Formation of C(sp3)–C(sp3) Bonds through Nickel-Catalyzed Decarboxylative Olefin Hydroalkylation Reactions

Article abstract of DOI:10.1002/chem.201602486

Olefins and carboxylic acids are among the most important feedstock compounds. They are commonly found in natural products and drug molecules. We report a new reaction of nickel-catalyzed decarboxylative olefin hydroalkylation, which provides a novel practical strategy for the construction of C(sp³)?C(sp³) bonds. This reaction can tolerate a variety of synthetically relevant functional groups and shows good chemo- and regioselectivity. It enables cross-coupling of complex organic molecules containing olefin groups and carboxylic acid groups in a convergent fashion.

Full text of DOI:10.1002/chem.201602486

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Accepted Article
Title: Formation of C(sp3)-C(sp3) Bonds through Nickel-catalyzed Decarboxylative
Olefin Hydroalkylation Reaction
Authors: Lei Liu; Xi Lu; Bin Xiao; Yao Fu
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Formation of C(sp3)-C(sp3) Bonds through Nickel-catalyzed
Decarboxylative Olefin Hydroalkylation Reaction
Xi Lu,[a, b] Bin Xiao,[a] Lei Liu,[b] Yao Fu*[a]
Abstract: Olefins and carboxylic acids are among the most
important feedstock compounds. They are commonly found in
natural products and drug molecules. We report a new reaction of
nickel-catalyzed decarboxylative olefin hydroalkylation, which
provides a novel practical strategy for the construction of C(sp3)-
C(sp3) bonds. This reaction can tolerate a variety of synthetically
relevant functional groups and shows good chemo- and regio-
selectivity. It enables cross-coupling of complex organic molecules
are poorly reactive either as nucleophiles or electrophiles.11
Very recently, we discovered that Ni can catalyze the
hydrocarbonation of un-activated olefins with alkyl halides
(Figure 2A).12 This surprising finding prompted us to develop
practically useful processes that could use alternative reagents
to complement the use of alkyl halides. We therefore aimed to
find conditions that allowed the hydrocarbonation of olefins
with aliphatic carboxylic acids. Recent advances have shown
that decarboxylative cross-coupling of aliphatic carboxylic
acids and derivatives can be accomplished by using
photocatalysts.13 Thus we tested the decarboxylative olefin
hydroalkylation process using the dual catalyst system of Ni
and photocatalyst (Figure 2B). We were delighted to observe
the desired product, but to our great surprise, control
experiments revealed that the Ni-only system can already
catalyze decarboxylative olefin hydroalkylation (Figure 2C).
containing olefin groups and carboxylic acid groups in
convergent fashion.
a
Carbon-carbon bond formation reactions are among the most
important transformations in organic synthesis because they
afford basic paradigms in the retrosynthetic analysis towards
complex molecules.1 As an increasingly popular strategy,
transition metal-catalyzed C(sp3)-C(sp3) cross-coupling
reactions enabled convergent synthesis of complex
molecules.2 For a long time, the use of alkyl organometallic
reagents and alkyl halides dominates the field of C(sp3)-C(sp3)
cross-coupling (Figure 1A).3-8 New C(sp3)-C(sp3) cross-
coupling reactions benefiting from readily available and stable
starting materials, such as olefins9 and carboxylic acids10,
present a continuing opportunity as well as challenge to
modern synthetic organic chemistry (Figure 1B).
a
Figure 2. Olefin hydroalkylation reactions.
Ru(bpy)3(PF6)2. DEMS =
diethoxymethylsilane. bpy = 2,2'-bipyridine. dtbpy = 4,4'-di-tert-butyl-2,2'-
bipyridine. NHPI = N-hydroxyphthalimide. DMAc = dimethylacetamide.
Figure 1. Strategies for alkyl-alkyl cross-coupling. TM = transition-metal.
On the basis of the above finding, we now report a new
reaction of Ni-catalyzed decarboxylative olefin hydroalkylation.
This reaction adds an important example to the toolbox of Ni-
catalyzed C(sp3)-C(sp3) cross-coupling reactions. As shown in
Figure 1C, our model reaction involved an NHPI ester 1 and
un-activated olefin 2.14 We used NiII salt as catalyst and dtbpy
as ligand according to our previous work. A systematic
screening of different bases and silanes was then carried out
to optimize the reaction performance (Table 1). Under the
Simple un-activated olefins are important feedstock
compounds in chemical industry, but these compounds usually
[a]
[b]
Dr. X. Lu, Prof. Dr. B. Xiao, Prof. Dr. Y. Fu
Hefei National Laboratory for Physical Sciences at the Microscale,
iChEM, CAS Key Laboratory of Urban Pollutant Conversion, Anhui
Province Key Laboratory of Biomass Clean Energy, University of
Science and Technology of China, Hefei 230026, China
Email: fuyao@ustc.edu.cn
.
optimal conditions (base = Mg(OAc)2 4H2O, silane = PMHS),
the GC yield was found to be 81% (with an isolated yield of
76%).
Prof. Dr. L. Liu
The scope of the Ni-catalyzed decarboxylative olefin
hydroalkylation is shown in Table 2. A variety of un-activated
olefins and aliphatic acid NIHP-esters can be successfully
transformed to the desired products with modest to good
yields within a short time (ca. 2-3 hours). Importantly, both
Department of Chemistry, Tsinghua University, Beijing 100084,
China
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.

