Ni-catalyzed two-component reductive dicarbofunctionalization of alkenes via radical cyclization

Article abstract of DOI:10.1039/c8cc00358k

A reductive dicarbofunctionalization reaction of alkenes has been developed and applied to the preparation of substituted carbo- and heterocycles. The reaction conditions avoid the use of air-sensitive organometallic reagents, and are compatible with a broad range of bromo-electrophiles and a wide variety of substituents to give cyclic products in excellent yields.

Full text of DOI:10.1039/c8cc00358k

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
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Ni‐Catalyzed Two‐Component Reductive Dicarbofunctionalization
of Alkenes via Radical Cyclization
Yulong Kuang, Xuefeng Wang, David Anthony and Tianning Diao*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A
reductive dicarbofunctionalization of alkenes has been previous reductive methods. We hypothesize that such a
developed and applied to the preparation of substituted carbo‐ and reaction could be used to prepare substituted pyrrolidine and
heterocycles. The reaction conditions avoid the use of air‐sensitive piperidine derivatives that are common pharmacophores
organometallic reagents, and are compatible with a broad range of (Scheme 1C).6,7 The results presented below validate this
bromo‐electrophiles and a wide variety of substituents to give hypothesis and show that a wide range of bromo‐alkene
cyclic products in excellent yields.
substrates undergo difunctionalization with a variety of aryl,
heteroaryl, and alkyl bromo‐electrophiles to afford
cyclopentane, pyrrolidine, piperidine, and tetrahydrofuran
derivatives. The broad scope and good functional group
tolerance makes this reaction an appealing method for
synthetic applications.
An appealing method to rapidly increase molecular complexity
is the 1,2‐dicarbofunctionalization of alkenes, which can enable
new disconnections in organic synthesis.1,2 Previous research on
dicarbofunctionalization of alkenes focused on the use of a
nucleophile and an electrophile to generate tri‐ and tetra‐
substituted patterns (Scheme 1A).1,2 Stoichiometric
organometallic nucleophiles often require glovebox
manipulations and are typically incompatible with electrophilic
functional groups, such as aldehydes and ketones. An
alternative strategy that bears a broad range of substrates with
excellent functional group tolerance would expand the
synthetic utility of olefin difunctionalization.
Reductive dicarbofunctionalization of alkenes with two
electrophiles would bypass the need for pre‐generation of
organometallic nucleophiles, thus broadening the scope,
increasing functional group tolerance, and avoiding handling
air‐sensitive organometallic reagents (Scheme 1B).3,4 Despite
recent examples of reductive dicarbofunctionalization using
aryl iodides as the electrophiles,5 a variant compatible with aryl
and alkyl bromides remains an unmet challenge (Scheme 1B).
Commercially available bromo‐electrophiles are 10 times more
abundant than iodo‐electrophiles. Moreover, tolerance of
functional groups, such as heterocycles, would largely expand
the utility of this strategy, which has not been demonstrated in
Scheme 1. Synopsis of 1,2‐Dicarbofunctionalization of Alkenes and Potential
Applications in Synthesis
a. Department, New York University
100 Washington Square E.
Radical cyclizations have been applied extensively to the
preparation of carbo‐ and heterocycles.8 Previous radical
cyclization often completes with the oxidation or reduction of
the radical (Scheme 2, dashed arrow).8,9 Nickel catalysts have
been recently characterized to generate alkyl radicals upon
New York, NY 10003
b. E‐mail: diao@nyu.edu
† Footnotes relaꢀng to the ꢀtle and/or authors should appear here.
