Palladium-Catalyzed Alkene Carboalkoxylation Reactions of Phenols and Alcohols for the Synthesis of Carbocycles

Article abstract of DOI:10.1021/acs.orglett.7b01975

Intermolecular alkene difunctionalization reactions between terminal alkenes bearing a pendant aryl or alkenyl triflate electrophile and exogenous alcohol or phenol nucleophiles are described. These transformations afford substituted indanyl or alkylidene

Full text of DOI:10.1021/acs.orglett.7b01975

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Alkene Carboalkoxylation Reactions of Phenols
and Alcohols for the Synthesis of Carbocycles
Derick R. White, Madeline I. Herman, 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: Intermolecular alkene difunctionalization reactions between
terminal alkenes bearing a pendant aryl or alkenyl triflate electrophile and
exogenous alcohol or phenol nucleophiles are described. These trans-
formations afford substituted indanyl or alkylidenecyclopentyl ethers in high
yield with excellent diastereoselectivity. The transformations proceed through
intermolecular capture of an intermediate [Pd(II)-alkene]+[OTf]− complex by
the alcohol or phenol nucleophile.
lkene difunctionalization reactions represent a powerful
synthetic tool for the rapid construction of two new bonds
transesterification reactions with alkoxides that would lead to
destruction of substrates such as 1.5
A
and up to two new stereocenters via 1,2-addition to an alkene.1
We recently reported a Pd-catalyzed alkene carboamination
reaction between 2-allylphenyl triflates 1 and exogenous amine
nucleophiles that affords cyclopentylamine derivatives 2 in good
yield and high stereoselectivity (Scheme 1).2 During the course
Despite these potential challenges, the development of a
coupling reaction between 1 and alcohols/phenols would
provide rapid access to O-substituted indanes and cyclo-
pentenoid derivatives, which are useful synthetic intermediates6
that are prevalent in pharmaceuticals,7 natural products,8
fragrances,9 agrochemicals,10 and materials.10 In addition, this
approach may have significant advantages over existing methods
for the construction of alkylidenecyclopentyl ether derivatives.
The most common methods for the synthesis of these
compounds involve substitution reactions of cycloalkyl halides
or Mitsunobu reactions of cyclic secondary alcohols.11
Substitution reactions between alcohols or alkoxides and
secondary alkyl electrophiles often require harsh reaction
conditions and suffer from (a) competing elimination reactions
and (b) competition between SN1 and SN2 pathways that leads to
mixtures of stereoisomers.12 The synthesis of ethers bearing 3°-
alkyl groups are particularly challenging since 3° alkyl halides do
not participate in SN2 reactions, and substitution reactions of
tertiary alcohols are often slow due to steric hindrance.13,14
In our preliminary studies, we investigated the reactivity of 2-
allylphenyl triflate derivatives 4a−f with phenol nucleophiles,
which we reasoned would be completely deprotonated under the
reaction conditions to provide nucleophilic phenoxides. The aryl
triflate substrates were prepared in three steps from the
corresponding phenols via O-allylation, aromatic Claisen
rearrangement, and then treatment with triflic anhydride. We
initially examined conditions that we previously developed with
amine nucleophiles,2 and we were pleased to discover that a
minor modification to these conditions (use of RuPhos15 as
ligand in place of BrettPhos)16 provided products in good to
excellent yield for most transformations.2,17 As shown in Scheme
2, electron-donating or -withdrawing substituents in the 4-
position of the aryl triflate (R1 = H, F, OCH3; 5a−j) were
Scheme 1. Pd-Catalyzed Intermolecular
Carboheterofunctionalization Reactions
of those studies, we observed that weak nucleophiles such as
amides or sulfonamides were not effectively coupled, whereas
more nucleophilic amines such as pyrrolidine or morpholine
afforded products in excellent yield. These effects are not
surprising, as the mechanism of these reactions involves capture
of cationic Pd−alkene complex 3 by the nucleophile, and the rate
of that process relative to that of potential competing side
reactions should be nucleophile dependent.
