Ni-catalysed reductive arylalkylation of unactivated alkenes

Article abstract of DOI:10.1039/c8sc04279a

In this protocol Ni-catalysed reductive arylalkylation of unactivated alkenes tethered to aryl bromides with primary alkyl bromides has been accomplished, providing a new path to construct diverse benzene-fused carbo- and heterocyclic cores including inda

Full text of DOI:10.1039/c8sc04279a

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DOI: 10.1039/C8SC04279A
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Ni-Catalysed Reductive Arylalkylation of Unactivated Alkenes†
a
a
Youxiang Jin, and Chuan Wang *
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
In this protocol a Ni-catalysed reductive arylalkylation of a two-component reaction to prepare benzene-fused cyclic
unactivated alkenes tethered to aryl bromides with primary alkyl compounds is still elusive. In this protocol we report a Ni-
bromides has been accomplished, providing a new entry to catalyzed reductive arylalkylation of tethered olefins with
construct diverse benzene-fused carbo- and heterocyclic cores various primary alkyl bromides providing an entry to benzene-
including indanes, tetrahydroisoquinolines, indolines and fused cyclic compounds, such as indanes, tetrahydro-
isochromanes. Notably, this new method circumvents the isoquinolines, indolines and isochromans, which are
pregeneration of organometallics and demonstrates high tolerance characteristic motifs in numerous biologically active
6
of a wide range of functional groups. The preliminary mechanistic compounds (Scheme 1B).
investigations suggest a reaction pathway with an-intermediate-
reduction.
A) Previous work:
R1
R2
R2
M
Ni- or Cu-cat.
Redox-Neutral
R3
3
+
R -X
Introduction
Y
Y
In recent years transition-metal catalyzed dicarbo-
functionalisation of unactivated alkenes has gained increasing
interest in the organic community, because simple olefin
precursors can be converted into structurally more complex
molecules in one single step with formation of two C-C bonds.
Significant progress has been achieved in this area using both
R1
M: BPin, 9-BBN, ZnX; X: Br or I;
R = Alkyl or Ar;
Y: CH , O, NBn.
3
2
B) Our work:
R2
R1
R4
R3
R3
redox-neutral1 and reductive strategy . For instance, aryl
-3
4,5
Br
R1
Ni-cat.
Reductive
organometallics containing a pendant olefinic unit were
successfully reacted with diverse alkyl or aryl halides as
electrophiles under redox-neutral conditions, to construct a
series of carbo- and heterocyclic cores, such indanes,
R4
+
Br
X
n
X
n
R2
X: CH , O, NR;
2
b-d
n= 0 or 1.
dihydrobenzofurans and indolines (Scheme 1A).2 However,
the use of pregenerated organometallics is less desirable from
the viewpoint of step economy and functional group tolerance.
In contrast, through reductive dicarbofunctionalisation two
different alkyl or aryl electrophiles can be directly installed
across the C-C double bonds under mild reaction conditions.
Although a few examples of reductive dicarbofunctionalisation
have been reported,4 application of this reductive strategy in
Scheme 1. Redox-neutral (A) and reductive (B) arylalkylation of tethered
alkenes for synthesis of benzene-fused cyclic compounds.
Results and Discussion
For optimization of the reaction conditions, we used the
bromobenzene 1a tethering a terminal olefinic unit and 4-
bromobutyl acetate (2a) as standard substrates (Table 1).
Systematic screening of the reaction parameters provided the
optimum conditions using NiBr as catalyst, L1 as ligand, DMA
2
as solvent and Zn as reducing agent at 55 ︒ C (entry 1).
Generally, all the reactions delivered a dimer compound 3a-1 in
,5
a. National Laboratory for Physical Science at the Microscale, Department of
Chemistry, Center for Excellence in Molecular Synthesis, Hefei University of
Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 20237 (P. R.
