Water-Accelerated Nickel-Catalyzed α-Crotylation of Simple Ketones with 1,3-Butadiene under pH and Redox-Neutral Conditions

Article abstract of DOI:10.1021/acscatal.0c00019

We report a nickel/NHC-catalyzed branched-selective α-crotylation of simple ketones using 1,3-butadiene as the alkylation agent. This reaction is regioselective and operated under pH and redox-neutral conditions. Water was used as the sole additive, which significantly accelerates the transformation.

Full text of DOI:10.1021/acscatal.0c00019

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Letter
Water-Accelerated Nickel-Catalyzed #-Crotylation of Simple
Ketones with 1,3-Butadiene under pH and Redox-Neutral Conditions
Tiantian Chen, Haijian Yang, Yang Yang, Guangbin Dong, and Dong Xing
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c00019 • Publication Date (Web): 16 Mar 2020
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ACS Catalysis
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Water-Accelerated Nickel-Catalyzed α-Crotylation of Simple
Ketones with 1,3-Butadiene under pH and Redox-Neutral
Conditions
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Tiantian Chen,† Haijian Yang,† Yang Yang,† Guangbin Dong*,‡ and Dong Xing*,†
†Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry
and Molecular Engineering, East China Normal University, Shanghai, China 200062
‡Department of Chemistry, University of Chicago, Chicago, IL 60637 (USA)
ABSTRACT: We report a nickel/NHC-catalyzed branched-selective -crotylation of simple ketones using 1,3-butadiene as the
alkylation agent. This reaction is regioselective and operated under pH and redox-neutral conditions. Water was used as the
sole additive, which significantly accelerates the transformation.
KEYWORDS: nickel, 1,3-butadiene, crotylation, ketone, pH-neutral, atom-economy
Carbon–carbon (C–C) bond formation is of central
importance in organic synthesis.1 From economical and
environmental perspectives, it would be ideal to construct
C–C bonds directly from simple chemical feedstocks in an
atom-economic manner without producing stoichiometric
byproducts.2 In this context, 1,3-butadiene, a “platform
chemical” with an annual production of >10 million tons for
the manufacture of rubbers, polymers and fine chemicals,3
has been an attractive candidate for the synthesis of value-
added compounds through C–C bond forming reactions.4
For example, Krische pioneered the use of 1,3-butadiene as
a masked crotyl nucleophile for reductive carbonyl addition
of aldehydes (Scheme 1A).4b,d Recently, a CuH-catalyzed
reductive coupling strategy has been developed by
Buchwald to realize crotylation of ketones (Scheme 1B).4l
On the other hand, while 1,3-butadiene is known to be
capable of generating electrophilic -allyl intermediates
with transition metals,5 it remains challenging to couple
such reactivity with less acidic nucleophiles, such as simple
ketones. The challenges lie in the tendency of 1,3-butadiene
for telomerization,5d,6 as well as the relatively low
nucleophilicity of simple ketones. Hence, the current scope
has been mainly limited to 1,3-dicarbonyl compounds.5
Considering the broad interest and significance on ketone
alkylation, an atom-economical -crotylation between
readily available simple ketones and feedstock 1,3-
butadiene could be a highly attractive method.
electrophile under base-free and redox-neutral conditions
(Scheme 1C).9,10 Notably, H2O is used as the sole additive,
which has been found to significantly accelerate the overall
reaction rate. This approach could be valuable from the
prospects of atom- and step-economies compared to the
conventional alkylation approaches.11
Scheme 1. Crotylation of Ketones and Aldehydes with 1,3-
Butadiene
Butadiene
Industrial feedstock
>10 million ton/year
A
) Crotylation of Aldehydes (Krische)
(
O
Ru-H
HO
HO
R'-OH
R
H
R
B
(
) Crotylation of Ketones (Buchwald)
O
Cu-H
R3SiH
R
R'
R
R'
C

this work
(
)
-C H Crotylation of Ketones (
)
O
O
Ni(0)/NHC
H2O
base,
TMSCl
conventional
approaches
OTMS
[catalyst]
X
or
X
atom-economic
redox neutral
strong base/acid free
highly regioselective
Recently, an elegant work by Zhou realized a Ni(0)-
catalyzed -allylation of ketones with substituted 1,3-
dienes via in situ-generation of enolates.7a While the
reaction exhibited an impressive scope and selectivity, the
non-aryl-substituted dienes gave much diminished yields
and the use of simple 1,3-butadiene for -crotylation
remains unknown. Besides, a strong base additive, i.e. KOt-
Bu, was required to generate enolate intermediates. As part
of our continuous research interests in developing
byproduct-free ketone -alkylation through metal-hydride
intermediates,8 here we report a Ni-catalyzed -crotylation
of various regular ketones using simple 1,3-butadiene as the
Our study started with acetophenone (1a) as the model
substrates. After thorough investigation of various reaction
parameters, the desired -crotylation product 3a was
ultimately obtained in 84% isolated yield (96% NMR yield)
with excellent regioselectivity (Table 1, entry 1). Using
Ni(COD)2/IMes as the catalyst and 1 equiv of H2O as the sole
additive, the reaction went full conversion with complete
branched selectivity in 2 hours at 130 oC. To gain insights into
the role of each reactant, a set of control experiments were
conducted. Among different NHC ligands tested, IMes gave the
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ACS Catalysis
Page 2 of 7
highest yield and selectivity while IAd as well as MeIMes and
desired -crotylation products (3m–3p) in good efficiency.
