Very efficient and broad-in-scope palladium-catalyzed Hiyama cross-coupling. the role of water and copper(I) salts

Article abstract of DOI:10.1039/c5ra03732h

A very high-yielding Pd-catalyzed cross-coupling between aryl halides and aryl(trialkoxy)silanes is achieved in the presence of Cu(i) and a measured amount of water. This novel methodology is useful for the generation of a wide range of biaryls, particularly non-para substituted derivatives, which are usually less reported.

Full text of DOI:10.1039/c5ra03732h

RSC Advances
View Article Online
View Journal | View Issue
COMMUNICATION
Very efficient and broad-in-scope palladium-
catalyzed Hiyama cross-coupling. The role of water
Cite this: RSC Adv., 2015, 5, 26796
and copper(I) salts†
Received 2nd March 2015
Accepted 9th March 2015
*
*
Carla I. Traficante, Ernesto G. Mata and Carina M. L. Delpiccolo
DOI: 10.1039/c5ra03732h
www.rsc.org/advances
A very high-yielding Pd-catalyzed cross-coupling between aryl halides Hiyama coupling did not achieve great success in its early days.
and aryl(trialkoxy)silanes is achieved in the presence of Cu(I) and a The reason was probably the intrinsic resistance of the orga-
measured amount of water. This novel methodology is useful for the nosilicon compounds to undergo cross-coupling reactions in
generation of a wide range of biaryls, particularly non-para substituted the absence of a signicant polarity at the C–Si bond. Aer the
derivatives, which are usually less reported.
introduction by Tamao et al.8 of silicon species containing
oxygen atoms, Hiyama coupling has expanded its use to a wide
range of substrates by improving reactivity and selectivity since
oxygen facilitate coordination to palladium atom, apart from
increasing polarity at the C–Si bond. Since then, an extensive
research has been carried out within this eld, establishing
different and very useful variants, such as those introduced by
DeShong,9 and Denmark.10
As part of our research dealing with the generation of
libraries of biologically promising compounds,11 we were
particularly interested in carboxy-substituted biaryl derivatives,
which have demonstrated attractive antimitotic properties as
modulators of tubulin dynamics.12 We notice that, despite of
the success of Hiyama coupling, most of the examples involving
synthetically accessible aryl(trialkoxy)silanes9b are referring to
the preparation of 40-substituted 1,10-biphenyl derivatives.
Reaction of ortho and meta-substituted aryl iodide with (3-
substituted-phenyl)triethoxysilanes is less described and, in
many cases, achieved in low to moderate yields.6,9a,13
Metal-catalyzed carbon–carbon bond forming reactions have
become crucial synthetic tools for preparing complex molecules
from simple precursors.1 Among them, the Hiyama reaction is
drawing increasing attention as a very attractive methodology
for obtaining biaryl and alkyl and vinyl aromatic derivatives.
Hiyama coupling is achieved by treating aryl or alkenyl halides
or pseudo halides with organosilicon compounds under palla-
dium catalysis and activation by a uoride ion or a base.2
Particularly, the synthesis of unsymmetrical biaryl moieties
have wide applications as polymers, agrochemicals, and phar-
maceutical intermediates.3 While Stille4 and Suzuki5 reactions
have been widely recognized for generating aryl–aryl coupling
products, the value of Hiyama reaction lays on the use of
organosilanes as coupling partners, due to their ease of prepa-
ration and handling, stability toward air/moisture, and low
toxicity compared to tin and boron reagents. Besides, Hiyama
coupling is interesting from the environmental point of view
since silicon waste is easily converted to innocuous silicon
dioxide by incineration.6
Hence, we decided to study the synthesis of methyl 30-
methoxybiphenyl-4-carboxylate (3aa) as model compound,
starting from methyl 4-iodobenzoate (1a) and the correspond-
ing aryl(triethoxy)silane (2a) in the presence of palladium
catalyst and TBAF (Table 1). Using standard conditions, 1.5
The importance of this methodology was established by
Hiyama and Hatanaka when they demonstrated that the high
affinity between silicon and uoride ions can accelerate the
rate-determining transmetalation step (Scheme 1).7
Better results were later obtained when uorophilicity of the
silanes was increased by introducing F–Si bounds.2a However,
equivalents
of
2a
and
TBAF,
catalytic
tetrakis-
(triphenylphosphine)–palladium(0) (0.025 equiv.), at 80 ꢀC in
dry THF, for 18 h, the expected biaryl 3aa was obtained in only
´
´
Instituto de Quımica Rosario (CONICET-UNR), Facultad de Ciencias Bioquımicas y
´
Farmaceuticas, Universidad Nacional de Rosario, Suipacha 531, 2000 Rosario,
Argentina. E-mail: mata@iquir-conicet.gov.ar; Fax: +54 341 4370477; Tel: +54 341
4370477
† Electronic supplementary information (ESI) available: See DOI:
10.1039/c5ra03732h
Scheme 1 Cross-coupling Hiyama reaction.
