Rhodium-Catalyzed Deoxygenation and Borylation of Ketones: A Combined Experimental and Theoretical Investigation

Article abstract of DOI:10.1021/jacs.0c07854

The rhodium-catalyzed deoxygenation and borylation of ketones with B2pin2 have been developed, leading to efficient formation of alkenes, vinylboronates, and vinyldiboronates. These reactions feature mild reaction conditions, a broad substrate scope, and excellent functional-group compatibility. Mechanistic studies support that the ketones initially undergo a Rh-catalyzed deoxygenation to give alkenes via boron enolate intermediates, and the subsequent Rh-catalyzed dehydrogenative borylation of alkenes leads to the formation of vinylboronates and diboration products, which is also supported by density functional theory calculations.

Full text of DOI:10.1021/jacs.0c07854

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Article
Rhodium-Catalyzed Deoxygenation and Borylation of Ketones:
A Combined Experimental and Theoretical Investigation
Lei Tao, Xueying Guo, Jie Li, Ruoling Li, Zhenyang Lin, and Wanxiang Zhao
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c07854 • Publication Date (Web): 27 Sep 2020
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Journal of the American Chemical Society
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Rhodium-Catalyzed Deoxygenation and Borylation of Ketones: A
Combined Experimental and Theoretical Investigation
Lei Tao,†,# Xueying Guo,‡, # Jie Li,† Ruoling Li,† Zhenyang Lin,*, ‡ and Wanxiang Zhao*,†
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†State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University,
Changsha, Hunan 410082, P. R. China
‡ Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR,
China
Supporting Information Placeholder
ABSTRACT: The rhodium-catalyzed deoxygenation and borylation of ketones with B2pin2 have been developed, leading to
efficient formation of alkenes, vinylboronates, and vinyldiboronates. These reactions feature mild reaction conditions, a broad
substrate scope, and excellent functional-group compatibility. Mechanistic studies support that the ketones initially undergo a Rh-
catalyzed deoxygenation to give alkenes via boron enolate intermediates, and the subsequent Rh-catalyzed dehydrogenative
borylation of alkenes leads to the formation of vinylboronates and diboration products, which is also supported by DFT
calculations.
INTRODUCTION
Cu-catalyzed oxygen abstraction from CO2 to form CO and
(Bpin)2O with high turnover numbers and frequencies (Figure
The availability and synthetic versatility of ketones have
rendered them valuable to the pharmaceutical, agrochemical,
and materials science.1 The manipulation of the carbonyl
group provides a generic entry into various functional
groups.2 Of particular importance to synthetic chemists is to
synthesize alkenes from ketones3 as the synthesis and
functionalization of alkenes is a central theme in organic
chemistry.4 In this context, the classical methods that the α-
carbon of ketones is uninvolved in the C=C bond formation
such as Wittig reaction,5a-d HWE-,5e-f Tebbe-,5g Peterson-,5h-i
and Julia-Lythgoe olefination5j-k have been well-established. In
contrast, deoxygenative olefinations that involve the α-carbon
in the construction of alkenes are much less explored. Among
them, the Shapiro reaction allows access to the alkenes via
hydrazones prepared from ketones and hydrazine,6a-b but it
suffers from limited substrate scope due to the use of strong
base (Figure 1a). The protected enolates and alcohols derived
from ketones can also be exploited in the alkene formation via
a reduction (metal-hydride involved)3b,6c-d or a dehydration
(strong acid involved, Figure 1a).6e-f In general, the existing
deoxygenative strategies require multi-step procedures,
organometallic reagents, or the use of strong base or acid
(Figure 1a).6 Therefore, the identification of distinct strategies
for the direct deoxygenation of ketones to the alkenes still
remains an important challenge, and it is highly desirable
given the importance of the alkenes in both academic and
industrial laboratories. Herein we report an eco-friendly
approach for the synthesis of olefins from ketones, which
avoids the use of halides, dipolar aprotic solvents, acid, and
excess base.
1b).8a The mechanism involves the insertion of Cu−Bpin into
(a) Ketone deoxygenation to alkenes
NHTs
base
N
R2
R1
R1
O
OR
R2
R2
R2
H
R1
alkenes
R1
carbon
ketones
O
H
acid
R2
R1
(b) Oxygen abstraction
CO2
CO
H2O
+
H2
+
+
+
Cu
Pd
B2pin2
(Bpin2)O
B2pin2
(Bpin)2O
O
H
R2
R1
ketones
R2
B2pin2
(Bpin)2O
+
M
+
R1
H
deoxygenation
our hypothesis
alkenes
(c) Ketone borylation
OM
OBpin
R2
known
R2
I
M
B2pin2
M
R1
R1
R1
Bpin
Bpin
II
O
a
b
R2
R1
OBpin
R2
ketones
R2
III
?
R1
M
H
H
alkenes
Bis(pinacolato)diboron (B2pin2) is among the most versatile
diboron reagents due to its stability and ease of handling, and
exhibits extensive applications in various boration reactions.7
R2
OBpin
R2
OBpin
R1
H
R1
R2
R1
IV
V
Bpin
vinylboronates
M
Interestingly,
B2pin2 can also be utilized an oxygen-
H
H
abstraction reagent to generate (Bpin)2O, although relevant
examples are rare.8 For example, Sadighi disclosed an elegant
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Figure 1. (a) Ketone deoxygenation to alkenes. (b) Oxygen
abstraction. (c) Ketone borylation.
