Lewis acid-promoted hydrofluorination of alkynyl sulfides to generate α-fluorovinyl thioethers

Article abstract of DOI:10.3762/bjoc.11.205

A new method for the preparation of α-fluorovinyl thioethers is reported which involves the hydrofluorination of alkynyl sulfides with 3HF·Et₃N, a process that requires Lewis acid activation using BF₃·Et₂O and TiF₄

Full text of DOI:10.3762/bjoc.11.205

Lewis acid-promoted hydrofluorination of alkynyl sulfides to
generate α-fluorovinyl thioethers
Davide Bello and David O'Hagan*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2015, 11, 1902–1909.
University of St Andrews, School of Chemistry, North Haugh, St
Andrews, Fife, KY16 9ST, UK
doi:10.3762/bjoc.11.205
Received: 02 July 2015
Email:
Accepted: 01 September 2015
Published: 14 October 2015
David O'Hagan* - do1@st-andrews.ac.uk
* Corresponding author
Associate Editor: V. Gouverneur
Keywords:
© 2015 Bello and O'Hagan; licensee Beilstein-Institut.
License and terms: see end of document.
alkynyl sulfides; α-fluorovinyl thioethers; hydrofluorination; Lewis
acids; organofluorine
Abstract
A new method for the preparation of α-fluorovinyl thioethers is reported which involves the hydrofluorination of alkynyl sulfides
with 3HF·Et3N, a process that requires Lewis acid activation using BF3·Et2O and TiF4. The method gives access to a range of
α-fluorovinyl thioethers, some in high stereoselectivity with the Z-isomer predominating over the E-isomer. The α-fluorovinyl
thioether motif has prospects as a steric and electronic mimetic of thioester enols and enolates, important intermediates in enzy-
matic C–C bond forming reactions. The method opens access to appropriate analogues for investigations in this direction.
Introduction
Organofluorine compounds have found wide use in tuning the We have recently begun to explore synthesis methods to
properties of performance compounds in medicinal and ma- prepare α-fluorovinyl thioethers, to open up the possibility
terials chemistry [1,2]. Also the electronegativity of fluorine has of exploring this motif as a mimetic for enols and enolates
been used to design and tune steric and electronic mimetics of of biochemically relevant thioesters. Thioesters of low
functional groups for applications in biomolecular chemistry. molecular weight carboxylic acids are found widely in
For example as illustrated in Figure 1, CF2-phosphonates be- metabolism, often as their co-enzyme A esters, and they
came popular mimetics of the phosphate group [3,4], and vinyl then undergo condensation reactions through enols or
fluorides were developed as analogues of the amide bond [5]. enolates to generate C–C bonds typified by the processes of
Difluorotoluene has proved to be a good spacial mimetic of the long chain fatty acid biosynthesis. α-Fluorovinyl thioethers,
thymine base in thymidine, and has been shown to act as a func- illustrated in Figure 2, have a spatial and electrostatic profile
tional and complementary template in enzymatic DNA syn- consistent with the potential to mimic these enzyme intermedi-
thesis [6].
ates.
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Beilstein J. Org. Chem. 2015, 11, 1902–1909.
Figure 1: Some spacial and electronic mimetics with fluorine as a design feature [3-6].
Figure 2: α-Fluorovinyl thioesters offer prospects as thioester enol/ate mimetics [7].
There is limited literature for preparing such analogues. We illustrated in Scheme 1. When 70% HF·Py was employed, up to
have previously described the preparation of α-fluorovinyl 70% conversion was achieved, but with over-fluorination to
thioethers by hydrofluorination of the corresponding alkynyl generate only the difluoromethylene thioether 4a (not isolated).
sulfides using HF·Py [7]; in this article we wish to report an im-
proved synthesis of α-fluoroalkenyl thioethers via Lewis acid- In view of the lack of control with HF·Py attention turned to
mediated hydrofluorination of alkynyl sulfides, a method which triethylamine trihydrogen fluoride (3HF·Et3N). This proved
brings us closer to being able to prepare analogues of particular unsuccessful presumably as it is a less acidic reagent compared
design for enzyme inhibition studies.
to HF·Py, and thus activation of alkynyl sulfide 1a was explored
by addition of a Lewis acid.
