Enantioselective Synthesis of Tertiary Allylic Fluorides by Iridium-Catalyzed Allylic Fluoroalkylation

Article abstract of DOI:10.1002/anie.201807474

Few allylic electrophiles containing two different substituents at a single allyl terminus and none in which one of the two substituents is a heteroatom, have been shown previously to react with iridium catalysts to form substitution products. We report that iridium-catalysts are uniquely suited to form tertiary allylic fluorides enantioselectively by the addition of a diverse range of carbon-centered nucleophiles at the fluorine-containing terminus of 3-fluoro-substituted allylic esters. The products contain tertiary stereogenic centers bearing a single fluorine, which are isosteric with common tertiary stereocenters containing a single hydrogen. Computational studies reveal the principal steric interactions influencing the stability of endo and exo π-allyl intermediates formed from 3,3-disubstituted allylic electrophiles.

Full text of DOI:10.1002/anie.201807474

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Accepted Article
Title: Enantioselective Synthesis of Tertiary Allylic Fluorides by Iridium-
Catalyzed Allylic Fluoroalkylation
Authors: Trevor W Butcher and John F. Hartwig
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Enantioselective Synthesis of Tertiary Allylic Fluorides by
Iridium-Catalyzed Allylic Fluoroalkylation
Trevor W. Butcher and John F. Hartwig*
Abstract: Few allylic electrophiles containing two different
substituents at a single allyl terminus and none in which one of the
two substituents is a heteroatom have been shown previously to react
with iridium catalysts to form substitution products. We report that
iridium-catalysts are uniquely suited to form tertiary allylic fluorides
enantioselectively by the addition of a diverse range of carbon-
centered nucleophiles at the fluorine-containing terminus of 3-fluoro-
substituted allylic esters. The products contain tertiary stereogenic
centers bearing a single fluorine, which are isosteric with common
tertiary stereocenters containing a single hydrogen. Computational
studies reveal the principal steric interactions influencing the stability
of endo and exo π-allyl intermediates formed from 3,3-disubstituted
allylic electrophiles.
Isosteric replacements of fluorine for hydrogen, including those at
stereogenic
centers,
imbue
favorable
properties
to
pharmaceutical candidates.[1] In this vein, fully substituted
stereogenic centers bearing a single fluorine atom are isosteric
with common tertiary stereogenic centers bearing a single
hydrogen. However, methods to prepare compounds containing
such units are underdeveloped.[2]
We considered that enantioselective allylic substitution could
provide a route to unusual, enantioenriched tertiary allylic
fluorides, but we recognized that metal-catalyzed addition of
fluoride to an allylic electrophile to form such products would
require the reaction of highly substituted allylic electrophiles,
which are soft and particularly unreactive in allylic substitution,
with a hard, poorly nucleophilic fluoride (Scheme 1-IA). [3][4][5] Thus,
an alternative approach would likely be needed to achieve the
synthesis of tertiary allylic fluorides by metal-catalyzed allylic
substitution.
Such an alternative could involve an enantioselective reaction
of carbon-centered nucleophiles with allylic electrophiles
containing a 3-fluoro and a 3-hydrocarbyl group. However,
enantioselective allylic substitution of 3,3-disubstituted allylic
esters in which one substituent is bound through a heteroatom
are rare, and no allylic substitution at a fluorine-containing site of
an allylic electrophile with any metal has formed enantioenriched
tertiary allylic fluorides. Palladium-catalyzed reactions of soft
nucleophiles with 3-fluoroallylic acetates forms the linear, achiral
fluoroalkene (Scheme 1-IIA).[6] Palladium-catalyzed allylic
substitution of hard nucleophiles forms nonfluorinated products
from two sequential substitutions (Scheme 1-IIB),[6a,7] and copper-
mediated allylic substitutions of analogous nucleophiles have
been limited to those with achiral copper complexes (Scheme 1-
IIC).[8]
Scheme 1. Strategies to Prepare Tertiary Allylic Fluorides by Asymmetric Allylic
Substitution and Allylic Fluoroalkylations with Various Metals
The iridium catalyst reported by our group could be particularly
well suited for such a reaction because it tends to favor reaction
at the more substituted end of allylic electrophiles (Scheme 1-
IB),[9] but iridium-catalyzed allylic substitutions of 3,3-disubstituted
allylic electrophiles are limited,[10] presumably due to the steric
demands of the catalyst. Thus, it was unclear if iridium-catalyzed
reactions of 3-fluoro allylic electrophiles would occur and if the
regioselectivity of such reactions would be analogous to that of
reactions of non-fluorinated electrophiles. We show that iridium-
catalyzed reactions of soft nucleophiles with 3-fluoro-3-
hydrocarbyl allylic electrophiles catalyzed by a metalacyclic
iridium complex form tertiary allylic fluorides with high
regioselectivity and enantioselectivity (Scheme 1-IID). These
reactions are the first enantioselective allylic substitutions to occur
at fluorinated electrophiles, show the value of preparing tertiary
allylic fluorides by formation of a carbon-carbon bond at a fluorine-
containing electrophile, and show the value of iridium catalysts for
this transformation.