Heteroaryl ketones bearing a 2-furyl or 2-thienyl group, as well
as N-methyl-2-acetylindole or 2-ferrocenyl methyl ketone, also
reacted smoothly in good to moderate yields with excellent
branched selectivity (3q–3t).
CPIMes bearing substituents on the unsaturated backbone also
showed good reactivity and regioselectivity (entries 3-5). IPr
gave a lower yield while maintaining excellent regioselectivity
(entry 2). Without H2O, 3a was obtained in only 43% yield
(entry 6). We concluded that the moderate reactivity came
from the trace amount of water in the butadiene/THF solution.
This is because when the substrates were pre-dried with 4 Å
molecular sieves before subjected to the reaction without
adding H2O, 3a was observed in less than 5% yield (entry 7).
These results suggest the critical role of water for this
transformation. When MeOH instead of H2O was added, this
reaction still proceeded but with decreased efficiency (entry 8).
When H2O was replaced with HFIP or TFE, the desired product
was not observed, indicating that more acidic proton source
may not be compatible with the current catalytic system (entry
9). Cyclopentyl methyl ether (CPME) as the solvent proved to
be superior in terms of both the reactivity and regioselectivity
(entries 10–13). Unsurprisingly, this transformation did not
proceed without Ni(COD)2 or IMes (entries 14 and 15).12
1
2
3
4
5
6
7
8
Scheme 2. Substrate Scope of Substituted Aryl Methyl
Ketonesa,b,c
O
O
Ni(COD)2 (10 mol %)
IMes (10 mol %)
H
9
R
R
H2O (1 equiv)
CPME, 130 o
C
10
11
12
13
14
15
16
17
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19
20
21
22
23
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60
1
2
3
(300 mol%)
O
Me
O
Me
O
Me
Me
Me
EtO
3a
3b
3c
, 74%
rr > 20:1
, 84%
, 79%
rr > 20:1
rr > 20:1
O
Me
O
Me
O
Me2N
F
F3C
3d
rr > 20:1
3e
rr > 20:1
3f
, 46%
, 77%
, 82%
rr > 20:1
Table 1. Condition Optimizationsa
O
O
Me
O
Me
O
Me
Me
O
Me
Ni(COD)2 (10 mol %)
IMes (10 mol %)
Ph
Ph
O
3a
H
EtO2C
MeO2C
Ph
H2O (1 equiv)
3g
, 88%
rr > 20:1
3h
rr > 20:1
3i
, 64%
rr >20:1
, 80%
CPME,130 oC, 2 h
2
1a
(300 mol%)
"standard" conditions
3a'
CF3
O
Me
O
Me
O
Me
Entry Variations from the "standard" conditions Yield of 3a (%)b rr (3a:3a')c
Me
MeO
1
2
3
4
none
96 (84)d
67
>20:1
>20:1
>20:1
>20:1
>20:1
3j d
3k
3l
IPr instead of IMes
IAd instead of IMes
MeIMes instead of IMes
,
79%
, 68%
, 69%
rr >20:1
rr: 15:1
rr > 20:1
95
O
Me
93
O
Me
O
Me
Me
CPIMes instead of IMes
without H2O
87
5
6
43
< 5
52
< 5
77
83
80
86
0
>20:1
--
Me
3o
7
without H2O; substrates treated with 4Å MS
3m
rr > 20:1
3n
, 50%
rr > 20:1
, 75%
, 83%
rr > 20:1
8
MeOH instead of H2O
>20:1
--
9e HFIP or TFE instead of H2O
10 toluene instead of CPME
11 m-xylene instead of CPME
12 THF instead of CPME
13 dioxane instead of CPME
14 without Ni(COD)2
O
Me
O
Me
O
Me
>20:1
10:1
>20:1
>20:1
--
F
O
S
F
3p
3q d
3r
, 68%
, 81%
,
84%
rr > 20:1
rr > 20:1
rr > 20:1
O
Me
O
Me
15 without IMes
0
--
Me
N
Me
N
3s
, 84%
rr > 20:1
3t
, 58%
rr > 20:1
N
Fe
N
N
R
Me
R
N
N
Mes
Mes
Mes
Mes
IMes
: (R = 2-mesityl)
(R = 2,6-iPr2)
(R = adamantyl)
aReaction conditions: 1 (0.2 mmol), 2 (0.6 mmol, 2 M solution in THF),
IPr
:
CPIMes
MeIMes
IAd
:
Ni(COD)2 (0.02 mmol), IMes (0.02 mmol), H2O (0.2 mmol) in CPME (0.4
b
c
mL) at 130 oC for 2 h. Isolated yields. Regioselectivity ratio (rr) was
determined by 1H NMR of the reaction mixture. dThe crotylation
products derived from dimerized butadiene were observed in a 1:10
ratio to the desired product.
aUnless otherwise noted, the reaction was run on a 0.2 mmol scale of
1a in 0.4 mL of solvent at 130 oC for 2 h, 2 was used as a 2 M solution
in THF. 1a:2 = 1:3. bYield determined by 1H NMR using 1,1,2,2-
c
tetrachloroethane as the internal standard. Regioselectivity ratio (rr)
is the ratio of 3a to 3a’, determined by 1H NMR of the reaction mixture.
dIsolated yield shown in parentheses. eHFIP: 1,1,1,3,3,3-
hexafluoroisopropanol; 2,2,2-trifluoroethanol.