Results and Discussion
Several methods for the synthesis of vinyl thioethers have been At this stage we were pleased to find that the use of BF3·Et2O
reported, including Wittig reactions [8], ionic and radical addi- allowed for a conversion of over 90% of 1a (16 h at room
tions of thiols to alkynes [9] and coupling of 1-alkenyl halides temperature). However, products 2a and 3a were obtained
with thiols, among others [10,11]. However, the literature for as a 4:1 mixture of Z/E-isomers, and they could only be isolated
the preparation of α-fluorovinyl thioethers is somewhat scarce. in a modest yield (35%) as shown in Scheme 2 and Table 1
The only account we are aware of involves the AIBN-promoted (entry 7).
thiodesulfonylation of aromatic fluorovinyl sulfones as reported
by Wnuk [12], a reaction which works in varying yields and Encouraged by this result, a number of Lewis acids were tested,
stereoselectivities.
including SnCl2, ZnCl2, Sc(OTf)3, AuCl·SMe2 and B(C6F5)3
(Table 1). The Lewis acids (1.5 equivalents) were added to a
Following from our previous experience [7] with terminal mixture of sulfide 1a and 3HF·Et3N (3.0 equivalents) at 0 ºC,
acetylene thioethers, we now explore this reaction with alkynyl but no reactions took place under these conditions. The
sulfides. In this regard 1a [13] was used as a model substrate HBF4·SiO2 reagent was chosen as a solid phase-supported
and was treated with 50% HF·Py in dichloromethane. This, HBF4 equivalent [14]; carrying out the reaction in the presence
however, resulted in a very poor conversion (~10%) and gave a of this reactant and 3HF·Et3N led to complete decomposition of
4:1 product mixture of the fluorinated products 2a and 3a as sulfide 1a.
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Beilstein J. Org. Chem. 2015, 11, 1902–1909.
Scheme 1: HF·Py mediated hydrofluorinations of 1a.
Scheme 2: BF3·Et2O/3HF·Et3N mediated hydrofluorination of 1a.
Table 1: Lewis acid screening.
Entry
Lewis acid
HF source
Time
Temp
Conversion
Yield
Z/E
1
2
3
4
5
6
7
8
SnCl2
3HF·Et3N
3HF·Et3N
3HF·Et3N
3HF·Et3N
3HF·Et3N
3HF·Et3N
3HF·Et3N
3HF·Et3N
16 h
16 h
16 h
16 h
16 h
16 h
16 h
16 h
0 °C to rt
0 °C to rt
0 °C to rt
0 °C to rt
0 °C to rt
0 °C to rt
0 °C to rt
0 °C to rt
0%
–
–
ZnCl2
0%
–
–
Sc(OTf)3
SiO2·HBF4
AuCl·SMe2
B(C6F5)3
BF3·Et2O
TiF4
0%
–
–
n.a.a
0%
–
–
–
–
0%
–
–
>90%
70%
35%
42%
4:1
4:1
aSubstrate decomposed.
With TiF4 the overall conversion was around 70%, and the The high conversion of 1a but low product (2a and 3a) isola-
hydrofluorinated product could be isolated in an improved yield tion is attributed to substrate decomposition. When the reaction
(42%, 4:1 Z:E).
is followed by 19F NMR (vide infra), the presence of the hydro-
fluorinated products 2a and 3a is obvious and the anion BF4−,
In order to improve the reaction yields, reactions with the when using BF3·Et2O, or TiF62− when using TiF4 are clearly
BF3·Et2O/3HF·Et3N and TiF4/3HF·Et3N systems were opti- identifiable. No other fluorinated species are detected, thus it
mised and the outcomes described in Table 2 and Table 3, res- does not appear that products 2a and 3a decompose.
pectively. Shorter reaction times (5 h) led to reduced conver-
sions (Table 2, entry 2) and BF3·Et2O or TiF4 are required to be A number of attempts were made to improve the yields and
stoichiometric, otherwise the reaction does not occur (Table 2, reduce starting material decomposition. At low temperatures the
entry 4) and an excess of BF3·Et2O over the alkynyl sulfide is reaction is sluggish and conversions are low (~20%), even with
required for an improved outcome (Table 2, entry 1).
prolonged reaction times (5 days, Table 2, entry 5). A second
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Beilstein J. Org. Chem. 2015, 11, 1902–1909.
Table 2: Optimisation of BF3·Et2O/3HF·Et3N mediated hydrofluorination.
