Base Catalysis Enables Access to α,α-Difluoroalkylthioethers

Article abstract of DOI:10.1021/acs.orglett.7b00386

A nucleophilic addition reaction of aryl thiols to readily available β,β-difluorostyrenes provides α,α-difluoroalkylthioethers. The reaction proceeds through an unstable anionic intermediate, prone to eliminate fluoride and generate α-fluorovinylthioethers. However, the use of base catalysis overcomes the facile β-fluoride elimination, generating α,α-difluoroalkylthioethers in excellent yields and selectivities.

Full text of DOI:10.1021/acs.orglett.7b00386

Letter
pubs.acs.org/OrgLett
Base Catalysis Enables Access to α,α-Difluoroalkylthioethers
Douglas L. Orsi, Brandon J. Easley, Ashley M. Lick, and Ryan A. Altman*
Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045, United States
S
* Supporting Information
ABSTRACT: A nucleophilic addition reaction of aryl thiols to readily
available β,β-difluorostyrenes provides α,α-difluoroalkylthioethers. The
reaction proceeds through an unstable anionic intermediate, prone to
eliminate fluoride and generate α-fluorovinylthioethers. However, the use of
base catalysis overcomes the facile β-fluoride elimination, generating α,α-
difluoroalkylthioethers in excellent yields and selectivities.
Scheme 1. Base Catalyst Enables Nucleophilic Addition to
gem-Difluoroalkenes
unctionalization reactions of alkenes are essential trans-
Fformations for synthetic organic chemistry. Although many
of these reactions occur via interactions of the alkene HOMO
with electrophiles,1 alkenes also react with nucleophiles through
the π* LUMO. To access the LUMO, alkenes typically require
activation by a limited set of π-electron-withdrawing groups
(EWG), such as carbonyl, nitrile, or nitro groups.1b Similar to
these EWGs, fluorinated substituents also activate alkenes for
nucleophilic attack.2 Unlike EWGs that activate the π-bond
through resonance and facilitate attack at the β-carbon,3
fluorination activates the alkene’s α-carbon for attack4 through
σ-withdrawing inductive effects, while also deactivating the β-
carbon through resonance effects.5 This activation of alkenes by
fluorine has been utilized in nucleophilic hydrofluorination
reactions to generate trifluoromethanes (Scheme 1a),4 and in
various acid-promoted intramolecular or base-mediated inter-
molecular C−F functionalization reactions to deliver mono-
fluorinated products.2,6 However, nucleophilic hydro-
functionalization reactions of difluoroalkenes with alternate
nucleophiles have not been generally developed.
Inspired by the use of gem-difluoroalkenes as mechanism-
based inhibitors,7 we envisioned that alternate heteroatom-
based nucleophiles, such as thiols, might undergo analogous
hydrofunctionalization reactions by nucleophilic addition
followed by protonation. However, prior attempts to add
thiols across gem-difluoroalkenes afforded α-fluorovinylth-
ioether products through an addition/elimination process
(Scheme 1b).2,6b,8 To avoid the elimination of F−, we present
a mild, base-catalyzed reaction to furnish α,α-difluoroalkylth-
ioethers in high yield and selectivity (Scheme 1c), which
complements earlier methods to access the α,α-difluoroalkylth-
ioether group, including: (1) nucleophilic substitution reactions
of silyated9 or halogenated10 difluoroalkyl intermediates that
require multistep preparations; (2) radical processes with
limited functional group compatibility;10b,c,11 or (3) oxidative
methods that utilize harsh fluorinating reagents.12 In contrast,
the present reaction uses only catalytic quantities of a mild base,
enabling access to products bearing many sensitive functional
groups. Thus, this reaction should facilitate access to bioactive
compounds bearing α,α-difluoroalkylthioethers, including anti-
cancer13 and anti-inflammatory14 agents and agrichemicals.15
After extensive optimization, we identified a general base-
catalyzed protocol for adding aryl thiols to β,β-difluorostyrenes.
