A Bond-Weakening Borinate Catalyst that Improves the Scope of the Photoredox α-C-H Alkylation of Alcohols

Article abstract of DOI:10.1055/s-0040-1707114

The development of catalyst-controlled, site-selective C(sp ³)-H functionalization reactions is currently a major challenge in organic synthesis. In this paper, a novel bond-weakening catalyst that recognizes the hydroxy group of alcohols through formation of a borate is described. An electron-deficient borinic acid-ethanolamine complex enhances the chemical yield of the α-C-H alkylation of alcohols when used in conjunction with a photoredox catalyst and a hydrogen atom transfer catalyst under irradiation with visible light. This ternary hybrid catalyst system can, for example, be applied to functional-group-enriched-peptides.

Full text of DOI:10.1055/s-0040-1707114

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–N
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K. Sakai et al.
Feature
Synthesis
A Bond-Weakening Borinate Catalyst that Improves the Scope of
the Photoredox -C–H Alkylation of Alcohols
Kentaro Sakai
R1
R1
Kounosuke Oisaki*
0
0
0
0-
0
0
0
2-0
4
9
9-8
1
6
8
PC
HAT
B
R2
H
R2
Motomu Kanai*
0
0
0
0-0
0
0
3-
1
9
7
7-7
6
4
8
+
HO
EWG
NH2
HO
EWG
blue LEDs
23 examples
(including amino acid derivatives)
up to 91% yield
Graduate School of Pharmaceutical Sciences, The University
of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
oisaki@mol.f.u-tokyo.ac.jp
R1
kanai@mol.f.u-tokyo.ac.jp
[B] =
F3C
R2
H
O
B
[B]
Dedicated to the late Professor Dieter Enders
O
C–H bond weakening
CF3
Received: 14.02.2020
Accepted after revision: 06.04.2020
Published online: 12.05.2020
development of catalyst-controlled, site-selective C(sp3)–H
functionalization reactions remains a formidable challenge.
One promising strategy to realize catalyst-controlled
site-selectivity is the use of bond-weakening catalysis
(Scheme 1, a). The weakening of N–H and O–H bonds via
coordination to low-valent metal complexes has been stud-
ied in the area of inorganic chemistry.6 The application of
DOI: 10.1055/s-0040-1707114; Art ID: ss-2020-z0092-fa
Abstract The development of catalyst-controlled, site-selective
C(sp3)–H functionalization reactions is currently a major challenge in
organic synthesis. In this paper, a novel bond-weakening catalyst that
recognizes the hydroxy group of alcohols through formation of a borate
is described. An electron-deficient borinic acid–ethanolamine complex
enhances the chemical yield of the -C–H alkylation of alcohols when
used in conjunction with a photoredox catalyst and a hydrogen atom
transfer catalyst under irradiation with visible light. This ternary hybrid
catalyst system can, for example, be applied to functional-group-
enriched peptides.
(a) Bond-weakening catalyst in conjunction with a PC-HAT hybrid system
H
H
HAT
cat
PC
cat
FG
H
FG
catalyst-controlled
selectivity
weakened
C–H bond
Key words photoredox catalyst, hydrogen atom transfer catalyst,
boron, bond-weakening, C–H functionalization
(b) Precedents of bond-weakening effects in conjunction with a PC-HAT hybrid system
MacMillan [ref. 9a]
Taylor [ref. 10]
Novel C–H functionalization reactions enable not only
innovative concise synthetic routes, but also the late-stage
functionalization of complex molecules, thus accelerating
the discovery of functional materials and medicinal lead
compounds.1,2 In particular, C(sp3)–H functionalizations
have shown great potential in drug discovery, as such reac-
tions facilitate the derivatization of sp3-rich carbon skele-
tons, which is advantageous in order to enhance success
rates in clinical trials.3
Ph Ph
B
O
P
H
O
O
H
HO
O
O
n-C5H11
OH
H
R
weakened by 2.5 kcal/mol
Oisaki and Kanai [ref. 5c]
weakened by 4.2–4.5 kcal/mol
limited to cis-1,2-diols
F3C
CF3
O
Si
H
[Si] =
[Si]
O
O
Me
Recently, hybrid catalyst systems that consist of a pho-
toredox catalyst (PC) and a hydrogen atom transfer (HAT)
catalyst have attracted significant attention from the syn-
thetic chemistry community, including our group.4,5 PC-
HAT hybrid catalysts generally functionalize unactivated
C(sp3)–H bonds under mild conditions with high functional
group tolerance. Most reported PC-HAT hybrid catalysts ex-
hibit innate selectivity: The C–H bond with the lowest
bond-dissociation energy (BDE) or the most hydridic C–H
bond in the substrate are preferentially converted. Thus, the
CF3
F3C
weakened by 2.3 kcal/mol
(c) Bond-weakening effects of borate formation supported by DFT calculations
R1
B
H
R1
B
H
H
R2
R3
interaction with [B]
R2
O
Me
O
Me
HO
Me
(R1–R3 = Ph, OH, OMe)
BDE
(kcal/mol)
92–94
88–89
93
Hypothesis: A larger bond-weakening effect may improve the reactivity.
Scheme 1 Strategies for C(sp3)–H functionalization reactions based on
a bond-weakening catalyst with a PC-HAT system
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–N
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
K. Sakai et al.
Feature
Synthesis
this phenomenon to synthetic organic chemistry has pro-
vided a new design principle for the molecular engineering
of synthetic catalysts.7,8 However, the oxidizing nature of
conventional PC-HAT hybrid systems is often incompatible
with low-valent metal complexes; instead, a redox-metal-
free bond-weakening system would be preferable to use in
conjunction with a PC-HAT hybrid system.
There have been previous reports of the use of bond-
weakening catalysts in conjunction with PC-HAT hybrid
systems to promote the selective -C–H alkylation of alco-
hols (Scheme 1, b).5c,9,10 Seminal work has been reported by
MacMillan and co-workers,9a who used dihydrogen phos-
phate as a hydrogen-bonding-acceptor catalyst to accelerate
the C–H alkylation of alcohols. The same catalytic system
was applied to the site-selective modification of carbo-
hydrates by Minnaard and co-workers.9b Recently, this
methodology was used for the synthesis of rare sugar iso-
mers through site-selective epimerization by Wendlandt
and co-workers.9c Taylor and co-workers have reported the
use of borinic acid10a and boronic acid10b bond-weakening
catalysts in conjunction with PC-HAT hybrid systems to re-
alize the site-selective C–H alkylation and redox isomeriza-
tion of carbohydrates, respectively. In these reactions, the
formation of cyclic borates between the boron catalysts and
the cis-1,2-diol moiety of the carbohydrates plays a key
role. Recently, our group has reported that Martin’s spirosi-
lane11 can act as a bond-weakening catalyst by forming a
silicate to promote the C–H alkylation of alcohols.5c Based
Biographical Sketches
Kentaro Sakai was born in
1994 and raised in Tochigi, Ja-
pan. He obtained his bachelor’s
degree (2017) and master’s de-
gree (2019) under the direction
of Professor Motomu Kanai at
The University of Tokyo. He is
currently a Ph.D. student at the
Graduate School of Pharmaceu-
tical Sciences, The University of
Tokyo. His current research fo-
cuses on the development of a
new methodology for selective
C(sp3)–H functionalization un-
der visible-light irradiation.
Kounosuke Oisaki was born
in 1980 in Tokushima, Japan,
and received his Ph.D. from The
University of Tokyo (UTokyo) in
2008 under the direction of Pro-
fessor Masakatsu Shibasaki. He
then moved to the University of
California-Los Angeles, USA, for
postdoctoral studies with Pro-
fessor Omar M. Yaghi. In 2010,
he returned to Japan and joined
Professor
Motomu
Kanai’s
istry Journals Award (2019). His
current research interest is di-
rected toward the development
of new synthetic organic chem-
istry, with a focus on organorad-
group at UTokyo as an assistant
professor. He is currently work-
ing as a lecturer (since 2016).
He has received The Pharma-
ceutical Society of Japan Award
for Young Scientists (2018), the
Mitsui Chemicals Catalysis Sci-
ence Award of Encouragement
(2018), the Chemist Award BCA
(2018), and the Thieme Chem-
ical-based
chemoselective
reagents/catalysis for C(sp3)–H
functionalizations and peptide/
protein modifications.
Motomu Kanai received his
bachelor’s degree from The Uni-
versity of Tokyo (UTokyo) in
1989 under the direction of the
late Professor Kenji Koga. He ob-
tained an assistant professor
position at Osaka University un-
der the direction of Professor
Kiyoshi Tomioka in 1992. He ob-
tained his Ph.D. from Osaka
University in 1995, and then
moved to the University of Wis-
consin, USA, for postdoctoral
studies with Professor Laura L.
Kiessling. In 1997, he returned
to Japan and joined Professor
Masakatsu Shibasaki’s group at
UTokyo as an assistant profes-
sor. After working as a lecturer
(2000–2003) and an associate
professor (2003–2010), he be-
came a professor at UTokyo in
2010. He served as a principle
investigator at ERATO Kanai Life
Science Project (2011–2017),
and is currently the head inves-
tigator of MEXT Grant-in-Aid for
Scientific Research on Innova-
tive Areas, ‘Hybrid Catalysis’
(2017–2022). He is a recipient
of The Pharmaceutical Society
of Japan Award for Young Scien-
tists (2001), the Thieme Jour-
nals Award (2003), the Merck-
Banyu Lectureship Award (MB-
LA) (2005), the Asian Core Pro-
gram Lectureship Award (2008
and 2010, from Thailand, Ma-
laysia, and China), the Thomson
Reuters 4th Research Front
Award (2016), and the Nagoya
Silver Medal (2020). His re-
search interests encompass the
design and synthesis of func-
tional molecules.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–N

