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1,1-Bis(dimethylamino)-2,2-difluoroethene, a diverse building block for the preparation of difluoroalkyl molecules. Acylation and condensation reactions
Journal of Fluorine Chemistry 229 (2020) 109432
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry journal homepage: www.elsevier.com/locate/fluor
1,1-Bis(dimethylamino)-2,2-difluoroethene, a diverse building block for the preparation of difluoroalkyl molecules. Acylation and condensation reactions
T
Yuelian Xu, Simon E. Lopez, William R. Dolbier Jr.* University of Florida, Department of Chemistry, PO Box 117200, Gainesville, 23611-7200, United States
ARTICLE INFO
ABSTRACT
Keywords: Fluorinated ketene aminal Acylation reactions
1,1-Bis(dimethylamino)-2,2-difluoroethene has been shown to be a diverse and highly effective building block for the preparation of a variety of fluorinated compounds. Reported here are preliminary results of its use for acylation reactions with acyl chlorides to form 2,2-difluoroketoacetamides as well as for its direct condensation with various acidic α-hydrogen carbon compounds to form a variety of functionalized difluoromethyl enamines.
1. Introduction Incorporation of fluorine atoms into organic molecules continues to play an important role in the development of biologically active compounds because of its common ability to improve their biological activity and to modify important physical properties, such as solubility and lipophilicity [1]. In particular, difluoroalkylated molecules have found a variety of applications as pharmaceuticals, agrochemicals, as well as within the field of materials chemistry [2]. Ketene aminals (or 1,1-enediamines) provide potentially diverse reactivity in the construction of organic compounds, with the ability to behave as both electrophiles and nucleophiles [3]. Similarly, difluoro enol ethers and bis-enol ethers such as 1 and 2, as well as the difluoro ketene hemiaminal 3, have been shown to be useful building blocks in condensations with aldehydes and ketones to provide difluoroalkyl esters in good yield (Fig. 1) [4,5]. In earlier work from our lab, 1,1-bis (dimethylamino)-2,2,2-trifluoroethane 4 (Fig. 2), was shown to act as a readily available precursor for the preparation of the isolable and relatively stable fluorinated building block, 1,1-bis(dimethylamino)-2,2difluoroethene 5, a difluoroketene aminal that exhibits both nucleophilic and electrophilic behavior [6]. As a nucleophile, it underwent high yield reactions (a) with water, bromine, or iodine, (b) with benzaldehydes, (c) with α, β − unsaturated carbonyl compounds, and (d) with methyl propiolate (Fig. 3a–d). As an electrophile, it underwent addition by alkyllithiums to form α-fluoro carboxamides (Fig. 3e). In continuing to develop the diversity of the chemistry of 1,1-difluoroketene amjnal 5 to produce new difluoroalkylated molecules, we would like to report additional chemistry of 5, namely its corresponding
⁎
Corresponding author. E-mail address: [email protected] (W.R. Dolbier).
https://doi.org/10.1016/j.jfluchem.2019.109432 Received 4 November 2019; Accepted 22 November 2019 Available online 23 November 2019 0022-1139/ © 2019 Elsevier B.V. All rights reserved.
acylation reactions with acyl chlorides and condensation reactions with diverse carbon α-acidic compounds. 2. Results and discussion 2.1. Acylation reactions of difluoro ketene aminal 5 It was found that the reaction of difluoroketene aminal 5 with acid chlorides 6 led to formation of 2,2-difluoroketoamide compounds 7. In initial experiments, the reaction led to immediate formation of a white solid, which upon aqueous acid workup produced low yields of the ketoamide products. However, it was luckily found that the addition of two equivalents of triethylamine led to the higher yields indicated in Fig. 4. As can be seen, better yields are obtained with aromatic acyl halides (7c-e), while the method is of less preparative interest when aliphatic acyl chlorides are used (7a-b). The low yields when using the aliphatic acid chlorides are probably due to competitive deprotonation of the acidic α-proton present in these acyl chlorides by the reagent affording N,N-dimethyl difluoroacetamide as by-product. 2.2. Condensation reactions of 5 with compounds bearing relatively acidic C–H bonds Considering the basicity and nucleophilicity of difluoro ketene aminal 5 at its β-carbon atom [5], it seemed likely that 5 would react to deprotonate various compounds 8 bearing relatively acidic α-hydrogens (Scheme 1). Proton transfer would provide the intermediate amidinium ion 9 along with carbanion 10, which could potentially
Journal of Fluorine Chemistry 229 (2020) 109432
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Fig. 1. Reaction of difluoro enol ethers, bis-enol ethers and hemiaminals. Fig. 2. Preparation of the fluorinated building block bis(dimethylamino)-2,2,2-trifluoroethene 5.
Fig. 3. Previously reported reactions of 1,1-bis(dimethylamino)-2-2-difluoroethene, 6.
