Cu-Catalyzed Carbonylative Silylation of Alkyl Halides: Efficient Access to Acylsilanes

Article abstract of DOI:10.1021/jacs.9b12043

A Cu-catalyzed carbonylative silylation of unactivated alkyl halides has been developed, enabling efficient synthesis of alkyl-substituted acylsilanes in high yield. A variety of functional groups are tolerated under the mild reaction conditions, and prim

Full text of DOI:10.1021/jacs.9b12043

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Communication
Cu-Catalyzed Carbonylative Silylation of
Alkyl Halides: Efficient Access to Acylsilanes
Li-Jie Cheng, and Neal P. Mankad
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 18 Dec 2019
Downloaded from pubs.acs.org on December 18, 2019
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Cu-Catalyzed Carbonylative Silylation of Alkyl Halides: Efficient
Access to Acylsilanes
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Li-Jie Cheng and Neal P. Mankad*
Department of Chemistry, University of Illinois at Chicago, 845 W. Taylor St., Chicago, IL 60607
Supporting Information Placeholder
(Scheme 1b).8 Although these protocols allow concise
ABSTRACT: A Cu-catalyzed carbonylative silylation of
synthesis of acylsilanes under mild conditions, the use of
unactivated alkyl halides has been developed, enabling
moisture sensitive substrates such as acyl chlorides or
efficient synthesis of alkyl-substituted acylsilanes in high
anhydrides restricts their wide application.9 In this regard,
yield. A variety of functional groups are tolerated under
carbonylation reactions stand out as an attractive
approach to synthesize acylsilanes, as they use CO to
introduce the carbonyl group into simple precursors.
Earlier, Seyferth and Weinstein reported the
carbonylation of organolithium compounds at -110 °C to
give acylsilanes.10 Later, Beller reported a more practical
palladium-catalyzed carbonylative silylation of aryl
iodides to form benzoylsilanes (Scheme 1c).11 However,
to our best knowledge, the synthesis of alkyl-substituted
acylsilanes via carbonylation of alkyl halides has not been
investigated. This is probably due to the fact that
compared to aryl electrophiles, the carbonylation of alkyl
electrophiles is still a challenge12 because of their
notoriously slow rate of oxidative addition as well as
competitive 훽-hydride elimination under carbonylative
conditions.
the mild reaction conditions, and primary, secondary and
tertiary alkyl halides are all applicable. The practical
utility of this method has been demonstrated in the
synthesis of acylsilanes bearing different silyl groups as
well as in situ reduction of a product to the corresponding
훼-hydroxylsilane in one pot. Mechanistic experiments
indicate that a silylcopper intermediate activates alkyl
halides by single electron transfer to form alkyl radical
intermediates, and that carbon-halogen bond cleavage is
not involved in the rate-determining step.
Organosilanes are highly important compounds and
widely used in organic synthesis and materials science.1
In particular, acylsilanes,2 in which silicon units are
attached to carbonyl groups, are versatile synthetic
building blocks that have been used in various intriguing
transformations with increasing frequency recently,
including methods involving Brook-type rearrangements
that are unique to the acyl silane moiety.3 Given the
importance of acylsilanes, much effort has been devoted
to their synthesis.4 However, most of the current methods
either require multi-step preparation or exhibit limited
substrate scope. For example, the classical route reported
Scheme 1. Synthesis of Acylsilanes
by
Brook
and
Corey
needs
tedious
protection/deprotection steps to access acylsilanes from
aldehydes via dithiane intermediates (Scheme 1a).4a, 4b
Although the direct addition of anionic silyl nucleophiles
to carboxylic acid derivatives provides acylsilanes in a
single step, it typically requires use of stoichiometric
silylcopper reagents5 or very reactive silyllithium
reagents that limit functional group compatibility.6
Notably, Pd-catalyzed silylation of acyl chlorides has
been reported to enable synthesis of acylsilanes using
disilane or silyltin reagents.7 In addition, Riant recently
developed the Cu-catalyzed silylation of anhydrides with
silylborane reagents to approach mainly benzoylsilanes
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Recently, our group has developed Cu-catalyzed
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r.t instead of 60 oC
60
90
72
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<5
<5
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carbonylative C-C coupling reactions of alkynes with
alkyl halides13 and reductive carbonylation of unactivated
alkyl halides14 based on the (NHC)Cu-H or (NHC)Cu-
Bpin catalysis (NHC = N-heterocyclic carbene).15 In
these reactions, acyl radicals were generated from alkyl
halides and then coupled with various organocopper
nucleophiles to afford corresponding carbonyl
compounds. We hypothesized that a related strategy
could serve as a platform for the synthesis of acylsilanes
from alkyl halides by trapping the acyl radical using
nucleophilic silylcopper species generated from the
copper catalysts and a silylborane16 (Scheme 1d). We
expected the formed acylsilanes would be inert towards
further nucleophilic addition of a second silylcopper
species. However, the major challenge to overcome with
this approach is the competitive direct silylation of alkyl
halides reported by Fu and Oestreich.17 Herein, we
present our development of a direct, catalytic synthesis of
alkyl-substituted acylsilanes from readily available alkyl
halides through a Cu-catalyzed carbonylative silylation
process.