We selected a styrene-based substrate to stabilize the proposed
intermediate anion (A) through resonance. Initial attempts to
functionalize difluorostyrene 1 with thiophenol involved
catalytic amounts of inorganic bases, which either generated
nonfluorinated disubstituted alkene 3 (likely arising from
sequential C−F functionalizations),8a,b or which did not react
(Figure 1). When higher quantities of inorganic base were
Received: February 6, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00386
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Organic Letters
Letter
difluorostyrenes (5a−n and 1), with selectivity generally
exceeding 25:1 (Scheme 2). The reaction tolerated many
a b
,
Scheme 2. Scope of Distinct β,β-Difluorostyrenes
Figure 1. Undesired reactivity with inorganic bases.
employed, large amounts of α-fluorovinylthioethers formed. In
contrast, catalytic quantities of organic bases generated the
desired α,α-difluoroalkylthioether in modest to excellent yield
and selectivity. Of the bases evaluated 1,1,3,3-tetramethyl-
guanidine (TMG) provided the best yield and selectivity for
product 2 over product 4 (entries 1−4). Notably, the use of
preformed PhSNa as a base only formed small amounts of
eliminated product 4 (entry 5), which suggests that ArSH
might not serve as the H+ donor, but rather TMG−H+.
Subsequent evaluation of solvents revealed that chlorinated
solvents provided the best yield and selectivity, with 1,2-
dichloroethane (DCE) proving optimal (entries 1, 5−11).
Several experiments support the proposed addition/proto-
nation pathway over a mechanism involving S-based radicals.
First, the reaction ran smoothly in the absence of light and O2,
which are known radical initiators. Second, although the
reaction utilizes TMG (which can have inorganic impurities
that can oxidize a thiolate),16 other amine bases that lack such
impurities (e.g., purified Et3N) are competent base catalysts
(Table 1, entry 2). Third, when running the reaction in CD2Cl2
a
Table 1. Optimization of the Reaction Conditions
b
b
entry
base
solvent
conv/yield [%]
2:4
1
2
3
4
TMG
Et3N
DCE
>99/96
>99/82
>99/67
>99/77
15/<1
94/60
>25:1
>25:1
>25:1
>25:1
N/A
DCE
e
DMAP
TBD
DCE
a
Standard conditions: 5a−n and 1 (1.0 equiv), PhSH (2.0 equiv),
TMG (5.0 mol %), DCE (0.25 M), temperature and time as indicated.
Selectivity >25:1 as determined by 19F NMR analysis of the reaction
mixture, unless otherwise indicated. Yields represent an average of two
DCE
c
5
PhSNa
TMG
TMG
TMG
TMG
TMG
TMG
DCE
6
7
8
9
PhNO2
DMF
PhMe
MeCN
DCM
DCE
4:1
b
c
d
>99/36
56/8
1:1.2
>25:1
1:3.5
>25:1
>25:1
runs. PhSH (3.0 equiv). Selectivity = 13:1. Selectivity = 6.6:1.
e
Selectivity = 8:1. PMB = 4-methoxybenzyl, Tf = trifluoromethyl-
83/15
sulfonate.
d
10
>99/88
>99/91
c
11
a
Standard conditions: 1 (1.0 equiv), PhSH (2.0 equiv), solvent (0.50
useful functional groups on the β,β-difluorostyrene, such as
halides (6c, 6i, 6k), ethers (2, 6a−c, 6h), thioethers (6b), and
nitrogenous functional groups (6d, 6e, 6l−n). Ortho-
substituted β,β-difluorostyrenes required higher reaction
temperatures (6c, 6g, 6i). Carbonyl-containing compounds
were also tolerated (6j, 6l), and notably a substrate bearing an
α,β-unsaturated ester reacted exclusively at the fluorinated
position, with no evidence of irreversible Michael addition (6j).
Electron-rich and -neutral β,β-difluorostyrenes generally
provided high yields and selectivities, and required low
temperatures and short reaction times (2, 6a−e, 6h). In
contrast, under standard reaction conditions, electron-deficient
substrates reacted sluggishly, affording products in modest
yields and selectivities. To reach full conversion, these reactions
required higher temperatures and longer times (6k−n).
However, these harsher conditions afforded more α-fluorovi-
nylthioether side product (6.6:1−13:1).
b
M), base (25 mol %), 80 °C, 4 h. Determined by 19F NMR
standardized with PhCF3 (1.0 equiv). Solvent (0.25 M), base (5.0 mol
%), 70 °C, 0.5 h. 40 °C. Reaction generated a sulfoxide side product.
