Pd-Catalyzed Alkene Difunctionalization Reactions of Malonate Nucleophiles: Synthesis of Substituted Cyclopentanes via Alkene Aryl-Alkylation and Akenyl-Alkylation

Article abstract of DOI:10.1021/acs.orglett.9b01258

The Pd-catalyzed coupling of malonate nucleophiles with alkenes bearing tethered aryl or alkenyl triflates is described. These alkene difunctionalization reactions afford malonate-substituted cyclopentanes that contain fused aryl or cycloalkenyl rings. Th

Full text of DOI:10.1021/acs.orglett.9b01258

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Pd-Catalyzed Alkene Difunctionalization Reactions of Malonate
Nucleophiles: Synthesis of Substituted Cyclopentanes via Alkene
Aryl-Alkylation and Akenyl-Alkylation
Derick R. White, Elsa M. Hinds,† Evan C. Bornowski,† and John P. Wolfe*
Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109-1055, United States
S
* Supporting Information
ABSTRACT: The Pd-catalyzed coupling of malonate nucle-
ophiles with alkenes bearing tethered aryl or alkenyl triflates is
described. These alkene difunctionalization reactions afford
malonate-substituted cyclopentanes that contain fused aryl or
cycloalkenyl rings. The transformations generate a five-
membered ring, two C−C bonds, and provide products
bearing up to three stereocenters with good chemical yield and generally high diastereoselectivity.
n recent years, transition metal-catalyzed alkene difunction-
alization reactions that form two carbon−carbon bonds
malonate substituted cyclopentanes have found prior utility as
synthetic intermediates.4,5 The results of our preliminary
studies are described in this manuscript.
I
have emerged as powerful tools for the construction of
substituted alkanes, heterocycles, and carbocycles.1 Our group
has described a new series of Pd-catalyzed alkene difunction-
alization reactions that involve the coupling of amine,2
alcohol/phenol,3 or indole1i nucleophiles with alkenes tethered
to aryl or alkenyl triflates (Scheme 1). The transformations
In initial experiments, we examined the coupling of 2-
allylphenyltriflate 4a with diethyl malonate using conditions
that previously were effective in analogous reactions of amines
or alcohol nucleophiles.2b,3 We were gratified to find those
conditions, which employed a Pd(OAc)2/BrettPhos catalyst,
LiOtBu as base, toluene solvent, and a temperature of 95 °C
also performed well with malonates. The desired product 5a
was obtained in 93% isolated yield on a 0.2 mmol scale, and
upon scale up to 1 mmol, the product was obtained in
comparable but slightly lower (84%) isolated yield (eq 3).
Scheme 1. Prior Studies
Given this initial success, we briefly surveyed the reactivity of
several different aryl triflate substrates. As shown in Scheme 2,
transformations of terminal alkene substrates 4b−d proceeded
smoothly to afford 5b−d in good chemical yield. Substrate 4d
that contains an allylic methyl group was converted to trans
disubstituted product 5d with high (>20:1) diastereoselectiv-
ity. However, reactions of substrates 4e−g that contain 1,2-
disubstituted alkenes were much more challenging.6 The
binding of the more sterically hindered alkene to the Pd-center
is less favorable, and these substrates are also prone to base-
mediated isomerization of the alkene. In addition, the sluggish
reactivity of these substrates led to other competing side
reactions such as base-mediated cleavage of the triflate to yield
the corresponding phenoxide. After some experimentation, we
found that decreasing the reaction temperature to 65 °C
generate functionalized cyclopentane derivatives in good yield
with high diastereoselectivity. For example, treatment of 1a
with morpholine in the presence of Pd(OAc)2, BrettPhos, and
LiOtBu afforded 2 in 76% yield with >20:1 dr (Scheme 1, eq
1), and similar conditions affected the coupling of 1a with 3-
phenylpropanol to provide 3 in 74% yield and >20:1 dr
(Scheme 1, eq 2).