C
K. Sakai et al.
Feature
Synthesis
on DFT calculations, the bond-weakening effect of the sili-
cate was estimated to be 2.3 kcal/mol.5c The same calcula-
tions indicated that the BDEs of the alcohol -C–H bonds
were reduced by 4–5 kcal/mol through the formation of an-
ionic borates; this reduction was greater than those in-
duced by silicates or hydrogen-bonding catalysts.12 The for-
mation of neutral boron ester species, however, did not
show a bond-weakening effect (Scheme 1, c). Thus, we hy-
pothesized that a PC-HAT-borate hybrid catalyst system
could result in higher reactivity and a broader substrate
scope for the -C–H alkylation of mono-alcohols compared
to those of the previously reported dihydrogen phosphate
and silicate systems due to the greater bond-weakening
ability of the in situ generated anionic borate species. In the
present study, we have identified an electron-deficient
borinic acid–ethanolamine complex as a novel C–H bond-
weakening catalyst for mono-alcohols. The system was
found to be applicable to amino acid derivatives, which
were not accessible under the conditions applied in previ-
ous studies.
To develop the boron-catalyzed -C–H alkylation of
simple mono-alcohols, we first screened various boron cat-
alysts in the presence of the commonly used PC
[Ir(dF(CF3)ppy)2(dtbpy)][PF6] (4a)13 and the HAT catalyst
quinuclidine (5a)9a–c,10,14 (Table 1). Vinyl diethyl phospho-
nate (1a) and ethanol (2a) were used as substrates. Under
irradiation from blue LEDs without any boron additive, the
desired C–H-alkylated product (3aa) was obtained in 28%
Table 1 Optimization of the Boron Sourcea
O
P
O
P
[Ir(dF(CF3)ppy)2(dtbpy)][PF6] (4a) (1 mol%)
quinuclidine (5a) (10 mol%)
[B] 6 (25 mol%)
OEt
OEt
HO
HO
H
OEt
OEt
Me
3aa
Me
2a
(2 equiv)
MeCN, fan, 20 h
blue LEDs (430 nm)
1a
Structure of [B] 6
Me
Me
OH
6e: R = CF3
6f: R = F
6g: R = H
O
6a: R = CF3
6b: R = H
6c: R = OMe
B
R
B(OH)2
F3C
B
Me
O
6h: R = OMe
Me
6d
R
R
O
NH2
O
NH2
O
NH2
B
B
F3C
B
CF3
F3C
CF3
CF3
CF3
6i
6j
6k
Entry
[B] 6
Yield (%)b
1
2
none
28
72
40
8
6a
6b
6c
6d
6e
6f
3
4
5
51
14
15
17
14
31
87 (84)c
82
0
6
7
8
6g
6h
6i
9
10
11
12
13
6j
6k
B(C6F5)3 (6l)
a Reaction conditions: acceptor 1a (1 equiv), EtOH (2a) (2 equiv), [Ir(dF(CF3)ppy)2(dtbpy)][PF6] (4a) (1 mol%), quinuclidine (5a) (10 mol%), [B] 6 (25 mol%), MeCN
([1a]final = 0.2 M), blue LED irradiation; the temperature of the reaction (25–33 °C) was controlled for 20 h using a fan.
b The yield of 3aa was determined by 1H NMR analysis (internal standard: nitromethane).
c [B] 6j (10 mol%) was used and the reaction time was shortened to 14 h.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–N

D
K. Sakai et al.
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Synthesis
yield (entry 1). We then added various boron catalysts to
the reaction mixture and evaluated their acceleration effect
(entries 2–13). The yield of 3aa changed dramatically de-
pending on the electronic characteristics of the boronic acid
(entries 2–4), with the electron-deficient boronic acid 6a
leading to a yield of 72%. In contrast, the electron-rich bo-
ronic acid 6c showed a detrimental effect on the yield (Ta-
ble 1, entry 4), probably due to inhibition of the activation
of the HAT catalyst by the competitive single-electron oxi-
dation of 6c.10b,15 The acceleration effect of the boronic acid
pinacol ester 6d was smaller than that of acid form 6a,
which suggests that steric hindrance may hamper the for-
mation of the borate (entry 5). Hoping to further enhance
the acceleration effect, we screened various borinic acids,
which are known to produce tetravalent borates more easi-
ly than boronic acids due to the higher Lewis acidity of the
boron center.16 Contrary to our expectations, the addition
of borinic acids 6e–h did not improve the yield, regardless
of the substituents (entries 6–9). We hypothesized that this
could be due to the relatively low chemical stability of the
borinic acids. We then investigated chemically stable borin-
ic acid–ethanolamine complex 6i,17 which bears a dynami-
cally exchangeable amino-alcohol ligand (entry 10). Com-
pared to borinic acid 6g, the use of 6i led to a significantly
improved yield (entry 8 vs 10). Based on the substitution ef-
fect observed for 6a–c, we then used the electron-deficient
Table 2 Optimization of the PC and HAT Catalystsa
O
P
O
P
PC 4 (1 mol%)
HAT catalyst 5 (10 mol%)
6j (10 mol%)
OEt
OEt
HO
HO
H
OEt
OEt
Me
3aa
Me
MeCN, fan, 14 h
blue LEDs (430 nm)
1a
2a
(2 equiv)
Structure of PC 4
Me
CF3
R1
F
R2
Me
OMe
Me
OMe
Me
N
Ir
N
N
4a: R1 = H, R2 = t-Bu
4b: R1 = CF3, R2 = H
4c: R1 = H, R2 = CF3
F
PF6
R2
Me
Me
F3C
N
F
MeO
N
OMe
BF4
R1
N
F
ClO4
MeO
OMe
Me
4e
4d
Structure of HAT catalyst 5
O
O
O
O
N
OH
OSO2Ph
P
O
OH
Na
N
N
N
N
5a
5b
5c
5d
5e
5f
Entry
PC
4a
HAT catalyst
Yield (%)b
1
2
5a
5a
5a
5a
5a
5b
5c
5d
5e
5f
84
63
60
4
4b
4c
4d
4e
4a
4a
4a
4a
4a
3
4
5
0
6
0
7
0
8
20
0
9
10
0
a Reaction conditions: acceptor 1a (1 equiv), EtOH (2a) (2 equiv), PC 4 (1 mol%), HAT catalyst 5 (10 mol%), 6j (10 mol%), MeCN ([1a]final = 0.2 M), blue LED
irradiation; the temperature of the reaction (25–33 °C) was controlled for 14 h using a fan.
b The yield of 3aa was determined by 1H NMR analysis (internal standard: nitromethane).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–N

