Catalytic Difluorination of Olefins

Article abstract of DOI:10.1021/jacs.6b01183

Molecular editing with fluorine is a validated strategy for modulating the structure and function of organic systems. In the current arsenal of catalytic dihalogenation technologies, the direct generation of the vicinal difluoride moiety from simple olefins without a prefunctionalization step remains conspicuously absent. Herein we report a catalytic, vicinal difluorination of olefins displaying broad functional group tolerance, using inexpensive p-iodotoluene as the catalyst. Preliminary efforts toward the development of an enantioselective variant are also disclosed.

Full text of DOI:10.1021/jacs.6b01183

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Communication
Catalytic Difluorination of Olefins
István Gábor Molnár, and Ryan Gilmour
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b01183 • Publication Date (Web): 15 Mar 2016
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Catalytic Difluorination of Olefins
István Gábor Molnár, Ryan Gilmour*
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Institute for Organic Chemistry, Westfälische WilhelmsꢀUniversität Münster, Corrensstrasse 40, 48149 Münster, Germany.
Supporting Information Placeholder
Scheme 1. Development of a catalytic, vicinal difluorination of
unactivated olefins.
ABSTRACT: Molecular editing with fluorine is a validated
strategy for modulating the structure and function of organic sysꢀ
tems. In the current arsenal of catalytic dihalogenation technoloꢀ
gies, the direct generation of the 1,2ꢀdifluoroethylene moiety from
simple olefins without a preꢀfunctionalization step remains conꢀ
spicuously absent. Herein we report a catalytic, vicinal difluorinaꢀ
tion of olefins displaying broad functional group tolerance, using
inexpensive pꢀiodotoluene as the catalyst. Preliminary efforts
towards the development of an enantioselective variant are also
disclosed.
Of the plethora of strategies employed to synthesize and modulate
function at the molecular level, structural editing by fluorine inꢀ
sertion has emerged as one of the most expansive.1 Routinely
exploited in the design of novel materials,2 chemical biology
tools3 and catalysts,4 the strength of fluorination lies in the ability
to induce localized polarity inversion [Hδ+→Fδꢀ], whilst unfavourꢀ
able steric interactions are mitigated. This unique balance of low
Van der Waals radius and high electronegativity renders fluoriꢀ
nated organic materials inimitable in their structural behavior. In
the absence of overriding steric factors, the lowꢀlying antibonding
orbital of the CꢀF bond (σCꢀF*) can participate in stabilizing hyꢀ
perconjugative interactions with πꢀsystems, nonꢀbonding electron
pairs or vicinal, electron rich sigma bonds: this latter scenario is
exemplified by the stereoelectronic gauche effect (Scheme 1,
upper).4a,5 Inherent to 1,2ꢀdifluoroethylene units, this counterintuiꢀ
tive effect aligns the fluorine atoms in a syn-clinal (φFCCF = 60°
) conformation, as a consequence of reinforcing hyperconjugative
interactions (σCꢀH→σCꢀF*).5 Since the remaining substituents are
necessarily positioned in a preꢀdetermined spacial arrangement,
this effect has found application in molecular design.5b Moreover,
the relative orientation of the CꢀF bond vectors themselves can be
employed to modulate the physicochemical properties of small
molecules, as a recent comparison of vicinal versus geminal
difluorination has demonstrated.6 The influence of fluorination
pattern on physical properties is even more pronounced in the
multivicinal fluoroalkanes (CHF)n.7 By telescoping the 1,2ꢀ
difluoroethylene substructure, linear hydrocarbonꢀteflon® hybrids
can be generated where the overall conformation can be encoded
by the relative stereochemical relationship. These wellꢀdefined
diastereomers differ from the parent hydrocarbon only in polarity
and conformation. Evaluating the, often unprecedented, physical
properties of these and related materials8 is complicated by chalꢀ
lenging synthesis campaigns, often requiring multiple deoxofluorꢀ
ination steps. This reliance on deoxofluorination chemistry, couꢀ
pled with the risk of competing elimination processes render the
syntheses challenging, despite being preparatively more attractive
