Nickel-Catalyzed Cross-Electrophile Coupling of Alkyl Fluorides: Stereospecific Synthesis of Vinylcyclopropanes

Article abstract of DOI:10.1021/jacs.6b07567

The stereospecific reductive cross-electrophile coupling reaction of 2-vinyl-4-halotetrahydropyrans for vinylcyclopropane synthesis is reported. The nickel-catalyzed reaction occurs with both alkyl fluorides and alkyl chlorides. To the best of our knowledge, this is the first reported cross-electrophile coupling reaction of an alkyl fluoride. Ring contraction proceeds with high stereospecificity, providing selective synthesis of either diastereomer of di- and trisubstituted cyclopropanes. The utility of this methodology is demonstrated by several synthetic applications including the synthesis of the natural product dictyopterene A. 2-Vinyl-4-fluorotetrahydrofurans also undergo stereospecific ring contractions, providing access to synthetically useful hydroxymethyl cyclopropanes.

Full text of DOI:10.1021/jacs.6b07567

Article
pubs.acs.org/JACS
Nickel-Catalyzed Cross-Electrophile Coupling of Alkyl Fluorides:
Stereospecific Synthesis of Vinylcyclopropanes
Lucas W. Erickson, Erika L. Lucas, Emily J. Tollefson, and Elizabeth R. Jarvo*
Department of Chemistry, University of California, Irvine, California 92697-2025, United States
S
* Supporting Information
ABSTRACT: The stereospecific reductive cross-electrophile coupling reaction
of 2-vinyl-4-halotetrahydropyrans for vinylcyclopropane synthesis is reported.
The nickel-catalyzed reaction occurs with both alkyl fluorides and alkyl
chlorides. To the best of our knowledge, this is the first reported cross-
electrophile coupling reaction of an alkyl fluoride. Ring contraction proceeds
with high stereospecificity, providing selective synthesis of either diastereomer
of di- and trisubstituted cyclopropanes. The utility of this methodology is
demonstrated by several synthetic applications including the synthesis of the natural product dictyopterene A. 2-Vinyl-4-
fluorotetrahydrofurans also undergo stereospecific ring contractions, providing access to synthetically useful hydroxymethyl
cyclopropanes.
Scheme 1. Reductive Cross-Electrophile Coupling and
Important Vinylcyclopropanes
INTRODUCTION
■
Alkyl fluorides are typically considered the least reactive of the
alkyl halides. Although alkyl iodides and bromides are potent
alkylating agents that often possess cytotoxicity, alkyl fluorides
are frequently employed as isosteres for the parent hydro-
carbons due to the ability of the C−F bond to mask reactive
C−H positions in bioactive agents.1,2 This decrease in reactivity
is apparent in transition-metal-catalyzed reactions.3−5 For
example, the use of aryl fluorides in cross-coupling reactions
is much less well developed than that of the corresponding
cross-coupling reactions of aryl chlorides, bromides, and
iodides.3,6 While alkyl fluoride cross-coupling reactions have
been established,7−9 more commonly, alkyl fluorides are
tolerated as unreactive moieties in nickel- and palladium-
catalyzed cross-coupling reactions.10 Similarly, cross-electro-
phile coupling reactions employ aryl and alkyl iodides,
bromides, and chlorides;11−13 however, to our knowledge,
there are no examples that employ fluorides as partners
(Scheme 1a). As part of our ongoing interest in the
development of stereospecific reactions of alkyl electrophiles,14
we report a stereospecific ring contraction of 4-fluorotetra-
hydropyrans to access vinylcyclopropanes (Scheme 1b).
Notably, this reaction engages two functional groups that are
considered poor electrophiles, an ether and an alkyl fluoride.
Consistent with cross-coupling and related reactions of aryl
fluorides,15,16 we find that a first-row transition metal catalyst,
specifically a nickel catalyst, is highly effective for this
transformation. Control of stereochemistry is robust and
predictable, providing straightforward access to either diaster-
eomer of the vinylcyclopropane products.
