Pd/BIPHEPHOS is an Efficient Catalyst for the Pd-Catalyzed S-Allylation of Thiols with High n-Selectivity

Article abstract of DOI:10.1002/adsc.201901250

The Pd-catalyzed S-allylation of thiols with stable allylcarbonate and allylacetate reagents offers several advantages over established reactions for the formation of thioethers. We could demonstrate that Pd/BIPHEPHOS is a catalyst system which allows the transition metal-catalyzed S-allylation of thiols with excellent n-regioselectivity. Mechanistic studies showed that this reaction is reversible under the applied reaction conditions. The excellent functional group tolerance of this transformation was demonstrated with a broad variety of thiol nucleophiles (18 examples) and allyl substrates (9 examples), and could even be applied for the late-stage diversification of cephalosporins, which might find application in the synthesis of new antibiotics. (Figure presented.).

Full text of DOI:10.1002/adsc.201901250

Title: Pd/BIPHEPHOS is an Efficient Catalyst for the Pd-Catalyzed S-
Allylation of Thiols with High n-Selectivity
Authors: Rolf Breinbauer, Thomas Schlatzer, Hilmar Schröder, Melanie
Trobe, Christian Lembacher-Fadum, Simon Stangl, Christoph
Schlögl, and Hansjörg Weber
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901250
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10.1002/adsc.201901250
Advanced Synthesis & Catalysis
VERY IMPORTANT PUBLICATION
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Pd/BIPHEPHOS is an Efficient Catalyst for the Pd-Catalyzed
S-Allylation of Thiols with High n-Selectivity
Thomas Schlatzer,a,‡ Hilmar Schröder,a,‡ Melanie Trobe,a Christian Lembacher-Fadum,a
Simon Stangl,a Christoph Schlögl,a Hansjörg Weber,a and Rolf Breinbauera,*
a
Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, A-8010 Graz, Austria
phone: (+43)-316-873-32400
fax: (+43)-316-873-32402
e-mail: breinbauer@tugraz.at
‡
These authors contributed equally.
Received: ((will be filled in by the editorial staff))
Dedicated to Professor Eric N. Jacobsen on the occasion of his 60th birthday.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. The Pd-catalyzed S-allylation of thiols with stable
allylcarbonate and allylacetate reagents offers several
advantages over established reactions for the formation of
thioethers. We could demonstrate that Pd/BIPHEPHOS is a
catalyst system which allows the transition metal-catalyzed S-
allylation of thiols with excellent n-regioselectivity.
Mechanistic studies showed that this reaction is reversible
under the applied reaction conditions. The excellent
functional group tolerance of this transformation was
demonstrated with a broad variety of thiol nucleophiles (18
examples) and allyl substrates (9 examples), and could even
be applied for the late-stage diversification of cephalosporins,
which might find application in the synthesis of new
antibiotics.
Keywords: crossover; isofunctional reaction;
isomerization; thioether; Tsuji-Trost allylation
allylation can be associated with two intrinsic
difficulties: a) S-nucleophiles can also function as
efficient ligands for Pd and poison the catalyst, and b)
thiols are easily oxidized and the reactions have to be
carried out under exclusion of air. We thus set out to
identify a suitable catalyst system, which would enable
the efficient S-allylation of thiol nucleophiles. As we
did not only envision its application for the synthesis
of small molecules but also intended its use for the
post-translational modification of Cys-containing
peptides and proteins,[9] we were aiming for a catalyst
which would favour the unbranched (“linear”) n-
isomer.
Introduction
Transition-metal catalyzed allylation reactions have
received considerable attention over the last few
decades, especially for the alkylation of C-, N- and O-
nucleophiles. In particular, the Pd-catalyzed allylation
(“Tsuji-Trost-allylation”) has become a precious tool
in organic synthesis,[1] which has shown its value even
in the total synthesis of natural products[2] and
pharmaceuticals.[3] Moreover, highly enantioselective
variants using chiral ligands allow full control of the
absolute stereoconfiguration of the synthesized
products.[4] Other metals such as Ir,[5] Fe,[6] and Rh[7]
have been demonstrated to serve as effective catalysts
for
this
transformation,
showing
different
Results and Discussion
regioselectivity. In contrast to the widespread use of
this transformation in organic synthesis the transition-
metal catalyzed allylation of S-nucleophiles has been
rarely studied, and only a few examples have been
reported.[8] The limited use of Pd-catalyzed S-
At the outset of our studies on Pd-catalyzed S-
allylation we performed an extensive reaction
optimization on a model reaction with 1-octanethiol
(1a) and methyl prenyl carbonate (2a) as
1
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10.1002/adsc.201901250
Advanced Synthesis & Catalysis
Table 1. Reaction optimization of the Pd-catalyzed S-allylation.