The scope of other ketones was then investigated (Scheme
3). As expected, cyclopentanone showed high reactivity, but
giving a mixture of mono and di-crotylation products (4a and
4a’) with a modest regioselectivity. In comparison, less reactive
cyclohexanone and cyclododecanone gave only the mono-
crotylation products in higher yields (4b and 4c). 1-Indanones
with different substituents proved to be excellent substrates,
generally affording the desired products in good yields with
excellent regioselectivity (4d–4h). Gratifyingly, linear aliphatic
ketones were also competent substrates. The coupling between
acetone and 1,3-butadiene yielded the crotylation product 4i
with a TON of 5 and excellent branched selectivity. When 4-
methyl-2-pentanone or cyclohexyl methyl ketone were used,
the -crotylation occured exclusively at the less hindered
With the optimized reaction conditions in hand, different
substituted acetophenones were tested first (Scheme 2). Both
electron-rich (3b–3d, 3i, 3k, 3l) and -deficient aryl ketones
(3e–3h, 3j) bearing various substituents at para-, ortho- or
meta- positions all worked well, affording the corresponding -
crotylation products in moderate to good yields with high to
excellent regioselectivities. Substituents such as fluoro (3e),
trifluoromethyl (3f, 3j), ethyl or methyl ester (3g, 3h) could all
be tolerated. 1-Naphthyl and 2-naphthyl ketones, as well as di-
substituted aryl ketones were good substrates, affording the
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ACS Catalysis
methyl side albeit in a lower efficiency (4j and 4k). In addition,
To gain some mechanistic understanding on this
transformation, deuterium-labelling experiment was
1
2
3
4
5
6
7
8
non-methyl linear ketones could also be employed as
substrates (4l–4n). Finally, alkene-substituted ketone 4o, the
progesterone-derived substrate with an α-stereocenter (4p)
and the ketone with a β-stereocenter (4q) were also found to
be suitable substrates.
a
conducted by adding D2O instead of H2O to the reaction system
(Scheme 4, eq 1). After 10 min, the desired product d-3a was
obtained in 60% yield, with H/D exchange at the terminal
methyl, the terminal alkenyl, as well as the ketone -
positions.14 Meanwhile, H/D scrambling was also observed at
the methyl position for the recovered acetophenone 1a.
Furthermore, H/D scrambling at the ketone α position was
observed when running the standard reaction with D2O but in
the absence of 1,3-butadiene (Scheme 4, eq 2). As a control
experiment, no H/D scrambling was observed without
Ni(COD)2 and IMes (Scheme 4, eq 3).
Scheme 3. Substrate Scope of Other Ketonesa,b,c
Ni(COD)2 (10 mol %)
IMes (10 mol %)
O
O
9
H
H2O (1 equiv)
CPME, 130 o
C
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
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56
57
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59
60
1
(300 mol%)
4
O
O
O
O
Me
Me
[e]
Me
Scheme 4. Deuterium-Labelling Studies
+
H (0.5 D)
O
4a [d]
dr 1:1, rr 3:1
4b [d]
4c
H
H
,
35%
,
60%, dr 1:1
rr 4:1
, 50%, dr 2:1
rr 3:1
4a',
38%
O
O
H (0.45 D)
Ni(COD)2 (10 mol %)
IMes (10 mol %)
Ph
H (0.47 D)
H
Ph
Ph
H
4d
78%, dr 1:1, rr >20:1
84%, dr 1:1, rr >20:1
46%, dr 1.3:1, rr 11:1
86%, dr 1.3:1, rr >20:1
80%, dr 1:1, rr >20:1
1a
+
(R = H):
O
(1)
(3)
(0.45 D)
H
H
H
4e
4f
(R = 5-F):
(R = 5-Cl):
Me
D O
(5 eq)
2
(0.55 D)(0.55 D)
CPME, 130 o
C
R
1a
d-
3a,
d-
60% yield
4g
4h
(R = 5-OMe):
(R = 6-Me):
10 min
30% recovered
2 (3 eq)
D2O
(5 eq)
O
Me
O
O
Me
O
Me
std. cond.