2
Journal of Fluorine Chemistry 229 (2020) 109432
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Fig. 4. Acylation of 1,1-bis(dimethylamino)-2,2-diifluoroethene 5. Scheme 1. Reaction of 1,1-bis(dimethylamino)-2,2-difluoroethene (5) with compounds bearing an acidic C-H bond.
Fig. 5. Condensation reactions 0f 5 with compounds bearing acidic α-hydrogens. (Note: In each case, these products were accompanied by N,N-dimethyl difluoroacetamide obtained from the hydrolysis of 5).
combine to form products, such as 11. In the event, it was found that products such as 11 were not observed in the reactions of difluoroketene aminal 5 with a variety of well-known compounds bearing acidic α-hydrogens. Instead, the
reactions in hexane solution at room temperature led to products 12 that presumably derived from the elimination of dimethyl amine from the initially-formed products 11 (Fig. 5). Thus, difluoroketene aminal 5 reacted with ethyl cyanoacetate and with nitromethane to give enamine 3
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Scheme 2. Similar results of Ghandi and Gibson [ref. 4] when using non-fluorinated ketene aminal 13.
12a and 12d, respectively, as mixtures of Z and E isomers. In its reactions with malonitrile and diethylmalonate, enamines 12b and 12c were isolated. In each case N,N-dimethyl difluoroacetamide was isolated as a side product, which indicated that simple hydrolysis of the starting ketene aminal 5 was competing with the condensation reaction. Although the observed isolated yields of these difluoromethyl enamines were modest, at best, the compounds are unique and may prove to have interesting reactivity and synthetic potential. Ghandi and Gibson observed similar chemistry using non-fluorinated ketene aminal 13 in their 1987 study (Scheme 2) [7].
hexane 9: EtOAc 1). Isolated yields of 7 are reported with respect to the difluoroketene aminal 5. 4.1.1. 2,2-Difluoro-N,N-dimethyl-3-oxopentanamide (7a) Yield 52 %; 1H NMR δ 1.15 (t, 3H, J = 7.1 Hz), 3.00 (t, 3H, J = 1.7 Hz), 3.15 (t, 3H, J = 1.7 Hz), 2.72 (q, 2H, J = 7.1 Hz); 19F NMR δ -110.0 (s, 2 F); 13C NMR δ 6.71, 30.60, 36.30 (m), 110.67 (t, J = 267.9 Hz), 161.27 (t, J = 27.2 Hz), 198.17 (t, J = 26.7 Hz). HRMS Calcd for C7H11F2NO2: 179.0758; Found: 179.0740. Anal. Calcd for C7H11F2NO2: C, 46.93; H, 6.15; N, 7.82. Found: C, 46.50; H, 6.17; N, 7.48.
3. Conclusions
4.1.2. 2,2-Difluoro-N,N-dimethyl-3-oxobutanamide (7b) Yield 27 %; 1H NMR δ 2.37 (t, 3H, J = 1.7 Hz), 3.00 (t, 3H, J = 0.7 Hz), 3.15 (t, 3H, J = 1.95 Hz); 19F NMR δ -110.1 (s, 2 F); 13C NMR δ 24.93, 36.43, 110.54 (t, J = 267.9 Hz), 161.27 (t, J = 28.1 Hz), 198.98 (t, J = 25.4 Hz). HRMS (CI) Calcd for C6H10F2NO2 (M + 1): 166.0680; Found: 166.0676. Anal. Calcd for C6H9F2NO2: C, 43.64; H, 5.45; N, 8.48. Found: C, 42.24; H, 5.44; N, 7.85.
Two additional examples serve to demonstrate the great diversity of nucleophilic/basic reactivity of fluorinated ketene aminal, 1,1-bis(dimethylamino)-2,2-difluoroethene 5. Acylation of 5 with a number of acid chlorides led to formation of 2,2-difluoro β-ketocarboxamide products upon acidic workup in low to moderate yields. 5 also underwent condensation reactions when allowed to react with a variety of well-known compounds bearing acidic α-hydrogens, such reactions producing α-difluoroalkyl-enamines in low to moderate yields.
4.1.3. 2,2-Difluoro-N,N-dimethyl-3-oxo-3-phenylpropanamide (7c) Yield 64 %; 1H NMR δ 3.13 (s, 3 H), 3.24 (t, 3H, J = 1.4 Hz), 7.47 (m, 2 H), 6.63 (m, 1 H), 8.09 (m, 2 H); 19F NMR δ -103.3 (s, 2 F); 13C NMR δ 36.79 (m), 111.56 (t, J = 264.4 Hz), 128.41, 128.70, 130.11, 133.70, 134.63, 161.54 (t, J = 27.2 Hz). HRMS Calcd for C11H12F2NO2: 228.0836; Found: 228.0841.