representative starting materials (Table 1). Initially we
screened 50 bidentate, phosphorous-based ligands
(Table S1) in combination with Pd(dba)2 as catalyst
precursor and monitored both conversion and
regioselectivity (n/i ratio) by GC-MS. In particular we
were interested if we could observe any trends
regarding the influence of the natural bite angle and
the electronic properties of the ligands on the reaction
outcome.[10] Phosphine ligands with large bite angles
(Table 1, entries 1-3), that are frequently used in Tsuji-
Trost allylations, did not lead to any conversion of 1a.
In contrast, bidentate phosphines with mid-sized bite
angles (Table 1, entries 4-8) exhibited significantly
higher conversions. Within this group, electron rich
alkyl phosphines (Table 1, entries 5 & 8) were inferior
to their corresponding aryl phosphines, indicating that
electron poor ligands could be beneficial for this
reaction. Moreover, structurally more rigid ligands
(Table 1, entries 6-8) were found to be superior. The
dppf ligand (Table 1, entry 7) meets these criteria and
was found to give full conversion of 1a and acceptable
regioselectivity (n/i = 92/8). Based on this parent
ligand, we tested members of the Josiphos,
Mandyphos and Walphos ligand families (Table 1,
entries 9-11), which unfortunately did not result in any
increased regioselectivity. To our delight, we were
instead able to identify the electron-deficient bidentate
phosphite BIPHEPHOS (Table 1, entry 12) as our
ligand of choice, affording the thioether 3aa with full
conversion and complete n-selectivity.
We next conducted optimization studies focusing
on the amount of catalyst as well as the reaction
temperature. The most suitable operating window of
our catalyst system was determined to be 2.0 mol%
PdL and 60 °C (Table S2 and S3). Decreased catalyst
concentration or temperature (Table 1, entries 13 &
14) led to lower regioselectivity at full conversion.
Finally, we were interested to see if other solvents
than acetonitrile can be used in Pd-catalyzed S-
allylation. Indeed, we could identify several solvents
that are suitable alternatives without affecting
conversion or selectivity of the reaction,
encompassing polar aprotic substitutes such as
propylene carbonate, NMP, DMSO, DME and EtOAc
(Table 1, entries 18-22) but also rather apolar CHCl3
or toluene (Table 1, entries 17 & 25). Moreover,
reactions in polar protic solvents such as MeOH (Table
1, entry 15) and even in fairly acidic CF3CH2OH and
HOAc (Table 1, entries 16 & 24) proved to be
successful. Importantly, aqueous solvent mixtures
(Table 1, entry 23) were also tolerated by our catalyst
system.[9] It is noteworthy that these solvents cover an
extremely broad range of polarities, which should
enable an easy adjustment of our methodology to any
thiol substrate addressing solubility issues. In total 31
solvents were considered in this screening (Table S4).
With our optimized conditions (Table 1, entry 12)
in hand we explored the scope of this system using
more elaborated thiol substrates and allylation
reagents. In order to assess the effect of the
nucleophilicity on the reaction yields, we subjected a
2
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10.1002/adsc.201901250
Advanced Synthesis & Catalysis
Scheme 1. Thiol and reagent scope of the Pd-catalyzed S-allylation.
series of substituted aromatic thiols (Scheme 1, entries
3ba-3ka) to S-allylation. To our delight, the reaction
yields were only slightly affected by electron-donating
converted to the corresponding thioester 3ra although
in moderate yield.
In addition, we explored the scope of the allylation
(Me, OMe) or -withdrawing groups (Cl, F, CF3, CO2H), reagents, which are rapidly and easily accessible from
and were consistently high (in most cases >80 %).
Sterically hindered ortho-disubstituted 3da, as well as
substrates bearing potentially interfering nucleophilic
groups were fully tolerated and selectively afforded
the S-allylated products (3ea, 3ga, 3ka) in high yield.