Entry
BF3·Et2O
(equiv)
3HF·Et3N
(equiv)
Time
Temp.
Solvent
Conversion
Yield
1
1.5
3.0
16 h
5 h
0 °C to rt
0 °C to rt
0 °C to rt
0 °C to rt
0 °C
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
THF
>90%
39%
>80%
–
35%
28%
30%
–
2
1.5
3.0
3
1.0
2.0
16 h
16 h
5 days
7 h
4
0.5
3.0
5
1.5
3.0
20%
20%
>95%
70%
25%
<5%
10%
n.a.e
–
6
1.5 × 2
1.5
3.0
0 °C
–
7
3.0
5 h
40 °C
30%
28%
–
8a
9
1.5
3.0
16 h
21 h
16 h
21 h
21 h
0 °C to rt
b
1.5 × 2
1.5
3.0 × 2
3.0
10
11
12
0 °C to rt
c
DCE
DCE
DCE
–
1.5
3.0
–
d
1.5 x 2
3.0 x 2
–
aBF3·Et2O and 3HF·Et3N were pre-mixed at 0 °C prior to adding starting material 1a. bMixture stirred for 16 hours at room temperature, then heated to
50 °C for 5 hours. cMixture stirred for 16 hours at room temperature, then stirred under reflux for 5 hours. dMixture stirred for 5 hours at room tempera-
ture, then stirred under reflux for 16 hours. eSubstrate decomposed.
addition of 1.5 equivalents of BF3·Et2O after a few hours at hydrofuran, Table 2, entry 9, dichloroethane, Table 2, entries
0 °C proved ineffective (Table 2, entry 6). On the other hand, 10–12).
warming the mixture to reflux (40 ºC for dichloromethane)
allowed for complete conversion in just 5 hours (Table 2, entry For the TiF4/3HF·Et3N reactions (Table 3) shorter reaction
7) although the isolated yield (30%) was relatively modest. times also afforded lower conversions, and sub-stoichiometric
Thus heating promotes the reaction but also substrate decompo- levels of TiF4 failed to initiate the reaction. Tetrahydrofuran and
sition. Pre-equilibration of BF3·Et2O and 3HF·Et3N at 0 °C dichloroethane at different temperatures were again not useful
prior to starting material 1a addition resulted in a 70% solvents.
conversion and a modest 28% yield (Table 2, entry 8).
When tetrahydrofuran or dichloroethane were explored as Having optimised the reaction to some extent with substrate 1a,
solvents the conversions were low, even when warming (tetra- a range of alkynyl sulfides [15] were now prepared and each
Table 3: Optimisation of TiF4/3HF·Et3N mediated hydrofluorination.
Entry
TiF4
(equiv)
3HF·TEA
(equiv)
Time
Temp.
Solvent
Conversion
Yield
1
2
3
4
5
1.5
1.5
0.5
1.5
1.5
3.0
3.0
3.0
3.0
3.0
5 h
0 °C to rt
DCM
DCM
DCM
THF
39%
>90%
–
–
16 h
16 h
16 h
16 h
0 °C to rt
42%
0 °C to rt
–
–
–
0 °C to rt or reflux
0 °C to rt, then reflux
–
DCE
10%
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Beilstein J. Org. Chem. 2015, 11, 1902–1909.
individually treated with both hydrofluorination protocols using When TiF4 was used, the reaction showed complete stereoselec-
BF3·Et2O/3HF·Et3N and TiF4/3HF·Et3N. The results are tivity, affording the Z-isomer of 2b in 55% yield.
summarised in Table 4. Cyclohexylethynyl(benzyl)sulfane (1b)
gave an improved outcome relative to 1a with higher yields and Replacement of the cyclohexyl moiety with a phenyl ring in 1c
better stereoselectivity. The BF3·Et2O reaction furnished an led to a fully stereoselective reaction both with BF3·Et2O and
inseparable 9:1 mixture of Z-2b and E-3b isomers in 48% yield. TiF4, giving the Z-stereoisomer 2c in 45% and 57% yields, res-
Table 4: Scope of BF3·Et2O and TiF4-mediated hydrofluorination reaction.