D O
)
1a
H (0.6 D)
1a
(2)
no H/D exchange
Cy
4k [d,g]
Ph
CPME,
(5 eq)
0.5 h
2
2
(w/o
4i [f]
4j [d,g]
130 oC, 2 h
H
,
TON: 5
,
30%
,
44%
Me
H
rr > 20:1
rr 15:1
rr 12:1
While some mechanistic details of the reaction remain
unclear and are the topic of the ongoing investigation, the
current data and literature precedents allow us to propose a
hypothesis of the catalytic cycle (Figure 2). First, the
nickel(0)/IMes catalyst coordinates with 1,3-butadiene to form
complex A.15-17 Protonation of complex A at the terminal
position of the bounded 1,3-butadiene leads to a nickel--allyl
intermediate B that bears a hydroxide ligand. The hydroxide
species should then deprotonate the ketone substrate to form
the corresponding enolate intermediate C. Alternatively, direct
oxidative addition of H2O to Ni(0) would generate the HO–Ni–
H species D.18,19 The hydride on the Ni could insert into the π
bond in 1,3-butadiene, while the hydroxide ligand could
deprotonate the ketone substrate to give the same
intermediate C. Given that proton-transfer steps are typically
reversible, both paths to intermediate C could be explained by
the observed deuterium-labelling experiments. Subsequent C–
C reductive elimination between the enolate and the allylic
fragment delivers the α-crotylation product and regenerates
the Ni(0) catalyst.
O
Me
O
Me
O
Ph
Ph
4m
Ph
n-Pr
4l
4n [d,g]
,
, 50%, dr 1.5:1
rr >20:1
, 53%, dr 1:1
rr: 4:1
32%, dr 1.5:1
rr: 4:1
O
O
Me
Me
Me
AcO
H
H
4p [d,g]
,
50%
4o
, 62%, rr 12:1
Me
dr 5:1, rr > 20:1
O
Me
O
Me
standard conditions
Ph
Ph
4q
, 60%, er 94:6, dr 1:1, rr 10:1
1q
, er 94:6
aUnless otherwise noted, the reaction was run with 1 (0.2 mmol), 2 (0.6
mmol, 2 M solution in THF), Ni(COD)2 (0.02 mmol), IMes (0.02 mmol),
H2O (0.2 mmol) in CPME (0.4 mL) at 130 oC for 2 h. bIsolated yields.
cRegioselectivity ratio (rr) was determined by H NMR of the reaction
1
mixture. d20 mol% of the catalyst. NMR yield for 4a’ as a mixture of
e
f
undistinguishable diastereomers. With 0.25 mL of acetone; TON was
based on Ni. g500 mol% of 2 was used.
To understand the role of H2O in this transformation, kinetic
monitoring of the parallel experiments with or without the
addition of H2O was conducted (Figure 1). With H2O, a high
reaction rate was observed without any induction period:
product 3a formed in nearly 60% yield within 5 min and the
reaction was almost completed within 15 min. By contrast, in
the absence of H2O, the reaction was very slow and less than 5%
of 3a was obtained after 2 h.13 This result implied the critical
role of H2O in accelerating the reaction rate of this
transformation.
Ni(0)-L
H2O
O
2
Ph
3a
L
NiII
H
L
L
HO
NiII
Ni
O
2
L
NiII
1a
A
H
Ph
C
O
Ph
D
H2O
L
O
NiII
Ph
HO
1a
H
B
Figure 2. Proposed reaction pathways
To show the synthetic utility of this transformation, a gram-
scale reaction was conducted. This reaction was easily scaled
up with only 2 mol% of the catalyst with no loss of yield
Figure 1. Parallel experiments with and without H2O
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Page 4 of 7
(Scheme 5A). The γ,δ-unsaturated ketone product could be
Guangbin Dong – Department of Chemistry, University of
Chicago, Chicago, Illinois 60637, United States; ORCID: 0000-
0003-1331-6015; E-mail: gbdong@uchicago.edu
transformed into different structural motifs.20 For example, 3a
could be readily converted into diol 5 in good yield. Diol 5 can
be transferred to Doremox® (6), a perfume additive,21 in a
single step, or 3-phenyl-3-methyl pyridine 7 in two steps
(Scheme 5B).22 The terminal olefin can also undergo
metathesis to give a cis enone product (8) (Scheme 5C). Finally,
this method was applied to the synthesis of apricoxib(11), an
orally active Cox-2 inhibitor and an anticancer agent (Scheme
5D).23 Starting from commerically available p-ethoxyl-
acetophenone 1c and 1,3-butadiene, apricoxib can now be
obtained in 61% yield over 3 steps with notable improvements
from the conventional route.24
1
2
3
4
5
6
7
8
Dong Xing
– Shanghai Engineering Research Center of
Molecular Therapeutics and New Drug Development, School of
Chemistry and Molecular Engineering, East China Normal
University, Shanghai 200062, China; ORCID: 0000-0003-3718-
4539; E-mail: dxing@sat.ecnu.edu.cn
Authors
9
Tiantian Chen – Shanghai Engineering Research Center of
Molecular Therapeutics and New Drug Development, School of
Chemistry and Molecular Engineering, East China Normal
University, Shanghai 200062, China
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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
Scheme 5. Synthetic Elaborations
Haijian Yang – Shanghai Engineering Research Center of
Molecular Therapeutics and New Drug Development, School of
Chemistry and Molecular Engineering, East China Normal
University, Shanghai 200062, China
A
3a
(
) Gram-scale synthesis of
O
O
2 mol %
)
Ni(COD)2
(
IMes (2 mol %)
H2O (1 equiv)
CPME, 130 o
12 h
C
2
1a
1.2 g
3a
Yang Yang – Shanghai Engineering Research Center of
Molecular Therapeutics and New Drug Development, School of
Chemistry and Molecular Engineering, East China Normal
University, Shanghai 200062, China
(300 mol%)
83%, 1.45 g
B
(
) Application to the synthesis of heterocycles
3a
BH3 Me2S
NaOH, H2O2
68%, dr 6:1
OH Me
Notes
CF3CO2H
75%
O
N
1) PCC
The authors declare no competing financial interests.