intermediates that participate in a broad range of trans-
formations, including transition-metal-catalyzed rearrangements
Vinylcyclopropanes occur in natural products such as trans-
chrysanthemic acid, FR-900848, ambruticin S, and constano-
lactone G and in medicinal agents including NS3 serine
protease inhibitors paritaprevir and simeprevir (Scheme
1c).17,18 Vinylcyclopropanes are also valuable synthetic
Received: July 29, 2016
© XXXX American Chemical Society
A
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and cycloaddition reactions.19−21 This reactivity has been
utilized in the synthesis of a variety of natural products
including linear triquinanes and Melodinus alkaloids.22 As such,
considerable synthetic effort has been directed toward synthesis
of vinylcyclopropanes. They can be prepared from dienes and
highly reactive α-diazocarbonyls or carbenoids or from enones
via Michael-initiated ring closing reactions.23,24 The majority of
these syntheses result in formation of hydroxymethyl- or acyl-
substituted vinylcyclopropanes. A strategy that provides
vinylcyclopropanes with different substituent patterns would
therefore be desirable.
additional ligand provided a greatly diminished yield of the
desired product (entry 5). Utilizing a nickel(II) precatalyst with
the addition of Xantphos as a ligand resulted in comparable
yield and dr (entry 6). Analysis of NOE data verified the
relative configuration, confirming that trans-1a resulted in trans-
2. To the best of our knowledge, this is the first reported
reductive cross-electrophile coupling with an alkyl fluoride.
To evaluate the breadth of the methodology we examined a
series of tetrahydropyrans where the alkyl fluoride was replaced
with another halide or pseudohalide leaving group. Utilizing
alkyl chloride trans-1b, we were pleased to see both high yield
and stereochemical fidelity when pyridine-based ligand, BPhen,
was employed (Table 1, entry 9). The more reactive alkyl
bromide trans-1c resulted in high yields of the vinyl-
cyclopropane; however, only modest levels of diastereoselec-
tivity were obtained (entries 11−14).29 A substrate bearing a
pseudohalide leaving group, alkyl tosylate trans-1d, provided
low yield with rac-BINAP and Xantphos (entries 15 and 16).
No product was observed with any pyridine-based ligands
(entries 17 and 18). Therefore, we concluded that fluoride- and
chloride-substituted tetrahydropyrans were suitable substrates
for the ring contraction.
RESULTS AND DISCUSSION
■
We recently reported a reductive cross-electrophile coupling
strategy toward the synthesis of arylcyclopropanes from 2-aryl-
4-chlorotetrahydropyrans.25 This strategy employs stable and
readily available starting materials and provides access to a
broad range of substituent patterns with predictable control of
stereochemistry. Since allylic ethers undergo facile nickel-
catalyzed cross-coupling reactions,26 we hypothesized that 4-
halo-2-vinyltetrahydropyrans would undergo ring contraction
to generate vinylcyclopropanes (Table 1). To test our
We set out to determine the absolute configuration of an
enantioenriched product to determine the stereochemical
course of the reaction. Based on our previous work with 2-
aryl-4-chlorotetrahydropyrans,25 we hypothesized that this
reaction would proceed with retention at the allylic ether and
inversion at the alkyl halide. In order to test this hypothesis,
enantioenriched trans-1b was synthesized.30 The absolute
configuration of trans-1b was assigned via X-ray crystallographic
analysis of a precursor.31 The reaction of trans-1b yielded trans-
2 with complete retention of dr and ee. Derivatization of trans-
2 provided a crystalline solid for X-ray analysis31 which affirmed
the absolute configuration of trans-2 (Scheme 2). As
Table 1. Examination of Leaving Groups and Ligands for
trans-4-Halotetrahydropyran
yield
(%)
1 dr
(trans/cis)
2 dr
(trans/cis)
entry
X
SM
ligand
1
2
3
4
5
F
F
F
F
F
F
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1c
1d
1d
1d
1d
rac-BINAP
Xantphos
BPhen
75
20:1
20:1
67
42
21
14
60
61
0
20:1
20:1
20:1
20:1
20:1
20:1
20:1
20:1
20:1
20:1
20:1
20:1
20:1
20:1
20:1
20:1
20:1
17:1
13:1
13:1
20:1
17:1
4:1
Scheme 2. Stereochemical Outcome of Ring Contraction
bipy
none
a
6
Xantphos
rac-BINAP
Xantphos
BPhen
7
Cl
8
Cl
9
Cl
>99
97
98
82
83
99
16
35
0
20:1
7:1
4:1
2:1
5:1
4:1
20:1
4:1
10
11
12
13
14
15
Cl
bipy
Br
rac-BINAP
Xantphos
BPhen
Br
Br
Br
bipy
OTs
OTs
OTs
OTs
rac-BINAP
Xantphos
BPhen
b
16
17
18
anticipated, the reaction proceeds with retention at the allylic
ether and inversion at the alkyl chloride. These results are
consistent with our prior work in ring contraction of aryl-
substituted tetrahydropyrans.25 Experiments to further refine
the mechanism of the ring contraction are ongoing.