The general reliance on fluorine incorporation as an editing stratꢀ
egy, together with the emergent interest in more densely fluoriꢀ
nated systems for fundamental research has led to explosive
growth in catalytic fluorination technologies. In particular, aryl
C(sp2)–F bond formation has matured at an astonishing pace,11
and elegant processes to permit direct C(sp3)–H fluorination have
been disclosed.12 However, to the best of our knowledge the direct
generation of vicinal difluoroalkanes in a catalytic paradigm reꢀ
mains conspicuously absent. We therefore questioned the feasibilꢀ
ity of developing a vicinal difluorination of olefins under catalyst
control (Scheme 1, lower) to complement the existing protocols
for dichlorination and dibromination.13 In 1998, a communication
by Hara, Yoneda and coꢀworkers disclosed the vicinal difluorinaꢀ
tion of monosubstituted olefins, and a single example of a disubꢀ
stituted, system using stoichiometric pꢀiodotoluene difluoride (1)
and Et3N•5HF.14 In view of this seminal study, and the rapid
growth of hypervalent iodine in catalysis, we envisaged the deꢀ
velopment of a catalytic processes based on the in situ generation
of 1 from commercially available pꢀiodotoluene (2).15 A study by
Shreeve and coꢀworkers has established that hypervalent ioꢀ
dine(III) reagents can be prepared in a facile manner by treatment
with Selectfluor® (3).16 This would minimize potential complicaꢀ
9
than strategies utilizing XeF2 or elemental fluorine (Scheme 1,
center).10
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tions resulting from direct reaction of the oxidant with the olefinic
standard indicated that the desired product was present in only
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substrate. Finally, several complications observed in the stoichioꢀ
metric transformation would have to be circumvented. The reacꢀ
tion is described as being highly capricious, requiring an inert
atmosphere and low temperature. Moreover, the HF composition
was also reported to be critical; a fact that was further complicated
by the limited commercial availability of Et3N•5HF.
19% yield. Varying the mixture of reagents A and B proved to
have a remarkable effect on the reaction efficiency, as indicated in
entries 4ꢀ14. Systematically increasing the ratio of HF relative to
the amine revealed 1:4.5 to be optimum (entry 7). Using additionꢀ
al HF did little to improve the transformation and applying this
protocol, it was possible to isolate the desired difluoride in 76%
yield (89% by 19F NMR). This subtle balance between HF content
and yield is fully in line with the observations by Hara et al. reꢀ
garding the role of HF as a Brønsted acid activator.20
Table 1. Identification of an efficient HF source and solvent.[a]
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Table 2. Optimization of concentration and temperature.[a]
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HF source
Solvent
Time
[h]
Conv.
[%] [b]
Yield
[%][c]
(amine:HF)[a]
1
2
3
4
5
6
7
8
ꢀ
DCE
DCE
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24
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<5
<5
<1
<1
Solvent:HF
source
Conc.
[mol/mL]
Temp.
[°C]
Conv.
[%][b]
Yield
[%][c]
A (1:3)
1
2
3[d]
4[e]
5
2:1
2:1
2:1
2:1
1:1
1:1
1:1
1:1
0.133
0.133
0.133
0.133
0.1
40
rt
0
>95
75
89(76)
69(61)
22(19)
68(59)
86(76)
89(75)
58(50)
89(76)
B (1:9.23)
A+B (1:3.5)
A+B (1:4)
A+B (1:4)
A+B (1:4.5)
A+B (1:5)
DCE
>95
15
19
DCE
11
24
DCE
72
66(55)
66(53)
89(76)
87(75)
87(72)
84(73)
17
rt
rt
rt
rt
rt
75
DCE
76
>95
>95
65
DCE
>95
>95
>95
>95
80
6
0.2
DCE
7
8[f]
0.4
11[d] A+B (1:4.5)
DCE (dry)
DCM
MeCN
THF
0.2
>95
12
13
14
A+B (1:4.5)
A+B (1:4.5)
A+B (1:4.5)
[a] General reaction conditions: alkene (0.20 mmol), pꢀiodotoluene (0.04
mmol), DCE (0.5 mL), HF source (0.5 mL, amine:HF ratio=1:4.5), and
Selectfluor® (0.30 mmol) in a 50 mL screwꢀcap PP vial at the indicated
temperature for 14 h. [b] Determined by 1H NMR from the crude reaction
mixture using ethyl fluoroacetate as internal standard. [c] 19F NMR yield
determined from the crude reaction mixture using ethyl fluoroacetate as
internal standard (isolated yield in parentheses). [d] Reaction time: 24 h.
[e] 30 mol% catalyst applied. [f] In a ca. 15 mL screwꢀcap Teflon® reacꢀ
tion vessel.