E
K. Sakai et al.
Feature
Synthesis
borinic acid–ethanolamine complex 6j, which dramatically
increased the yield of the C–H alkylation (87% yield) (entry
11). Upon introduction of additional electron-deficient tri-
fluoromethyl groups on the aromatic rings (6k), an acceler-
ation effect that was merely similar to that of 6j was ob-
served (entry 12). When we used tris(pentafluorophe-
nyl)borane (6l), the desired reaction was completely
inhibited, which implies that the ligand exchange on the
boron center is important for the C–H alkylation (entry 13).
Based on the aforementioned screening results, we identi-
fied 6j as the optimal boron catalyst. Further tuning of the
reaction parameters confirmed that a comparable perfor-
mance could be obtained when the reaction time was
shortened to 14 hours and the loading of 6j was reduced to
10 mol% (entry 11, yield in parentheses).
Next, we screened various PCs 4 (Table 2, entries 1–5).
When we added organic dyes 4d18 or 4e19 instead of 4a, al-
most none of the desired product was obtained (entries 4
and 5). The iridium photoredox catalysts 4b20 or 4c20
achieved C–H alkylation (entries 2 and 3), albeit the yields
were lower than that obtained with 4a. The lower reduction
potential of 4b/4c compared to that of 4a [E1/2(IrII/IrIII)
= –1.37 V for 4a, –0.69 V for 4b, –0.79 V for 4c; all potentials
vs SCE in MeCN]9a,20 might lead to inefficient catalyst regen-
eration; alternatively, the higher oxidation potential of
4b/4c [E(IrIII*/IrII) = +1.21 V for 4a, +1.68 V for 4b, +1.65 V for
4c; all potentials vs SCE in MeCN]9a,20 might lead to the de-
composition of 6j. We also screened several quinuclidine
derivatives (5b–d)5c,21 and other HAT catalysts (5e22 and
5f5b). In these cases, the desired reaction did not proceed
smoothly (entries 6–10).
After determining the optimal reagent combination (4a,
5a and 6j), we further optimized the reaction parameters
(Table 3). A solvent screening indicated that with the excep-
tion of DMF, which contains weak C–H bonds, polar aprotic
solvents showed good results (entries 1–4), and MeCN af-
forded the best result (entry 1). Less polar solvents such as
CH2Cl2, benzotrifluoride, and 1,4-dioxane led to poor reac-
tivity (entries 5–7). Next, we changed the ratio of substrates
and the concentration (entries 8–12). The use of an excess
of the alcohol (entry 1 vs 8) or a lower concentration of 1a
(entry 1 vs 12) slightly improved the yield. On the other
hand, an excess of the acceptor (entry 1 vs 10) or a higher
concentration of 1a (entry 1 vs 11) had a negative effect on
the yield. Based on this optimization process, we identified
the conditions in entry 12 as being optimal.
Subsequently, we conducted control experiments (Table
4). In the absence of the PC or the HAT catalyst or the light
source, 3aa was not obtained. Accordingly, the PC and HAT
catalysts, as well as the blue light irradiation are essential
for this reaction.
Table 4 Control Experimentsa
Table 3 Optimization of the Reaction Parametersa
O
P
O
P
[Ir(dF(CF3)ppy)2(dtbpy)][PF6] (4a) (1 mol%)
quinuclidine (5a) (10 mol%)
H
6j (10 mol%)
O
P
OEt
OEt
HO
O
P
[Ir(dF(CF3)ppy)2(dtbpy)][PF6] (4a) (1 mol%)
quinuclidine (5a) (10 mol%)
H
6j (10 mol%)
H2O
OEt
OEt
OEt
OEt
HO
HO
Me
OEt
Me
2a
(2 equiv)
MeCN, fan, 14 h
blue LEDs (430 nm)
OEt
1a
3aa
Me
Me
2a
(y equiv)
solvent, fan, 14 h
blue LEDs (430 nm)
1a
(x equiv)
3aa
Entry
Variation from the ‘standard’ reaction conditions Yield (%)b
Entry
Solvent
Concentration
[1a]final
Ratio of
1a/2a
Yield (%)b
1
2
3
4
none
89
0
absence of PC 4a
absence of HAT catalyst 5a
absence of LED irradiation
1
2
MeCN
DMSO
acetone
DMF
0.2 M
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:5
1:1
5:1
1:2
1:2
84
80
54
31
12
26
15
89
74
71
48
89
0
0.2 M
0
3
0.2 M
a Reaction conditions: acceptor 1a (1 equiv), EtOH (2a) (2 equiv),
[Ir(dF(CF3)ppy)2(dtbpy)][PF6] (4a) (1 mol%), quinuclidine (5a) (10 mol%), 6j
(10 mol%), MeCN ([1a]final = 0.1 M), blue LED irradiation; the temperature of
the reaction (25–33 °C) was controlled for 14 h using a fan.
b The yield of 3aa was determined by 1H NMR analysis (internal standard:
nitromethane).
4
0.2 M
5
DCM
0.2 M
6
PhCF3
0.2 M
7
1,4-dioxane
MeCN
MeCN
MeCN
MeCN
MeCN
0.2 M
8
0.2 M
To obtain further insight into the operational mecha-
nism of the boron catalyst, we examined its structure–
activity relationship (Table 5). When borinic acid 6e was
used, a smaller acceleration effect was observed, perhaps
due to the insufficient chemical stability of 6e (entry 1 vs
2). The addition of only ethanolamine did not improve the
yield (entry 3 vs 9). Next, we added borinic acid 6e and etha-
nolamine without pre-complexation to form 6j. Although the
yield was greatly improved (entry 4 vs 9), the improvement
9
0.2 M
10
11
12
0.2 M ([2a]final
)
0.4 M
0.1 M
a Blue LED irradiation; the temperature of the reaction (25–33 °C) was con-
trolled for 14 h using a fan.
b The yield of 3aa was determined by 1H NMR analysis (internal standard:
nitromethane).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–N

F
K. Sakai et al.
Feature
Synthesis
Table 5 Structure–Activity Relationship Study of the Boron Catalystsa
When ethanol (2a) was used, 3aa was obtained in 85%
yield (Table 6, entry 1). The reaction with methanol (2b)
produced the expected C–H alkylation product 3ab in a
lower yield (35%), most likely due to the instability of the
primary carbon radical generated by the HAT process (en-
try 2). Despite the expected stability of the carbon radical
intermediate, the yield was moderate (50%) when 2-propa-
nol (3c) was used as the substrate (entry 3). The steric hin-
drance of 2c may have hampered the formation of the bo-
rate with 6j. On the other hand, a substrate bearing a -ter-
tiary carbon (2d) afforded the corresponding product 3ad
in 81% yield (entry 4). The conditions were also applicable
to a long-chain alcohol (2e) and a cyclic alcohol (2f), which
furnished the desired products in 76% (entry 5) and 75%
yield (entry 6), respectively. The reaction proceeded in ex-
cellent yield even for alcohols with electron-withdrawing
groups (83% and 91% yield for entries 7 and 8, respectively).
When a mono-protected diol 2i was used, the C–H alkyla-
tion proceeded selectively at the -position adjacent to the
hydroxy group (entry 9). Subsequently, we examined alco-
hol substrates bearing multiple C–H bonds with similar BDE
values.
O
[Ir(dF(CF3)ppy)2(dtbpy)][PF6] (4a) (1 mol%)
P
O
quinuclidine (5a) (10 mol%)
[B] 6e or 6j (10 mol%)
additive (10 mol%)
OEt
OEt
P
HO
HO
H
OEt
OEt
Me
Me
2a
(2 equiv)
MeCN, fan, 14 h
blue LEDs (430 nm)
1a
3aa
Entry
[B]
Additive
none
Yield (%)b
1
2
3
6j
89
51
25
6e (borinic acid)
none
none
HO
NH2
NH2
NH2
4
5
6e (borinic acid)
62
64
HO
O
6e (borinic acid)
6
7
6a (boronic acid)
6a (boronic acid)
none
54
32
HO
NH2
NH2
8
9
6a (boronic acid)
48
32
O
Despite the presence of cyclic ether -C–H bonds (2j) or
N-heterocyclic -C–H bonds (2k), which are generally more
reactive than the -C–H bonds of alcohols, the C–H alkyla-
tion selectively occurred at the -C–H bonds of the alcohol
to afford the desired products in high yields (80% and 84%,
respectively) (Table 6, entries 10 and 11).23
none
none
a Reaction conditions: acceptor 1a (1 equiv), EtOH (2a) (2 equiv),
[Ir(dF(CF3)ppy)2(dtbpy)][PF6] (4a) (1 mol%), quinuclidine (5a) (10 mol%),
[B] (6e or 6j) (10 mol%), additive (10 mol%), MeCN ([1a]final = 0.1 M), blue
LED irradiation; the temperature of the reaction (25–33 °C) was controlled
for 14 h using a fan.
b The yield of 3aa was determined by 1H NMR analysis (internal standard:
nitromethane).
Next, the substrate scope of the acceptor was examined
using ethanol (2a) or 1-hexanol (2e) as the alcohol sub-
strate (Table 7). Acceptors with a phosphonate, nitrile, am-
ide, ester, or sulfone as the electron-withdrawing group
were found to be applicable in this reaction. When esters
were used as the acceptors, the corresponding lactones
were isolated after acidic work-up (entries 7–9). A range of
acrylates and a vinylsulfone produced the desired products
in moderate to high yields (entries 1, 3–7 and 10). For acryl-
amides, a primary amide (1d), secondary amides (1e and
1f), and a tertiary amide (1g) afforded the desired products
in good yield (entries 3–6). The -substituent of the accep-
tors was not problematic. When methacrylic acid deriva-
tives or -phenyl methyl acrylate were used, the reaction
proceeded smoothly to afford excellent product yields (en-
tries 2, 8 and 9).
Finally, we attempted the C–H alkylation of functional-
group-enriched molecules (Scheme 2). When the protected
amino acid 2l or homoserine (Hse)-containing dipeptide
2m was used, the reaction proceeded in 34% and 75% yield,
respectively. Of note, 2l was rather unreactive in the HAT
process. The reaction of 2l in the absence of 6j or under pre-
viously reported conditions did not proceed at all.12 These
results demonstrate the potential utility of the current hy-
brid catalyst system for the late-stage modification of pep-
tides.
was not as great as that achieved using pre-formed 6j. The
use of 6e with 2-methoxyethylamine instead of ethanol-
amine showed a similar acceleration effect (entry 5).
These results suggest that the positive effect of 6j can-
not be simply attributed to the independent contributions
of 6e and ethanolamine. As the amine has a positive effect
only in the presence of the boron catalyst, the amine moi-
ety likely promotes the formation of the borate by assisting
in the deprotonation of the alcohol substrates.
Interestingly, when the combination of boronic acid 6a
and ethanolamine (Table 5, entry 6 vs 7) or 2-me-
thoxyethylamine (entry 6 vs 8) was examined, both amines
were observed to have a negative effect on the yield. In the
presence of the amines, boronic acid 6a was completely de-
composed after the reaction (confirmed by 1H NMR analysis
of the crude mixture). The amines may facilitate the oxida-
tive decomposition of boronic acid 6a,10b,15 leading to a de-
creased amount of the active bond-weakening catalyst.
We then examined the substrate scope using the opti-
mized conditions (Tables 6 and 7). First, the scope of the al-
cohol substrates was examined using 1a as an acceptor (Ta-
ble 6).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–N

