Nickel(0)-Catalyzed Hydroalkylation of 1,3-Dienes with Simple Ketones

Article abstract of DOI:10.1021/jacs.8b09346

We developed a highly regioselective addition of 1,3-dienes with simple ketones by nickel-hydride catalyst bearing DTBM-SegPhos ligand. A wide range of aromatic and aliphatic ketones directly coupled with 1,3-dienes, providing synthetically useful γ,δ-unsaturated ketones in high yield and regioselectivity. The asymmetric version of the reaction was also realized in high enantioselectivity by using novel chiral ligand DTBM-HO-BIPHEP. The utility of this hydroalkylation was demonstrated by facile product modification and enantioselective synthesis of (R)-flobufen.

Full text of DOI:10.1021/jacs.8b09346

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Communication
Nickel(0)-Catalyzed Hydroalkylation of 1,3-Dienes with Simple Ketones
Lei Cheng, Ming-Ming Li, Li-Jun Xiao, Jian-Hua Xie, and Qi-Lin Zhou
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b09346 • Publication Date (Web): 05 Sep 2018
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Nickel(0)-Catalyzed Hydroalkylation of 1,3-Dienes with Simple Ke-
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Lei Cheng,a Ming-Ming Li,a Li-Jun Xiaoa,*, Jian-Hua Xie,a,b Qi-Lin Zhoua,b,*
a State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, and b Collaborative Inno-
vation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, China.
E-mail: 1120140207@mail.nankai.edu.cn; qlzhou@nankai.edu.cn
Supporting Information Placeholder
hydroalkylation of 1,3-dienes) in high yield with excellent
ABSTRACT: We developed a highly regioselective addition
regioselectivity for the 1,2-addition product (that is, the
product of Markovnikov addition).8 We also accomplished
an asymmetric version of this reaction with high enantiose-
lectivity by using a C2-symmetric biaryl bisphosphine ligand.
This protocol allowed us to realize regio- and enantioselec-
tive addition of unstabilized carbon nucleophiles to unsatu-
rated hydrocarbons.
of 1,3-dienes with simple ketones by nickel-hydride catalyst
bearing DTBM-SegPhos ligand. A wide range of aromatic and
aliphatic ketones directly coupled with 1,3-dienes, providing
synthetically useful γ,δ-unsaturated ketones in high yield and
regioselectivity. The asymmetric version of the reaction was
also realized in high enantioselectivity by using novel chiral
ligand DTBM-HO-BIPHEP. The utility of this hydroalkyla-
tion was demonstrated by facile product modification and
enantioselective synthesis of (R)-Flobufen.
Scheme 1. Transition-Metal-Catalyzed Hydroalkyla-
tion of Unsaturated Hydrocarbons with Carbonyl
Compounds
Transition-metal-catalyzed addition of enols/enolates to
unsaturated hydrocarbons is a useful and atom-economical
method for construction of C–C bonds from readily available
starting materials.1 In particular, coupling reactions of
enols/enolates with 1,3-dienes, allenes, and alkynes provide
an efficient route to functionalized allylic compounds and
have been attracting increasing attention.2 These coupling
reactions usually involve addition of M–H to the unsaturated
hydrocarbon to generate an electrophilic metal-π-allyl in-
termediate, which reacts with the nucleophilic carbonyl
compound. Since Hata et al. reported the palladium-
catalyzed addition of 1,3-dicarbonyl compounds to dienes in
the early 1970s,3 significant progress has been made on palla-
dium- and rhodium-catalyzed coupling of stabilized carbon
nucleophiles with unsaturated hydrocarbons such as 1,3-
dienes, allenes, and alkynes (Scheme 1a),4 and the asymmet-
ric version of this transformation has also been achieved.5
However, the coupling of unstabilized carbon nucleophiles
such as enols/enolates of simple ketones with these unsatu-
rated hydrocarbons has not been well explored.6
We began by attempting to couple phenylbutadiene (1a)
and acetophenone (2a) using a Ni(COD)2/monophosphine
catalyst under the previously reported hydroarylation condi-
tions.7 However, none of the desired 1,2-addition product
(3a) was detected. We then explored different ligands and
Recently, we developed a protocol for nickel-catalyzed hy-
droarylation reactions of styrenes and 1,3-dienes with or-
ganoboron compounds.7 In these reactions, an alcohol reacts
with Ni(0) to generate the active catalyst species Ni–H. We
reasoned that the Ni–H species could catalyze hydroalkyla-
