Silicon-Carbon Bond Formation via Nickel-Catalyzed Cross-Coupling of Silicon Nucleophiles with Unactivated Secondary and Tertiary Alkyl Electrophiles

Article abstract of DOI:10.1021/jacs.6b03465

A wide array of cross-coupling methods for the formation of C-C bonds from unactivated alkyl electrophiles have been described in recent years. In contrast, progress in the development of methods for the construction of C-heteroatom bonds has lagged; for

Full text of DOI:10.1021/jacs.6b03465

Communication
pubs.acs.org/JACS
Silicon−Carbon Bond Formation via Nickel-Catalyzed Cross-Coupling
of Silicon Nucleophiles with Unactivated Secondary and Tertiary
Alkyl Electrophiles
Crystal K. Chu, Yufan Liang, and Gregory C. Fu*
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States
S
* Supporting Information
significant challenges.6,7 In the case of the coupling of an
organic nucleophile with a silicon electrophile (Figure 1b),8 this
ABSTRACT: A wide array of cross-coupling methods for
the formation of C−C bonds from unactivated alkyl
electrophiles have been described in recent years. In
contrast, progress in the development of methods for the
construction of C−heteroatom bonds has lagged; for
example, there have been no reports of metal-catalyzed
cross-couplings of unactivated secondary or tertiary alkyl
halides with silicon nucleophiles to form C−Si bonds. In
this study, we address this challenge, establishing that a
simple, commercially available nickel catalyst (NiBr2·
diglyme) can achieve couplings of alkyl bromides with
nucleophilic silicon reagents under unusually mild
conditions (e.g., −20 °C); especially noteworthy is our
ability to employ unactivated tertiary alkyl halides as
electrophilic coupling partners, which is still relatively
uncommon in the field of cross-coupling chemistry.
Stereochemical, relative reactivity, and radical-trap studies
are consistent with a homolytic pathway for C−X bond
cleavage.
approach has rarely proved to be effective for secondary or
tertiary alkylmetal reagents.9,10
In principle, the umpolung variant of Figure 1b, i.e., the
coupling of an alkyl electrophile with a silicon nucleophile
(Figure 1c), could provide an attractive approach for the
synthesis of tetraorganosilanes. In practice, however, progress
has been rather limited. Indeed, to the best of our knowledge,
catalyzed methods have been restricted to couplings of activated
alkyl electrophiles (e.g., allylic, benzylic, and propargylic),11
with the exception of a single study that reported the cross-
coupling of disilanes with methyl and ethyl (but not n-propyl)
halides catalyzed by either palladium (up to 92% yield at
110 °C) or nickel (up to 48% yield at 110 °C).12,13
During the past years, we have devoted considerable effort to
the development of metal-catalyzed cross-coupling reactions of
alkyl electrophiles.14 Initially, we focused on the use of carbon
nucleophiles to effect C−C bond formation, but recently we
have turned our attention to the construction of C−heteroatom
bonds. In 2012, we reported our first success in addressing this
challenge, specifically, the coupling of alkyl halides with diboron
compounds to generate alkylboranes (C−B bond forma-
tion).15,16 In the interim, we have continued to pursue the
possibility that versatile methods can be developed for the
construction of other C−X bonds, and we describe herein our
progress with respect to C−Si bond formation. In particular, we
establish that commercially available NiBr2·diglyme, without an
added ligand, catalyzes the cross-coupling of an array of
unactivated secondary and tertiary alkyl electrophiles with
silicon nucleophiles under mild conditions (eq 1).
rganosilicon compounds play an important role not only
1
Oin organic chemistry but also in fields ranging from
materials science2 to agrochemistry3 to medicinal chemistry.4
For example, in the pharmaceutical industry, the investigation
of silicon analogues of known drugs, as well as of entirely new
silicon-containing molecules, has become an active area of
research.4
Two of the most common methods for the synthesis of
tetraorganosilanes, each of which has significant limitations, are
outlined in Figure 1a,b.5 In the case of olefin hydrosilylation
(Figure 1a), issues of reactivity (e.g., hindered substrates) and
regioselectivity (e.g., 1,2-disubstituted olefins) can present
In initial studies, we applied the conditions that we had
developed for the borylation of alkyl halides with pinB−Bpin
(pin = pinacolato)15 to the corresponding silylation with pinB−
SiMe2Ph (eq 2). Unfortunately, we obtained only a trace of the
desired alkylsilane (<1%). Furthermore, our attempts to
Received: April 4, 2016
Figure 1. Three approaches for the synthesis of tetraorganosilanes.