26796 | RSC Adv., 2015, 5, 26796–26800
This journal is © The Royal Society of Chemistry 2015

View Article Online
Communication
RSC Advances
Table 1 Optimization of the cross-coupling reactions using methyl 4-iodobenzoate (1a) and the aryl(triethoxy)silane 2a
Entry
Catalyst (equiv.)
Co-catalyst (equiv.)
Solvent
Producta (%)
1
2
3
4
5
6
7
8
9
Pd(PPh3)4 (0.025)
Pd(PPh3)4 (0.025)
Pd(PPh3)4 (0.025)
Pd(PPh3)4 (0.025)
—
Pd(PPh3)4 (0.025)
Pd(PPh3)4 (0.025)
Pd(PPh3)4 (0.025)
Pd(OAc)2 (0.025)
—
—
THF (anhydrous)
THF (no anhydrous)
THF (no anhydrous)
THF (5% H2O)
THF (5% H2O)
THF (5% H2O)
THF (5% H2O)
THF (50% H2O)
THF (5% H2O)
3aa (19)/4 (33)
3aa (44)
3aa (85)
3aa (93)
NR
CuI (2)
CuI (2)
CuI (2)
CuI (2)
CuI (2)
CuI (2)
CuI (2)
NRb
3aa (88)c
1a/3aa/5d
3aa/5d
a
b
c
Yield calculated aer purication by column chromatography. NR ¼ no reaction. No TBAF was added. CsF was added instead of TBAF.
d
Determined from the 1H NMR spectrum of the crude reaction mixture.
19% isolated yield (entry 1). Interestingly, the ethyl ester water might speed up the formation of an inactive silanol
analogue 4 was the major product (33%). Formation of 4 could polymer which decreases the reactivity of the silane.
be explained by a Pd-catalyzed transesterication with an ethoxy Regarding palladium source, Pd(OAc)2 was not as efficient as
group which can be generated by a nucleophilic cleavage of one Pd(PPh3)4 giving a mixture of 3aa and the homocoupling
Si–O bond by the uoride coming from the TBAF.14 Yield of 3aa product 5 (entry 9).
increased from 19 to 45% without evidence of ethyl ester
To evaluate the scope and efficiency of the optimized
formation, under the same conditions but using non-anhydrous methodology, we have synthesized a range of biaryl derivatives,
THF (entry 2). Later, by adding 2 equivalents of CuI, isolated achieving the same excellent results (Table 2). Complete
yield of 3aa was improved to 85% (entry 3). The addition of conversion was obtained, in all cases with very high isolated
stoichiometric copper(I) salts has been suggested to improve yields. Both para and meta-substituted methyl iodobenzoates
efficiency in Pd-catalyzed cross-coupling reactions,15 including (1a–b) reacted smoothly with various para and meta-substituted
Hiyama coupling.16 CuI has also proven to have a benecial aryltriethoxysilanes carrying an electron-donating or an
effect by preventing homocoupling of the aryl halide.17
electron-withdrawing group (entries 1–13). Moreover, in the
Recently, the role of water in Hiyama reaction has began to case of the ortho-substituted methyl iodobenzoate (1c), coupling
be considered. Denmark noticed that hydration level of TBAF with triethoxy(3-methoxyphenyl)silane (2a) and triethoxy(p-
was crucial for the success of this cross-coupling during the tolyl)silane (2c) gave also the corresponding 30 and 40-
synthesis of natural product isodomoic acid H,18 while Sajiki substituted biphenyl-2-carboxylates (3ca and 3cc) in very high
found that the addition of a measured amount of water isolated yield (82 and 88%), albeit longer reaction times were
signicantly increase the yield of Hiyama cross-coupling required (entries 14 and 16). Apart from carboxy-substituted
between aryl halides and aryltriethoxysilanes.19 For this iodides, other aryl iodides were tested (entries 17–30). They
reason we decided to add 5% of water to the best conditions have proven to be very effective substrates for our Hiyama
obtained until that moment. To our delight, methyl 30- coupling conditions, including those bearing strong electron-
methoxybiphenyl-4-carboxylate (3aa) was isolated by column donating groups (entries 27–30). Following our aim to apply
chromatography in 93% yield (entry 4). Based on entry 5, we the Hiyama reaction to compounds of greater complexity and
could assume that CuI is only a co-catalyst, since no reaction interest, we decided to use the optimized conditions on b-lac-
was observed in the absence of Pd. Furthermore, TBAF is tam derivatives. Thus, biaryl-contained b-lactams (3id and 3ie)
absolutely necessary since no reaction occurred in its absence where obtained in very high isolated yield (entries 31 and 32,
(entry 6). Nevertheless, TBAF is not the only uoride source Table 2).
