Fluoromethylene Transfer from Diarylfluoromethylsulfonium Salts: Synthesis of Fluorinated Epoxides

Article abstract of DOI:10.1002/chem.201900349

Diarylfluoromethyl sulfonium salts are efficient fluoromethylene transfer reagents equivalent to fluorocarbene, which is difficult to access. This was demonstrated by the development of a monofluorinated Johnson–Corey–Chaykovsky reaction with ketones and aldehydes, delivering uncommon 2-unsubstituted fluoroepoxides. This is the first evidence for the feasibility of sulfur fluoromethylylide and its action as a reaction intermediate.

Full text of DOI:10.1002/chem.201900349

A Journal of
Accepted Article
Title: Fluoromethylene Transfer from Diarylfluoromethylsulfonium Salts:
Synthesis of Fluorinated Epoxides
Authors: Janis Veliks and Armands Kazia
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COMMUNICATION
Fluoromethylene Transfer from Diarylfluoromethylsulfonium
Salts: Synthesis of Fluorinated Epoxides
[
a]
[a]
Janis Veliks* , and Armands Kazia
Abstract: Diarylfluoromethyl sulfonium salts are efficient
fluoromethylene transfer reagents equivalent to fluorocarbene, which
is difficult to access. This was demonstrated by the development of a
monofluorinated Johnson-Corey-Chaykovsky reaction with ketones
and aldehydes, delivering uncommon 2-unsubstituted fluoroepoxides.
This is the first evidence for the feasibility of sulfur fluoromethylylide
and its action as a reaction intermediate.
transformation. Olah and co-workers have shown that S-
monofluoromethyl-S-phenyl-2,3,4,5-tetramethylphenylsulfonium
tetrafluoroborate (1) is a bench stable and remarkably versatile
reagent for the monofluoromethylation of various nucleophiles.[
We were intrigued as to whether fluormethylsulfonium salt 1 could
be used to generate sulfur fluoromethylylide, for participation in
the Johnson-Corey-Chaykovsky fluoromethylenation.
12]
The abundance of organofluorine compounds in medicinal and
agrochemical portfolios has fueled enormous progress in the
development of new synthetic methodologies in the area of
fluorine chemistry.[1] However, direct monofluoromethylene
(
:CHF) transfer remained underdeveloped due to an extreme
[
2]
instability of fluorocarbenoids and a limited availability of
suitable reagents (Figure 1. A). Furthermore, computational
studies predict that diazofluoromethane is not a viable species[3]
(
Figure 1. B). Freons of type CHFX
2
may be used as
fluorocarbene precursors, but they are expensive, difficult to
handle and restricted due to their ozone depleting properties.[4] To
overcome this issue several indirect methods for accessing the
fluoromethylene synthon have been developed which require
extra synthetic steps, such as reduction of halofluoro- or
phenylsulfide moieties.[5] Another successful example is the
fluorinated sulfoximine reagent developed by Hu and
coworkers.[ The aforementioned reagents are suitable for the
fluoromethylenation of alkenes, with only a single example of
direct monofluoromethylene (:CHF) transfer to a carbonyl moiety
Figure 1. A Fluorocarbene and fluoromethylene synthon. B Reagents for the
direct fluoromethylenation. C Fluoromethylenation of aldehydes and ketones.
6]
[
7]
Luisi very recently succeeded in monofluormethylenation of
known to date . Availability of solid, bench stable reagents for
this purpose would be of great value in the areas of medicinal[1b],
ketones to furnish 2-unsubstituted fluoroepoxides using lithiated
fluoroiodomethane[
7]
(Figure
reaction
1.
with
B).
aldehydes
However,
and
agrochemical and material[8] chemistries.