[*]
T. W. Butcher, Prof. J. F. Hartwig
Department of Chemistry, University of California
Berkeley, CA 94720 (USA)
jhartwig@berkeley.edu
Supporting information for this article is given via a link at the end of
the document
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triazabicyclo[4.4.0]dec-5-ene (TBD) provided products with lower
regioselectivities than did reactions conducted with isolated,
cyclometalated catalysts C1 or C2 (Scheme 2, entries 11–12).
The reaction of allylic electrophile 1a-OC(O)CF3 required only 2
mol% of the catalyst C2 and a slight excess of the nucleophile
(1.1 equiv) to ensure that allylic fluoride 3aa formed in excellent
yield (Scheme 2, entry 13).
Scheme 2. Evaluation of Reaction Conditions for Allylic Fluoroalkylation
To initiate studies on potential enantioselective allylic
fluoroalkylation, we studied reactions of 2-methyl diethyl malonate
(2a) with 3-fluorocinnamyl electrophiles (1a-LG) bearing a range
of leaving groups in the presence of cyclometalated iridium-allyl
catalysts C1 and C2 under conditions similar to those developed
for the iridium-catalyzed allylic alkylation of malonates with
nonfluorinated allylic electrophiles (Scheme 2).[11] Malonates
containing a substituent at the 2 position were studied because
the fluoroalkylation products from those malonates lacking this
substituent are known to eliminate fluoride by an E1cB process.[6a]
Initial studies demonstrated that fluorocinnamyl electrophiles
bearing common leaving groups for allylic substitution, such as
benzoate and methyl carbonate, reacted with incomplete
conversion after 24 hours at ambient temperature (Scheme 2,
entries 1–2).
Scheme 3. Scope of Nucleophiles for the Asymmetric Allylic Fluoroalkylation
Reaction
Thus, we tested reactions of 3-fluoroallylic electrophiles
bearing more labile leaving groups, such as diethyl phosphate,
chloride, or trifluoroacetate. These reactions formed the tertiary
allylic fluoride 3aa as the sole constitutional isomer in excellent
yields and with excellent enantioselectivities (Scheme 2, entries
3–5). Reactions conducted in the presence of a cyclometalated
The scope of nucleophiles that undergo this branched-
selective and enantioselective substitution of 3-fluorocinnamyl
trifluoroacetate (1a-OC(O)CF3) catalyzed by complex C2 is
shown in Scheme 3. Diethyl malonic esters bearing primary alkyl
groups (2a-2d) underwent iridium-catalyzed allylic fluoroalkylation
with 3-fluorocinnamyl trifluoroacetate (1a-OC(O)CF3) to form
allylic fluorides 3aa–3ad in 73–98% yield and uniformly excellent
enantioselectivities. Di(para-methoxybenzyl) malonic esters
bearing methyl (2e) and isopropyl (2f) substituents also
underwent fluoroalkylation in high yields, although higher loadings
of the catalyst were required for the complete reaction of these
iridium-phosphoramidite
complex
bearing
ortho-anisyl
substituents (C2) were faster and provided allylic fluoride 3aa in
higher yields than those conducted in the presence of the
analogous catalyst bearing phenyl substituents (C1) (Scheme 2,
entries 6–10). Reactions conducted with catalysts generated in
situ from [Ir(COD)Cl]2, ligand L1 or ligand L2, and 1,5,7-
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substrates (3ae–3af). The enantioselectivities of the reactions of
these malonates (3ae–3af) were lower than those of less
hindered malonates (3aa–3ad). Diethyl malonic esters bearing
substituents more sterically demanding than an isopropyl group,
such as a tert-butyl group, were unreactive under the standard
reaction conditions.