With the optimal reaction conditions determined the scope
1
2
3
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5
6
7
8
of ketone was then investigated. As shown in Table 2, the mild
reaction conditions were applicable to a broad range of
ketones to produce alkene products with excellent
stereoselectivity (E/Z > 20:1). The aryl alkyl ketones with
different chain lengths all reacted smoothly with B2pin2 to
afford the corresponding products 2a-d in good yields. The
substrates with ortho-, meta-, or para-substituent all
successfully participated in the olefination to afford the alkene
product 2e-g. A variety of functional groups, including
electron-withdrawing and
CO2, boryl migration, CO release, and σ-bond metathesis
between B2pin2 and Cu−OBpin, which is further confirmed by
density functional theory (DFT) studies by Lin and Marder.8b
In addition, Prabhu and Song recently demonstrated that
B2pin2 could abstract oxygen from H2O to deliver H2 and
(Bpin)2O with the aid of Pd catalyst (Figure 1b).8c-f These
strategies have inspired us to explore the use of B2pin2 in
transition metal-catalyzed direct deoxygenation of ketones for
the formation of alkene (Figure 1b).
9
Table 1. Optimization of Reaction Conditionsa
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[RhCl(cod)]2 (3 mol%)
ligand (7.5 or 18 mol%)
B2pin2 (1.1 equiv)
Me
O
The copper-catalyzed diboration of ketones and aldehydes
with B2pin2 to produce the product II was pioneered by
Sadighi and Clark (Figure 1c, path a).9 Mechanistically, the
carbonyl group undergoes 1,2-insertion with Cu−Bpin to
generate intermediate I (M = Cu), and the subsequent σ-bond
metathesis with B2pin2 delivers the product II (Figure 1c).9a
The DFT calculations studied by Lin and Marder also support
this Cu−Bpin addition mechanism, and showed that the
intermediate I can isomerize to the thermodynamically
favored intermediate III via boryl migration.10 The
intermediate III with a metal−carbon bond, we assume, might
go through β-hydride elimination to form boron enolate IV
and M−H. Subsequently, the addition of the M−H to boron
enolate IV followed β-OBpin elimination11 via the
intermediate V could yield the alkene product. The overall
conversion is B2pin2 abstracting oxygen from ketones to
generate alkenes and (Bpin)2O (Figure 1b). Moreover, the
alkene generated might go further transformations with
Me
Ph
Ph
base (50 mol%)
solvent (1.5 mL), 70 C, 10 h
1a
2a
2a
entry
ligand
PBu3
base
solvent
(%)
K2CO3
hexane
hexane
1
2
35
0
PCy3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
PPh3
hexane
hexane
hexane
3
4
5
0
0
MePPh2
DPEPhos
76 (71)b
Xantphos
dppe
hexane
hexane
hexane
6
7
8
0
0
K2CO3
Na2CO3
DPEPhos
68
Li2CO3
DPEPhos
hexane
9
73
Cs2CO3
KF
DPEPhos
DPEPhos
DPEphos
hexane
hexane
hexane
10
11
12
59
72
58
B2pin2,7
such
as
diboration,
hydroboration,
and
dehydroboration. Consequently, although the deoxygenative
olefination of ketones is intriguing given that alkenes are
feedstock chemicals in pharmaceutical, agrochemical, and
material sciences, the realization of this protocol would be
quite challenging due to numerous possible pathways.
-
K2CO3
K2CO3
DPEPhos
DPEPhos
DME
DCE
13
14
23
32
DPEPhos
DPEPhos
K2CO3
K2CO3
1
THF
15
22
0
16c
hexane
RESULTS AND DISCUSSION
aYields were determined by H NMR analysis with CH2Br2 as
internal standard. Bidentate phosphine ligands (7.5 mol%)
and monodentate phosphine ligands (18 mol%). bIsolated
yield. cNo B2pin2.
Optimization of Reaction Parameters. To test our
hypothesis, we began our investigation into the proposed
deoxygenation using propiophenone 1a as the model
substrate in the presence of [RhCl(cod)]2 and B2pin2. Initially,
we examined various phosphine ligands. As shown, the
deoxygenative olefination is highly sensitive to both steric and
electronic properties of ligands (Table 1, entries 1-7). For
instance, although the desired alkene 2a was obtained in 35%
yield when PBu3 was employed (entry 1), more sterically
hindered PCy3 resulted in no formation of the desired product
2a (entry 2). Moreover, electron-deficient PPh3 and MePPh2
gave no reaction compared with electron-rich ligands (entries
3-4 vs entries 1-2). We then turned our attention to
bisphosphine ligands. To our delight, the yield was increased
to 76% using DPEPhos as the ligand (entry 5). Other bidentate
phosphine ligands such as Xantphos and dppe were also
tested, but none of them gave better results (entries 6-7). The
examination of bases revealed that K2CO3 was the best choice
for this deoxygenative olefination (entries 8-11). It is worth
noting that the yield decreased significantly in the absence of
base (entry 12). In addition to hexane, other solvents
including DME, DCE, and THF all gave inferior yields (entries
13-15). Not surprisingly, no desired product 2a was observed
without added B2pin2 (see more details in the supporting
information (SI)).
electron-donating groups, such as F (2i), OTBS (2k), CF3 (2l),
and OPiv (2m) were well tolerated. Notably, the functional
group on the alkyl chain was also compatible (2n). Other
aromatic rings, such as naphthalene (2o) and thiophene (2p)
were suitable substrates. The α-aryl ketones proceeded
smoothly to furnish 1,2-diaryl alkenes 2q-r in excellent yields
and stereoselectivity when MePPh2 was used as the ligand.
