Synthesis of Sulfanylated Difluoroalkenes: Electrophilic

Letter pubs.acs.org/OrgLett

Synthesis of Sulfanylated Difluoroalkenes: Electrophilic Difluoromethylidenation of Dithioesters with Difluorocarbene Ryo Takayama, Atsushi Yamada, Kohei Fuchibe, and Junji Ichikawa* Division of Chemistry, Faculty of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Ibaraki 305−8571, Japan S Supporting Information *

ABSTRACT: Electrophilic difluoromethylidenation of dithioesters was achieved in high yields via the reaction with difluorocarbene. When aryl or alkyl dithiocarboxylates were treated with trimethylsilyl 2,2-difluoro-2-fluorosulfonylacetate in the presence of 5 mol % of a Proton Sponge catalyst, the in situ generated difluorocarbene reacted with the dithioesters to afford 2-sulfanylated 1,1-difluoro-1-alkenes via difluorothiiranes. This reaction can be considered as an electrophilic counterpart of the Wittig-type difluoromethylidenation of carbonyl compounds with nucleophilic difluoromethylene ylides.

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wing to the importance of 1,1-difluoro-1-alkenes in medicinal,1 synthetic,2 and applied chemistry,3 their utility has been widely extended over the past decades.4 The conventional methods for the synthesis of 1,1-difluoroalkenes involve the Wittig-type reactions with nucleophilic difluoromethylidenating agents such as difluoromethylene ylides (Scheme 1, eq 1).5 In addition, other routes have been

Motivated by the versatility of the sulfur functionality, sulfanylated 1,1-difluoro-1-alkenes have recently attracted our attention, mainly because of their potential application in synthetic chemistry, pharmacology, and related areas. However, access to these sulfur-substituted derivatives is hindered by the scarcity of efficient methods for their synthesis, and furthermore, the previous methods required strongly basic conditions.11 Recently, we have developed the organocatalyzed generation of difluorocarbene (:CF2)12 from trimethylsilyl 2,2-difluoro-2fluorosulfonylacetate (TFDA)13 under mild conditions.14 Controlling the rates of the generation of difluorocarbene allowed us to perform the O- and S-selective difluoromethylation of ketones,14a amides,14b and thioamides.14c Moreover, the chemoselective difluorocyclopropanation followed by the Nazarov cyclization led to the regioselective synthesis of αfluorocyclopentenones.14d To synthesize the aforementioned 2-sulfanyl-1,1-difluoro-1alkenes and to explore other difluorocarbene-mediated reactions apart from the difluoromethylene (−CF2−) introduction, we envisioned a difluoromethylidene (CF2) introduction to dithioesters (Scheme 1, eq 2, Barton− Kellogg-type reaction).15 The reaction of dithioesters with difluorocarbene would produce thiiranes (thiacyclopropanes) via thiocarbonyl ylides followed by desulfurization of the thusgenerated difluorothiiranes to afford the desired sulfanylated 1,1-difluoro-1-alkenes. It is worth mentioning that the generation of difluorothiiranes from dithioesters and the subsequent synthesis of difluoroalkenes have not been reported previously.16 We first tackled the electrophilic difluoromethylidenation to sulfanylated 1,1-difluoro-1-alkenes using phenyl (1a) and methyl (1b) benzenedithioates as model substrates (Table 1).17 Phenyl dithioate 1a was treated with TFDA (2.0 equiv

Scheme 1. Synthesis of 1,1-Difluoro-1-alkenes

developed, i.e., (i) the transition-metal-catalyzed cross-coupling reactions6 and (ii) the β-fluorine eliminations from trifluoromethyl compounds7 as well as (iii) the SN2′-type8 and SN1′type reactions9 that afford 1,1-difluoroalkenes bearing carbon, nitrogen, or silicon substituents at the allylic positions.10 © 2017 American Chemical Society

