Stereospecific Intramolecular Reductive Cross-Electrophile Coupling Reactions for Cyclopropane Synthesis

Article abstract of DOI:10.1021/jacs.5b03870

The stereospecific reductive cross-electrophile coupling reaction of 2-aryl-4-chlorotetrahydropyrans to afford disubstituted cyclopropanes is reported. This ring contraction presents surprises with respect to the stereochemical outcome of reaction of the

Full text of DOI:10.1021/jacs.5b03870

Communication
pubs.acs.org/JACS
Stereospecific Intramolecular Reductive Cross-Electrophile Coupling
Reactions for Cyclopropane Synthesis
Emily J. Tollefson, Lucas W. Erickson, and Elizabeth R. Jarvo*
Department of Chemistry, University of California, Irvine, California 92697-2025, United States
S
* Supporting Information
Scheme 1. Asymmetric Reductive Cross-Electrophile
Coupling Strategies
ABSTRACT: The stereospecific reductive cross-electro-
phile coupling reaction of 2-aryl-4-chlorotetrahydropyrans
to afford disubstituted cyclopropanes is reported. This ring
contraction presents surprises with respect to the stereo-
chemical outcome of reaction of the alkyl halide moiety.
While cross-coupling and reductive cross-electrophile
coupling reactions of alkyl halides are typically stereo-
ablative, using a chiral catalyst to set the stereocenter, this
transformation proceeds with high stereochemical fidelity
at the alkyl halide and ether bearing stereogenic centers.
This approach provides straightforward access to highly
substituted cyclopropanes in two steps from commercially
available aldehydes.
or miners and organometallic chemists “the devil’s copper”
1
Fcan provide intrigue and vexation. In addition to providing
Recent work in our laboratory demonstrated Ni-catalyzed
stereospecific cross-coupling reactions of alkyl ethers and esters
under Kumada, Negishi, and Suzuki-type conditions.9 We
hypothesized that these electrophiles would also participate in
stereospecific cross-electrophile coupling reactions, since
oxidative addition of the low-valent Ni catalyst with the benzylic
ether should be a common elementary step in both mechanisms.
Here we report the stereospecific ring contractions of 2-aryl-4-
chlorotetrahydropyrans to afford substituted cyclopropanes
(Scheme 1C), via an intramolecular reductive cross-coupling
reaction10 of a benzylic ether and an alkyl halide. Notably, it is
strictly stereospecific with respect to both electrophilic functional
groups. As anticipated at the outset, oxidative addition at the
benzylic ether proceeds with high stereochemical fidelity.9a One
surprising feature of this transformation is that the alkyl halide
bearing stereogenic center reacts with high stereospecificity (vide
infra). This result is unusual, as prior Ni-catalyzed reactions of
alkyl halides were stereoablative.8
In addition to affording a stereospecific cross-electrophile
coupling, this reaction provides straightforward and scalable
access to substituted cyclopropanes, important organic motifs
found in many natural products and medicinal agents.11 The
strained nature and reactivity of cyclopropanes make them
valuable synthetic intermediates and mechanistic probes, and as
such the development of their asymmetric synthesis has been an
area of intensive research.12 By effecting a skeletal rearrangement
of the tetrahydropyran starting material, this reductive cross-
coupling reaction provides cyclopropanes bearing a synthetic
inexpensive alternatives to precious palladium catalysts, nickel
complexes present a diverse range of elementary reactions,
including both polar and single-electron chemistry.2 Indeed,
mechanistic ambiguity has been a challenge in rational design of
new catalytic transformations. At the same time, the unique
reactivity patterns offered by Ni catalysts can provide advantages
in certain settings. For example, Ni catalysts are particularly well
suited for reactions employing alkyl halides and pseudohalides,
due to their ability to engage sluggish electrophilic partners and
reduced propensity for β-hydride elimination.3 For these
reasons, Ni catalysts have been critical for development of
cross-coupling reactions of alkyl electrophiles and in recent
development of reductive cross-electrophile coupling reactions.4
In a reductive cross-electrophile coupling reaction, two
electrophilic partners, typically alkyl or aryl halides, are coupled
in the presence of exogenous reducing agent. This strategy
circumvents synthesis of an organometallic reagent, as would be
required for a traditional cross-coupling reaction.4 Weix et al.