4. Experimental Melting points were recorded using a Fisher-Johns melting point apparatus and are uncorrected. 1H, 13C, and 19F NMR spectra were obtained at 300, 75.4, and 282 MHz, respectively, using Varian VXR300, Gemini-300, and Mercury 300 spectrometers. For 1H and 13C, chemical shifts are reported in ppm (δ) downfield from tetramethylsilane as an internal reference (δ 0.0). In the case of 19F, CFCl3 was used as an internal standard (δ 0.0). Splitting patterns are abbreviated as follows: s, singlet, d, doublet, t, triplet, q, quartet and m, multiplet. EI and CI mass spectra were recorded on a Finnegan MAT 25Q (high resolution) spectrometer. Methane was generally employed in obtaining CI mass spectra. Analytical thin-layer chromatography (TLC) was performed on silica gel 60F-254 plates. Flash chromatography was performed using standard procedures on Kieselgel (230–400 mesh). All reagents were purchased from Aldrich or Fisher Scientific, and were used without further purification except for chromatography solvents, which were distilled before use. Moisture sensitive reactions were carried out under an argon atmosphere in glassware that was flame-dried with an inert gas sweep. 1,1-Bis(dimethylamino)2,2-difluoroethene 5 was prepared following our previously reported procedure [5].
4.1.4. 2,2-Difluoro-N,N-dimethyl-oxo-3-(4-fluorophenyl)propanamide (7d) Yield 54 %; 1H NMR δ 3.00 (s, 3 H), 3.13 (s, 3 H), 7.13 (t, 2H, J = 8.6 Hz), 8.09 (dd, 2H, J = 5.3 Hz, J = 8.1 Hz); 19F NMR δ -102.0 (m, 1 F), -103.22 (s, 2 F); 13C NMR δ 36.45, 111.40 (t, J = 264.54 Hz), 115.84 (d, J = 21.8 Hz), 128.02, 132.83 (d, J = 9.2 Hz), 161.18 (t, J = 26.3 Hz), 164.60, 68.0, 184.89 (t, J = 27.5 Hz). HRMS (EI) Calcd for C11H10F3NO2: 245.0664; Found: 245.0619. 4.1.5. 2,2-Difluoro-N,N-dimethyl-3-oxo-3-(4-methoxyphenyl)propenamide (7e) Yield 58 %; 1H NMR δ 2.87 (s, 3 H), 2.96 (s, 3 H), 3.71 (s, 3 H), 6.81 (d, 2H, J = 8.8 Hz), 7.93 (d, 2H, J = 8.8 Hz); 19F NMR δ -102.75 (s, 2 F); 13C NMR δ 36.22, 36.30, 55.5, 111.37 (t, J = 263.4 Hz), 113.76, 123.97, 132.23, 161.20 (t, J = 26.4 Hz), 164.52, 184.37 (t, J = 26.3 Hz). HRMS (EI) Calcd for C12H13F2NO3: 257.0863; Found 257.0866.
4.1. General procedure for the acylation of 1,1-bis(dimethylamino)-2,2difluoroethene 5
4.2. General procedure for the condensation reactions of 1,1-bis (dimethylamino)-2,2-difluoroethene 5 with compounds (8) bearing acidic αhydrogens
To a solution of 1,1-bis(dimethylamino)-2,2-difluoroethene 5 (1.7 g, 10 mmol) solution in dry ether (5 mL) and dry hexane (5 mL) was added the corresponding acid chloride 6 (10 mmol) and triethylamine (1.4 mL, 20 mmol) at 0° C. The reaction mixture was stirred at 0° C for 10 min. Methylene chloride (20 mL) was then added and the mixture washed with brine (2 × 10 mL) and water (10 mL). The organic layer was then dried (MgSO4), filtered and evaporated in vacuo. The residue was either distilled or purified by column chromatography (silica,
To a solution of 1,1-bis(dimethylamino)-2,2-difluoroethene 5 (1.7 g, 10 mmol) solution in dry ether (5 mL) and dry hexane (5 mL) was added the corresponding carbon acidic substrates 8 (8 mmol) at room temperature. After evaporation of the solvent in vacuo, the residue was either distilled or purified by column chromatography (silica, hexane 8: EtOAc 2). Yields are reported with respect to substrates 8. 4
Journal of Fluorine Chemistry 229 (2020) 109432
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Major compound: 1H NMR δ 3.13 (s, 6 H), 5.59 (t, 1H, J = 52.8 Hz), 6.64 (s, 1 H); 19F NMR δ -117.27 (d, 2 F, J = 50.9 Hz) ; 13C NMR δ 42.09, 07.59 (t, J = 244.3 Hz), 16.18, 150.23 (t, J = 21.7 Hz). Minor compound: 1H NMR δ 3.13 (s, 6 H), 6.60 (s, 1 H), 7.94 (t, 1H, J = 52.5 Hz); 19F NMR δ -121.82 (d, 2 F, J = 53.3 Hz). HRMS (EI) Calcd for C5H8O2N2F2: 166.0554; Found: 166.0582. Elemental Anal. Calcd. for C5H8O2N2F2: C 36.14, H 4.82, N 16.86; Found: C 36.06, H 4.75, N 16.43.