Sulfur ylides may be used as carbene equivalents[9] and are
central in the Johnson-Corey-Chaykovsky reaction.[10] We
fluoroiodomethyllithium
acetophenone derivatives does not afford fluoroepoxides. The
closely related fluorinated sulfoximines developed by Hu and co-
envisioned the use of sulfur ylides for fluoromethylene transfer,
however, only decomposition of fluoromethyldimethyl sulfonium
tetrafluoroborate has been reported.[11] Additionally, the lack of
data on the ability of fluoromethylsulfonium salts to generate
sulfur ylides and participate in Johnson-Corey-Chaykovsky
reactions raised doubts over their suitability for the proposed
workers [
6a-c]
are capable of direct monofluoroalkenyl (:CRF,
where R = Alk) transfer to ketones via a carbanion intermediate
to deliver substituted fluoroepoxides. Monofluoromethylene
transfer (:CHF) has not been demonstrated using the Hu reagent,
and aldehydes are not tolerated under the reported reaction
conditions as well. Other synthetic routes to fluorinated epoxides
[
13]
include: a) oxidation of vinyl fluorides;
b) base promoted
[
14]
cyclization of fluorohalohydrines; c) Darzens type reaction with
[
a]
Dr. Janis Veliks, Armands Kazia
Latvian Institute of Organic Synthesis
Aizkraukles 21, LV-1006, Riga, Latvia
E-mail: janis.veliks@osi.lv
carbonyl compounds;[
15]
d) nucleophilic substitution of
bromoepoxide with fluoride source.[16] Fluorinated epoxides are
known to be of inherently low stability and tend to undergo
1
,2-fluorine migration,[6a] limiting access to these compounds.
Supporting information for this article is given via a link at the end of
the document.
Here we disclose the first example of fluoromethylsuflonium salt
1 as a competent fluromethylene transfer reagent, and its ability
to participate in
a fluorinated Johnson-Corey-Chaykovsky
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reaction under mild conditions, giving access to uncommon
n-BuLi, 20 min, -78 °C, then 2, 18 h, -78 °C to RT. [d] Determined by
19
3
F NMR using CF COOEt as internal reference. Isolated yields in
2-unsubstituted fluoroepoxides.
parenthesis.
Initial attempts to trap sulfur fluoromethyl ylide A involved
treating sulfonium salt 1 with n-buthyllithium and subsequently
quenching with deuterated benzoic acid or D O. However, only
decomposition of sulfonium salt 1 with a loss of fluoride was
p-Nitrobenzaldehyde 2h was selected as a model
substrate to test the feasibility of monofluoromethylenation
using sulfonium salt 1. Our initial attempt to generate the
desired ylide in THF using n-BuLi followed by the addition of
2
observed. When reagent 1 was treated with NaH in CDCl
3
the
1
H and 19F NMR spectra showed the formation of a deuterated
2
h was not successful (Table 1, entry 1). Gratifyingly, when
sulfonium salt and aldehyde 2h were combined in
,4-dioxane followed by NaH addition, the desired product 3h
was observed in moderate yield (entry 2). Solvent screening
Table 1, entry 2 to 7) identified acetonitrile as the optimal
solvent. When, under the same conditions,
sulfonium salt 1-D
1
2
/D in addition to the decomposition products
1
4
and 5 (Scheme 1). This unprecedented deuteration of sulfonium
1
salts in CDCl
intermediate.
3
suggests fluoromethylylide A as probable
(
p-nitroacetophenone 2e was used as substrate (entry 8) the
reaction proceeded with moderate yield but incomplete
conversion. Higher loading of
1 (entry 9) and lower
temperature (entry 10) gave the optimal reaction conditions.
Further increasing the loading of sulfonium salt 1 was not
beneficial, giving a slight decrease in yield (entry 11). The
optimal reaction conditions therefore consist of treating 2e with
1
(1.5 eq) and NaH (1.6 eq) in MeCN at 0 °C, giving the desired
product with excellent yield as a mixture of diastereomers.
Typically, the reaction is complete within 3 to 4 hours.
Scheme 1. Deuteration of
determined by H and F NMR
1
via sulfur fluoromethyl ylide A. NMR ratio
.
1
[a]
19
[b]
This result motivated further exploration of sulfonium salt 1 as a
competent fluoromethylene group transfer reagent.
Table 1. Reaction Optimization.