pioneered the Ni-catalyzed reductive cross-coupling of aryl and
alkyl halides with a variety of electrophilic partners (Scheme
1A).5 Recently, they reported cross-electrophile coupling of
benzylic alcohols and benzylic chlorides with aryl halides.6
Reisman et al. reported stereoconvergent reductive cross-
coupling reactions of racemic benzylic chlorides with acid
chlorides or vinyl bromides to provide products with good yield
and high ee (Scheme 1B).7 Stereoconvergent methods capitalize
on the stereoablative nature of oxidative addition of Ni
complexes with alkyl halides and employ a chiral ligand to set
the desired stereocenter.8
Received: April 14, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b03870
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Journal of the American Chemical Society
Communication
handle appropriate for further functionalization as part of target-
or diversity-oriented synthetic strategies.
With optimized reaction conditions in hand, we next examined
the stereospecificity of the reaction. Because Ni-catalyzed
reactions using alkyl halides are typically stereoconvergent and
are thought to proceed through alkyl radical intermediates, we
were interested in determining whether cis- and trans-8 would
afford the same diastereomer of product and whether use of a
chiral ligand would influence the diastereomeric ratio. We
subjected both cis- and trans-8 to reactions employing rac-BINAP
and were surprised to see that the reaction was not stereo-
convergent, but was highly stereospecific with respect to the alkyl
halide (Table 2). Chloride cis-8 afforded cis-9 in high yield and
To test our hypothesis for a stereospecific ring contraction, we
designed test substrate tetrahydropyran cis-8. As a starting point,
we examined this substrate under the same catalyst conditions we
employed in our previous Kumada-type cross-coupling reactions
of aryl-substituted tetrahydropyrans.9a Using a combination of
Ni(cod)2 and rac-BINAP, in the presence of MeMgI, we found
that cis-8 afforded cis-9 in excellent yield and as a single
diastereomer (Table 1, entry 1). The relative configuration of 9
was assigned as cis by X-ray crystallographic analysis of a
derivative and NOE NMR experiments.13
Table 2. Substrate Control of Stereochemistry
Table 1. Optimization of Reaction Conditions
a
b
Isolated yield after column chromatography. Determined by 1H
NMR. Nap = 2-naphthyl.
a
1
Yield determined by H NMR based on comparison to PhTMS as
b
internal standard. All reagents were weighed on the benchtop, and
excellent dr (entry 1). Similarly, trans-8 yielded trans-9 with high
yield and dr (entry 4). Introduction of enantioenriched catalyst
does not perturb the high level of stereospecificity: in all cases,
the reaction occurred cleanly with inversion at the benzylic ether
and retention at the alkyl halide bearing a stereogenic center
(entries 2, 3, 5, and 6). These results are not consistent with
initiating the reaction by oxidative addition of the alkyl halide
moiety.17 This stereochemical outcome in the reaction of an alkyl
halide with a low-valent Ni complex is unusual and has significant
implications for the mechanism of this transformation, which is
currently under investigation.
To determine whether the reaction proceeds with net
inversion or retention at the reactive centers, we prepared
enantioenriched trans-8.18 As anticipated, ring contraction
proceeded with high enantiospecificity (es; eq 1).19 Product 9
was derivatized, and absolute configuration was assigned by X-ray
crystallographic analysis.13 Surprisingly, we found that reaction at
the benzylic ether occurred with net retention.20 The alkyl
chloride moiety reacted with inversion. While this stereo-
chemical outcome is unexpected, it appears to be consistent in
this ring contraction (vide infra).
the reaction was purged with N2 before addition of MeMgI.
To determine what components of the reaction were
necessary, we examined both the Ni catalyst and the Grignard
reagent. We first removed Ni(cod)2 and rac-BINAP from the
reaction and saw no conversion of the starting material,
indicating the reaction is indeed Ni-catalyzed (entry 2). We
found that catalyst loadings as low as 2.5 mol% resulted in full
conversion to product in 24 h at rt (entry 3). Other bidentate
phosphine ligands, such as DPEphos, were not as effective in the
reaction (entry 4). We also examined alternative Ni precatalysts.
