The Hiyama Cross-Coupling Reaction at Parts Per Million Levels of Pd: In Situ Formation of Highly Active Spirosilicates in Glycol Solvents

Article abstract of DOI:10.1002/asia.201901155

A palladium NNC-pincer complex at a 5 mol ppm loading efficiently catalyzed the Hiyama coupling reaction of aryl bromides with aryl(trialkoxy)silanes in propylene glycol to give the corresponding biaryls in excellent yields. This method was applied to the syntheses of adapalene and a biaryl-type liquid-crystalline compound, as well as to the derivatization of dextromethorphan and norfloxacin. ESI-MS and NMR analyses of the reaction mixture suggested the formation of pentacoordinate spirosilicate intermediates in situ. Preliminary theoretical studies revealed that the glycol-derived silicate intermediates formed in situ are quite reactive silicon reagents in the transmetalation step.

Full text of DOI:10.1002/asia.201901155

DOI: 10.1002/asia.201901155
Communication
The Hiyama Cross-Coupling Reaction at Parts Per Million Levels of
Pd: In Situ Formation of Highly Active Spirosilicates in Glycol
Solvents
Shun Ichii, Go Hamasaka, and Yasuhiro Uozumi*[a]
cations of the Hiyama coupling reaction. Although many types
Abstract:
A
palladium NNC-pincer complex at
a
of organosilicon reagents have been developed to permit the
Hiyama coupling processes to proceed under milder condi-
tions with wide functional-group tolerance,[4,5] the reduction of
the catalyst loading to ppm levels remains a challenging re-
search objective.[6] In this context, the development of efficient
and general methods for the Hiyama coupling reaction with
ppm loadings of the relevant palladium catalysts is highly de-
sired.
5 molppm loading efficiently catalyzed the Hiyama cou-
pling reaction of aryl bromides with aryl(trialkoxy)silanes
in propylene glycol to give the corresponding biaryls in
excellent yields. This method was applied to the syntheses
of adapalene and a biaryl-type liquid-crystalline com-
pound, as well as to the derivatization of dextromethor-
phan and norfloxacin. ESI-MS and NMR analyses of the re-
action mixture suggested the formation of pentacoordi-
nate spirosilicate intermediates in situ. Preliminary theoret-
ical studies revealed that the glycol-derived silicate inter-
mediates formed in situ are quite reactive silicon reagents
in the transmetalation step.
We recently reported that the palladium NNC-pincer com-
plex 1 is a good catalyst precursor for the generation of highly
active monomeric palladium(0) species and we have described
its applications in the allylic arylation of allyl acetates with
sodium tetraarylboronates[7] and in the Heck reaction of aryl
halides with activated alkenes.[8] Encouraged by these success-
ful results, we attempted to apply this catalyst system to the
Hiyama coupling reaction at an extremely low catalyst loading.
Here, we report a successful example of a Hiyama coupling re-
action in the presence of a ppm loading of the palladium cata-
lyst. A 5 molppm loading of complex 1 catalyzed the Hiyama
coupling reaction of a wide variety of aryl bromides with aryl(-
trialkoxy)silanes in propylene glycol. 29Si NMR and ESI-MS ex-
periments revealed that glycol-derived pentacoordinate spiro-
silicates were formed in situ from the widely available aryl(trial-
koxy)silanes. These silicate intermediates play a crucial role in
realizing the efficient coupling reaction.
