Ni-Catalyzed Regiodivergent and Stereoselective Hydroalkylation of Acyclic Branched Dienes with Unstabilized C(sp3) Nucleophiles

Article abstract of DOI:10.1021/jacs.0c08319

Two complementary regiodivergent [(P,N)Ni]-catalyzed hydroalkylations of branched dienes are reported. When amides are employed as unstabilized C(sp3) nucleophiles, a highly regioselective 1,4-addition process is favored. The addition products are obtained in high yield and with excellent stereocontrol of the internal olefin. With use of a chiral ligand and imides as carbon nucleophiles, a 3,4-addition protocol was developed, enabling construction of two contiguous tertiary stereocenters in a single step with moderate to high levels of diastereocontrol and excellent enantiocontrol. Both methods operate under mild reaction conditions, display a broad scope, and show excellent functional group tolerance. The synthetic potential of the 3,4-hydroalkylation reaction was established via a series of postcatalytic modifications.

Full text of DOI:10.1021/jacs.0c08319

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Article
Ni-Catalyzed Regiodivergent and Stereoselective Hydroalkylation
of Acyclic Branched Dienes with Unstabilized C(sp3) Nucleophiles
Wen Shao, Celine Besnard, Laure Guénée, and Clément Mazet
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c08319 • Publication Date (Web): 01 Sep 2020
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Ni-Catalyzed Regiodivergent and Stereoselective Hydroalkylation of
Acyclic Branched Dienes with Unstabilized C(sp3) Nucleophiles
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Wen Shao,† Céline Besnard,‡ Laure Guénée,‡ Clément Mazet*,†
† Department of Organic Chemistry, University of Geneva, 30 quai Ernest Ansermet, 1211 Geneva, Switzerland.
‡ Laboratory of Crystallography, University of Geneva, 24 quai Ernest Ansermet, 1211 Geneva, Switzerland.
ABSTRACT: Two complementary regiodivergent [(P,N)Ni]-catalyzed hydroalkylations of branched dienes are reported.
When amides are employed as unstabilized C(sp3) nucleophiles, a highly regioselective 1,4-addition process is favored. The
addition products are obtained in high yield and with excellent stereocontrol of the internal olefin. Using a chiral ligand
and imides as carbon nucleophiles, a 3,4-addition protocol was developed enabling construction of two contiguous tertiary
stereocenters in a single step with moderate to high levels of diastereocontrol and excellent enantiocontrol. Both methods
operate under mild reaction conditions, display broad scope and show excellent functional group tolerance. The synthetic
potential of the 3,4-hydroalkylation reaction was established via a series of post-catalytic modifications.
base, linear 1,3-dienes could be coupled with unstabilized
■ INTRODUCTION
C-nucleophiles using in situ generated enolates from sim-
ple ketones.6 The 3.4-addition products were obtained
The development of novel methods for the diastereoselec-
tive and enantioselective construction of adjacent stereo-
centers based on C–C bond forming reactions is a resound-
ing challenge in chemical synthesis.1 The atom-economical
intermolecular hydroalkylation of conjugated dienes has
recently emerged as an enabling strategy because it pro-
vides access to synthetically useful compounds with an al-
lylic stereocenter, compounds that would be difficult to
prepare using conventional protocols. The influence of the
substitution pattern of dienes on reactivity and selectivity
and the diversity of insertion modes conceivable for a tran-
sition metal catalyst across the conjugated double bonds
pose major difficulties for their selective functionalization.
Consequently, in its most demanding version, the success-
ful development of a metal-catalyzed hydroalkylation of
dienes requires addressing altogether chemoselectivity, re-
gioselectivity, diastereoselectivity and –ultimately– enanti-
oselectivity challenges.2,3
To date, there is only a handful of reports on the selective
intermolecular hydroalkylation of 1,3-dienes (Figure 1). In
2004, Hartwig described the first Pd-catalyzed enantiose-
lective addition of a stabilized C(sp3) nucleophile to a sym-
metric diene (which obviated potential regioselectivity is-
sues), furnishing the product in excellent yield but modest
enantiomeric excess.4 Over a decade later, a series of break-
through studies were reported by the Malcolmson group,
which disclosed highly enantioselective Pd-catalyzed addi-
tions of a variety of activated C-centered nucleophiles to
terminal, internal and even branched dienes.5 The prod-
ucts were typically obtained with excellent level of enanti-
ocontrol and the combined scope of these methods is par-
ticularly broad. Zhou and coworkers demonstrated that, in
presence of a Ni catalyst and a catalytic amount of a strong
Figure 1. Transition metal-catalyzed intermolecular enan-
tioselective and diastereoselective hydroalkylations of acy-
clic 1,3-dienes.
