Copper-Catalyzed Borylative Methylation of Alkyl Iodides with CO as the C1 Source: Advantaged by Faster Reaction of CuH over CuBpin

Article abstract of DOI:10.1002/anie.202102197

CuH and CuBpin are versatile catalysts and intermediates in organic chemistry. However, studies that involve both CuH and CuBpin in the same reaction is still rarely reported due to their high reactivity. Now, a study on CuH- and CuBpin-catalyzed borylative methylation of alkyl iodides with CO as the C1 source is reported. Various one carbon prolongated alkyl boranes (RCH₂Bpin and RCH(Bpin)₂) were produced in moderate to good yields from the corresponding alkyl iodides (RI). In this cooperative system, CuH reacts with alkyl iodide faster than CuBpin.

Full text of DOI:10.1002/anie.202102197

Angewandte
Communications
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How to cite: Angew. Chem. Int. Ed. 2021, 60, 11730–11734
International Edition:
German Edition:
doi.org/10.1002/anie.202102197
doi.org/10.1002/ange.202102197
Borylmethylation
Copper-Catalyzed Borylative Methylation of Alkyl Iodides with CO as
the C1 Source: Advantaged by Faster Reaction of CuH over CuBpin
Fu-Peng Wu and Xiao-Feng Wu*
Dedicated to Professor Christian Bruneau
Abstract: CuH and CuBpin are versatile catalysts and
intermediates in organic chemistry. However, studies that
involve both CuH and CuBpin in the same reaction is still
rarely reported due to their high reactivity. Now, a study on
CuH- and CuBpin-catalyzed borylative methylation of alkyl
iodides with CO as the C1 source is reported. Various one
carbon prolongated alkyl boranes (RCH2Bpin and RCH-
(Bpin)2) were produced in moderate to good yields from the
corresponding alkyl iodides (RI). In this cooperative system,
CuH reacts with alkyl iodide faster than CuBpin.
Copper complexes are undoubtedly one of the most
prevalent transition metals for organic transformations due
to their abundancy and low toxicity.[1] Among the numerous
achievements, Chan-Lam, Ullman[2] and Glaser[3] coupling
are representative examples on the use of copper catalysts
during the past decades. With the increasing interests in
transition metal catalysts, the development of active metal
intermediates with high reactivity, easy manipulation, and
broad applicability, have experienced significant advances in
recent years. Recently, remarkable new organic transforma-
tions were achieved employing copper(I) hydride (CuH)[4] or
copper(I) boryl (CuBpin)[5] as the active catalytic species.
Actually, CuH was discovered in the early 1800s,[6] and started
to be explored in synthetic organic chemistry by Stryker since
1980s.[7] During the last decades, CuH species together with
an appropriate ligand have been shown undergo efficient
insertion reactions with a range of unsaturated substrates,
reactions including hydroamination,[8] hydroarylation,[9]
hydroamidation[10] and so on.[11] On the other hand, copper-
catalyzed borofunctionalization[5a] of unsaturated substrates
offers a promising strategy for the synthesis of organoboron
compounds. The key step in the borofunctionalization
reactions is the generation and migration insertion of
CuBpin (Scheme 1a). Despite the impressive achievements,
the use of highly reactive CuH and CuBpin in the same
reaction is rarely studied.[12]
Scheme 1. Strategies for CuH and CuBpin cooperation.
On the other hand, carbonylative coupling reaction of
C(sp3)-hybridized electrophiles is still a challenge due to their
lower rate of oxidative addition than b-hydride elimination.
Several recent reports from Mankadꢀs group described the
critical role of copper catalysis in the carbonylation of alkyl
electrophiles (Scheme 1b).[13,14] For example, they developed
the first procedure on copper-catalyzed carbonylative bory-
lation of alkyl halides with B2pin2 toward the synthesis of alkyl
potassium acyltrifluoroborates.[14b] A Cu-catalyzed reductive
carbonylation of alkyl iodides to give one-carbon-extended
alcohol products was developed in 2018 as well.[14c] The
reaction was shown to proceed via two times CuH-mediated
reductions with aldehyde as the intermediate. Additionally,
a copper-catalyzed deoxygenative gem-diborylation and gem-
silylborylation of aldehydes and ketones was reported by Liu,
Lan and their co-workers.[15] The borylation or silylation of a-
oxyboronates was promoted by base. However, the trans-
forming of aldehydes or ketones into the corresponding a-
oxyboronates require the presence of copper catalyst and
B2pin2.
[*] F.-P. Wu, Prof. Dr. X.-F. Wu
Leibniz-Institut fꢀr Katalyse e.V. an der Universitꢁt Rostock
Albert-Einstein-Straße 29a, 18059 Rostock (Germany)
and
Dalian National Laboratory for Clean Energy, Dalian Institute of
Chemical Physics, Chinese Academy of Sciences
116023, Dalian, Liaoning (China)
Under all those backgrounds, we hypothesized that
a borylative methylation could be achieved by trapping the
alkyl radical using both Cu-H and Cu-Bpin species under CO
atmosphere. However, the major challenge of this approach is
the competition between direct borylation or protonation of
alkyl halides and CO insertion, and also the competitive
reaction between CuH and CuBpin intermediates. Herein, we
present a study on CuH/CuBpin-catalyzed borylative meth-
E-mail: xiao-feng.wu@catalysis.de
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202102197.
