Tertiary alkylations of aldehydes, ketones or imines using benzylic organoboronates and a base catalyst

Article abstract of DOI:10.1246/BCSJ.20200122

The KHMDS-catalyzed tertiary alkylation of aldehydes, ketones or imines using tertiary benzylic organoboronates is reported. This protocol permitted the use of tertiary benzylic alkylboronates as the tertiary alkyl anion for construction of highly congested contiguous sp³ carbon centers. The mild and transition-metal-free reaction conditions are attractive features of the protocol.

Full text of DOI:10.1246/BCSJ.20200122

Advance Publication Cover Page
Tertiary Alkylations of Aldehydes, Ketones or Imines Using Benzylic
Organoboronates and a Base Catalyst
Yukiya Sato, Kei Nakamura, Kenya Yabushita,
Kazunori Nagao, and Hirohisa Ohmiya*
Advance Publication on the web May 15, 2020
doi:10.1246/bcsj.20200122
© 2020 The Chemical Society of Japan
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Publication manuscripts.

Tertiary Alkylations of Aldehydes, Ketones or Imines Using Benzylic
Organoboronates and a Base Catalyst
Yukiya Sato, Kei Nakamura, Kenya Yabushita, Kazunori Nagao, and Hirohisa Ohmiya*1
1Division of Pharmaceutical Sciences, Graduate School of Medical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192,
Japan
E-mail: ohmiya@p.kanazawa-u.ac.jp
Hirohisa Ohmiya
Hirohisa Ohmiya received his Ph.D. degree from Kyoto University in 2007 under the supervision of Professor Koichiro
Oshima. He spent one year as a JSPS postdoctoral fellow in the group of Professor Timothy F. Jamison at MIT. In 2008,
he became an Assistant Professor at Hokkaido University working with Professor Masaya Sawamura. He was promoted
to Associate Professor in 2010. Since 2017, he has been a Full Professor at Kanazawa University. He is acting as JST
PRESTO Researcher (2019–2023). He received The Chemical Society of Japan Award for Young Scientists (2014) and
The Young Scientists’ Prize, The Commendation for Science and Technology by MEXT (2015).
Abstract
The KHMDS-catalyzed tertiary alkylation of aldehydes,
In a study on new methodology based on the formation of a
secondary a-alkoxyalkyl anion from the aldehyde,[6] our focus
has been the generation of a tertiary alkyl anion and its
application to C(sp3)–C(sp3) bond formation. We report here the
tertiary alkylations of aldehydes, ketones, or imines using teriary
benzylic organoboronates and a base catalyst (Figure 1B).[7] The
reaction involves the generation of tertiary alkyl anions from
organoboronates under mild and transition-metal-free reaction
conditions. The protocol allows the construction of highly
congested contiguous sp3-carbon centers.
ketones or imines using tertiary benzylic organoboronates is
reported. This protocol permitted the use of tertiary benzylic
alkylboronates as the tertiary alkyl anion for construction of
highly congested contiguous sp3 carbon centers. The mild and
transition-metal-free reaction conditions are attractive features
of the protocol.
Keywords: Base catalyst, Organoboron, 1,2-Addition,
Alkylation
1. Introduction
2. Results and Discussion
The demand for construction of sp3-carbon-rich chemical
scaffolds in pharmaceuticals and bioactive natural products has
increased recently.[1] C(sp3)–C(sp3) bond formation using a
tertiary alkyl organometallic nucleophile is a direct and reliable
approach for realizing highly congested sp3-carbon-rich
chemical scaffolds. Tertiary alkylboron compounds are
particularly attractive organometallic reagents because of their
high chemical stability and widespread availability (Figure
1A).[2] Recent progress in the catalytic preparation of tertiary
alkylborons from various simple organic molecules is
remarkable.[3] Nevertheless, catalytic C(sp3)–C(sp3) bond
formation using tertiary alkylborons is still in its infancy given
the limited progress in recent years.[4] Specifically, 1,2-addition
of tertiary alkylborons to carbon–heteroatom bonds is limited to
the use of aldehydes with a rhodium catalyst and imines under
an iridium-based photoredox catalyst as reported by
Aggarwal[5a] and Molander[5b], respectively.