Moreover, the benzyl alkyl ketone was reactive to deliver
olefin 2s in moderate yield, although no alkenes were
obtained when dialkyl ketones were treated with the standard
reaction conditions. In addition, cyclic ketones were
competent substrates to provide product 2t-u. Particularly
noteworthy, instead of the desired styrene, vinylboronate 3aa
was isolated when acetophenone 1aa was tested.12 We
speculate that the vinylboronate 3aa should be generated
from styrene via Rh-catalyzed dehydrogenative borylation.13
Taking into consideration the significant importance of
vinylboronates in organic synthesis and their extensive
applications in the preparation of pharmaceuticals,
biologically active molecules, functional material molecules
and polymers,14 an efficient synthesis of vinylboronates is
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Journal of the American Chemical Society
highly desirable. Conventionally, vinylboronates were
prepared from alkynes via hydroboration15 or from alkenes
1
via dehydrogenative borylation.13,16 The deoxygenative
borylation of ketones would be an important complement to
the existing protocols for the preparation of vinylboronates,17
and enrich the potential of ketones as well. To this end, we
optimized the deoxygenative borylation reaction using
acetophenone as the model substrate. Pleasingly, the desired
vinylboronate 3aa was provided in 80% yield when
acetophenone was treated with [RhCl(cod)]2 (5 mol%),
MePPh2 (30 mol%), B2pin2 (1.8 equiv), and LiOAc (50 mol%)
in THF for 5 h (see details in SI).
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Table 2. Synthesis of Olefins from Ketonesa
O
[RhCl(cod)]2 (3 mol%)
R
DPEPhos (7.5 mol%), B2pin2 (1.1 equiv)
R
O
Ar
Ar
K2CO3 (50 mol%)
PPh2
PPh2
hexane (2.5 mL), 70 C, 10 h
DPEPhos
1
2
MeO
nPr
nPr
OMe
Me
Me
Et
nPr
MeO
OMe
2a
2b
2c
2d
2e
2f
, 84%
, 71%
, 68%
, 67%
F
, 70%
, 75%
nPr
nPr
nPr
nPr
nPr
Me
Ph
TBSO
MeO
2g
2h
2i
2j
2k
, 73%
, 71%
, 68%
nPr
, 64%
, 72%
nPr
OTBS
nPr
nPr
S
F3C
PivO
2l
2m
2n
2o
2p
, 41%
, 53%
, 75%
, 70%
nPr
, 55%
Bpin
MeO
b
b
c
d
e
2q
2r
2s
2t
2u
, 46%
3aa
, 85%
, 92%
, 51%
, 63%
aReactions conditions: 1 (0.5 mmol), B2pin2 (1.1 equiv), [RhCl(cod)]2 (3 mol%), DPEPhos (7.5 mol%), K2CO3 (50 mol%), hexane
b
(2.5 mL), 70 °C, 10 h; E/Z > 20/1. Isolated yields were reported. Reactions performed on 0.3 mmol scale; [RhCl(cod)]2 (2 mol%),
MePPh2 (12 mol%), CF3CO2Na (50 mol%), THF (1.5 mL). cLiF instead of K2CO3. dP(nBu)3 (18 mol%), CF3CO2Na (50 mol%), THF (2.5
mL), 100 °C. eP(nBu)3 (18 mol%), CF3CO2Na (50 mol%), THF (2.5 mL), 70 oC.
The scope of ketone for this deoxygenative borylation was
then examined. For ease of separation, the vinylboronates
were converted to the corresponding vinyl iodides. As
demonstrated in Table 3, a broad range of ketones were
germane to this transformation. The acetophenones with
different substituents at different positons on phenyl ring all
proceeded smoothly to give the vinylboronate products in
moderate to good yields. For example, both ortho-OMe and
meta-OMe underwent desired reaction pathway to provide
the corresponding products 4ab-ac. Moreover, multi-
substituted acetophenones were also compatible (4ae-ag).
The mild reaction conditions tolerated a variety of functional
groups, such as F, Cl, protected alcohols, ester, SMe, NMe2,
Bpin, acetal and alkene, which enables this protocol for
further downstream diversification. Notably, citronellol and
abietic acid-derived substrates (4at-au) successfully
participated in this deoxygenative borylation. Other aromatic
rings, such as furan, naphthalene, thiophene, indole, and
pyrene, were incorporated in products 4av-az. Additionally,
we were pleased to find that tri-substituted vinylboronates
could also be opportunely generated from the corresponding
alkyl aryl ketones via the simple modifications of the standard
reaction conditions. Particularly noteworthy, cyclic ketones
such as cyclohexanone and cyclopentanone were suitable to
afford cyclic vinylboronates in moderate yields although alkyl
alkyl ketones resulted in low yields due to the formation of
alcohols via hydrobration.