Received: July 20, 2017 Published: September 21, 2017 5050

DOI: 10.1021/acs.orglett.7b02222 Org. Lett. 2017, 19, 5050−5053

Letter

Organic Letters Table 1. Optimization of Reaction Conditionsa

within 1 min, which improved the yield of 4b up to 82% (Table 1, entry 8, method B). A wide variety of sulfanylated 1,1-difluoro-1-alkenes 4 were synthesized by the described electrophilic difluoromethylidenation of dithioesters (Scheme 2).17 Phenyl dithioates 1a and Scheme 2. Synthesis of Sulfanylated 1,1-Difluoro-1alkenes*,a

yieldb,c (%) entry

1

conditions

3

4

5

1 2 3 4 5 6 7 8e

1a 1a 1a 1a 1a 1b 1b 1b

40 °C, 0.5 h 60 °C, 0.5 h 90 °C, 0.5 h reflux, 0.5 h 60 °C, 0.5 h, then 100 °C, 0.5 h 60 °C, 0.5 h reflux, 0.5 h reflux, 0.5 h

7 40 2 −b −b 5 −b −b

trace 46 84 90 90 (87)d 41 67 82

−b −b 2 5 −b trace 14 6

a Unless otherwise noted, TFDA was added over 5 min. bNot detected by 19F NMR analysis. c19F NMR yield based on an internal standard (CF3)2C(C6H4p-Me)2. dIsolated yield is indicated in parentheses. e TFDA was added over 1 min.

over 5 min) in toluene in the presence of 5 mol % of Proton Sponge [1,8-bis(dimethylamino)naphthalene, 2] at 40 °C (Table 1, entry 1). Although visible gas evolution indicated that decomposition of TFDA proceeded at this temperature, the expected thiirane intermediate 3a was generated only in 7% yield (determined by 19F NMR analysis), and a considerable amount of the starting dithioate 1a remained unchanged according to TLC analysis. In contrast, performing the reaction at 60 °C led to complete conversion of 1a, affording 3a and the desired difluoroalkene 4a in 40% and 46% yields, respectively (Table 1, entry 2).18 The reaction at higher temperatures (90 °C, Table 1, entry 3 or refluxing temperature, Table 1, entry 4) resulted in complete conversion of 3a to afford 4a in 84−90% yields, along with the undesired difluorocyclopropanation product 5a in 2−5% yields. To prevent the overreaction to tetrafluorocyclopropane 5a, 1a was treated with TFDA at 60 °C for 30 min before increasing the temperature (Table 1, entry 5). After confirming that 1a was consumed completely by TLC analysis and that difluorocarbene generation (gas evolution) reached completion, the reaction mixture comprising 3a and 4a was heated at 100 °C for 30 min. Thus, sulfanylated difluoroalkene 4a was isolated in 87% yield with high selectivity (method A).19,20 The electron-donating methyl dithioate 1b was unexpectedly less reactive than phenyl dithioate 1a toward thiirane formation.21 The reaction of 1b at 60 °C led to the corresponding thiirane in decreased total yield (3 + 4, 46%, Table 1, entry 6, vs 86%, Table 1, entry 2). When the reaction was performed at reflux temperature (Table 1, entry 7), thiirane was formed in an increased 81% yield of 4b + 5b, albeit along with 14% yield of undesired cyclopropane 5b. To reduce the contact time of 4b with difluorocarbene and to suppress the undesired cyclopropanation, addition of TFDA was completed

*

Method A: 2 (5 mol %), TFDA (2 equiv) over 5 min, toluene, 60 °C for 0.5 h, then 100 °C for 0.5 h. Method B: 2 (5 mol %), TFDA (2 equiv) over 1 min, toluene, reflux, 0.5 h. aIsolated yield. b19F NMR yield based on an internal standard (CF3)2C(C6H4p-Me)2.

1c−f underwent difluoromethylidenation by method A to afford the corresponding products 4a and 4c−f in 70−87% yields. Sterically demanding 1g,h underwent the reaction by method B to give the corresponding 4g,h in 94% and 80% yields, respectively. Dithioester 1i, bearing an m-chlorosubstituted phenyl group, also afforded the corresponding 4i by method B in 92% yield. Alkanedithioate 1j and alkyl dithioates 1b and 1k−n afforded the corresponding products 4b and 4j−n by method B in 58−90% yields. From these results, it can be concluded that electron-deficient (specifically, S-arylated) and sterically less demanding dithioesters (1a and 1c−f) require method A owing to their high reactivity, whereas electron-rich (specifically S-alkylated, 1b and 1j−n) or sterically demanding (1g,h) dithioesters are less reactive and their cyclization can be performed by method B. 5051

