Transition-Metal-Free Cross-Coupling by Using Tertiary Benzylic Organoboronates

Article abstract of DOI:10.1002/anie.202010251

The transition-metal-free cross-coupling of alkyl or aryl electrophiles by using tertiary benzylic organoboronates is reported. This reaction involves the generation of tertiary alkyl anions from organoboronates in the presence of an alkoxide base and then their substitution reactions. This protocol allows the simple and efficient construction of quaternary carbon centers.

Full text of DOI:10.1002/anie.202010251

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Accepted Article
Title: Transition-Metal-Free Cross-Coupling Using Tertiary Benzylic
Organoboronates
Authors: Mitsutaka Takeda, Kazunori Nagao, and Hirohisa Ohmiya
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Transition-Metal-Free Cross-Coupling Using Tertiary Benzylic
Organoboronates
Mitsutaka Takeda,[a] Kazunori Nagao,[a] and Hirohisa Ohmiya*[a][b]
Abstract: The transition-metal-free cross-coupling of alkyl or aryl
electrophiles using tertiary benzylic organoboronates is reported.
This reaction involves the generation of tertiary alkyl anions from
organoboronates in the presence of an alkoxide base and then their
substitution reactions. This protocol allows the simple and efficient
construction of quaternary carbon centers.
The reaction involves the generation of tertiary alkyl anions from
organoboronates in the presence of an alkoxide base and then
their substitution reactions under mild and transition-metal-free
conditions. This protocol allows the simple and efficient
construction of quaternary carbon centers.
A. Cross-couplings of tertiary alkylborons
TM
The preparation of quaternary carbon centers using cross-
coupling reactions has been identified as a key challenge in
organic synthesis. Cross-coupling reactions using a tertiary alkyl
organometallic nucleophile are a direct and reliable approach for
realizing highly congested quaternary carbon centers. Tertiary
alkylboron compounds are particularly attractive organometallic
reagents due to their high chemical stability and widespread
availability (Figure 1A, top).[1] Recent progress in the catalytic
preparation of tertiary alkylborons from various simple organic
molecules has been remarkable.[2] Nevertheless, cross-coupling
using tertiary alkylborons is still in its infancy given the limited
progress in recent years.[3,4] In particular, C(sp3)–C(sp3) cross-
coupling between tertiary alkylborons and alkyl electrophiles is
quite difficult. Obstacles to transition-metal catalysis are the slow
transmetalation from sterically encumbered nucleophiles and the
reductive elimination from the in situ-generated alkylmetal
complex, which is prone to β-hydride elimination.
problematic steps
■ transmetalation
■ reductive elimination
C
X
C
Bpin
nucleophilic
substitution
tertiary alkylboron
BASE
–
C
X
C
Figures
1B, C, D
carbanion
B. Aggarwarl’s work
R1 R2
Li+
–
Ar
R2
Bpin
R3
+
+
+
BF–
R3
R1
C. Morken’s work
R1 R2
R1 R2
NaOtBu
R3
Br
R3
pinB
pinB
Bpin
R4
R4
D. Tertiary alkylative cross-coupling of alkyl or aryl electrophiles (this work)
Alkylborons serve as alkyl anion equivalents through the
formation of borate species in the presence of an appropriate
base. However, cross-coupling using borate species, which is
derived from a tertiary alkylboron and a base, is underdeveloped
(Figure 1A, bottom). For example, Aggarwal and co-workers
demonstrated SE2’-type C(sp3)–C(sp3) cross-couplings between
trisubstituted allylboronates and activated alkyl electrophiles
such as tropylium cation, benzodithiolylium, and Eschenmoser’s
salt using organolithium reagents as a base (Figure 1B).[5]
Morken and co-workers revealed that the borate complex, which
is derived from 1,1-diborylalkanes and alkoxide bases, could
undergo deborylative C(sp3)–C(sp3) cross-coupling using alkyl
halides (Figure 1C).[6a] On the other hand, the process using
tertiary alkylborate species has not yet been applied to C(sp3)–
C(sp2) cross-coupling using aryl electrophiles.