4.2.1. Ethyl 2-cyano-3-(dimethylamino)-4,4-difluorobut-2-enoate (12a), Yield: 36 %; bp 145−147 °C/1 Torr. Reaction gave a mixture of Z and E isomers with a ratio of 81:19 (not isolated separately) Major compound: 1H NMR δ 1.25 (t, 3H, J = 6.9 Hz), 3.31 (s, 6 H), 4.16 (q, 2H, J = 6.9 Hz), 7.59 (t, 1H, J = 52.5 Hz); 19F NMR δ -117.3 (d, 2 F, J = 50.9 Hz) ; 13C NMR δ 13.93, 44.22, 61.15, 75.76, 108.32 (t, J = 243.9 Hz), 117.3, 161.76, (t, J = 21.8 Hz), 165.02. Minor compound: 1H NMR δ 1.25 (t, 3H, J = 6.9 Hz), 3.11 (s, 6 H), 4.16 (q, 2H, J = 6.9 Hz), 6.52 (t, 1H, J = 51.9 Hz); 19F NMR δ -120.9 (d, 2 F, J = 50.9 Hz) ; 13C NMR δ 13.93, 44.22, 60.99, 75.76, 111.25 (t, J = 247.4 Hz), 117.35, 158.34, (t, J = 20.6 Hz), 162.32. HRMS (EI) Calcd for C9H12O2N2F2: 218.0867; Found: 218.0900. Elemental Anal., Calcd. for C9H12O2N2F2: C 49.54, N 12.84, H 5.50; Found: C 49.46, N 13.04, H 5.89.
Acknowledgement Support of this research in part by the National Science Foundation (CHE-9521971) is gratefully acknowledged. References
4.2.2. Diethyl 2-(1-(dimethylamino)-2,2-difluoroethylidene)malonate (12b) Yield: 30 %; 1H NMR δ 1.24 (t, 6H, J = 7.2 Hz), 3.0 (s, 6 H), 4.6 (q, 4H, J = 7.2 Hz), 7.0 (t, 1H, J = 53.3 Hz); 19F NMR δ -118.1 (d, 2 F, J = 53.3 Hz); 13C NMR δ 14.01, 43.02 (t, J = 3.0 Hz), 60.70, 99.49 (t, J = 6.3 Hz), 110.83 (t, J = 244.3 Hz), 155.52 (t, J = 20.7 Hz), 166.57; HRMS (EI) Calcd for C11H17O4NF2: 265.1126; Found: 265.1139.
[1] (a) For recent reviews, see: E.P. Gillis, K.J. Eastman, M.D. Hill, D.J. Donnelly, N.A. Meanwell, J. Med. Chem. 58 (2015) 8315; (b) J. Wang, M. Sánchez-Roselló, J.L. Aceña, C. del Pozo, A.E. Sorochinsky, S. Fustero, V.A. Soloshonok, H. Liu, Chem. Rev. 114 (2013) 2432; (c) T. Liang, C.N. Neumann, T. Ritter, Angew. Chem. Int. Ed. 52 (2013) 8214; (d) C. Hollingworth, V. Gouverneur, Chem. Commun. 48 (2012) 929; (e) O.A. Tomashenko, V.V. Grushin, Chem. Rev. 111 (2011) 4475; (f) J. Hu, W. Zhang, F. Wang, Chem. Commun. (2009) 7465. [2] (a) K. Müller, C. Faeh, F. Diederich, Science 317 (2007) 1881; (b) S. Purser, P.R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 37 (2008) 320. [3] (a) L.-F. Yang, Synlett 25 (2014) 2964; (b) B.-Q. Wang, C.-H. Zhang, X.-X. Tian, J. Lin, S.-J. Yan, Org. Lett. 20 (2018) 660. [4] (a) Y. Kodama, H. Yamaha, M. Okumura, M. Shiro, T. Taguchi, Tetrahedron 51 (1995) 12217; (b) O. Kitagawa, T. Taguchi, Y. Kobayashi, Tetrahedron Lett. 29 (1988) 1803. [5] G. Blond, T. Billard, B.R. Langlois, Chem. Eur. J. 8 (2002) 2917. [6] (a) Y. Xu, W.R. Dolbier Jr., X.X. Rong, J. Org. Chem. 62 (1997) 1576; (b) Y. Xu, W.R. Dolbier Jr., J. Org. Chem. 62 (1997) 6503; (c) Y. Xu, F. Tian, W.R. Dolbier Jr., J. Org. Chem. 64 (1999) 5599; (d) Y. Xu, W.R. Dolbier Jr., Tetrahedron 54 (1998) 6319. [7] S.S. Ghandi, M.S. Gibson, Can. J. Chem. 65 (1987) 2717.