Yield of
T
entry[a]
1/2/base
R1
Solvent[b]
3
d.r.
°C
d]
[
%] [
1
2
3
4
5
6
7
8
9
1/1/1.1[c]
1/1/1.5
H
H
THF
-78
RT
RT
RT
RT
RT
RT
RT
RT
0
0
-
1,4-dioxane
57
55
52
0
1.7:1
1.4:1
1.2:1
-
1/1/1.5
H
2 2
CH Cl
1/1/1.5
H
THF
1/1/1.5
H
DMF
1/1/1.5
H
CHCl
3
81
83
54
72
1:1
1/1/1.5
H
MeCN
MeCN
MeCN
MeCN
MeCN
1.4:1
1.3:1
1:1
1.1/1/1.5
1.5/1/1.6
1.5/1/1.6
2.0/1/2.2
Me
Me
Me
Me
Scheme 2. Scope of the monofluoromethylenation. aIsolated yields unless
1
0
1
96(97)
87
1:1
otherwise stated. bYield was determined by H NMR using 1.0 eq of EtOAc
1
c
as an internal reference. Conditions: 2.0 eq 1, 4.0 eq NaH, CHCl
3
(0.1 M),
1
0
1:1
0
°C, 1-5 h.
[
a]
Reaction conditions: To a mixture of 1 (0.138 mmol) and 2 in a solvent
(0.05 M) under Ar atmosphere was added 60% NaH (in paraffin oil). The
solvent was evaporated under reduced pressure and the crude reaction
mixture was analysed by H and F NMR. Anhydrous solvents. 1.1 eq
After establishing reaction conditions for the Johnson-
Corey-Chaykovsky fluoromethylenation, the substrate scope
1
19
[b]
[c]
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COMMUNICATION
was investigated (Scheme 2). The reaction conditions are
compatible with variety of aryl substituted ketones and
aldehydes 2. Functional groups such as nitro, cyano, ester,
amide, trifluoromethyl and sulfone are tolerated, affording
products 3a-n in moderate to high yields. Electron withdrawing
groups are known to increase the stability of fluorinated
formation of fluoromethylylide is a fast and possibly reversible
process in chloroform, competing with nucleophilic attack of ylide
at the carbonyl group. Chloroform-d could act either reversibly as
an acid, exchanging proton to deuteron via intermediate B, or
alternatively ylide A could be regenerated by a second reaction of
B with another equivalent of NaH. (Scheme 3a).
In order to probe the influence of fluorine on the reactivity of
sulfonium salts we performed a competition experiment whereby
fluoromethyl sulfonium salt 1 and methyldiphenylsulfonium
epoxides,[6a] meaning
a range of compounds could be
chromatographically isolated on silica gel pretreated with
6c]
Et
3
N[
or alumina. To our surprise, ketone 2o with an
unsubstituted phenyl ring gave product 3o in a good isolated
yield after chromatography. Substrates bearing electron
donating groups on the aryl ring did not afford the desired
products (see 3p) due to instability of the corresponding
epoxides. Halogenated acetophenones efficiently participate in
tetrafluoroborate (7) were reacted with ketone 2b delivering
fluorinated epoxide 3b in excellent yield (Scheme 3b). Only traces
of nonfluorinated epoxide 6 were observed by 1H NMR. This
demonstrates the positive effect of fluorine on the reactivity of
sulfonium salts compared to their nonfluorinated counterparts.
This could be attributed to higher acidity of the fluromethyl group
compared to the methyl group of sulfonium salts. Fluorine could
also increase the nucleophilicity of the ylide intermediate A. This
offers a rationale as to why competing decomposition of 1 to
deliver nonfluorinated sulfonium salt 5 (Scheme 1) does not have
a detrimental effect on chemoselectivity of the reaction.