R
1 R2
R3
Cl
X
R3
Ar1
R4
or
R4
1 R2
Bpin
KOtBu
R
+
or
Ar1
R
1 R2
Ar2
Ar1
Ar2
X = CN, OMe, F
Figure 1. Construction of quaternary carbon centers through cross-couplings
using tertiary alkylborons.
In numerous studies in this laboratory, we found that the
reaction of tertiary benzylboronate 1a (0.3 mmol) and 4-
chlorotetrahydro-2H-pyran (2a) (0.2 mmol) with a stoichiometric
amount of KOtBu (0.3 mmol) occurred in dioxane (1 mL) at
100 °C to produce the cross-coupling product 3aa in 87%
isolated yield (Table 1, entry 1).
Here, we report tertiary alkylative cross-coupling of alkyl or
aryl electrophiles using benzylic organoboronates (Figure 1D).[7]
The choice of bases was critical in the cross-coupling reaction
(Table 1, entries 2–6). The use of other alkali metal-based
tertiary butoxide bases, NaOtBu and LiOtBu, resulted in
moderate and no product yield, respectively (entries 2 and 3).
Highly basic and sterically demanding KHMDS was less
effective (entry 4). A small alkoxide base, KOMe, slightly
diminished the product yield (entry 5). The reaction efficiency
tended to increase as the ionic radius of the metal increased
[a]
[b]
M. Takeda, Dr. K. Nagao, Prof. Dr. H. Ohmiya
Division of Pharmaceutical Sciences, Graduate School of Medical
Sciences, Kanazawa University
Kakuma-machi, Kanazawa 920-1192, Japan
E-mail: ohmiya@p.kanazawa-u.ac.jp
Homepage: http://seimitsu.w3.kanazawa-u.ac.jp/eng/index
JST, PRESTO
4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan
(Li+ < Na+ < K+).[6a] PhLi showed moderate reactivity (entry 6).
[5]
Supporting information for this article is given as a link at the end of
the document.
The effect of the leaving group of the alkyl electrophile was
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10.1002/anie.202010251
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also evaluated (Table 1, entries 7–11). The reaction with
secondary alkyl fluoride resulted in recovery of the substrate
(entry 7). Secondary alkyl bromide and iodide gave a trace
amount of the desired alkylation product, along with an alkene
as the E2 elimination product (entries 8 and 9). Alkyl tosylate
underwent the desired alkylation reaction (entry 10), but alkyl
mesylate did not afford the product (entry 11).
A sugar derivative could be tertiary-alkylated with three benzyl
ether moieties remaining untouched (3ai). When a substrate
having a stereogenic center next to the halogenated carbon was
subjected to the reaction conditions, trans alkylated product 3bj
was obtained due to the steric nature. Primary alkyl chlorides
were found to be competent coupling partners (3ak, 3al). Two
enantioenriched secondary alkyl chlorides were examined, but
the reactions didn’t proceed (Table 2, bottom).
Table 1. Screening of conditions for cross-coupling between 1a and 2a.[a]
Table 2. Substrate scope of C(sp3)–C(sp3) cross-coupling [a]
KOtBu
R
2 R3
Me Ph
R5
2 R3
Cl
R
Cl
R5
Me Ph
Bpin
KOtBu
Me
+
dioxane
100 oC, 3 h
+
R1
Me
R1
R4
Bpin
dioxane
O
R4
100 oC, 3 h
O
1
2
3
1a
2a
3aa
alkyl boronates
Me Ph
Entry
Change from standard conditions
Yield (%)
of 3aab
Me Ph
Me
Me Ph
Me Ph
Ph
1
2
none
97 (87)
O
O
O
O
NaOtBu instead of KOtBu
LiOtBu instead of KOtBu
53
0
3
3ba, 68%
3ca, 49%
3da, 56%
3ea, 68%
4
KHMDS instead of KOtBu
KOMe instead of KOtBu
47
60
51
0
5
Me Ph
Me Ph
Me Ph
Me Me
Me
Me
6
PhLi instead of KOtBu
PhMe2Si
Me
O
O
O
O
7
F as leaving group instead of Cl
Br as leaving group instead of Cl
I as leaving group instead of Cl
OTs as leaving group instead of Cl
OMs as leaving group instead of Cl
8
0
3ga, 53%
3ha, 21%
OMe
3fa, 49%
3ia, n.d.
