Nickel-Catalyzed Ring-Opening Allylation of Cyclopropanols via Homoenolate

Article abstract of DOI:10.1021/acs.orglett.1c02072

We report herein a nickel-catalyzed ring-opening allylation of cyclopropanols with allylic carbonates that occurs under mild and neutral conditions. The reaction displays linear selectivity for both linear and branched acyclic allylic carbonates and is also applicable to cyclic allylic carbonates, affording a variety of δ,?-unsaturated ketones in moderate to good yields. Mechanistic experiments are in accord with a catalytic cycle involving decarboxylative oxidative addition of allylic carbonate to Ni(0), alkoxide exchange with cyclopropanol, cyclopropoxide-to-homoenolate conversion on Ni(II), and C-C reductive elimination.

Full text of DOI:10.1021/acs.orglett.1c02072

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Letter
Nickel-Catalyzed Ring-Opening Allylation of Cyclopropanols via
Homoenolate
Yoshiya Sekiguchi, Yan Ying Lee, and Naohiko Yoshikai*
Cite This: Org. Lett. 2021, 23, 5993−5997
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ABSTRACT: We report herein a nickel-catalyzed ring-opening
allylation of cyclopropanols with allylic carbonates that occurs under
mild and neutral conditions. The reaction displays linear selectivity for
both linear and branched acyclic allylic carbonates and is also
applicable to cyclic allylic carbonates, affording a variety of δ,ε-
unsaturated ketones in moderate to good yields. Mechanistic
experiments are in accord with a catalytic cycle involving
decarboxylative oxidative addition of allylic carbonate to Ni(0),
alkoxide exchange with cyclopropanol, cyclopropoxide-to-homoenolate conversion on Ni(II), and C−C reductive elimination.
Scheme 1. Allylation of Metal Homoenolates
etal homoenolates have proved to serve as versatile
organometallic species for the synthesis of β-function-
M
alized carbonyl compounds through interception with various
electrophiles.1 Among such transformations is the allylic
substitution, which represents one of the most extensively
explored C−C coupling reactions of organometallic reagents.
Nakamura and Kuwajima demonstrated the reaction of
preformed zinc homoenolate derived from 1-siloxy-1-alkox-
ycyclopropane with allylic chlorides under copper or nickel
catalysis with SN2′ or SN2 selectivity, respectively, thus
affording δ,ε-unsaturated esters (Scheme 1a).2 Recently,
cyclopropanols have emerged as direct precursors to (catalytic)
metal homoenolates for various C−C and C−heteroatom
bond formations.1a−d As one of the pioneering studies in this
context, in 2012, Cha and co-workers reported ring-opening
allylation of cyclopropanols with allylic halides or phosphates
mediated by stoichiometric amounts of Et2Zn and CuCN·
2LiCl (Scheme 1b).3,4 The reaction was proposed to involve
reversible generation of zinc homoenolate from zinc cyclo-
propoxide and its transmetalation with copper. In parallel with
the copper catalysis of the preformed zinc homoenolate, the
reaction displayed high SN2′ selectivity.
Despite the significant progress in catalytic transformations
of cyclopropanols via homoenolates, allylic substitution with
SN2 or linear selectivity remains underdeveloped. Recent
reports by Ma and co-workers on the palladium-catalyzed
coupling between cyclopropanols and propargyl carbonates or
2,3-allenic carbonates suggest the feasibility of such trans-
formations,5 while their studies underlined the difficulty of
suppressing β-hydride elimination of palladium homoenolate
to give enone as an undesirable byproduct.6 We report herein a
nickel-catalyzed ring-opening coupling between cyclopropanols
and various allylic carbonates with linear selectivity (Scheme
1c), which involves catalytically generated nickel homoenolate
as the key intermediate7,8 and is complementary to Cha’s
Received: June 20, 2021
Published: July 22, 2021
https://doi.org/10.1021/acs.orglett.1c02072
Org. Lett. 2021, 23, 5993−5997
© 2021 American Chemical Society
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Letter
allylation. The present reaction features neutral and non-
cryogenic conditions without using stoichiometric metal
reagents and allows the use of linear, branched, and cyclic
allylic carbonates, thus offering an approach to various δ,ε-
unsaturated ketones that is complementary to others such as
the conjugate addition of allyl nucleophiles9 or enolate
alkylation with homoallyl electrophiles.10 The products are
amenable to various derivatizations employing both the
carbonyl and the olefin moieties as synthetic handles.