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preferentially with high enantioselectivity but in low dia-
Table 1. Reaction optimizationa
Page 2 of 8
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stereomeric ratio when vicinal stereocenters were formed.
The Zi group disclosed an elegant [Cu/Pd] dual catalytic
system for the addition of weakly nucleophilic aldimine es-
ters to linear dienes, affording the products in high yield,
excellent ee and high dr. Particularly worthy of note is the
perfectly stereodivergent nature of the process, which pro-
vided access to all four possible stereoisomeric products
when 2 adjacent stereocenters were generated.7 Inspired by
seminal work from the Meek group,8 Dong and Wang re-
cently reported an enantioselective Pd-catalyzed hydroal-
kylation of linear dienes using azlactones as stabilized C-
nucleophiles.9 The products were isolated in good yield,
high dr and high levels of enantiocontrol. In spite of the
above achievements, the number of efficient diastereo-
and enantioselective hydroalkylations of dienes remains
limited. The development of selective methods based on
the combination of unstabilized carbon-centered nucleo-
philes and underexplored –yet valuable– diene subclasses
would undeniably represent an important addition to the
protocols currently available.
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en-
try
Nu
L
base
solvent
conv.
(%)b
<5
3,4-/1,4-additionb
(n equiv)
nonec
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1
2a
2a
2a
2a
2a h
3a
3a
2a
L1
L2
L1
L1
L1
L1
L1
L1
mesitylene
EtOHe
THF
-
2d
3f
4 f
5g
6
tBuOK (0.2)
tBuOK (2.0)
MeOK (0.2)
MeOK (0.2)
MeOK (0.2)
BTMG (1.0)
BTMG (1.0)
<5
-
>95
>95
>95
>95
>95
<5
1:19 (E/Z 2.5:1)
1:>25 (E/Z 9:1)
1:>25 (E/Z 15:1)
6.2:1 (dr 2.7:1)
6.5:1 (dr 2.8:1)
-
THF
THF
THF
7
THF
8
THF
We disclose here the identification of two regiodivergent
and complementary Ni-catalyzed stereoselective hydroal-
kylations of branched dienes using unstabilized C(sp3) nu-
cleophiles derived from simple amides and imides.10
a Reaction conditions: 1a (0.1 mmol), 2a or 3a (0.2 mmol). b
Determined by H NMR using an internal standard. 1.0
equiv. trifluoroethanol. d 100 °C. e 0.2 M. f 50 °C. g 48 h. h 1.2
equiv.
1
c
■ RESULTS AND DISCUSSION
Having identified two complementary protocols for the
hydroalkylation of branched dienes, we first decided to ex-
plore the scope of the Ni-catalyzed 1,4-regioselective pro-
cess using amides as carbon nucleophiles (Figure 2). For 2-
aryl substituted 1,3-dienes, independently of any electronic
perturbation, the regioselectivity was uniformly high and
the addition products were isolated in good to excellent
yield with stereoselectivity varying from 1.7:1 to 15:1. Nota-
bly, 2-heteroaryl dienes (1j-1l) and a cyano-containing sub-
strate (1i) were compatible with the mild reaction condi-
tions. By contrast, 2-alkyl 1,3-dienes such as 1m did not par-
ticipate productively in the reaction. Variation of the struc-
ture of the C-nucleophile proved to be particularly in-
formative. A variety of secondary amides, containing for
instance a pyrrolidine, a piperidine or a morpholine unit,
were suitable candidates for the addition reaction (5ab-
5ae). Remarkably, N-isopropyl-2-phenylacetamide, a pri-
mary amide derivative, was engaged successfully in the hy-
droalkylation reaction with perfect chemoselectivity (5af).
Introduction of electron-donating or electron-withdraw-
ing substituents at the para-, ortho- or even meta- position
of the aryl ring was also well-tolerated (5ag-5ak), as was
the case with a 3-pyridine moiety (5al). In all these reac-
tions, regioselectivity and stereoselectivity were excellent.