1,1-Diboration products were observed in some cases when
we investigated the deoxygenative borylation of ketones. In
view of extensive applications of 1,1-diborylalkenes in organic
synthesis and limited approaches for their preparation,18 we
further explored this diboration reaction. Pleasingly, the
desired diboration products were obtained in moderate to
good yields by using HCO2Na instead of LiOAc and increasing
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Page 4 of 11
loading of B2pin2 to 3.5 equivalents (see more details in SI).
1
Next, we looked into the scope of ketones for this Rh-
catalyzed diboration reaction. As depicted in Table 4, a series
of ketones performed well to provide the 1,1-diborylalkene
products. Numerous substituents at different positions have
no deleterious effects on the yields. Furthermore, a diverse set
of functional groups such as halides, OH, NH2, CO2Me, and
Bpin are compatible. It is worth noting that the ketones
derived from citronellol and abietic acid were suitable to
furnish the corresponding products 5v and 5w in 44% and
60% yields, respectively. Naphthalenes (5x-y) and
heteroaromatic rings such as furan (5z), thiophene (5aa), and
indole (5ab) were also tolerated, yielding the diboration
products in high efficiency. Noticeably, the use of methyl alkyl
ketone allowed access to alkyl substituted 1,1-diborylalkene
5ac in 43% yield with slightly modified reaction conditions.
To demonstrate the utility of the deoxygenation and
deoxygenative borylation reactions, a sequence of synthetic
applications were carried out (Scheme 1). Treatment of
ketone 1′ with Rh-catalyzed deoxygenation conditions
generated alkene 6 in 72% yield, which is a precursor for the
synthesis of LY223982, a specific inhibitor of leukotriene B4
receptor.19 We then performed a gram-scale reaction of
acetophenone with B2pin2 to deliver the vinylboronate 3aa
(1.25 g) that was used for various subsequent
derivatizations.20 The chlorination and bromination in the
presence of CuCl2 and CuBr2 were first investigated, and
proved to be successful to give vinyl chloride 7 and vinyl
bromide 8 in good yields. The vinylboronate 3aa also
underwent a Cu-mediated azidation to afford vinyl azide 9 in
55% yield. Moreover, the Chan-Lam coupling of 3aa with
methallyl alcohol proceeded smoothly to form vinyl ether 10.
The Pd-catalyzed Suzuki coupling and Mizoroki−Heck reaction
of 3aa were explored as well, which gave (E)-stilbene 11 and
diene 12 in 64% and 53% yields, respectively. The synthetic
utility of
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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25
26
27
28
29
30
31
32
33
34
35
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37
38
39
40
41
42
43
44
45
46
47
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50
51
52
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Table 3. Synthesis of Vinylboronates from Ketonesa
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Journal of the American Chemical Society
[RhCl(cod)]2 (5 mol%)
MePPh2 (30 mol%)
B2pin2 (1.8 equiv)
O
1
2
3
4
Bpin
I
R1
NaOH (aq, 3.0 M)
I2 (0.2 M in THF)
R1
R1
R2
R2
R2
LiOAc (50 mol%)
THF (2.0 mL), 70 C, 5 h
1
3
4
5
6
Me
I
I
I
I
MeO
I
Me
I
O
7
8
9
O
OMe
, 57% (80%)
Me
, 59% (68%)
4aa
4ab
4ac
4ad
, 57% (74%)
, 58% (80%)
, 65% (74%)
4ae
4af
, 62% (76%)
4ah
4ai
4aj
Me,
Pr,
Ph,
, 56% (80%)
, 68% (78%)
, 51% (56%)
, 56% (72%)
4an
4ao
4ap
OBn,
OPiv,
SMe,
, 58% (68%)
, 43% (50%)
, 52% (60%)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
O
I
i
I
I
O
R =
O
4ak
F,
4aq
NMe2,
4ar
, 43% (80%)
, 51% (56%)
O
O
R
4al,
Cl,
48% (54%)
Bpin,
49% (80%)
4ag
, 64% (84%)
4as
, 56% (74%)
4am,
OTBS,
I
iPr
I
I
I
O
Me
Me
H
H
MeO
O
Me
Me
Me
O
O
Me
Me
b
4aw
, 45% (52%)
Bpin
4av
, 60% (70%)
Bpin
4au
, 40% (62%)
4at
, 61% (76%)
I
nPr
nPr
I
I
MeO
N
Me
S
Me
3bb, 53% (73%)c
c
4ay
3bd
, 51% (82%)
Bpin
3ba
, 40% (60%)
4ax
, 48% (56%)
4az
, 38%(54%)
Bpin
Bpin
nPr
Bpin
nPr
Bpin
nPr
N
Bpin
4
TBSO
3bc
F
OTBS
Me
c
c
c
c
d
d
3be
3bf
3bg
3bh
, 36%
, 57% (74%)
, 47% (65%)
, 41% (52%)
, 40% (56%)
, 43%
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 4. Synthesis of 1,1-Diborylalkenes from Ketonese
[RhCl(cod)]2 (5 mol%)
MePPh2 (30 mol%), B2pin2 (3.5 equiv)
O
Bpin
Bpin
Ar
Me
Ar
HCO2Na (50 mol%), THF (1.5 mL)
50 C, 5 h
1
5
OMe
Bpin
Bpin
, 86%
MeO
Bpin
Bpin
Me
Bpin
H2N
Bpin
Bpin
, 70%
Bpin
Bpin
, 81%
Bpin
, 65%
5a
5b
5f
5c
5d
5e
, 75%
5l
Me, , 85% OTBS, , 64%
Me
Bpin
Bpin
i
Bpin
5g
5h
5m
Pr, , 71% OBn,
, 67%
5n
O
O
Bpin
Bpin
Bpin
O
O
Ph, , 73% CO2Me, , 58%
R =
Bpin
Bpin
5i
5o
F, , 80% SMe, , 76%
R
5j 5p
OH, , 54%Bpin, , 66%
Cl, , 77% NMe2, , 78%
Me
5k
5q
5s
iPr
, 69%
5t
, 79%
5r
, 81%
Bpin
Bpin
Bpin
Me
Bpin
Me
O
O
H
H
Bpin
Me
Bpin
O
O
O
5u
O
Me
Me
5v
5w
, 82%
Bpin
Bpin
, 44%
, 60%
Bpin
Bpin
Bpin
Bpin
Bpin
Bpin
nHex
Bpin
Bpin
Bpin
Me
N
Bpin
S
MeO
Me
Me
, 60%
Me
O
f
5ac
, 43%
5x
5y
5z
5aa
5ab
, 58%
, 71%
, 78%
, 45%
aReactions conditions, 1st step: 1 (0.3 mmol), B2pin2 (1.8 equiv), [RhCl(cod)]2 (5 mol%), MePPh2 (30 mol%), LiOAc (50 mol%), THF (2 mL), 70 °C , 5
h. 2nd step: NaOH, I2, THF, rt, 2 h; isolated yields for 2 steps were reported and the yields shown in parentheses are 1H NMR yields of vinylboronates.