We sought to explore the use of malonates as carbon
centered nucleophiles in alkene aryl-alkylation or alkenyl-
alkylation variants of these transformations. Malonate anions
are good nucleophiles with basicity that is comparable to that
of phenoxides, so the feasibility of the transformation seemed
high. Importantly, the resulting malonate-substituted cyclo-
pentane products could be further elaborated through
manipulation of the malonate or functionalization of the
double bond in alkenyl-triflate derived products. Moreover,
Received: April 10, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01258
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Letter
a b c
, ,
a b c
, ,
Scheme 2. Reactions of Aryl Triflates
Scheme 3. Reactions of Alkenyl Triflates
a
Conditions: 1.0 equiv 4, 1.2 equiv diethyl malonate, 1.4 equiv
LiOtBu, 4 mol % Pd(OAc)2, 6 mol % BrettPhos, toluene (0.1 M), 95
°C, 16 h. Reactions were conducted on a 0.1−0.25 mmol scale.
b
Diastereomeric ratios were determined by 1H NMR analysis.
Diastereomeric ratios were identical for crude reaction mixtures and
c
isolated compounds unless otherwise noted. Yields are average
d
isolated yields of two or more experiments. Reaction was conducted
e
using (BrettPhos)Pd(allyl)(Cl) in place of Pd(OAc)2. Reaction was
conducted using 2.2 equiv of LiOtBu and 3.6 equiv of diethyl
malonate, a substrate concentration of 0.8 M, and a reaction
temperature of 65 °C.
a
Conditions: 1.0 equiv 1, 1.2 equiv diethyl malonate, 1.4 equiv
LiOtBu, 4 mol % Pd(OAc)2, 6 mol % BrettPhos, toluene (0.1 M), 95
°C, 16 h. Reactions were conducted on a 0.1−0.25 mmol scale.
b
Diastereomeric ratios were determined by 1H NMR analysis.
diminished the amount of alkene isomerization, and when the
amounts of diethyl malonate and base were increased to 3.6
and 2.2 equiv, respectively, products 5e−g were obtained in
modest yield and excellent (>20:1) diastereoselectivity.
As shown in Scheme 3, the reactions are also effective using
alkenyl triflate substrates 1a−k. The substrates can easily be
prepared from the corresponding cyclic ketones via allylation
followed by enol triflate formation.7 Transformations of
terminal alkene substrates 1a−f proceeded smoothly under
our standard conditions to afford 6a−f in good yield and
generally high diastereoselectivity. The presence of heter-
oatoms in the starting material is well tolerated (6b−c), as was
the presence of a methyl group at the internal position of the
alkene (6d and 6f). In addition, malonates bearing an allyl (6f)
or benzyl substituent (6i) were also effective coupling partners,
although use of smaller ligands (RuPhos or S-Phos) was
required.
Reactions of alkenyl triflate substrates bearing tethered
internal alkenes proved to be even more challenging than the
corresponding reactions of aryl triflates. Efforts to employ
either the standard conditions, or the conditions that were
effective with aryl triflates, led to very low yields of desired
products (<5%), along with significant amounts of a side
product resulting from reduction of the triflate group. We
reasoned that a smaller phosphine ligand might lead to
improved results, as complexation of the more sterically
Diastereomeric ratios were identical for crude reaction mixtures and
c
isolated compounds unless otherwise noted. Yields are average
d
isolated yields of two or more experiments. Reaction was conducted
e
using RuPhos as ligand. Reaction was conducted using 2.2 equiv of
LiOtBu and 3.6 equiv of diethyl malonate, a substrate concentration of
f
g
0.8 M. Reaction was conducted using S-Phos as ligand. Reaction was
h
conducted using Pd(acac)2 in place of Pd(OAc)2. Reaction was
conducted in xylenes solvent at 110 °C.
hindered 1,2-disubstituted alkenes to the metal center is more
difficult. As such, we explored the use of different phosphine
ligand palladium sources7 and after some experimentation
found that the combination of Pd(acac)2 and either S-Phos or
RuPhos provided the best results for most internal alkene
substrates (1g−k). In all cases, products bearing three
stereocenters were generated with >20:1 diastereoselectivity,
with products resulting from anti-addition of the alkenyl group
and the malonate to the double bond. Not surprisingly, the
coupling of a substituted malonate with a disubstituted alkene
proceeded in lower yield. However, the transformation of
substrate 1i bearing an alkenyl methyl group proceeded in
considerably lower yield than the analogous reaction of 1g,
which contained an alkenyl phenyl substituent.