3
this reaction with CHCl as solvent, giving products 3r and 3s
in moderate to good yields. In addition, linear and cyclic
aliphatic ketones or aldehydes participate well in the reaction,
giving good to high yields of 3t and 3u, respectively. The
substrate scope is broad and mainly limited by the stability of
the
resultant
fluoroepoxides
3
rather
than
the
fluoromethylenation itself, as the decomposition products
originating from fluoroepoxide 3 are always observed for
unproductive substrates.[17]
Vinyl substituted ketone 2v has been used to probe
selectivity towards 1,2-addition versus 1,4-addition (Scheme 3c).
Fluoromethylenation proceeds preferably at the carbonyl moiety
to give fluoroepoxide 3v. However, a complex mixture of
cyclopropanated diastereomers 8–which could originate from the
conjugate addition–can be observed by 19F NMR as well.
In summation, we have demonstrated the first evidence for
the feasibility of sulfur fluoromethylylide, generated from
diarylfluoromethylsulfonium tetrafluroborate, as
a
reaction
intermediate. This resulted in the development of an efficient and
general method for the formation of uncommon 2-unsubsituted
fluoroepoxides, highlighting the unexplored and vast potential of
fluoromethylsulfonium salts as direct fluoromethylene transfer
reagents. With this, we offer a bench stable, easy to operate and
efficient synthetic equivalent to the otherwise very challenging
fluorocarbene synthon.
Acknowledgements
Finnancial support by ERDF project Nr.1.1.1.5/17/A/003. Prof. Dr.
Aigars Jirgensons for scientific advise. Renāte Melngaile, Artūrs
Sperga for the synthesis of 1. LIOS analytical service for NMR
and elemental analysis. Dr. Stephen Hyde for proofreading.
Keywords: Johnson-Corey-Chaykovsky reaction •
fluoromethylenation • sulfur fluoromethylylide • fluorinated
epoxides • Fluoromethylene transfer
[
1]
Reviews covering recent progress in fluorine chemistry: a) V.
Gouverneur, K. Seppelt, Chem. Rev. 2015, 115, 563–565; b) S. Purser,
P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 2008, 37,
Scheme 3. Reactivity and properties of sulfonium salt 1.
3
20–330; c) C. Ni, M. Hu, J. Hu, Chem. Rev. 2014, 115, 765–825. d) S.
Fustero, D. M. Sedgwick, R. Román, P. Barrio, Chem. Commun. 2018,
4, 9706–9725; e) Ni, J. Hu, Chem. Soc. Rev. 2016, 45, 5441–5454; f)
To corroborate our indirect observation of ylide formation in
CDCl
be transferred from CDCl
Indeed, when fluoromethylenation of ketone 2s was performed in
the CDCl , deuterium incorporation into fluoroepoxide 3s/3s-D
was observed in a ratio of 1:1.2 (Scheme 3a). This suggests that
3
(Scheme 1) we have investigated whether deuterium can
5
3
via ylide to the fluorinated epoxide 3.
S. Preshlock, M. Tredwell, V. Gouverneur, Chem. Rev. 2016, 116, 719–
766.
[2]
a) X. Shen, J. Hu, Eur. J. Org. Chem. 2014, 4437–4451; b) E. David, G.
Milanole, P. Ivashkin, S. Couve-Bonnaire, P. Jubault, X. Pannecoucke,
3
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Chem. Eur. J. 2012, 18, 14904–14917; c) Modern Synthesis Processes
and Reactivity of Fluorinated Compounds, Ed. 1 (Eds.: H. Groult, F.
Leroux, A. Tressaud), Academic Press, Elsevier, 2017, pp. 318-327; d)
D. C. Kail, P. Malova Krizkova, A. Wieczorek, F. Hammerschmidt, Chem.
Eur. J. 2014, 20, 4086–4091. e) S. Molitor, V. H. Gessner, Chem. Eur. J.
[9]
For sulfur ylide chemistry: a) A. C. B. Burtoloso, R. M. P. Dias, I. A.
Leonarczyk, Eur. J. Org. Chem. 2013, 5005–5016; b) R. Appel, N.
Hartmann, H. Mayr, J. Am. Chem. Soc. 2010, 132, 17894–17900; c) J.