bThe reaction was performed at 80 oC for 8 h for 1st step. c[RhCl(nbd)]2 (3 mol%), Me2PPh (18 mol%), B2pin2 (2.0 equiv), CF3CO2Na (50 mol%), DME
(1.5 mL), 70 °C, 10 h. 10 mol% Xantphos and 1.6 equiv B2pin2. eReactions conditions: 1 (0.3 mmol), B2pin2 (3.5 equiv), [RhCl(cod)]2 (5 mol%),
d
MePPh2 (30 mol%), HCOONa (50 mol%), THF (1.5 mL), 50 °C, 5 h. Isolated yields were reported. f[RhCl(cod)]2 (3 mol%), PEt3 (54 mol%), CF3CO2Na
(50 mol%), toluene (1.5 mL), 70 °C, 10 h.
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Scheme 1. Synthetic Applications
1
LY223982
(a) Synthesis of
(c) Synthesis of pyrene derivative
2
O
3
4
5
6
7
8
9
4
OTBS
4
OTBS
a
i
j
6
Bpin
54%
, 72%
MeO
1'
MeO
3az,
O
HO2C
CO2H
OMe
k
O
3
ref 19
LY223982
10
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12
13
14
15
16
17
18
19
20
21
22
23
24
25
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27
28
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34
35
36
37
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40
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42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13,
78% yield
(b) Gram-scale reaction and synthetic transformations
O
(d) Synthesis of temarotene derivative
Me Me
Ph
Me
COOEt
Me Me
Cl
, 53%
b
Ph
Bpin
7
i
j
12
, 53%
c
h
Bpin
, 79%
Ph
5ad
Me Me
Me Me
Me Me
Bpin
3aa, 1.25 g
14
Ph
l
d
g
Br
, 61%
Ph
Me Me
Ph
, 64%
8
Ph
Ph
Ph
Bpin
m
11
f
e
Me
O
Me Me
Me Me
N3
, 55%
Ph
16
15
, 73%
, 68%
Ph
Me
9
10
, 47%
Reaction conditions: (a) standard conditions in Table 2. (b) 1aa (10 mmol), B2pin2 (1.8 equiv), [RhCl(cod)]2 (1 mol%), MePPh2 (6 mol%), LiOAc (50
mol%), THF (30 mL) , 70 °C , 10 h. (c) CuCl2 (3.0 equiv), MeOH/H2O, 80 oC, 6 h. (d) CuBr2 (3.0 equiv), MeOH/H2O, 80 oC, 6 h. (e) CuSO4 (0.6 equiv),
NaN3 (1.5 equiv), MeOH, rt, 4 h. (f) methallyl alcohol (0.5 mL), Cu(OAc)2 (2.0 equiv), NEt3 (4.0 equiv), rt, 4 h. (g) Pd(OAc)2 (5 mol%), PtBu3 HBF4 (10
.
mol%), PhI (1.0 equiv), K2CO3 (3.0 equiv), dioxane/H2O, 100 oC, 5 h. (h) Pd(OAc)2 (10 mol%), ethyl acrylate (3.0 equiv), Na2CO3 (2.0 equiv), DMA, O2,
o
rt, 5 h. (i) AlCl3 (1.2 equiv), acetyl chloride (1.05 equiv), DCM, 0 C - rt, 18 h. (j) standard conditions for mono- or double-dehydrogenative
borylation. (k) Pd(OAc)2 (5 mol%), PtBu3 HBF4 (10 mol%), 1-bromopyrene (1.0 equiv), K2CO3 (4.0 equiv), dioxane/H2O, 100 oC, 5 h. (l) Pd(OAc)2 (3
.
mol%), Bu-Johnphos (4 mol%), PhI (1.0 equiv), KOH (2.0 equiv), DMF, 30 C, 12 h. (m) Pd(PtBu3)2 (5 mol%), MeI (1.5 equiv), Cs2CO3 (2.0 equiv),
t
o
dioxane/H2O, 50 oC, 6 h.