Ph
OH
2) NH2OH HCl
59% (2 steps)
Ph
Me
Ph
Me
OH
6
5
7
6
( )
Doremox
ACKNOWLEDGMENT
C
3a
(
) Olefin metathesis of
Grubbs catalyst
Z-selective (1 mol%)
Financial supports from Natural Science Foundation of China
(NSFC: 21772043) and Natural Science Foundation (CHE-
1855556) are acknowledged. We also thank the Shanghai
Pujiang program for financial support (19PJ1403000). We
acknowledge Prof. Jian Zhou for the generous support on
chemicals. We thank Dr. Ziqiang Rong and Dr. Yan Xu for
insightful discussions. Dr. Z. Rong is also thanked for checking
the experiments.
OH
O
Me
3a
+
THF, rt, 6 h
54% yield, 66% Z
Ph
8
Me
N
N
Me
Me
Ru
O
O
N
O
O
i-Pr
Grubbs catalyst Z-selective
D
(
) Application to the synthesis of apricoxib
N
REFERENCES
Me
(1) (a) Cain, D. Carbon-Carbon Bond Formation, vol. 1 (Ed.:
Augustine, R. L.), Marcel Dekker, New York, 1979, pp. 85-250. (b)
Smith, M. B. March, J. March’s Advanced Organic Chemistry, 7th Ed;
Wiley: New York, 2001.
(2) (a) Trost, B. The Atom Economy--a Search for Synthetic
Efficiency. Science 1991, 254, 1471–1477. (b) Sheldon, R. A. Atom
Efficiency and Catalysis in Organic Synthesis. Pure Appl. Chem.
2000, 72, 1233-1246. (c) Sheldon, R. A. The E Factor: Fifteen Years
on. Green Chem. 2007, 9, 1273-1283.
(3) (a) Dahlmann, M.; Grub, J.; Löser, E. Butadiene. Ullmann’s
Encyclopedia of Industrial Chemistry, Wiley-VCH: Weinheim,
Germany, 2011. (b) Morrow, N. L. The Industrial Production and
Use of 1,3-Butadiene. Environ. Health Perspect. 1990, 86, 7-8. (c)
White, W. C. Butadiene Production Process Overview. Chem.-Biol.
Interact. 2007, 166, 10-14.
(4) For selected examples: (a) Ogoshi, S.; Tonomori, K.-i.; Oka,
M.-a.; Kurosawa, H. Reversible Carbon−Carbon Bond Formation
between 1,3-Dienes and Aldehyde or Ketone on Nickel(0). J. Am.
Chem. Soc. 2006, 128, 7077-7086. (b) Zbieg, J. R.; Yamaguchi, E.;
McInturff, E. L.; Krische, M. J. Enantioselective C-H Crotylation of
Primary Alcohols via Hydrohydroxyalkylation of Butadiene.
Science 2012, 336, 324. (c) Cho, H. Y.; Morken, J. P.
Diastereoselective Construction of Functionalized Homoallylic
Alcohols by Ni-Catalyzed Diboron-Promoted Coupling of Dienes
and Aldehydes. J. Am. Chem. Soc. 2008, 130, 16140-16141. (d)
McInturff, E. L.; Yamaguchi, E.; Krische, M. J. Chiral-Anion-
prior route
Br2
9
17% yield
N
ref. 20
O
O
Me
O
EtO
sulfanilamide
AcOH, CH3CN
reflux
10
SO2NH2
11
EtO
EtO
1c
89%
apricoxib (
)
-crotylation
74%
ozonolysis
93%

In summary, we have developed
a nickel-catalyzed
regioselective α-crotylation of simple ketones with 1,3-
butadiene for preparing synthetically useful γ,δ-unsaturated
ketones. The reaction is operated under pH and redox-neutral
conditions without forming stoichiometric byproducts. Water
plays a critical role as a mediator and significantly accelerats
the reaction. The high scalability and broad functional group
tolerance could make this method attractive for complex
molecule synthesis. Efforts on more detailed mechanistic
studies are ongoing.
AUTHOR INFORMATION
Corresponding Author
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ACS Catalysis
Dependent Inversion of Diastereo- and Enantioselectivity in
Hydrofunctionalization of 1,3-Dienes. ACS. Catal. 2020, 10, 1060-
1076.
(8) (a) Huang, Z.; Lim, H. N.; Mo, F.; Young, M. C.; Dong, G.
Carbonyl Crotylation via Ruthenium-Catalyzed Butadiene
Hydrohydroxyalkylation. J. Am. Chem. Soc. 2012, 134, 20628-
20631. (e) McCammant, M. S.; Liao, L.; Sigman, M. S. Palladium-
Catalyzed 1,4-Difunctionalization of Butadiene to Form Skipped
Polyenes. J. Am. Chem. Soc. 2013, 135, 4167-4170. (f) Grayson, M.