With the optimized catalytic system in hand, we first
explored the reaction of various cyclopropanols with cinnamyl
carbonate 2a (Scheme 2). A series of 1-arylcyclopropanols
Scheme 2. Reaction of Various Cyclopropanols with
a
Cinnamyl Carbonate 2a
The present study commenced with exploration of the
coupling between 1-phenylcyclopropanol (1a) and tert-butyl
cinnamyl carbonate (2a) (Table 1). Our initial attempts
a
Table 1. Optimization of Reaction Conditions
b
entry
ligand
none
dppe
solvent
yield (%)
1
2
3
4
5
6
7
8
9
THF
THF
THF
THF
THF
toluene
DMF
tBuOMe
MeCN
MeCN
MeCN
28
32
30
29
51
54
60
69
73
76
84
dppp
DPEphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
c
10
c d
,
11
a
The reaction was performed using 0.10 mmol each of 1a and 2a (0.3
b
M). Determined by GC using mesitylene as an internal standard.
c
d
The reaction was performed at 23 °C. 0.10 mmol of 1a and 0.12
a
b
mmol of 2a were used.
The reaction was performed on a 0.3 mmol scale. The result of a 2
mmol scale reaction is shown in the parentheses.
focused on palladium catalysts in light of their widespread use
in allylic substitution as well as cyclopropanol-derived
homoenolate chemistry.1a−d,5 However, these attempts gave
the linear allylation product 3aa only in low yield (<34%)
along with undesirable byproducts such as acrylophenone or
cyclopropyl cinnamyl ether, which would have been formed via
β-hydride elimination of the palladium homoenolate5 or O-
allylation of the cyclopropanol, respectively (see Table S1). On
the other hand, Ni(cod)2 (10 mol %) was found to promote
the reaction in THF at 60 °C to afford 3aa in a moderate yield
of 28% but without forming the above undesirable byproducts.
Note also that the ring-opening isomerization of 1a to
propiophenone was largely suppressed.
While the use of common diphosphine ligands such as dppe,
dppp, and DPEphos in combination with Ni(cod)2 had
negligible impact on the yield of 3aa or proved even
detrimental (see Table S2), Xantphos was found to improve
the reaction efficiency to give 3aa in 51% yield (entry 5). Upon
screening of solvents with the Ni(cod)2/Xantphos catalyst,
MeCN was identified as the optimal solvent among others
such as toluene, DMF, and tBuOMe, improving the yield of
3aa to 73% (entries 6−9). The reaction temperature could be
lowered to room temperature (23 °C) without a decrease in
the efficiency (entry 10), and further improvement was
achieved using a slight excess (1.2 equiv) of 2a, affording
3aa in 84% yield (entry 11).
participated in the desired allylation to afford the correspond-
ing δ,ε-unsaturated ketones 3aa−3ka in moderate to good
yields (55−89%). A variety of substituents such as methyl,
methoxy, trifluoromethyl, chloro, and bromo groups were
tolerated on the para- or meta-position. A substituent on the
ortho position, such as methoxy group, could also be tolerated,
albeit with somewhat lower yield (see 3ia). The reaction of 1a
could be performed on a 2 mmol scale to afford 3aa in 80%
yield. 1-(2-Naphthyl)- and 2-thienyl-substituted cyclopropa-
nols also smoothly participated in the reaction to afford the
desired products 3ja and 3ka, respectively, in good yields. 1-
Alkylcyclopropanols bearing primary or secondary alkyl groups
were also amenable to the reaction with 2a, furnishing the
desired products 3la and 3ma in good yields. Furthermore,
1,2-disubstituted cyclopropanols 1n and 1o underwent
selective cleavage of the less substituted C−C bond to
produce the α-branched ketone products 3na and 3oa,
respectively.