TBD = 1,5,7-triazabicyclo[4.4.0]dec-5-ene.
c
d
e
(which can transfer ·D)17 D was not incorporated into the
product. Fourth, reactions run in the presence of radical traps
(e.g., 1,4-dicyanobenzene and BHT) proceed to full conversion
and comparable yields. In contrast, reactions run in the
presence of TEMPO, both with and without TMG, gave no
desired product and generated (PhS)2, presumably by transfer
of H· from PhSH to TEMPO and subsequent homocoupling of
the resulting PhS·. Thus, under our conditions, S-based radicals
are not likely reactive intermediates.
The optimized reaction conditions enabled coupling between
thiophenol and a broad spectrum of functionalized β,β-
B
DOI: 10.1021/acs.orglett.7b00386
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Organic Letters
Letter
To determine whether the reduced selectivity arose from the
instability of the product or of the anionic intermediate A,
purified products 2, 6d, and 6n were resubjected to the reaction
conditions (Scheme 3a). 19F NMR analysis of the reaction
A broad scope of functionalized aryl thiol nucleophiles were
also tolerated (Scheme 5). Aryl thiols bearing halides (10h,
a b
,
Scheme 5. Scope of Distinct Aryl Thiols
Scheme 3. Decomposition of Anionic Intermediate A
Reduces the Selectivity for e−-Deficient Substrates
mixtures showed no evidence of degradation, suggesting that β-
fluoride elimination from A occurs more rapidly for electron-
deficient species than for electron-rich or -neutral species
(Scheme 3b).
Further, under the optimized conditions heteroaromatic gem-
difluoroalkenes reacted smoothly (Scheme 4). Electron-rich
a
Standard conditions: 1 (1.0 equiv), ArSH 9a−j and PhSH (2.0
equiv), TMG (5.0 mol %), DCE (0.25 M), temperature and time as
indicated. Selectivity >25:1 as determined by 19F NMR analysis of the
ab
,
Scheme 4. Scope of Heteroaromatic β,β-Difluorostyrenes
b
reaction mixtures. Yields represent an average of two runs. ArSH (3.0
equiv).
10e), ethers (10a, 10b, 10f), trifluoromethane (10g), carbonyl
groups (10b), and even a secondary amide (10c) afforded α,α-
difluoroalkylthioether products, confirming that electron-rich
and -neutral as well as weakly electron-deficient aryl thiols
generally reacted smoothly. Thiols bearing strong electron-
withdrawing groups (e.g., nitrile 10i) required higher temper-
atures and extended reaction times. Notably, all reactions
demonstrated excellent selectivity (>25:1) regardless of the
nature of the nucleophile. Finally, the mild conditions tolerated
many useful protecting groups, including a Ts-protected indole
(8a), an acetal (8b), a Boc-protected amine (8f), benzyl- and p-
methoxylbenzyl-protected alcohols and amines (6c, 6h, 8e),
and an acetyl-protected amine (10c), all potentially useful in
multistep synthetic sequences.
While aryl thiol nucleophiles reacted efficiently, alkyl thiols
reacted poorly, giving mainly addition/elimination products,
presumably due to a mismatched thiol−base pair. To assess
whether a dual nucleophile system could avoid this undesired
reactivity of alkyl thiols, an aryl thiol was reacted with 1 in the
presence of an alkyl thiol under the harshest conditions
explored (Figure 2). Under these conditions, the aryl thiol
selectively coupled to form aryl thioether 2 with <1% formation
of alkyl thioether 11, likely because the increased acidity of the
aryl thiol allows preferential deprotonation, and the resulting
thiolate is more nucleophilic than the neutral thiol. Further,
attempts to use the present conditions for reactions of alcohol
and N-heterocycle nucleophiles proved ineffective. To address
a
Standard conditions: 7a−n (1.0 equiv), PhSH (2.0 equiv), TMG (5.0
mol %), DCE (0.25 M), temperature and time as indicated. Selectivity
>25:1 as determined by 19F NMR analysis of the reaction mixture.
b
Yields represent an average of two runs. PhSH (3.0 equiv). Ts = 4-
toluenesulfonyl.
and -deficient N-based heterocycles (indole 8a, pyridine 8b,
pyrrole 8c) and S-based heterocycles (benzothiophene 8d,
phenothiazine 8e, thiazole 8f) all provided good yields and
selectivity, suggesting that the reaction conditions should apply
to a broad spectrum of biologically relevant heteroaromatic
compounds.