<5
<1
[a] General reaction conditions: alkene (0.20 mmol), pꢀiodotoluene (0.04
mmol), solvent (1.0 mL), HF source (0.5 mL), and Selectfluor® (0.30
mmol) in a 50 mL screwꢀcap PP vial at 40 °C for the indicated time. A:
Triethylamine trihydrofluoride and B: Olah’s reagent. (Calculated amine
1
to HF ratio in parentheses). [b] Determined by H NMR from the crude
reaction mixture using ethyl fluoroacetate as internal standard. [c] 19F
NMR yield determined from the crude reaction mixture using ethyl
fluoroacetate as internal standard (isolated yield in parentheses). [d] Perꢀ
formed with anhydrous DCE and under an argon atmosphere.
Having identified suitable conditions to effect this transformation,
the influence of modifying reaction parameters was studied (4→5,
Table 2). Of particular importance was the need to identify condiꢀ
tions in which the reaction would proceed at ambient temperature.
Initially, the concentration was fixed at 0.133 M and the effects of
temperature variations were studied (entries 1ꢀ4). Immediately
evident was the erosion of reaction efficiency at lower temperaꢀ
tures, and that increasing the catalyst loading was ineffective (cf.
entries 2 and 4). However, by fixing the solvent to HF ratio at 1:1
it was possible to obtain the desired product in good yield, irreꢀ
spective of concentration (up to 76% isolated yield). With an opꢀ
timized system for catalytic difluorination based on I(I)/I(III)
catalysis in hand, efforts were invested in exploring the scope and
limitations of the transformation. To expedite isolation and strucꢀ
tural analysis of the product difluorides, alkyl spacers were initialꢀ
ly employed to separate the terminal olefin from the functional
group of interest. The results are summarized in Table 3, where
both isolated yields and NMR yields based on 19F NMR spectrosꢀ
copy (in parentheses) are provided. In contrast to existing state-of-
the-art technologies for direct fluorination of olefins, these condiꢀ
tions proved to be extremely well tolerated by an array of funcꢀ
tional groups.
Cognizant that the success of this investigation hinged on the
identification of a suitable HF source, the difluorination of a modꢀ
el olefin bearing a pendant ester moiety was chosen as a benchꢀ
mark transformation (4→5, Table 1). Since highly electron rich
olefins are known to undergo direct reaction with Selectfluor®,17
and I(III)ꢀmediated fluorination often elicits rearrangements in
such systems,18 this investigation focused on unactivated, terminal
olefin feedstocks. Commercially available Et3N•3HF and
Pyr(HF)x were examined as reagent and coꢀsolvent, and are reꢀ
ferred to as sources A and B, respectively in Table 1. Mixtures of
these reagents are described in terms of the combined amine:HF
ratio (amine = Et3N + pyridine).19 Initially, dichloroethane (DCE)
was used as the solvent with Selectfluor® (1.5 eq.) as oxidant and
pꢀiodotoluene as the organocatalyst (20 mol%). Reactions were
performed at 40 °C with the HF source as a coꢀsolvent for the
time indicated, and monitored by 19F NMR spectroscopy. The
control study, in which the reaction was attempted in the absence
of the HF source led to <5% conversion after 14 h (entry 1). This
finding was again observed when using the Et3N•3HF (A) (entry
2). Switching to Olah’s reagent Pyr(HF)X (B, 70% w/w) resulted
in almost quantitative consumption of the olefin as determined by
1H NMR spectroscopy with an internal standard (entry 3). Howꢀ
ever, 19F NMR analysis with ethyl fluoroacetate as the internal
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Table 3. Exploring the substrate scope and functional group tolerance of the title reaction.[a]
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[a] General reaction conditions: The alkene (0.20 mmol), catalyst (0.04 mmol), DCE (0.5 mL), HF source (0.5 mL, ratios above), and Selectfluor® (0.30
mmol) were stirred in a ca. 15 mL screwꢀcap Teflon® reaction vessel at room temperature for the time indicated. Numbers refer to isolated yield. (19F NMR
yield in parentheses determined from the crude reaction mixture using ethyl fluoroacetate as internal standard). [b] Significant amount of homoꢀcoupled side
1
product observed, full details in the SI. [c] Conversion 93% via H NMR using ethyl fluoroacetate as internal standard. [d] Tosylꢀmigrated regioisomer
isolated as major side product. Full details in the SI. [e] Conversion 85% via 1H NMR using ethyl fluoroacetate as internal standard. [f] Reaction performed
on a 0.18 mmol scale.
