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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc
first methanofullerene derivatives of Sc
3
N@C2n (2n
=
68 and 80). Synthesis of the
3
N@D5h-C80
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Authors
Xiao-Yu Lu, * Mei-Lan Hong, Hai-Pin Zhou, Yue Wang, Jin-Yu Wang, Xiu-Tao Ge
Affiliations
a: School of Materials and Chemical Engineering, ChuZhou University, Chu Zhou, 239000, China.
b: School of Chemistry and Chemical Engineering, AnHui University, He Fei, 230601, China.
Acknowledgements
We are very grateful for the support of my PHD supervisor.

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Trisubstituted Olefine Synthesis via NiꢀCatalyzed
Hydroalkylation of internal Alkynes with nonꢀ
activated Alkyl Halides
Cite this: DOI: 10.1039/x0xx00000x
Author Full Name,*a Author Full Name b and Author Full Name c
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
The stereoselective synthesis of triꢀsubstituted alkenes is
challenging. Here, we report a Niꢀcatalyzed regioꢀ and stereoꢀ
selective hydroalkylation of internal alkynes with nonꢀ
activated alkyl halides. This method without using sensitive
organometallic reagents and shows good functional group
compatibility, and enabling efficient synthesis of many triꢀ
substituted olefines from readily available coupling partners.
It also provides
a
straightforward method for the
modification of bioactive organic molecules.
Alkenes are one of the most widely occurring and important
classes of organic compounds, which are widely used in chemical,
1
materials, and pharmaceutical industries. In the past century
numerous methods of synthesis of olefins have been developed, such
as elimination reactions, the reduction of alkynes, Wittigꢀtype
reaction and the Julia–Kocienski. In addition, many significant
transition metal catalytic methods have also been reported, for
example, Heck reactions, the semiꢀhydrogenation of alkynes, olefin
metathesis, and crossꢀcoupling reactions of alkenyl metal reagents or
Scheme 1 Hydroalkylation of Alkynes with Alkyl Electrophiles
2
alkenyl halides.
Recently, intermolecular hydrocarbonation
The triꢀsubstituted alkenes have a high demand and the efficient
regioꢀ and stereoselective synthesis of triꢀsubstituted alkenes bearing
three different carbonꢀlinked groups presents a particular challenge
in modern organic synthesis. Over the past decades, transition metal
catalyzed crossꢀcoupling reactions of triꢀsubstituted alkenyl halides
or triꢀsubstituted alkenyl metal reagents have regarded as a versatile
reactions between alkynes and electrophilic reagents are considered
as one of the most attractive methods for the synthesis of olefins.
Because this method can synthesize a diverse array of substituted
olefins by controlling the regioꢀ and stereoꢀselectivity. However,
most of the hydrocarbonation reactions of alkynes are πꢀ
3ꢀ8
electrophiles.
Hydrocarbonation crossꢀcoupling reactions of
14
and straightforward method for their synthesis. These coupling
partners need to have the corresponding stereoꢀconfigurations.
However, stereoselective synthesis of these coupling partners is
alkynes with alkyl electrophiles are less. In 2015, Lalic group
reported copperꢀcatalyzed hydroalkylation of terminal alkynes with
9
alkyl triflates (Scheme 1a). Hu group reported the ironꢀcatalyzed
15
difficult. Here, we report the first example of nickelꢀcatalyzed
regioꢀ and stereoꢀselective hydroalkylation of nonꢀfunctionalized
internal alkynes with nonꢀactivated alkyl halides (Scheme 1e). Not
only arylꢀalkyl substituted alkynes, but also alkylꢀalkyl substituted
alkynes, can be successfully transformed into the desired products.
This method without using sensitive organometallic reagents and
both of the starting materials are readily available, thus enabling
efficient synthesis of many triꢀsubstituted olefines. Due to the mild
reductive coupling of terminal arylalkynes with alkyl halides
10
(
Scheme 1b). In 2016, Fu realized Niꢀcatalyzed Markovnikov
11
hydroalkylation of alkynes with alkyl halides (Scheme 1c).