China). E-mail: chuanw@ustc.edu.cn
†Electronic Supplementary Information (ESI) available: Experimental procedure,
spectra data, NMR-data, and HPLC-data, See DOI: 10.1039/x0xx00000x
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a 1:1 diastereomeric ratio as the major by-product and its yields and tertiary bromides, which failed to yield the arylalkylation
View Article Online
DOI: 10.1039/C8SC04279A
are aslo exhibited in the table (entries 2-23). Furthermore, the products.
formation of a slight amount of reductive Heck product 3a-2,
debromination product 3a-3 and cross-coupling product 3a-4
was also observed. In comparison, replacing either or both of
Table 1. Variation of the reaction parameters for the Ni-catalysed reductive
arylalkylation reaction
a
these bromide precursors by their iodo-analogues gave rise to
increasing amount of the reductive Heck product 3a-2 in the
products mixtures (entries 2-4). The use of other pyridine-based
ligands L2-L6 resulted in lower reaction efficiency (entries 5-9).
Ni-salts screening indicated that the studied reactions could be
promoted by both Ni(II)- and Ni(0)-catalysts (entries 10-13).
Performing the reaction in other polar solvents including DMF
and NMP led to decreased yields (entries 14 and 15), whereas
the reaction was completely shut down using THF or MeCN as
solvent (entry 16 and 17). The reaction employing Mn instead
of Zn as reducing agent yielded the product in a diminished yield
Me
OAc
Ni-salt (15 mol%)
ligand (15 mol%)
Br
Br
OAc
+
4
4
Zn (4 equiv)
DMA
55 °C, 10 h
Me
1a
2a
3a
Major by-product:
Me
Me
3a-1
(entry 18). In addition, the temperature impact on this reaction
Minor by-products:
was also investigated and both raising and lowering the reaction
temperature had detrimental effect on the reaction efficiency
Me
Me
H
(
entries 19 and 20). Moreover, reducing the amount of alkyl
bromide 4, NiBr or Zn-powder all resulted in lower yields
entries 21-23).
OAc
4
2
(
Me
Me
After establishing the best reaction conditions, we started to
evaluate the substrate spectrum of this Ni-catalyzed reductive
arylalkylation reaction by varying the structure of both pendant
alkenes 1 and alkyl bromides 2 (Table 2). First, we studied the
influence of the alkene substitution pattern on the outcome of
this reaction. In the case of disubstituted terminal olefins all the
reactions provided the products 3a-e in moderately good yields.
Remarkably, the reactions employing 1,1,2-trisubstituted
alkenes also proceeded smoothly under the optimum reaction
conditions yielding the products 3f and 3g in excellent
diastereoselectivities, although the E/Z ratios of the alkene
precursors are nearly 1:1. The high diastereocontrol indicates
that this Ni-catalyzed reaction is probably not initiated by the
radical addition of alkyl group to the C-C double bond. When
3a-2
3a-3
3a-4
CN
N
NH
N
N
NH2
NH2
N
N
L1
L2
HN
L3
N
N
N
N
N
N
N
L4
L5
L6
Entry Variation from the optimum
conditions
Yield 3a
Yield :3a-1
b
(%)c
9
(%)
69 (67 )
1
,2-disubstituted and monosubstituted alkenes were as used
d
1
2
3
4
none
substrates, no desired products were delivered due to the high
tendency to undergo Heck reaction. Next, the examination of
substituent effect on the phenyl ring was undertaken. To our
delight, all the substrates bearing electron-withdrawing or
donating groups turned out to be suitable substrates providing
the corresponding products 3h-m, 3w and 3ae in moderate to
good yields. Furthermore, our method is not limited to
synthesis of indane derivatives. A series of indolines 3n-p, 3ah
and tetrahydroisoquinolines 3q-t and an isochromane 3u were
also successfully prepared through this Ni-catalysed reaction.