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.6b03465
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 2. Silylation of Unactivated Secondary Alkyl
Bromides: Scope
increase the efficiency of C−Si bond formation with this
reagent were unsuccessful.
We therefore turned our attention to the use of other silicon
nucleophiles, and we determined that a silylzinc halide17 can
serve as a suitable coupling partner under the appropriate
conditions (Table 1). Thus, in the presence of 2.0 mol % NiBr2·
Table 1. Silylation of an Unactivated Secondary Alkyl
Bromide: Effect of Reaction Parameters
a
Yields were determined by GC analysis with the aid of a calibrated
internal standard (averages of two experiments).
a
b
Yields of purified products (averages of two experiments). Catalyst
loading: 5.0 mol % NiBr2·diglyme.
diglyme, the cross-coupling of an unactivated secondary alkyl
bromide with ClZn−SiMe2Ph can be achieved in good yield
under remarkably mild conditions (−20 °C, 84% yield; entry 1).
ClZn−SiMe2Ph can be prepared via Li−SiMe2Ph using standard
Schlenk techniques and, if desired, stored under nitrogen at
−35 °C for at least 1 month without deterioration.
Essentially no C−Si bond formation is observed in the
absence of the nickel catalyst (entry 2). Under these conditions,
the other silicon nucleophiles that we have examined are not
useful coupling partners (e.g., entries 3 and 4), and an array of
complexes of other transition metals do not serve as effective
catalysts (entries 5−8).18 The use of a mixture of DMA and
THF as the solvent is important (entry 9).19 If the cross-
coupling is conducted with less catalyst, with less nucleophile,
or at room temperature, there is a small deleterious effect on
the yield (entries 10−12). The method is not highly air- or
moisture-sensitive (entries 13 and 14). This is the first nickel-
catalyzed cross-coupling of alkyl electrophiles that we have
developed that does not employ an added ligand.
electrophiles. The method is compatible not only with an ether,
a carbamate, an aniline, a sulfonamide, an aryl chloride, and an
ester, but also with heterocycles such as a furan and an indole;
however, in a preliminary study, an electrophile that included a
thiophene was not a useful coupling partner, nor was an
unactivated secondary alkyl chloride or tosylate (<2% yield).
On a gram scale, the cross-coupling illustrated in entry 1 of
Table 2 proceeds in 81% yield in the presence of 1.0 mol %
NiBr2·diglyme. Finally, we have determined that our standard
conditions for the silylation of secondary alkyl bromides can
also be applied to the silylation of a corresponding iodide
(eq 3).21
NiBr2·diglyme is an effective catalyst for the silylation of
an array of unactivated secondary alkyl bromides at −20 °C
(Table 2).20 C−Si bond formation proceeds in good yield with
hindered (entries 2 and 3) and functionalized (entries 4−10)
Although considerable progress has been described in recent
years in the discovery of methods for the cross-coupling of
B
DOI: 10.1021/jacs.6b03465
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
unactivated secondary alkyl electrophiles, advances in the case
of tertiary electrophiles have been rather limited.22 We were
therefore pleased to find that the simple standard conditions
that we have developed for silylations of secondary alkyl
bromides can be applied directly to tertiary bromides, with
the only difference being the use of a higher catalyst loading
(10 mol %; Table 3). Both acyclic (entries 1−3) and cyclic
the same mixture of diastereomers (7:1 exo:endo, eqs 6 and 7;
at partial conversion, each alkyl bromide remains a single
stereoisomer), consistent with a common intermediate in the
two cross-couplings.