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Table 2. Substrate scope of the cross-coupling of N-hydroxyphthalimide
primary and secondary aliphatic acid esters can be converted.
The reaction can also be applied to both cyclic (3) and acyclic
(4) aliphatic acid esters. With respect to cyclic substrates, the
size of the rings (5-7) posed no problem for the transformation.
Due to its mild reaction conditions, the decarboxylative olefin
hydroalkylation process showed excellent compatibility with a
variety of synthetically relevant functional groups such as ether
(8, 9), sulfonamide (8, 9), aryl fluoride (8), aryl chloride (9), aryl
bromide (10), ester (11, 12) and carbamate (12). Base-
sensitive groups such as nitrile (13), ketone (14) and silicon
ether (15) can be well tolerated. Heterocycles such as pyran
(16), furan (17), thiophene (18), pyrrole (19) and pyridine (20)
also survived in the reaction.
esters with alkenes. a
Table 1. Optimization of the reaction conditions. a
a The reactions were conducted in 0.2 mmol scale, GC yield. 1 eq. 1, 2.5 eq.
2, 10% Ni(PPh3)2Cl2, 15% dtbpy, 3 eq. base, 200 L (for liquid) or 200 mg
a
The reactions were conducted in 0.2 mmol scale, isolated yield. 1 eq.
(for solid) silane,
1
mL DMAc, 40 oC,
3
hours. PMHS
=
NHPI-ester, 2.5 eq. alkene, 10% Ni(PPh3)2Cl2, 15% dtbpy,
3 eq.
Mg(OAc)2 4H2O, 200 uL PMHS, 1 mL DMAc, 40 oC, 2-3 hours. Ts = tosyl.
.
Poly(methylhydrosiloxane).
Boc = t-butyloxycarbonyl. BPin = pinacol boronate ester. Bz = benzoyl.
Regarding to chemo-selectivity, a terminal olefin 21 afforded
the desired product without any reaction at the internal alkene
group. An arylboronate ester 22 selectively underwent the Ni-
catalyzed C(sp3)-C(sp3) cross-coupling reaction with its
carbon-boron bond intact affording further functionalization
possibility.15 Furthermore, the tolerance of epoxide16 (23) and
aldehyde (24) groups demonstrated that, this reaction offers
important advantages over the previous transition metal-
catalyzed C(sp3)-C(sp3) cross-coupling reactions using alkyl
organometallic reagents. Finally, the decarboxylative olefin
hydroalkylation reaction can be successfully conducted in the
presence of unprotected phenol (25) or alcohol (26) groups.
In a scale-up reaction of the NIPH ester of dehydrocholic
acid (27) containing three base-sensitive ketone groups, we
obtained the olefin hydroalkylation product 29 successfully
with a satisfactory yield of 55% (Scheme 1). This gram-scale
reaction highlights the practicality of the new Ni-catalyzed
C(sp3)-C(sp3) cross-coupling reaction.
Scheme 1. Gram scale reaction. 10% Ni(PPh3)2Cl2, 15% dtbpy, 3 eq.
.
Mg(OAc)2 4H2O, 2 mL PMHS, 10 mL DMAc, 40 oC, 3 hours.
To further demonstrate the synthetic utility of the new
decarboxylative olefin hydroalkylation reaction, we explored its

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application as an efficient tool for the modification of complex
molecules in a convergent fashion (Scheme 2). The coupling
of the NIPH-ester of lithocholic acid (30) with a cinchonidine
derivative (31) resulted in the formation of 32 with high chemo-
selectivity and good yield 63%. In this transformation, the
toleration of a basic amine, quinoline, and a free alcohol group
highlights the excellent functional group compatibility.
functional group tolerance regarding both of the coupling
partners. Furthermore, this reaction provides efficient access
for the convergent modification of complex organic molecules
containing olefin groups and carboxylic acid groups. Our next
challenge was the extension of the reaction to tertiary
carboxylic acid derivatives and internal olefins.
Acknowledgements
This study was supported by the National Basic Research
Program of China (973 program; No. 2012CB215306,
2013CB932800), NSFC (21325208, 21361140372, 21532004,
21572212, 21472181), IPDFHCPST (2014FXCX006), CAS
(KFJ-EW-STS-051), FRFCU and PCSIRT.
Keywords: Nickel
•
C-C bond formation
•
olefin
hydroalkylation • decarboxylative cross-coupling
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COMMUNICATION
We report a novel Nickel-
catalyzed decarboxylative
olefin hydroalkylation for
the construction of C(sp3)-
C(sp3) bonds.
Xi Lu, Bin Xiao, Lei Liu, Yao
Fu*
Page No. – Page No.
Formation of C(sp3)-C(sp3)
Bonds
through
Nickel-
catalyzed Decarboxylative
Olefin
Hydroalkylation
Reaction