9
3
10
11
31
0
H
Ph
S
Me
Me
Me
Me
Me
Me
[a] Reaction conditions: 1a (0.3 mmol), 2a (0.2 mmol), KOtBu (0.3 mmol),
dioxane (1 mL), 100 °C, 3 h. [b] 1H NMR yield. Yield of the isolated product is
in parentheses. KHMDS, potassium hexamethyldisilazide. OTs, tosylate. OMs,
mesylate.
O
Me
O
O
O
3ja, 12%
3ka, 60%
3la, 28%
3ma, 22%
alkyl chlorides
With these optimized reaction conditions in hand, the scope of
the alkylboronates was investigated (Table 2, top).[8] Methyl,
vinyl, benzyl, and allyl groups instead of the butyl group of 1a
were tolerated (3ba–ea). The benzyl boronates having a bulky
substituent such as an isopropyl or cyclohexyl group participated
in the reactions to construct the highly congested contiguous sp3
carbon centers (3fa, 3ga). Replacement of the butyl group with a
SiMe2Ph substituent was tolerated, although the product yield
was low (3ha). The reaction with a non-benzyl boronate resulted
in no product being formed (3ia). Thus, the applicability of this
protocol seems to be limited to benzyl boronates, the results
indicating that the reaction would proceed through the formation
of the benzyl anion from the organoboronate (vide infra). A
secondary benzyl boronate drastically diminished the reaction
efficiency (3ja). Conversion of the phenyl group to other
aromatic rings such as the 1-naphthyl group was allowed in the
reaction (3ka). A methoxy substituent at the para-position of the
aromatic ring of the benzyl boronate resulted in low yield (3la).
Thiophene underwent the reaction, although the yield was
moderate (3ma).
Me Ph
Me Ph
Me Ph
nBu
Me Ph
Me
nBu
nBu
nBu
Me
3ab, 94%
3ac, 62%
3ad, 88%
3ae, 78%
Me Ph
Me Ph
nBu
Me Ph
Me Ph
O
nBu
OBn
nBu
nBu
O
NBn
OBn
O
OBn
3ai, 25%
3ag, 88%
3ah, 35%
3af, 73%
OSiMe2tBu
Me Me
Ph
Me
Me Ph
nBu
Me Ph
nBu
OBn
Me
trans-3bj, 58%[b]
3al, 97%
3ak, 71%
unsuccessful examples
N
H
H
H
Cl
H
H
H
Cl
The scope of alkyl chlorides was also examined in cross-
coupling using tertiary benzyl boronates (Table 2, middle).
Acyclic alkyl chloride was a suitable substrate (3ab). This
protocol was applied to various cyclic alkyl chlorides. Thus, 4-,
5-, 6-, 7- and 8-membered aliphatic rings could be utilized as
coupling partners (3ac–3af). The piperidine derivative and
acetal-substituted cyclohexyl chloride were allowed (3ag, 3ah).
[a] Reaction conditions: 1 (0.3 mmol), 2 (0.2 mmol), KOtBu (0.3 mmol),
dioxane (1 mL), 100 °C, 3 h. [b] The product was isolated after desilylation.
To understand how the borate intermediate, which is derived
from a tertiary alkylboronate and an alkoxide base, reacted with
the alkyl chloride, several experiments were conducted (Figure
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2). First, when enantioenriched chiral tertiary alkylboronate (R)-
1a was used as a substrate, a complete loss of chirality in the
product was observed (Figure 2A).[9] Subsequently, the reaction
of alkyl chloride 2a and benzyl potassium reagent, prepared by
the treatment of cumene 1b-H and Schlosser’s base,[10] was
examined (Figure 2B). The result was comparable to the
reaction of 1b and 2a shown in Table 2. In addition, NMR
yielded no product. The boron-substituted benzonitrile was
possible (5ad). Aryl nitriles having tBu, CF3, or OMe substituents
participated in the reaction, although the product yields were low
(5ae–5ag). Importantly, this reaction with the simple benzonitrile
afforded the corresponding product in good yield (5ah).