Table 3. Silylation of Unactivated Tertiary Alkyl Bromides:
Scope
We have examined the relative reactivity of alkyl bromides as
a function of the level of substitution of the carbon that bears
bromine (eqs 8 and 9). If the stability of the radical is the
dominant factor, then the anticipated ordering would be tertiary >
secondary > primary; on the other hand, if steric effects are
dominant, then the expected ordering would be tertiary <
secondary < primary. Through competition experiments, we have
determined that more substituted alkyl bromides are more
reactive, consistent with the generation of a radical intermediate
in the C−X cleavage step.24 Furthermore, the addition of 2,2,6,6-
tetramethylpiperidin-1-oxyl (TEMPO), which can rapidly trap
alkyl radicals,25 inhibits C−Si bond formation.26
a
b
Yields of purified products (averages of two experiments). Catalyst
loading: 2.0 mol % NiBr2·diglyme.
(entries 4−6) unactivated tertiary alkyl bromides serve as
suitable cross-coupling partners. A preliminary attempt to
silylate a tertiary alkyl iodide under the same conditions pro-
vided a promising result (eq 4).
In conclusion, we have described the first metal-catalyzed
cross-coupling reactions of unactivated secondary and tertiary
alkyl electrophiles to form C−Si bonds, thus expanding such
nickel-catalyzed couplings beyond the construction of C−C
and C−B bonds. With the aid of a simple, commercially
available catalyst, both secondary and tertiary alkyl bromides
react with silicon nucleophiles under unusually mild conditions
(e.g., − 20 °C) to furnish alkylsilanes in good yield; a variety of
functional groups are compatible with the method. Stereo-
chemical and reactivity studies are consistent with a radical
pathway for C−X cleavage in this new bond-forming process.
Additional efforts to expand the scope of metal-catalyzed
coupling processes are underway.
Having established that the scope of this new C−Si bond-
forming process is broad with respect to the electrophile, we
shifted our focus to the use of other silicon nucleophiles and
determined that, in the presence of 10 mol % NiBr2·diglyme,
other silylating agents also serve as effective cross-coupling
partners (eq 5).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.6b03465.
■
S
Our working hypothesis is that C−Br bond cleavage in these
silylation reactions proceeds through a radical intermediate, as
in our previous nickel-catalyzed cross-couplings of unactivated
alkyl halides to generate C−C and C−B bonds,15,23 and this
suggestion is supported by our preliminary mechanistic studies.
For example, exo- and endo-2-bromonorbornane react to afford
Procedures and characterization data (PDF)
AUTHOR INFORMATION
Corresponding Author
*gcfu@caltech.edu
■
C
DOI: 10.1021/jacs.6b03465
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
(14) (a) For an early report, see: Netherton, M. R.; Dai, C.;
Notes
Neuschutz, K.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 10099. (b) For
̈
The authors declare no competing financial interest.
a recent report and leading references, see: Liang, Y.; Fu, G. C. J. Am.
Chem. Soc. 2015, 137, 9523.
ACKNOWLEDGMENTS
(15) Dudnik, A. S.; Fu, G. C. J. Am. Chem. Soc. 2012, 134, 10693
(nickel catalyst; primary, secondary, and tertiary electrophiles).
(16) For contemporaneous work by others, see: (a) Yang, C.-T.;
Zhang, Z.-Q.; Tajuddin, H.; Wu, C.-C.; Liang, J.; Liu, J.-H.; Fu, Y.;
Czyzewska, M.; Steel, P. G.; Marder, T. B.; Liu, L. Angew. Chem., Int.
Ed. 2012, 51, 528 (copper catalyst; primary and secondary
electrophiles). (b) Ito, H.; Kubota, K. Org. Lett. 2012, 14, 890
(copper catalyst; primary and secondary electrophiles). (c) Yi, J.; Liu,
J.-H.; Liang, J.; Dai, J.-J.; Yang, C.-T.; Fu, Y.; Liu, L. Adv. Synth. Catal.