that can be used, CsF was equally efficient, giving similar yield
Since biaryl derivatives substituted with heteroatoms are
of the coupling product 3aa (entry 7). The addition increasing present in biologically active structures,21 we have extended the
amount of water (entry 8), produced a mixture of 3aa, the scope to the reaction with heteroaryl iodides and silanes. The 3-
starting material and homocoupling product 5. Such result iodopyridine (1j), 2-iodothiophene (1k) and triethoxy(thiophen-
was in agreement with a report by Sajiki and co-workers,20 2-yl)silane (2g) successfully underwent the coupling reaction to
where they assumed that the addition of a large excess of give the desired products in very high yields (Scheme 2).
This journal is © The Royal Society of Chemistry 2015
RSC Adv., 2015, 5, 26796–26800 | 26797

View Article Online
RSC Advances
Communication
Table 2 Synthesis of a variety of biaryl compounds by optimized reaction conditions
Entry
Aryl iodide
Silane
Product
Yielda (%)
1
2
3
4
5
6
7
8
4-I, R1 ¼ COOMe (1a)
4-I, R1 ¼ COOMe (1a)
4-I, R1 ¼ COOMe (1a)
4-I, R1 ¼ COOMe (1a)
4-I, R1 ¼ COOMe (1a)
4-I, R1 ¼ COOMe (1a)
4-I, R1 ¼ COOMe (1a)
3-I, R1 ¼ COOMe (1b)
3-I, R1 ¼ COOMe (1b)
3-I, R1 ¼ COOMe (1b)
3-I, R1 ¼ COOMe (1b)
3-I, R1 ¼ COOMe (1b)
3-I, R1 ¼ COOMe (1b)
2-I, R1 ¼ COOMe (1c)
2-I, R1 ¼ COOMe (1c)
2-I, R1 ¼ COOMe (1c)
4-I, R1 ¼ COMe (1d)
4-I, R1 ¼ COMe (1d)
4-I, R1 ¼ COMe (1d)
4-I, R1 ¼ COMe (1d)
4-I, R1 ¼ COMe (1d)
4-I, R1 ¼ Me (1e)
R2 ¼ 3-OMe (2a)
R2 ¼ –H (2b)
3aa
3ab
3ac
3ad
3ae
3af
93
84
98
86
93
77
90b
93
78
78b
76
92
85
82c
90c
88c
91
88
93
85
91
76
93
62d
88
93
65
71
95
92
R2 ¼ 4-Me (2c)
R2 ¼ 4-OMe (2d)
R2 ¼ 4-Cl (2e)
R2 ¼ 4-CF3 (2f)
R2 ¼ 3-OMe (2a)
R2 ¼ 3-OMe (2a)
R2 ¼ –H (2b)
3aa
3ba
3bb
3bb
3bc
3bd
3be
3ca
3cb
3cc
3da
3db
3dc
3dd
3de
3ea
3ed
3ee
3fa
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
R2 ¼ –H (2b)
R2 ¼ 4-Me (2c)
R2 ¼ 4-OMe (2d)
R2 ¼ 4-Cl (2e)
R2 ¼ 3-OMe (2a)
R2 ¼ –H (2b)
R2 ¼ 4-Me (2c)
R2 ¼ 3-OMe (2a)
R2 ¼ –H (2b)
R2 ¼ 4-Me (2c)
R2 ¼ 4-OMe (2d)
R2 ¼ 4-Cl (2e)
R2 ¼ 3-OMe (2a)
R2 ¼ 4-OMe (2d)
R2 ¼ 4-Cl (2e)
R2 ¼ 3-OMe (2a)
R2 ¼ 4-OMe (2d)
R2 ¼ –H (2b)
4-I, R1 ¼ Me (1e)
4-I, R1 ¼ Me (1e)
I, R1 ¼ H (1f)
I, R1 ¼ H (1f)
3fd
3gb
3gd
3fd
3ed
4-I, R1 ¼ NEt2 (1g)
4-I, R1 ¼ NEt2 (1g)
4-I, R1 ¼ OMe (1h)
4-I, R1 ¼ OMe (1h)
R2 ¼ 4-OMe (2d)
R2 ¼ –H (2b)
R2 ¼ 4-Me (2c)
31
R2 ¼ 4-OMe (2d)
3id
68
32
R2 ¼ 4-Cl (2e)
3ie
90
a
b
c
d
Yield calculated aer purication by column chromatography. Reaction carried out using 0.5 equiv. of CuI. Reaction time: 40 h. Yield
1
calculated by H NMR from an inseparable mixture of cross-coupling product 3ee and homocoupling product from the silane 2e.