tion reactions between 1,3-dienes and simple ketones to yield
γ,δ-unsaturated ketones (Scheme 1b). Herein, we report the
nickel-catalyzed addition of simple ketones to 1,3-dienes (i.e.,
found
that
2,2'-bis(diphenylphosphino)-1,1'-biphenyl
(BIPHEP) gave 3a in 5% yield. After extensive screening of
additional ligands (see SI, Table S1), we were delighted to
find
methoxyphenyl)phosphino]-4,4'-bi-1,3-benzodioxole (DTBM-
SegPhos) was suitable, providing 3a in 65% yield and none of
the 1,4-addition product. In the hopes of further improving
the yield, we evaluated several bases and found that the use
that
5,5'-Bis[di(3,5-di-t-butyl-4-
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t
of BuOK (20 mol %) dramatically increased the yield of 3a
(to 93%).9 A variety of ketones 2 were allowed to react with
phenylbutadiene (1a) (Table 1). All of the tested ketones regi-
oselectively gave products of 1,2-addition (>99:1). Aromatic
ketones bearing substituents with various electronic and
steric properties (2b–2p), as well as heteroaromatic ketones
(2q, 2r), were suitable substrates, providing the correspond-
ing products in moderate to high yield (55–94%). Notably,
relatively inert nucleophiles such as aliphatic ketones, cyclo-
hexanecarboxaldehyde, and phenylacetate also showed good
reactivity in the reaction with 1a, giving desired products 3t–
3z in 61–98% yield. In the reaction of nonsymmetric alkyl
ketone, butan-2-one, coupling occurred at the CH2 instead of
CH3 group (3u); this outcome differs from that of previously
reported reactions involving an enamide directing strategy.10
In addition, our protocol could be used to derivatize estrone
3-methyl ether (2aa), indicating that the reaction conditions
are mild enough to be used for complex molecules.
the isolated C=C bond of substrate 1m was tolerated under
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the reaction conditions.
Table 2. Hydroalkylation of Various Dienesa
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a Reaction conditions: 1a (0.2 mmol), 2 (0.1 mmol), Ni(COD)2 (10
mol %), DTBM-SegPhos (11 mol %), BuOK (20 mol %), EtOH
t
Table 1. Hydroalkylation of Phenylbutadiene with
Various Ketonesa
(1.0 mL), 100 °C, 72 h. Isolated yields.
To further expand the utility of the reaction, we directed
our efforts toward achieving an asymmetric version (Table 3).
Systematic evaluation of chiral ligands in the reaction be-
tween 1a and 2a revealed that (S)-DTBM-SegPhos was an
effective ligand, enantioselectively giving 5a with an er of
92:8. The use of (S)-DTBM-MeO-BIPHEP increased the en-
antioselectivity of the reaction from 92:8 er to 94:6 er. We
then prepared a novel ligand, (S)-DTBM-HO-BIPHEP, which
bears two hydroxyl groups. This ligand gave an even higher
enantioselectivity (96:4 er). In contrast, (R,Sp)-JosiPhos, (S)-
BINAP, and (S)-SDP exhibited little or no chiral induction.
Table 3. Ligand Effect on Ni-Catalyzed Asymmetric
Hydroalkylation of Phenylbutadiene and Acetophe-
nonea
a Reaction conditions: 1a (0.2 mmol), 2 (0.1 mmol), Ni(COD)2 (10
t
mol %), DTBM-SegPhos (11 mol %), BuOK (20 mol %), EtOH
(1.0 mL), 100 °C, 72 h. Isolated yields. Diastereoselectivity were
determined by 1H NMR analysis. b 1.2 equivalent of diene. c React-
d
e
ed at 80 °C. Performed with DTBM-MeO-BIPHEP. 10 equiva-
lent of acetone.
a Reaction conditions: 1a (0.2 mmol), 2 (0.1 mmol), Ni(COD)2 (10
mol %), chiral ligand (11 mol %), BuOK (20 mol %), EtOH (1.0
mL), 80 °C, 72 h. Isolated yields. Enantioselectivity determined
by chiral HPLC. b 40 mol % base was used.
We then examined the addition reactions of various 1,3-
dienes 1 with acetophenone (2a) (Table 2). Aryl dienes gave
corresponding 1,2-addition products 4a–4h in moderate to
good yield with excellent regioselectivity (>99:1). The pres-
ence of a strongly electron-withdrawing substituent, CF3, on
the phenyl ring of the aryl diene led to a decreased yield
(53%, 4e). Furyl diene 1i provided desired product 4i in 81%
yield. Notably, alkyl 1,3-dienes also worked well, giving only
1,2-addition products 4j–4m in moderate yield. In addition,
t
By using (S)-DTBM-HO-BIPHEP as the ligand, we pre-
pared a number of γ,δ-unsaturated ketones bearing a β-chiral
center (Table 4). Aryl dienes reacted with acetophenone to
give addition products 5a–5f in moderate to good yield (42–
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48 h; (c) KMnO4, NaIO4, K2CO3, tBuOH/H2O = 1:1, 0–20 °C, 24 h.