N.; Krische, M. J.; Houk, K. N. Ruthenium-Catalyzed Asymmetric
Hydrohydroxyalkylation of Butadiene: The Role of the Formyl
Hydrogen Bond in Stereochemical Control. J. Am. Chem. Soc. 2015,
137, 8838-8850. (g) Li, X.; Meng, F.; Torker, S.; Shi, Y.; Hoveyda, A.
H. Catalytic Enantioselective Conjugate Additions of (pin)B-
Substituted Allylcopper Compounds Generated in situ from
Butadiene or Isoprene. Angew. Chem. Int. Ed. 2016, 55, 9997-10002.
(h) Jiang, L.; Cao, P.; Wang, M.; Chen, B.; Wang, B.; Liao, J. Highly
Diastereo- and Enantioselective Cu-Catalyzed Borylative Coupling
of 1,3-Dienes and Aldimines. Angew. Chem. Int. Ed. 2016, 55,
13854-13858. (i) Sleet, C. E.; Tambar, U. K. Copper-Catalyzed
Aminothiolation of 1,3-Dienes via a Dihydrothiazine Intermediate.
Angew. Chem. Int. Ed. 2017, 56, 5536-5540. (j) Tortajada, A.;
Ninokata, R.; Martin, R. Ni-Catalyzed Site-Selective Dicarboxylation
of 1,3-Dienes with CO2. J. Am. Chem. Soc. 2018, 140, 2050-2053. (k)
Xiong, Y.; Zhang, G. Enantioselective 1,2-Difunctionalization of 1,3-
Butadiene by Sequential Alkylation and Carbonyl Allylation. J. Am.
Chem. Soc. 2018, 140, 2735-2738. (l) Li, C.; Liu, R. Y.; Jesikiewicz, L.
T.; Yang, Y.; Liu, P.; Buchwald, S. L. CuH-Catalyzed Enantioselective
Ketone Allylation with 1,3-Dienes: Scope, Mechanism, and
Applications. J. Am. Chem. Soc. 2019, 141, 5062-5070. (m) Yang, J.;
Liu, J.; Neumann, H.; Franke, R.; Jackstell, R.; Beller, M. Direct
Synthesis of Adipic Acid Esters via Palladium-catalyzed
Carbonylation of 1,3-Dienes. Science 2019, 366, 1514-1517.
(5) (a) Kuniyuki, T.; Akihisa, M.; Go, H. Palladium-catalyzed
Reactions of 1,3-Dienes with Active Methylene Compounds. IV.
Palladium-diphosphine Complex Catalysts. Bull. Chem. Soc. Jpn.
1972, 45, 1183-1191. (b) Baker, R.; Popplestone, R. J. Reactions of
Active Methylene and Carbonyl Compounds with Myrcene
Catalysed by Palladium and Nickel Complexes. Tetrahedron Lett.
1978, 19, 3575-3578. (c) Andell, O. S.; Bäckvall, J.-E.; Moberg, C.
Nickel- and Palladium-catalyzed Additions of Nucleophiles to
Cyclic 1,3-Dienes. Acta Chem. Scand. 1986, 40b, 184-189. (d) Wilke,
G. Contributions to Organo-Nickel Chemistry. Angew. Chem. Int. Ed.
1988, 27, 185-206. (e) Jolly, P. W.; Kokel, N. Reaction of 1,3-Dienes
with Nucleophiles Catalysed by [1,2-Bis(dialkylphosphino)-ethane]
palladium Complexes. Synthesis 1990, 1990, 771-773. (f) Adamson,
N. J.; Wilbur, K. C. E.; Malcolmson, S. J. Enantioselective
Intermolecular Pd-catalyzed Hydroalkylation of Acyclic 1,3-Dienes
with Activated Pronucleophiles. J. Am. Chem. Soc. 2018, 140,
2761−2764. (g) Yang, X.-H.; Davison, R. T.; Nie, S.-Z.; Cruz, F. A.;
McGinnis, T. M.; Dong, V. M. Catalytic Hydrothiolation: Counterion-
Controlled Regioselectivity. J. Am. Chem. Soc. 2019, 141, 3006-3013.
(h) Zhang, Q.; Yu, H.; Shen, L.; Tang, T.; Dong, D.; Chai, W.; Zi, W.,
Stereodivergent Coupling of 1,3-Dienes with Aldimine Esters
Enabled by Synergistic Pd and Cu Catalysis. J. Am. Chem. Soc. 2019,
141, 14554-14559.
1
2
3
4
5
6
7
8
Transition Metal-catalyzed Ketone-directed or Mediated C-H
Functionalization. Chem. Soc. Rev. 2015, 44, 7764–7786. (b) Mo, F.;
Dong, G. Regioselective Ketone α-Alkylation with Simple Olefins via
Dual Activation. Science 2014, 345, 68–72. (c) Mo, F.; Lim, H. N.;
Dong, G. Bifunctional Ligand-Assisted Catalytic Ketone α-
Alkenylation with Internal Alkynes: Controlled Synthesis of Enones
and Mechanistic Studies. J. Am. Chem. Soc. 2015, 137, 15518–15527.