Nishikata group reported Cuꢀcatalyzed tandem reactions enable
12
transꢀ and cisꢀhydroꢀtertiaryꢀalkylations (Scheme 1d). However,
these elegant works can only realize terminal alkynes
13
hydroalkylation reaction, which afford diꢀsubstituted olefins.
This journal is © The Royal Society of Chemistry 2012
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8CC01577E
DOI: 10.1039Jo/Curnal Name
conditions, this new approach shows good functional group >30:1). Finally, control experiments indicated that the reaction
compatibility. Also, it provides a method to modification of complex almost shut down without using nickel source (entry 15).
organic molecules.
a,b
Table 2 Scope of crossꢀcouping .
Table 1 Optimization of the reaction conditions.
.
1
0% NiBr2 diglyme
1
2 mol% dtbbpy
I
2
.5 eq K2CO3
Ph
+
Ph
3
eq DEMS
0
.7 ml DMAC
3
0 oC, 10 h
Ph
Ph
Ph
3c, 72%
3a, 81%
3b, 72%
F
Ph
O
Ph
PMP
Ph
CF3
3
d, 73%
Ph
3f, 43%
3i, 75%
3
e, 66%
NCbz
NTs
N
Ph
Ph
Ph
Ph
3
g, 77%
NBz
Ent
ry
1
2
3
4
5
6
7
Cat.
(10 %)
Ligand
(12 %)
dtbbpy
L1
L2
L3
L4
L5
L6
L7
L8
L9
dtbbpy
dtbbpy
dtbbpy
dtbbpy
Base
(2.5 eq)
Cs CO
Solvent
(0.6 ml)
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
Yield%
3h, 61%
a
Ph
N
3a
32
5
trace
4
8
7
5
4
Ph
N
EtOOC
NiBr ·diglyme
2
2
3
3
3
3
3
3
3
3
3
3
n-C6H13
3l, 40%
NiBr ·diglyme
Cs CO
n-C6H13
3k
, 65%
2
2
NC
NiBr ·diglyme
Cs CO
2
2
3j,63%
NiBr ·diglyme
Cs CO
2
2
NTs
O
Ph
Ph
N
NiBr ·diglyme
Cs CO
2
2
N
NiBr ·diglyme
Cs CO
Ph
2
2
n-C4H9
3n, 67%
n-C6H13
Ph
NiBr ·diglyme
Cs CO
F3C
2
2
8
9
NiBr ·diglyme
Cs CO
3o, 74%
2
2
3m, 56%
NiBr ·diglyme
Cs CO
trace
trace
15
38
50
Bn
2
2
PMP
1
1
1
1
1
0
1
2
3
4
NiBr ·diglyme
Cs CO
Ph
O
N
2
2
Ph
Ph
NiBr ·diglyme
NaOAc
CsF
LiOMe
O
2
NiBr ·diglyme
2
3p, 44%
3r, X = Br 68%
3
q, 58%
NiBr ·diglyme
2
Ts
Ts
Ts
c
N
N
N
NiBr ·diglyme
K CO
85(81)
2
2
3
b
1
5
ꢀ
dtbbpy
K
2
CO
3
trace
a
o
n-C H
n-C5H9
3t, 55%
6
13
n-C5H9
The reaction was carried out at 30 C for 10 h under Ar atmosphere. 3 equiv
diethoxymethylsilane as a hydride donor. Yields determined by GC analysis use
N
Cl
b
3s, 69%
3u, 61%
biphenyl as internal standard (average of two GC runs). Without NiBr
2
·diglyme.
c
Yield of isolated product. DMAC = N,NꢀDimethylacetamide.
Ts
N
NBz
We began our study by choosing commercially available 1ꢀ
Phenylꢀ1ꢀpropyne (1a) and iodocyclohexane (2a) as the model
substrates (Table 1). On the basis of previous work on Niꢀcatalyzed
hydroalkylation of alkynes with alkyl halides, we first examined
N
Ph
3v,62%
3w
,
36%
3x
, 51%
11
a
o
previously reported catalytic conditions for the reaction.
The reactions were conducted on a 0.2 mmol scale at 30 C. Yields of
isolated products after 10 h. Bz = benzoyl, DEMS = diethoxymethylsilane. Ts
Gratifyingly, we observed the product in moderate yield (entry 1).