Palladium-catalyzed cross-coupling reactions are recognized as
an indispensable class of organic transformations in modern
synthetic chemistry.[1] A variety of organometallic reagents
have been utilized in CÀC bond-forming processes. Among
these, the Suzuki–Miyaura cross-coupling reaction of organo-
boron compounds is the most widely employed in the fields of
pharmaceuticals, agrochemicals, and materials chemistry,[2] be-
cause it generally proceeds with excellent functional-group tol-
erance under mild conditions without producing hazardous
waste. Despite these advantages of the Suzuki–Miyaura reac-
tion, Hiyama cross-coupling has emerged as a viable alterna-
tive for efficient CÀC bond-forming processes, because of the
striking features of organosilicon compounds, such as their
low toxicity, low cost, and ready availability and because of the
rich natural abundance of silicon as an element. However, or-
ganosilicon compounds are generally less reactive than orga-
noboron compounds owing to the low degree of polarization
of the SiÀC bond. Consequently, high loadings of palladium
catalyst (mol% levels) are inevitably required to bring about ef-
ficient Hiyama coupling reactions, leading to serious problems
of contamination of the resulting products by toxic palladium
metal.[3] This drawback has limited the range of industrial appli-
We began our studies with the optimization of the reaction
conditions (Table 1). 4-Bromotoluene (2a) and trimethoxy(phe-
nyl)silane (3a) were chosen as substrates, and the reaction was
initially performed under typical Hiyama coupling conditions
by using Pd(OAc)2 and PPh3 as the catalyst system and tetrabu-
tylammonium fluoride (TBAF) as the base in DMF (Table 1).[9]
The reaction in the presence of 1.0 mol% of the catalyst gave
the coupling product 4aa in 87% yield (entry 1), whereas re-
ducing the catalyst loading to 0.1 mol% significantly lowered
the yield of 4aa to 2% only (entry 2). This result clearly
showed the difficulty involved in reducing the catalyst loading
under the classical Hiyama coupling conditions. During the
screening of various solvents, we found that glycol solvents
were very effective in this transformation (see Supporting In-
formation for details). When ethylene glycol or propylene
glycol was employed as the solvent, the yield increased to 45
and 69%, respectively (entries 3 and 4).[10] Moreover, potassium
fluoride (KF) was found to be a more suitable base, affording
the desired product in a higher yield (entries 5 and 6). Under
these reaction conditions, the catalyst loading was successfully
reduced to 100 molppm without a decrease in the yield
(entry 7). However, in the reaction at a 10 molppm loading of
[a] S. Ichii, Dr. G. Hamasaka, Prof. Dr. Y. Uozumi
Institute for Molecular Science
SOKENDAI (The Graduate University for Advanced Studies), and JST-ACCEL
Myodaiji, Okazaki 444-8787 (Japan)
E-mail: uo@ims.ac.jp
Supporting information and the ORCID identification number(s) for the au-
thor(s) of this article can be found under:
https://doi.org/10.1002/asia.201901155.
This manuscript is part of a special collection celebrating the 100th Annual
Meeting of the Chemical Society of Japan (CSJ). Click here to see the Table
of Contents of the special collection.
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Table 1. Optimization of the Conditions for the Hiyama Coupling
Reaction.[a]
Entry Catalyst
Pd loading
Base Solvent
Yield [%]
[b]
1
2
3
4
5
6
7
Pd(OAc)2/PPh3 1.0 mol%
TBAF DMF
TBAF DMF
TBAF ethylene glycol 45
TBAF propylene glycol 69
86
2
[b]
Pd(OAc)2/PPh3 0.1 mol%
[b]
Pd(OAc)2/PPh3 0.1 mol%
[b]
Pd(OAc)2/PPh3 0.1 mol%
[b]
Pd(OAc)2/PPh3 0.1 mol%
KF
KF
ethylene glycol 73
propylene glycol >99
propylene glycol 97
[b]
Pd(OAc)2/PPh3 0.1 mol%
[b]
Pd(OAc)2/PPh3 100 molppm KF
[b]
8[c]
9[c]
10[c,d]
11[c,d]
12[c,d,e]
Pd(OAc)2/PPh3 10 molppm KF
propylene glycol 3
1
1
1
1
10 molppm KF
10 molppm KF
5 molppm
5 molppm
propylene glycol 65
propylene glycol 96
propylene glycol 86
propylene glycol >99
KF
KF
[a] Reaction conditions: 2a (0.5 mmol), 3a (1.0 mmol), base (1.0 mmol),
solvent (1.0 mL), 808C, 4 h. Yields were determined by GC with mesity-
lene as the internal standard. [b] Pd(OAc)2/PPh3 (1:2) [c] 12 h. [d] 3a
(0.6 mmol, 1.2 equiv)+KF (1.5 mmol, 3.0 equiv) were used. [e] 1008C.