bipy
0
a
b
NiCl2(dme) used instead of Ni(cod)2. Yield determined by 1H
NMR based on comparison to PhTMS as internal standard.
hypothesis, we utilized trans-4-fluoro-2-((E)-styryl)tetrahydro-
2H-pyran (trans-1a). This compound is readily prepared by a
Prins reaction of the corresponding aldehyde in the presence of
HBF4·OEt2.27,28 A series of nickel catalysts prepared in situ
from Ni(cod)2 and bidentate ligands were evaluated. Using a
BINAP-ligated nickel complex we obtained a 75% yield of the
desired vinylcyclopropane trans-2 with high diastereoselectivity
(entry 1). Alternative ligands including Xantphos and pyridine-
derived ligands BPhen and bipy resulted in diminished yield
and stereospecificity (entries 2−4).29 Use of Ni(cod)2 with no
After establishing the optimal conditions and determining
the stereochemical outcome for trans-1a−d, we turned to the
more challenging synthesis of cis-disubstituted cyclopropanes.
These substrates provide a more stringent test of the reaction’s
stereospecificity, since the cis diastereomers of cyclopropanes
are disfavored from a thermodynamic perspective. With most of
the cis-substituted tetrahydropyran substrates (cis-1a−d), the
prior conditions provided low yield or low diastereoselectiv-
ity.31 With 4-fluorotetrahydropyran cis-1a, we observed accept-
able yield and high stereospecificity with Xantphos (Table 2,
B
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1b provided high stereospecificity and moderate yield with
Xantphos (entry 4)32 and high yield and moderate stereo-
specificity with Phen (entry 6), indicating a trade-off between
yield and selectivity for this substrate. 4-Bromotetrahydropyran
cis-1c afforded a moderate yield and low stereospecificity with
rac-BINAP and Phen (entries 8 and 10). The addition of
tetrabutylammonium bromide as an additive resulted in a
modest increase in yield and stereospecificity (entry 9).33 As
anticipated, a low yield was observed when tosylate cis-1d was
subjected to the reaction conditions (entry 11). Generally,
reactions featuring low yields were either the result of
byproduct formation or low reactivity of the starting material.32
With conditions in hand for ring contraction to generate
both cis- and trans-substituted cyclopropanes, we aimed to
expand the scope of the reaction. We focused our studies on
alkyl fluorides due to ease of synthesis and potential use in a
wide range of synthetic applications. We synthesized several
substrates with both aryl and alkyl substituents on the vinyl
moiety, beginning with a variety of para-substituted cinnamal-
dehyde derivatives (Table 3). For all substrates, NOE’s were
measured to assign the relative configuration of both starting
materials and products. Using Xantphos as the ligand, trans-4
was generated in good yield and diastereoselectivity. Interest-
ingly, when we subjected the cis diastereomer to identical
reaction conditions, we observed a decreased dr. We found that
increasing the catalyst loading to 10 mol % resulted in
formation of cis-4 with significantly improved diastereoselec-
tivity.34 To evaluate the chemoselectivity of the reaction, we
prepared a substrate featuring an aryl fluoride in addition to the
Table 2. cis-4-Halotetrahydropyran Ligand and Leaving
Group Screen
yield
(%)
1 dr
(cis/trans)
2 dr
(cis/trans)
entry
X
SM
ligand
1
2
3
4
5
6
7
8
F
F
F
1a
1a
1a
1b
1b
1b
1c
1c
1c
1c
1d
Xantphos
rac-BINAP
Phen
56
41
26
47
71
92
30
58
65
68
8
20:1
20:1
20:1
20:1
20:1
20:1
20:1
20:1
20:1
20:1
8:1
20:1
9:1
9:1
20:1
4:1
6:1
2:1
2:1
5:1
2:1
1:1
Cl
Xantphos
rac-BINAP
Phen
Cl
Cl
Br
Xantphos
rac-BINAP
rac-BINAP
Phen
Br
a
9
Br
10
11
Br
OTs
rac-BINAP
a
Bu4NBr (1.0 equiv) added.
entry 1). Here, both rac-BINAP and Phen provided decreased
yield and dr compared with Xantphos (entries 2 and 3).