Substrates 1g and 1h, which differ in the nature of their R
substituent (H vs CO2Et), were transformed to 6g and 6h,
respectively, in comparable yield. However, the outcome of
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DOI: 10.1021/acs.orglett.9b01258
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Letter
related cyclopentane-derived substrates 1j and 1k was much
different, as 1j was converted to 6k in 79% yield, but the
coupling of 1k with diethyl malonate afforded 6l in only 21%
yield. The difference in the reactivity of 1j and 1k is likely due
to a Thorpe-type effect,8 but the difference in reactivity of
cyclohexene substrate 1h and cyclopentane substrate 1k is
presumably a result of ring strain in the transition state for the
formation of bicyclo[3.3.0]octane product 6l.
Scheme 5. Proposed Mechanism
We also briefly examined the reactivity of acyclic alkenyl
triflate substrate 7. As shown in eq 4, this transformation
afforded spirocyclic compound 8 in 82% yield with >20:1 dr.
However, preliminary efforts to employ other acyclic alkenyl
triflates led to complex mixtures of products; future efforts will
be directed toward improving the desired reactivity of these
substrates.
carbopalladation of the alkene through chairlike conformation
11. The resulting intermediate 12 then affords the product 6
via reductive elimination, which also regenerates the active
Pd(0) catalyst. The stereochemical outcome of these reactions
is consistent with prior models involving minimization of
nonbonding interactions in chairlike transition states similar to
11.2,3
In conclusion, we have developed a new Pd-catalyzed alkene
difunctionalization reaction between malonate nucleophiles
and alkenes bearing tethered alkenyl or aryl triflate electro-
philes. The transformations generate two carbon−carbon
bonds and provide products that contain up to three
stereocenters with good to excellent diastereoselectivity. We
have also demonstrated that use of smaller phosphine ligands
allows for transformations of substrates bearing 1,2-disub-
stituted alkenes. Future studies will be directed toward
expanding the scope of these transformations to other types
of carbanion nucleophiles.
Although we have focused the bulk of our preliminary
studies on reactions of diethyl malonate as a nucleophile, other
activated methylene nucleophiles can be employed in these
transformations. As shown in Scheme 4, the coupling of 1a
Scheme 4. Reactions of Other Activated Methylene
Nucleophiles
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01258.
Experimental procedures, characterization data, copies of
1H and 13C NMR spectra for all new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jpwolfe@umich.edu.
ORCID
with ethyl acetoacetate proceeded under standard conditions
to afford 9a in 83% yield as a 1:1 mixture of diastereomers
epimeric at the stereocenter adjacent to the carbonyl groups
(Scheme 4, eq 5). Use of triethyl phosphonoacetate provided
9b in 55% yield and 1:1 dr,9 although use of LiHMDS as base
was needed to obtain optimal results (Scheme 4, eq 6). The
reactivity of ethyl cyanoacetate proved to be more challenging,
but after some optimization we found that use of (BrettPhos)-
Pd(allyl)(Cl) as the precatalyst,10 combined with Cs2CO3 as
base and dioxane as solvent, provided 9c in 50% yield (Scheme
4, eq 7). Although the coupling reactions of 1a with other
malonate derivatives provided moderate amounts of the
desired products, efforts to combine internal alkene substrates
(e.g., 1g) with these nucleophiles were unsuccessful.
John P. Wolfe: 0000-0002-7538-6273
Author Contributions
†These authors made equal contributions to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the NIH-NIGMS (GM 124030) for
financial support of this work. E.M.H. was partially supported
by a University of Michigan Rackham dissertation fellowship.
REFERENCES
■
The mechanism of these reactions is likely similar to that of
related transformations of amine or alcohol nucleophiles.2b,3 As
shown in Scheme 5, oxidative addition of the alkenyl (or aryl)
triflate to Pd(0) generates intermediate 10, which then
undergoes coordination of the alkene to Pd followed by anti-
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D
DOI: 10.1021/acs.orglett.9b01258
Org. Lett. XXXX, XXX, XXX−XXX