Dehydrogenative Borylation and Silylation of Styrenes Catalyzed by Copper-Carbenes

Article abstract of DOI:10.1021/acscatal.6b02594

Readily available copper precatalysts, (NHC)CuOtBu (NHC = N-heterocyclic carbene), catalyze dehydrogenative borylation and silylation of styrenes with moderate to high yields, using ketone additives as sacrificial oxidants. This method provides access to

Full text of DOI:10.1021/acscatal.6b02594

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Letter
Dehydrogenative Borylation and Silylation
of Styrenes Catalyzed by Copper-Carbenes
Thomas J Mazzacano, and Neal P. Mankad
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b02594 • Publication Date (Web): 29 Nov 2016
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Dehydrogenative Borylation and Silylation of Styrenes Catalyzed by
Copper-Carbenes
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Thomas J. Mazzacano and Neal P. Mankad*
Department of Chemistry, University of Illinois at Chicago, 845 W. Taylor St., Chicago, Illinois 60607, USA
ABSTRACT: Readily available copper pre-catalysts, (NHC)CuOtBu (NHC = N-heterocyclic carbene), catalyze dehydrogenative
borylation and silylation of styrenes with moderate to high yields, using ketone additives as sacrificial oxidants. This method pro-
vides access to trisubstituted vinylboronates and vinylsilanes without requiring noble metal catalysis.
KEYWORDS: copper, carbene, borylation, silylation, dehydrogenative, base metal catalysis
Vinylboronates are valuable synthetic intermediates due to
their use as coupling partners in Suzuki-Miyaura reactions,1
which allow complex products to be constructed from simple
building blocks. Two methods for synthesizing vinylboronic
esters (VBEs) are Cu-catalyzed hydroboration of alkynes2,3
(Figure 1a) and dehydrogenative borylation of alkenes (includ-
ing styrenes, α-olefins, and 1,1-disubstituted alkenes) cata-
lyzed by precious metals such as Pd, Ru, or Rh4-8 (Figure 1b).
tion, as well (Figure 1c). The method is versatile and robust
and can be used to synthesize trisubstituted vinylboronate and
vinylsilane products unavailable by alkyne hydrofunctionali-
zation.
OBpin
R'
R
R'
NHC Cu E
E
Bpin
R
NHC Cu O
R'
NHC Cu
R'
E
O
1/2
NHC Cu H
R
2
R'
R'
E
E = Bpin or SiMe2Ph
Figure 2. Hypothetical mechanism for Cu-catalyzed dehydrogena-
tive borylation and silylation reactions (NHC = N-heterocyclic
carbene).
Recently, Bertrand reported a Cu-catalyzed dehydrogenative
borylation of terminal alkynes,16 indicating that copper-
carbene catalysis may be a promising candidate for the analo-
gous transformation with alkenes. However, a challenge to
overcome is the issue of selectivity, as copper-carbene cataly-
sis also is well known for alkene hydroboration17,18 (Figure
1a). These alkene hydroboration reactions proceed through
copper-boryl intermediates that insert alkenes to generate β-
boroalkylcopper intermediates.19 Catalytic turnover is typical-
ly achieved by intercepting the latter with an H+ donor such as
an alcohol. Sadighi has shown that β-boroalkylcopper inter-
mediates readily undergo β-hydride elimination to release
VBEs,20 but the VBEs re-insert into the transient copper-
hydride dimer21,22 under stoichiometric conditions. Our hy-
pothesis was that a ketone additive could be used to trap the
Figure 1. Previous work on (a) Cu-catalyzed hydroboration and
(b) noble metal-catalyzed dehydrogenative borylation reactions,
and (c) this work on Cu-catalyzed dehydrogenative borylation.