Xantphos would prove to be our most consistent and versatile
ligand, performing best for the majority of our substrates (vide
infra). When Xantphos provided unsatisfactory yields or dr with
other substrates, we typically evaluated alternative ligands rac-
BINAP, bipy, BPhen, Phen, and 3. 4-Chlorotetrahydropyran cis-
Table 3. Substrate Scope
a
Reactions were performed with 10 mol % loading of Ni(cod)2 and ligand.
C
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alkyl fluoride. Employing bipy in the ring contraction of the
trans diastereomer, the desired product trans-5 was obtained in
modest yield with retention of the diastereomeric ratio. No
reaction occurred at the aryl fluoride, despite the presence of
Grignard reagent in the reaction mixture.6 For the cis
diastereomer, cis-5 was obtained with high stereospecificity by
employing 10 mol % catalyst with Phen as the ligand of choice.
A series of 4-arylcinnamaldehyde derivatives were examined;
products trans-6, cis-6, and trans-7 were formed in good yields
and high diastereoselectivity using Xantphos as the ligand.
We aimed to expand the scope beyond substrates containing
the styrenyl motif to include other vinyl tetrahydropyrans
(Table 3). After evaluation of a series of ligands, 2,6-dipyrazol-
1-ylpyridine (3) was identified as the optimal ligand for the ring
contraction to afford trans-8 in excellent yield and 5:1 dr.
Ligand 3 was also the most effective ligand in the ring
contraction to afford the cis diastereomer (cis-8). Branched
product cis-9 was generated in a modest yield. We attribute the
decrease in yield for cis-9 compared to cis-8 to steric
encumbrance that interferes with ligation of the olefin to the
nickel catalyst.26 Increasing the catalyst loading had no effect on
dr or yield with any of these nonstyrenyl substrates.
ideal ligand for these systems. Formation of secondary alcohol
11 using C-6-substituted tetrahydropyrans 10a and 10b
(entries 1 and 2) proceeded in excellent stereospecificity,
with a higher yield being obtained using alkyl fluoride 10a
(entry 1). To challenge the method with synthesis of
trisubstituted cyclopropanes we examined a series of 3-methyl
and 4-methyltetrahydropyrans (12, 14, and 16, entries 3−6).
These reactions also evaluate the impact of additional
stereogenic centers on the stereospecificity of the reaction.
Consistent with our prior work in ring-opening reactions of
related substrates,25,35 reactions were highly stereospecific,
allowing for controlled synthesis of either 13 or 15 by selection
of the appropriate starting material. Due to the typical difficulty
of synthesizing quaternary stereocenters, one of our priorities
was to utilize this chemistry to synthesize a vinylcyclopropane
product that featured a quaternary stereocenter. Tertiary alkyl
chloride 16 provided an excellent yield and diastereomeric ratio
of trisubstituted cyclopropane 17 bearing a quaternary
stereogenic center (entry 6). Additionally, ring contractions
of substrates 12b and 14 were performed on a >1 g scale
without diminished yield or stereospecificity, indicating that the
method is amenable to large-scale reactions (entries 4 and 5).
These results indicate that our methodology can tolerate
substitution around the ring, enabling facile and selective
synthesis of stereoisomeric trisubstituted vinylcyclopropanes.
We sought to apply the ring contraction to the synthesis of
hydroxymethyl vinylcyclopropanes (e.g., 19). This substituent
pattern is present in natural products such as chrysanthemol
and madolin H. Furthermore, hydroxymethyl vinylcyclopro-
panes and close derivatives have been employed as starting
materials for a wide range of transition metal and Lewis acid
catalyzed addition reactions and rearrangements.20 These
compounds are traditionally prepared by Simmons−Smith or
carbene-mediated reactions;23,24 we envisioned that they would
be straightforward to prepare from suitably substituted
tetrahydrofurans. Both diastereomers of 2-vinyl-3-fluorotetra-
hydrofuran 18 were prepared to evaluate the stereospecificity of
the reaction.36−38 We were pleased to see that each
diastereomer reacted with high stereospecificity (Scheme 3a).
In order to broaden the applications of this chemistry, we
examined substrates containing additional substitution on the
tetrahydropyran ring to access more highly substituted
cyclopropanes (Table 4). As we observed with most
disubstituted tetrahydropyrans, Xantphos proved to be the
Table 4. Ring Contractions of Trisubstituted THPs
Scheme 3. Hydroxymethylcyclopropanes
a
Reactions performed at a scale of >1 g.