4.2.3. 2-(1-(Dimethylamino)-2,2-difluoroethylidene)malononitrile (12c) The reaction was completed in 1 h, a yellow solid was isolated by column chromatography, Yield 22 %; 1H NMR δ 3.39 (s, 6 H), 6.70 (t, H, J = 51.4 Hz); 19F NMR δ -117.92 (d, 2 F, J = 51.4 Hz); 13C NMR δ 43.62, 110.22 (t, J = 248.3 Hz), 114.16, 114.32, 158.59(t, J = 2.22 Hz); HRMS (EI) Calcd for C7H7N3F2: 171.0668; Found 171.0643. 4.2.4. 3,3-Difluoro-N,N-dimethyl-1-nitroprop-1-en-2-amine (12d) Yield 52 %; yellow solid. Reaction gave a mixture of Z and E with a ratio of 30:1 (not isolated separately).
5
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry journal homepage: www.elsevier.com/locate/fluor
1,1-Bis(dimethylamino)-2,2-difluoroethene, a diverse building block for the preparation of difluoroalkyl molecules. Acylation and condensation reactions
T
Yuelian Xu, Simon E. Lopez, William R. Dolbier Jr.* University of Florida, Department of Chemistry, PO Box 117200, Gainesville, 23611-7200, United States
ARTICLE INFO
ABSTRACT
Keywords: Fluorinated ketene aminal Acylation reactions
1,1-Bis(dimethylamino)-2,2-difluoroethene has been shown to be a diverse and highly effective building block for the preparation of a variety of fluorinated compounds. Reported here are preliminary results of its use for acylation reactions with acyl chlorides to form 2,2-difluoroketoacetamides as well as for its direct condensation with various acidic α-hydrogen carbon compounds to form a variety of functionalized difluoromethyl enamines.
1. Introduction Incorporation of fluorine atoms into organic molecules continues to play an important role in the development of biologically active compounds because of its common ability to improve their biological activity and to modify important physical properties, such as solubility and lipophilicity [1]. In particular, difluoroalkylated molecules have found a variety of applications as pharmaceuticals, agrochemicals, as well as within the field of materials chemistry [2]. Ketene aminals (or 1,1-enediamines) provide potentially diverse reactivity in the construction of organic compounds, with the ability to behave as both electrophiles and nucleophiles [3]. Similarly, difluoro enol ethers and bis-enol ethers such as 1 and 2, as well as the difluoro ketene hemiaminal 3, have been shown to be useful building blocks in condensations with aldehydes and ketones to provide difluoroalkyl esters in good yield (Fig. 1) [4,5]. In earlier work from our lab, 1,1-bis (dimethylamino)-2,2,2-trifluoroethane 4 (Fig. 2), was shown to act as a readily available precursor for the preparation of the isolable and relatively stable fluorinated building block, 1,1-bis(dimethylamino)-2,2difluoroethene 5, a difluoroketene aminal that exhibits both nucleophilic and electrophilic behavior [6]. As a nucleophile, it underwent high yield reactions (a) with water, bromine, or iodine, (b) with benzaldehydes, (c) with α, β − unsaturated carbonyl compounds, and (d) with methyl propiolate (Fig. 3a–d). As an electrophile, it underwent addition by alkyllithiums to form α-fluoro carboxamides (Fig. 3e). In continuing to develop the diversity of the chemistry of 1,1-difluoroketene amjnal 5 to produce new difluoroalkylated molecules, we would like to report additional chemistry of 5, namely its corresponding
⁎
Corresponding author. E-mail address: [email protected] (W.R. Dolbier).
https://doi.org/10.1016/j.jfluchem.2019.109432 Received 4 November 2019; Accepted 22 November 2019 Available online 23 November 2019 0022-1139/ © 2019 Elsevier B.V. All rights reserved.