DOI: 10.1021/acs.orglett.7b02222 Org. Lett. 2017, 19, 5050−5053

Organic Letters

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Sodium chloro- and bromodifluoroacetates were also examined as a difluorocarbene source. Dithioester 1b underwent difluoromethylidenation with these sodium salts to give difluoroalkene 4b, albeit in 41% (X = Cl) and 31% (X = Br) yields along with 48% (X = Cl) and 57% (X = Br) recoveries of 1b, respectively, at high temperature (160 °C, Scheme 3). Thus, the milder organocatalytic difluorocarbene generation from TFDA proved to be the method of choice for the synthesis of sulfanylated 1,1-difluoro-1-alkenes.

Letter

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02222. Experimental procedures and spectra of new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

Scheme 3. Difluoromethylidenation of Dithioesters with Sodium Halodifluoroacetates

*E-mail: [email protected]. ORCID

Junji Ichikawa: 0000-0001-6498-326X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research is supported by JSPS KAKENHI Grant No. JP15K05414 (K.F.), JSPS KAKENHI Grant No. JP16K13943 (J.I.), and JSPS KAKENHI Grant No. JP16H04105 (J.I.). Tosoh F-Tech, Inc. is acknowledged for the generous gift of dibromodifluoromethane.

This electrophilic, Barton−Kellogg-type difluoromethylidenation of dithioesters is complementary to the nucleophilic, Wittig-type difluoromethylidenation of aldehydes. Thus, while the nucleophilic difluoromethylidenation failed to produce the sulfanylated difluoroalkene 4a from dithioester 1a (0% yield) (Scheme 4, eq 2),22 the electrophilic method afforded 4a in

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Scheme 4. Comparative Study on Difluoromethylidenation

a

REFERENCES

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CBr2F2 (2 equiv), P(NMe2)3 (4 equiv), THF, −78 °C to rt.

87% yield (Scheme 4, eq 1). On the other hand, the electrophilic difluoromethylidenation was not suitable for ophenylbenzaldehyde (0% yield) (Scheme 4, eq 3), which was in contrast successfully subjected to nucleophilic difluoromethylidenation to give the corresponding difluorostyrene in 87% yield (Scheme 4, eq 4).23 In conclusion, electrophilic difluoromethylidenation of dithioesters was achieved using organocatalytically generated difluorocarbene. The reaction proceeded via thiirane intermediates following a Barton−Kellogg-type mechanism to afford various sulfanylated 1,1-difluoro-1-alkenes in good to excellent yields. This electrophilic difluoromethylidenation proved, therefore, to be complementary to the conventional nucleophilic Wittig-type difluoromethylidenation of carbonyl compounds. 5052

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(19) When 0.89 mmol of difluoroalkene 4a was obtained (89% yield), 24.9 mg of yellow crystaline material was isolated. Elemental analysis of this material indicated that the sulfur content of this sample was 91.63% (0.71 mmol sulfur atom). Facile sulfur elimination from fluorine-substituted thiiranes was mensioned in ref 16. In addition, when difluoromethylidenation of 1a was performed with 1.0 equiv of TFDA, 4a was obtained in 88% yield. These results suggest that the thiirane intermediates underwent desulfurization without the aid of the second molecule of difluorocarbene. (20) Monothioesters RC(S)OR′ were inactive, and the corresponding products were obtained in less than 10% yield. Monothioesters RC(O)SR′ did not afford sulfanylated 1,1difluoro-1-alkenes. (21) The low reactivity of electron-rich dithioesters for thiirane formation can be rationalized by retarding the nucleophilic ring closure of intermediary difluoromethylene thiocarbonyl ylides (Scheme 1, eq 2). (22) (a) Naae, D. G.; Burton, D. J. Synth. Commun. 1973, 3, 197. (b) Hayashi, S.-i.; Nakai, T.; Ishikawa, N.; Burton, D. J.; Naae, D. G.; Kesling, H. S. Chem. Lett. 1979, 8, 983. (23) Fuchibe, K.; Morikawa, T.; Ueda, R.; Okauchi, T.; Ichikawa, J. J. Fluorine Chem. 2015, 179, 106.

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DOI: 10.1021/acs.orglett.7b02222 Org. Lett. 2017, 19, 5050−5053