Subsequently, diverse primary alkyl bromides were reacted
with various pendant olefins. Of note is that this Ni-catalysed
reaction demonstrates high compatibility of a wide range of
functional moieties including alcohol (3y), boronate (3z), acetal
e
Iodo-analogue of 1a used
Iodo-analogue of 2a used
32
10
17
19 (8 )
e
18 (31 )
e
Both Iodo-analogues of 1a and
a used
10 (30 )
2
5
6
7
8
9
1
1
1
L2 instead of L1
L3 instead of L1
L4 instead of L1
L5 instead of L1
L6 instead of L1
NiI
Ni(OTf)
NiBr
30
45
54
32
0
61
32
63
63
43
68
0
49
2
13
50
0
0
1
2
2
instead of NiBr
2
8
4
8
7
3
8
0
0
2
instead of NiBr
2
2
•glyme instead of NiBr
2
13
Ni(COD) instead of NiBr
2
2
1
1
1
1
1
4
5
6
7
8
DMF instead of DMA
NMP
THF instead of DMA
MeCN instead of DMA
Mn instead of Zn
75︒C instead of 55︒C
35︒C instead of 55︒C
1.2 equiv 2a used
0
(
3aa), imide (3ac and 3ae), nitrile (3ad), ester (3af and 3ah),
aldehyde (3ag) and ketone (3ai). Moreover, the reaction using
a and 2a was performed on a one-gram scale furnishing the
51
62
27
50
63
50
17
19
8
2
2
2
2
2
0
1
2
3
1
13
13
7
product 3a still in a 65 % yield with 5 mol% catalyst loading. A
limitation of this method was observed in the case of secondary
10 mol% NiBr
2 equiv Zn used
2
used
2
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a
b
c
Unless otherwise specified, reactions were performed on a 0.2 mmol scale
Ratios determined by gas chromatography. GC-Yields using n-dodecane as
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d e
of aryl bromide 1a with 2 equiv bromobutyl acetate (2a), 15 mol% NiBr , 15 an internal standard. Yield of the isolated product. Yield of 3a-2.
mol% ligand L1 and 4 equiv Zn as reductant in 0.5 mL DMA at 55︒C for 10 h.
2
DOI: 10.1039/C8SC04279A
Table 2. Evaluation of the substrate scope the Ni-catalysed reductive arylalkylation reaction.a,b
R2
R1
R4
m
R3
CN
N
NiBr2 (15 mol%)
Br
R3
R1
R4
ligand L1 (15 mol%)
N
+
Br
NH2
X
m
Zn (4 equiv)
X
n
DMA, 55 °C, 10 h
R2
n
1
2
3
L1
R2
R1
1
67 % (65c)
61 %
Me
OAc
3a R = Me,
2
R3
OAc
3
Me
*
OAc
3f R = Me, 58 %
7
4
3h R = 4-Cl,
65 %
1
3
3
3
3
b R = Et,
*
d
dr> 95:5
ie R = 5-MeO, 52 %
3
3
4
1
6
4
c R = n-Pr, 55 %
4
2
3
g R = Et, 50 %
3je R = 5-F,
3
53 %
61 %
58 %
1
d R = i-Pr, 46 %
dr> 95:5d
5
3
3k
R = 5-CF ,
1
3
e R = c-Hex, 58 %
3
3l R = 6-F,
OAc
Me
OAc
3qe R= Me,
65 %
70 %
51 %
61 %
Me
OAc
3ne R= Me,
3oe R= 2-Methyl allyl,
R= Bn;
61 %
Me
4
57 %
50 %
4
3r R= 2-Methyl allyl,
3s R= Bn,
4
3p
N
R
N
3t
R= Ts,
R
e
3
m , 40 %
F
Et
Me
Ph
Me
Me
R4
Me
Me
4
n-Oct
n-Bu
5
3y R = OH,
51 %
4
4
3
z R = BPin, 42 %
3
O
MeO
3u, 62 %
3v, 73 %
3w, 65 %
3x, 71 %, dr= 50:50d
Me
CO2Et
O
Me
NPhth
R4
Me
Me
4
5
O
3ab R = OMe,
57 %
50 %
60 %
EtO C
2
4
3
3
ac R = NPhth,
3
4
4
3
ad R = CN,
3af 63 %
3aa, 67 %
3ae, 57 %
O
Me
OHC
H
O
Me
O
Me
H
H
O
Me
6
O
5
Me
Me
N
3
ai, 55 %, dr= 50:50f
Me 3ah, 63 %, dr= 50:50f
3ag, 53 %
a
Unless otherwise specified, reactions were performed on a 0.4 mmol scale of aryl bromides 1 with 2 equiv alkyl bromides 2, 15 mol% NiBr
2
, 15 mol% ligand
b
c
L1 and 4 equiv Zn as reductant in 1.0 mL DMA at 55︒C for 10 h. Yields of the isolated products. Reaction was performed on a 1 g scale using 5 mol% NiBr
and 5 mol% ligand L1 at 65︒C for 12 h. Determined by C-NMR-spectroscopy. Reaction were performed at 70︒C. Determined by HPLC-analysis.