Of particular note, using N,N-dimethyl-2-phenylpropana-
mide and LiHMDS/tBuOK as a combination of bases, 5am
a product with a congested -quaternary center was gen-
erated, albeit in a slightly diminished yield and stereose-
lectivity (51% yield, E/Z 5:1). Finally, even though the regi-
oselectivity and stereoselectivity decreased markedly, we
found that esters could be employed as C(sp3) nucleophiles
using 2 equiv of base and by running the reaction at 50 °C
We recently reported a Ni-catalyzed enantioselective 3,4-
hydroamination of 1,3-dienes using primary aliphatic
amines, which occur with excellent Markovnikov selectiv-
ity.11 Therefore, we initially set out to develop a related sys-
tem for the 3,4-hydroalkylation of branched dienes with
amides as carbon nucleophiles. Unfortunately, subjecting
the model coupling partners 1a and 2a to our original pro-
tocol did not deliver any addition product (Table 1, entry
1). No reaction took place under the conditions developed
by the Zhou group for the hydroalkylation of linear dienes
using simple ketones despite the relatively similar pKa val-
ues of the C-nucleophiles (entry 2; pKa (2a/DMSO) = 26.6, pKa
= 26.5).12 With L1, when tBuOK was employed
(acetone/DMSO)
as base in THF, quantitative conversion to alkylation prod-
ucts resulting from 3,4-addition (4aa) and 1,4-addition
(5aa) was observed, with a marked preference for the latter
(entry 3). Although 5aa was not our initial target, the pres-
ence of two stereogenic elements and two functional han-
dles in its structure prompted us to further explore condi-
tions favoring its formation. Pleasingly, with a catalytic
amount of MeOK, an extended reaction time and only 1.2
equivalents of 2a, 5aa was generated as the sole regioiso-
meric hydroalkylation product with excellent control of
the internal olefin geometry (rr >25:1, E/Z 15:1) (entries 4-
5). We found that the product of 3,4-hydroalkylation (6aa),
could be obtained majoritarily by substituting amide 2a for
imide 3a (entry 6).13 The use of Barton’s base (BTMG) for
the in situ generation of the carbon-centered nucleophile
gave a homogeneous solution and led to slightly improved
regioselectivity and diastereoselectivity (entry 7).14 Of note,
no addition reaction occurred when attempting to gener-
ate the enolate of 2a with BTMG (entry 8).
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Figure 2. Scope of the stereoselective Ni-catalyzed 1,4-hydroalkylation of branched dienes using 2-phenylacetamide deriv-
atives. 1a-m (0.2 mmol) and 2a-o (1.2 equiv.). Yield of isolated product after purification by column chromatography. Regi-
oisomeric ratio and stereoselectivity determined by 1H NMR. a 48 h. b 2.0 equiv. of nucleophile (amide or ester). c 50 °C. d 120
h. e LiHMDS (1.0 equiv.) and tBuOK (0.1 equiv.) instead of MeOK. f 2.0 equiv. of base. g Combined yield (4+5).
(5an, 5ao). The stereochemistry of the internal double
bond initially assigned on the basis of 2D NMR experi-
ments was confirmed with the resolution of the X-ray
structure of 5da. Much to our dismay, all efforts to develop
an enantioselective variant of this addition process were
unsuccessful, despite an extensive screening of chiral (P,N)
and (P,P) ligands (See SI for details). The absence of stere-
oinduction can be ascribed either to poor facial selectivity
upon nucleophilic addition and/or poor control of the eno-
late stereochemistry. Nonetheless, because no enantioin-
duction was observed both with 2a and 2m, post-catalytic
enantiomerization can be reasonably excluded.15
Reasoning that the use of imides in place of amides in
the Ni-catalyzed 3,4-hydroalkylation of diene may posi-
tively influence the stereoselective outcome of the reac-
tion, we directly set out to develop an enantioselective var-
iant of this process. Several chiral ligands were surveyed
using the optimized conditions developed with L1 (Table
2). Whereas DTBM-Segphos (L2), the chiral ligand em-
ployed by Zhou and coworkers for the hydroalkylation of
linear dienes using simple ketones proved ineffective,
BenzP* (L3) which we used in the enantioselective hy-
droamination of branched dienes led to a mixture of 3 re-
gioisomers (entries 1-2). These isomeric products, which
result from formal 3,4-addition (6aa), 1,4-addition (7aa)
and 4,1-addition (8aa), were obtained quasi-quantitatively
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tested (6ma). Several imides, readily prepared from 2-oxa-
Page 4 of 8
Table 2. Chiral ligand surveya
1
zolidinone and the appropriate acyl chloride, were ex-
plored next (Figure 3, B). The product of 3,4-hydroalkyla-
tion was always generated preferentially (rr 1.3:1–10:1) in ex-
cellent enantioselectivity (88–91% ee), with the exception
of 6ae (67% ee). Products with a para methoxy- (6ab), a
para fluoro- (6ad), a meta chloro-substituent (6af), a
naphthyl group (6ag) as well as a dioxolane moiety (6ac)
were formed with appreciable catalytic efficiency, in high
diastereo- and enantioselectivity and with acceptable regi-
oselectivity (dr> 5:1, ca. 90% ee). Although the net catalytic
performances were affected, we found that a para-methyl
ester could be accommodated by using MeOK instead of
BTMG as base (6ae). A sterically demanding ortho-methyl
arene affected reactivity, regio- and diastereoselectivity,
but not enantioselectivity (6ah: 91% ee). Similar data were
obtained for a substrate with a cinnamyl substituent (6ai).