The results showed that the previously conditions were not suitable.
Next we examined other bidentate nitrogen ligands, such as
phenanthroline family ligands (L1ꢀL2) and pyrox family ligands
=
4ꢀtoluenesulfonyl.
With the optimized conditions in hand, we explored the
scope of hydroalkylation reaction of internal alkynes. As shown
in Table 2, our protocol exhibited an excellent regioꢀ and
stereoꢀselective (product ratio >25:1, determined by GC and
(L3ꢀL4). Disappointingly, these ligands are useless to increase the
yield. Then we used triꢀnitrogen ligands instead of the bidentate
nitrogen ligands (L5ꢀL7 ). However, the desired product remained
very bad. We also tested some phosphine ligands (L8ꢀL9).
Disappointingly, it did not afford any desired product. Following,
we have to screen a series of bases (entry 11ꢀ14). Gratifyingly, when
use K CO as the base, we obtained the optimal reaction conditions
1
HNMR). The coupling partners with different functional
groups can be successfully converted into the desired products
with modest to excellent yields. Both cyclic and acyclic alkyl
halides can be transformed. Due to the mild reaction conditions,
the hydroalkylation of internal alkynes is compatible with lots
of synthetically relevant functional groups, such as
2
3
(85% GC yield and 81% isolated yield, entry 14, product ratio
2
| J. Name., 2012, 00, 1-3
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COMMUN AT77ION
IC01
trifluoromethyl (3e), amine (3g), fluoride (3f), amide (3h, 3j),
In order to explore the reaction mechanism, several experiments
and sulfonamide (3i). Some baseꢀsensitive functional groups were conducted. First, when we added 1.0 equiv. 2,2,6,6ꢀ
such as ester (3k) and nitrile (3l) groups can be well tolerated. tetramethylpiperidineoxy (TEMPO), the reaction was completely
Even more active groups, such as ketone (3m), were inhibited. Nest, we tested an experiment between 2da with phenylꢀ1ꢀ
compatible in the reaction. The success of the reaction inspired propyne (Eq (2)). A mixture of linear coupling product (3da) and
us to apply them to the crossꢀcoupling of primary alkyl halides. ringꢀcyclized product (4da) were obtained. The above results were
1
0, 16
For example 3p, it can straightforward use of this kind of consistent with a radicalꢀtype mechanism of the alkyl halides.
compound. Activated secondary αꢀbromo amide (3r) war also a Nonetheless, the detailed reaction process was not clear at now. Our
good substrate except alkyl iodides. Furthermore, heterocycles, preliminary view is that the reaction goes through the L NiH
n
for example, pyrrolidine (3i), piperidine (3j), naphthaline (3s), intermediate and then the intermediate reacts with internal alkynes
and pyridine (3t) are tolerated in either of the two coupling by cis addition. The detailed mechanism is under study.
substrates. Aryl–Cl bonds (3u) did not hinder the reaction.
Next, we examined whether lower activity alkylꢀalkyl
substituted alkynes could involve in the reaction. Fortunately,
the present conditions were applicative for these substrates.
Alkyl halides bearing sulfonamide (3v), amide (3w), and amine
(
3x) groups reacted under these conditions to afford the desired
products in moderate yields.
In summary, for the first time, we have developed a nickelꢀ
catalyzed regioꢀ and stereoꢀselective hydroalkylation of nonꢀ
functionalized internal alkynes with nonꢀactivated alkyl halides. This
method without using sensitive organometallic reagents and both of
the starting materials are readily available, thus enabling efficient
synthesis of many of the single configuration triꢀsubstituted olefines.
Due to the mild conditions, this new approach shows good
functional group compatibility. Not only arylꢀalkyl substituted
alkynes, but also alkylꢀalkyl substituted alkynes, can be successfully
converted into the desired products.
Notes and references
Scheme 2. Modification of complex molecules.
†
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
We next demonstrated the efficient of this regioꢀ and stereoꢀ DOI: 10.1039/b000000x/.
selective hydroalkylation of internal alkynes for the lateꢀstage
modification of complex active molecules (Scheme 2). Modification
of fructose derivative (1aa), which was of great interest in life
sciences, with 1ba resulted in the formation of 1ca in moderate yield
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