78%) with high enantioselectivity (95.5:4.5–97:3 er). Notably,
c
d
Use a mixture of phenylbutadienes formed from Z/E isomers.
1
2
3
4
5
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7
8
the stereochemistry of the diene had little influence on the
yield, regioselectivity, or enantioselectivity. An approximate-
ly 2:1 mixture of E- and Z-phenylbutadienes exclusively yield-
ed the 1,2-addition product with only an (E)-olefin (5b). Oth-
er aromatic ketones, including substituted acetophenones, 2-
acetyl-naphthalene, and 2-acetyl-thiophene also showed
moderate to good yield (5g–5n, 52–91%) and good enantiose-
lectivity (91:9–96: 4 er) in the reaction with phenylbutadiene.
Phenyl-ethyl ketone, aliphatic ketones, and phenylacetate
can also react with phenylbutadiene to give addition prod-
ucts (5p–5t) in good enantioselectivities (89.5:10.5–92.5:7.5
er), but with low diastereoselectivities (1.1:1–1.4:1 dr). Alkyl-
substituted dienes reacted with ketones to afford addition
products in lower yields and moderate enantioselectivities
(5u–5w).
e
10 equivalent of acetone and reacted at 90 °C. 5 equivalent of
f
ketone. Performed with (S)-DTBM-MeO-BIPHEP and reacted
at 90 °C.
The chiral products contained carbonyl and olefin func-
tional groups, which allowed them to be transformed to oth-
er useful compounds (Table 4). For example, the carbonyl
group of 5l could be hydrogenated in the presence of a chiral
spiro iridium catalyst developed in our group,11 yielding γ-
methyl alcohol 6a in 98% yield with high diastereoselectivity
(dr = 20:1). The olefin group of 5l could be converted to diol
6b in 64% yield with high enantioselectivity and diastereose-
lectivity by means of Sharpless dihydroxylation.12 Oxidative
cleavage of the C=C bond of 5l provided convenient, enanti-
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oselective access to (R)-flobufen,
a nonsteroidal anti-
Table 4. Enantioselective Hydroalkylationa and
Product Transformationsb
inflammatory drug that also exhibits immunomodulatory
properties.13
Ni(COD)2 (10 mol %)
(S)-DTBM-HO-BIPHEP
To gain some insight into the reaction mechanism, we
conducted deuterium-labeling experiments with EtOD
(Scheme 2a). The occurrence of H/D exchange in diene 1a
(eq. 1), and 100% deuterium incorporation into the methyl
group of product 3a (eq. 2), revealed that a Ni–H intermedi-
ate was generated from the alcohol and that insertion of the
terminal double bond of the diene into the Ni–H bond was
reversible and faster than attack of the enol/enolate. On the
basis of our experimental results and our previous work,7,14
we propose the catalytic cycle shown in Scheme 2b. First, the
oxidative addition of the alcohol to Ni(0) generates Ni–H
intermediate A. Insertion of diene 1a into the Ni–H bond of A
affords π-allylnickel intermediate B. Another possible path-
way to intermediate B is the complexation of Ni(0) with
diene and alcohol to give intermediate C, followed by direct
generation of B via LLHT mechanism.14,15 Intermediate D is
formed by a ligand exchange reaction in which the alcohol
moiety of B is replaced by the enolate of ketone 2a. Subse-
quent reductive elimination delivers hydroalkylation product
3a and regenerates the Ni(0) catalyst.