3 atm CO instead of 6 atm
1 atm CO instead of 6 atm
a Reaction performed on 0.05 mmol scale. b Yield determined
by 1H NMR integration against an internal standard.
We began our work by studying the reaction of 1-
iodooctane with PhMe2Si-Bpin under 6 atm CO pressure.
After intensive investigation,18 we found that the desired
acylsilane 2a could be selectively generated in 93% yield
when commercially available IPrCuCl was used as
catalyst in the presence of NaOPh as the base and 1,4-
dioxane as solvent (Table 1, entry 1). A control
experiment demonstrated that copper catalyst was
necessary for the reaction to occur (Table 1, entry 2). The
structure of NHC ligand had a significant effect on the
reaction: while ClIPr ligand gave slightly lower yield
(Table 1, entry 3), SIPr and MeIPr ligands dramatically
decreased the yield (Table 1, entry 4-5). Interestingly, less
sterically hindered IMes ligand gave no product, and the
alkyl silane 3a was generated in high yield (Table 1, entry
6). The use of a less reactive electrophile, 1-bromooctane,
provided the product in only 16% yield, and no reactivity
was found with 1-chlorooctane (Table 1, entry 7-8). No
desired acylsilane product was found when other bases
such as NaOMe and NaOtBu were used, although low
yield of product was obtained with LiOMe (Table 1, entry
9-11). Reducing the amount of PhMe2Si-Bpin to 1.2
equivalents or amount of NaOPh to 2.0 equivalents still
affords the product in 89% and 83% yield, respectively
(Table 1, entry 12-13). Changing the solvent to THF gave
the product in slightly lower yield, and much lower yield
was obtained with toluene as solvent (Table 1, entry 14-
15). Performing the reaction at room temperature led to
generation of a significant amount of alkyl silane
byproduct (Table 1, entry 16). It is noteworthy that,
although we typically performed reactions under 6 atm
CO pressure, conducting the reaction either under 3 atm
or under atmospheric CO pressure also afforded the
desired product in 90% and 72% yield, respectively
(Table 1, entry 17-18).
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Table 1. Optimization Studiesa
variations from optimal
conditions
2a
3a
entry
(%)b
(%)b
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2
3
4
5
None
93
0
<5
0
No IPrCuCl
ClPrCuCl instead of IPrCuCl
MePrCuCl instead of IPrCuCl
SIPrCuCl instead of IPrCuCl
83
30
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<5
<5
<5
IMesCuCl instead of
IPrCuCl
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<5
80
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Octyl-Br instead of Octyl-I
Octyl-Cl instead of Octyl-I
NaOMe instead of NaOPh
NaOtBu instead of NaOPh
LiOMe instead of NaOPh
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0
<5
0
With the optimal conditions in hand, we next
investigated the substrate scope. The mild reaction
conditions allow the use of a variety of alkyl iodides
containing different remote functional groups, including
benzyl ether (2c), chloroalkyl (2d) and terminal alkenes
(2n). Heterocycles such as furan (2e) and thiophene (2f)
were also compatible, although moderate yield was found
with the substrate bearing an indolyl group (2g). The
trifluoromethyl, ester, cyano, chloro and bromo groups on
a remote phenyl ring (2h-2l) also survived during the
reaction. However, deiodinaton side reaction was
observed with the iodo-substituted substrate (2m). Under
the same reaction conditions, the alkyl electrophile scope
could be extended from primary alkyl iodides to
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<5
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1.2 equiv PhMe2Si-Bpin
instead of 1.5
12
89
<5
2.0 equiv NaOPh instead of
3.0
13
14
15
83
75
25
<5
<5
<5
THF instead of 1, 4-dioxane
toluene instead of 1, 4-
dioxane
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secondary alkyl iodides. Both acylic and cyclic alkyl
the acylsilane could be further reduced by the same
copper catalyst (Scheme 2d). Thus, this method also
provides an efficient way to access to synthetically useful
훼-hydroxylsilanes20 from alkyl halides in one pot.