G
K. Sakai et al.
Feature
Synthesis
Table 6 Substrate Scope of the Alcoholsa
O
P
[Ir(dF(CF3)ppy)2(dtbpy)][PF6] (4a) (1 mol%)
quinuclidine (5a) (10 mol%)
6j (10 mol%)
H
O
P
OEt
OEt
HO
R1 R2
HO
R1 R2
OEt
OEt
MeCN, fan, 14 h
1a
2
blue LEDs (430 nm)
3
Entry
1
Acceptor
Alcohol
Product
Yield (%)b
O
P
O
P
HO
H
H
85
2a
2b
2c
1a
OEt
OEt
OEt
Me
3aa
OEt
OEt
HO
HO
Me
2
3
35
50
O
P
O
P
HO
1a
1a
3ab
3ac
OEt
OEt
OEt
O
P
O
P
HO
Me
H
Me
OEt
OEt
OEt
OEt
HO
Me
Me
4
81
O
P
O
P
HO
Me
H
2d
1a
OEt
OEt
OEt
OEt
Me
3ad
3ae
HO
Me
Me
5
6
76
75
O
P
H
O
P
2e
1a
1a
OEt
HO
HO
Me
OEt
OEt
OEt
HO
n-C5H11
O
P
O
P
H
2f
OEt
OEt
OEt
OEt
3af
HO
7
8
83
91
H
H
O
O
O
OEt
OEt
O
P
P
P
P
2g
2h
1a
1a
OEt
HO
HO
F
3ag
OEt
HO
HO
F
O
P
OEt
OEt
CF3
OEt
3ah
3ai
OEt
CF3
9
58
O
P
OEt
OEt
H
2i
1a
OEt
HO
OBz
OEt
HO
OBz
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–N

H
K. Sakai et al.
Feature
Synthesis
Table 6 (continued)
Entry
10
Acceptor
Alcohol
Product
Yield (%)b
80
HO
H
O
P
O
P
1a
OEt
OEt
2j
OEt
OEt
HO
3aj
H
O
H
O
11
84
HO
H
O
P
O
P
1a
OEt
OEt
OEt
OEt
2k
HO
3ak
H
N
H
Bz
N
Bz
a Reaction conditions: acceptor 1a (1 equiv), alcohol 2 (2 equiv), 4a (1 mol%), 5a (10 mol%), 6j (10 mol%), MeCN ([1a]final = 0.1 M), blue LED irradiation; the
temperature of the reaction (25–33 °C) was controlled for 14 h using a fan.
b Yield of isolated product.
O
P
reduces 10 to form a carbanionic species. Subsequent pro-
tonation and alcohol exchange produce the C–H alkylated
product 3, and the catalytic cycle is closed.
OEt
HO
OEt
HO
Cbz
OMe
N
H
Cbz
OMe
N
H
O
BDE (kcal/mol)
O
1a
[Ir(dF(CF3)ppy)2(dtbpy)][PF6] (4a)
(1 mol%)
quinuclidine (5a) (10 mol%)
6j (10 mol%)
87.6
H
92.9
H
7
3al (34%, dr = 1:4)
2l
[B]
O
OEt
OEt
Ir(III)*
R
O
R
OH
P
N
2
8
MeCN, fan, 14 h
blue LEDs (430 nm)
H+
HO
Ir(III) (4a)
PC
HAT
B
HAT
SET
Ir(II)
6j
H
N
Cbz
HO
N
H
H
2H+
Cbz
N
O
N
H
SET
5a
[B]
O
O
R
O
6j
O
H+
9
t-Bu
O
O
t-Bu
EWG
OH
EWG
2m
3am (75%, dr = 1:1)
EWG
Scheme 2 C–H alkylation of amino acid derivatives
[B]
R
R
O
1
3
10
Scheme 3 Proposed catalytic cycle for the -C–H alkylation of alco-
hols. BDE values calculated by DFT (R = Me).
A plausible catalytic cycle is shown in Scheme 3. First,
PC 4a is excited by irradiation with visible light. The photo-
excited Ir(III)* species [E(IrIII*/IrII) = +1.21 V vs SCE]9a oxidiz-
es HAT catalyst 5a (E1/2 = +1.10 V vs SCE)24,25 to generate
quinuclidinium radical 7 and the Ir(II) species. Anionic bo-
rates 8 are formed in situ from alcohol substrate 2 and
borinic acid–ethanolamine complex 6j to lower the BDE by
ca. 5 kcal/mol, which facilitates the subsequent HAT pro-
cess. The quinuclidinium radical 7 (BDE of N+–H bond: 100
kcal/mol)25 homolytically cleaves the -C–H bond of borate
8 to generate reactive carbon radical 9, and the HAT catalyst
is regenerated after releasing a proton.26 The thus generated
carbon radical 9 is trapped by acceptor 1 to form stabilized
radical 10. The Ir(II) species [E1/2(IrII/IrIII) = –1.37 V vs SCE]9a
In conclusion, we have conducted a DFT-calculation-
guided screening of bond-weakening borate catalysts and
identified electron-deficient borinic acid–ethanolamine
complex 6j as an effective catalyst component for the -C–H
alkylation of alcohols. The newly established PC-HAT-
borate hybrid catalyst system enhances the reaction yield
and broadens the substrate scope, probably due to the
greater bond-weakening effect of the borate relative to that
of silicates. Our reaction system can also transform amino
acids or peptides, which are inert to silicate- or hydrogen-
bonding-based bond-weakening systems.
Thieme. All rights reserved. Synthesis 2020, 52, A–N

I
K. Sakai et al.
Feature
Synthesis
Table 7 Substrate Scope of the Acceptorsa
R1
R2
EWG
[Ir(dF(CF3)ppy)2(dtbpy)][PF6] (4a) (1 mol%)
quinuclidine (5a) (10 mol%)
6j (10 mol%)
H
R1
EWG
HO
HO
R2
MeCN, fan, 14 h
1
2a or 2e
blue LEDs (430 nm)
3
Entry
1
Acceptor
Alcohol
H
Product
Yield (%)b
CN
CN
70
86c
81
1b
2e
2e
3be
HO
HO
Me
Me
n-C5H11
Me CN
2
3
Me
CN
H
1c
3ce
HO
HO
n-C5H11
O
O
HO
H
H
2a
2a
1d
NH2
NH2
Me
3da
3ea
3fa
HO
HO
HO
HO
Me
O
4
5
6
63
58
54
O
HO
t-Bu
t-Bu
1e
1f
N
H
Me
Me
N
H
Me
O
O
O
O
HO
HO
H
H
2a
2a
Ph
Ph
N
H
N
H
Me
O
1g
Me
H
NMe2
NMe2
3ga
Me
7
8
90d
O
O
2e
2e
1h
HO
Me
Me
OMe
O
3he
3ie
3ja
n-C5H11
85c,d
H
O
O
Me
Me
1i
HO
HO
MeO
EtO
n-C5H11
9
78c,d
O
O
O
H
H
Ph
2a
2a
Ph
1j
Me
Me
Me
10
76
SO2Ph
SO2Ph
HO
1k
3ka
HO
Me
a Reaction conditions: acceptor 1 (1 equiv), alcohol 2 (2 equiv), 4a (1 mol%), 5a (10 mol%), 6j (10 mol%), MeCN ([1a]final = 0.1 M), blue LED irradiation; the
temperature of the reaction (25–33 °C) was controlled for 14 h using a fan.
b Yield of isolated product.
c The dr was 1:1.0 to 1:2.9. See the Supporting Information for details.
d After blue LED irradiation, an acidic work-up (Amberlyst®-15; 100 mg, 3 h, 50 °C) was conducted.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–N