D. Neuhaus, R. Oost, J. Merad, N. Maulide, Top. Curr. Chem. 2018, 376,
DOI 10.1007/s41061-018-0193-4; d) J. D. Neuhaus, A. Bauer, A. Pinto,
N. Maulide, Angew. Chem. Int. Ed. 2018, 57, 16215–16218; Angew.
Chem. 2018, 130, 16448–16452. e) Y. Duan, J.-H. Lin, J.-C. Xiao, Y.-C.
Gu, Org. Lett. 2016, 18, 2471–2474.
2017, 23, 12372–12379; f) G. Parisi, M. Colella, S. Monticelli, G.
Romanazzi, W. Holzer, T. Langer, L. Degennaro, V. Pace, R. Luisi, J.
Am. Chem. Soc. 2017, 139, 13648–13651.
[
[
3]
4]
For diazofluoromethane: a) A. I. Boldyrev, P. V. R. Schleyer, D. Higgins,
C. Thomson, S. S. Kramarenko, J. Comput. Chem. 1992, 13, 1066–
[10] For examples of Johnson-Corey-Chaykovsky reaction, see: a) A. W.
Johnson, R. B. Lacount, J. Am. Chem. Soc. 1961, 83, 417–423; b) E. J.
Corey, M. Chaykovsky, J. Am. Chem. Soc. 1965, 87, 1353–1364; c) Y.
Duan, B. Zhou, J.-H. Lin, J.-C. Xiao, Chem. Commun. 2015, 51, 13127–
13130; d) O. Zhurakovskyi, Y. E. Türkmen, L. E. Löffler, V. A. Moorthie,
C. C. Chen, M. A. Shaw, M. R. Crimmin, M. Ferrara, M. Ahmad, M.
Ostovar, J. V. Matlock, V. K. Aggarwal, Angew. Chem. Int. Ed. 2018, 57,
1346–1350; Angew. Chem. 2018, 130, 1360–1364.
1078; b) L. A. Zapata, S. López, P. Ruiz, J. Quijano, R. Notario, Struct.
Chem. 2016, 28, 597–605. For other fluorinated diazoalkanes: L.
Mertens, R. M. Koenigs, Org. Biomol. Chem. 2016, 14, 10547–10556.
For review on fluorinated carbenes: a) D. L. S. Brahms, W. P. Dailey,
Chem. Rev. 1996, 96, 1585–1632. For CHFBr
2
as a reagent for
monofluorocarbene generation: b) M. Schlosser, G. Heinz, Angew.
Chem. Int. Ed. Engl. 1968, 7, 820–821; M. Schlosser, G. Heinz, Angew.
[11] Y. Xu, M. Fletcher, W. R. Dolbier, J. Org. Chem. 2000, 65, 3460–3465.
[12] a) G. K. S. Prakash, I. Ledneczki, S. Chacko, G. A. Olah, Org. Lett. 2008,
10, 557–560; b) A. M. Rydzik, I. K. H. Leung, A. Thalhammer, G. T.
Kochan, T. D. W. Claridge, C. J. Schofield, Chem. Commun. 2014, 50,
1175–1177; c) Y. V. Reddy, A. H. K. A. Temimi, J. Mecinović, Org. Biomol.
Chem. 2017, 15, 1350–1354.
Chem. 1968, 80, 849–850. For CHFI
2
as
a
reagent for
monofluorocarbene generation, see: c) N. Kawabata, M. Tanimoto, S.
Fujiwara, J. L. Hahnfeld, D. J. Burton, Tetrahedron Lett. 1975, 16, 1819–
1
1
1
822; d) N. Kawabata, M. Tanimoto, S. Fujiwara, Tetrahedron 1979, 35,
919–1923; e) J. Nishimura, J. Furukawa, J. Chem. Soc. D 1971, 1375–
376. For CHF
2
I as a reagent for monofluorocarbene generation, see: f)
[13] For epoxidation of vinyl fluorides, see: a) O. A. Wong, Y. Shi, J. Org.
Chem. 2009, 74, 8377–8380; b) C. Gosmini, T. Dubuffet, R. Sauvêtre,
J.-F. Normant, Tetrahedron: Asymmetry 1991, 2, 223–230.