In numerous studies in this laboratory, we have found that the
reaction between tertiary alkylboronate 1a (0.2 mmol), easily
prepared by copper-catalyzed conjugate addition with
bis(pinacolato)diboron (B2pin2) and b,b-disubstituted a,b-
unsaturated ester,[3b] and benzaldehyde (2a) (0.24 mmol)
occurred in the presence of a catalytic amount of KHMDS (20
mol %) in THF at 80°C to provide the desired g-lactone (3aa)
with an 88% yield (Table 1, entry 1). Other alkali metal
hexamethyldisilazides such as NaHMDS and LHMDS were less
effective (entries 2 and 3). The use of a less nucleophilic
alkoxide base gave only a moderate yield, although a significant
amount of deborylprotonated product 4a was observed (entries
4 and 5).
Table 1. Screening of conditions for allylation of 1a with 2aa
O
O
O
A. Preparation and application of tertiary alkylborons
Ph
Me
Ph
H
Ph
H
O
O
Me
Ph
B2pin2
Me Ph
Bpin
2a
3aa
carbon
elecrophiles
cat. Cu/NHC
EtO
EtO
KHMDS
(20 mol %)
simple
molecules
O
Ph Me
H
1a
under-
THF, 80 oC, 3 h
established
Bpin
EtO
developed
4a
tertiary alkylboron
congested contiguous
sp3-carbon centers
Entry
Change from standard conditions
Yield (%)
of 3aab, c
98 (88)
29
Yield (%)
of 4ab
B. Base-catalyzed 1,2-addition of tertiary benzylic alkylboronates (this work)
1
2
3
4
5
none
0
0
0
base
NaHMDS instead of KHMDS
LHMDS instead of KHMDS
KOtBu instead of KHMDS
KOMe instead of KHMDS
2 Ar
2 Ar
R
R
simple
molecules
XH
0
R1
Bpin
R1
X
R3 R4
54
68
46
32
R3 R4
tertiary alkylboron
aReaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), KHMDS (20
Figure 1. Preparation and application of tertiary alkylborons

mol %), THF (1 mL), 80 °C, 3 h. b1H NMR yield based on 1a. Yield of
the isolated product is in parentheses. cdiastereomeric ratio (1:1).
KHMDS: potassium hexamethyldisilazide. NaHMDS: sodium
hexamethyldisilazide. LHMDS: lithium hexamethyldisilazide.
umpolung b-functionalization of a,b-unsaturated carbonyls has
[8,9]
been extensively studied.
For example, N-heterocyclic
carbene (NHC) catalysis enabled the generation of a b-
carbonylalkyl anion (homoenolate) from a a,b-unsaturated
aldehyde and its application to carbon–carbon bond formation.[8]
However, this process has not yet been applied to the formation
of a tertiary b-carbonylalkyl anion from b,b-disubstituted a,b-
unsaturated carbonyls.
It should be noted that this overall process represents a
reductive
umpolung
b-functionalization
of
b,b-
disubstituted a,b-unsaturated carbonyls. The reductive
Table 2. Scope of substratesa,b
X
O
HO
Z
X
R3 R4
R
2 R1
Bpin
O
R2
B2pin2
O
2
X
or
R1
R2
R1
R2
cat. Cu/NHC
Z
R1
KHMDS (20 mol %)
THF, 80 oC, 3 h
Z
R4
R4
R3
R3
1
Z = OEt, Ph
Z = OEt
Z = Ph
3
Aldehydes, Ketones & Imines with 1a
O
O
O
O
O
O
O
O
O
O
O
O
Ph
Me
Ph
Me
Ph
Me
Ph
Me
Ph
Me
Ph
Me
O
O
H
H
H
H
H
H
CF3
Cl
OMe
SMe
F
3ab, 73% (1:1.1)
3ac, 85% (1:1)
3adc, 54% (1:1.6)
3ae, 81% (1:1.1)
3af, 77% (1:1.1)
3ag, 54% (1:1.1)
O
O
O
O
O
O
Me
O
O
O
O
O
O
Ph
Me
Ph
Me
Ph
Me
Ph
Me
Ph
Me
Ph
Me
S
H
H
H
H
H
H
N
Br
3ai, 66% (1:1.2)
3aj, 75% (1:1.1)
3ak, 80% (1:1.1)
3al, 36% (1:1.5)
3am, 33% (1:1.1)
3ah, 76% (1:1)
O
O
O
O
O
O
O
O
O
O
O
O
Ph
Me
Ph
Me
Ph
Me
Ph
Me
Ph
Me
Ph
Me
H
H
Me
H
NBoc
Me
3ap, 47%d
3aq, 93% (1:1.1)
3ase, 66% (1:1.7)
3an, 64% (1:1.1)
3ao, 52% (1:1.1)
3ar, 93% (1:1.2)
O
O
O
O
O
O
O
N
Ph
N
Ph
N
Ph
O
O
Ph
Me
Ph
Me
Ph
Me
Ph
Me
Ph
Me
Ph
Me
H
Me
H
H
Me
Me
CF3
OMe
3atf, 70%
3ax, 89%g (1:1.4)
3au, 73%
3av, 61% (1:1)
3aw, 83%g (1:1.2)
3ay, 74%g (1:1.3)
Alkylboronates with 2a
O
O
O
O
O
HO
Ph
O
O
O
O
O
O
Ph
Ph
Me
Me
Ph
Me
Ph
Ph
Ph
Ph
Ph
Ph
H
Et
Me
Me
CF3
MeO
H
H
H
H
H
H
from sec-alkylboronate
3gai, 58% (1:1.4)
3ba, 77% (1:1)
3ca, 67% (1:1.3)
3dae, 28% (1:1.1)
3ea, 0%
3fah, 50%d
b
aReaction conditions: 1 (0.2 mmol), 2 (0.24 mmol), KHMDS (20 mol %), THF (1 mL), 80°C, 3 h. Number in parenthesis is diastereomeric ratio.