We next examined the reaction of 1a with various allylic
carbonates (Table 2). Substituted cinnamyl carbonates
smoothly participated in the allylation to afford the
corresponding products in good yields (entries 1 and 2). An
alkyl-substituted linear allylic carbonate also gave the linear
allylation product in good yield (entry 3). Branched allylic
carbonates derived from 1-(hetero)aryl allyl alcohols gave rise
to the linear products in moderate to good yields (entries 4
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Letter
a
yield (entry 10). The ligand-free conditions proved also
effective for a five-membered allyl carbonate (2j) and a six-
membered tertiary allylic carbonate (2k), affording the
corresponding products 3aj and 3ak, respectively, in good
yields (entries 11 and 12). Notably, the reaction of 1a with cis-
configured cyclic carbonate 2l gave rise to the product 3al as a
single diastereomer (entry 13). The diastereochemistry of 3al
was assigned to be trans, which suggested stereochemical
inversion as a mechanistic feature of the present allylation.
To gain insight into the reaction mechanism of the present
ring-opening allylation, several experiments were performed.
First, the reaction of a cinnamyl/cyclopropyl mixed carbonate
4 under the standard conditions afforded the δ,ε-unsaturated
ketone 3aa in good yield (Scheme 3a), which was most likely
Table 2. Reaction of 1a with Various Allylic Carbonates
Scheme 3. Mechanistic Experiments
initiated by oxidative addition of the cinnamyl moiety followed
by decarboxylation, ring-opening of the resulting cyclo-
propoxide to homoenolate, and C−C bond-forming reductive
elimination. The reaction of 4 in the presence of 1 equiv of
cyclopropanol 1c afforded a mixture of 3aa and 3ca in 31% and
51% yields, respectively (Scheme 3b). This result indicates that
exchange between the cyclopropoxide ligand derived from 4
and 1c is faster than the cyclopropoxide ring-opening and
reductive elimination. On the other hand, in the presence of 1
equiv of cinnamyl carbonate 2b, the reaction of 4 afforded 3aa
the major product (35%) along with a small amount of 3ab
(7%) (Scheme 3c). This outcome suggests that alkoxide
exchange between two distinct π-allylnickel(II) species derived
from 4 and 2b could operate to some extent. Note that the
possibility of intermolecular outer-sphere attack of nickel(II)
homoenolate onto π-allylnickel(II) species could be ruled out
as the mechanism of C−C bond formation by the exclusive
formation of the trans-configured 3al from the cis-configured
2l, which would instead support the inner-sphere mechanism.
The low combined yield (42%) could be attributed to the
accumulation of allylnickel(II) tert-butoxide, which would not
have a path to regenerate Ni(0) in the absence of
cyclopropanol. Exposure of 1a to the standard conditions in
the absence of 2a caused only sluggish ring-opening isomer-
ization to propiophenone (Scheme 3d).
a
The reaction was performed on a 0.3 mmol scale under the
b
conditions in Table 1, entry 11. 1j was used instead of 1a, and the
reaction was performed on a 0.6 mmol scale. The reaction was
performed without Xantphos.
c
and 5). Likewise, a tertiary allylic carbonate 2f underwent the
reaction with 1a and 1j, producing the β-prenylated ketones
3af and 3jf, respectively, in moderate yields (entries 6 and 7).
Furthermore, the reaction of 1a with branched allylic
carbonates derived from the products of Morita−Baylis−
Hillman reaction between aldehyde and acrylate ester also
afforded the linear allylation products with moderate E-
stereoselectivity with respect to the newly formed CC bond
(entries 8 and 9).
Under the standard conditions, the reaction of 1a with a
cyclic allyl carbonate derived from cyclohex-2-en-1-ol (2i) was
sluggish and gave the product 3ai only in 25% yield. Upon
additional screening, the reaction was found to proceed
smoothly in the absence of Xantphos, affording 3ai in 70%
Scheme 4 illustrates a plausible catalytic cycle of the present
nickel-catalyzed ring-opening allylation reaction. Oxidative
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Thus, the reaction in the presence of a large excess tBuOK (4
equiv) gave the diastereomer with cis configuration with
respect to the benzoyl and phenyl groups with the
diastereomeric ratio of 4:1.12 By contrast, the use of a catalytic
amount of t-BuOK (0.2 equiv) resulted in the opposite
diastereomer with virtually perfect selectivity (trans/cis >
20:1). We speculate that chelation of the oxygen atoms of the
enolate and the epoxide by a potassium cation during the
cyclization step is responsible for the preferential formation of
the more sterically congested cis isomer under the former
conditions. Finally, we found that the treatment of 3aa with
tBuOK (30 mol %) resulted in dehydrative and dehydrogen-
ative cycloaromatization to give o-terphenyl (8) albeit in a
moderate yield (Scheme 5c). To our knowledge, this is an
unprecedented type of cycloaromatization, and its scope and
mechanism will be the subject of further investigation.13
In summary, we have developed nickel-catalyzed ring-
opening allylation of cyclopropanols with allylic carbonates
to afford δ,ε-unsaturated ketones under mild and neutral
conditions. The reaction displays linear selectivity for both
linear and branched acyclic allylic carbonates and is also
applicable to cyclic allylic carbonates. The stereochemical
probe and control experiments suggest that the reaction
involves π-allylnickel(II) cyclopropoxide and its homoenolate
isomer as the key intermediates. Further studies on catalytic
transformations of cyclopropanols via homoenolates are
underway in our laboratories.14
Scheme 4. Plausible Catalytic Cycle
addition of allyl carbonate 2 to a Ni(0) species and subsequent
decarboxylation would form a π-allylnickel(II) tert-butoxide
species A. Exchange of the tert-butoxide ligand of A with
cyclopropanol 1 would give rise to a π-allylnickel(II)
cyclopropoxide species B, which would rearrange to a π-
allylnickel(II) homoenolate C through β-carbon elimination.