2012, 354, 1685 (palladium and nickel catalysts; primary and
secondary electrophiles). (d) Joshi-Pangu, A.; Ma, X.; Diane, M.;
Iqbal, S.; Kribs, R. J.; Huang, R.; Wang, C.-Y.; Biscoe, M. R. J. Org.
Chem. 2012, 77, 6629 (palladium catalyst; primary electrophiles).
(17) Hemeon, I.; Singer, R. D. In Science of Synthesis; Theime:
Stuttgart, Germany, 2002; Vol. 4, Chapter 4.4.9.
(18) Rudolph, A.; Lautens, M. Angew. Chem., Int. Ed. 2009, 48, 2656.
(19) Preliminary studies indicate that a lower yield of cross-coupling
product is observed if less than ∼20 equiv of DMA is present. Possible
roles for DMA include binding to nickel or increasing the dielectric
constant of the reaction medium.
(20) Notes: (a) Small amounts of products derived from hydro-
debromination of the electrophile or from homocoupling of the
nucleophile are sometimes observed. (b) Under our standard
conditions, the addition of ligand 1 is deleterious for cross-coupling.
(21) We have not yet attempted to separately optimize the yield for
this family of electrophiles.
■
Support has been provided by the National Institutes of Health
(National Institute of General Medical Sciences, R01-
GM62871) and the Gordon and Betty Moore Foundation
(Caltech Center for Catalysis and Chemical Synthesis). We
thank Dr. Alexander S. Dudnik for preliminary observations
and Dr. Junwon Choi for helpful discussions.
REFERENCES
■
(1) Handbook of Reagents for Organic Synthesis: Reagents for Silicon-
Mediated Organic Synthesis; Fuchs, P. L., Ed.; Wiley: Chichester, U.K.,
2011.
(2) Organosilicon Chemistry V: From Molecules to Materials; Auner, N.,
Weis, J., Eds.; Wiley-VCH: Weinheim, Germany, 2004.
(3) Flusilazole, silthiofam, and simeconazole are examples of
tetraorganosilanes that are employed in the agrochemical industry.
(4) For a recent review with leading references, see: Franz, A. K.;
Wilson, S. O. J. Med. Chem. 2013, 56, 388.
(5) The development of new strategies for the synthesis of
organosilanes continues to be an active area of research. For an
example of the synthesis of organosilanes (allylsilanes and vinylsilanes)
through a silyl-Heck approach, see: McAtee, J. R.; Martin, S. E. S.;
Ahneman, D. T.; Johnson, K. A.; Watson, D. A. Angew. Chem., Int. Ed.
2012, 51, 3663.
(6) For overviews of recent advances as well as leading references,
see: (a) Nakajima, Y.; Shimada, S. RSC Adv. 2015, 5, 20603.
(b) Troegel, D.; Stohrer, J. Coord. Chem. Rev. 2011, 255, 1440.
(7) (a) For a recent example of isomerization during the
hydrosilylation of internal olefins, see: Buslov, I.; Becouse, J.; Mazza,
S.; Montandon-Clerc, M.; Hu, X. Angew. Chem., Int. Ed. 2015, 54,
14523. (b) For an example of poor regioselectivity in the
hydrosilylation of internal olefins, see: Benkeser, R. A.; Muench, W.
C. J. Am. Chem. Soc. 1973, 95, 285.
(8) For leading references, see: Science of Synthesis; Theime: Stuttgart,
Germany, 2002; Vol. 4, Chapter 4.4.
(9) We are aware of only a few examples, most of which proceed in
low yield and/or involve special (reactive) coupling partners. See:
(22) For selected examples of cross-couplings of unactivated tertiary
alkyl halides, see: (a) Tsuji, T.; Yorimitsu, H.; Oshima, K. Angew.