f
cKHMDS (30 mol %) was used. dDiastereomeric ration was not determined. eThe reaction was carried out at 100 ˚C. Acetone (0.3 mmol) was used.
gZnCl2 (20 mol %), KHMDS (80 mol %), THF (1 mL), 80°C, 3 h. h18-crown-6 (20 mol %) was added. i2a (0.4 mmol) was used.
Under optimized reaction conditions, we next explored the
scope of the substrate in the base-catalyzed 1,2-addition reaction
(Table 2). A broad array of aryl aldehydes was found to act as
suitable substrates (Table 2, top). Both electron-rich and
electron-poor functional groups did not affect the product yield
(3ab–ah). Halogen substituents were well tolerated (3af–ah).
The aromatic aldehyde possessing an o-substituent was coupled
with 1a to give the corresponding g-lactone product (3ai).
Naphthalene and heteroaromatic rings such as thiophene and
pyridine were also found to be good substrates (3aj–al). The
reaction with cinnamyl aldehyde gave only the 1,2-adduct
product (3am). In addition to aromatic aldehydes, aliphatic
aldehydes participated in the reaction. For example, a-branched
aldehydes underwent the reaction (3an–ap). However, the use of
unbranched aliphatic aldehydes was not successful, possibly due
to the occurrence of the self-aldol reactions (data not shown).
The protocol was also possible with ketones, allowing the
construction of highly congested continuous quaternary carbon
centers (Table 2). Acetophenone, which bears an acidic a-proton,
underwent the 1,2-addition to give the desired product in
excellent yield (3aq). The cyclopropyl or the cyclohexyl group
participated in this reaction (3ar, as). The reaction with the
simple molecule acetone gave the b,b-dimethyl-g-lactone (3at)
in high yield. Cyclohexanone was coupled with organoboron to
give a spirolactone scaffold (3au), which is found in many
bioactive compounds. The presence of an alkene moiety in the
ketone substrate was tolerated (3av).

Imines were evaluated as coupling partners (Table 2). The
addition of catalytic amounts of zinc salt was required to
improve the product yield.[10] The reaction of electron-rich and
electron-poor imines afforded the corresponding lactams (3aw–
ay). The reactions with ketimine under several conditions
resulted in no conversion of the substrate (data not shown).
Next, we investigated the scope of the b-
carbonylalkylboronates, which are prepared through copper-
catalyzed borylation of a,b-unsaturated carbonyls (Table 2). An
ethyl group instead of the methyl substituent at the b-position
was tolerated (3ba). A trifluoromethyl group on the aromatic
ring at the b-position did not affect the product yield (3ca).
However, a methoxy group drastically diminished the reaction
efficiency (3da). The reaction with b,b-dialkyl borylacrylate
resulted in no product being formed (3ea). Thus, the
applicability of this protocol seems to be limited to
benzylboronates, the results indicating that the reaction would
proceed through the formation of the benzyl anion from the
organoboronate (vide infra). The reaction with b-
ketoalkylboronate proceeded to afford the corresponding
hemiketal product in high yield (3fa). The protocol is not limited
to cases with tertiary alkylboronates. The secondary
alkylboronate derived from borylation of cinnamyl ester was
also found to be a suitable substrate (3ga). Although the data was
not shown, the ring-fused alkylboron compounds did not work
at all.
alkylboronates were conducted (Figures 2A–C). When the chiral
b-borylacrylate (S)-1a was subjected to the optimal conditions,
a complete loss of chiral information was observed (Figure 2A).