C
DOI: 10.1021/acs.orglett.7b00386
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Letter
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this limitation, we are currently optimizing alternate conditions
for these nucleophiles.
In summary, we developed a new base-catalyzed strategy to
generate α,α-difluoroalkylthioethers by directly adding aryl
thiol nucleophiles to β,β-difluorostyrenes. This reaction
proceeds via an unstable anionic intermediate that is prone to
eliminate F−; however, the mild conditions avoid this undesired
unimolecular elimination. The catalytic reaction enables access
to a variety of functionalized α,α-difluoroalkylthioethers in high
yield and selectivity versus the α-fluorovinylthioether. Com-
bined with direct preparations of β,β-difluorostyrenes2 by
olefination18 and cross-coupling19 chemistry, the present
reaction should facilitate access to this underutilized functional
group in medicinal and agricultural chemistry.
ASSOCIATED CONTENT
* Supporting Information
■
(10) (a) Betterley, N. M.; Surawatanawong, P.; Prabpai, S.;
Kongsaeree, P.; Kuhakarn, C.; Pohmakotr, M.; Reutrakul, V. Org.
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S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00386.
Experimental procedures, spectroscopic data for new
compounds, and mechanistic experiments (PDF)
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(12) (a) Brigaud, T.; Laurent, E. Tetrahedron Lett. 1990, 31 (16),
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AUTHOR INFORMATION
■
́
1995, 36 (45), 8243−6. (c) Gouault, S.; Guerin, C.; Lemoucheux, L.;
Corresponding Author
*E-mail: raaltman@ku.edu.
ORCID
Lequeux, T.; Pommelet, J.-C. Tetrahedron Lett. 2003, 44, 5061−4.
(13) Dixon, D. D.; Grina, J.; Josey, J. A.; Rizzi, J. P.; Schlachter, S. T.;
Wallace, E. M.; Wang, B.; Wehn, P.; Xu, R.; Yang, H. Preparation of
cyclic sulfone and sulfoximine analogs as HIF-2α inhibitors. WO
2015095048, 2015.
Douglas L. Orsi: 0000-0001-6731-5494
Ryan A. Altman: 0000-0002-8724-1098
Notes
(14) Chen, W.; Igboko, E. F.; Lin, X.; Lu, H.; Ren, F.; Wren, P. B.;
Xu, Z.; Yang, T.; Zhu, L. Preparation of 1-(cyclopent-2-en-1-yl)-3-(2-
hydroxy-3-(arylsulfonyl)phenyl)urea derivatives as CXCR2 inhibitors.
WO 2015181186, 2015.
The authors declare no competing financial interest.
(15) (a) Kumamoto, K.; Miyazaki, H. Preparation of sulfanylmethyl-
pyrazole derivatives and analogs as pesticides. WO 2009028727, 2009.
(b) Dallimore, J. W. P.; El Qacemi, M.; Kozakiewicz, A. M.; Longstaff,
A.; Mclachlan, M. M. W.; Peace, J. E. Preparation of herbicidal
isoxazoline derivatives. WO 2011033251, 2011.
ACKNOWLEDGMENTS
■
We thank the donors of the Herman Frasch Foundation for
Chemical Research (701-HF12), and the Madison and Lila Self
Graduate Fellowship (D.L.O.) for supporting this work. NMR
Instrumentation was provided by NIH Shared Instrumentation
Grants S10OD016360 and S10RR024664, NSF Major
Research Instrumentation Grants 9977422 and 0320648, and
NIH Center Grant P20GM103418. We thank Ms. Caitlin N.
Kent of The University of Kansas Department of Medicinal
Chemistry for preparing compound 7d.
(16) We thank a reviewer for noting the potential of trace impurities
in TMG to initiate a radical reaction.
(17) Bohm, A.; Bach, T. Chem. - Eur. J. 2016, 22 (44), 15921−15928.
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DOI: 10.1021/acs.orglett.7b00386
Org. Lett. XXXX, XXX, XXX−XXX