We found that Ni(acac)2, a more stable Ni precatalyst, provided
lower conversion than Ni(cod)2 (entry 5). However, with the
addition of 12 mol% of 1,5-cyclooctadiene conversion to product
is restored (entry 6). This catalyst system is also amenable to set
up on the benchtop, avoiding use of a glovebox (entry 7).
Based on our previous development of Ni-catalyzed alkyl-
Heck reactions, we hypothesized that the Grignard reagent acts
as a reducing agent to effect catalyst turnover.14 Removing the
Grignard reagent resulted in full recovery of starting material;
using only 1 equiv resulted in 54% yield (entries 8 and 9,
respectively).15 Use of commercial MeMgBr affords 80% yield of
9 (entry 10). We found that the identity of the Grignard reagent
was not crucial. Switching to PhMgBr from MeMgI had no
detrimental effect (entry 11). Using PhMgBr, we also isolated 1
equiv of biphenyl side product, supporting our hypothesis that
the Grignard reagent acts to reduce the Ni catalyst.
Unfortunately, after examining milder reducing agents, e.g.,
dimethylzinc or manganese powder, we found that a Grignard
reagent is required in order for the reaction to proceed (entry
12). While this is not an ideal reducing agent, it is readily available
and straightforward to handle.16
We envisioned that this reaction would provide a robust and
scalable strategy to synthesize single diastereomers of cyclo-
propanes from commercially available aldehydes. To demon-
strate that this strategy is amenable to larger scale, we performed
the two-step sequence on a 5.3 mmol scale (Scheme 2). Prins
cyclization of 10 with 3-buten-1-ol employing ZnCl2 and p-TSA
proceeded smoothly to afford cis-8 in 80% yield and 20:1 dr.21
B
DOI: 10.1021/jacs.5b03870
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Journal of the American Chemical Society
Communication
Scheme 2. Amenability to Scale Up
Table 4. Scope of Trisubtituted Tetrahydropyrans
With 1 g of cis-8 in hand, we determined that ring contraction
with only 1 mol% catalyst provides cis-9 in 93% yield and 20:1 dr.
This strategy provides a straightforward method for conversion
of the requisite aldehyde to the cyclopropane in two steps and
with reliable control of relative stereochemistry.
Having established the robustness of this reaction, we turned
our attention to determining the scope. We examined a range of
aryl-substituted tetrahydropyrans (Table 3). Reactions of
Table 3. Scope of Ring Contraction Reaction
a
b
Isolated yield after column chromatography. Reported as (cis:trans)
c
1
determined by H NMR. Reaction performed without addition of
MgI2 and with 5 mol% catalyst loading. Nap = 2-naphthyl.
1 equiv of MgI2 afforded cyclopropane 24 in 88% yield and >99%
es (entry 1). In related Kumada-type cross-coupling reactions, we
observed that MgI2 accelerates reactions of sluggish substrates.22
We hypothesize that the Lewis acidic salts coordinate the
benzylic ether, facilitating oxidative addition of the C−O bond.
Derivatization and X-ray crystallographic analysis demonstrated
that the reaction occurred with retention at the benzylic ether
and inversion at the alkyl chloride.13 This stereochemical
outcome is consistent with our earlier observations (eq 1).
Adding MgI2 also resulted in good conversion of 25, with a larger
substituent at the C6 position, to 26 (entry 2). To challenge the
reaction, we examined if substitution at the reactive centers
would be tolerated. The use of tertiary chloride 27 afforded 28,
containing a quaternary center, in 62% yield and good transfer of
stereochemical information (entry 3).
In beginning to examine the broader scope, we set out to
determine if the tetrahydropyran scaffold was integral to
reactivity. We first examined a smaller cyclic ether, tetrahydro-
furan 29. Subjecting tetrahydrofuran cis-29 to the reaction
afforded cis-30 in 87% and 20:1 dr (Scheme 3a), indicating that
Scheme 3. Application to Alternative Substrate Classes
a
b
Isolated yield after column chromatography. Determined by 1H
c
NMR. Reaction performed on a 1.0 mmol scale.
benzofuran- and benzothiophene-substituted tetrahydropyrans
proceed in good yields and dr (entries 1−3). In an effort to
challenge the transformation, we examined simple furan-
containing substrates 15 and 17. Both 2- and 3-substituted
furans yielded desired product in excellent yield and with transfer
of stereochemical information (entries 4 and 5). We found that
6-methoxy-2-naphthalene substituted THP cis-19 proceeded in
97% yield and 20:1 dr and was amenable to a larger 1.0 mmol
scale reaction (entries 6 and 7). Reaction of trans-19 likewise
proceeded with clean transfer of stereochemical information to
afford trans-20 in 97% yield (entry 8).