The use of chiral alkylboronate (R)-1h having a hydrocarbon
backbone resulted in some erosion of enantiomeric purity
(Figure 2B). The reaction of (S)-1l and 2a occurred with
complete stereospecificity (Figure 2C). The derivatization of 3la
to (R)-5la by PCC oxidation indicated that the addition
proceeded with retention of configuration. These are in contrast
to the disappearance of the chirality in the reaction with (S)-1a
(Figure 2A vs Figures 2B, 2C). We assumed that the 1,2-addition
of the boron-ate derived from (R)-1h or (S)-1l would be faster
than racemization of the chiral benzyl anion formed by a
significant C–B bond cleavage.[11] The observed drop of
stereospecificity in 3ha bearing sterically hindered butyl group
is consistent with this assumption.
A.
O
KHMDS
(20 mol %)
O
O
Me Ph
Bpin
+
O
EtO
H
Ph
Ph
Me
THF
Ph
80 oC, 3 h
H
2a
(S)-1a, 84%ee
3aa, 88%
d.r. 1:1
racemic
B.
KHMDS
(40 mol %)
Me Ph
Me Ph
Me
2a
+
Me
OH
Ph
Bpin
dioxane
100 oC, 3 h
H
(R)-1h, 98%ee
3ha, 52%
d.r. 1:1
84%ee/83%ee
C.
Table 3. Scope of substratesa, b
KHMDS
(40 mol%)
Me Ph
Me Ph
Me Ph
Et Bpin
PCC
+
2a
OH
Et
Ph
dioxane
100 oC, 3 h
Et
DCM
2 R3
X
R
2 R3
25 oC, 2 h
R
H
Ph
KHMDS (40 mol %)
dioxane, 80 oC, 3 h
O
XH
+
Bpin
R1
R1
(S)-1l, 99%ee
R4 R5
(R)-5la, 65%
99% ee
3la
66%, d.r. 1:1
R
4 R5
1
2
3
D. Possible pathway
Me Ph
H
Me Ph
H
Me Ph
R
2 R3
OH
Ph
Me
OH
OH
Ph
X
R1
3
Bpin
–
N
Me3Si
SiMe3
4 R5
R
2 R3
Ph
H
R
K+
R1
Bpin
3ja, 35% (1:2)
Ph
OH
3ha, 52% (1:1.1)
3ia, 27% (1:1.6)
1
B
H
Me Ph
H
Ph
Me
NHPh
Ph
Me
OH
Ph
Me
R
2 R3
O
H
R
2 R3
K+
H
–
R
2 R3
–
X–
R1
B
O
R1
K+
R1
3hw, 68%c
3ka, 70%d (1:1.1)
3ku, 39%
Me3Si
N
R
4 R5
SiMe3
aReaction conditions: 1 (0.2 mmol), 2 (0.24 mmol), KHMDS (40 mol %),
1,4-dioxane (1 mL), 80°C, 3 h. bNumber in parenthesis is diastereomeric
ratio. cDiastereomeric ration was not determined. dKHMDS (20 mol %)
was used.
C
A
Me3Si
Me3Si
X
N
Bpin
R4 R5
The carbonyl group at the b-position of the alkylboronates is
not necessary for promotion of the reaction (Table 3). For
example, the reaction between tertiary alkylboronate 1h and
benzaldehyde 2a gave the corresponding product in moderate
yield (3ha). The alkylboronates having a bulky substituent
participated in the reactions to construct the highly congested
contiguous sp3 carbon centers, although the product yields were
low (3ia and 3ja). The same substrate 1h was also applicable to
the reactions with imine (3hw). The secondary alkylboronate 1k
having a hydrocarbon backbone served as a substrate (3ka and
3ku).
B
2
E. Another reaction pathway in case of 1a–g
+
K
+
O
K
–
B
2 R3
Bpin
O
KHMDS
pinB
R
R2
O
O
O
–
Z
R3
Z
R3
Z
H
H
R2
1
D
E
Z = OEt, Ph
Figure 2. Mechanistic considerations
Based on the experiments outlined above, a reaction pathway
for the KHMDS-catalyzed alkylation was proposed as shown in
To gain insights into the mechanism of the base-catalyzed 1,2-
addition of alkylboronates, the experiments using the chiral

see: a) H. Ito, H. Yamanaka, J.-i. Tateiwa, A. Hosomi,
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For catalytic transformation of tertiary alkylborons, see: a)
C. Sandford, V. K. Aggarwal, Chem. Commun. 2017, 53,
5481. b) D. N. Primer, G. A. Molander. J. Am. Chem. Soc.