11730
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ylation of alkyl electrophiles. It is noteworthy that the
reactivity of CuH toward alkyl iodide in this context is
faster than CuBpin (Scheme 1c).
can be generated preferentially in 52% yield by carefully fine-
tuning the loading of LiOtBu. It is important to mention that
direct borylation product (RBpin) could be detected as well
during the optimization process.
To study this borylative methylation transformation, (2-
iodoethyl)cyclohexane 1a, bis(pinacolato)diboron (B2pin2)
(2.5 equiv) and methyldiethoxysilane (DEMS) (1.2 equiv)
were selected as the model substrates for detailed studies. As
shown in Table 1, by using CuCl as the catalyst and NaOEt as
the base at 1008C under 3 bar CO atmosphere for 16 h, the
desired diborane product 2a was successfully obtained in
60%, and no borylmethylation product 3a was detected. In
the testing of copper catalyst system, CuCl with different
NHC ligands were tested, such as IPr, IMes, MeIPr, MeIMes,
and SIMes, decreased catalytic activities were obtained
(Table 1, entries 2–6). The loading of base has a significant
effect on the reaction outcome (for details see the Supporting
Information, Tables S5), and the best result was achieved
using 2.1 equivalents of NaOEt, which delivered the desired
product 2a in 63% yield (Table 1, entry 7). The yield can be
further improved to 71% by increasing the CO pressure to
10 bar (Table 1, entry 8). Ethylcyclohexane was the major
byproduct formed via the protonation of 1a. It is worth
pointing out that the reactivity of CuH is not affected by the
high concentration of B2pin2. Impressively, the main boryl-
methylation product 3a was obtained by increasing the
loading of DEMS and reducing B2pin2 to 1.2 equivalents.
Further evaluation of a range of base revealed that LiOtBu
was identified as the best choice and providing the product 3a
in 47% yield (Table 1, entries 9–14). The desire product 3a
With the optimal reaction conditions in hand, we first
investigated the scope of alkyl iodides for this borylative
methylation. As shown in Table 2, this procedure shows good
versatility, and a variety of valuable functional groups are
tolerated. Iodomethane (2h), iodoethane (2i), and other alkyl
iodides with different carbon chain length (2a–2k) were
tested; the corresponding products were successfully pre-
pared in moderate to good yields. Alkyl iodides containing
synthetically relevant functional groups such as trifluoro-
methyl (2l), pentafluoroethyl (2m), and alkene (2v) under-
went this transformation smoothly. In addition, ether-con-
taining alkyl iodides (2n–2r) can be utilized in this borylative
methylation reaction as well. Heterocycles such as thiophene
(2s), pyrrole (2t), and indole (2u) were also compatible here.
More complexed alkyl iodide (vitamin E, 2w) was success-
fully transformed under our optimal conditions, giving the
target product in moderate yield. The use of ICy·HBF4 as the
ligand was required for the reaction of less reactive second
alkyl iodides (2x and 2y). Subsequently, a scope on carbon-
ylative borylmethylation was also performed (Table 3). Sim-
ilarly, alkyl iodides bearing difference chain length (3a, 3b
and 3c), ether (3d), pyrrole (3e), and indole (3 f) able to
produce the borane products in moderate yields.
Furthermore, several related leaving groups were also
tested, such as Br, OTs and Oms, no positive effect on this
borylative methylation reaction
could be obtained. Finally, in the
Table 1: Optimization of the reaction conditions.
testing of other boron sources, for
instance, B2nep2, B2cat2, and Bpin-
SiMe2Ph, decreased or no yield
could be achieved (Table 4).
To illustrate the usefulness of
this borylative methylation proce-
dure, further transformations of
the obtained 1,1-diborylalkane
product 2a were conducted. As
showed in Scheme 2, benzylbory-
lalkane 4a can be achieved via
a Suzuki–Miyaura cross-coupling
Entry
[Cu]
B2pin2
[equiv]
DEMS
[equiv]
Base
Yield [%]
2a
3a
1
2
3
4
5
6
7
CuCl
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
3.0
3.0
3.0
3.0
3.0
3.0
3.0
NaOEt (2.0)
NaOEt (2.0)
NaOEt (2.0)
NaOEt (2.0)
NaOEt (2.0)
NaOEt (2.0)
NaOEt (2.1)
NaOEt (2.1)
NaOEt (2.1)
NaOtBu (2.1)
LiOtBu (2.1)
KOtBu (2.1)
LiOMe (2.1)
NaOtAmyl (2.1)
LiOtBu (1.5)
60
14
26
55
27
17
63
0
0
10
0
9
7
0
0
42
18
47
0
with bromobenzene, which selec-
IPrCuCl
IMesCuCl
MeIPrCuCl
MeIMesCuCl
SIMesCuCl
CuCl
CuCl
CuCl
CuCl
CuCl
[16]
À
tively activating one C B bond.
