be of
practical interest.
I
and/or biologically active compounds has encouraged the quest
for productive enantioselective catalytic reactions. In particular,
transition-metal asymmetric catalysis has become one of the
most attractive approaches because of its high selectivity,
activity, and sustainability.1 In this approach, the search for the
appropriate enantiopure ligand is crucial if the highest levels of
reactivity and selectivity are to be attained.1 One of the simplest
ways of achieving chiral ligands is to derivatize or transform
natural chiral products. In this respect, carbohydrates are highly
functional compounds with several stereogenic centers. This
modular nature offers a wide variety of opportunities for the
derivatization and tailoring of synthetic tools in the search for
the best ligand for each particular reaction.2
Most heterodonor ligands developed for this process are
phosphorus−oxazoline compounds. More recently, the search
has moved to the design of heterodonor P−X compounds
containing more robust X-groups (i.e., pyridine, thioether,
amine, etc.). P,S-ligands have scarcely been evaluated, although
some have proved to be potentially useful in this reaction.6
Notably, Evans and co-workers reported the successful
application of phosphinite−thioether ligands derived from
chiral β-hydroxysulfoxides. These ligands were effective in the
allylic substitution of model substrates S1 (rac-1,3-diphenyl-3-
acetoxyprop-1-ene) and S2 (rac-3-acetoxycyclo-hexene) but
had low enantioselectivity for such unhindered linear substrates
such as S3 (rac-1,3-dimethyl-3-acetoxyprop-1-ene). They also
required a low temperature (−20 °C) to achieve high ee. The
minor role of thioether-based ligands in this process can be
found in the formation of mixtures of diastereomeric thioether
complexes (because the S-atom becomes a stereogenic center
The Pd-catalyzed allylic substitution reaction is one of the
most powerful and versatile tools for constructing chiral C−C
and C−X bonds.3 Most of the successful ligands developed for
this process use either C2-symmetrical scaffolds, to restrict the
number of diastereomeric transition states, or the ability of the
ligand to direct the approach to one of the allylic terminal
atoms, by means of either a secondary ligand−nucleophile
interaction or an electronic differentiation.3 In this latter
strategy, the use of heterodonor ligands allows the ability to
electronically distinguish between the two allylic terminal
carbons due to the distinct trans influences of the donor
atoms.3 All these strategies have led to the discovery of several
privileged ligands that provide high levels of enantioselectivity
(i.e., DACH-phenyl Trost ligand, PHOX, etc.). However,
asymmetric induction is highly dependent on the steric
demands of the substrate. Thus, most of the privileged catalytic
systems only afford high enantioselectivities for either hindered
or unhindered substrates. Recently the use of phosphite
containing ligands has been found to have an extremely
positive effect on catalytic performance.4 The π-acceptor
Received: February 4, 2014
Published: March 24, 2014
© 2014 American Chemical Society
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Letter
when coordinated to the metal) and the difficulty in controlling
their interconversion in solution.7 Nevertheless, if the ligand
scaffold can control the S-coordination, this feature may be
extremely beneficial because then the chirality moves closer to
the metal. In this respect, we recently found that the furanoside
backbone in thioether−phosphite ligands L1−L5 can control
the thioether coordination to iridium.8
In our search for more versatile and more stable Pd-catalysts,
we herein report the successful application of furanoside
phosphite−thioether ligands L1−L5 (Figure 1) in the Pd-allylic
fewer successful catalyst systems for S2. We were pleased to
identify Pd−L3c as one of the very few catalytic systems able to
provide excellent enantiocontrol for both types of hindered and
unhindered substrates (ee’s up to >99% and 96%, respectively)
at room temperature. These results compare favorably with
those reported in the literature.3,4
We then went on to study the allylic substitution of S1 using
a wide range of C, N, and O nucleophiles, among which are the
more challenging functionalized malonates, β-diketones, and
alkyl alcohols (Table 2). Several malonates, including those that
Table 2. Allylic Substitution of S1 with C-, N-, and O-
a
Nucleophiles Using the Pd−L3c Catalytic System
Figure 1. Furanoside thioether−phosphite ligands L1−L5a−c.