2
d
13
e
f
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DOI: 10.1039/C8SC04279A
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H O
Consequently, the Negishi coupling reaction pathway is less
likely for the studied reaction.
Br
2
DMA, 55 °C
0 h
+
Zn
Zn
X
1
Me
Me
1
a
Me
OAc
4
H O
2
DMA, 55 °C
0 h
Br
OAc
+
X
Me
OAc
3
aj, 32 %
NiBr2 (15 mol%)
L1 (15 mol%)
1
Br
4
E/Z= 73:27
+
2a
+
2a
Zn (4 equiv)
DMA
Scheme 2. Stoichiometric reactions of bromides 1a and 2a with Zn-powder
Me
Me
OAc
4
55 °C, 10 h
Ni(COD)2
A)
(1 equiv)
L1
3aj', 0 %
Me
Br
H2O
(1 equiv)
Scheme 4. Radical clock experiment for the Ni-catalyzed reductive
arylalkylation.
DMA
5 °C, 10 h
Me
3a-1, 42 %
5
Me
3 % recovered
1
a
Me
4
Me
Me
OAc
NiBr2 (15 mol%)
L7 (15 mol%)
Br
Br
OAc
+
4
*
Me
4
Zn (4 equiv)
DMA
3a-3, 6 %
3a-2, 9 %
55 °C, 10 h
Me
1a
2a
3a
Ni(COD)2
(1 equiv)
L1
B)
60 %, 58 %ee
Me
OAc
Br
O
N
2a (1 equiv)
(1 equiv)
4
N
iPr
DMA
55 °C, 10 h
L7
Me
1a
3a
trace
Scheme 5. Ni-catalysed arylalkylation employing a chiral oxazoline ligand.
Ni(COD)2
(1equiv)
L1
C)
Me
OAc
Br
2a (1 equiv)
(1 equiv)
4
Next, we carried out a stoichiometric reaction between
Ni(COD) and the aryl bromide 1a. After 10 h the reaction was
2
Zn ( 4 equiv)
DMA
Me
1a
quenched with water and it turned out that nearly half of the
starting material was recovered and the major product was the
dimer 3a-1 (Scheme 3A). If the alkyl bromide 2a was added to
the reaction mixture instead of water, only trace of the desired
product 3a was formed in this case (Scheme 3B). In contrast, the
5
5 °C, 2 h
3a
30 %
Me
Me
Me
Me
sequential stoichiometric reactions of Ni(COD)
in the presence of Zn furnished the product 3a in a 30 % yield
Scheme 3C). These results suggest that Zn is required in a step
2
with 1a and 2a
3
a-1, 31 %
3a-2, 27 %
(
Scheme 3. Stoichiometric control experiments for the Ni-catalyzed reductive
of an-intermediate-reduction instead of serving as a terminal
reductant in this Ni-catalysed reaction, which is likely initiated
by the oxidative addition of aryl bromide to a Ni(0)-species
followed by an intramolecular migratory insertion. A similar
process was reported very recently by Kong et al. in a Ni-
arylalkylation.