Substrate
Conversion and yield
Productsa
1a
R = Bn
R1 = n-Bu
BF3·Et2O
TiF4
>90%, 35%
Z/E 4:1
70%, 42%
Z/E 4:1
1b
R = Bn
R1 = Cy
BF3·Et2O
TiF4
>90%, 48%
Z/E 9:1
80%, 55%
Z only (2b)
1c
R = Bn
R1 = Ph
BF3·Et2O
TiF4
60%, 45%
Z only
>90%, 57%
Z only
1d
R = Cy
R1 = Ph
BF3·Et2O
TiF4
complete, 47%
Z only
>90%, 68%
Z only
1e
R = Ph
R1 = cyclopropyl
BF3·Et2O
TiF4
>80%, 47%
Z/E 3:2
90%, 69%
Z/E 7:3
1f
BF3·Et2O
TiF4
80%, 40%
Z only (contains 2% 4f)
R = Ph
R1 = t-Bu
>90%, 62%
Z only (contains 2% 4f)
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Beilstein J. Org. Chem. 2015, 11, 1902–1909.
Table 4: Scope of BF3·Et2O and TiF4-mediated hydrofluorination reaction. (continued)
1g
R = Ph
R1 = Ph
BF3·Et2O
TiF4
75%, 32%
Z only
80%, 41%
Z only
1h
R = Ph
R1 =
BF3·Et2O
TiF4
27%,b 9%
Z only
35%,b 17%
Z only
4-MeOPh
1i
R = Ph
R1 =
BF3·Et2O
TiF4
90% compound 5 [16], 45%
only traces of fluorinated products
4-NO2Ph
15%,b 5%
Z only
1j
R = Ph
R1 = 4-CF3Ph
BF3·Et2O
TiF4
<5%,b NO products isolated
<5%,b NO products isolated
–
aThe regiochemistry of all products was determined by NMR analysis. The Z/E stereochemistry was determined by calculating the vinyl moieties H–F
coupling constants. bReaction times were 16 hours for all entries except for substrates 1h, 1i, and 1j (7 days).
pectively. We then maintained the phenyl moiety on the alkyne The formation of this byproduct could not be avoided; in fact
side of the sulfide, and replaced the benzyl group with a cyclo- lower temperatures or shorter reaction times did not change the
hexyl fragment directly connected to the sulfur atom (com- outcome, and the contaminant 4f could always be detected (and
pound 1d). This material allowed too for a stereoselective reac- not removed) from the desired product 2f.
tion, giving rise to the Z-stereoisomer of 2d in 47% and 68%
yields, respectively. At this stage we decided to explore two We were also interested in exploring the electronic effects of
simple variations of the groups directly connected to the ethynyl para-substitution of the phenyl group directly attached to the
moiety, that are, a cyclopropyl group and the bulky tert-butyl ethynyl moiety on the reaction outcome; thus we selected com-
group. Thus, we reacted cyclopropylethynyl(phenyl)sulfane pounds 1g–j and reacted them under our hydrofluorinating
(1e) with BF3·Et2O, obtaining an inseparable 3:2 mixture of conditions. Phenylethynyl(phenyl)sulfane (1g) represented the
Z-2e and E-3e isomers in 47% yield. The reaction with TiF4 “unactivated” compound in the series. Although the stereoselec-
showed a better stereoselectivity, furnishing a 7:3 Z/E mixture tivity was complete with the Z-isomer of 2g as the sole product,
in 69% yield.
the yields were unexpectedly low both with BF3·Et2O and TiF4
(32% and 41%, respectively).
Interestingly, the reaction of tert-butylethynyl(phenyl)sulfane
(1f) with BF3·Et2O and TiF4, while being completely stereose- We thought that the electron-donating 4-methoxy group would
lective, furnished the Z-stereoisomer 2f in 40% and 62% yields, release enough electron density towards the triple bond to
respectively, along with a 2% of difluorinated compound 4f. increase the yields, and possibly shorten the reaction times.
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Beilstein J. Org. Chem. 2015, 11, 1902–1909.
Thus, we prepared compound 1h and then reacted it with our philic counter ion; in the case of TiF4, [TiF6]2− was the only
hydrofluorinating systems; surprisingly, almost no reaction took species present in solution, and we were unable to detect any
place during 16 hours, and it was necessary to extend the reac- penta-coordinated [TiF5]− species. It has been reported that an
tion time to 7 days to obtain the desired product 2h, which was excess of hydrofluoric acid positions the equilibrium between
isolated in 9% yield from the BF3·Et2O reaction and in 17% [TiF5]− and [TiF6]2− in favour of the latter [17]. Moreover
when TiF4 was employed. It appears that the methoxy group is [TiF6]2− is rather unreactive [18], similar to the BF4− anion. We
able to efficiently coordinate the Lewis acid reactants and thus then analysed both reaction mixtures by 19F NMR, separately in
almost prevent the reaction from occurring.
