Intra- and Intermolecular Nickel-Catalyzed Reductive Cross-Electrophile Coupling Reactions of Benzylic Esters with Aryl Halides

Article abstract of DOI:10.1002/anie.201601206

Nickel-catalyzed cross-electrophile coupling reactions of benzylic esters and aryl halides have been developed. Both inter- and intramolecular variants proceed under mild reaction conditions. A range of heterocycles and functional groups are tolerated under the reaction conditions. Additionally, the first example of a stereospecific cross-electrophile coupling of a secondary benzylic ester is described. Crossed off: Nickel-catalyzed cross-electrophile coupling reactions of benzylic esters and aryl halides have been developed. Both inter- and intramolecular variants proceed under mild reaction conditions, and a range of heterocycles and functional groups are tolerated. Additionally, the first example of a stereospecific cross-electrophile coupling of a secondary benzylic ester is described.

Full text of DOI:10.1002/anie.201601206

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International Edition: DOI: 10.1002/anie.201601206
German Edition: DOI: 10.1002/ange.201601206
Cross-Coupling
Intra- and Intermolecular Nickel-Catalyzed Reductive Cross-
Electrophile Coupling Reactions of Benzylic Esters with Aryl Halides
Mikhail O. Konev, Luke E. Hanna, and Elizabeth R. Jarvo*
Abstract: Nickel-catalyzed cross-electrophile coupling reac-
tions of benzylic esters and aryl halides have been developed.
Both inter- and intramolecular variants proceed under mild
reaction conditions. A range of heterocycles and functional
groups are tolerated under the reaction conditions. Addition-
ally, the first example of a stereospecific cross-electrophile
coupling of a secondary benzylic ester is described.
N
ickel-catalyzed reductive cross-electrophile coupling
reactions have recently undergone rapid advances with
respect to synthetic utility and mechanistic understanding.[1]
Their mild reaction conditions can provide advantages to
traditional cross-coupling reactions. For example, reductive
coupling reactions offer an attractive strategy toward intra-
molecular cyclization reactions because they do not require
installation of both electrophilic and organometallic func-
tional groups into the starting material.[2] We envisioned
a cross-electrophile reductive coupling reaction would pro-
vide straightforward synthesis of 1-arylindanes and tetralins,
common motifs in natural products and pharmaceutical
agents (Scheme 1).[3,4]
Scheme 1. Intramolecular reductive cross-electrophile coupling reac-
tion for synthesis of indanes and tetralins. Piv=pivaloyl.
While intermolecular reductive coupling reactions have
undergone rapid development in recent years,[1,5] few intra-
molecular variants have been reported. The group of Peng
disclosed a stoichiometric nickel-catalyzed reductive coupling
reaction to access nitrogen- and oxygen-containing hetero-
cycles (Scheme 2a).[6] In 2014, Gong and co-workers reported
a catalytic intramolecular cyclization of dihaloalkanes to
access 5- and 6-membered rings (Scheme 2b).[7] Recently,
À
much interest has focused on the use of C O electrophiles in
reductive coupling reactions.[1b,c,8,9] Our laboratory has
reported a reductive ring-contraction of 4-chlorotetrahydro-
pyrans to generate cyclopropanes (Scheme 2c).[10] To further
expand the scope of intramolecular cross-electrophile cou-
pling reactions, we targeted cyclization reactions of benzylic
esters with aryl halides to afford valuable indanes and
tetralins (Scheme 2d). These reactions would also comple-
ment recent efforts to develop intermolecular reductive
coupling reactions to include alcohol derivatives.[11] Herein
we report the intra- and intermolecular reductive cross-
electrophile coupling reactions of benzylic pivalates with aryl
halides and provide evidence for a stereospecific cyclization
reaction.
Scheme 2. Nickel-catalyzed intramolecular reductive cross-electrophile
coupling reactions. BINAP=2,2’-bis(diphenylphosphanyl)-1,1’-
binaphthyl, cod=1,5-cyclooctadiene, DMA=N,N-dimethylacetamide,
DMF=N,N-dimethylformamide,
[*] M. O. Konev, L. E. Hanna, Prof. Dr. E. R. Jarvo
Department of Chemistry, University of California, Irvine
Irvine, CA 92697 (USA)
We designed the secondary benzylic pivalate 9 as a model
substrate (see Table1), based on our previous work in cross-
coupling reactions of benzylic electrophiles.[12] These sub-
E-mail: erjarvo@uci.edu
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201601206.
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Table 2: Scope of the intramolecular cross-electrophile coupling.
strates are easily prepared by lithiation of an arene and
addition into the corresponding bromophenyl aldehyde.
Additionally, benzylic pivalate esters are less reactive than
their halide counterparts. Reaction of 9 in the presence of
catalytic NiBr2-glyme, bathophenanthroline (BPhen), and
Zn0 provided the desired product 10 in excellent yield with
negligible yields of hydrodehalogenation (Table 1, entry 1).
Table 1: Optimization of reaction conditions.
Entry Variation from standard
reaction conditions
Yield
9 [%][a] 10 [%][a] 11 [%][a]
1
2
3
4
5
6
7
8
9
none
<2
59
80
26
20
86
98
100
93
25
90
9
<2
25
<2
13
<2
49
Ac instead of Piv
Mn instead of Zn
dppf instead of BPhen
bipy instead of BPhen
terpyridine instead of BPhen
pybox instead of BPhen
no ligand
no NiBr2-glyme
pyridine (40 mol%)
NaI (25 mol%)
42
25
<2
<2
<2
<2
4
<2
<2
<2
<2
61
10
11
12