L.-P. B. Beaulieu, J. F. Schneider, A. B. Charette, J. Am. Chem. Soc.
2013, 135, 7819–7822; g) C. Navuluri, A. B. Charette, Org. Lett. 2015,
1
7, 4288–4291.
[14] For base promoted cyclization of fluorohalohydrines, see: a) P. Duhamel,
B. Leblond, J.-M. Poirier, J. Chem. Soc. Chem. Commun. 1993, 476–
477; b) P. Duhamel, B. Leblond, L. Bidois-Séry, J.-M. Poirier, J. Chem.
Soc. Perkin Trans. 1 1994, 2265–2271.
[
[
5]
6]
Indirect methods for the introduction of monofluormethylene synthon. For
example via halofluorocarbene: a) J. Oliver, U. Rao, M. Emerson,
Tetrahedron Lett. 1964, 5, 3419–3425. Via chlorofluoromethyl phenyl
sulfide: b) M. Kirihara, T. Ogata, A. Itou, S. Naito, M. Kishida, K.
Yamazaki, H. Tabata, H. Takahashi, Chem. Lett. 2013, 42, 1377–1379.
Fluorinated sulfoximines for fluoroepoxide synthesis: a) W. Zhang, J. Hu,
Adv. Synth. Catal. 2010, 352, 2799–2804; b) T. Luo, R. Zhang, W. Zhang,
X. Shen, T. Umemoto, J. Hu, Org. Lett. 2014, 16, 888–891; c) T. Luo, R.
Zhang, X. Shen, W. Zhang, C. Ni, J. Hu, Dalton Trans. 2015, 44, 19636–
[15] For Darzen type reaction with carbonyl compounds, see: a) M. Shimizu,
T. Hata, T. Hiyama, Tetrahedron Lett. 1997, 38, 4591–4594; b)
Lemonnier Gꢀrald, L. Zoute, J.-C. Quirion, P. Jubault, Org. Lett. 2010,
12, 844–846.
[16] Nucleophilic substitution: J. Leroy, J. Bensoam, M. Humiliere, C.
Wakselman, F. Mathey, Tetrahedron 1980, 36, 1931–1936.
19641. Fluorinated sulfoximines for fluorocyclopropane synthesis: d) X.
[17] Example of decomposition pathway of 3:
Shen, W. Zhang, L. Zhang, T. Luo, X. Wan, Y. Gu, J. Hu, Angew. Chem.
Int. Ed. 2012, 51, 6966–6970; Angew. Chem. 2012, 124, 7072–7076.
During a submission process of this manuscript independently a new
method has been published for the synthesis of 2-unsubstituted
fluoroepoxides employing fluoroiodomethyllithium reaction with ketones:
S. Monticelli, M. Colella, V. Pillari, A. Tota, T. Langer, W. Holzer, L.
Degennaro, R. Luisi, V. Pace, Org. Lett. 2019, 21, 584–588.
a) T. Fujiwara, D. O’Hagan, J. Fluorine Chem. 2014, 167, 16–29; b) R.
Berger, G. Resnati, P. Metrangolo, E. Weber, J. Hulliger, Chem. Soc.
Rev. 2011, 40, 3496–3508.
[
[
7]
8]
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Chemistry - A European Journal
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COMMUNICATION
COMMUNICATION
Sulfur fluoromethylylide in action:
Diarylfluoromethyl sulfonium salts are
efficient fluoromethylene transfer
reagents. This was demonstrated by
the development of a monofluorinated
Johnson-Corey-Chaykovsky reaction
with ketones and aldehydes,
Janis Veliks*, Armands Kazia
Page No. – Page No.
Fluoromethylene Transfer from
Diarylfluoromethylsulfonium Salts:
Synthesis of Fluorinated Epoxides
delivering uncommon 2-unsubstituted
fluoroepoxides. This is the first
evidence for the feasibility of sulfur
fluoromethylylide and its action as a
reaction intermediate.
This article is protected by copyright. All rights reserved.