D
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Scheme 4. Synthetic Applications of Stereospecific Reductive Ring Contractions
Under standard reaction conditions employing the ligand
Xantphos, trans-18 provided trans-19 in excellent yield and
diastereoselectivity. Similarly, cis-18 gave cis-19 in 92% yield
and 18:1 dr. Both diastereomers of 19 have been utilized in
late-metal-catalyzed rearrangement reactions. For example,
trans-19 has been alkylated by 3-iodopropane and subjected
to a rhodium-catalyzed rearrangement to provide bicyclic ether
20 (Scheme 3b).39 Likewise, a derivative of cis-19 undergoes a
gold-catalyzed rearrangement to form cycloheptadiene 21.40
With the nickel-catalyzed ring contraction method devel-
oped, we aimed to demonstrate its synthetic utility. One benefit
of utilizing alkyl fluorides as electrophiles is their lack of
reactivity under many common reaction conditions. To
demonstrate orthogonal cross-coupling reactions, we designed
substrate cis-22, which displays the requisite functional groups
for a traditional cross-coupling reaction as well as the ring
contraction. We subjected cis-22 to Suzuki−Miyaura cross-
coupling reaction conditions, which yielded cis-23.41 As
anticipated, palladium-catalyzed cross-coupling proceeded
smoothly at the aryl bromide, and no reaction occurred at
the alkyl fluoride or allylic ether (Scheme 4a). Subsequent
submission to ring contraction conditions resulted in excellent
yields and diastereoselectivity of cis-7. Therefore, the cross-
electrophile coupling is orthogonal to standard cross-coupling
reactions. The ring contraction can also be used sequentially
with other cyclopropanation reactions for synthesis of
polycyclopropanes such as the natural products U-106305
and 3-myliene. For example, ring contraction of the requisite
tetrahydropyran provided vinylcyclopropane 13 (Scheme 4b).
A subsequent Simmons−Smith reaction under standard
conditions provided dicyclopropane 24.42
consistent with those previously reported.46 Notably, this
synthesis proceeded in five steps from commercially available
material, and yielded the natural product in excellent
diastereoselectivity.
SUMMARY
■
We report the nickel-catalyzed reductive cross-electrophile
coupling of 2-vinyl-4-halotetrahydropyrans to access vinyl-
cyclopropanes. The ring contraction is stereospecific at both
the allylic ether and alkyl halide, providing controlled access to
di- and trisubstituted cyclopropanes. This is the first reported
reductive cross-electrophile coupling reaction to utilize fluoride
as a leaving group. Orthogonal reactions, including Suzuki
cross-coupling and cyclopropanation reactions are demonstra-
ted, and the reaction is applied in the synthesis of a natural
product, dictyopterene A. Further development of alkyl fluoride
cross-electrophile coupling reactions and mechanistic studies to
further elucidate the mechanism of the ring contraction are
underway.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.6b07567.
■
S
Crystallographic information file for cis-(−)-1D (CIF)
Crystallographic information file for trans-(−)-SI-4
(CIF)
Crystallographic information file for cis-(+)-SI-3(CIF)
Experimental details and characterization data (NMR
spectra and SFC traces) (PDF)
The new cross-electrophile coupling reaction can also be
employed as a key step in the synthesis of the seaweed
pheromone dictyopterene A.43,44 Several previous synthetic
approaches have utilized diazo or carbenoid reagents to furnish
the cyclopropane moiety. Our route to this natural product
began with a Prins cyclization of the commercially available
trans-2-heptenal to provide tetrahydropyran trans-25 (Scheme
4c). Subjection of 25 to the nickel-catalyzed ring contraction
gave alcohol 26, which upon further synthetic manipulation
afforded ( )-dictyopterene A (27).45,46 Spectral data were
AUTHOR INFORMATION
Corresponding Author
*erjarvo@uci.edu
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by NSF-CHE-1464980 and the DoEd
GAANN (PA200A120070 to E.L.L.). We acknowledge Dr.
■
E
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(46) The minor diastereomer, cis-28, is carried through the synthetic
sequence; cis-29 undergoes rapid sigmatropic rearrangement. See the
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(29) See the Supporting Information for results with a more
extensive range of ligands.
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(31) See the Supporting Information for more details.
(32) For example, reaction of substrate cis-1b provided the following
product distribution:
(33) Other standard additives such as MgI2 and CsF provided lower
yields and/or diastereoselectivity; see the Supporting Information for
details.
(34) With 5 mol % catalyst, cyclopropane cis-4 was obtained in 4:1 dr
(53% yield); with 10 mol % catalyst, it was obtained in 19:1 dr (61%).
F
DOI: 10.1021/jacs.6b07567
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX