Designing Homogeneous Copper-Free Sonogashira Reaction through a Prism of Pd-Pd Transmetalation

Article abstract of DOI:10.1021/acs.orglett.0c01227

Simultaneous introduction of two different palladium (pre)catalysts, one tuned to promote oxidative addition to (hetero)aryl bromide and another to activate terminal alkyne substrate, leads to productive Pd-Pd transmetalation, subsequent reductive elimina

Full text of DOI:10.1021/acs.orglett.0c01227

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Letter
Designing Homogeneous Copper-Free Sonogashira Reaction
through a Prism of Pd−Pd Transmetalation
̌
Bruno A. Martek, Martin Gazvoda, Damijana Urankar, and Janez Kosmrlj*
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ABSTRACT: Simultaneous introduction of two different palladium (pre)catalysts,
one tuned to promote oxidative addition to (hetero)aryl bromide and another to
activate terminal alkyne substrate, leads to productive Pd−Pd transmetalation,
subsequent reductive elimination, and formation of disubstituted alkyne. This
conceptually novel rational design of copper-free Sonogashira reaction enabled facile
identification of the reaction conditions, suitable for the synthesis of alkyl, aryl, and
heteroaryl substituted alkynes at room temperature with as low as 0.125 mol % total Pd loading.
Contrary to a previous belief, it has been recently postulated
by us19,20 and others21 that the mechanism of copper-free
alkynylation operates through a process that resembles copper
cocatalyzed variant, but the role of copper is played by
palladium (Scheme 2). It builds on transmetalation (TM)
lthough the palladium catalyzed C−C bond formation
Abetween aryl or vinyl halides and terminal alkynes by
Heck1 and Cassar2 evolved into the most effective tool for the
synthesis of disubstituted alkynes, it is the copper cocatalyzed
variant that has mostly entered industrial applications (Scheme
1).3,4
Scheme 2. General Representation of Bicyclic Mechanism of
Copper-Free Alkynylation That Is Synergistically Catalyzed
by Two Pd Species
Scheme 1. General Representation of Pd-Catalyzed and
Copper Cocatalyzed Alkynylation Reaction
This is exemplified by the synthesis of many Food and Drug
Administration (FDA) approved active pharmaceutical ingre-
dients (APIs),3a,d including Terbinafine (Sandoz, squalene
epoxide inhibitor),5 Ponatinib (Ariad Pharmaceuticals, tyro-
sine-kinase inhibitor),6 Tazarotene (Allergan, receptor-selec-
tive retinoid),7 and Eniluracil (GlaxoSmithKline, dihydropyr-
imidine dehydrogenase inactivator).8 As reported by Sonoga-
shira et al.,9 alkynylation in the presence of copper salts
proceeds under much milder conditions.3,4,10 Copper
additives, however, promote Glaser−Hay11 competitive
homocoupling of alkyne and interfere with some functional
groups potentially present in the coupling partners like azide,
amine, and alkyne. During the isolation process, removal of
copper cocatalyst may complicate the workup and purification,
especially in the synthesis of APIs.12,13 When it comes to a bulk
industrial process, recovery of the precious metal from spent
catalysts is more challenging for the copper cocatalyzed than
the copper-free process.14,15 Although homogeneous copper-
free alkynylation has witnessed tremendous improvements, it
mostly benefited from development of novel ligands3,4,10b,16
and technologies. Aqueous micellar catalysis developed by the
groups of Lipshutz,17 and Sparr and Parmentier18 is a notable
example of the latter.
between two distinct palladium species, oxidative addition
(OA) intermediate A that is generated within Pd1-Cycle, and
acetylide B from the Pd2-Cycle. Ideally for the productive
alkynylation, the concentrations of both reactive intermediates
in the reaction mixture are kept equimolar throughout the
process. Increasingly favorable formation of A over B from the
single (pre)catalyst decelerates or even terminates the cross-
coupling and promotes undesired homocoupling side reaction
into biaryls instead. Likewise, acetylide B as a (pre)catalyst sink
potentially leads to 1,3-diyne and/or enyne byproducts. This
condition, however, is rather difficult to meet rationally by
Received: April 6, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01227
© XXXX American Chemical Society
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introducing a single palladium source/ligand combination that
has so far been exclusively applied for the copper-free
alkynylation.3,4
Pd-PyMIC (1 mol %), and 1,4-diazabicyclo[2.2.2]octane
(DABCO, 1.4 equiv) as a base in acetonitrile at room
temperature. We aimed to design the reaction conditions that
would enable cross-coupling at room temperature (22 °C). By
screening through the ligands L, only CataCXium A (L7)
provided reasonable conversion to product 3a (20%).