Replacement of the butyl with methyl, allyl, or cyclohexyl
substituents in the tertiary alkylboronate also provided the
products in high yield (5bi, 5ea and 5ga). 2-Cyanothiophene, 2-
cyanofurane and 2-pyrimidinecarbonitrile didn’t participate in this
reaction (data not shown).
The reactions with aryl electrophiles having other leaving
groups were examined (Table 3, middle). When 1a was
subjected to the reaction with 4- or 2-methoxypyridine, C–OMe
bond cleavage was observed (5aa and 5ab). 4- or 2-
Cyanomethoxybenzenes reacted with the tertiary alkylboronate
(5aj and 5ak). It was found that cyanomethoxybenzene has
different functional groups that can be activated depending on
the position of the substituent (see 5ag in Table 3, top). This
selectivity depended on the conjugative effect, electrostatic
attraction, and inductive effects. [14g]
spectroscopic studies support the formation of
a benzyl
carbanion through an alkoxide-mediated deborylative pathway
(see Figures S1–S6 in Supporting Information). These
experimental results indicated significant C–B bond cleavage
before the reaction with 2a. [11] Although the reduction potential
of the alkyl chloride is high, the reaction pathway involving single
electron transfer from the tertiary alkylborate to the alkyl chloride
followed by radical–radical coupling could also be considered.[12]
To gain further mechanistic information, the reaction with a
cis/trans mixture of 2m, which is used in typical radical clock
experiments, was conducted (Figure 2C). As a result, trans
alkylated product 3bm was obtained with recovery of the trans
isomer of substrate 2m. This result supported the idea that the
reaction would proceed through the SN2 type mechanism with
the alkyl chloride.
The protocol was applicable to fluorobenzene derivatives
(Table 3, bottom). Simple fluorobenzene participated in this
reaction (5ah). When substrates having cyano or phenyl groups
were subjected to the reaction, the corresponding products were
obtained in good yields (5aj and 5al).
A.
Me Ph
KOtBu
Me Ph
Me
+
Me
2a
Bpin
(R)-1a, 97% ee
dioxane
100 oC, 3 h
O
Table 3. Substrate scope of C(sp3)–C(sp2) cross-coupling [a]
3aa
58%, racemic
R1 R2
KOtBu
X
R1 R2
Bpin
Ar2
+
Ar1
B.
Ar1
dioxane
120 oC, 3 h
Ar2
Me Ph
Me
KOtBu/nBuLi
4
Me Ph
2a
1
5
Me Ph
(X = CN, OMe, F)
25 o
C
5 days
–
+
c-hexane
25 oC, 2 days
Me
Me
H
K
O
X = CN
1b-H
3ba, 48%
aryl nitrile
Me Ph
Me Ph
Me Ph
N
NC
Ar2
nBu
nBu
nBu
C.
Me Me
Me Ph
Me Ph
Me Bpin
N
N
5aa, 96%
5ab, 91%
5ac, n.d.
Me
Me
O
O
Me
1b
Me
Me
Me
Ph
KOtBu
trans-3bo, 27%
Me Ph
nBu
Me Ph
nBu
Me Ph
nBu
Me Ph
nBu
+
dioxane
100 oC, 3 h
OMe
Cl
Cl
O
O
Me
Me
tBu
Bpin
CF3
not detected
O
O
Me
O
O
5ad, 91%
5ae, 22%
5af, 27%
5ag, 39%
2o
cis/trans = 34:66
trans-2o
42% recovered
Me Ph
Me Ph
Me
Me Ph
Me Ph
Figure 2. Mechanistic studies
nBu
N
N
Encouraged by the results shown above, we turned our
attention to C(sp3)–C(sp2) cross-coupling with aryl electrophiles.
The high nucleophilicity of the tertiary benzylborate would be
effective for SNAr-type cross-coupling. Indeed, our protocol was
applicable to C(sp3)–C(sp2) cross-couplings using aryl
electrophiles having CN,[13] OMe[14] and F[15] leaving groups.