Electronic Supplementary Information (ESI) available: details of any supplementary
information available should be included here. See DOI: 10.1039/x0xx00000x
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halogen abstraction.10,11 We speculate that the radical
Mono‐substituted substrates without the Thorpe‐Ingold
generated from an alkyl bromide with a Ni catalyst could cyclize effect underwent reductive cyclization in good yields (Scheme
with a tethered alkene (Scheme 2). The resulting radical is then 3A). The unsubstituted carbochain, however, favors direct
trapped by a Ni(II) aryl intermediate, which is formed from the coupling with PhBr prior to cyclization. In order to explore the
oxidative addition of PhBr to Ni(0). Reductive elimination from practicality of the method, we carried out a gram‐scale reaction
the Ni(III) intermediate would give the difunctionalization of
1
using standard Schlenk techniques without the use of
gloveboxes (Scheme 3B). The reaction proceeded to high
conversion to
product.1,2
2
.
Scheme 2. Adaptation of Radical Cyclization to Ni‐Catalyzed Alkene
Dicarbofunctionalization
Scheme 3. Substituents Effect and Reaction on Scale.
We set out to test our design by evaluating Ni catalysts
under reductive conditions. The coupling of 6‐bromoalkene
with PhBr was chosen as the model reaction (Table 1). Three
products were observed in a series of experiments: from the
desired reductive difunctionalization, from reductive
cyclization, and from radical dimerization. Recent advances in
1
With optimized conditions in hand, the substrate scope of
this reaction, with respect to the coupling partner, was then
investigated (Table 2). The reaction appears to be relatively
insensitive to the electronic properties of the aryl bromide: both
electron‐rich (entry 2) and electron‐deficient (entries 3‐8) para‐
substituted aryl bromides undergo effective coupling in
excellent yields. The optimized conditions also showed high
compatibility with electrophiles with varying steric effects, and
tolerated meta‐ and ortho‐substituents well (entries 9‐12).
Reactive functional groups, including chloride (entry 4), ketone
(entry 6), aldehyde (entry 7), alkene (entry 8), and ester groups
(entry 10) are conserved. Pyridines, which are conventionally
problematic in transition metal catalysis, due to their strong
coordination capability, did not inhibit the reactions (entries 13‐
15). Similarly high yields were observed with indole and
thiophene derivatives (entries 16‐18).
2
3
4
Ni‐catalyzed reductive coupling reveal the beneficial effect of
bidentate nitrogen ligands.4,12 The use of di‐tBu‐bpy (4,4'‐di‐
tert‐butyl‐2,2'‐bipyridine) formed
2 in 76% yield (Table 1, entry
1). The yield of
2
was optimized to 91% by replacing di‐tBu‐bpy
with phenanthroline (entry 2), while the use of more hindered
neocuproine resulted in a lower yield (entry 3). It is noteworthy
that in the absence of PhBr, the reaction formed
quantitative yield with di‐tBu‐bpy as the ligand (entry 8).
4 in
Table 1. Optimization of Reaction Conditionsa
In addition to sp2 hybridized electrophiles, the reaction
conditions are compatible with alkyl bromides (Table 2, entries
19‐23). The yields for alkyl electrophiles were generally lower
than those with aryl electrophiles, with a substantial amount of
4
observed as the byproduct. We attribute the reduced yields
to slower activation of alkyl bromides relative to aryl
bromides,13 which causes the cyclized radical intermediate to
accumulate and dimerize. In the presence of an alkyl chloride
substituent, the coupling is selective for the bromide, and the
chloride substituent survives the conditions (entry 20).
After assessing the scope of aryl and alkyl bromides, we
examined the use of other electrophiles (Table 2, entries 24‐27).
Given the versatile reactivity of Ni with aryl iodides and pseudo‐
halides,14 we investigated PhI as the coupling partner. PhI gave
slightly lower yield of
2 compared to that of PhBr (entry 24),
with concomitant formation of biphenyl as the major by‐
product, resulting from reductive coupling of PhI. Mesylates are
anticipated to be harder to activate, and 2‐naphthyl mesylate
a 0.1 mmol scale，2 equiv of PhBr, 2 equiv. of Zn. DMA = N,N‐dimethylacetamide,
DMF = N,N‐dimethylformamide, HMPA = hexamethylphosphoramide. b Calibrated
NMR yields using CH3NO2 as an internal standard. Isolated yields in parentheses. c
No PhBr.
undergoes coupling with
1
to give 37% yield (entry 25). PhCl is
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Table 3. Scope of Alkenes and Synthesis of N‐ and O‐Heterocyclesa
inert (entry 26), whereas BnCl can be activated to give a modest
yield of the product (entry 27).