Scheme 2. Control Experiments
(a)
(d)
nPr
O
(72% D)
[RhCl(cod)]2 (5 mol%)
MePPh2 (30 mol%)
B2pin2 (1.8 equiv)
H/D
[RhCl(cod)]2 (3 mol%)
Me2PPh (18 mol%)
B2pin2 (1.5 equiv)

Me
O

Me
Bpin
CD3
nPr
2d
, 22%
H/D
(73% D)
Bpin
LiOAc (50 mol%)
CF3CO2Na (50 mol%)
THF (2.0 mL), 70 C, 5 h
DME (1.5 mL), 70 C, 10 h
1d
Me
nPr
, 18%
Me
d-1ae, 95% D
3ba
d-3ae, 58%
(e)
(b)
Me
(40% D)
H/D
O
[RhCl(cod)]2 (3 mol%)
Me2PPh (18 mol%)
B2pin2 (1.2 equiv)
Me
Bpin
Bpin
nPr
CD3
nPr
H/D
(41% D)
[RhCl(cod)]2 (5 mol%)
MePPh2 (30 mol%)
B2pin2 (1.8 equiv)
CF3CO2Na (50 mol%)
2d
3ba
DME (1.5 mL), 70 C, 10 h
, 85%
Me
d-3ae', 66%
(40% D)
Me
d-1ae, 95% D
LiOAc (50 mol%)
THF (2.0 mL), 70 C, 5 h
d-1ae:1ee = 1:1
H/D
(f)
O
[RhCl(cod)]2 (5 mol%)
MePPh2 (30 mol%)
B2pin2 (1.8 equiv)
MeO
Bpin
MeO
Me
Bpin
H/D
(36% D)
LiOAc (50 mol%)
OMe
OMe
1ee
THF (2.0 mL), 70 C, 1.5 h
3aa
, 78%
d-3ee', 72%
(g)
(c)
[RhCl(cod)]2 (5 mol%)
Xantphos (10 mol%)
B2pin2/HBpin (5/1)
[RhCl(cod)]2 (5 mol%)
MePPh2 (30 mol%)
B2pin2 (1.5 equiv)
Bpin
OBpin
Bpin
Bpin
Bpin
, 82%
LiOAc (50 mol%)
HCO2Na (50 mol%)
THF (2.0 mL), 70 C, 5 h
3bg
THF (1.5 mL), 50 C, 5 h
17
3aa
5a
20% (for 2 steps)
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1
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3
Journal of the American Chemical Society
O
illustrated by synthesizing an isomer of temarotene 16 from
OBpin
Bpin
commercially available tetrahydronaphthalene 14 via Friedel-
Crafts acetylation, Rh-catalyzed deoxygenative diboration, and
stereoselective Suzuki-Miyaura coupling reactions.22
R
Me
Rh-H
R
R
Me
Rh
A
B2pin2
or HBpin
4
MECHANISTIC STUDIES
Rh
Rh-H
Cycle I
5
6
To gain more insights into the reaction mechanism, we
carried out a series of control experiments. First, the
deuterium-labeled substrate d-1ae reacted efficiently with
B2pin2 under the standard reaction conditions, leading to the
formation of vinylboronate d-3ae with 72% deuterium
incorporation at α-positon (Scheme 2a), indicating the α−H is
originated from the methyl group. Moreover, we conducted a
crossover experiment using a mixture of deuterated 3,5-
dimethylacetophenone and 3,5-dimethoxyacetophenone
(Scheme 2b), and found that the H/D scrambled products
were obtained in 66% and 72% yields, respectively.
Furthermore, boron enolate 17, a possible intermediate, was
subjected to the standard reaction conditions (Scheme 2c).