Triphenylphosphine-based ligands L1−L3 promoted conver-
sions of 2a into the products that were tentatively identified as
Based on the mechanistic rationale, herein we present a
novel concept for the design of palladium catalyzed copper-free
alkynylation. It features simultaneous introduction of two
different palladium (pre)catalysts into the reaction mixture,
one tuned to facilitate oxidative addition to aryl halide in Pd1-
Cycle, and another one to activate terminal alkyne in Pd2-Cycle.
Initially, we selected (PhCN)2PdCl2 as a source of palladium
to operate in the Pd1-Cycle and set a brief screening (vide
infra) through a selection of commercially available phosphine-
based ligands shown in Table 1. These Pd/ligand combina-
1
enynes as based on the H NMR resonances appearing in the
olefinic regions of spectra (Supplementary Figure S1), with 1a
remaining unconsumed. This is not surprising because the
formation of enynes from terminal alkynes in the presence of
palladium and bulky phosphine ligands was previously
reported by Trost et al.23 and Colacot et al.10b
As indicated in the systematic investigation by Mårtensson
et al.,28 solvent composition and base are important for
copper-free alkynylation. With L7 as the ligand of choice,
under the same reaction conditions as indicated in Table 1,
1,4-dioxane afforded the highest 35% conversion to 3a over the
other tested solvents: MeCN (affording 20% of 3a), N-
methylpyrrolidone (NMP, 13%), N,N-dimethylformamide
(DMF, 17%), MeOH (15%), i-PrOH (14%), EtOAc (22%),
tetrahydrofuran (THF, 19%), and toluene (<1%). Prolonged
reaction time in 1,4-dioxane from 24 to 72 h increased the
conversion to 50% (Supplementary Table S1).
Table 1. Phosphine Ligand Evaluation in Model
Alkynylation Reaction
a
With 1,4-dioxane as the solvent of choice, the effect of the
base was evaluated. Different organic amines (pyrrolidine,
NEt3, t-BuNH2, i-Pr2NEt, Cy2NMe, DBU, DBN, TMG, and
DABCO), organic and inorganic carbonates (KOAc, KOPiv,
K2CO3, Cs2CO3), phosphate (K3PO4), and hydroxide (KOH)
were tested under the reaction conditions from Table 1 (see
Supplementary Table S1). Notable 35 and 38% conversions
could only be achieved with DABCO and K2CO3, respectively.
By prolonging the reaction time to 72 h, K2CO3 (70%
conversion) turned out to be more effective over DABCO
(50% conversion).
Finally, the effect of the palladium source was briefly
evaluated in the reaction between 1a (2 mmol) and 2a (2.8
mmol) under the same reaction conditions as above [L7 (0.08
mmol, 4 mol %), Pd-PyMIC (0.02 mmol, 1 mol %), K2CO3
(2.8 mmol), 1,4-dioxane (1 mL), rt, 24 h] with other Pd2+
complexes (0.04 mmol, 2 mol %) including (PhCN)2PdBr2
(affording 17% yield of 3a), (MeCN)2PdCl2 (7%), Pd(OAc)2
(22%), and Pd(TFA)2 (29%), as well as Pd(dba)2 (10%) as an
example of Pd0 source. Initially selected (PhCN)2PdCl2
affording 38% of 3a proved superior (Supplementary Table
S2). The reduction of Pd2+ to Pd0 has been addressed
elsewhere,3,4,10b,16d,22 whereas in the Pd2-Cycle, palladium
remains in Pd2+.
To ascertain whether under the above optimized reaction
conditions the double-palladium manifold indeed plays the
anticipated role in the catalysis from Scheme 2, we conducted
the following test experiments (Table 2). A mixture of 1a, 2a,
and K2CO3 in 1,4-dioxane was exposed to 2 mol % of
(PhCN)2PdCl2, 4 mol % of L7, and 1 mol % of Pd-PyMIC for
24 h, affording 3a in 38% yield (Table 2, entry 1). An excess of
(PhCN)2PdCl2 over Pd-PyMIC (B from Scheme 2) was
employed because the formed is a precatalyst, which must
undergo several transformations before turning into the
catalytically active species A, including Pd2+ to Pd0 reduction,
ligand L7 coordination, and oxidative addition to 1a.