Scheme 1. 29Si NMR and ESI-MS Experiments for a Mixture of Trimethoxy(-
phenyl)silane and KF in Glycol Solvents.
the catalyst, then yield of 4aa fell markedly to 3%, even on
prolonging the reaction time to 12 hours (entry 8). We there-
fore decided to apply the palladium NNC-pincer complex 1 in
the Hiyama coupling reaction. When the reaction was carried
out in the presence of a 10 molppm loading of 1, the yield im-
proved significantly to 65% (entry 9). Furthermore, the yield in-
creased further on changing the amount of 3a to 1.2 equiva-
lents and that of KF to 3.0 equivalents (entry 10). Finally, the re-
action proceeded in quantitative yield with a 5 molppm load-
ing of 1 when the reaction temperature was raised to 1008C
(entry 12).
activities of related catechol-derived pentacoordinate spirosili-
cates have been studied extensively,[11] and silicates have re-
cently attracted attention as precursors of alkyl radical in pho-
tocatalytic reactions.[12] Hiyama coupling reactions in the pres-
ence of organobis(catecholato)silicates have also been inde-
pendently reported by the groups of Hosomi[5a] and
DeShong.[13] Nevertheless, the reactivity of glycol-derived pen-
tacoordinate spirosilicates in CÀC bond-forming reactions re-
mains unexplored.
To understand the reactivity of the pentacoordinate spirosili-
cate intermediates formed in situ, we conducted preliminary
theoretical studies on the transmetalation step (Scheme 2). By
electrochemical methods, Jutand and co-workers elucidated
the roles of fluoride ion in the Hiyama coupling reaction.[14]
Fluoride ions react with [Ar-Pd-X], formed by oxidative addi-
tion of ArX to Pd0 species, to generate [Ar-Pd-F] species. Trans-
metalation occurs between [Ar-Pd-F] and PhSi(OMe)3 via a
four-membered cyclic transition state, whereas the fluorosili-
cate [PhSi(OMe)3F]À is not reactive. DFT calculations on the
transmetalation of [CH2 =CH-Pd-F] with CH2 =CHSiMe3 have
been performed by Sakaki and Hiyama and their co-workers.[15]
In accord with these reports, we set up model reactions of
[Ph-Pd-F(PPh3)] (7) with the silicate intermediate 5 and with
PhSi(OMe)3 (3a). First, the phenyl groups of the arylsilanes 3a
and 5 coordinate to the palladium center, and the fluorine
ligand of 7 begins to interact with the silyl groups to form the
hexacoordinate spirosilicate Int-a and the pentacoordinate sili-
To gain insight into the reason for the high efficiency of the
present method, we performed 29Si NMR and ESI-MS analyses
of the reaction mixture (Scheme 1). After the reaction of trime-
thoxy(phenyl)silane (3a) with KF in ethylene glycol for two
hours, the resulting mixture was analyzed by 29Si NMR spec-
troscopy and ESI-MS. In the 29Si NMR spectra, the signal of 3a
at À57.8 ppm completely disappeared, and a new signal was
observed at À93.1 ppm. ESI-MS experiments on the resulting
product revealed the formation of an ethylene glycol-derived
pentacoordinate spirosilicate 5 (Scheme 1a). A single-crystal x-
ray analysis of silicate
5 clearly confirmed its structure
(Scheme 1b). The propylene glycol-derived pentacoordinate
spirosilicate 6 also formed under similar reaction conditions
(Scheme 1c). From these results, the spirosilicates-generated in
situ appear to be key intermediates in permitting the Hiyama
coupling reaction to proceed efficiently. The structures and re-
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Scheme 2. Results of Theoretical Studies on the Transmetalation Step. (a) Transmetalation of an arylpalladium fluoride 7 with the pentacoordinate spirosilicate
5. (b) Transmetalation of an arylpalladium fluoride 7 with trimethoxy(phenyl)silane (3a). Geometries were optimized at the B3LYP/6-31G(d,p) level for C, H; at
the 6-31+G(d,p) level for O, F, Si, P and K; and at the LanL2DZ level for Pd. Relative Gibbs free energies were obtained by single-point energy calculations at
the B3LYP/6-311+ +G(2d,p) level for C, H, O, F, Si, P, and K, and at the SDD level for Pd with the SMD solvation model (DMF).