OBpin
[RhCl(cod)]2
B2pin2, base
H
Rh-Bpin
R
Bpin
B2pin2
or HBpin
R
H
E
B
7
8
9
Cycle II
Rh-OBpin
OBpin
Rh
Rh
Bpin
R
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17
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60
R
R
H
D
C
H
Figure 2. Proposed Mechanism
the deoxygenative borylation was further demonstrated by
the synthesis of pyrene derivative 13, a photoinitiator for
cationic polymerizations.21 Finally, the practicability of the
diboration reaction was
Bpin
Cycle I
O
L
Rh
L
L
L
TS1
L
pinB
O
26.9
(11.2)
Rh
H
L
L
L
O
pinBO
pinBO
Ph
L
Rh
L
Rh
H
L
L
1aa
TS3
L
Rh
L
Bpin
Rh
TS2
Ph
TS4
3.5
(-7.1)
6.8
OBpin
L
4.1
(-7.6)
L
L
(-3.7)
L
0.0
L
CAT
L
pinBO Rh
L
IM4
-9.4
(-23.3)
pinB
Bpin
L
pinBO Rh
-10.9
(-22.7)
-10.9
(-26.6)
L
pinB Bpin
-14.7
(-29.0)
L
L
TS6
pinBO
B2pin2
L
Rh
H
pinBO
TS5
-20.9
(-37.7)
L
Rh
L
L
pinBO
Ph
-24.7
(-41.1)
L
Rh
L
L
-26.8
(-29.1)
-26.9
(-45.0)
pinBOBpin
L
CH3
P
styrene
IM1
L
IM2
L
L
L =
pinB Rh
L
IM3
L
pinBO Rh
pinBO Rh
L
L
pinB Bpin
-54.8
(-54.4)
L
L
CAT
IM5
IM6
-H elimination
-O elimination
catalyst regeneration
1,2-addition
re-insertion
Bpin
Cycle II
L
Rh
pinB
L
Bpin
H
H
Rh
L
H
L
Bpin
Bpin
L
Rh
TS7-bi8
L
L
Rh
L
L
H
Bpin
20.2
(3.1)
L
bi-TS9
L
bi-TS10
L
TS10
9.2
(9.7)
styrene
-1.5
6.1
(9.6)
10.9
(0.1)
5.4
(5.6)
3aa
pinB Rh
L
2.6
(3.1)
2.2
(4.7)
0.0
(0.0)
HBpin
L
CAT
-3.7
(2.7) B2pin2
L
L
(-18.6)
-5.0
(-16.0)
Bpin
H
L
Rh Bpin
H
Bpin
Rh
Bpin
H
H
-13.7
(-12.9)
Bpin
Rh
H
Bpin
Bpin
L
L
L
L
Rh
L
L
CAT
L
L
L
Rh
L
L
Rh
L
Rh
L
H
L
L
L
IM7
bi-IM8
bi-IM9
bi-IM10
-H elimination
IM11
IM12
catalyst regeneration
coordination
dissociation

1,2-addition
7
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Figure 3. Free Energy Profiles Calculated for the Most Favorable Pathway Connecting the Deoxygenation (Cycle I) and Borylation (Cycle
II) Catalytic cycles. Relative Free Energies and ElectronicEnergies (in parentheses) Are Given in kcal•mol−1.
1
2
3
4
5
6
7
8
9
As anticipated, the desired vinylboronate 3bg was produced
albeit in 20% yield. In addition, the treatment of aryl alkyl
ketone 1d with the deoxygenative borylation conditions led to
the generation of alkene 2d and vinylboronate 3ba (Scheme
2d). Besides, the alkene 2d and styrene could be efficiently
converted into the corresponding vinylboronate 3ba and 3aa
in 85% and 78% yields, respectively (Scheme 2e-f). These
results suggested that alkenes are the intermediates of the
deoxygenative borylation of ketones. Lastly, to verify the
diboration products 5 were produced from vinylboronates 3,
compound 3aa was subjected to the standard conditions for
the diboration. Predictably, the desired product 5a was
isolated in high yield (Scheme 2g).
nucleophilic behavior found in many copper(I)-boryl
species.25 The intermediate IM1 then undergoes β-hydride
elimination, followed by migration insertion and then β-OBpin
elimination to give styrene and L3Rh-OBpin (IM5). Finally, -
bond metathesis between B2pin2 and IM5 regenerates
Rh−Bpin and completes Cycle I.
The borylation process starts with coordination of styrene
to the catalyst Rh−Bpin, followed by a ligand dissociation to
form bi-IM8 (‘bi’ here stands for coordination of two
phosphine ligands). Here, instead of being square planar, bi-
IM8 adopts a trigonal-pyramidal geometry, which is very
unusual for a d8 metal center. We reason that the boryl ligand
is formally cationic in view of the fact that Rh is more
electronegative than B (2.28 versus 2.04, see Table of Periodic
Properties of the Elements, Sargent-Welch Scientific
Company), and as a result the metal center is formally d10
leading to the observed unusual geometry and the
abovementioned electrophilic behavior of the boryl ligand.
Then, bi-IM8 undergoes addition of Rh−B to the styrene
olefinic bond, followed by β-hydride elimination and the
ligand substitution to give the dehydrogenative C-H
borylation product 3aa and the metal hydride Rh−H (IM11).
Finally, IM11 undergoes σ-bond metathesis with another
molecule of B2pin2 regenerates Rh−Bpin and completes Cycle
II.
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60
Based on the results of mechanistic experiments, we
proposed a dual catalytic cycle for the deoxygenation and
borylation (Figure 2). Initially, the rhodium−Bpin generated
from [RhCl(cod)]2 and B2pin2 in the presence of base23
undergoes 1,2-addition to
a carbonyl group to give
intermediate A, which goes through β-hydride elimination to
afford Rh−H and boron enolate B. The subsequent migration
insertion of the intermediate
B into Rh−H delivers
alkylrhodium C, which allows the formation of alkenes and
Rh−OBpin via β-OBpin elimination. Eventually, the σ-bond
metathesis between B2pin2 (or HBpin) and Rh−OBpin
regenerates the Rh−Bpin (Cycle I). With regard to the
boryaltion (Cycle II), the 1,2-migration insertion of the alkene
generated from the Cycle I into Rh−Bpin formed intermediate
D. Followed by a simple rotation along the C−C bond in D, β-
hydride elimination results in the generation of the
vinylboronate 3 and Rh−H. Subsequently, the Rh−Bpin is
regenerated from Rh−H and B2pin2 (or HBpin). Expectedly, the
vinylboronate could undergo the second dehydrogenative
borylation (Cycle II) to yield the diboration product 5.