To synthesize cyclopropanes with a more complex range of
substituent patterns, we examined a series of trisubstituted
tetrahydropyrans (Table 4). Subjecting enantioenriched 2,4,6-
trisubstituted tetrahydropyran 23 to the standard reaction
conditions resulted in only partial conversion. However, adding
decreasing the carbon tether is not detrimental to the reaction.
We were also interested if an unstrained, acyclic scaffold would
provide substrates that are competent in the reaction. We
subjected primary chloride 31 to standard reaction conditions
(Scheme 3b). Cyclopropane 32 was obtained in 71%, indicating
that acyclic primary chlorides are indeed tolerated.
As our reaction is amenable to cyclopropanes bearing simple
heteroaromatic rings, we sought to exploit these functional
groups to obtain alkyl-substituted cyclopropanes. Kobayashi et
al. demonstrated that 2-substituted furans can be oxidized to
form 2-enonic acids.23 This functionality translates nicely as a
C
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Communication
cross-coupling of an alkyl tosylate with aryl bromide: Liu, J.-H.; Yang, C.-
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building block to prepare biologically active scaffolds, such as
halicholactone, a lipoxygenase inhibitor, and its family
members.24 We envisioned that our method could be used to
synthesize analogs of this class of natural products. 2-Furan-
substituted cyclopropane cis-33 was oxidized using the reported
conditions (Scheme 4). 2-Enonic acid 34 was obtained in 66%
yield with no loss of stereochemistry.
Scheme 4. Oxidation of Furan 33
2008, 73, 3680. (e) Castano, A. M.; Echavarren, A. M. Organometallics
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Am. Chem. Soc. 2014, 136, 14951. (b) Tollefson, E. J.; Hanna, L. E.;
Jarvo, E. R. Acc. Chem. Res. 2015, DOI: 10.1021/acs.accounts.5b00223.
(10) Synthesis of cyclopentanes by Ni-catalyzed reductive coupling:
Xue, W.; Xu, H.; Liang, Z.; Qian, Q.; Gong, H. Org. Lett. 2014, 16, 4984.
(11) (a) Salaun, J. In Topics in Current Chemistry; de Meijere, A., Ed.;
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2014, 46, 979. (b) Ring-contraction of dihydropyrans via [1,4]-Wittig
rearrangement: Mori-Quiroz, L. M.; Maleczka, R. E. J. Org. Chem. 2015,
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In summary, stereospecific synthesis of di- and trisubstituted
cyclopropanes is achieved via a Ni-catalyzed reductive cross-
electrophile coupling of 2-aryl-4-chlorotetrahydropyrans. The
ring contraction is stereospecific with respect to both the
benzylic ether and the alkyl halide moieties. Efforts to expand the
scope and elucidate the mechanism of the transformation are
underway.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details and characterization data. The Supporting
Information is available free of charge on the ACS Publications
website at DOI: 10.1021/jacs.5b03870. For crystallographic data
see also CCDC 1059382, 1413565, and 1414041.
AUTHOR INFORMATION
Corresponding Author
*erjarvo@uci.edu
■
(13) See Supporting Information for details.
(14) Harris, M. R.; Konev, M. O.; Jarvo, E. R. J. Am. Chem. Soc. 2014,
136, 7825.
(15) Replacing Grignard reagent with 2 equiv of MgI2 resulted in no
conversion of 8, consistent with a required terminal reducing agent.
(16) Failure of alternative reducing agents is consistent with
transmetalation of the Grignard reagent prior to oxidative addition of
benzylic ether.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by NSF-CHE-1464980 and the
University of California (Chancellor’s Fellowship and Graduate
Opportunity Fellowship to E.J.T.). We acknowledge Dr. Joseph
Ziller for X-ray crystallographic data and Dr. John Greaves for
mass spectrometry data.
(17) (a) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 1340. (b) For
stereoconvergent cross-coupling reactions of these substrates, see ref 9a.
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DOI: 10.1021/jacs.5b03870
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