Moreover, diborylalkane 2a serves
as an excellent alkylation reagent
and can be converted into high-
value product in good yield, such as
alkylation of quinoline N-oxides.
For a better mechanistic under-
8[b]
9[b,c]
10[b,c]
11[b,c]
12[b,c]
13[b,c]
14[b,c]
15[b,c]
71 (68)[d]
24
13
10
0
13
9
standing,
experiments
several
were
mechanistic
performed
CuCl
CuCl
CuCl
CuCl
(Scheme 3). When a radical-trap-
ping reagent TEMPO was added to
the diborylmethylation reaction,
product 2a could not be observed
and the radical-trapped product 5a
was isolated in 42% yield (Sche-
35
0
0
52 (47)[d]
[a] Reaction conditions: 1a (0.2 mmol), [Cu] (10 mol%), B2pin2, [Si-H], base, CO (3 bar), 1,4-dioxane
(0.2 M), stirred at 1008C for 16 h, yields were determined by GC analysis using hexadecane as the
internal standard. [b] CO (10 bar). [c] THF (0.2 M) as solvent. [d] Isolated yield.
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Table 2: Reaction scopes: Testing of alkyl iodides for borylative methylation with CO as the C1 source.[a]
[a] Standard conditions: 1 (0.2 mmol), CuCl (10 mol%), B2pin2 (2.5 equiv), DEMS (1.2 equiv), NaOEt (2.1 equiv), 1,4-dioxane (0.2 M), CO (10 bar),
stirred at 1008C for 16 h, isolated yield. [b] ICy·HBF4 (10 mol%) as the ligand.
Table 3: Reaction scopes: Testing of alkyl iodides for borylative meth-
Table 4: Testing of the leaving groups and boron sources.
ylation.[a]
[a] Reaction conditions: 1 (0.2 mmol), CuCl (10 mol%), [B] (2.5 equiv),
DEMS (1.2 equiv), NaOEt (2.1 equiv), CO (10 bar), 1,4-dioxane (0.2 M),
stirred at 1008C for 16 h, yields were determined by GC analysis using
hexadecane as internal standard.
[a] Standard conditions: 1 (0.2 mmol), CuCl (10 mol%), B2pin2
(1.2 equiv), DEMS (3.0 equiv), LiOtBu (1.5 equiv), THF (0.2 M), CO
(10 bar), stirred at 1008C for 16 h, isolated yield; A part of the
inseparable borylation of iodoalkanes are in brackets [b] Yield of the
corresponding alcohol after oxidation.
me 3a). In addition, a radical clock experiment was per-
formed in this reaction with (iodomethyl)cyclopropane as the
coupling partner. The corresponding diborylalkane 2v,
derived from radical ring oping, was obtained in 37% yield
(Scheme 3a). The radical trapping and clock experiment
confirmed that a radical intermediate may participated in this
diborylmethylation process. In our control experiments, 2a
was successfully used to produce 3a in 32% yields, indicating
that this is also a possible pathway for 3a production
(Scheme 3b, i). The target gem-diborylation product can be
produced in 13% yield from aldehyde under our standard
conditions (Scheme 3b, ii). This result shown that aldehyde
Scheme 2. Select derivatization reaction with 2a.
can be the intermediate, however fine tunings are needed to
improve the reaction efficiency as this transformation is
known to be very sensitive with reaction parameters. No
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Scheme 4. Proposed mechanism.
In summary, an interesting CuH- and CuBpin-catalyzed
borylative methylation of alkyl iodides with CO as the C1
source has been developed. Various alkyl iodides were
transformed into the desired borane and diborane compounds
in moderate to good yields. In this cooperative carbonylation
system, CuH reacts with alkyl iodide faster than CuBpin.
Scheme 3. Mechanistic experiments.
desired product could be detected in the absence of copper
catalyst proven the important of copper catalyst for the
borylation step which is agree with previous report (Sche-
me 3b, iii).[15] Finally, the possibility that this reaction go
through acylboran intermediate can be excluded as well. As
no acylbroan could be detected in 11B NMR in our control
experiment in the absence of DEMS (Scheme 3b, iv).
Acknowledgements
We thank the Chinese Scholarship Council for financial
support. We also thank the analytical department of Leibniz
Institute for Catalysis at the University of Rostock for their
excellent analytical service.
Based on the above information and relevant previous
reports,[14,15]
a possible reaction pathway is proposed
Conflict of interest
(Scheme 4). Initially, the copper catalyst reacted with metal
alkyl oxide MOR’ and silane to generate the Cu-H complex.
Subsequently, Cu-H reacted with alkyl iodide via radical
intermediate and produce acyl-Cu-H II complex after a CO
coordination and insertion step. Subsequently, the aldehyde
was formed after reductive elimination.[14c] In the catalytic
cycle on the right, Cu-Bpin, generated from B2pin2 and
The authors declare no conflict of interest.
Keywords: alkyl iodides · borylmethylation · carbonylation ·
copper boryl · copper hydride
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Manuscript received: February 11, 2021
Revised manuscript received: March 1, 2021
Accepted manuscript online: March 10, 2021
Version of record online: April 16, 2021
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