When the imide moiety was substituted by a 1,3-ketoesters
preferential 3,4-hydroalkylation occurred with reduced re-
gioselectivity and enantioselectivity but with excellent di-
astereoselectivity (6aj). Finally, an X-ray analysis was ob-
tained for 6ab, and the absolute and relative configura-
tions of all other hydroalkylation products were assigned
by analogy.
2
3
4
5
6
7
8
9
b
entry
L
Conv. (%)b
6aa : 7aa : 8aab
-
dr6aa
-
ee6aa (%)c
1
L2
L3
L4
L5
L6
L7
L8
L9
L9
<5
-
2
>95
95
3.8 : 4.2 : 1
7.3 : 1 : 1.1
16.3 : 2.8 : 1
11.3 : 1 : 1.9
6.1 : 1 : 6
2.8:1
3.3:1
3.3:1
5.3:1
5.3:1
2.3:1
5.3:1
7.0:1
77
18
3
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3
4d
80
5
>95
51
87
70
–79
92
92
6
7
59
5.7 : 1 : 1.7
11.1 : 1 : 1.9
13 : 1 : 2.1
8
9e
>95
>95
To demonstrate the synthetic potential of the 3,4-hy-
droalkylation protocol, several post-catalytic derivatiza-
tions were conducted using diastereomerically pure 6aa
(Figure 4). Complete reduction of the imide moiety into
the corresponding primary alcohol 9 was achieved without
epimerization using lithium borohydride. Subsequent
acidic treatment led to the selective formation of tetrahy-
drofuran derivative 10, the structure of which is character-
ized by three contiguous stereocenters (dr 19:1). Ester 11
was obtained in excellent yield and enantiospecificity us-
ing the ytterbium-catalyzed esterification of imides inde-
pendently developed by the Evano and Stevens/Frantz
groups.17 Hydrogenation of the 1,1-disubstituted alkene
unit in 6aa was accomplished under mild reaction condi-
tions using Pd(C). The reduced product (12) was generated
quantitatively in a 5.3 dr. The relative stereochemistry of
the major isomer was established by X-ray crystallographic
analysis. Hydrolysis of 6aa was conducted under basic con-
ditions using H2O2 as nucleophile under strongly basic
conditions (LiOH).18 Finally, we demonstrated that the
corresponding carboxylic acid (13) could be engaged in
late-stage modifications using highly functionalized syn-
thetic intermediates. Sitagliptin, an anti-diabetic drug con-
taining a primary amine and Ciproflaxin ester, a broad-
spectrum antibiotic containing a secondary amine, were
both efficiently converted to the corresponding amides 14
and 15 respectively using EDC•HCl as peptide coupling re-
agent.
a
b
Reaction conditions: 1a (0.1 mmol), 3a (0.2 mmol). De-
termined by H NMR using an internal standard. Deter-
mined by HPLC using a chiral stationary phase. Using
MeOK (0.2 equiv.) as base. 3a (1.2 equiv.), BTMG (0.2
1
c
d
e
equiv.), 48 h.