Encouraged by these results, we tested heterocyclic
thiols (Scheme 1, entries 3la-3oa) that could
potentially act as potent ligands for palladium and
thereby hamper the catalytic process. Fortunately, also
these substrates were smoothly converted to their
corresponding thioethers even at a lower reaction
temperature of 35 °C, which was crucial to avoid
thermal S→N allyl migration.[11] Cysteine derivatives
were another class of non-aromatic thiols we were
particularly interested in, since these represent highly
functionalized molecules that can occur in their S-
prenylated form in peptides and proteins in nature.[12]
We thus chose protected cysteine and glutathione as
model substrates, which could be readily prenylated
(3pa) and farnesylated (3qc) in very good yields
(>80 %), demonstrating the versatility of this catalytic
system. Even fairly acidic thiobenzoic acid was
the corresponding allylic alcohols in a single step and
very high yields (see Supporting Information). For this
Scheme 2. Late-stage diversification of antibiotic cefalotin
via Pd-catalyzed activation of the allylic acetate moiety
under conservation (A) or loss (B) of the carboxyl group.
3
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10.1002/adsc.201901250
Advanced Synthesis & Catalysis
purpose, we subjected various acyclic and more rigid
cyclic allylic carbonates to Pd-catalyzed S-allylation
of 1-octanethiol (1a) yielding the desired thioethers
(Scheme 1, entries 3aa-3ah) in excellent yields (in
most cases >90 %). For all employed reagents only the
allylic carbonate moiety was activated by the Pd
catalyst, while other double bonds remained pristine
(i.e. no double bond migration or isomerization was
observed).
Importantly, all thioethers of Scheme 1 were
isolated in form of their unbranched n-isomer as
confirmed by 1H-NMR spectroscopy, highlighting the
extraordinary regioselectivity of the Pd/BIPHEPHOS
system.
As a next step we were eager to see if this
methodology can be applied to the challenging
environment of a complex natural product. We noticed
that the important class of cephalosporin antibiotics
contains an allylic acetate moiety, which could be
tested as an electrophile in the Pd-catalyzed S-
allylation. This would be of immediate relevance as
several thioether derivatives at this position are in
clinical use as antibiotics.[13] For this purpose, we
chose cefalotin, an antibiotic agent, as a representative
substrate for late-stage diversification using several
organic thiols (Scheme 2). The corresponding
thioethers 5 and 6 were readily isolated after
preparative HPLC purification in satisfying yields. To
the best of our knowledge, this represents the first
Tsuji-Trost allylation of a cephalosporin at C3’,
directly starting from a native substrate. Previous
literature precedents[14] either rely on strong Lewis
acids (e.g. BF3) and/or require protecting groups.
Interestingly, if 1-octanethiol is used as reagent, the
resulting product tends to decarboxylate especially at
elevated temperature to form 7 in 39 % yield.
Finally, we sought to investigate the mechanism of
the Pd-catalyzed S-allylation. First experiments
suggested that the unbranched thioether is formed
selectively, irrespective of the regiochemistry of the
allylic carbonate as indicated by GC-MS reaction
monitoring (Scheme 3A). This corroborates a common
π-allylic intermediate upon Pd-mediated reagent
activation, which is then attacked by the thiol.
However, if no thiol was present, the branched allylic
carbonate 2f* was quantitatively isomerized to the
unbranched derivative 2f according to 1H-NMR
spectroscopy (Scheme 3B).
In a further experiment we observed that 1a was
completely consumed after only 15 min but only in
moderate regioselectivity (n/i = 87/13). The n/i ratio,
however, was found to constantly improve over time
to afford the pure n-thioether 3aa after 5 h (Scheme 3C,
Table S5) although complete conversion was already
reached.[9] This clearly indicates that the S-allylation is
reversible under Pd-catalyzed conditions. Importantly,
the isomerization takes place only in the presence of
the Pd catalyst, whereas an intermolecular SN2’ attack
by thiolate can be excluded (Scheme 3D). Further
evidence for the reversibility of this reaction is given
by crossover experiments that result in scrambling of
the allyl moieties (Scheme 3E,F), indicating that
Scheme 3. Mechanistic studies of the Pd-catalyzed S-
allylation.
ligand exchange at Pd is possible. The outcome of this
successful crossover experiment with thioethers might
also imply an opportunity for the scale-up of this
reaction as an isofunctional metathesis reaction,[15] in
which thioether substrates could be a more convenient
form of the reagent as the notoriously odorous and
oxidation sensitive thiols.
4
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10.1002/adsc.201901250
Advanced Synthesis & Catalysis
Conclusion
Song, D. Zhang, X.-Y. Liu, Y. Qin, Angew. Chem. Int.