Table 2. Scope of Electrophilesa
a
0.1 mmol scale，2 equiv of ArBr, 2 equiv of Zn, 10 mol% Ni, 12 mol%
phenanthroline. Isolated yields. The assignment of the diastereomers is facilitated
by NOESY experiments. b NMR yield in parenthesis.
Previous 2‐component difunctionalization of alkenes are
restricted to the formation of 5‐membered rings.1 Under our
conditions, piperidine derivative 15 is obtained in 41% yield. The
desired pathway competes against the direct reductive coupling
of the alkyl bromide with PhBr without cyclization, which is
consistent with the anticipated slow 6‐exo‐trig cyclization.8a The
use of 3‐bromopyridine as a coupling partner formed piperidine
16. The importance of these results is apparent in the context
of synthesizing biologically active molecules. For example, 15 is
an epigenetic polycomb repressive complex 2 (PRC2) inhibitor,20
while 16 is an intermediate to a somatostatin SST1 receptor
antagonist (Scheme 1C).7
In addition to N‐heterocycles, tetrahydrofuran derivatives
are accessible by the difunctionalization of allyl bromoethyl
ethers. For this class of substrates, at least one substituent is
needed to promote the cyclization, while unsubstituted allyl
bromoethyl ether undergoes direct coupling without
cyclization. The high diastereoselectivity of cis‐19 is attributed
to stabilization of the chair conformation by the anomeric
effect.17
a
0.1 mmol scale，2 equiv of ArBr, 2 equiv of Zn, 10 mol% Ni, 12 mol%
phenanthroline. Entries 19‐23: 0.2 mmol scale, 4 equiv of RBr, 5 mol% Ni, 6 mol%
phenanthroline. b Isolated yields.
The optimized difunctionalization reaction is readily
applicable to synthesizing heterocycles (Table 3). Many
pharmacophores share the 3‐benzyl pyrrolidine
including a modulator of the cholesterol biosynthetic pathway6
(Scheme 1C) and a calcium‐sensing receptor antagonist.15 The
present reaction offers a more efficient route to 6 compared to
previous preparation.16 The reductive difunctionalization is
particularly useful when various substituents on the olefins
6 motif,
exhibit little influence on the yields
(7‐12). The
diastereoselectivity is consistent with previous observations in
radical cyclization8a,17 and follows the Beckwith‐Houk model.18
3‐Bromopyridine proved to be a competent coupling partner
under the standard conditions to give 13 in 82% yield, a key
intermediate en route to an anti‐soluble epoxide hydrolase
(sEH) inhibitor 14, which is a potential cardiovascular disease
treatment.19
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Preliminary mechanistic studies are carried out to probe the
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In
summary,
the
Ni‐catalyzed
reductive
radical pathway. Both cis‐ and trans‐20 proceeded to give a dicarbofunctionalization of alkenes provides efficient access to
mixture of cis‐ and trans‐18 in the same ratio (Scheme 4). The substituted pyrrolidine, piperidine, and tetrahydrofuran
poor diastereoselectivity reflects the small energy difference in derivatives, many of which are of pharmaceutical importance.
the chair and boat conformations and is consistent with This new method features a broad substrate scope and good
previous radical cyclization initiated by tin hydride.21 Moreover, functional group tolerance, and represents an important
the lack of influence of the starting stereocenter supports the alternative to the redox neutral dicarbofunctionalization
formation of a radical upon halogen abstraction by Ni.
reactions.
This work was supported by the National Science
Foundation under award number CHE‐1654483.
Conflicts of interest
The authors declare no conflict of interest.
Scheme 4. Effect of the Stereocenter in the Substrate
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