CONCLUSIONS
In conclusion, we have developed a rhodium-catalyzed
deoxygenation and borylation reaction of ketones to
stereoselectively produce alkenes, vinylboronates, and
vinyldiboronates under mild reaction conditions. These
protocols exhibit high efficiency and excellent functional-
group tolerance. Mechanistically, the ketones initially
underwent a Rh-catalyzed deoxygenation to afford the
alkenes, which subsequently reacted with B2pin2 to generate
DFT Calculations. To investigate the feasibility of the
proposed dual catalytic cycle shown in Figure 2, we carried
out DFT calculations at the B97X-D level of theory
considering the catalyst L3RhBpin (L = PPh2Me) and the
reaction PhMeC=O (1aa) + 2 B2pin2  PhCH=CHBpin + HBpin
+ (Bpin)2O. In the dual cycle, the first cycle is a deoxygenation
process involving the generation of styrene PhCH=CH2
(PhMeC=O + B2pin2  PhCH=CH2 + (Bpin)2O) while the
second cycle is a borylation process corresponding to
the
vinylboronates
or
diboration
products
via
dehydrogenative borylation. Mechanistic studies supported a
boron enolate intermediate was involved in the
deoxygenation. The DFT calculations also verified the
proposed deoxygenation and dehydrogenative borylation
processes. Moreover, the synthetic utility of these approaches
has been demonstrated by the diversification of the products
and the synthesis of biologically active and functional
molecules. These noteworthy reactions are anticipated to find
applications in organic synthesis and material science.
dehydrogenative C-H borylation of styrene (PhCH=CH2
+
B2pin2  PhCH=CHBpin (3aa) + HBpin). Figure 3 shows the
energy profiles calculated for the most favorable pathway
connecting the first (Cycle I) and second (Cycle II) catalytic
cycles. The energy profiles calculated for an alternative and
less favorable pathway connecting the two cycles (Cycles I′
and II′) are given in the Supporting Information. This
alternative pathway considers species with other possible
coordination numbers around the metal center.
The deoxygenation process starts with 1,2-addition of the
active catalyst Rh−Bpin bond to the carbonyl group of 1aa to
give the addition intermediate IM1, being the rate-limiting
step with an energy barrier of 26.9 kcal•mol−1, which is
reasonable considering that the reaction temperature is 70 oC.
Interestingly, the boryl ligand here acts as electrophilic in the
addition step, which is similar to what was found in the
platinum(II)-boryl catalyzed diboration of acyclic α,β-
unsaturated carbonyl compounds24, but is different from the
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures, characterization and NMR spectra
for obtained compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail:
Wanxiang Zhao: zhaowanxiang@hnu.edu.cn
Zhenyang Lin: chzlin@ust.hk
8
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Journal of the American Chemical Society
Catalyzed Cross-Coupling with Ketones or Aldehydes via N-
Tosylhydrazones. J. Am. Chem. Soc. 2020, 142, 10592−10605.
Author Contributions
#These authors contributed equally
1
2
3
4
(4) (a) Mackenzie, K. In The Chemistry of Alkenes; Patai, S., Ed.;
Wiley: New York, 1964; pp 338−413. (b) Ma, S.-M.; Zhang, J.-L. In
Comprehensive Organic Synthesis; Knochel, P., Molander, G. A., Eds.;
Elsevier Ltd.: Amsterdam, Vol. 4, 2014. (c) Dong, Z.; Ren, Z.; Thompson,
S. J.; Xu, Y.; Dong, G. Transition-Metal-Catalyzed C−H Alkylation Using
Alkenes. Chem. Rev. 2017, 117, 9333−9403.
ORCID
Wanxiang Zhao: 0000-0002-6313-399X
Notes
The authors declare no competing financial interests.
5
6
7
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(5) For the Wittig reaction, see: (a) Maryanoff, B. E.; Reitz, A. B. The
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Hoffmann, R. W. Wittig and His Accomplishments: Still Relevant
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83, 1733−1738. (f) Boutagy, J.; Thomas, R. Olefin Synthesis with
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Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. Olefin Homologation with
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Direct Synthesis of Olefins by Reaction of Carbonyl Compounds with
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Benzothiazoles. Tetrahedron Lett. 1991, 32, 1175−1178. (k)
Blakemore, P. R. The Modified Julia Olefination: Alkene Synthesis via
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(6) (a) Maruoka, K.; Oishi, M.; Yamamoto, H. The Catalytic Shapiro
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14479−14490. (d) Chulsky, K.; Dobrovetsky, R. Metal-Free Catalytic
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Korstanje, T. J.; de Waard, E. F.; Jastrzebski, J. T. B. H.; Klein Gebbink, R.
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Dioxomolybdenum Complexes as Excellent Catalysts for the
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ACKNOWLEDGMENT
We thank Prof. Jianwei Sun (HKUST) for helpful discussions
and Prof. Yuqin Zou (Hunan University) for the analysis of XPS
data. Financial support from the National Natural Science
Foundation of China (Grant No. 21971059, 21702056), the
National Program for Thousand Young Talents of China, the
Research Grants Council of Hong Kong (HKUST 16304017),
and the Fundamental Research Funds for the Central
Universities are greatly appreciated.
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TOC
Bpin
Bpin
R1
R2 = H
B
Rh
B
Rh
O
B
R2
R2
R1
Rh
R1
B
Rh
B
Rh
Bpin
R1
B = B2pin2
R2
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