J
K. Sakai et al.
Feature
Synthesis
31P NMR (159 MHz, CDCl3):  = 32.8.
HRMS (ESI): m/z [M + Na]+ calcd for C8H19NaO4P: 233.0913; found:
All reagents (except for some borinic acids and borinic acid–ethanol-
amine complexes) and solvents were purchased from common chem-
ical suppliers and used without further purification. Alcohol -C–H
alkylation reactions were carried out in dried and degassed MeCN,
DMSO, CH2Cl2, DMF, 1,4-dioxane, benzotrifluoride, or acetone under
an argon atmosphere. Analytical TLC was performed on Merck silica
gel 60F254 plates. Flash column chromatography was performed using
silica gel (60, spherical, 40–50 m; Kanto Chemicals) or a Biotage®
Isolera™ One 3.0 instrument with a pre-packed Biotage® SNAP Ultra
column. Infrared (IR) spectra were recorded using a JASCO FT/IR 410
Fourier transform IR spectrophotometer. NMR spectra were recorded
using JEOL ECX500 (1H NMR: 500 MHz; 13C NMR: 125 MHz), JEOL
ECZ500 (1H NMR: 500 MHz; 13C NMR: 125 MHz), or JEOL ECS400 (1H
NMR: 400 MHz; 13C NMR: 100 MHz; 11B NMR: 126 MHz; 19F NMR:
369 MHz; 31P NMR: 159 MHz) spectrometers. Residual traces of the
hydrogenated solvents were used as an internal reference for the
chemical shifts in the 1H NMR and 13C NMR spectra. In the 19F NMR
spectra, the chemical shifts are reported relative to the external stan-
dard hexafluorobenzene ( = –164.90). In the 11B NMR spectra, the
chemical shifts are reported relative to the external reference BF3·Et2O
( = 0.00). In the 31P NMR spectra, the chemical shifts are reported rel-
ative to the external reference triphenylphosphine ( = –6.00). Cou-
pling constants (J) are reported in hertz (Hz), while multiplicities are
described using standard abbreviations. ESI-mass spectra were mea-
sured using a Bruker micrOTOF spectrometer or a JEOL JMS-T100LC
AccuTOF spectrometer for HRMS. DART-mass spectra were measured
using a JEOL JMS-T100LC AccuTOF spectrometer for HRMS. ESI-mass
spectra were measured using a JEOL JMS-T100LC AccuTOF spectrom-
eter for LRMS. Gel permeation chromatography (GPC) was performed
on a recycling preparative HPLC LC9210 NEXT system (Japan Analyti-
cal Industry Co., Ltd.). The synthesis of boron sources 6e and 6j and
substrates 1j, 2i, and 2k is described in the Supporting Information.
233.0917.
Diethyl (3-Hydroxypropyl)phosphonate (3ab)
Colorless oil; yield: 6.9 mg (35%); Rf = 0.18 (CH2Cl2/MeOH, 20:1).
IR (CH2Cl2): 3397, 2983, 2933, 1229, 1027, 962, 750 cm–1
1H NMR (400 MHz, CDCl3):  = 4.18–4.04 (m, 4 H), 3.71 (t, J = 5.7 Hz, 2
H), 2.23 (br s, 1 H; overlaps with the signal for water), 1.93–1.80 (m, 4
H), 1.33 (t, J = 7.3 Hz, 6 H).
13C NMR (100 MHz, CDCl3):  = 62.7 (d, J = 13.4 Hz), 61.9 (d, J = 6.7 Hz),
25.8 (d, J = 4.8 Hz), 22.8 (d, J = 144.0 Hz), 16.6 (d, J = 5.7 Hz).
.
31P NMR (159 MHz, CDCl3):  = 32.7.
HRMS (ESI): m/z [M + Na]+ calcd for C7H17NaO4P: 219.0757; found:
219.0767.
Diethyl (3-Hydroxy-3-methylbutyl)phosphonate (3ac)
Pale-yellow oil; yield: 11.3 mg (50%); Rf = 0.38 (CH2Cl2/MeOH, 20:1).
IR (CH2Cl2): 3404, 2973, 2930, 1223, 1027, 961 cm–1
1H NMR (400 MHz, CDCl3):  = 4.17–4.03 (m, 4 H), 1.90–1.72 (m, 5 H;
overlaps with the signal for water), 1.33 (t, J = 7.3 Hz, 6 H), 1.23 (s, 6
.
H).
13C NMR (125 MHz, CDCl3):  = 69.8 (d, J = 15.5 Hz), 61.7 (d, J = 6.0 Hz),
35.8 (d, J = 4.8 Hz), 28.9, 20.6 (d, J = 140.7 Hz), 16.5 (d, J = 6.0 Hz).
31P NMR (159 MHz, CDCl3):  = 33.1.
HRMS (ESI): m/z [M + Na]+ calcd for C9H21NaO4P: 247.1070; found:
247.1067.
Diethyl (3-Hydroxy-4-methylpentyl)phosphonate (3ad)
Photocatalytic C–H Alkylation of Alcohols; General Procedure
Colorless oil; yield: 19.3 mg (81%); Rf = 0.26 (CH2Cl2/MeOH, 20:1).
IR (CH2Cl2): 3397, 2959, 2873, 1234, 1029, 962, 749 cm–1
.
[Ir(dF(CF3)ppy)2(dtbpy)][PF6] (4a) (1.1 mg, 1.0 mol, 1 mol%), quinu-
clidine (5a) (1.1 mg, 0.010 mmol, 10 mol%), and 2,2-bis[4-(trifluoro-
methyl)phenyl)-1,3,24-oxazaborolidine (6j) (3.6 mg, 0.010 mmol, 10
mol%) were added to a dried screw-cap vial. Degassed MeCN (1.0 mL,
[1]final = 0.1 M), alcohol 2 (0.20 mmol, 2.0 equiv) and Michael acceptor
1 (0.10 mmol, 1.0 equiv) were added to the vial under an argon atmo-
sphere or in a glove box, before the vial was sealed with the screw
cap. The vial was removed from the glove box and then placed near
the 430 nm light source [Valore VBP-L24-C2 with a 38 W LED lamp;
VBL-SE150-BBB(430)]. The temperature (25–33 °C) was controlled
using a strong fan, and the vial was irradiated for 14 h with the blue
LEDs under constant stirring. After evaporation of all volatiles, the
residue was purified by flash column chromatography (GPC was used
for the purification of 3aj and 3ie) to afford the targeted C–H alkyla-
tion products 3.
1H NMR (400 MHz, CDCl3):  = 4.17–4.03 (m, 4 H), 3.92–3.35 (m, 1 H),
2.17 (br s, 1 H), 2.01–1.89 (m, 1 H), 1.86–1.74 (m, 2 H), 1.70–1.57 (m,
2 H), 1.32 (t, J = 7.1 Hz, 6 H), 0.93 (d, J = 6.0 Hz, 3 H), 0.91 (d, J = 6.4 Hz,
3 H).
13C NMR (125 MHz, CDCl3):  = 76.6 (d, J = 13.1 Hz), 61.8 (d, J = 3.6
Hz), 61.8 (d, J = 3.6 Hz), 33.8, 27.1 (d, J = 4.8 Hz), 22.5 (d, J = 140.7 Hz),
18.8, 17.7, 16.6 (d, J = 6.0 Hz).
31P NMR (159 MHz, CDCl3):  = 33.0.
HRMS (ESI): m/z [M + Na]+ calcd for C10H23NaO4P: 261.1226; found:
261.1223.
Diethyl (3-Hydroxyoctyl)phosphonate (3ae)
Pale-yellow oil; yield: 20.2 mg (76%); Rf = 0.21 (CH2Cl2/MeOH, 20:1).
IR (CH2Cl2): 3399, 2930, 2859, 1228, 1031, 962 cm–1
.
Diethyl (3-Hydroxybutyl)phosphonate (3aa)
Pale-yellow oil; yield: 17.9 mg (85%); Rf = 0.29 (CH2Cl2/MeOH, 20:1).
1H NMR (500MHz, CDCl3):  = 4.16–4.03 (m, 4 H), 3.65–3.61 (m, 1 H),
2.18 (br s, 1 H), 1.96–1.76 (m, 3 H), 1.69–1.59 (m, 1 H), 1.48–1.20 (m,
8 H), 1.32 (t, J = 7.2 Hz, 6 H), 0.88 (t, J = 6.9 Hz, 3 H).
13C NMR (125 MHz, CDCl3):  = 71.6 (d, J = 13.1 Hz), 61.8 (d, J = 6.0 Hz),
61.8 (d, J = 6.0 Hz), 37.4, 32.0, 30.2 (d, J = 4.8 Hz), 25.5, 22.2 (d, J =
139.5 Hz), 16.6 (d, J = 6.0 Hz), 14.2.
IR (CH2Cl2): 3397, 2978, 1239, 1029, 963, 789 cm–1
.
1H NMR (400 MHz, CDCl3):  = 4.17–4.03 (m, 4 H), 3.90–3.82 (m, 1 H),
2.18 (br s, 1 H), 1.96–1.61 (m, 4 H), 1.32 (t, J = 7.3 Hz, 6 H), 1.21 (d, J =
6.4 Hz, 3 H).
13C NMR (125 MHz, CDCl3):  = 67.4 (d, J = 15.5 Hz), 61.8 (d, J = 4.8
Hz), 61.7 (d, J = 6.0 Hz), 31.7 (d, J = 4.8 Hz), 23.2, 22.0 (d, J = 140.7 Hz),
16.5 (d, J = 6.0 Hz).
31P NMR (159 MHz, CDCl3):  = 32.9.
HRMS (ESI): m/z [M + Na]+ calcd for C12H27NaO4P: 289.1539; found:
289.1539.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–N