Stabilized carbon nucleophiles beyond malonates also
formed substitution products in high yields and high
enantioselectivities. For example, malononitriles bearing methyl
(2g), allyl (2h), and methoxymethyl ether (2i) substituents at the
nucleophilic carbon reacted in the presence of triethylamine and
catalyst C2 to provide allylic fluorides 3ag, 3ah, and 3ai in
uniformly high yields and high enantioselectivities. Product 3ai is
particularly valuable because its precursor (2i) is synthetically
equivalent to a cyano acyl anion.[10a] Methyl Meldrum’s acid (2j),
which is less nucleophilic than acyclic malonic esters possessing
comparable steric properties,[12] underwent allylic fluoroalkylation
to form product 3aj in 66% yield and 89:11 er, and the conjugate
base of fluorobis(phenylsulfonyl)methane reacted to provide
allylic fluoride 3ak in acceptable yield and excellent
enantioselectivity.[13]
A crystallographic analysis of the major enantiomer of 3ak
established the absolute configuration as (S). If fluorine is
considered to occupy the position of hydrogen at the stereogenic
center of the allylic substitution product, the configuration of 3ak
is analogous to that of products obtained from the allylic alkylation
of malonates with nonfluorinated allylic electrophiles,[11]
demonstrating that iridium-catalyzed allylic substitutions of
fluorinated and nonfluorinated allylic electrophiles likely occur
through analogous allyliridium intermediates.
Scheme 4. Scope of Electrophiles for the Asymmetric Allylic Fluoroalkylation
Reaction
The diastereoselectivity of the iridium-catalyzed asymmetric
allylic alkylations of prochiral nucleophiles is typically low, except
when conditions are carefully designed to favor one diastereomer
over the other. Stoltz has established that the diastereoselectivity
in the iridium-catalyzed allylic alkylation of β-keto esters can be
controlled by choice of the counterion for the nucleophile and
ligand for the iridium catalyst.[18] We investigated several ligands,
This allylic substitution also occurs with a range of allylic
phosphates (Scheme 4).[14] Fluorinated cinnamyl electrophiles
bearing neutral, electron-withdrawing, and moderately electron-
donating substituents on the aryl group afforded products 3bi, 3ci,
3di, and 3ei in excellent yields and enantioselectivities.[15]
Consistent with cinnamyl electrophiles bearing ortho substituents
bases, and additives for the diastereoselective
allylic
fluoroalkylation of ethyl 2-oxocyclohexanecarboxylate (2l) and
found that the reactions of this β-keto ester could provide either
diastereomer 3al or 3al’ as the major product depending on the
choice of base (Scheme 5).[19] Product 3al was isolated as a
single diastereomer in 58% yield and product 3al’ was isolated as
a single diastereomer in 26% yield for the reaction with sodium
tert-butoxide. Reactions conducted with a mixture of lithium tert-
butoxide and magnesium tert-butoxide afforded the opposite
diastereomer (3al’) as the major product in 45% isolated yield and
3al as a minor product in 11% isolated yield, indicating that the
present fluoroalkylation reaction can provide either diastereomer
3al or 3al’ containing two vicinal, fully substituted stereogenic
centers in acceptable yield.
undergoing iridium-catalyzed allylic substitutions with lower
16]
enantioselectivities than their unsubstituted analogs,[11,
the
reaction of the 3-fluoro ortho-methyl cinnamyl electrophile
provided the product 3fa with only moderate enantioselectivity.
Finally, aliphatic 3-fluoroallylic electrophiles underwent this
iridium-catalyzed process, although the reaction of such
substrates is sensitive to the steric properties of the alkyl group
present at the 3 position. The reaction of 3-butyl-3-fluoro allyl
diethyl phosphate (1g) gave allylic fluoride 3ge in 73% yield and
94:6 er; the reaction of the more hindered 3-cyclohexyl-
substituted electrophile 1h also gave the branched allylic fluoride
(3he), although in a lower yield (58%) and enantioselectivity
(74:26 er).[17]
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To understand the differences between reactions of typical
allylic electrophiles and those reported here, we conducted
studies to reveal how fluorine affects the structure and energetics
of the π-allyl iridium intermediates. To do so, we computed the
lowest-energy structures of the endo and exo π-allyl iridium
complexes bearing fluorinated and nonfluorinated cinnamyl
groups by DFT (Scheme 7).[21] The differences in energy between
the endo and exo π-allyl complexes for which X=H and X=F were
markedly different. Although Ir-endo-H was computed to be 3.13
kcal/mol more stable than Ir-exo-H, Ir-endo-F was computed to
be only 0.23 kcal/mol more stable than Ir-exo-F.
The structures of the fluorinated and nonfluorinated π-allyl
iridium complexes are distinct. The Ir–C3 bond distances in the
structures of Ir-endo-F and Ir-exo-F are much longer than those
in the structures of Ir-endo-H and Ir-exo-H, whereas the Ir–C1
bond distances in each of the four computed structures are nearly
identical. Therefore, the presence of fluorine at the anti position of
C3 leads to canting of the allyl plane from the metal, causing the
structures of the fluorinated π-allyl intermediates to approach an
η1 geometry. The two endo π-allyl complexes contain a steric
clash between the X atom of the allyl group and a hydrogen atom
on the COD ligand (HCOD), whereas the two exo π-allyl complexes
contain a steric clash between the central methine hydrogen of
the allyl group (HC2) and a hydrogen atom of the COD ligand
(HCOD).[22]
Scheme
oxocyclohexanecarboxylate
5.