A tentative mechanism for this undescribed version of the the attack of the uoride from TBAF to give the pentacoordinate
aryl(trialkoxy)silane-type Hiyama coupling, involving the arylsilicate anion C.22 Aer the active complex C is formed, a
combination of adding copper salts and a measured amount of transmetalation occurs in the presence of CuI to give the
water, is outlined in Scheme 3. It was theorized that a small organocuprate intermediate D,17 which, in turn, is subjected to
amount of water could lead to a partial hydrolysis of the ary- a further transmetalation to give the organopalladium species
lalkoxysilanes (A) giving a mixture of the corresponding arylsi- which nally undergoes a reductive elimination to give the
lanol derivatives (B).20 The electrophilic character of the silicon desired biaryl compound and regenerate the palladium(0)
atom is strengthened by the formation of silanols B, facilitating catalyst.23
26798 | RSC Adv., 2015, 5, 26796–26800
This journal is © The Royal Society of Chemistry 2015

View Article Online
Communication
RSC Advances
Acknowledgements
´
Support from CONICET, ANPCyT, Fundacion Prats and Uni-
versidad Nacional de Rosario from Argentina is gratefully
acknowledged. C.I.T. thanks CONICET for fellowship.
Notes and references
1 J. F. Hartwig, Organotransition metal chemistry: from bonding
to catalysis, University Science Books, Sausalito, CA, 2010.
2 (a) Y. Hatanaka and T. Hiyama, J. Org. Chem., 1989, 54, 268;
(b) Y. Hatanaka, S. Fukushima and T. Hiyama, Chem. Lett.,
1989, 18, 1711; (c) Y. Nakao and T. Hiyama, Chem. Soc.
Rev., 2011, 40, 4893; (d) H. F. Sore, W. R. J. D. Galloway
and D. R. Spring, Chem. Soc. Rev., 2012, 41, 1845.
3 (a) Transition Metals for Organic Synthesis: Building Blocks and
Fine Chemicals, ed. M. Beller and C. Bolm, Wiley-VCH,
Scheme 2 Hiyama reaction using 3-iodopyridine (1j), 2-iodothio-
phene (1k) and triethoxy(thiophen-2-yl)silane (2g) as substrates.
Weinheim,
2nd
edn,
2004;
(b)
Handbook
of
Organopalladium Chemistry for Organic Synthesis, ed. E.-I.
Negishi and A. de Meijere, John Wiley, New York, 2002.
4 (a) J. W. Labadie and J. K. Stille, J. Am. Chem. Soc., 1983, 105,
669; (b) M. M. Heravi, E. Hashemi and F. Azimian,
Tetrahedron, 2014, 70, 7.
5 N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457.
6 T. Yanase, Y. Monguchi and H. Sajiki, RSC Adv., 2012, 2, 590.
7 Y. Hatanaka and T. Hiyama, J. Org. Chem., 1988, 53, 918.
8 K. Tamao, K. Kobayashi and Y. Ito, Tetrahedron Lett., 1989,
30, 6051.
9 (a) M. E. Mowery and P. DeShong, Org. Lett., 1999, 1, 2137; (b)
A. S. Manoso, C. Ahn, A. Soheili, C. J. Handy, R. Correia,
W. M. Seganish and P. DeShong, J. Org. Chem., 2004, 69,
8305; (c) W. Seganish and P. DeSong, Org. Lett., 2004, 6,
4379; (d) K. H. Shukla and P. DeShong, J. Org. Chem., 2008,
73, 6283.
10 (a) S. E. Denmark and C. S. Regens, Acc. Chem. Res., 2008, 41,
1486; (b) W.-T. T. Chang, R. C. Smith, C. S. Regens,
A. D. Bailey, N. S. Werner and S. E. Denmark, Org. React.,
2011, 75, 213.