A series of control experiments were carried out to explore
the mechanism of this Ni-catalyzed ring opening reaction. First,
we reacted Zn-powder with both bromide precursors under the
standard reaction conditions and the results indicated that no
organozincs were formed in the reaction mixture (Scheme 2).
5
catalysed reductive diarylation of activated olefins.
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R2
R1
R4
m
a chiral oxazoline ligand (Scheme 5). In this case the product 3a
was furnished in a moderate enantioselectivity. This report
View Article Online
DOI: 10.1039/C8SC04279A
R3
R3
Br
clearly excludes the possibility of a radical-mediated cyclisation,
which is supposed to provide the product as a racemic mixture.
Based on the aforementioned experimental results we
proposed the following plausible mechanism for this Ni-
catalyzed reaction (Scheme 6). Initially, under the reductive
reaction conditions a Ni(0)-species I is generated, which
undergoes oxidative addition with aryl bromides 1, to afford a
Ni(II) complex II. Next, the ring closure is accomplished via an
intramolecular non-radical migratory insertion. The generated
Ni(II) species III stays in equilibrium with an alkyl radical IV and
Ni(I)LnBr before the Zn-mediated reduction to the Ni(I) species
V. The subsequent oxidative addition of alkyl bromides 2
involving the formation of a cage VI and the following
recombination provides a Ni(III) intermediate VII. Finally, the
reductive elimination on the Ni(III) complex VII furnishes the
products 3 and the Ni(I) species VIII, which is subsequently
reduced to the Ni(0)-species I for the next catalytic cycle.
R1
1
/2 Zn 1/2 ZnBr2
X
X
n
3
Ni(I)BrLn
Ni(0)Ln
n
1
R2
VIII
I
R2
R1
R3
Ni(III)LnBr
Ni(II)LnBr
X
R1
m
R4
X
n
II
n
R2
VII
R2
R1
R2
R1
Ni(II)LnBr
Ni(II)LnBr
R4
X
X
n III
m
R2
n
1/2 Zn
/2 ZnBr2
VI
R1
Ni(I)Ln
1
R4
Br
X
m
Conclusions
2
n
R2
V
In conclusion, we have developed a Ni-catalysed reductive
arylalkylation of unactivated alkenes tethered to aryl bromides
with an array of primary alkyl bromides, providing a new entry
to synthesize benzene-fused cyclic compounds such as indanes,
tetrahydroisoquinolines, indolines and isochromanes with an
all-carbon-stereogenic center. This new method is distinguished
R1
Ni(I)LnBr +
X
n
IV
Scheme 6. Proposed mechanism of the Ni-catalyzed reductive arylalkylation. by avoidance of the use of pregenerated organometallics, high
tolerance of a broad range of functional moieties and base-free
reaction conditions. The preliminary mechanistic studies
Subsequently, we conducted the reaction using TEMPO as a
radical scavenger and in this case the reaction was completely
shut down revealing that a radical species might be involved in
the key step of this reaction. It is not surprising since alkyl
bromide can easily form radicals in Ni-catalyzed reductive
indicate that this Ni-catalysed reaction proceeds in a reaction
pathway with an-intermediate-reduction. Further investiga-
tions into the asymmetric version of this reaction are in progress
and will be published in due course.
coupling reactions according to the numerous reports in the
literature.7 However, it is unknown whether the migratory Conflicts of interest
,8
insertion of Ni-Ar into the C-C double bond proceeds in a radical
There is no conflict to declare.
pathway or not under the reductive conditions. In order to gain
more insights into the mechanism of this reaction, a radical
clock experiment employing a cyclopropyl-substituted alkene as
substrate was conducted (Scheme 4). In this case a ring opening
Acknowledgements
This work is supported by “1000-Youth Talents Plan” starting up
funding, National Natural Science Foundation of China (Grant No.