K
K. Sakai et al.
Feature
Synthesis
Diethyl [2-(1-Hydroxycyclohexyl)ethyl]phosphonate (3af)
31P NMR (159 MHz, CDCl3):  = 32.5.
HRMS (ESI): m/z [M + Na]+ calcd for C16H25NaO6P: 367.1281; found:
Pale-yellow oil; yield: 19.8 mg (75%); Rf = 0.26 (CH2Cl2/MeOH, 20:1).
IR (CH2Cl2): 3399, 2981, 2931, 2857, 1219, 1030, 964 cm–1
.
367.1265.
1H NMR (500 MHz, CDCl3):  = 4.14–4.03 (m, 4 H), 1.94 (br s, 1 H),
1.87–1.78 (m, 2 H), 1.76–1.69 (m, 2 H), 1.62–1.42 (m, 7 H), 1.39–1.22
(m, 3 H), 1.31 (t, J = 7.2 Hz, 6 H).
13C NMR (125 MHz, CDCl3):  = 70.6 (d, J = 15.5 Hz), 61.7 (d, J = 6.0 Hz),
37.2, 34.6, 25.9, 22.2, 19.5 (d, J = 141.9 Hz), 16.6 (d, J = 6.0 Hz).
Diethyl [3-Hydroxy-3-(tetrahydro-2H-pyran-4-yl)propyl]phos-
phonate (3aj)
Pale-yellow oil; yield: 22.3 mg (80%); Rf = 0.15 (CH2Cl2/MeOH, 20:1).
IR (CH2Cl2): 3398, 2949, 2845, 1233, 1029, 962 cm–1
.
1H NMR (500 MHz, CDCl3):  = 4.15–4.03 (m, 4 H), 3.99 (ddd, J = 11.6,
11.6, 3.6 Hz, 2 H), 3.40–3.33 (m, 3 H), 2.40 (br s, 1 H; overlaps with the
signal for water), 1.98–1.35 (m, 9 H), 1.32 (t, J = 7.2 Hz, 6 H).
13C NMR (125 MHz, CDCl3):  = 75.1 (d, J = 11.9 Hz), 68.1, 67.9, 61.9 (d,
J = 3.6 Hz), 61.8 (d, J = 3.6 Hz), 41.1, 29.2, 28.7, 27.0 (d, J = 4.8 Hz), 22.2
(d, J = 140.7 Hz), 16.6 (d, J = 6.0 Hz).
31P NMR (159 MHz, CDCl3):  = 33.6.
HRMS (ESI): m/z [M + Na]+ calcd for C12H25NaO4P: 287.1383; found:
287.1389.
Diethyl (5-Fluoro-3-hydroxypentyl)phosphonate (3ag)
Pale-yellow oil; yield: 20.1 mg (83%); Rf = 0.18 (CH2Cl2/MeOH, 20:1).
IR (CH2Cl2): 3384, 2982, 2910, 1232, 1028, 965 cm–1
1H NMR (400 MHz, CDCl3):  = 4.74–4.49 (m, 2 H), 4.17–4.02 (m, 4 H),
3.90–3.84 (m, 1 H), 2.66 (br s, 1 H), 1.98–1.65 (m, 6 H), 1.32 (t, J = 7.3
Hz, 6 H).
13C NMR (125 MHz, CDCl3):  = 81.7 (d, JC–F = 162.2 Hz), 68.1 (dd, JC–P
12.5 Hz and JC–F = 4.8 Hz), 62.0 (d, JC–P = 6.0 Hz), 61.9 (d, JC–P = 6.0 Hz),
37.8 (d, JC–F = 19.1 Hz), 30.5 (d, JC–P = 4.8 Hz), 22.2 (d, JC–P = 140.7 Hz),
16.6 (d, JC–P = 6.0 Hz).
19F NMR (369 MHz, CDCl3):  = –220.0 to –220.3 (m).
31P NMR (159 MHz, CDCl3):  = 32.7.
HRMS (ESI): m/z [M + Na]+ calcd for C9H20FNaO4P: 265.0975; found:
31P NMR (159 MHz, CDCl3):  = 32.9.
HRMS (ESI): m/z [M + Na]+ calcd for C12H25NaO5P: 303.1332; found:
.
303.1331.
Diethyl [3-(1-Benzoylpiperidin-4-yl)-3-hydroxypropyl]phospho-
nate (3ak)
=
Pale-yellow oil; yield: 32.1 mg (84%); Rf = 0.23 (CH2Cl2/MeOH, 20:1).
IR (CH2Cl2): 3390, 2982, 2932, 2861, 1629, 1444, 1241, 1029, 964, 710
cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.37 (br m, 5 H), 4.75 (br m, 1 H), 4.14–
4.02 (m, 4 H), 3.77 (br m, 1 H), 3.43–3.41 (m, 1 H), 2.92–2.70 (br m, 3
H), 1.96–1.57 (m, 7 H), 1.43–1.18 (m, 2 H), 1.31 (t, J = 6.9 Hz, 6 H).
13C NMR (125 MHz, CDCl3):  = 170.4, 136.3, 129.6, 128.5, 126.9, 74.5
(d, J = 10.7 Hz), 61.9 (d, J = 6.0 Hz), 61.9 (d, J = 4.8 Hz), 48.0, 42.4, 42.3,
29.0, 28.3, 27.2 (d, J = 3.6 Hz), 22.3 (d, J = 140.7 Hz), 16.6 (d, J = 6.0 Hz).
265.0983.
Diethyl (6,6,6-Trifluoro-3-hydroxyhexyl)phosphonate (3ah)
Pale-yellow oil; yield: 26.6 mg (91%); Rf = 0.47 (CH2Cl2/MeOH, 10:1).
IR (CH2Cl2): 3376, 2985, 2935, 1253, 1135, 1030, 964 cm–1
1H NMR (400 MHz, CDCl3):  = 4.18–4.02 (m, 4 H), 3.72–3.67 (m, 1 H),
2.74 (br s, 1 H), 2.43–2.27 (m, 1 H), 2.23–2.06 (m, 1 H), 1.92–1.60 (m,
6 H), 1.32 (t, J = 7.3 Hz, 6 H).
13C NMR (125 MHz, CDCl3):  = 127.5 (q, JC–F = 274.2 Hz), 69.9 (d, JC–P
10.7 Hz), 62.1 (d, JC–P = 6.0 Hz), 62.0 (d, JC–P = 6.0 Hz), 30.5 (q, JC–F = 28.6
Hz), 30.5 (d, JC–P = 4.8 Hz), 29.6 (q, JC–F = 2.4 Hz), 22.3 (d, JC–P = 140.7
Hz), 16.6 (d, JC–P = 6.0 Hz).
19F NMR (369 MHz, CDCl3):  = –65.9 (t, J = 19.9 Hz).
31P NMR (159 MHz, CDCl3):  = 32.6.
HRMS (ESI): m/z [M + Na]+ calcd for C10H20F3NaO4P: 315.0944; found:
31P NMR (159 MHz, CDCl3):  = 32.8.
HRMS (ESI): m/z [M + Na]+ calcd for C19H30NNaO5P: 406.1754; found:
.
406.1740.
4-Hydroxynonanenitrile (3be)
=
Colorless oil; yield: 10.9 mg (70%); Rf = 0.14 (n-hexane/EtOAc, 4:1).
IR (CH2Cl2): 3432, 2930, 2859, 2247, 1458, 1056, 655 cm–1
.
1H NMR (400 MHz, CDCl3):  = 3.75–3.69 (m, 1 H), 2.53–2.49 (m, 2 H),
1.88–1.80 (m, 1 H), 1.73–1.64 (m, 1 H), 1.54 (br s, 1 H), 1.51–1.26 (m,
8 H), 0.89 (t, J = 6.9 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 120.1, 70.2, 37.6, 32.6, 31.8, 25.3, 22.7,
14.1, 13.9.
315.0941.
HRMS (ESI): m/z [M + Na]+ calcd for C9H17NNaO: 178.1202; found:
178.1202.
5-(Diethoxyphosphoryl)-3-hydroxypentyl Benzoate (3ai)
Pale-yellow oil; yield: 20.0 mg (58%); Rf = 0.21 (CH2Cl2/MeOH, 20:1).
4-Hydroxy-2-methylnonanenitrile (3ce)
IR (CH2Cl2): 3378, 2981, 2932, 1717, 1277, 1235, 1117, 1027, 963, 714
Obtained as inseparable diastereomers (dr = 1:1.3).
cm–1
.
Colorless oil; yield: 14.5 mg (86%); Rf = 0.23 (n-hexane/EtOAc, 4:1).
IR (CH2Cl2): 3440, 2930, 2859, 2241, 1458, 1095, 750 cm–1
1H NMR (400 MHz, CDCl3):  = 8.04–8.02 (m, 2 H), 7.59–7.55 (m, 1 H),
7.44 (dd, J = 8.0, 8.0 Hz, 2 H), 4.65–4.59 (m, 1 H), 4.43–4.38 (m, 1 H),
4.15–4.04 (m, 4 H), 3.84–3.80 (m, 1 H), 3.14 (br s, 1 H), 1.98–1.68 (m,
6 H), 1.31 (t, J = 7.1 Hz, 6 H).
13C NMR (125 MHz, CDCl3):  = 167.1, 133.2, 130.2, 129.7, 128.5, 68.2
(d, J = 13.1 Hz), 62.1, 61.9 (d, J = 6.0 Hz), 61.8 (d, J = 6.0 Hz), 36.6, 30.3
(d, J = 4.8 Hz), 22.3 (d, J = 140.7 Hz), 16.6 (d, J = 6.0 Hz).
.
1H NMR (400 MHz, CDCl3):  (major diastereomer) = 3.75–3.69 (m, 1
H), 2.90–2.81 (m, 1 H), 1.87–1.80 (m, 1 H), 1.74–1.24 (m, 10 H), 1.34
(d, J = 7.3 Hz, 3 H), 0.89 (t, J = 6.9 Hz, 3 H).
1H NMR (400 MHz, CDCl3):  (minor diastereomer) = 3.88–3.82 (m, 1
H), 3.03–2.94 (m, 1 H), 1.74–1.24 (m, 11 H), 1.34 (d, J = 7.3 Hz, 3 H),
0.89 (t, J = 6.9 Hz, 3 H).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–N