Scheme 3 Plausible metal catalyzed mechanism of the Hiyama cross-
coupling with copper iodide and measured amount of water.
11 (a) S. A. Testero and E. G. Mata, Org. Lett., 2006, 8, 4783; (b)
´
L. Mendez, S. A. Testero and E. G. Mata, J. Comb. Chem.,
2007, 9, 189; (c) A. A. Poeylaut-Palena and E. G. Mata, J.
Conclusions
´
Comb. Chem., 2009, 11, 791; (d) L. Mendez and E. G. Mata,
In summary, we have developed a novel version of the Hiyama
reaction in which the role of Cu(I) and a small amount of water
is crucial for achieving very high yields, aer purication by
column chromatography. The reaction conditions were found
to be applicable to the preparation of unsymmetrical biaryl
compounds. Particularly outstanding is the generation of non-
linearly substituted biphenyl derivatives, such as, for instance,
3,30, 3,40 and 4,30-disubstituted biphenyl derivatives, which
syntheses are scarcely reported and oen achieved in low to
moderate yields. From the best of our knowledge, the combi-
J. Comb. Chem., 2010, 12, 810; (e) A. A. Poeylaut-Palena,
S. A. Testero and E. G. Mata, Chem. Commun., 2011, 47,
´
´
1565; (f) E. Cortes, L. Mendez, E. G. Mata, R. Abonia,
J. Quiroga and B. Insuasty, Mol. Diversity, 2012, 16, 839; (g)
´
P. G. Cornier, D. B. Boggian, E. G. Mata and
C. M. L. Delpiccolo, Tetrahedron Lett., 2012, 53, 632; (h)
A. La-Venia, S. A. Testero, M. P. Mischne and E. G. Mata,
Org. Biomol. Chem., 2012, 10, 2514; (i) P. G. Cornier,
´
C. M. L. Delpiccolo, D. B. Boggian and E. G. Mata,
Tetrahedron Lett., 2013, 54, 4742.
nation of adding copper salts and a measured amount of water 12 L. Laraia, J. Stokes, A. Emery, G. J. McKenzie,
has not been yet applied to Hiyama coupling involving
synthetically accessible aryl(trialkoxy)silanes. Further studies
A. R. Venkitaraman and D. R. Spring, ACS Med. Chem.
Lett., 2014, 5, 598.
are in progress to extend of use of this protocol to the genera- 13 C. I. Tracante, C. M. L. Delpiccolo and E. G. Mata, ACS
tion of libraries of biologically promising compounds.
Comb. Sci., 2014, 16, 211.
This journal is © The Royal Society of Chemistry 2015
RSC Adv., 2015, 5, 26796–26800 | 26799

View Article Online
RSC Advances
Communication
14 C. M. So, H. W. Lee, C. P. Lau and F. Y. Kwong, Org. Lett., 20 T. Yanase, S. Mori, Y. Monguchi and H. Sajiki, Chem. Lett.,
2009, 11, 317. 2011, 40, 910.
15 J. Z. Deng, D. V. Paone, A. T. Ginnetti, H. Kurihara, 21 (a) K. L. Billingsley and S. L. Buchwald, Angew. Chem., 2008,
S. D. Dreher, S. A. Weissman, S. R. Stauffer and
C. S. Burgey, Org. Lett., 2009, 11, 345.
120, 4773; (b) E. Tyrell and P. Brookes, Synthesis, 2004, 4, 469.
22 C. J. Handy, A. S. Manoso, W. T. McElroy, W. M. Seganish
and P. DeShong, Tetrahedron, 2005, 61, 12201.
¨
16 F. Louerat and P. C. Gros, Tetrahedron Lett., 2010, 51, 3558.
17 P. Pierrat, P. Gros and Y. Fort, Org. Lett., 2005, 7, 697.
18 S. E. Denmark, J. H.-C. Liu and J. M. Muhuhi, J. Am. Chem.
Soc., 2009, 131, 14188.
19 Y. Monguchi, T. Yanase, S. Mori and H. Sajiki, Synthesis,
2013, 45, 40.
23 Since we proposed that Cu(I) may be regenerated aer the
transmetalation process, a couple of test reactions were
performed using 0.5 equiv. of CuI, obtaining similar yields
to those using 2 equiv. of the Cu salt (Table 2, entries 7
and 10).
26800 | RSC Adv., 2015, 5, 26796–26800
This journal is © The Royal Society of Chemistry 2015