Due to the dependency of reaction efficiency on substrate
nucleophilicity, we were curious as to whether oxygen
nucleophiles could be employed in analogous carboalkoxylation
reactions. We felt that these reactions may be challenging to
develop since alcohols and phenols are considerably less
nucleophilic than aliphatic amines. In addition, Pd-catalyzed
oxidation of alcohols to aldehydes or ketones is well established,3
and competing cross-coupling of the aryl/alkenyl triflate with the
alcohol to afford an enol ether or aryl ether may also be
problematic.4 Aryl and alkenyl triflates can also undergo
Received: June 28, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01975
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Organic Letters
Letter
3). After screening several other chiral ligands, the (R)-SDP
ligand was found to deliver 5p with high enantioselectivity (96:4
Scheme 2. Alkene Carboalkoxylation Reactions between o-
Allylphenyl Triflates and Phenols
a
Scheme 3. Asymmetric Alkene Carboalkoxylation
er) but modest chemical yield (27%), and these conditions did
not prove to be general as efforts to employ other phenol
nucleophiles have thus far produced very low yields of the desired
products. Thus, the asymmetric transformations, although
feasible, will require further catalyst development to increase
scope and efficiency.
Our prior studies with amine nucleophiles suggested that
alkenyl triflates may also function as electrophiles in the alkene
carboalkoxylation reactions.2b As such, we prepared a series of
both cyclic and acyclic alkenyl triflates bearing pendant alkenes in
two to four steps from ketones via alkylation followed by
subsequent O-triflation of the kinetic enolate. As shown in
Schemes 4 and 5, the coupling reactions of the alkenyl triflate
substrates with a variety of phenols were highly efficient and
afforded the desired products with excellent diastereoselectivity.
For some specific substrate combinations one of two ligands
(BrettPhos and RuPhos) and one of two bases (t-BuONa and t-
BuOLi) proved to be superior to the other. But in many cases, the
two ligands or bases could be interchanged without substantial
impact on chemical yield or stereoselectivity. Phenols bearing
chloro or fluoro groups were viable coupling partners, as was the
heterocyclic phenol 5-hydroxyquinoline. Primary and secondary
aliphatic alcohols were coupled without significant competing
oxidation to the corresponding aldehydes or ketones. The
isolated yields of 7e−g, which derive from ethanol, hexanol, or
cyclopentanol, were low, but this is mainly due to the volatility of
these products, as 1H NMR yields (shown in parentheses) were
significantly higher. Moreover, the coupling of the heavier 3-
phenylpropanol with 6a afforded 7h in 74% yield. Although the
transformations were effective with a variety of alcohol
nucleophiles, efforts to employ hydroxide as the nucleophile
were unsuccessful due to competing hydrolysis of the triflate.20
The scope of this method with respect to the alkenyl triflates is
also quite broad, as substrates bearing fused dihydropyran (6e)
or dihydropyridine (6d) groups were transformed to 7l−n in
high yield and >20:1 dr. Reactions of cyclohexenyl and
cyclopentenyl triflates 6b, 6h, and 6i that contain a substituent
in the homoallylic position also proceeded smoothly to afford
7i−j, 7r, and 7s−t in good yield with excellent diastereose-
lectivity (>20:1). Gratifyingly, tertiary-substituted ethers 7k and
7o were also formed in good yield with 8:1 and >20:1 dr,
respectively, from substrate 6c or 6g that contains a 1,1-
disbustituted alkene.21 These latter results stand in stark contrast
to our previous investigations using amine nucleophiles, as efforts
to couple 1,1-disubstituted alkenes with amines led to very low
a
Reaction conditions: Pd(OAc)2 (4 mol %), RuPhos (10 mol %), Ar-
OH (1.2 equiv), t-BuOLi (1.4 equiv), 4a−f (1.0 equiv, 0.1 mmol), [0.1
M]. Yields are isolated yields. Xylenes was used as solvent. The
reaction was conducted on a 1.0 mmol scale. Mesitylene was used as
solvent. Toluene was used as solvent. RuPhos (6 mol %) and t-
b
c
d
e
f
BuONa (1.4 equiv) base were used as ligand and base.