Repeating the reaction in the absence Pd-PyMIC but with
higher 3 mol % loading of (PhCN)2PdCl2 (and 6 mol % of L7)
a
NMR yields are reported as determined from at least two
consecutive runs.
tions have already proven to promote the formation of
catalytically active Pd0 species, subsequent oxidative addition,
and reductive elimination (RE) in a range of cross-
couplings.3,4,10b,16d,22
To build on Pd2-Cycle, we decided to avoid the phosphine-
based palladium complexes. Although their ability to activate
terminal alkynes into acetylides of type B is well-establish-
ed,10b,23 the propensity of phosphines to dissociate and
exchange24 could lead to undesired scrambling between the
reactive palladium species from both cycles, leading to
uncontrolled side reactions or even termination of the process.
Instead, we selected N-heterocyclic carbene (NHC) ligand of a
pyridine (Py) functionalized mesoionic (MIC) structure
(PyMIC),19,25 possessing coordination abilities to a metal
beyond phosphines and even NHCs. B-like NHC acetylide
Pd2+ complexes are well-documented,26 and their formation is
also evident from many Pd-NHC promoted copper-free and
copper cocatalyzed alkynylations.27 All of the above applies to
the Pd-PyMIC complex (Table 1) that has proven to have an
exceptional stability, promoting copper-free alkynylation in hot
water under aerobic conditions.19
For the test reaction, we selected 4-bromotoluene (1a, 1
equiv) and phenylacetylene (2a, 1.4 equiv) as the model
substrates (Table 1). The reaction conditions employed
(PhCN)2PdCl2 (2 mol %), phosphine ligand L (4 mol %),
B
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a
generally efficient to couple electronically less demanding
partners, i.e., electron-deficient aryl bromides with electron-
rich alkynes. As evident from Table 3, cross-couplings between
various combinations of electron-rich, electron deficient, and
sterically demanding (hetero)aryl bromides and different
terminal alkynes were achieved at room temperature.
To provide evidence that Pd−Pd transmetalation is indeed
operating, independently prepared oxidative addition adduct
4a and palladium acetylide 5 were let to react in isolated
segment of the catalytic cycle from Scheme 2 (Scheme 3).
Table 2. Test Experiments Proving the Concept
(PhCN)2PdCl2/
L7 (mol %,
mol %)
Pd-
PyMIC
(mol %)
total Pd
content
(mol %)
yield
b
entry
base
(%)
1
2
3
4
5
6
2, 4
2, 4
3, 6
3, 6
1
1
3
3
3
3
3
3
K2CO3
DABCO
K2CO3
DABCO
K2CO3
DABCO
38
35
9
<1
<1
<1
3
3
a
Conditions: 1a (2 mmol), 2a (2.8 mmol), (PhCN)2PdCl2 (0−3 mol
Scheme 3. Reaction between Independently Prepared
Complexes 4 and 5
%), L7 (0−6 mol %), Pd-PyMIC (0−3 mol %), base (2.8 mmol), 1,4-
dioxane (1 mL), rt, 24 h. NMR yields determined from at least two
b
consecutive runs.
to keep the same overall concentration of Pd (3 mol %) the
same as above gave significantly lower 9% yield of 3a (Table 2,
entry 3). Finally, the reaction with 3 mol % of Pd-PyMIC, but
in the absence of (PhCN)2PdCl2 and L7, resulted in only trace
amounts of product 3a formation (entry 5). The results were
consistent with those obtained by using DABCO in place of
K2CO3, where only minute amounts of 3a could be detected
either in the absence of (PhCN)2PdCl2/L7 or Pd-PyMIC
(compare entries 2, 4, and 6). Some product 3a formation in
entry 3 is not unexpected as it is known that palladium
precatalyst formed from L7 promotes copper-free alkynylation
in micellar medium.18 Nevertheless, significantly faster
reactions in the presence of Pd-PyMIC as well as the proof
of concept can be grasped from Table 2.