L
K. Sakai et al.
Feature
Synthesis
13C NMR (125 MHz, CDCl3):  = 123.7, 123.1, 69.6, 69.0, 41.7, 41.1,
38.1, 37.8, 31.8, 31.8, 25.2, 22.7, 22.7, 21.9, 18.6, 17.7, 14.1 (three
methylene carbon signals overlap with those of the diastereomers).
1H NMR (500 MHz, CDCl3):  = 4.51–4.45 (m, 1 H), 2.54–2.51 (m, 2 H),
2.35–2.28 (m, 1 H), 1.89–1.81 (m, 1 H), 1.77–1.70 (m, 1 H), 1.62–1.55
(m, 1 H), 1.50–1.25 (m, 6 H), 0.89 (t, J = 7.2 Hz, 3 H).
HRMS (ESI): m/z [M + Na]+ calcd for C10H19NNaO: 192.1359; found:
13C NMR (125 MHz, CDCl3):  = 177.4, 81.2, 35.7, 31.6, 29.0, 28.2, 25.0,
192.1356.
22.6, 14.1.
HRMS (ESI): m/z [M + Na]+ calcd for C9H16NaO2: 179.1043; found:
179.1049.
4-Hydroxypentanamide (3da)
Pale-yellow oil; yield: 9.5 mg (81%); Rf = 0.25 (CH2Cl2/MeOH, 10:1).
IR (CH2Cl2): 3347, 2968, 2928, 1663, 1411, 1068, 762 cm–1
.
3-Methyl-5-pentyldihydrofuran-2(3H)-one (3ie)
Obtained as inseparable diastereomers (dr = 1:2.5).
1H NMR (400 MHz, CD3CN):  = 6.84 (br s, 1 H), 6.24 (br s, 1 H), 3.93
(d, J = 4.6 Hz, 1 H), 3.76–3.67 (m, 1 H), 2.29 (t, J = 7.6 Hz, 2 H), 1.74–
1.56 (m, 2 H), 1.10 (d, J = 6.4 Hz, 3 H).
13C NMR (100 MHz, CD3CN):  = 176.0, 67.3, 35.5, 32.8, 24.0.
HRMS (ESI): m/z [M + Na]+ calcd for C5H11NNaO2: 140.0682; found:
Colorless oil; yield: 14.5 mg (85%); Rf = 0.31 (n-hexane/EtOAc, 5:1).
IR (CH2Cl2): 2933, 2862, 1771, 1457, 1378, 1189, 1011, 926 cm–1
1H NMR (400 MHz, CDCl3):  (major diastereomer) = 4.36–4.29 (m, 1
H), 2.73–2.60 (m, 1 H), 2.51–2.44 (m, 1 H), 1.78–1.25 (m, 12 H), 0.89
(t, J = 6.9 Hz, 3 H).
.
140.0687.
1H NMR (400 MHz, CDCl3):  (minor diastereomer) = 4.53–4.46 (m, 1
H), 2.73–2.60 (m, 1 H), 2.17–2.07 (m, 1 H), 2.02–1.95 (m, 1 H), 1.78–
1.25 (m, 11 H), 0.89 (t, J = 6.9 Hz, 3 H).
N-(tert-Butyl)-4-hydroxypentanamide (3ea)
Pale-yellow solid; yield: 10.9 mg (63%); Rf = 0.35 (CH2Cl2/MeOH,
13C NMR (125 MHz, CDCl3):  = 180.3, 179.8, 78.9, 78.6, 37.5, 36.1,
35.6, 35.6, 35.5, 34.2, 31.7, 31.6, 25.2, 25.1, 22.6, 16.0, 15.3, 14.1 (two
methylene carbon signals overlap with those of the diastereomers).
20:1).
IR (CH2Cl2): 3300, 2967, 2926, 1650, 1550, 1454, 1363, 1225, 1079
cm–1
.
HRMS (ESI): m/z [M + Na]+ calcd for C10H18NaO2: 193.1199; found:
193.1205.
1H NMR (500 MHz, CDCl3):  = 5.59 (br s, 1 H), 3.87–3.79 (m, 1 H),
3.08 (br s, 1 H), 2.35–2.22 (m, 2 H), 1.85–1.75 (m, 1 H), 1.71–1.61 (m,
1 H), 1.33 (s, 9 H), 1.19 (d, J = 6.0 Hz, 3 H).
13C NMR (125 MHz, CDCl3):  = 173.3, 67.7, 51.5, 34.4, 34.3, 28.9, 23.8.
5-Methyl-3-phenyldihydrofuran-2(3H)-one (3ja)
Obtained as inseparable diastereomers (dr = 1:2.9).
HRMS (ESI): m/z [M + Na]+ calcd for C9H19NNaO2: 196.1308; found:
196.1315.
Colorless oil; yield: 13.8 mg (78%); Rf = 0.27 (n-hexane/EtOAc, 5:1).
IR (CH2Cl2): 2979, 2933, 1769, 1455, 1388, 1175, 1119, 1053, 949,
753, 698 cm–1
.
4-Hydroxy-N-phenylpentanamide (3fa)
1H NMR (400 MHz, CDCl3):  (major diastereomer) = 7.40–7.34 (m, 2
H), 7.32–7.27 (m, 3 H), 4.68–4.59 (m, 1 H), 3.90 (dd, J = 12.8, 8.7 Hz, 1
H), 2.79 (ddd, J = 12.8, 8.7, 5.5 Hz, 1 H), 2.03 (ddd, J = 12.8, 12.8, 10.8
Hz, 1 H), 1.51 (d, J = 6.4 Hz, 3 H).
1H NMR (400 MHz, CDCl3):  (minor diastereomer) = 7.40–7.34 (m, 2
H), 7.32–7.27 (m, 3 H), 4.85–4.77 (m, 1 H), 3.94 (dd, J = 9.6, 7.3 Hz, 1
H), 2.55 (ddd, J = 13.3, 7.3, 7.3 Hz, 1 H), 2.36 (ddd, J = 13.3, 9.6, 6.0 Hz,
1 H), 1.47 (d, J = 6.4 Hz, 3 H).
Colorless solid; yield: 11.1 mg (58%); Rf = 0.14 (n-hexane/EtOAc, 1:1).
IR (CH2Cl2): 3302, 2967, 2927, 1663, 1599, 1543, 1498, 1443, 1074,
692 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.72 (br s, 1 H), 7.50 (d, J = 7.6 Hz, 2 H),
7.31 (dd, J = 7.6, 7.6 Hz, 2 H), 7.10 (dd, J = 7.6, 7.6 Hz, 1 H), 3.95–3.90
(m, 1 H), 2.59–2.49 (m, 2 H), 2.21 (br s, 1 H), 1.97–1.90 (m, 1 H), 1.81–
1.74 (m, 1 H), 1.24 (d, J = 6.3 Hz, 3 H).
13C NMR (125 MHz, CDCl3):  = 172.0, 138.0, 129.1, 124.5, 120.0, 67.7,
34.4, 34.2, 24.0.
13C NMR (125 MHz, CDCl3):  = 177.3, 177.0, 137.2, 136.7, 129.1,
129.0, 128.2, 127.8, 127.7, 127.7, 75.3, 75.1, 47.8, 45.8, 39.9, 38.1,
21.2, 21.0.
HRMS (ESI): m/z [M + Na]+ calcd for C11H15NNaO2: 216.0995; found:
216.1005.
HRMS (ESI): m/z [M + Na]+ calcd for C11H12NaO2: 199.0730; found:
199.0732.
4-Hydroxy-N,N-dimethylpentanamide (3ga)
Colorless oil; yield: 7.8 mg (54%); Rf = 0.35 (CH2Cl2/MeOH, 20:1).
IR (CH2Cl2): 3408, 2965, 2929, 1628, 1401, 1265, 1125, 1072 cm–1
1H NMR (500 MHz, CDCl3):  = 3.86–3.80 (m, 1 H), 3.13 (br s, 1 H),
3.02 (br s, 3 H), 2.96 (br s, 3 H), 2.57–2.43 (m, 2 H), 1.86–1.80 (m, 1 H),
1.78–1.71 (m, 1 H), 1.20 (d, J = 6.3 Hz, 3 H).
13C NMR (125 MHz, CDCl3):  = 174.0, 67.9, 37.6, 35.8, 33.6, 30.3, 23.9.
HRMS (ESI): m/z [M + Na]+ calcd for C7H15NNaO2: 168.0995; found:
4-(Phenylsulfonyl)butan-2-ol (3ka)
.
Colorless oil; yield: 16.2 mg (76%); Rf = 0.23 (n-hexane/EtOAc, 1:1).
IR (CH2Cl2): 3494, 2969, 2928, 1447, 1303, 1145, 1086, 743, 688 cm–1
1H NMR (400 MHz, CDCl3):  = 7.94–7.91 (m, 2 H), 7.67 (dddd, J = 7.6,
7.6, 1.4, 1.4 Hz, 1 H), 7.60–7.56 (m, 2 H), 3.97–3.89 (m, 1 H), 3.34–3.17
(m, 2 H), 1.99–1.90 (m, 1 H), 1.83–1.74 (m, 1 H), 1.21 (d, J = 6.4 Hz, 3
H).
.
168.0994.
13C NMR (125 MHz, CDCl3):  = 139.2, 133.9, 129.5, 128.1, 66.3, 53.2,
31.7, 23.8.
5-Pentyldihydrofuran-2(3H)-one (3he)
HRMS (ESI): m/z [M + Na]+ calcd for C10H14NaO3S: 237.0556; found:
237.0556.
Colorless oil; yield: 14.0 mg (90%); Rf = 0.24 (n-hexane/EtOAc, 5:1).
IR (CH2Cl2): 2933, 2861, 1775, 1460, 1182, 1021 cm–1
.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–N