CD2Cl2, in the presence of sulfide 1a, after stirring at room
temperature for 2 hours. This showed the presence of 2a and 3a,
Conversely, and as expected, the 4-nitro group had a detri- as well anions BF4− or [TiF6]2− and also an excess 3HF·Et3N.
mental effect on the reaction outcome. When 4-nitro-
phenyl(ethynyl)sulfane (1i) was treated with TiF4, it took nearly In light of these observations, our working hypothesis is that the
7 days to observe some reaction progress, and the desired Lewis acid acts to increase the acidity of the 3HF·Et3N by
Z-isomer of 2i could be isolated in only 5% yield. However, sequestering fluoride ions as relatively unreactive metal fluo-
when 1i was reacted with the BF3·Et2O, the starting material rides; thus, the alkynyl sulfides are activated by protonation
was completely consumed in 16 hours, but only traces of the possibly through an intermediate such as A as illustrated in
desired compound 2i could be detected, with thioester 5 being Scheme 3. Such an intermediate would then be susceptible to
the main reaction product (45% yield). An explanation for this fluoride ion attack, and progress to the reaction products. The
behaviour can be drawn from the fact that the 4-nitrophenyl major cis stereoselectivity is consistent with the attack of an
group surely must increase the triple bond electrophilicity, intermediate such as A from the less hindered face, opposite to
hence any trace of water present in the reaction mixture could the R1 substituent (Scheme 3).
lead to an intermediate enol thioester which would in turn
readily convert to the stable thioester 5. Nonetheless, ensuring
rigorously anhydrous reaction conditions and using fresh
BF3·Et2O could not prevent the formation of 5, while the same
compound was never detected when TiF4 was used, even after
extended reaction times.
Because of the peculiar reactivity of electron-poor alkynyl
Scheme 3: Proposed Lewis acid-mediated hydroflurination of sulfides
1.
sulfide 1i with respect to BF3·Et2O and TiF4, we decided to
carry out a further test with compound 1j, with the intention of
having the 4-trifluoromethylphenyl group removing electron-
density from the triple bond, thus possessing a reactivity similar Conclusion
to that of nitro compound 1i. Surprisingly, compound 1j was In summary, we have developed a mild method for the syn-
found mostly unreacted after 7 days, and NMR analysis of the thesis of α-fluorovinyl thioethers. The method involves the
crude reaction mixtures did indicate the presence of product 2j hydrofluorination of alkynyl sulfides by 3HF·Et3N and requires
only in traces (<5% conversion). Since 1j behaved in a similar activation using BF3·Et2O or TiF4. The reactions display
way both with BF3·Et2O and TiF4, we could only conclude that moderate to good stereoselectivity in favour of the Z-hydrofluo-
the formation of thioester 5 from sulfide 1i was due to some rination product, and this opens the way forward for making
very specific side-reaction promoted by the nitro group, appropriate analogues as potential steric and electronic
possibly with its participation in the reaction process.
mimetics of thioester enols and enolates relevant to particular
enzymatic transformations.
19F NMR was used to probe changes in the Lewis acids in the
reaction. Ratios of 1:2 Lewis acid:3HF·Et3N mixtures in
CD2Cl2 were stirred at room temperature for 2 hours, and the
aliquots (0.7 mL) were assayed in Teflon NMR tubes. 19F NMR
indicated that for each Lewis acid, BF3 and TiF4, respectively
had disappeared, forming the corresponding anions BF4−
(−150.75 ppm) and [TiF6]2− (75.37 ppm), respectively. Broad
peaks corresponding to the excess 3HF·Et3N reagent were
present. BF4− is known to be an inherently inert, non-nucleo-
Supporting Information
Supporting Information File 1
Experimental part and NMR spectra of synthesised
compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-11-205-S1.pdf]
1908

Beilstein J. Org. Chem. 2015, 11, 1902–1909.
Acknowledgements
We thank EPSRC for supporting this work and DO’H is
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grateful for a Royal Society Wolfson Research Merit Award.
This is an Open Access article under the terms of the
Creative Commons Attribution License
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