Both of these methods, though useful, have limitations. Al-
kyne hydroboration does not provide access to many tri- or
tetrasubstituted VBEs, although recent reports indicate that
alkyne carboboration can be used as an alternative.9-12 On the
other hand, dehydrogenative borylation of alkenes does give
rise to a wider range of VBE products but typically requires
use of noble metals. Examples of base metal catalysts for de-
hydrogenative borylation are comparatively rare.13-15 In this
Letter, we report conditions for Cu-catalyzed dehydrogenative
borylation of alkenes that extends to dehydrogenative silyla-
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copper-hydride species and drive catalytic turnover for VBE
formation. Conveniently, copper-carbene catalysis for ketone
hydroboration is very efficient,23 while ketones do not undergo
copper-catalyzed diboration like aldehydes do.24 In the hypo-
thetical catalytic scheme (Figure 2), then, the ketone additive
acts as a sacrificial oxidant that accepts a borane equivalent to
drive catalysis towards dehydrogenative borylation and away
from hydroboration.
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Our initial studies showed that dehydrogenative borylation
of styrene could be achieved in benzene solution at 80°C in
excellent yields with the pre-catalyst, (IPr)CuOtBu, the dibo-
ron reagent, B2pin2, and benzophenone as a stoichiometric
additive (Table 1, Entry 1). The initial experiments used 2
equivalents of styrene relative to B2pin2, but only a small de-
crease in yield was observed upon decreasing styrene loading
to 1 equivalent (Entry 2). The yield decreased significantly
when THF was used as the reaction solvent or when catalyst
loading was lowered (see Supporting Information). The role of
the ketone was verified by lowering benzophenone loading to
0.5 equivalents and observing a significant decrease in VBE
yield (Entry 3), thereby demonstrating that the ketone is nec-
essary for catalytic turnover. For the more challenging sub-
strate α-methylstyrene, the same conditions gave low yield of
the corresponding trisubstituted VBE (Entry 4). Upon screen-
ing various ketones, 6-undecanone was found to give higher
yields (Entry 5). Upon screening various NHC ligands, the
6Mes ligand was found to give optimal results (Entry 6). The-
se two ligands (IPr and 6Mes) and these two ketones (benzo-
phenone and 6-undecanone) were then screened for maximiz-
ing yield of all subsequent substrates. We believe that these
yields are indicative of overall conversion, as hydroboration or
diboration side products were only observed in trace amounts
(<5%) in typical reactions.
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Figure 3. Scope of dehydrogenative borylation. Conditions A:
NHC = IPr, ketone = benzophenone, solvent = benzene (reflux).
Conditions B: NHC = 6Mes (10% loading), ketone = 6-
undecanone, solvent = benzene (reflux). Conditions C: NHC =
IPr, ketone = 6-undecanone, solvent = toluene (reflux). Yields
1
determined by H NMR integration against an internal standard
(averages of 2-3 runs each).
Table 2. Robustness screen of dehydrogenative borylation
Table 1. Optimization for dehydrogenative borylation
Entry
additive
Yield of
(%)a
1
Additive
retained (%)a
1
2
3
4
5
6
7
8
9
butyronitrile
bromobenzene
benzothiophene
pyridine
71
75
87
54
87
84
82
8
>99
>99
>99
82
Entry
R
NHC
ketone
Yield
(%)a
1b
2
3b,c
H
IPr
benzophenone 96
benzophenone 89
benzophenone 36
benzophenone 16
6-undecanone 57
6-undecanone 68
allylbenzene
ethyl benzoate
5-decyne
>99
>99
85
H
IPr
H
IPr
4
Me
Me
Me
IPr
1-octyne
50
5
6d
IPr
benzaldehyde
cyclohexylamine
9
9
6Mes
10
0
9
a Determined by 1H NMR integration against an internal stand-
a
Determined by GC integration against an internal standard
(decane), reported as averages of 2-3 runs.
b
c
ard (hexamethylbenzene). 2:1 styrene:B2pin2. 0.5 equivalents
of ketone. d 10% catalyst loading.