acylation reactions with acyl chlorides and condensation reactions with diverse carbon α-acidic compounds. 2. Results and discussion 2.1. Acylation reactions of difluoro ketene aminal 5 It was found that the reaction of difluoroketene aminal 5 with acid chlorides 6 led to formation of 2,2-difluoroketoamide compounds 7. In initial experiments, the reaction led to immediate formation of a white solid, which upon aqueous acid workup produced low yields of the ketoamide products. However, it was luckily found that the addition of two equivalents of triethylamine led to the higher yields indicated in Fig. 4. As can be seen, better yields are obtained with aromatic acyl halides (7c-e), while the method is of less preparative interest when aliphatic acyl chlorides are used (7a-b). The low yields when using the aliphatic acid chlorides are probably due to competitive deprotonation of the acidic α-proton present in these acyl chlorides by the reagent affording N,N-dimethyl difluoroacetamide as by-product. 2.2. Condensation reactions of 5 with compounds bearing relatively acidic C–H bonds Considering the basicity and nucleophilicity of difluoro ketene aminal 5 at its β-carbon atom [5], it seemed likely that 5 would react to deprotonate various compounds 8 bearing relatively acidic α-hydrogens (Scheme 1). Proton transfer would provide the intermediate amidinium ion 9 along with carbanion 10, which could potentially
Journal of Fluorine Chemistry 229 (2020) 109432
Y. Xu, et al.
Fig. 1. Reaction of difluoro enol ethers, bis-enol ethers and hemiaminals. Fig. 2. Preparation of the fluorinated building block bis(dimethylamino)-2,2,2-trifluoroethene 5.
Fig. 3. Previously reported reactions of 1,1-bis(dimethylamino)-2-2-difluoroethene, 6.
2
Journal of Fluorine Chemistry 229 (2020) 109432
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Fig. 4. Acylation of 1,1-bis(dimethylamino)-2,2-diifluoroethene 5. Scheme 1. Reaction of 1,1-bis(dimethylamino)-2,2-difluoroethene (5) with compounds bearing an acidic C-H bond.
Fig. 5. Condensation reactions 0f 5 with compounds bearing acidic α-hydrogens. (Note: In each case, these products were accompanied by N,N-dimethyl difluoroacetamide obtained from the hydrolysis of 5).
combine to form products, such as 11. In the event, it was found that products such as 11 were not observed in the reactions of difluoroketene aminal 5 with a variety of well-known compounds bearing acidic α-hydrogens. Instead, the
reactions in hexane solution at room temperature led to products 12 that presumably derived from the elimination of dimethyl amine from the initially-formed products 11 (Fig. 5). Thus, difluoroketene aminal 5 reacted with ethyl cyanoacetate and with nitromethane to give enamine 3
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Scheme 2. Similar results of Ghandi and Gibson [ref. 4] when using non-fluorinated ketene aminal 13.
12a and 12d, respectively, as mixtures of Z and E isomers. In its reactions with malonitrile and diethylmalonate, enamines 12b and 12c were isolated. In each case N,N-dimethyl difluoroacetamide was isolated as a side product, which indicated that simple hydrolysis of the starting ketene aminal 5 was competing with the condensation reaction. Although the observed isolated yields of these difluoromethyl enamines were modest, at best, the compounds are unique and may prove to have interesting reactivity and synthetic potential. Ghandi and Gibson observed similar chemistry using non-fluorinated ketene aminal 13 in their 1987 study (Scheme 2) [7].
hexane 9: EtOAc 1). Isolated yields of 7 are reported with respect to the difluoroketene aminal 5. 4.1.1. 2,2-Difluoro-N,N-dimethyl-3-oxopentanamide (7a) Yield 52 %; 1H NMR δ 1.15 (t, 3H, J = 7.1 Hz), 3.00 (t, 3H, J = 1.7 Hz), 3.15 (t, 3H, J = 1.7 Hz), 2.72 (q, 2H, J = 7.1 Hz); 19F NMR δ -110.0 (s, 2 F); 13C NMR δ 6.71, 30.60, 36.30 (m), 110.67 (t, J = 267.9 Hz), 161.27 (t, J = 27.2 Hz), 198.17 (t, J = 26.7 Hz). HRMS Calcd for C7H11F2NO2: 179.0758; Found: 179.0740. Anal. Calcd for C7H11F2NO2: C, 46.93; H, 6.15; N, 7.82. Found: C, 46.50; H, 6.17; N, 7.48.
3. Conclusions
4.1.2. 2,2-Difluoro-N,N-dimethyl-3-oxobutanamide (7b) Yield 27 %; 1H NMR δ 2.37 (t, 3H, J = 1.7 Hz), 3.00 (t, 3H, J = 0.7 Hz), 3.15 (t, 3H, J = 1.95 Hz); 19F NMR δ -110.1 (s, 2 F); 13C NMR δ 24.93, 36.43, 110.54 (t, J = 267.9 Hz), 161.27 (t, J = 28.1 Hz), 198.98 (t, J = 25.4 Hz). HRMS (CI) Calcd for C6H10F2NO2 (M + 1): 166.0680; Found: 166.0676. Anal. Calcd for C6H9F2NO2: C, 43.64; H, 5.45; N, 8.48. Found: C, 42.24; H, 5.44; N, 7.85.