1772183), the Fundamental Research Funds for the Central
Universities (WK2060190086), as well as by the University of Science
and Technology of China
product 3aj was obtained in 32 % yield, whereas the formation
of unrearranged product 3aj’ was not observed. This result
could be rationalized by a cyclisation involving an aryl radical,
which is generated through the interaction of aryl bromide with
the Ni-catalyst. Alternatively, the initial migratory insertion
could be non-radical, but the resultant Ni-alkyl species after
cyclisation might undergo homolyptic Ni-Alkyl bond cleavage,
affording the same C-centered radical as the one generated in
the aryl-radical-mediated ring closure. Moreover, the high
diastereoselectivities of 3f and 3g also support the formation of
this alkyl radial, otherwise similar diastereomeric ratios would
be obtained as their trisubstituted alkene-precursors. To
differentiate these two possible pathways mentioned above we
conducted the Ni-catalysed reductive arylalkylation employing
2
.
Notes and references
1
For a review on redox-neutral dicarbofunctionalisation of
unactivated alkenes, see: S. KC and R. Giri, J. Org. Chem., 2018,
8
3, 3013.
2
For selected examples on two-component redox-neutral
dicarbofunctionalisation of unactivated alkenes see: (a) V. B.
Phapale, E. Buñuel, M. García-Iglesias and D. J. Cárdenas,
Angew. Chem. Int. Ed., 2007, 46, 8790; (b) H. Cong and G. C.
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Fu, J. Am. Chem. Soc.,2014, 136, 3788; (c) W. You and M. K.
Brown, J. Am. Chem. Soc., 2014, 136, 14730; (d) S. Thapa, P.
Basnet and R. Giri, J. Am. Chem. Soc., 2017, 139, 5700; (e) S.
KC, P. Basnet, S. Thapa, B. Shrestha and R. Giri, J. Org. Chem.,
View Article Online
DOI: 10.1039/C8SC04279A
2
018, 83, 2920..
3
For selected examples on three-component redox-neutral
dicarbofunctionalisation of unactivated alkenes see: (a) K.
Mizutani, H. Shinokubo and K. Oshima, Org. Lett., 2003, 5,
3
959; (b) J. Terao, Y. Kato and N. Kambe, Chem. Asian J., 2008,
, 1472; (c) B. Shrestha, P. Basnet, R. K. Dhungana, S. KC, S.
3
Thapa, J. M. Sears and R. Giri, J. Am. Chem. Soc., 2017, 139,
1
0653; (d) J. Derosa, Van T. Tran, M. N. Boulous, J. S. Chen and
K. M. Engle, J. Am. Chem. Soc., 2017, 139, 10657; (e) J. Derosa,
V. A. van der Puy, Van T. Tran, M. Liu, K. M. Engle, Chem. Sci.,
2
018, 9, 5278; (f) S. KC, R. K. Dhungana, B. Shrestha, S. Thapa,
N. Khanal, P. Basnet, R. W. Lebrun and R. Giri, J. Am. Chem.
Soc., 2018, 140, 9801; (g) P. Gao, L.-A. Chen and M. K. Brown,
J. Am. Chem. Soc., 2018, 140, 10653; (h) W. Li, J. W. Boon and
Y. Zhao, Chem. Sci., 2018, 9, 600.
4
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6
| Chemical Science, 2018, 00, 1-3
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Page 7 of 7
PleaseC dh oe mn oi ct a al dS cj ui es nt cme argins
View Article Online
DOI: 10.1039/C8SC04279A
Chemical Science
EDGE ARTICLE
Graphical Abstract
R2
R1
R4
R3
Reductive
Ni-Catalysis
R3
Br
R1
R4
+
Br
X
3
5 Examples
X
n
40-73 %
R2
n
A Ni-catalyzed reductive two-component arylalkylation of unactivated olefins has been accomplished providing an entry to a variety of
benzene-fused carbo- and heterocyclic compounds.
This journal is © The Royal Society of Chemistry 20xx
Chemical Science., 2018, 00, 1-3 | 7
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