Diastereoselective
Fluoroalkylation
of
Ethyl
2-
The allylic fluorides we report are versatile building blocks
because they contain multiple functional groups (alkene, ester,
nitrile, ketone) that can serve as synthetic handles. As shown in
Scheme 6, malononitrile 3ei underwent a one-pot methanolysis to
form α-fluoro ester 5 in 95% yield, and malononitrile 3ai
underwent a similar transformation to form α-fluoro amide 6 in
89% yield.[10a, 20] Malononitrile 3ai also underwent hydrogenation
in acceptable yield to afford tertiary fluoride 7. Malonate 3aa
underwent reductive ozonolysis and subsequent lactonization to
form β-fluorolactone 8 in 53% yield and 1.5:1 dr. Finally, β-
ketoester 3al’ underwent diastereoselective reduction in the
presence of NaBH4 to provide alcohol 9 in 94% yield and 28:1 dr.
Scheme 7. Computational Studies of π-Allyl Iridium Intermediates
We suggest that the steric clash between HCOD and X (either
H or F), which is present only in endo π-allyl complexes, tends to
destabilize endo π-allyl complexes when X is larger than a
hydrogen atom. This effect of the fluorine results in a smaller
difference in energy between the endo and exo diastereomers of
the π-allyl complexes for which X=F than for those π-allyl
complexes for which X=H. Although this analysis cannot
rationalize the enantioselectivities of the overall reaction, these
studies reveal the specific steric interactions that render allylic
substitutions of 3,3-disubstituted allylic electrophiles challenging
to achieve with cyclometalated iridium phosphoramidite catalysts.
Such computational information and the results of these catalytic
processes will guide the future development of catalysts that
engage allylic electrophiles of increasing steric demand.
Scheme 6. Diversification of Tertiary Allylic Fluorides
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Soc. 2014, 136, 1230-1233; c) B. Zhang, X. G. Zhang, Chem. Commun.
2016, 52, 1238-1241.
In summary, we have developed an enantioselective allylic
substitution of 3-fluoro allylic electrophiles with soft carbon
nucleophiles to provide tertiary allylic fluorides. The present
reaction proceeds with a range of stabilized carbon nucleophiles
and aryl- and alkyl-substituted fluorinated allylic electrophiles. The
[8]
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tertiary allylic fluoride products undergo
a
range of
transformations to provide α-fluoroesters and amides, β-
fluorolactones, tertiary alkyl fluorides, and γ-fluoro alcohols.
Future work will be devoted to expanding the scope of 3,3-
disubstituted allylic electrophiles that undergo iridium-catalyzed
allylic substitution.
[10] a) S. E. Shockley, J. C. Hethcox, B. M. Stoltz, Angew. Chem., Int. Ed.
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Acknowledgements
[13] a) T. Fukuzumi, N. Shibata, M. Sugiura, H. Yasui, S. Nakamura, T. Toru,
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We thank the NSF (CHE-1565886) for financial support, as well
as Nicholas S. Settineri for assistance with X-ray
crystallographic analyses. T.W.B. gratefully acknowledges the
National Science Foundation for a predoctoral fellowship.
[14] We elected to prepare allylic diethyl phosphates because they exhibit
improved stability over allylic trifluoroacetates.
[15] Fluorinated cinnamyl diethyl phosphates bearing highly electron-rich aryl
substituents, such as a para-methoxyphenyl group, were unstable on
silica and decomposed to the corresponding aryl vinyl ketones. The
corresponding fluorinated cinnamyl methyl carbonate was stable but
exhibited poor reactivity.
Keywords: iridium • allylic substitution • fluorine • allylic fluoride
[1]
[2]
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[17] For these substrates, the linear isomer of the product was observed: The
crude branched to linear ratio was 5:1 for compound 3ge and 4:1 for
compound 3he. The reported yields refer to the isolated yield of the
single (branched) constitutional isomer.
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[19] See the Supporting Information for details.
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[21] See the Supporting Information for details.
[22] The nonbonded contact distances were smaller than the sum of van der
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[4]
[5]
[6]
[7]
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Trevor W. Butcher and John F. Hartwig*
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Enantioselective Synthesis of Tertiary
Allylic Fluorides by Iridium-Catalyzed
Allylic Fluoroalkylation
Fluorine in a tight spot: Highly congested tertiary allylic fluorides were prepared
by the allylic substitution of γ-fluoro allylic electrophiles. Iridium catalysis enabled
the branched-selective and enantioselective allylic fluoroalkylation of hindered, soft
nucleophiles, providing access to fluorinated molecules which would be challenging
to prepare by other methods.
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