Specifically, the C(sp3)–C(sp2) cross-coupling between tertiary
alkylboronate 1a (0.2 mmol) and 4-cyanopyridine (4a) (0.1
mmol) occurred with a stoichiometric amount of KOtBu (0.2
mmol) in dioxane (0.5 mL) at 120 °C to produce the cross-
coupling product 5aa in 96% yield.
5bi, 94%
5ea, 77%
5ah, 68%
5ga, 88%
X = OMe
aryl ether
CN
Me Ph
nBu
Me Ph
Me Ph
nBu
Me Ph
nBu
MeO
Ar2
N
nBu
N
CN
5aa, 82%
5ab, 88%
5aj, 67%
5ak, 88%
X = F
aryl fluoride
Me Ph
nBu
Me Ph
nBu
Me Ph
nBu
F
Ar2
CN
Ph
With the optimized reaction conditions in hand, a variety of
aryl nitriles were subjected to this reaction (Table 3, top). 2-
Cyanopyridine was also tolerated, however, 3-cyanopyridine
5ah, 41%
5aj, 94%
5al, 66%
[a] Reaction conditions: 1 (0.2 mmol), 4 (0.1 mmol), KOtBu (0.2 mmol),
dioxane (0.5 mL), 120 °C, 3 h.
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10.1002/anie.202010251
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COMMUNICATION
2429−2437; c) C. Hwang, W. Jo, S. H. Cho, Chem. Commun. 2017, 53,
7573–7576; d) W. Jo, S.-y. Baek, C. Hwang, J Heo, M.-H. Baik, S. H. Cho,
J. Am. Chem. Soc. 2020, 142, 13235–13245.
Considering that aryl ethers or aryl fluorides are effective, the
reaction with aryl electrophiles would proceed through an ionic
SNAr mechanism. However, the reaction with aryl nitriles gave
the low yield and the small amount of homo-coupled product
which stems from tertiary benzylboronate was detected. Thus,
the reaction pathway of aryl nitriles would be contaminated with
a radical SNAr mechanism involving a single electron transfer
from tertiary benzylborate.[4c, 5a, 16]
[7] Y. Sato, K. Nakamura, K. Yabushita, K. Nagao, H. Ohmiya, Bull. Chem.
Soc. Jpn. 2020, 93, 1065–1069.
[8] In some cases, deborylprotonated product was detected.
[9] Treatment of (R)-1a and KOtBu in dioxane at 100 ˚C afforded the
deborylprotonated product. When PhLi was used instead of KOtBu on the
reaction between (R)-1a and 2a, a complete loss of chirality in 3aa was
observed
[10] W. Y. Lee, J. M. Salvador, K. Bodige, Org. Lett. 2000, 2, 931–932.
[11] R. D. Grigg, J.W. Rigoli, R. V. Hoveln, S. Neale, J. M. Schomaker, Chem.
Eur. J. 2012, 18, 9391–9396.
In summary, a transition-metal-free cross-coupling reaction for
the construction of quaternary carbon centers from tertiary
benzylboronates has been demonstrated. The protocol enabled
the use of alkyl or aryl electrophiles. Thus, this transformation
has expanded the scope of tertiary alkylative cross-coupling
using organoboronates. The reaction involves the generation of
tertiary alkyl anions from organoboronates in the presence of an
alkoxide base followed by their substitution reactions. Extending
the scope of this reaction to electrophiles is in progress.
[12] H. Fischer, J. Phys. Chem. 1969, 73, 3834–3838.
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Acknowledgements
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This work was supported by JSPS KAKENHI Grant Number
JP18H01971 (Scientific Research (B)), JP17H06449 (Hybrid
Catalysis), and JP20J20600 (JSPS Fellows) as well as JST,
PRESTO Grant Number JPMJPR19T2.
Keywords: cross-coupling
·
tertiary alkylation
·
tertiary
alkylboronate · quaternary carbon center · transition-metal-free
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10.1002/anie.202010251
Angewandte Chemie International Edition
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The tertiary alkylative cross-coupling of alkyl or aryl electrophiles using benzylic organoboronates is reported. This reaction involves
the generation of tertiary alkyl anions from organoboronates in the presence of an alkoxide base and then their substitution reactions
under mild and transition-metal-free conditions.
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