M
K. Sakai et al.
Feature
Synthesis
Methyl (S)-2-{[(Benzyloxy)carbonyl]amino}-5-(diethoxyphos-
phoryl)-3-hydroxypentanoate (3al)
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707114.
Obtained as inseparable diastereomers (dr = 1:4).
S
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Pale-yellow oil; yield: 14.2 mg (34%); Rf = 0.46 (CH2Cl2/MeOH, 10:1).
IR (CH2Cl2): 3357, 2983, 1751, 1724, 1533, 1439, 1211, 1054, 1026,
965, 749, 699 cm–1
.
References
1H NMR (400 MHz, CDCl3):  = 7.36–7.28 (m, 5 H), 5.93 (br d, J = 9.6
Hz, 1 H), 5.15–5.08 (m, 2 H), 4.36 (dd, J = 9.6, 2.3 Hz, 1 H), 4.19–4.18
(m, 1 H), 4.13–4.01 (m, 4 H), 3.76 (s, 3 H), 1.92–1.78 (m, 4 H), 1.32–
1.25 (m, 6 H).
13C NMR (125 MHz, CDCl3):  (major diastereomer) = 171.5, 156.9,
136.4, 128.7, 128.3, 128.2, 71.8 (d, J = 11.9 Hz), 67.3, 62.3 (d, J = 6.0
Hz), 62.1 (d, J = 6.0 Hz), 58.7, 52.7, 27.2 (d, J = 4.8 Hz), 22.5 (d, J = 140.7
Hz), 16.5 (d, J = 6.0 Hz).
13C NMR (125 MHz, CDCl3):  (minor diastereomer) = 170.7, 156.5,
136.2, 128.7, 128.6, 128.4, 72.8 (d, J = 11.9 Hz), 67.4, 62.0 (d, J = 6.0
Hz), 58.8, 52.6, 26.6 (d, J = 4.8 Hz), 22.4 (d, J = 141.9 Hz), 16.5 (d, J = 6.0
Hz) (two doublet signals of the minor diastereomer overlap with
those of the major diastereomer).
(1) (a) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Angew. Chem. Int.
Ed. 2012, 51, 8960. (b) Wencel-Delord, J.; Glorius, F. Nat. Chem.
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P.; Krska, S. W. Chem. Soc. Rev. 2016, 45, 546.
(2) For recent reviews on C(sp3)–H functionalization reactions, see:
(a) He, J.; Wasa, M.; Chan, K. S. L.; Shao, Q.; Yu, J.-Q. Chem. Rev.
2017, 117, 8754. (b) Lu, Q.; Glorius, F. Angew. Chem. Int. Ed.
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B.-F.; Ma, J.-A. Chem. Soc. Rev. 2019, 48, 4921.
31P NMR (159 MHz, CDCl3):  = 32.3 (major diastereomer), 32.2 (mi-
nor diastereomer).
HRMS (ESI): m/z [M + Na]+ calcd for C18H28NNaO8P: 440.1445; found:
440.1438.
(3) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52, 6752.
(4) For reviews on C(sp3)–H functionalization reactions via the HAT
mechanism under irradiation with visible light, see: (a) Shaw,
M. H.; Twilton, J.; MacMillan, D. W. C. J. Org. Chem. 2016, 81,
6898. (b) Capaldo, L.; Ravelli, D. Eur. J. Org. Chem. 2017, 2056.
(c) Hu, X.-Q.; Chen, J.-R.; Xiao, W.-J. Angew. Chem. Int. Ed. 2017,
56, 1960.
tert-Butyl (2-{[(Benzyloxy)carbonyl]amino}-6-(diethoxyphos-
phoryl)-4-hydroxyhexanoyl)glycinate (3am)
Obtained as inseparable diastereomers (dr = 1:1).
Colorless oil; yield: 39.6 mg (75%); Rf = 0.58 (CH2Cl2/MeOH, 10:1).
IR (CH2Cl2): 3315, 2980, 2933, 1725, 1677, 1528, 1368, 1226, 1157,
(5) (a) Tanaka, H.; Sakai, K.; Kawamura, A.; Oisaki, K.; Kanai, M.
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Enomoto, T.; Kondo, M.; Masaoka, S.; Oisaki, K.; Kanai, M. Chem.
Eur. J. 2018, 24, 8051. (c) Sakai, K.; Oisaki, K.; Kanai, M. Adv.
Synth. Catal. 2020, 362, 337. (d) Kato, S.; Saga, Y.; Kojima, M.;
Fuse, H.; Matsunaga, S.; Fukatsu, A.; Kondo, M.; Masaoka, S.;
Kanai, M. J. Am. Chem. Soc. 2017, 139, 2204. (e) Fuse, H.; Kojima,
M.; Mitsunuma, H.; Kanai, M. Org. Lett. 2018, 20, 2042.
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1028, 965 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.35–7.29 (m, 5 H), 7.18 (br s, 0.5 H),
7.01 (br s, 0.5 H), 6.29 (br d, J = 8.0 Hz, 0.5 H), 5.97 (br d, J = 6.0 Hz, 0.5
H), 5.10 + 5.08 (s + s, 2 H), 4.47 (br m, 0.5 H), 4.42–4.41 (br m, 0.5 H),
4.13–4.01 (m, 4 H), 3.97–3.92 (m, 1 H), 3.89–3.78 (m, 2 H), 1.95–1.69
(m, 6 H), 1.45 + 1.45 (s + s, 9 H), 1.32–1.28 (m, 6 H).
13C NMR (125 MHz, CDCl3):  = 172.2, 171.9, 168.9 (another signal
may overlap this peak), 157.0, 156.3, 136.3, 136.2, 128.7, 128.6, 128.3,
128.2, 128.2, 128.2, 82.5, 82.3, 68.8 (d, J = 11.9 Hz), 68.7 (d, J = 13.1
Hz), 67.3, 67.1, 62.0, 62.0, 61.9, 61.9, 61.9, 61.9, 53.1, 52.9, 42.1, 42.1,
40.5, 39.6, 30.3 (d, J = 4.8 Hz), 30.2 (d, J = 4.8 Hz), 28.2, 22.4 (d, J =
140.7 Hz), 22.2 (d, J = 140.7 Hz), 16.5 (d, J = 6.0 Hz) (another signal
may overlap this peak).
The J values of the signals at  = 62.0–61.9 are difficult to be deter-
mine because of overlapping with the signals of diastereomers.
31P NMR (159 MHz, CDCl3):  = 32.7, 32.6.
HRMS (ESI): m/z [M + Na]+ calcd for C24H39N2NaO9P: 553.2285; found:
553.2285.
(7) (a) Spiegel, D. A.; Wiberg, K. B.; Schacherer, L. N.; Medeiros, M.
R.; Wood, J. L. J. Am. Chem. Soc. 2005, 127, 12513. (b) Pozzi, D.;
Scanlan, E. M.; Renaud, P. J. Am. Chem. Soc. 2005, 127, 14204.
(c) Chciuk, T. V.; Flowers, R. A. II. J. Am. Chem. Soc. 2015, 137,
11526.
Funding Information
This work was supported by the Japan Society for the Promotion of
Science (JSPS) KAKENHI grants [JP19J23157 (JSPS Fellows) (to K. S.),
JP18H04239 (Precisely Designed Catalysts with Customized Scaffold-
ing), JP18K06545 (Scientific Research C) (to K.O.), and JP17H06442
(Hybrid Catalysis) (to M.K.)], and the TOBE MAKI Scholarship Founda-
(8) Tarantino, K. T.; Miller, D. C.; Callon, T. A.; Knowles, R. R. J. Am.
Chem. Soc. 2015, 137, 6440.
tion (K.S.).
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© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–N

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K. Sakai et al.
Feature
Synthesis
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© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–N