<2
12
25
79
68
4
NiCl2-glyme instead of NiBr2-
glyme
13
DMF instead of DMA
<2
44
35
[a] Determined by 1H NMR spectroscopy using PhTMS as an internal
standard. dppf=1,1’-bis(diphenylphosphanyl)ferrocene, TMS=trime-
thylsilyl.
Less sterically encumbered esters, such as acetate, provided
lower conversion under the reaction conditions (entry 2).
Alternative reducing agents such as Mn0 also provided lower
yields (entry 3). Utilizing phosphine and other aromatic
nitrogen-containing ligands, such as bipy or pybox, resulted
in a dramatic decrease in product formation (entries 4–7). In
the absence of a ligand or a nickel catalyst, the desired
cyclization does not occur (entries 8 and 9). Additives known
to promote reactivity in other reductive cross-electrophile
coupling reactions were also examined.[13] The addition of
either pyridine or NaI favored hydrodehalogenation
(entries 10 and 11).
Yield is that of the isolated product. [a] Reaction run with 15 mol% NiBr2-
glyme and 458C. [b] Reaction run at 458C. [c] Both starting material and
product are 1:1 d.r. TBS=tert-butyldimethylsilyl, Ts =4-toluenesulfonyl.
N-tosylindoles 22–24 were obtained in good yields. Substrates
containing methoxy, fluoro, silyl, and ester substituents were
also well-tolerated under the reaction conditions. Notably,
these cyclization reactions proceed smoothly without the aid
of a Thorpe–Ingold effect.[15]
Having established reaction conditions for the cyclization
of the model substrate 9, we set out to investigate the scope of
the transformation (Table 2). Cyclization of a series of
napthylic esters provides the tetralins 12 and 14, which
correspond to the core of bicunningines A and B[14] and the
tetracyclic indanes 10, 13, and 15. Benzofuran and benzo-
thiophene moieties were well-tolerated, thus providing good
yields for both indanes and tetralins (16–18, 20 and 21).
Additionally, substrates containing N-heterocycles were
found to undergo the desired cyclization. The pyridine-
substituted indane 19 can be synthesized in 65% yield and the
Next, we sought to determine whether these reaction
conditions could be directly applied to an intermolecular
variant of the cross-electrophile coupling reaction. With
primary benzylic esters, this work would be complimentary
to that of Weix and co-workers, forming similar diaryl-
methane products without the need of a cobalt cocatalyst.[9b]
Implementation of our previous intramolecular coupling
reaction conditions yielded minimal desired product, with
dimerization of the benzylic electrophile being the major
product (see the Supporting Information). Interestingly,
switching the ligand to dppf increased the yield of the desired
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Table 4: Stereospecific cyclization.
diarylmethane to 98% and suppressed the formation of the
dimer.[16]
With suitable reaction conditions identified, we examined
the scope of the intermolecular cross-electrophile coupling
reaction (Table 3). Coupling of naphthylic pivalates pro-
Table 3: Scope of intermolecular cross-electrophile coupling reaction.
Yield is that of the isolated product. The es value was determined by SFC.
mechanism. Investigation of the mechanistic details is ongo-
ing.
In summary, the intramolecular reductive cyclization for
the synthesis of indanes and tetralins has been developed.
Additionally, the synthesis of diarylmethanes by an intermo-
lecular cross-electrophile coupling of primary benzylic esters
and aryl iodides is also described. The reactions are tolerant
of a variety of heterocycles and functional groups. We have
also demonstrated stereospecific cross-electrophile coupling
reaction of benzylic esters for synthesis of enantioenriched 1-
arylindanes and tetralins.
Yield is that of the isolated product. [a] Used 1.1 equiv of 4-iodoanisole.
[b] Reaction run at 408C. FG=functional group.
ceeded at room temperature in high yields (25–27). Ortho-
substitution did not hinder desired reactivity, thus forming 26
in high yield. Iodobenzene derivatives containing aryl ether,
methyl benzoate, and fluoro functional groups were also well-
tolerated. Furyl- and thiophenyl-substituted pivalates pro-
vided high yields of diarylmethanes at slightly elevated
temperatures (28–31).[17] Simple benzylic esters, for example,
benzyl pivalate, were unreactive under the optimized reaction
conditions even upon heating of the reaction mixture, as were
indole- and pyridyl-substituted pivalates. Additionally, excess
aryl iodide is observed upon workup and the desired reaction
can proceed with as little as 1.1 equivalents of aryl iodide.
Finally, we sought to determine whether the intramolec-
ular cyclization could proceed in an enantiospecific fashion.
While several examples of stereoconvergent reductive cou-
pling reactions have been reported,[5a,9b,11b,13b,18] to the best of
our knowledge, there is only one example of an enantiospe-
cific reductive coupling reaction.[1b,c,8] Subjecting (R)-9 to the
optimized reaction conditions afforded (S)-10 in 90% yield in
88% enantiomeric excess with 92% enantiospecificity
Acknowledgments
This work was supported by NSF-CHE-1464980 and DoEd
GAANN (PA200A120070 to L.E.H.)
Keywords: cross-coupling · cyclization · heterocycles · nickel ·
zinc
How to cite: Angew. Chem. Int. Ed. 2016, 55, 6730–6733
Angew. Chem. 2016, 128, 6842–6845
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Received: February 2, 2016
Published online: April 21, 2016
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