enantioselectivity was observed (7k, 54%,er 61:39). Albeit enꢀ
couraging, this proof of concept reiterates Denmark’s observation
that routes to “enantioenriched vicinal dihalide products remain
comparatively underdeveloped” and thus constitute an ongoing
challenge in contemporary asymmetric catalysis.13 It is interesting
to note that catalyst 8 proved to be more effective in the enantiꢀ
oselective chromane cyclization (7p, er 70.5:29.5). Consistent
with previous mechanistic hypotheses pertaining to the stoichioꢀ
metric variant, it seems reasonable that product formation (4→5)
is the result of two discrete C(sp3)ꢀF bond forming processes
(Scheme 3).13a,14 In situ generation of the aryliodonium difluoride
1, and engagement of the olefin substrate 4 generates a transient
cation (9). This facilitates an activation ꢀ displacement sequence
via intermediates 9 and 10 to generate the 1,2ꢀdifluoroethylene
system 5 with regeneration of 2, thereby completing the catalytic
cycle. The postulated intermediacy of cation 9 is further supported
by the intramolecular cyclization to generate the fluorinated
chromane 7p.
In summary, an operationally simple catalytic vicinal difluorinaꢀ
tion of simple olefins is reported using inexpensive, commercially
available reagents. It is envisaged that this expansion of the cataꢀ
lystꢀbased dihalogenation arsenal to include 1,2ꢀdifluorination
will accelerate interrogation of more stereochemically complex
organofluorine systems,22 and inspire the design of enantioselecꢀ
tive variants.23 Efforts to expand the substrate scope are ongoing
and will be disclosed in due course.
Scheme 2. Towards an enantioselective difluorination.
Terminal olefins proved to be viable substrates and in addition to
esters (7a, 76% isolated yield), it was possible to directly difluoriꢀ
nate in the presence of unprotected alcohols (7b, 39%),
phthalimides (7c, 74% yield), α,βꢀunsaturated esters (7d, 67%),
acetates (7e, 71%), tosylates (7f,g, up to 76%) and also the alꢀ
lylbenzene scaffold (7h, 68%) (Table 3). Allylic alcohol ethers
could also be smoothly processed to the corresponding difluoroꢀ
ethylene analogs (7iꢀ7m) in up to 76% isolated yield (Table 3,
center). It was also possible to extend this operationally simple
method to include the 1,1ꢀdisubstituted ether derived from 2ꢀ
methylꢀ2ꢀpropenꢀ1ꢀol (7n, 50%) and acetylated quinine under
forcing conditions (7o, dr 5:1, 80%). Intriguingly, attemptes to
difluorinated a phenol derivative generated the fluorochromane
scaffold 7p in 60% yield. In an attempt to induce enantioselectiviꢀ
ty, the standard difluorination conditions B were repeated using
the chiral, nonꢀracemic aryl iodide derivative 8 (Scheme 2).21 It
proved difficult to drive the reaction to completion and modest
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Scheme 3. Tentative mechanistic proposal.
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For selected examples see (a) O’Hagan, D. J. Org. Chem.
2012, 48, 5247ꢀ4249. (b) Hunter, L.; Kirsch, P.; Slawin, A. M.
1
2
3
4
5
6
7
Z.; O’Hagan, D. Angew. Chem. Int. Ed. 2009, 48, 5457ꢀ5460.
(c) Hunter, L; O’Hagan, D. Org. Biomol. Chem. 2008, 6, 2843ꢀ
2848. (d) Nicoletti, M.; O’Hagan, D.; Slawin, A. M. Z. J. Am.
Chem. Soc. 2005, 127, 482ꢀ483.
Allꢀcis 1,2,3,4,5,6ꢀhexafluorocyclohexane, is reported to have
the largest dipole moment of any organic material Keddie, N.;
Slawin, A. M. Z.; Lebl, T.; Philp, D.; O’Hagan, D. Nat. Chem.
2015, 7, 483ꢀ488.
(8)
(9)
(10)
(11)
Tius, M. A. Tetrahedron 1995, 51, 6605ꢀ6634.
Sandford, G. J. Fluorine Chem. 2007, 128, 90ꢀ124.