C−C bond-forming reductive elimination of C would furnish
the allylation product 3 while regenerating the Ni(0) species.
The δ,ε-unsaturated ketones obtained by the present
allylation are amenable to further transformations utilizing
both the olefinic and carbonyl functionalities, as illustrated in
Scheme 5. With the geminal methyl groups at the olefinic
ASSOCIATED CONTENT
* Supporting Information
■
sı
Scheme 5. Product Transformations
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02072.
Experimental procedures and spectral data of all new
compounds. (PDF)
Accession Codes
CCDC 2090722 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Naohiko Yoshikai − Division of Chemistry and Biological
Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University, Singapore 637371,
Singapore; Graduate School of Pharmaceutical Sciences,
Tohoku University, Sendai 980-8578, Japan; orcid.org/
0000-0002-8997-3268; Email: naohiko.yoshikai.c5@
tohoku.ac.jp
Authors
terminus, 3jf proved to be a suitable substrate for FeCl3-
catalyzed intramolecular carbonyl−olefin metathesis,10 afford-
ing the cyclopentene derivative 5 in 50% yield (82% brsm)
(Scheme 5a). Epoxidation of 3aa with mCPBA and subsequent
treatment of the product 6 with t-BuOK resulted in the
intramolecular addition of ketone enolate to the epoxide in a 5-
exo-tet fashion to afford the cyclopentanol derivative 7
(Scheme 5b).11 Interestingly, the diastereoselectivity of the
latter step was controlled by the amount of tBuOK added.
Yoshiya Sekiguchi − Division of Chemistry and Biological
Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University, Singapore 637371,
Singapore
Yan Ying Lee − Division of Chemistry and Biological
Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University, Singapore 637371,
Singapore
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E. Regio- and Stereoselectivity in the Cyclization of Enolates Derived
from 4,5-, 5,6-, and 6,7-Epoxy-1-Phenyl-1-Alkanones. Competition
between C- and O-Alkylation. Tetrahedron 1999, 55, 5853−5866.
(12) The diastereochemistry of the major isomer was confirmed by
the X-ray crystallographic analysis of the analogous product (cis-7-Br;
CCDC 2090722) obtained from 3fa. See the Supporting Information
for details.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02072
Notes
The authors declare no competing financial interest.
(13) We speculate that the reaction involves Cope rearrangement of
the enolate or enol form of 3aa, dehydration, 6π electrocyclization,
and dehydrogenative aromatization.
(14) (a) Sekiguchi, Y.; Yoshikai, N. Enantioselective Conjugate
Addition of Catalytically Generated Zinc Homoenolate. J. Am. Chem.
Soc. 2021, 143, 4775−4781. (b) Yang, J.; Sekiguchi, Y.; Yoshikai, N.
Cobalt-Catalyzed Enantioselective and Chemodivergent Addition of
Cyclopropanols to Oxabicyclic Alkenes. ACS Catal. 2019, 9, 5638−
5644.
ACKNOWLEDGMENTS
■
This work was supported by the Ministry of Education
(Singapore) and Nanyang Technological University
(MOE2016-T2-2043 and RG101/19). We thank Dr. Yongxin
Li (Nanyang Technological University) for his assistance with
the X-ray crystallographic analysis.
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