substitution of both hindered and unhindered substrates with a
large number of nucleophiles, including synthetically useful
functionalized malonates, β-diketones, and alkyl alcohols. These
ligands possess the benefits of the mixed donor groups, the
higher stability of thioether groups, and the additional control
given by the adaptability of the chiral cavity due to the biaryl-P
group. They are also easily prepared in a few steps from cheap
D-(+)-xylose. We also demonstrate the potential application of
the new Pd−thioether−phosphite catalytic systems by the
practical synthesis of chiral carbo- and heterocycles.
Bearing in mind that the stereochemical outcome of this
process is highly dependent on the substrate, to make the initial
evaluation of thioether−phosphite ligands L1−L5a−c, we
chose the allylic alkylation of two model substrates with
different steric properties: (a) hindered S1 and (b) unhindered
S2, using dimethyl malonate (Table 1). Due to the presence of
less bulky anti substituents, the enantioselectivity for cyclic
substrate S2 is more difficult to control. There are, therefore,
Table 1. Pd-Catalyzed Allylic Alkylation of Substrates S1−S2
with Dimethyl Malonate As Nucleophile Using Ligands L1−
a
Reactions were run at 23 °C with [PdCl(η3-C3H5)]2 (0.5 mol %),
b
a
DCM as solvent, ligand (1 mol %), BSA (3 equiv), and KOAc. Full
conversions were achieved after 12 h. Enantiomeric excess
L5a−c
c
d
determined by chiral HPLC or GC. Reactions carried out using 2
mol % [PdCl(η3-C3H5)]2, 4 mol % ligand, and Cs2CO3 (3 equiv). Full
conversions were achieved in all cases except for entry 11 (74%
conversion).
were α-substituted, reacted cleanly with S1 to afford products
3−6 in high yields and enantioselectivities (ranging from 92%
to 99% ee). The use of acetylacetone as a nucleophile also
provided high enantioselectivities (ee’s up to 99%; Table 2,
entry 5). Enantiocontrol was also excellent when N-
nucleophiles were used (compound 8; 99% ee). Even more
interesting are the near-perfect enantioselectivities achieved in
the etherification of S1 using several aliphatic alcohols
(compounds 9−13; ee’s up to >99%). These results surpass
the best results achieved using Pd-(S,R)-FerroNPS5i and Pd-
CycloN2P2-Phos5j catalytic systems, specifically designed for
this purpose.9
a
Reactions were run at 23 °C with [PdCl(η3-C3H5)]2 (0.5 mol %),
b
DCM as solvent, ligand (1 mol %), BSA (3 equiv), and KOAc. Full
c
We also tested Pd−L3c in the allylic substitution of cyclic
substrate S2 using a range of C-, N-, and O-nuleophiles (Table
conversions were achieved after 3 h. Determined by chiral HPLC.
d
e
After 6 h. Determined by chiral GC.
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Letter
3). In all cases, enantioselectivities were as high as those
obtained using dimethyl malonate (ee’s up to 98%), except
enantioselectivities can also be obtained for the more
demanding substrates S3 and S4 (ee’s up to 96% for S3 and
>95% for S4) which usually react with lower yields and
enantioselectivities than the corresponding model S1 substrate.
The good performance also extended to the allylic substitution
of other cyclic substrates with different ring sizes (rac-3-
acetoxycyclopentene S5 and rac-3-acetoxycycloheptene S6;
Figure 2). It should be noted that the enantiocontrol was
excellent in both cases, but especially in the allylic substitution
of rac-3-acetoxycyclopentene (compounds 23 and 24), which is
usually substituted less enantioselectively than the six-
membered cyclic substrate S2.
Table 3. Allylic Substitution of S2 with C-, N-, and O-
a
Nucleophiles Using the Pd−L3c Catalytic System
The allylic substitution of functionalized nucleophiles can be
used in a large variety of synthetic applications, such as the
preparation of chiral carbocycles (R)-27 and (−)-28 by simple
tandem reactions, involving the allylic alkylation of the
appropriate substrate (S1 and S2) with dimethyl allylmalonate,
and a subsequent ring-closing metathesis (Scheme 1a).10a In
Scheme 1. Representative Synthetic Applications of
Sequential Processes Involving Allylic Substitution of
Functionalized Nucleophiles/Cyclation Reactions
a
Reactions were run at 23 °C with [PdCl(η3-C3H5)]2 (0.5 mol %),
b
DCM as solvent, ligand (1 mol %), BSA (3 equiv), and KOAc. Full
conversions were achieved after 12 h. Enantiomeric excess
c
d
determined by chiral HPLC or GC. Reaction carried out using 2
mol %[PdCl(η3-C3H5)]2, 4 mol % ligand, and Cs2CO3 (3 equiv).
when dimethyl methylmalonate was used as the nucleophile,
which led to a slightly lower enantioselectivity (compound 14;
87% ee). Excellent enantioselectivities were therefore obtained
using allyl- and propargyl-substituted malonates (compounds
15 and 16), acetylacetone (compound 17), and benzylamine
(compound 18). We could also reach high enantioselectivities
and yields in the etherification of S2 (entry 6). Pd−L3c is the
first catalytic system that can etherificate both substrate types
linear S1 (Table 2, entries 7−11) and cyclic S2 with high ee’s9
and, therefore, could be used for the synthesis of compounds
with ether groups next to a chiral carbon. These compounds are
key intermediates for preparing a wide range of biologically
active compounds.
The scope of these new catalytic systems was further studied
by using other linear substrates with different steric require-
ments (rac-1,3-dimethyl-3-acetoxyprop-1-ene S3 and rac-(E)-
ethyl-2,5-dimethyl-3-hex-4-enylcarbonate S4) than those of
substrate S1 (Figure 2, compounds 20−22). We were pleased
to see that if ligands are appropriately tuned, high yields and
both cases, the corresponding carbocycles 27 and 28 were
obtained in high yields with no loss in enantiomeric excess.
Similarly, the heterocycle (R)-29 is achieved by sequential
allylic etherification of S1 with allyl alcohol and a ring-closing
metathesis reaction (Scheme 1b). Another example is the
cycloisomerization of the 1,6-enyne 16, formed from the allylic
alkylation of S2 with dimethyl propargylmalonate, following the
methodology described by Uozumi et al.10b to yield the
carbobicycle hydrindane (3aR,7aS)-30 (Scheme 1c).
In summary, a series of furanoside thioether−phosphite
ligands L1−L5a−c have therefore been used with success in the
Pd-allylic substitution of substrates with different steric
requirements by applying a large variety of nucleophiles.
These ligands, which are prepared from inexpensive D-xylose,
also include the benefits of the heterodonors, the higher
stability of thioether groups, and the additional control given by
the adaptability of the chiral cavity due to the biaryl-P group. By
selecting the ligand components we have been able to identify
catalytic systems that can create new C−C, C−N, and C−O
bonds, in several substrate types (hindered and unhindered)
using a wide range of nucleophiles in high yields and
enantioselectivities (ee’s up to >99%). Of particular note are
the excellent enantioselectivities obtained in the etherification
of linear and cyclic substrates, which represent the first example
of a successful etherification of both substrate types. So, the
exceptional ligand family presented here competes very well
with other ligand sets that gave successful selectivities in the
Figure 2. Pd-allylic substitution of S3−S6. Full conversions were
achieved. 0.5 mol % [PdCl(η3-C3H5)]2, CH2Cl2 as solvent, ligand (1
mol %), rt, 18 h.
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Synlett 2004, 1113. For alkyl alcohols, see: (h) Iourtchenko, A.;
Sinou, D. J. Mol. Catal. A 1997, 122, 91. (i) Lam, F. L.; Au Yeung, T.
T.-L.; Kwong, F. Y.; Zhou, Z.; Wong, K. Y.; Chan, A. S. C. Angew.
Chem., Int. Ed. 2008, 47, 1280. (j) Ye, F.; Zheng, Z.-J.; Li, L.; Yang, K.-
F.; Xia, C. G.; Xu, L.-W. Chem.Eur. J. 2013, 19, 15452.
̀
(k) Caldentey, X.; Pericas, M. A. J. Org. Chem. 2010, 75, 2628.
(l) Liu, Z.; Du, H. Org. Lett. 2010, 12, 3054. (m) Kato, M.; Nakamura,
T.; Ogata, K.; Fukuzawa, S. Eur. J. Org. Chem. 2009, 5232. For a
recent report based on Ir-catalysts, see: (n) Ueno, S.; Hartwig, J. F.
Angew. Chem., Int. Ed. 2008, 47, 1928.
(6) Few phosphinite/phosphine−thioether ligands have been
successfully applied, and those that do are limited in substrate and
nucleophile scope (usually S1 and dimethylmalonate as the
nucleophile). See: (a) Evans, D. A.; Campos, K. R.; Tedrow, J. S.;
́
Michael, F. E.; Gagne, M. R. J. Am. Chem. Soc. 2000, 122, 7905 (up to
98%, 90%, and 65% ee at −20 °C for S1, S2, and S3, respectively).
(b) Nakano, H.; Okuyama, Y.; Hongo, H. Tetrahedron Lett. 2000, 41,
allylic substitution of substrates using a large variety of C-, O-,
and N-nucleophiles, including the much less investigated α-
substituted malonates and alkyl alcohols. Furthermore, the
potential application of the new Pd−thioether−phosphite
catalytic systems has been proven by the stereoselective
preparation of carbo- and heterocycles by simple tandem
reactions, involving allylic alkylation/ring-closing metathesis or
allylic alkylation/cycloisomerization of 1,6-enyne reactions,
with no loss in enantiomeric excess. Thus, for the first time,
the capacity of an easily accessible and very modular sugar-
based thioether-phosphite ligand library in the successful
enantioselective Pd-allylic substitution of substrates with a
large variety of nucleophiles has been revealed.
ASSOCIATED CONTENT
* Supporting Information
■
S
4615 (up to 94% ee at −30 °C for S1). (c) García Mancheno, O.;
̃
́ ́
Priego, J.; Cabrera, S.; Gomez Arrayas, R.; Llamas, T.; Carretero, J. C.
Experimental details and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. 2003, 68, 3679 (up to 97% ee at −20 °C for S1).
(d) Enders, D.; Peters, R.; Runsink, J.; Bats, J. W. Org. Lett. 1999, 1,
́
1863 (up to 97% ee at −20 °C for S1). (e) Guimet, E.; Dieguez, M.;
AUTHOR INFORMATION
Corresponding Authors
■
Ruiz, A.; Claver, C. Tetrahedron: Asymmetry 2005, 16, 959 (up to 93%
ee at 0 °C for S1). (f) Reference 5k (up to 96% ee at rt for S1).
(7) Masdeu-Bulto,
Chem. Rev. 2003, 242, 159.
(8) Coll, M.; Pamies, O.; Dieg
9215.
́
A. M.; Dieg
́
uez, M.; Martin, E.; Gom
́
ez, M. Coord.
*E-mail: montserrat.dieguez@urv.cat.
*E-mail: oscar.pamies@urv.cat.
Notes
̀
́
uez, M. Chem. Commun. 2011, 47,
(9) The etherification reactions using alkyl alcohols are restricted to
S1-type substrates with a maximum ee of 96%. There is only one
report using cyclic substrate S2 (ref 5h).
(10) (a) Dugal-Tessier, J.; Dake, G. R.; Gates, D. P. Org. Lett. 2010,
12, 4667. (b) Nakai, Y.; Uozumi, Y. Org. Lett. 2005, 7, 291.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We would like to thank the Spanish Government for providing
Grant CTQ2010-15835, the Catalan Government for Grant
2009SGR116, and the ICREA Foundation for providing M.
́ ̀
Dieguez and O. Pamies with financial support through the
ICREA Academia awards.
REFERENCES
■
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