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iodides gave the desired product in good yield. Increasing
the steric hindrance of secondary alkyl iodide (2o-2r) had
no effect on the yield. Ether (2s) and N-Boc (2t)
functional groups within the cyclic electrophile were both
tolerated. Moreover, we were delighted to find this
method was also applicable to the more challenging
tertiary alkyl electrophiles (2u-2y). Tertiary alkyl
bromides were found to give products in higher yield than
the corresponding iodides, which possibly suffer from
elimination side reactions under the basic conditions.
Scheme 2. Synthetic Utility
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Table 2. Substrate Scope of Alkyl Halidesa
Next, several control experiments were performed to
explore the mechanism. Previously, we have identified
that copper-catalyzed carbonylative C-C coupling13 and
reductive carbonylation of alkyl halides14 proceed via
alkyl radical intermediates. For carbonylative silylation,
our observations are also consistent with a radical
mechanism. For example, when the TEMPO was added
into the reaction, the product formation was inhibited and
1
radical trapping product 7 was detected by H NMR
(Scheme 3a). In addition, radical clock experiment was
performed with iodoalkane 10, and the cyclization
product 11 was isolated in 86% yield (Scheme 3b). We
also prepared silylcopper species IPrCu-SiMe2Ph (13)21
and performed stoichiometric reactions of 13 with
primary alkyl iodide (1a) and tertiary alkyl iodide (1u)
under CO atmosphere. The corresponding acylsilanes
were formed in 54% and 99% yield, respectively (Scheme
3c), indicating that the silylcopper intermediate activates
both primary and tertiary alkyl iodides by single electron
transfer to enable a radical carbonylation process. This is
contrast to our previous findings13b that no reaction was
observed between an alkenylcopper intermediate and
tertiary electrophiles in the absence of an initiator to start
an atom transfer carbonylation (ATC) radical chain
pathway.22 Moreover, we examined the relative rates of
product formation in a set of competition experiments
between primary, secondary, tertiary alkyl iodides.
Interestingly, similar yields of products were detected
a The reaction was conducted on 0.2 mmol scale. All yields
are isolated yields. b t-Butyl iodide was used as substrate.
To demonstrate the practical utility of this
methodology, we performed the reaction on 2.0-mmol
scale, obtaining the expected acylsilane in good yield
(Scheme 2a). In addition, the mild reaction conditions
provide the opportunity for late-stage carbonylative
silylation of natural products or drugs. For example, when
an estrone derivative 4 was subjected to the reaction
conditions, acylsilane 5 was diastereoselectively obtained
in excellent yield (Scheme 2b). Furthermore, apart from
PhMe2Si-Bpin as a silyl source, the less reactive Et3Si-
Bpin was also proved to be a good coupling partner at
elevated temperature,19 although Ph2MeSi-Bpin gave the
product in low yield under standard reaction conditions
(Scheme 2c). Moreover, after the reaction was complete,
by adding a hydrosilane to the reaction mixture, we found
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(Scheme 3d), which contrasts with previous reports that
more substituted alkyl halides tend to be more reactive
due to the generation of more thermodynamically stable
tertiary alkyl radicals.23 We reason that in our
carbonylative silylation reaction, the carbon-halogen
bond cleavage is not involved in the rate-determining
step.
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Scheme 3. Mechanistic studies
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In summary, we have developed an unprecedented
procedure to synthesize alkyl-substituted acylsilanes
from unactivated alkyl iodides via a Cu-catalyzed
carbonylative silylation. This protocol is applicable to
primary, secondary, and tertiary alkyl halides, and a
variety of functional groups can be tolerated under the
mild reaction conditions. The utility of this method was
demonstrated by the late-stage carbonylative silylation of
an estrone derivative as well as preparation of the
acylsilanes bearing different silyl groups. In addition, the
formed acylsilanes can be further reduced in situ by
adding a hydrosilane reagent. In contrast to our previous
findings in carbonylative C-C coupling reaction where
primary and tertiary electrophiles went through different
reaction pathways, mechanistic experiments indicate that
the silylcopper intermediate activates both classes of
alkyl iodides by single electron transfer to enable a radical
carbnylation process, with carbon-halogen bond cleavage
not being involved in the rate-determining step.
ASSOCIATED CONTENT
Supporting Information. The Supporting Information is
available free of charge on the ACS Publications website.