Two additional examples serve to demonstrate the great diversity of nucleophilic/basic reactivity of fluorinated ketene aminal, 1,1-bis(dimethylamino)-2,2-difluoroethene 5. Acylation of 5 with a number of acid chlorides led to formation of 2,2-difluoro β-ketocarboxamide products upon acidic workup in low to moderate yields. 5 also underwent condensation reactions when allowed to react with a variety of well-known compounds bearing acidic α-hydrogens, such reactions producing α-difluoroalkyl-enamines in low to moderate yields.
4.1.3. 2,2-Difluoro-N,N-dimethyl-3-oxo-3-phenylpropanamide (7c) Yield 64 %; 1H NMR δ 3.13 (s, 3 H), 3.24 (t, 3H, J = 1.4 Hz), 7.47 (m, 2 H), 6.63 (m, 1 H), 8.09 (m, 2 H); 19F NMR δ -103.3 (s, 2 F); 13C NMR δ 36.79 (m), 111.56 (t, J = 264.4 Hz), 128.41, 128.70, 130.11, 133.70, 134.63, 161.54 (t, J = 27.2 Hz). HRMS Calcd for C11H12F2NO2: 228.0836; Found: 228.0841.
4. Experimental Melting points were recorded using a Fisher-Johns melting point apparatus and are uncorrected. 1H, 13C, and 19F NMR spectra were obtained at 300, 75.4, and 282 MHz, respectively, using Varian VXR300, Gemini-300, and Mercury 300 spectrometers. For 1H and 13C, chemical shifts are reported in ppm (δ) downfield from tetramethylsilane as an internal reference (δ 0.0). In the case of 19F, CFCl3 was used as an internal standard (δ 0.0). Splitting patterns are abbreviated as follows: s, singlet, d, doublet, t, triplet, q, quartet and m, multiplet. EI and CI mass spectra were recorded on a Finnegan MAT 25Q (high resolution) spectrometer. Methane was generally employed in obtaining CI mass spectra. Analytical thin-layer chromatography (TLC) was performed on silica gel 60F-254 plates. Flash chromatography was performed using standard procedures on Kieselgel (230–400 mesh). All reagents were purchased from Aldrich or Fisher Scientific, and were used without further purification except for chromatography solvents, which were distilled before use. Moisture sensitive reactions were carried out under an argon atmosphere in glassware that was flame-dried with an inert gas sweep. 1,1-Bis(dimethylamino)2,2-difluoroethene 5 was prepared following our previously reported procedure [5].
4.1.4. 2,2-Difluoro-N,N-dimethyl-oxo-3-(4-fluorophenyl)propanamide (7d) Yield 54 %; 1H NMR δ 3.00 (s, 3 H), 3.13 (s, 3 H), 7.13 (t, 2H, J = 8.6 Hz), 8.09 (dd, 2H, J = 5.3 Hz, J = 8.1 Hz); 19F NMR δ -102.0 (m, 1 F), -103.22 (s, 2 F); 13C NMR δ 36.45, 111.40 (t, J = 264.54 Hz), 115.84 (d, J = 21.8 Hz), 128.02, 132.83 (d, J = 9.2 Hz), 161.18 (t, J = 26.3 Hz), 164.60, 68.0, 184.89 (t, J = 27.5 Hz). HRMS (EI) Calcd for C11H10F3NO2: 245.0664; Found: 245.0619. 4.1.5. 2,2-Difluoro-N,N-dimethyl-3-oxo-3-(4-methoxyphenyl)propenamide (7e) Yield 58 %; 1H NMR δ 2.87 (s, 3 H), 2.96 (s, 3 H), 3.71 (s, 3 H), 6.81 (d, 2H, J = 8.8 Hz), 7.93 (d, 2H, J = 8.8 Hz); 19F NMR δ -102.75 (s, 2 F); 13C NMR δ 36.22, 36.30, 55.5, 111.37 (t, J = 263.4 Hz), 113.76, 123.97, 132.23, 161.20 (t, J = 26.4 Hz), 164.52, 184.37 (t, J = 26.3 Hz). HRMS (EI) Calcd for C12H13F2NO3: 257.0863; Found 257.0866.