8
9
(a) Cook, A.; Sanford, M. S. CꢀHal Bond Formation by Arene
CꢀH Activation. In Catalytic Transformations via C-H Activa-
tion, Vol. 2; Science of Synthesis, Yu, J.ꢀQ., Ed.; Thieme, 2015,
183–219; (b) McMurtrey, K. B.; Sanford, M. S. CꢀF Bondꢀ
Forming Reactions. In Cross-Coupling and Heck-Type Reac-
tions from the Science of Synthesis Reference Library. Vol. 2,
John P. Wolfe, Ed., Thieme, 2012, 551–565; (c) Campbell, M.;
Ritter, T. Chem. Rev. 2015, 115, 612–633.
(a) Pitts, C. R.; Bloom, S.; Woltornist, R.; Auvenshine, D. J.;
Ryzhkov, L. R.; Siegler, M. A.; Lectka, T. J. Am. Chem. Soc.
2014, 136, 9780–9791; (b) Bloom, S.; Knippel, J. L.; Lectka,
T. Chem. Sci. 2014, 5, 1175–1178; (c) Pitts, C. R.; Bloom, M.
S.; Bume, D. D.; Zhang, Q. A.; Lectka, T. Chem. Sci. 2015, 6,
5225–5229.
(a) For an excellent review see Cresswell, A. J.; Eey, S. T.ꢀC.;
Denmark, S. E. Angew. Chem. Int. Ed. 2015, 54, 15642ꢀ15682;
(b) Cresswell, A. J.; Eey, S. T.ꢀC.; Denmark, S. Nat. Chem.
2015, 7, 146ꢀ152; (c) For examples of enantioselective vicinal
halogenation of allylic alcohols see Nicolaou, K. C.; Simmons,
N. L.; Ying, Y.; Heretsch, P. M.; Chen, J. S. J. Am. Chem. Soc.
2011, 133, 8134ꢀ8137 (chlorination); Hu, D. X.; Shibuya, G.
M.; Burns, N. Z. J. Am. Chem. Soc. 2013, 135, 12960ꢀ12963
(bromination); (d) For I(II)ꢀcatalyzed dichlorination and diꢀ
bromination see Stodulski, M.; Goetzinger, A.; Kohlhepp, S.
V.; Gulder, T. Chem. Commun. 2014, 50, 3435ꢀ3438.
Hara, S.; Nakahigashi, J.; IshiꢀI, K.; Sawaguchi, M.; Fukuhara,
T.; Yoneda, N. Synlett 1998, 495ꢀ496. Also see Sawaguchi,
M.; Hara, S.; Fukuhara, T.; Yoneda, N. J. Fluorine Chem.
2000, 104, 277ꢀ280.
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ASSOCIATED CONTENT
Supporting Information
NMR spectra and experimental procedures. Supporting inforꢀ
mation is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*ryan.gilmour@uniꢀmuenster.de
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Notes
The authors declare no competing financial interest.
For the discovery of aryliodonium(III) difluorides see Weinꢀ
land, R. F.; Stille, W. Chem. Ber. 1901, 34, 2631ꢀ2633. Also
see Edmunds, J. J.; Motherwell, W. B. J. Chem. Soc., Chem.
Commun., 1989, 881ꢀ883. For a review on hypervalent iodine
chemistry see Wirth, T. Angew. Chem. Int. Ed. 2005, 44, 3656ꢀ
3665.
Author Contributions
All authors have given approval to the final version of the manuꢀ
script.
(16)
For a facile synthesis of hypervalent iodine(III) reagents using
Selectfluor® see Ye, C.; Twamley, B.; Shreeve, J. M. Org Lett.
2005, 7, 3961ꢀ3964.
ACKNOWLEDGMENT
We acknowledge generous financial support from the WWU
Münster and the DFG (SFB 858, and Excellence Cluster EXC
1003). This manuscript is dedicated to Prof. Scott E. Denmark.
(17)
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Selectfluor® can react directly with highly electron rich subꢀ
strates. See Lal, G. S. J. Org. Chem. 1993, 58, 271ꢀ2796.
For a recent example of the hypervalent iodine mediated fluorꢀ
ination of styrene derivatives to generate 2,2ꢀ
difluoroethylarenes see Kitamura, T.; Muta, K.; Oyamada, J. J.
Org. Chem. 2015, 80, 10431ꢀ10436.
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