Experimental procedures & spectral data (PDF)
Based on these results and our previous work on
carbonylation of alkyl halides,12 we propose the following
catalytic mechanism (Scheme 4). First, silylcopper(I)
complex A was generated by the reaction of PhMe2Si-
Bpin with IPrCuOPh, which forms from IPrCuCl and
AUTHOR INFORMATION
Corresponding Author
,
NaOPh.24 25 Next, consistent with the radical silylation of
* npm@uic.edu
alkyl halides proposed by Oestreich,17b a single electron
transfer (SET) between compound A and the alkyl halide
generates an alkyl radical R ･ along with the
silylcopper(II) complex B. The radical species R･ then
undergoes carbonylation to give an acyl radical species
C,19 which is expected to be more reactive than the alkyl
radical species C and thus favorably collapses with
copper (II) complex B to form the copper(III)
intermediate D. Finally, reductive elimination affords the
acylsilane and regenerates the copper(I) catalyst.
ACKNOWLEDGMENT
Funding was provided by the NSF (CHE-1664632). We
thank Siling Zhao for donating some alkyl iodides.
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5
(a) Capperucci, A.; Degl’Innocenti, A.; Faggi, C.; Ricci, A.;
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6 (a) Fleming, I.; Ghosh, U. Synthesis of Acylsilanes from Amides and
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17
(a) Chu, C. K.; Liang, Y.; Fu, G. C. Silicon–Carbon Bond
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Nucleophiles with Unactivated Secondary and Tertiary Alkyl
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18 See Supporting Information for more details.
19
When the reaction was performed at 60°C, the starting material
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1a had only 30% conversion and acylsilane 6 was observed in 29%
yield by 1H NMR analysis.
20
For recent synthesis of 훼-hydroxylsilanes, see: (a) Cirriez, V.;
Rasson, C.; Hermant, T.; Petrignet, J.; Álvarez, J. D.; Robeyns, K.;
Riant, O. Copper-Catalyzed Addition of Nucleophilic Silicon to
Aldehydes. Angew. Chem. Int. Ed. 2013, 52, 1785–1788; (b) Rong, J.;
Oost, R.; Desmarchelier, A.; Minnaard, A. J.; Harutyunyan, S. R.
Catalytic Asymmetric Alkylation of Acylsilanes. Angew. Chem. Int.
Ed. 2015, 54, 3038–3042; (c) Nagy, A.; Collard, L.; Indukuri, K.;
Leyssens, T.; Riant, O. Enantio-, Regio- and Chemoselective Copper-
Catalyzed 1,2-Hydroborylation of Acylsilanes. Chem. Eur. J. 2019, 25,
8705-8708.
21
Kleeberg, C.; Cheung, M. S.; Lin, Z.; Marder, T. B. Copper-
Mediated Reduction of CO2 with pinB-SiMe2Ph via CO2 Insertion
into a Copper–Silicon Bond. J. Am. Chem. Soc. 2011, 133, 19060-
19063.
22
Reviews on radical carbonylation: (a) Schiesser, C. H. Wille, U.
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23 (a) Dudnik, A. S.; Fu, G. C. Nickel-Catalyzed Coupling Reactions
of Alkyl Electrophiles, Including Unactivated Tertiary Halides, To
Generate Carbon−Boron Bonds. J. Am. Chem. Soc. 2012, 134, 10693-
10697. (b) Wang, G.-Z.; Shang, R.; Cheng, W.-M.; Fu, Y. Irradiation-
Induced Heck Reaction of Unactivated Alkyl Halides at Room
Temperature. J. Am. Chem. Soc. 2017, 139, 18307-18312.
24
PhMe2Si-Bpin was reported to react with IPrCuOtBu to afford
IPrCu-SiMe2Ph, which was fully characterized: Kleeberg, C.; Cheung,
M. S.; Lin, Z.; Marder, T. B. Copper-Mediated Reduction of CO2 with
pinB-SiMe2Ph via CO2 Insertion into a Copper Silicon Bond. J. Am.
Chem. Soc. 2011, 133, 19060.
25
It is worthy to note that in the recent silylation work (ref 17b),
Oestreich has proposed an ionic release of silicon nucleophile pathway
to form a similar silylcopper intermediate, in which the formation of
PhMe2Si- from PhMe2Si-Bpin and base was found to be favorable by
density functional theory (DFT) analysis. In our case, no reaction was
observed when PhMe2Si-Bpin and NaOPh were stirred in 1,4-dioxane
at 60°C for 12 h.
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