The dehydrogenative borylation method was applied to a
variety of styrene substrates (Figure 3). Electron-neutral and –
rich VBE derivatives 1 and 2 were produced in high yields
while the electron-poor derivative 3 was produced in low
yield, regardless of the conditions employed. The VBE deriva-
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tives 4 and 5 with meta- and ortho-substitution were produced that higher catalyst loadings, higher temperatures, and a two-
1
2
3
4
5
6
7
8
in moderate to high yields, while borylation of 4-vinylpyridine
to produce 6 was not observed. Under the conditions described
above, trisubstituted derivative 7 was produced in moderate
yield from α-methylstyrene. The trisubstituted isomer 8 was
produced in high yield from trans-β-methylstyrene, although
higher temperatures were required to achieve high conversion.
The ability to access product 7 is noteworthy, as it would be
unavailable from alkyne hydroboration. The stoichiometric
byproducts resulting from ketone hydroboration are readily
removed from the products using column chromatography.
fold excess of the styrene substrate were all necessary to
achieve reasonable yields. Furthermore, in many cases the
NHC ligand SIMes gave superior results to IPr. Unlike the
borylation chemistry, for dehydrogenative silylation the identi-
ty of the ketone had only a minor effect on yield.
The scope of this reaction is shown in Figure 4. Electron-
neutral, -rich, and –poor vinylsilane derivatives 9, 10, and 11
were produced in moderate to high yields. Trisubstituted vi-
nylsilanes 12 and 13 also were produced catalytically, alt-
hough only low yields were achieved under conditions we
examined. Nonetheless, the ability to access 12 is noteworthy
because it would be unavailable from alkyne hydrosilylation.
Again, the stoichiometric byproducts resulting from ketone
hydroboration are readily removed from the products using
column chromatography. The functional group tolerance of the
dehydrogenative silylation reaction closely mirrors that of
dehydrogenative borylation, as determined by a Glorius ro-
bustness screen (Table 3).
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Functional group tolerance was probed by exposing the syn-
thesis of 1 to Glorius’s robustness screening method.25 Several
reactive functional groups including an ester, a nitrile, a bro-
moarene, benzothiophene, and pyridine were tolerated (Table
2, Entries 1-7), indicating that the method is robust and could
be used in various late-stage borylation scenarios. An internal
alkyne did not have any negative impact on yield of 1 (Entry
7), but 1-octyne did poison the reaction (Entry 8). Benzalde-
hyde also shut down formation of 1 and was quantitatively
consumed under the reaction conditions (Entry 9). In both of
these cases, it is likely that the additive undergoes competitive
hydroboration. The protic additive cyclohexylamine had a
similar effect (Entry 10), and in this case hydroboration of
styrene was observed as expected.17
Table 3. Robustness screen of dehydrogenative silylation
Next, we targeted expanding the scope of this methodology
to include dehydrogenative silylation. Vinylsilanes also are
useful synthetic intermediates that participate in a number of
important transformations.26 Vinylsilanes can be synthesized
by alkyne hydrosilylation27,28 or by dehydrogenative silylation
of alkenes. The latter typically requires precious metal cata-
lysts such as Ru, Rh, or Ir,29,30 although some base metal sys-
tems have emerged31 including a recent Cu-catalyzed radical
process.32
Entry
additive
Yield of
(%)a
1
Additive
retained (%)a
1
2
3
4
5
6
7
8
9
butyronitrile
bromobenzene
benzothiophene
pyridine
59
55
63
58
68
62
50
6
>99
>99
>99
82
allylbenzene
ethyl benzoate
5-decyne
>99
52
75
1-octyne
33
benzaldehyde
0
0
10
cyclohexylamine 10
13
a
Determined by GC integration against an internal standard
(decane), reported as averages of 2-3 runs.
In conclusion, we have developed dehydrogenative boryla-
tion and silylation reactions of styrenes, allowing access to
vinylboronates and vinylsilanes including trisubstituted de-
rivatives that would be unavailable from alkyne hydrofunc-
tionalization. The key to dictating selectivity for C-H func-
tionalization over C=C functionalization was the use of a sac-
rificial ketone to act as a HBpin acceptor. While the use of the
non-precious metal Cu to catalyze these reactions advances the
potential sustainability of these reactions, further studies are
necessary to obviate the non-economical use of B2pin2 and the
resulting need for a sacrificial HBpin acceptor.