At this point, the scope of alkynylation was evaluated with
different bromides 1 and alkynes 2 (Table 3). Based on several
experiments with these coupling partners, aimed at increasing
the yields of 3, decreasing Pd loading and confirming
reproducibility of the process, some observations were made,
as follows. (i) Although K2CO3 performed better in the model
reaction between 1a and 2a into 3a (Supplementary Table S1),
DABCO was more efficient to produce 3b, d, e and was used
for the syntheses of 3c, f−s (Table 3). (ii) In some instances,
the above identified (PhCN)2PdCl2/L7/Pd-PyMIC loadings
of 2.0/4.0/1.0 mol % (Conditions A) could even be lowered to
0.25/0.50/0.25 mol % (Conditions B). Conditions B are
Trifluoromethyl functionalized substrates and CDCl3 as a
reaction solvent were selected to enable sensitive monitoring of
the reaction by NMR. A mixture of 4a and 5 in a 1:1 molar
ratio turned from colorless to dark brown immediately after
dissolution in CDCl3 at room temperature. NMR spectra
indicated consumption of both 4a and 5, and complete
1
conversion to diarylalkyne 3s as judged by H and 19F{H}
NMR (Figure 1, Supplementary Figures S37 and S38). The
results were consistent with those obtained by reacting 4b and
5, leading to nonsymmetrical alkyne 3i (Supplementary
Figures S39 and S40).
As a part of our anticancer investigations,29 we have been
interested in multitargeted antifolate LY231514 (Eli Lilly and
Company), which is FDA approved for chemotherapy in
combination with other platinum drugs. Multi kilogram scale
preparation of synthetic intermediate 3t was achieved by Pd/
Cu cocatalyzed coupling between 1m with 2i at 50 °C in 83%
yield (Scheme 4).30 With herein identified (PhCN)2PdCl2/
L7/Pd-PyMIC system, starting compounds 1m and 2i reacted
a
Table 3. Substrate Scope Screening
a
b
NMR yield determined from at least two consecutive runs. The figure in parentheses refers to isolated pure product. 2.5 mL of 1,4-dioxane was
used.
C
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total Pd loadings. Pd−Pd transmetalation has been confirmed
by reactions of independently prepared reactive intermediates,
i.e., oxidative addition adducts and palladium acetylide.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01227.
Experimental procedures and analytic data for the
compounds described and copies of NMR spectra
(PDF)
AUTHOR INFORMATION
Corresponding Author
1
Figure 1. Selected regions of H (left) and 19F{H} NMR (right)
CDCl3 spectra of (a) complex 4a, (b) complex 5, (c) an equimolar
mixture of 4a and 5 (Scheme 3), 20 min after dissolution, and (d)
authentic product 3s.
■
̌
Janez Kosmrlj − Faculty of Chemistry and Chemical
Technology, University of Ljubljana, SI-1000 Ljubljana,
Slovenia; orcid.org/0000-0002-3533-0419;
Email: janez.kosmrlj@fkkt.uni-lj.si
Scheme 4. Alkynylation is a Step in the Synthesis of
LY231514
Authors
Bruno A. Martek − Faculty of Chemistry and Chemical
Technology, University of Ljubljana, SI-1000 Ljubljana,
Slovenia; orcid.org/0000-0001-8387-0519
Martin Gazvoda − Faculty of Chemistry and Chemical
Technology, University of Ljubljana, SI-1000 Ljubljana,
Slovenia; orcid.org/0000-0003-3421-0682
Damijana Urankar − Faculty of Chemistry and Chemical
Technology, University of Ljubljana, SI-1000 Ljubljana,
Slovenia
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01227
in the absence of copper additives already at room temperature
to afford 3t in 90% yield of isolated pure product (Scheme 4).
Scalability of the double-palladium manifold was tested in
the reaction of 1b (25 mmol scale) with 2a to form 3b.
Analytically pure product 3b (4.692 g) was obtained with no
need of column chromatography purification. In addition, the
overall palladium content could be decreased from 0.50 mol %
(Table 3, Conditions B) down to 0.125 mol % (Scheme 5).
Increasing the scale also resulted in the increase of the yield of
3b from 86% (Table 3, Conditions B) to 91% (Scheme 5).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge the financial support from the
Slovenian Research Agency (Research Core Funding Grant
P1-0230, Young Researcher Grant to B.A.M., and Projects J1-
8147 and J1-9166).
REFERENCES
Scheme 5. Multigram Scale Synthesis of 3b
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