(d) Lim, H. N.; Dong, G. Catalytic Intramolecular Ketone Alkylation
with Olefins by Dual Activation. Angew. Chem. Int. Ed. 2015, 54,
15294-15298. (e) Xing, D.; Dong, G. Branched-Selective
Intermolecular Ketone α-Alkylation with Unactivated Alkenes via
an Enamide Directing Strategy. J. Am. Chem. Soc. 2017, 139, 13664–
13667. (f) Xing, D.; Qi, X.; Marchant, D.; Liu, P.; Dong, G. Branched-
Selective Direct α-Alkylation of Cyclic Ketones with Simple Alkenes.
Angew. Chem. Int. Ed. 2019, 58, 4366-4370. For related DFT
calculations, see: (g) Dang, Y.; Qu, S.; Tao, Y.; Deng, X.; Wang, Z.-X.
Mechanistic Insight into Ketone α-Alkylation with Unactivated
Olefins via C–H Activation Promoted by Metal–Organic
Cooperative Catalysis (MOCC): Enriching the MOCC Chemistry. J.
Am. Chem. Soc. 2015, 137, 6279–6291. (h) Li, X.; Wu, H.; Lang, Y.;
Huang, G. Mechanism, Selectivity, and Reactivity of Iridium- and
Rhodium-catalyzed Intermolecular Ketone α-Alkylation with
Unactivated Olefins via an Enamide Directing Strategy. Catal. Sci.
Technol. 2018, 8, 2417–2426. (i) Yang, H.; Xing, D. Palladium-
catalyzed Diastereo- and Enantioselective Allylic Alkylation of
Oxazolones with 1,3-Dienes under Base-free Conditions. Chem.
Commun. 2020, doi: 10.1039/D0CC00265H.
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(9) For
a preprinted related but unpublished work on
September 11, 2018: DOI: 10.26434/chemrxiv.7072646.
(10) For selected reviews on Ni-catalyzed C-H functionalization,
see: (a) Tasker, S. Z.; Standley, E. A.; Jamison, T. F. Recent Advances
in Homogeneous Nickel Catalysis. Nature 2014, 509, 299-309. (b)
Castro, L. C. M.; Chatani, N. Nickel Catalysts/N,N′-Bidentate
Directing Groups: An Excellent Partnership in Directed C–H
Activation Reactions. Chem. Lett. 2015, 44, 410-421. (c) Zhan, B.;
Liu, B.; Hu, F.; Shi, B. Recent Progress on Nickel-catalyzed Direct
Functionalization of Unactivated C-H bonds. Chin. Sci. Bull. 2015,
60, 2907-2917. (d) Yamaguchi, J.; Muto, K.; Itami, K. Nickel-
Catalyzed Aromatic C–H Functionalization. Top. Curr. Chem. 2016,
374, 55.
(11) (a) Graening, T.; Hartwig, J. F. Iridium-Catalyzed Regio- and
Enantioselective Allylation of Ketone Enolates. J. Am. Chem. Soc.
2005, 127, 17192-17193. (b) Chen, M.; Hartwig, J. F. Iridium-
Catalyzed Enantioselective Allylic Substitution of Unstabilized
Enolates Derived from α,β-Unsaturated Ketones. Angew. Chem. Int.
Ed. 2014, 53, 8691-8695. (c) Liang, X.; Wei, K.; Yang, Y.-R. Iridium-
catalyzed Enantioselective Allylation of Silyl Enol Ethers Derived
from Ketones and α,β-Unsaturated Ketones. Chem. Commun. 2015,
51, 17471-17474.
(12) Substituted 1,3-dienes such as phenyl- or alkyl-substituted
1,3-dienes, 1,3-cyclohexadiene, as well as isoprene which is also a
feedstock reagent, also underwent this transformation with high
efficiency. For detailed results, see the Supporting Information.
(13) The reaction without H2O was run under strictly anhydrous
conditions and all substrates were pre-dried with 4 Å molecular
sieves. For details, see the Supporting Information.
(14) A large KIE (4.5) was observed for the reaction between
acetophenone 1a and 1-phenyl-1,3-butadiene, for details, see the
Supporting Information.
(6) (a) Smutny, E. J. Oligomerization and Dimerization of
Butadiene under Homogeneous Catalysis. Reaction with
Nucleophiles and the Synthesis of 1,3,7-Octatriene. J. Am. Chem. Soc.
1967, 89, 6793-6794. (b) Takahashi, S.; Shibano, T.; Hagihara, N.
The Dimerization of Butadiene by Palladium Complex Catalysts.
Tetrahedron Lett. 1967, 8, 2451-2453. (c) Behr, A.; Becker, M.;
Beckmann, T.; Johnen, L.; Leschinski, J.; Reyer, S. Telomerization:
Advances and Applications of a Versatile Reaction. Angew. Chem.
Int. Ed. 2009, 48, 3598-3614.
(7) (a) Cheng, L.; Li, M.; Xiao, L.-J.; Xie, J.-H.; Zhou, Q.-L. Nickel(0)-
Catalyzed Hydroalkylation of 1,3-Dienes with Simple Ketones. J.