Figure 4. Scope of dehydrogenative silylation. Yields were deter-
mined by H NMR integration against an internal standard (aver-
ages of 2-3 runs each).
ASSOCIATED CONTENT
Supporting Information
1
The Supporting Information is available free of charge on the
ACS Publications website.
The desired dehydrogenative silylation was achieved by us-
ing commercially available PhMe2SiBpin in place of B2pin2.
Initial experimentation (see Supporting Information) indicated
Experimental procedures & spectral data (PDF)
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Semba, K.; Nakao, Y. J. Am. Chem. Soc. 2014, 136,
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AUTHOR INFORMATION
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Zhou, Y.; You, W.; Smith, K. B.; Brown, M. K. An-
gew. Chem. Int. Ed. 2014, 53, 3475.
Alfaro, R.; Parra, A.; Alemán, J.; García Ruano, J. L.;
Tortosa, M. J. Am. Chem. Soc. 2012, 134, 15165.
Smith, K. B.; Logan, K. M.; You, W.; Brown, M. K.
Chem. Eur. J. 2014, 20, 12032–12036.
Motry, D. H.; Brazil, A. G.; Smith, M. R. J. Am.
Chem. Soc. 1997, 119, 2743–2744.
Hartwig, J. F.; Muhoro, C. N. Organometallics 2000,
19, 30–38.
Wang, C.; Wu, C.; Ge, S. ACS Catal. 2016, 7585–
7589.
Romero, E. A.; Jazzar, R.; Bertrand, G. Chem. Sci.
2016, doi: 10.1039/C6SC02668K.
Noh, D.; Chea, H.; Ju, J.; Yun, J. Angew. Chem. Int.
Ed. 2009, 48, 6062.
Feng, X.; Jeon, H.; Yun, J. Angew. Chem. Int. Ed.
2013, 52, 3989.
Semba, K.; Fujihara, T.; Terao, J.; Tsuji, Y. Tetrahe-
dron 2015, 71, 2183.
Laitar, D. S.; Tsui, E. Y.; Sadighi, J. P. Organometal-
lics 2006, 25, 2405.
Mankad, N. P.; Laitar, D. S.; Sadighi, J. P. Organo-
metallics 2004, 23, 3369.
Jordan, A. J.; Lalic, G.; Sadighi, J. P. Chem. Rev.
2016, 116, 8318–8372.
Bagherzadeh, S.; Mankad, N. P. Chem. Commun.
2016, 52, 3844.
Laitar, D. S.; Tsui, E. Y.; Sadighi, J. P. J. Am. Chem.
Soc. 2006, 128, 11036.
Collins, K. D.; Glorius, F. Nature Chem. 2013, 5,
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* npm@uic.edu
Author Contributions
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the manu-
script.
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Funding Sources
9
No competing financial interests have been declared.
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ACKNOWLEDGMENT
Funding was provided by the NSF (CHE-1362294) and the ACS
Green Chemistry Institute (Pharmaceutical Roundtable Grant).
N.P.M. is an Alfred P. Sloan Research Fellow, and T.J.M. is a
Paaren Graduate Fellow (UIC). Prof. Justin Mohr and his group
provided access to a GC and a Biotage purification system. The
authors would like to thank Prof. Kevin Brown (Indiana) for valu-
able discussions. T.J.M. dedicates this manuscript to the 2016
Chicago Cubs.
ABBREVIATIONS
6Mes,
tetrahydropyrimidin-2-ylidene;
diisopropylphenyl)imidazol-2-ylidene; pin, pinacolate; SIMes,
1,3-bis(2,4,6-trimethylphenyl)imidazolin-2-ylidene; VBE, vinyl-
boronic ester.
1,3-bis(2,4,6-trimethylphenyl)-3,4,5,6-
IPr, 1,3-bis(2,6-
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