tolerated, as were substituents adjacent to the C(aryl)−OTf bond
(5k−q), although in some cases lower yields were obtained with
these more hindered substrates. A substrate (4f) bearing an
allylic substituent was efficiently converted to 5r in 98% yield and
>20:1 dr.18
As expected, the combined nucleophilicity of the phenol and
electrophilicity of the aryl triflate had a significant impact on
reactivity and chemical yield. In general, couplings between
electron-poor aryl triflates and electron-rich phenol nucleophiles
proceed at lower reaction temperatures and shorter reaction
times (e.g., 5g, 95 °C/1 h) than are required for the coupling of
electron-rich aryl triflates and electron-poor phenol nucleophiles
(e.g., 5f, 130 °C/16 h and 5n, 160 °C/13.5 h). This is likely due
to the influence of the arene substituent on the electrophilicity of
the metal center in intermediate 3 (Scheme 1), as electron-
donating groups will diminish the electrophilicity of the metal,
but electron-withdrawing groups increase the electrophilicity of
the metal and thereby increase the reactivity of the coordinated
alkene toward nucleophilic attack.19
We have previously shown that Pd-catalyzed couplings of
substituted 2-allylphenyl triflate derivatives with amines proceed
with high levels of enantioselectivity (up to 99:1 er) when
(S)-tBuPhox is used as the ligand.2a As such, we examined an
analogous asymmetric carboalkoxylation reaction between 2-
allyl-1-naphthyl triflate (4e) and 4-methoxyphenol. Unfortu-
nately, only a trace amount of product was generated (Scheme
B
DOI: 10.1021/acs.orglett.7b01975
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Letter
Scheme 4. Alkene Carboalkoxylation Reactions between
Cyclic Alkenyl Triflates and Phenols or Alcohols
Scheme 5. Alkene Carboalkoxylation Reactions between
a
a
Acyclic Alkenyl Triflates and Phenols or Alcohols
a
Reaction conditions: Pd(OAc)2 (4 mol %), RuPhos (6 mol %), t-
BuONa (1.4 equiv), R−OH (1.2 equiv), 8a−g (1.0 equiv, 0.1 mmol),
toluene (0.1 M), 95 °C, 15 min to 16 h. Yields are isolated yields.
b
CPhos (6 mol %) was used as the ligand.
The mechanism of the alkene carboalkoxylation reactions is
likely similar to that of our previously reported carboamination
reactions,2 and involves oxidative addition of the aryl/alkenyl
triflate to Pd(0) followed by alkene complexation to afford
intermediate 3. This intermediate can then undergo anti-
oxypalladation followed by C−C bond-forming reductive
elimination to afford the product. The stereochemical outcome
of the transformations shown in Schemes 4 and 5 may derive
from reaction through a chairlike conformation of this
intermediate in the alkene oxypalladation step. As shown in
Scheme 6, reaction of substrates 6 through a chair/half-chair
a
Reaction conditions: Pd(OAc)2 (4 mol %), BrettPhos (10 mol %), t-
Scheme 6. Stereochemical Model
BuONa (1.4 equiv), R−OH (1.2 equiv), 6a−i (1.0 equiv, 0.1 mmol),
b
toluene (0.1 M), 95 °C, 14−24 h. Yields are isolated yields. t-BuOLi
c
(1.4 equiv) was used as base. The reaction was conducted at 70 °C.
d
e
BrettPhos (6 mol %) was used. Crude yields in parentheses were
determined by 1H NMR integration using phenanthrene as an internal
f
standard. Diastereomeric ratio was determined after Boc deprotection.
g
This product contained 4% of an inseparable alkene regioisomer.
yields of the desired products.2b The coupling of tetrasubstituted
alkenyl triflate 6j with 1-naphthol afforded 7u in 73% yield (eq
1).
conformation (10) would afford products 7 with the observed
stereochemistry. Similarly, substrates 8 are converted to
alkylidenecyclopentyl ethers 9 via chairlike conformations 11
in which the larger homoallylic substituent R1 is positioned in a
pseudoequatorial orientation to avoid a 1,3-diaxial interaction
with the alkene R2 group. The modest (4:1) dr obtained in the
conversion of 8d to 9d may be due to a small difference in energy
for equatorial vs axial orientation of the relatively small OBn
group. Alternatively, it is also possible that there may be a
stereoelectronic preference for axial orientation of the OBn
group similar to that observed in additions of nucleophiles to
oxocarbenium ions.23 However, the reasons for the modest dr in
conversion of 8g to 9g are unclear, as both the steric and
Transformations of dienyl triflates 8a−g provided ether-
substituted alkylidenecyclopentanes 9a−g in good yields with
moderate to excellent stereocontrol. The diastereoselectivities in
reactions of 8c−e were dependent on the size of the substituent
adjacent to the triflate, with larger substituents leading to higher
selectivities. Substrate 8e was transformed to tertiary alkyl ether
9e in moderate yield but with high stereocontrol. In addition,
substrates 8f−g were converted to spirocyclic products 9f−g in
good yield.22
C
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Organic Letters
Letter
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stereoelectronic effects should be complementary and lead to the
formation of 9g with high selectivity, but this was not observed.