Am. Chem. Soc. 2018, 140, 11627-11630. For a recent review on the
hydrofunctionalization of 1,3-dienes with nucleophiles, see: (b)
Adamson, N. J.; Malcolmson, S. J. Catalytic Enantio- and
Regioselective Addition of Nucleophiles in the Intermolecular
(15) (a) Mifleur, A.; Mérel, D. S.; Mortreux, A.; Suisse, I.; Capet, F.;
Trivelli, X.; Sauthier, M.; Macgregor, S. A. Deciphering the
Mechanism of the Nickel-Catalyzed Hydroalkoxylation Reaction: A
Combined Experimental and Computational Study. ACS Catal.
2017, 7, 6915-6923. (b) for a similar pathway with palladium, see:
Jolly, P. W. η3-Allylpalladium Compounds. Angew. Chem. Int. Ed.
1985, 24, 283-295.
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(16) Attempts to characterize complex A were unfruitful, for a
related discussion, see reference 14a.
Addition of O−H Bonds of Methanol and Water to IrI Complexes
Having Peraryldiphosphane Ligands. Angew. Chem. Int. Ed. 1998,
37, 3381-3383. (d) Dorta, R.; Rozenberg, H.; Shimon, L. J. W.;
Milstein, D. Oxidative Addition of Water to Novel Ir(I) Complexes
Stabilized by Dimethyl Sulfoxide Ligands. J. Am. Chem. Soc. 2002,
124, 188-189.
1
2
3
4
5
6
7
8
(17) A nickel-based metallacycle from Ni(0) and 1,3-butadiene
as the intermediate is also possible. Generation of such type of
metallacycles is known, see: R. H. Crabtree, The Organometallic
Chemistry of the Transition Metal, Wiley & Sons, New York, 3rd ed.,
2001, pp. 125–128.
(18) (a) Shirakawa, E.; Takahashi, G.; Tsuchimoto, T.; Kawakami,
Y. Nickel-catalysed Addition of Organoboronates to 1,3-Dienes.
Chem. Commun. 2002, 2210-2211. (b) Xiao, L.-J.; Cheng, L.; Feng,
W.-M.; Li, M.-L.; Xie, J.-H.; Zhou, Q.-L. Nickel(0)-Catalyzed
Hydroarylation of Styrenes and 1,3-Dienes with Organoboron
Compounds. Angew. Chem. Int. Ed. 2018, 57, 461-464.
(19) For selected reports on the oxidative addition of water to
other transition metal complexes, see: (a) Milstein, D.; Calabrese, J.
C.; Williams, I. D. Formation, Structures, and Reactivity of cis-
Hydroxy-, cis-Methoxy-, and cis-Mercaptoiridium Hydrides.
Oxidative Addition of Water to Ir(I). J. Am. Chem. Soc. 1986, 108,
6387-6389. (b) Burn, M. J.; Fickes, M. G.; Hartwig, J. F.; Hollander, F.
J.; Bergman, R. G. Synthesis of Monomeric Ruthenium Hydroxo
Complexes (PMe3)4Ru(R)(OH) (R = H, Me) and a Unique Dimeric
(20) For detailed results on a series of other types of synthetic
elaboration of 3a, see the Supporting Information.
(21) Firmenich. US Patent 005 219 836A, June 15, 1993.
(22) Hilf, J. A.; Holzwarth, M. S.; Rychnovsky, S. D. Route to Highly
Substituted Pyridines. J. Org. Chem. 2016, 81, 10376-10382.
(23) (a) Rao, P. P.; Grover, R. K. Apricoxib, a COX-2 Inhibitor for
the Potential Treatment of Pain and Cancer. IDrugs 2009, 12, 711.
(b) Kiguchi, K.; Ruffino, L.; Kawamoto, T.; Franco, E.; Kurakata, S.-i.;
Fujiwara, K.; Hanai, M.; Rumi, M.; DiGiovanni, J. Therapeutic Effect
of CS-706, a Specific Cyclooxygenase-2 Inhibitor, on Gallbladder
Carcinoma in BK5.ErbB-2 Mice. Mol. Cancer Ther. 2007, 6, 1709-
1717.
(24) Mandal, P. K.; Freiter, E. M.; Bagsby, A. L.; Robertson, F. M.;
McMurray, J. S. Efficient Synthesis of Apricoxib, CS-706, a Selective
Cyclooxygenase-2 Inhibitor, and Evaluation of Inhibition of
Prostaglandin E2 Production in Inflammatory Breast Cancer Cells.
Bioorg. Med. Chem. Lett. 2011, 21, 6071-6073.
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Ruthenium
Hydroxo-water
Complex
[trans-
Ru(H)(OH)(DMPE)2.cntdot.H2O]2. J. Am. Chem. Soc. 1993, 115,
5875-5876. (c) Tani, K.; Iseki, A.; Yamagata, T. Facile Oxidative
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ACS Catalysis
O
O
Ni(0)/IMes
1
2
3
H
+
H2O
130 oC, 2 h
4
5
atom-economic
redox neutral
strong base/acid free
highly regioselective
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