cate Int-b, respectively. Here, a slightly higher activation barrier
is required for the formation of TS-Ia (11.9 kcalmolÀ1) com-
pared with that for TS-Ib (8.1 kcalmolÀ1), due to the steric
effect of the larger silicate moiety of 5. Subsequently, a palladi-
um-carbon bond starts to form via TS-IIa and TS-IIb. The sili-
con center adopts a hexacoordinated octahedral structure in
TS-IIa, whereas the geometry around the silicon center in TS-
IIb is understood to be trigonal bipyramidal. Notably, the palla-
dium-carbon bond formation from Int-a occurs with a very low
activation barrier of 1.8 kcalmolÀ1. In sharp contrast, this pro-
cess with trimethoxy(phenyl)silane (3a) requires a significantly
higher activation barrier of 15.2 kcalmolÀ1. Consequently, these
calculation results strongly support the assumption that the
glycol-derived pentacoordinate spirosilicates are quite reactive
in the transmetalation step.
5 molppm loading of 1. Sterically hindered 1-naphthyl and 2-
tolyl bromides were also compatible with this reaction. Howev-
er, 2-bromo-1,3-dimethylbenzene required
a 100 molppm
loading of the catalyst to afford the corresponding product
4sa in a reasonable yield. Notably, heteroaromatic bromides
were also suitable substrates, affording the corresponding
products 4ta–4za in high yields.
Next, we focused on the scope with respect to aryl- or alke-
nyl(triethoxy)silanes (Scheme 4). Aryl- or (alkenyl)triethoxysi-
lanes were chosen as silicon reactants instead of trimethoxysi-
lanes because of their ready availability. Indeed, triethoxy(phe-
nyl)silane exhibited a similar reactivity to that of 3a, affording
the coupling product 4aa in 91% yield. Electron-rich and elec-
tronically neutral arylsilanes coupled efficiently with 4-bromo-
toluene (2a) in the presence of a 5 molppm loading of the cat-
alyst to give the corresponding biaryls 4ab–4ah in yields of 72
to 99%. On the other hand, electron-deficient aryl(triethoxy)si-
lanes 3l, 3j, and 3k were less reactive owing to their low nu-
cleophilicity, so that a 100 molppm loading of the catalyst was
required to promote their coupling reactions efficiently. Addi-
tionally, alkenyl(triethoxy)silanes also served as good substrates
in the transformation, providing the desired products 4qm
and 4an in high yields.
To further demonstrate the utility of our reaction system, we
examined several of its synthetic applications. The method was
applied a synthesis of adapalene (10)[16] on about a seven-
gram scale. The target molecule was successfully synthesized
in 93% yield without chromatographic purification (Scheme 5).
Moreover, this method was applicable to the derivatization of
drug molecules. The reaction of an aryl bromide-tethered nor-
floxacin[17] with 4-[4-(triethoxysilyl)phenyl]morpholine proceed-
ed nicely to furnish the derivative 11 in 85% yield. A triethoxy-
We next investigated the scope of the reaction of various
aryl bromides with trimethoxy(phenyl)silane (3a) (Scheme 3).