in a 3.8:4.2:1 ratio. Furthermore, 6aa was generated with
promising diastereo- and enantioselectivity levels (dr 2.8:1;
77% ee). A series of chiral phosphinooxazoline ligands de-
rived from L1 were tested next and the most representative
results are disclosed in entries 3-8 of Table 2 (See SI for de-
tails). Overall, the highest regioselectivity, diastereoselec-
tivity and enantioselectivity were obtained for derivatives
possessing an aromatic substituent at the stereogenic cen-
ter  to the N-donor atom, and L9 –a novel member of this
ligand class– was the optimal candidate. Extending the re-
action time and adjusting the relative stoichiometry be-
tween all reagents enabled us to further improve the cata-
lytic performances (rr 4.1, dr 7.0:1, 92% ee; entry 9).16
These mild conditions were subsequently used to delin-
eate the scope of the 3,4-hydroalkylation of branched
dienes by first varying the nature of the electrophilic com-
ponent (Figure 3, A). Isolation of the major diastereoiso-
meric product in pure form was strongly influenced by the
extent of regio- and diastereocontrol. Thus, regioselectivity
ranging from 1.8:1 to 6.8:1 were paralleled by yields varying
between 41% and 71%. Most diastereoselectivity levels were
greater than 5:1. The lowest value was obtained for 1h, a
diene with an ortho-fluoro substituent (dr 2.5:1), while the
highest was obtained for 1d, a diene with an extended 
system (dr 11:1). Modulations of the electronic density of
the 2-(hetero)aryl substituent were well tolerated. Enanti-
oselectivity was very high in all cases (87-94% ee). No re-
action took place when a 2-alkyl substituted diene was
■ CONCLUSION
In addition to stereoselectivity, regioselectivity is often a
major challenge in diene hydrofunctionalization reactions.
In this article, we have reported two complementary re-
giodivergent Ni-catalyzed hydroalkylations of branched
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Figure 3. Scope of the diastereoselective and enantioselective Ni-catalyzed 3,4-hydroalkylation of branched dienes using
imides and a -ketoester. 1a-m (0.2 mmol) and 3a-j (1.2 equiv.). Yield reported for the major diastereoisomer, isolated after
purification by column chromatography. Regioisomeric ratio (rr) expressed as the ratio between 6 and all other isomers
(7+8) as determined by 1H NMR with an internal standard. Enantiomeric excess determined by HPLC using a chiral station-
ary phase. a 48 h. b MeOK (0.2 equiv.) as base.
Figure 4. Post-catalytic derivatizations starting from diastereomerically pure 6aa. Yields of isolated products after purifi-
cation. Diastereomeric ratio determined by 1H NMR with an internal standard. Enantiomeric excess determined by HPLC
using a chiral stationary phase.
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Page 6 of 8
dienes with unstabilized C(sp3) nucleophiles. The first sys-
tem uses an achiral C1-symmetric phosphinooxazoline lig-
and and simple amides which, once deprotonated in situ,
undergo a highly 1,4-selective addition process with excel-
lent stereocontrol of the trisubstituted C=C bond genera-
ted. The method displays a broad scope in both the nucle-
ophilic and electrophilic component, enabling the use of
sensitive functionalities and heteroaromatic-containing
precursors. Switching to imides as carbon nucleophiles fa-
vored formation of the 3,4-addition products. The con-
struction of the two vicinal tertiary stereocenters was
achieved with moderate to high diastereoselectivity and
excellent enantioselectivity by means of a novel chiral
(P,N) ligand. Notably, a wide range of functional groups
were compatible with the mild conditions employed and
several post-catalytic derivatizations were conducted to
measure the synthetic potential of the method. Studies
aiming at understanding the factors that determine reac-
tivity and selectivity for both systems are currently ongo-
ing in our laboratories.19
Saha, B.; RajanBabu, T. V. Nickel(0)-Catalyzed Asymmetric Hy-
drocyanation of 1,3-Dienes. Org. Lett. 2006, 8, 4657. (d) Chen, Q.-
A.; Kim, D. K.; Dong, V. M. Regioselective Hydroacylation of 1,3-
Dienes by Cobalt Catalysis. J. Am. Chem. Soc. 2014, 136, 3772. (e)
Adamson, N. J.; Hull, E.; Malcolmson, S. J. Enantioselective Inter-
molecular Addition of Aliphatic Amines to Acyclic Dienes with a
Pd-PHOX Catalyst. J. Am. Chem. Soc. 2017, 139, 7180. (f) Mifleur,
A.; Mérel, D. S.; Mortreux, A.; Suisse, I.; Capet, F.; Trivelli, X.;
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ASSOCIATED CONTENT
Experimental procedures, characterization of all new com-
pounds and X-ray data for compounds (E)-5da, (2R,3S)-6ab
and (2R,3R,4S)-12 (CCDC 2018944-2018946). This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* clement.mazet@unige.ch
ACKNOWLEDGMENT
This work was supported by the Swiss National Science Foun-
dation (200021_188490) and the University of Geneva. Sté-
phane Rosset (University of Geneva) is acknowledged for
measuring HRMS.
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1
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