4.1. General procedure for the acylation of 1,1-bis(dimethylamino)-2,2difluoroethene 5
4.2. General procedure for the condensation reactions of 1,1-bis (dimethylamino)-2,2-difluoroethene 5 with compounds (8) bearing acidic αhydrogens
To a solution of 1,1-bis(dimethylamino)-2,2-difluoroethene 5 (1.7 g, 10 mmol) solution in dry ether (5 mL) and dry hexane (5 mL) was added the corresponding acid chloride 6 (10 mmol) and triethylamine (1.4 mL, 20 mmol) at 0° C. The reaction mixture was stirred at 0° C for 10 min. Methylene chloride (20 mL) was then added and the mixture washed with brine (2 × 10 mL) and water (10 mL). The organic layer was then dried (MgSO4), filtered and evaporated in vacuo. The residue was either distilled or purified by column chromatography (silica,
To a solution of 1,1-bis(dimethylamino)-2,2-difluoroethene 5 (1.7 g, 10 mmol) solution in dry ether (5 mL) and dry hexane (5 mL) was added the corresponding carbon acidic substrates 8 (8 mmol) at room temperature. After evaporation of the solvent in vacuo, the residue was either distilled or purified by column chromatography (silica, hexane 8: EtOAc 2). Yields are reported with respect to substrates 8. 4
Journal of Fluorine Chemistry 229 (2020) 109432
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Major compound: 1H NMR δ 3.13 (s, 6 H), 5.59 (t, 1H, J = 52.8 Hz), 6.64 (s, 1 H); 19F NMR δ -117.27 (d, 2 F, J = 50.9 Hz) ; 13C NMR δ 42.09, 07.59 (t, J = 244.3 Hz), 16.18, 150.23 (t, J = 21.7 Hz). Minor compound: 1H NMR δ 3.13 (s, 6 H), 6.60 (s, 1 H), 7.94 (t, 1H, J = 52.5 Hz); 19F NMR δ -121.82 (d, 2 F, J = 53.3 Hz). HRMS (EI) Calcd for C5H8O2N2F2: 166.0554; Found: 166.0582. Elemental Anal. Calcd. for C5H8O2N2F2: C 36.14, H 4.82, N 16.86; Found: C 36.06, H 4.75, N 16.43.
4.2.1. Ethyl 2-cyano-3-(dimethylamino)-4,4-difluorobut-2-enoate (12a), Yield: 36 %; bp 145−147 °C/1 Torr. Reaction gave a mixture of Z and E isomers with a ratio of 81:19 (not isolated separately) Major compound: 1H NMR δ 1.25 (t, 3H, J = 6.9 Hz), 3.31 (s, 6 H), 4.16 (q, 2H, J = 6.9 Hz), 7.59 (t, 1H, J = 52.5 Hz); 19F NMR δ -117.3 (d, 2 F, J = 50.9 Hz) ; 13C NMR δ 13.93, 44.22, 61.15, 75.76, 108.32 (t, J = 243.9 Hz), 117.3, 161.76, (t, J = 21.8 Hz), 165.02. Minor compound: 1H NMR δ 1.25 (t, 3H, J = 6.9 Hz), 3.11 (s, 6 H), 4.16 (q, 2H, J = 6.9 Hz), 6.52 (t, 1H, J = 51.9 Hz); 19F NMR δ -120.9 (d, 2 F, J = 50.9 Hz) ; 13C NMR δ 13.93, 44.22, 60.99, 75.76, 111.25 (t, J = 247.4 Hz), 117.35, 158.34, (t, J = 20.6 Hz), 162.32. HRMS (EI) Calcd for C9H12O2N2F2: 218.0867; Found: 218.0900. Elemental Anal., Calcd. for C9H12O2N2F2: C 49.54, N 12.84, H 5.50; Found: C 49.46, N 13.04, H 5.89.
Acknowledgement Support of this research in part by the National Science Foundation (CHE-9521971) is gratefully acknowledged. References
4.2.2. Diethyl 2-(1-(dimethylamino)-2,2-difluoroethylidene)malonate (12b) Yield: 30 %; 1H NMR δ 1.24 (t, 6H, J = 7.2 Hz), 3.0 (s, 6 H), 4.6 (q, 4H, J = 7.2 Hz), 7.0 (t, 1H, J = 53.3 Hz); 19F NMR δ -118.1 (d, 2 F, J = 53.3 Hz); 13C NMR δ 14.01, 43.02 (t, J = 3.0 Hz), 60.70, 99.49 (t, J = 6.3 Hz), 110.83 (t, J = 244.3 Hz), 155.52 (t, J = 20.7 Hz), 166.57; HRMS (EI) Calcd for C11H17O4NF2: 265.1126; Found: 265.1139.
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4.2.3. 2-(1-(Dimethylamino)-2,2-difluoroethylidene)malononitrile (12c) The reaction was completed in 1 h, a yellow solid was isolated by column chromatography, Yield 22 %; 1H NMR δ 3.39 (s, 6 H), 6.70 (t, H, J = 51.4 Hz); 19F NMR δ -117.92 (d, 2 F, J = 51.4 Hz); 13C NMR δ 43.62, 110.22 (t, J = 248.3 Hz), 114.16, 114.32, 158.59(t, J = 2.22 Hz); HRMS (EI) Calcd for C7H7N3F2: 171.0668; Found 171.0643. 4.2.4. 3,3-Difluoro-N,N-dimethyl-1-nitroprop-1-en-2-amine (12d) Yield 52 %; yellow solid. Reaction gave a mixture of Z and E with a ratio of 30:1 (not isolated separately).
5