Bromobenzenes 2 bearing an electron-donating substituent
coupled efficiently with trimethoxy(phenyl)silane (3a) in the
presence of a 5 molppm loading of complex 1 in propylene
glycol to give the corresponding biaryls 4ba, 4ca, and 4da in
high yields. The reactions of substrates with halo or carbonyl
groups also proceeded well to furnish products 4 fa–4ma in
good yields. Under our reaction conditions, the chloro group
in 4 fa remained completely intact. Unfortunately, bromoben-
zenes bearing highly electron-withdrawing substituents, such
as cyano or nitro groups, were less reactive in this transforma-
tion; higher catalyst loadings were required to promote the re-
action efficiently, and the coupling products 4na and 4pa
were then obtained in yields of 95 and 93%, respectively. 4-
Bromobenzonitrile substituted with an electron-donating 3-
methoxy group coupled smoothly to furnish 4oa, even with a
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Scheme 4. Scope of Aryltriethoxysilanes.[a] [a] Reaction conditions: 1
(2.5ꢁ10À6 mmol), 2a (0.5 mmol), 3 (0.6 mmol), KF (1.5 mmol), propylene
glycol (1.0 mL), 1008C, 12 h. Isolated yields are reported. [b] 1
(100 molppm).
Scheme 3. Scope of Aryl Bromides.[a] [a] Reaction conditions: 1
(2.5ꢁ10À6 mmol), 2 (0.5 mmol), 3a (0.6 mmol), KF (1.5 mmol), propylene
glycol (1.0 mL), 1008C, 12 h. Isolated yields are reported. [b] 1 (0.1 mol%).
[c] 1 (100 molppm).
silylated dextromethorphan[18] also coupled readily with 1-
bromo-3,5-bis(trifluoromethyl)benzene to give product 12 in
90% yield. Additionally, the liquid-crystalline compound 13[19]
was also synthesized under the same reaction conditions
(Scheme 6).
In summary, we have developed a simple, efficient, and gen-
eral method for performing the Hiyama coupling reaction at
ppm levels of a Pd catalyst. A 5 molppm loading of complex 1
catalyzed the Hiyama coupling reaction of a wide variety of
aryl bromides with aryl(trialkoxy)silanes in propylene glycol to
give the corresponding biaryls in excellent yields. NMR and
ESI-MS analyses of the reaction mixture suggested the forma-
tion of a pentacoordinate spirosilicate intermediate in situ. Pre-
liminary theoretical studies revealed that the glycol-derived sili-
cate intermediates significantly facilitate the transmetalation
step. Moreover, this method was successfully applied to a mul-
tigram-scale synthesis of adapalene, the synthesis of a liquid-
crystalline compound, and the functionalization of two drug
molecules.
Scheme 5. Synthesis of Adapalene on aꢀ7 g Scale.
Acknowledgements
This research project was supported by JST-ACCEL program
(JPMJAC1401). We appreciate funding from the JSPS KAKENHI
Grant Number 17J05446, the JSPS (Grant-in-Aid for Young Sci-
entists (B) No. 17K14524), and from Mitsubishi Gas Chemical
Company, Inc. (Mitsubishi Gas Chemical Award in Synthetic Or-
ganic Chemistry, Japan). We thank Dr. Pondchanok Chinapang,
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Conflict of interest
The authors declare no conflict of interest.
Keywords: alkoxysilanes · aryl bromides · aryltrialkoxysilanes ·
Hiyama coupling reaction · pincer complex · spirosilicates
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Manuscript received: August 19, 2019
Revised manuscript received: September 25, 2019
Accepted manuscript online: September 27, 2019
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COMMUNICATION
Shun Ichii, Go Hamasaka,
Yasuhiro Uozumi*
&& – &&
The Hiyama Cross-Coupling Reaction
at Parts Per Million Levels of Pd: In
Situ Formation of Highly Active
Spirosilicates in Glycol Solvents
A palladium NNC-pincer complex at a
5 molppm loading efficiently catalyzed
the Hiyama coupling reaction of aryl
bromides with aryl(trialkoxy)silanes in
propylene glycol to give the corre-
sponding biaryls in excellent yields.
Glycol-derived pentacoordinate spirosili-
cates formed in situ significantly facili-
tate the transmetalation step.
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