Ed. 2017, 56, 3703-3707.
We could establish Pd/BIPHEPHOS as a highly
[3] Selected examples: a) G. Xu, D. Tang, Y. Gai, G.
Wang, H. Kim, Z. Chen, L. T. Phan, Y. S. Or, Z. Wang,
Org. Process Res. Dev. 2010, 14, 504-510; b) D. J.
Plata, M. R. Leanna, M. Rasmussen, M. A.
McLaughlin, S. L.Condon, F. A. J. Kerdesky, S. A.
King, M. J. Peterson, E. J. Stoner, S. J. Wittenberger,
Tetrahedron 2004, 60, 10171-10180; c) M. Palucki,
J. M. Um, N. Yasuda, D. A. Conlon, F.-R. Tsay, F. W.
Hartner, Y. Hsiao, B. Marcune, S. Karady, D. L.
Hughes, P. G. Dormer, P. J. Reider, J. Org. Chem.
efficient system for the Pd-catalyzed S-allylation of
thiols. The outstanding n-regioselectivity of this
system results from a combination of intrinsic ligand
properties together with the reversible nature of this
reaction. In comparison to established methods for the
preparation of thioethers, the Pd/BIPHEPHOS system
is distinguished by its very well accessible allylacetate
and allylcarbonate substrates, its high functional group
tolerance and the mild reaction conditions transferable
to many different solvents. These features allow the
application of this reaction for the late-stage
diversification of small molecules, as shown for
cephalosporin antibiotics in this work, and can even be
extended to the modification of peptides and
proteins.[9] The reversible character of this catalytic
reaction offers opportunities to be exploited in
isofunctional transformations.
2002, 67, 5508-5516; d)
G. R. Humphrey, R. A.
Miller, P. J. Pye, K. Rossen, R. A. Reamer, A.
Maliakal, S. S. Ceglia, E. J. J. Grabowski, R. P.
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[4] Reviews: a) B. M. Trost, D. L. Van Vranken, Chem.
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Experimental Section
General Procedure for the Pd-Catalyzed S-Allylation
In a flame-dried and argon-flushed Schlenk flask, equipped
with a Teflon-coated magnetic stirring bar, Pd(dba)2
(12 µmol, 2 mol%) and BIPHEPHOS (12 µmol, 2 mol%)
were suspended in anhydrous CH3CN (2.0 mL) and stirred
in a pre-heated oil bath at 60 °C for 30 min to obtain a bright
yellow solution. Then allylic carbonate (0.72 mmol, 1.2 eq.)
and thiol (0.60 mmol, 1 eq.) were added and the resulting
mixture was stirred at 60 °C (or lower) until complete
consumption of the starting material (according to GC-MS
or TLC). The reaction mixture was cooled to rt and
concentrated under reduced pressure. The crude product
was purified via flash column chromatography to afford the
desired compound.
[5] Review: a) G. Helmchen, A. Dahnz; P. Duebon, M.
Schelwies, R. Weihofen, Chem. Commun. 2007, 675-
691; Examples for S-allylation: b) M. Roggen, E. M.
Carreira, Angew. Chem. Int. Ed. 2012, 51, 8652-8655;
c) N. Gao, S.-C. Zheng, W.-K. Yang, X.-M. Zhao, Org.
Lett. 2011, 13, 1514-1516.
[6] Example for S-allylation: M. S. Holzwarth, W. Frey, B.
Plietker, Chem. Commun. 2011, 47, 11113-11115.
[7] Selected examples: a) P. A. Evans, L. J. Kennedy,
Tetrahedron Lett. 2001, 42, 7015-7018; b) B. Schmidt,
L. Staude, J. Org. Chem. 2011, 76, 2220-2226.
Acknowledgements
We gratefully acknowledge financial support by the Austrian
Science Fund (FWF) (Project P29458) and NAWI Graz.
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10.1002/adsc.201901250
Advanced Synthesis & Catalysis
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6
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Advanced Synthesis & Catalysis
FULL PAPER
Pd/BIPHEPHOS is an Efficient Catalyst for the Pd-
Catalyzed S-Allylation of Thiols with High n-
Selectivity
Adv. Synth. Catal. Year, Volume, Page – Page
Thomas Schlatzer, Hilmar Schröder, Melanie
Trobe, Christian Lembacher-Fadum, Simon Stangl,
Christoph Schlögl, Hansjörg Weber, and Rolf
Breinbauer*
7
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