Chem., Int. Ed. 2002, 41, 4137. (b) Mitamura, Y.; Asada, Y.; Murakami,
K.; Someya, H.; Yorimitsu, H.; Oshima, K. Chem. - Asian J. 2010, 5,
1487. (c) Reference 15. (d) Zultanski, S. L.; Fu, G. C. J. Am. Chem.
Soc. 2013, 135, 624. (e) Wu, X.; See, J. W. T.; Xu, K.; Hirao, H.;
Roger, J.; Hierso, J.-C.; Zhou, J. Angew. Chem., Int. Ed. 2014, 53,
13573. Also see: (f) Wang, X.; Wang, S.; Xue, W.; Gong, H. J. Am.
Chem. Soc. 2015, 137, 11562.
(23) For recent discussions and leading references, see: (a) Liang, Y.;
Fu, G. C. Angew. Chem., Int. Ed. 2015, 54, 9047. (b) Schley, N. D.; Fu,
G. C. J. Am. Chem. Soc. 2014, 136, 16588.
(24) We have observed similar trends in nickel-catalyzed borylations
of unactivated alkyl bromides (see ref 15).
́ ́
(a) Brefort, J.-L.; Corriu, R. J. P.; Guerin, C.; Henner, B. J. L.; Man, W.
W. C. W. C. Organometallics 1990, 9, 2080. (b) Itami, K.; Terakawa,
K.; Yoshida, J.-i.; Kajimoto, O. J. Am. Chem. Soc. 2003, 125, 6058 (one
example reported on page S6 of the Supporting Information, 22%
yield). (c) Eisch, J. J.; Gupta, G. J. Organomet. Chem. 1979, 168, 139
(cyclopropyl-MgBr as the nucleophile, 37% yield). (d) Kang, K.-T.;
Yoon, U. C.; Seo, H. C.; Kim, K. N.; Song, H. Y.; Lee, J. C. Bull.
Korean Chem. Sci. 1991, 12, 57 (a silacyclobutane as the electrophile).
(10) For an example of an unsuccessful coupling (0% yield), see:
Murakami, K.; Hirano, K.; Yorimitsu, H.; Oshima, K. Angew. Chem.,
Int. Ed. 2008, 47, 5833.
(25) Henry-Riyad, H.; Montanari, F.; Quici, S.; Studer, A.; Tidwell,
T. T.; Vogler, T. In Handbook of Reagents for Organic Synthesis; Fuchs,
P. L., Ed.; Wiley: Chichester, U.K., 2013; pp 620−626.
(26) For details, see the Supporting Information.
(11) For selected examples, see: (a) Lefort, M.; Simmonet, C.; Birot,
M.; Deleris, G.; Dunogues, J.; Calas, R. Tetrahedron Lett. 1980, 21,
1857. (b) Tobisu, M.; Kita, Y.; Ano, Y.; Chatani, N. J. Am. Chem. Soc.
2008, 130, 15982. (c) Vyas, D. J.; Oestreich, M. Angew. Chem., Int. Ed.
2010, 49, 8513. (d) Hazra, C. K.; Oestreich, M. Org. Lett. 2012, 14,
4010. (e) Zarate, C.; Martin, R. J. Am. Chem. Soc. 2014, 136, 2236.
(f) Huang, Z.-D.; Ding, R.; Wang, P.; Xu, Y.-H.; Loh, T.-P. Chem.
Commun. 2016, 52, 5609.
(12) Eaborn, C.; Griffiths, R. W.; Pidcock, A. J. Organomet. Chem.
1982, 225, 331. After the submission of our study, a report of copper-
catalyzed silylation of primary alkyl triflates was described. See:
Scharfbier, J.; Oestreich, M. Synlett 2016, 27, 1274.
(13) For related work, see: (a) Copper-catalyzed couplings that
proceed in low (<40%) yield: Okuda, Y.; Morizawa, Y.; Oshima, K.;
Nozaki, H. Tetrahedron Lett. 1984, 25, 2483. (b) Rhodium-catalyzed
substitution of a cyano group with a silyl group (48% yield): ref 11b.
D
DOI: 10.1021/jacs.6b03465
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