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Molander, Chem. Sci., 2017, 8, 3512.
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aldehydes, see: a) A. Ros, V. K. Aggarwal, Angew. Chem.
Int. Ed. 2009, 48, 6289–6292. b) J. Yi, S. O. Badir, R. Alam,
G. A. Molander, Org. Lett. 2019, 21, 4853.
For methodology based on the formation of a secondary a-
alkoxyalkyl anion from aldehyde, see: a) M. Takeda, K.
Yabushita, S. Yasuda, H. Ohmiya, Chem. Commun. 2018,
54, 6776. b) K. Yabushita, A. Yuasa, K. Nagao, H. Ohmiya,
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800.
Figure 2D. Initially, the reaction between KHMDS and the
alkylboronate 1 produces the organoborate intermediate A as a
tertiary alkyl anion equivalent.[7b, 12, 13] Then, the reaction of
borate A with 2 forms the 1,2-adduct C with the formation of
aminoboron B. Finally, C reacts with B to produce 3 with
regeneration of KHMDS. When 1 has an ester group at the b-
position, C undergoes an intramolecular substitution to give the
g-lactone and the alkoxide anion, which can act as a base catalyst
for the next cycle. In the case of b-carbonylalkylboronates 1a–g,
a-deprotonation by KHMDS might cause the facile formation of
the organoborate D due to the intramolecular coordination of the
enolate to the boron center (D→E, Figure 2E). This borate would
lead to the facile C–B bond cleavage causing the problematic
racemization before 1,2-addition event. This mechanism
provides the good explanation to the result of Figure 2A.
3. Conclusion
In summary, KHMDS-catalyzed tertiary alkylation of
aldehydes, ketones or imines using tertiary benzylic
organoboronates has been demonstrated. The protocol enabled
the use of tertiary benzylic alkylboronates as tertiary alkyl anions
for the construction of the highly congested contiguous sp3
carbon centers. The mild and transition-metal-free reaction
conditions are attractive features of the protocol. Extending the
scope of the reaction to electrophiles and further mechanistic
studies are in progress.
4. Experimental
Procedure for Lewis Base-Catalyzed Tertiary and Secondary
Alkylations of Aldehydes and Ketones. b-Borylacrylate 1a
(63.6 mg, 0.2 mmol) was placed in a schlenk tube containing a
magnetic stirring bar. The tube was sealed with a rubber septum,
and then evacuated and filled with nitrogen. THF (1.0 mL),
KHMDS (8.0 mg, 0.04 mmol) and benzaldehyde (2a) were
sequentially added to the tube. After 3 h stirring at 80 ˚C, the
reaction mixture was diluted with ethyl acetate (1 mL) then
filtered through a short plug of silica gel with ethyl acetate as an
eluent. After volatiles were removed under reduced pressure,
flash column chromatography on silica gel (100:0–90:10,
hexane/EtOAc) gave 3aa (44.3 mg, 0.175 mmol) in 88% yield.
4-Methyl-4,5-diphenyldihydrofuran-2(3H)-one (3aa). The
product 3aa was purified by flash chromatography on silica gel
(100:0–90:10, hexane/EtOAc) (Table 1, entry 1; 44.3 mg, 0.18
mmol, 88% isolated yield). The diastereomeric ratio is 1:1
determined by 1H NMR.
4.
5.
6.
Acknowledgement
This work was supported by JSPS KAKENHI Grant Number
JP18H01971 to Scientific Research (B), JSPS KAKENHI Grant
Number JP17H06449 (Hybrid Catalysis), and Kanazawa
University SAKIGAKE project 2018 (to H.O.).
7.
For
selected
reviews
on
transition-metal-free
transformation of boron compounds, see: a) S. Roscales, A.
G. Csákÿ, Chem. Soc. Rev. 2014, 43, 8215. b)A. B. Cuenca,
R. Shishido, H. Ito, E. Fernandez, Chem. Soc. Rev. 2017,
46, 415. Our selected papers on organophosphine-
catalyzed reactions with boron compounds, see: c) K.
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