In conclusion, the Pd-catalyzed coupling of aryl or alkenyl
triflates bearing pendant alkenes represents a new method for the
stereoselective synthesis of a variety of 2-indanyl ethers and
ether-substituted alkylidenecyclopentane derivatives. The prod-
ucts are generated in good yields and high diastereoselectivities
in most cases, and a number of functional groups, including
chloro, fluoro, quinoline, ester, alkene, ether, and carbamate
groups, are tolerated. In addition, this method also provides
access to 3°-alkyl ethers that are difficult to access in a
stereocontrolled fashion. Future studies will be directed toward
improving enantioselectivities in reactions of prochiral sub-
strates.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01975.
1
Experimental procedures, characterization data, and H
and 13C NMR spectra for all new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jpwolfe@umich.edu.
ORCID
(12) (a) Winstein, S.; Roberts, R. M. J. Am. Chem. Soc. 1953, 75, 2297.
(b) Feuer, H.; Hooz, J. In The Chemistry of the Ether Linkage; Patai, S.,
Ed.; Wiley: New York, 1967; p 445.
(13) (a) Subramanian, R. S.; Balasubramanian, K. K. Synth. Commun.
1989, 19, 1255. (b) Sankara Subramanian, R. S.; Balasubramanian, K. K.
Tetrahedron Lett. 1989, 30, 2297. (c) Shi, Y.-J.; Hughes, D. L.;
McNamara, J. M. Tetrahedron Lett. 2003, 44, 3609. (d) Lanning, M. E.;
Fletcher, S. Tetrahedron Lett. 2013, 54, 4624.
John P. Wolfe: 0000-0002-7538-6273
Notes
The authors declare no competing financial interest.
(14) Shintou, T.; Mukaiyama, T. J. Am. Chem. Soc. 2004, 126, 7359.
(15) Milne, J. E.; Buchwald, S. L. J. Am. Chem. Soc. 2004, 126, 13028.
(16) Fors, B. P.; Watson, D. A.; Biscoe, M. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2008, 130, 13552.
(17) BrettPhos ligand may also be utilized to afford product in good
yield, although slightly better results were usually obtained with RuPhos.
(18) The trans-1,2-disubstituted indane product stereochemistry
matches that of previous investigations utilizing 2-(but-3-en-2-yl)phenyl
triflate and pyrrolidine nucleophile; see ref 2b.
ACKNOWLEDGMENTS
■
We thank the University of Michigan for financial support of this
work. D.R.W.’s studies were also supported in part by a Bristol-
Myers Squibb Graduate Research Fellowship, for which he is
grateful. We thank Ms. Janelle Kirsch, University of Michigan
Department of Chemistry, for assistance with stereochemical
assignments.
(19) For studies on highly electrophilic cationic-Pd activation of
alkenes, see: Hahn, C.; Morvillo, P.; Vitagliano, A. Eur. J. Inorg. Chem.
2001, 2001, 419.
(20) The main side products observed in the transformations
described in Schemes 2−5 result from base-mediated cleavage of the
triflate to afford the corresponding phenol or ketone (after enol
tautomerization), or from reduction of the aryl or alkenyl triflate starting
material.
(21) Efforts to employ substrates bearing 1,2-disubstituted alkenes
have thus far produced only small amounts of desired products.
(22) Efforts to prepare an unsubstituted analog of 8 (R1, R2, R3 = H)
have thus far been unsuccessful due to the formation of inseparable
mixtures of enol triflate regioisomers that result from modest
regioselectivity during enolate generation.
(23) Electrostatic stabilization for pseudoaxial conformers of
oxocarbenium ions by heteroatom substituents in nucleophilic
substitution reactions has previously been proposed: Ayala, L.;
Lucero, C. G.; Romero, J. A. C.; Tabacco, S. A.; Woerpel, K. A. J. Am.
Chem. Soc. 2003, 125, 15521.
REFERENCES
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D
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