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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 Downloaded from http://pubs.acs.org on November 29, 2016
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Dehydrogenative Borylation and Silylation of Styrenes Catalyzed by Copper-Carbenes 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 provides 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 (including styrenes, α-olefins, and 1,1-disubstituted alkenes) catalyzed 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 hydrofunctionalization. OBpin R'
R
R'
NHC Cu E
E Bpin
R NHC Cu O
NHC Cu R'
E
R'
O R'
R'
1/2 NHC Cu H
2
R
E
E = Bpin or SiMe 2Ph
Figure 2. Hypothetical mechanism for Cu-catalyzed dehydrogenative borylation and silylation reactions (NHC = N-heterocyclic carbene).
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. Alkyne 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 dehydrogenative borylation are comparatively rare.13-15 In this Letter, we report conditions for Cu-catalyzed dehydrogenative borylation of alkenes that extends to dehydrogenative silyla-
Recently, Bertrand reported a Cu-catalyzed dehydrogenative borylation of terminal alkynes,16 indicating that coppercarbene catalysis may be a promising candidate for the analogous transformation with alkenes. However, a challenge to overcome is the issue of selectivity, as copper-carbene catalysis also is well known for alkene hydroboration17,18 (Figure 1a). These alkene hydroboration reactions proceed through copper-boryl intermediates that insert alkenes to generate βboroalkylcopper intermediates.19 Catalytic turnover is typically achieved by intercepting the latter with an H+ donor such as an alcohol. Sadighi has shown that β-boroalkylcopper intermediates readily undergo β-hydride elimination to release VBEs,20 but the VBEs re-insert into the transient copperhydride dimer21,22 under stoichiometric conditions. Our hypothesis was that a ketone additive could be used to trap the
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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 hypothetical 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. 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 diboron 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 decrease 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 necessary for catalytic turnover. For the more challenging substrate α-methylstyrene, the same conditions gave low yield of the corresponding trisubstituted VBE (Entry 4). Upon screening 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). These two ligands (IPr and 6Mes) and these two ketones (benzophenone and 6-undecanone) were then screened for maximizing 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 (99
2
bromobenzene
75
>99
3
benzothiophene
87
>99
4
pyridine
54
82
5
allylbenzene
87
>99
6
ethyl benzoate
84
>99
7
5-decyne
82
85
8
1-octyne
8
50
9
benzaldehyde
9
9
cyclohexylamine
0
9
10 a
Determined by GC integration against an internal standard (decane), reported as averages of 2-3 runs.
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 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. Functional group tolerance was probed by exposing the synthesis of 1 to Glorius’s robustness screening method.25 Several reactive functional groups including an ester, a nitrile, a bromoarene, 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). Benzaldehyde 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 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 catalysts such as Ru, Rh, or Ir,29,30 although some base metal systems have emerged31 including a recent Cu-catalyzed radical process.32
that higher catalyst loadings, higher temperatures, and a twofold 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 identity of the ketone had only a minor effect on yield. The scope of this reaction is shown in Figure 4. Electronneutral, -rich, and –poor vinylsilane derivatives 9, 10, and 11 were produced in moderate to high yields. Trisubstituted vinylsilanes 12 and 13 also were produced catalytically, although 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 robustness screen (Table 3). Table 3. Robustness screen of dehydrogenative silylation
Entry
additive
Yield of 1 (%)a
Additive retained (%)a
1
butyronitrile
59
>99
2
bromobenzene
55
>99
3
benzothiophene
63
>99
4
pyridine
58
82
5
allylbenzene
68
>99
6
ethyl benzoate
62
52
7
5-decyne
50
75
8
1-octyne
6
33
9
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 borylation and silylation reactions of styrenes, allowing access to vinylboronates and vinylsilanes including trisubstituted derivatives that would be unavailable from alkyne hydrofunctionalization. The key to dictating selectivity for C-H functionalization over C=C functionalization was the use of a sacrificial 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 determined by 1H NMR integration against an internal standard (averages of 2-3 runs each).
The desired dehydrogenative silylation was achieved by using commercially available PhMe2SiBpin in place of B2pin2. Initial experimentation (see Supporting Information) indicated
ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Experimental procedures & spectral data (PDF)
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AUTHOR INFORMATION
(9)
Corresponding Author
(10)
*
[email protected] (11)
Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.
(12) (13)
Funding Sources
(14)
No competing financial interests have been declared.
(15)
ACKNOWLEDGMENT
(16)
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 valuable discussions. T.J.M. dedicates this manuscript to the 2016 Chicago Cubs.
(17) (18) (19) (20) (21)
ABBREVIATIONS 6Mes, 1,3-bis(2,4,6-trimethylphenyl)-3,4,5,6tetrahydropyrimidin-2-ylidene; IPr, 1,3-bis(2,6diisopropylphenyl)imidazol-2-ylidene; pin, pinacolate; SIMes, 1,3-bis(2,4,6-trimethylphenyl)imidazolin-2-ylidene; VBE, vinylboronic ester.
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