Me
O
O
HO
HO
PAr2
PAr2
H
(11 mol %)
tBuOK (40 mol%)
EtOH, 80 °C, 72 h
Ar
R
+
5
1
2
(S)-DTBM-HO-BIPHEP
Me
O
Me
O
R
R
R = H
R = H
5a
5bc
, 78% yield, 96:4 er
R = 4-Me
5g, 58% yield, 95:5 er
5h 76% yield, 91:9 er
,
5i, 65% yield, 95:5 er
, 72% yield, 95.5:4.5 er
, 52% yield, 96:4 er
, 64% yield, 96:4 er
, 49% yield, 97:3 er
R = 4-CF3
R = 4-OMe 5c
R = 3,5-(OMe)2
R = 3-Me
R = 4-Me
R = 3-Me
R = 2-Me
5d
5e
5j
,
54% yield, 95:5 er
5k, 76% yield, 92:8 er
5l
R = 3-F
5f
,
42% yield, 97:3 er
R = 4-(2',4'-F2)C6H2
,
78% yield, 96:4 er
Me
O
Me
O
Me
O
S
Me
, 91% yield, 1.1:1 dr
5o
5n, 91% yield, 96:4 er
5m, 86% yield, 95.5:4.5 er
Me
90.5:9.5 er (88:12 er)
O
Me
O
Me
O
Me
Me
Me
Me
nPr
, 71% yield, 1.3:1 dr
92.5:7.5 er (90.5:9.5 er)
Me
5qe, 72% yield, 1.2:1 dr
5re
5pd
, 52% yield, 94:6 er
90.5:9.5 er (89.5:10.5 er)
Me
O
Me
O
O
nC5H11
OEt
Me Me
, 72% yield, 1.1:1 dr
Ph
Scheme 2. Deuterium-Labeling Experiments and
Proposed Mechanism
5se
5uf
, 45%, 87.5:12.5 er
5t, 70% yield, 1.4:1 dr
90.5:9.5 er (88:12 er)
89.5:10.5 er (88:12 er)
Me
O
Me
Me
Me
Me
O
5wf, 48%, 89:11 er
5vf
, 40%, 86:14 er
OH Me
Ar
O
Me
a)
Ph
Ar
Ph
Ar = 4-(2',4'-F2)C6H2
Ar = 4-(2',4'-F2)C6H2
6a
, 98% yield, 96.5:3.5 er
dr = 20:1
(R)- or (S)-5l, 96:4 er
b)
c)
O
Me
CO2H
O
Me OH
Ph
Ar
Ar
Ar = 4-(2',4'-F2)C6H2
OH
Ar = 4-(2',4'-F2)C6H2
6b, 64% yield, 99:1 er
dr = 20:1
(R)-(+)-Flobufen
, 75% yield, 98:2 er
6c
a
Reaction conditions: 1 (0.2 mmol), 2 (0.1 mmol), Ni(COD)2 (10
t
mol %), Chiral ligand (11 mol %), BuOK (20 mol %), EtOH (1.0
mL), 100 °C, 72 h. Isolated yields. Enantioselectivity and dia-
stereoselectivity were determined by chiral HPLC. The data in
parentheses are the enantioselectivity of minor isomers. Rea-
gents and conditions: (a) H2 (10 atm), [Ir]-(R)-SpiroPAP, BuOK,
b
t
t
EtOH, rt, 1 h; (b) AD-mix β, MeSO2NH2, BuOH/H2O = 1:1, 0 °C,
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project (B06005) of the Ministry of Education of China for
1
financial support.
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REFERENCES
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In summary, we have developed a protocol for highly regi-
oselective addition reactions between 1,3-dienes and simple
ketones mediated by a nickel catalyst with DTBM-SegPhos as
a ligand. A wide range of aromatic and aliphatic ketones
could be directly coupled with 1,3-dienes, providing syntheti-
cally useful γ,δ-unsaturated ketones in high yield and regi-
oselectivity. An asymmetric version of the reaction was also
realized with high enantioselectivity by using the novel chiral
ligand DTBM-HO-BIPHEP. Moreover, the chiral products of
the reaction are versatile building blocks in synthetic chemis-
try, as demonstrated by the synthesis of the bioactive com-
pound (R)-flobufen. Further studies will focus on elucidating
the reaction mechanism and on application of Ni-BIPHEP
catalysts to other enantioselective hydrofunctionalization
reactions.
ASSOCIATED CONTENT
Supporting Information
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: xxx
Experimental procedures, optimization, characterization
(PDF)
AUTHOR INFORMATION
Corresponding Author
*1120140207@mail.nankai.edu.cn
*qlzhou@nankai.edu.cn
ORCID
Li-Jun Xiao: 0000-0002-3998-3628
Qi-Lin Zhou: 0000-0002-4700-3765
Notes
The authors declare no competing financial interests.
(15) For ligand-to-ligand hydrogen transfer (LLHT) mechanism in
other nickel-catalyzed reactions, see: (a) Guihaumé, J.; Halbert, S.;
Eisenstein, O.; Perutz, R. N. Organometallics 2012, 31, 1300. (b) Bair,
J. S.; Schramm, Y.; Sergeev, A. G.; Clot, E.; Eisenstein, O.; Hartwig, J.
ACKNOWLEDGMENT
We thank the National Natural Science Foundation of China
(Nos. 21421001, 21325207, 21421062, 21532003) and the “111”
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F. J. Am. Chem. Soc. 2014, 136, 13098. (c) Nett, A. J.; Montgomery, J.;
Zimmerman, P. M. ACS Catal. 2017, 7, 7352. (d) ref 14.
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