Access to α,α-Difluoro-γ-amino Acids by Nickel-Catalyzed Reductive Aryldifluoroacetylation of N-Vinylacetamide

Abstract

A nickel-catalyzed reductive aryldifluoroacetylation of N-vinylacetamide with ethyl chloro(difluoro)acetate and aryl iodides is described. This chelating amide carbonyl group-assisted strategy provides rapid access to a variety of protected α,α-difluoro-γ-amino acids that might have potential applications in peptide chemistry and protein engineering. An advantage of this method is its synthetic simplicity, with no preparation of organometallic reagents.

The introduction of fluorinated amino acids into peptides and/or proteins has attracted considerable attention[1] owing to the unique properties of fluorine atoms.[2] Replacement of a C–H bond by a C–F bond can improve the pharmacological properties, metabolic stability, and lipophilicity of peptides.[1] [3] Additionally, fluorinated groups can induce conformational changes in peptides or can serve as probes for pharmacological studies.[1,2,4] As a result, fluorinated amino acids have important applications in biological tracers, mechanistic probes, and enzyme inhibitors. Consequently, the development of efficient methods for the synthesis of fluorinated amino acids is of great interest.

Dicarbofunctionalization of olefins by simultaneous installation of two functional groups across a C=C double bond represents a straightforward and efficient route to complex molecules (Scheme [1]A).[5] We recently developed a chelating-group-assisted strategy for nickel-catalyzed dicarbofunctionalization of olefins,[6] in which arylboronic acids, difluoroalkyl halides, and enamides are combined in an efficient synthesis of α,α-difluoro-γ-amino acids (Scheme [1]B). To expand the substrate scope of this strategy, we sought to use an aryl halide instead of an arylboronic acid as one of the coupling partners[7] [8] because this would eliminate the need to prepare an organometallic reagent from the corresponding aryl halide,[9] thereby providing a complementary approach to our previous work (Scheme [1]C). A crucial issue for this method is the suppression of the side reaction involving the competing hydrodehalogenation of difluoroalkyl halides under the reductive reaction conditions, because difluoroalkyl halides are prone to undergo protonation by a radical pathway in the presence of reductants such as low-valent metals.[10]

Here, we report a reductive nickel-catalyzed aryldifluoroalkylation of an enamide with various aryl iodides and a chloro(difluoro)acetate. The reaction overcomes the problem of formation of a hydrodehalogenated byproduct and proceeds under mild conditions with broad substrate scope that includes carbohydrate-containing substrates, providing an efficient access to α,α-difluoro-γ-amino acids.

We began our studies by choosing commercially available N-vinylacetamide (1), 4-iodo-1,1'-biphenyl (2a), and ethyl bromo(difluoro)acetate (3a) as model substrates (Table [1]).[11] Unfortunately, none of the desired product 4a was obtained. Instead, large amounts of the hydrodehalogenated byproduct ethyl difluoroacetate (5) (37%) were obtained when the reaction was carried out with 1 (1.0 equiv), 2a (1.5 equiv), and 3a (1.5 equiv) in the presence of NiCl₂·DME (5 mol%), 2,2′-bipyridine (L1, 5 mol%), and Zn powder (2.0 equiv) in N,N′-dimethylacetamide (DMA) at room temperature (Table [1], entry 1). In an attempt to suppress this hydrodehalogenation side reaction, we used the relatively inert substrate ethyl chloro(difluoro)acetate (3b) as the fluorine source in the hope that this would improve the reaction efficiency, because the stronger C–Cl bond in 3b should slow down the generation of the difluoroacetyl radical, thereby favoring radical trapping by enamide 1. As hoped, the reaction of 3b did give the desired product 4a in 34% yield, while 5 was produced in only 5% yield; however, a 12% yield of the byproduct 6a, formed by cross-coupling of 2a and 3b, was also obtained (entry 2). Encouraged by these results, we examined a series of bpy-based ligands (entries 2–5). The yield of 4a improved to 43% with 4,4′-di-tert-butyl-2,2′-bipyridine (L2) as the ligand (entry 3). However, the electron-rich ligand L3 showed less activity, and the electron-deficient ligand L4 showed no activity (entries 4 and 5). The use of 1,10-phenanthroline (L5; phen) with a more rigid structure gave 4a in 70% isolated yield with only small amounts of byproducts 5 and 6a (5 and 6%, respectively) (entry 6). The phenanthroline derivatives L6 and L7 gave lower yields (entries 7 and 8), and only a 3% yield of 4a was obtained with terpyridine L8 as the ligand (entry 9). Among the tested nickel salts and solvents (entries 10–13; for details, see the Supporting Information), the combination of NiCl₂·DME and DMA remained the best choice (entry 6). Ni(COD)₂ also catalyzed the reaction, but gave only a 23% yield of 4a (entry 13). No reaction occurred without a nickel catalyst or a ligand (entries 14 and 15), demonstrating that these play essential roles in promoting the reaction.

Table 1 Representative Results for the Optimization of the Ni-Catalyzed Aryldifluoroacetylation of N-Vinylacetamide (1)^a

Entry	3	[Ni]	L	Yieldb (%)
				4a	5	6a
1	3a	NiCl2·DME	L1	nd	37	1
2	3b	NiCl2·DME	L1	34	5	12
3	3b	NiCl2·DME	L2	43	2	2
4	3b	NiCl2·DME	L3	28	2	nd
5	3b	NiCl2·DME	L4	nd	2	nd
6	3b	NiCl2·DME	L5	75 (70)c	5	6
7	3b	NiCl2·DME	L6	37	6	4
8	3b	NiCl2·DME	L7	12	2	6
9	3b	NiCl2·DME	L8	3	5	nd
10	3b	NiBr2·DME	L5	45	4	6
11	3b	NiBr2·diglyme	L5	45	4	3
12	3b	Ni(OTf)2	L5	nd	nd	nd
13	3b	Ni(COD)2	L5	23	2	1
14	3b	NiCl2·DME	–	nd	nd	nd
15	3b	–	L5	nd	2	nd

^a Reaction conditions (unless otherwise specified): 1 (0.4 mmol, 1.0 equiv), 2a (0.6 mmol, 1.5 equiv), 3 (1.5 equiv), Zn (2.0 equiv), DMA (4 mL).

^b Determined by ¹⁹F NMR with fluorobenzene as an internal standard. The yields of 5 and 6a were calculated based on 3; nd = not detected.

^c Isolated yield.

With the optimized reaction conditions in hand, we examined the reactions of a variety of aryl iodides. These gave the corresponding protected α,α-difluoro-γ-amino acids 4 in moderate to good yields (Scheme [2]). Generally, aryl iodides bearing electron-donating substituents were less reactive than those with electron-withdrawing substituents (4c–h). The reaction exhibited a broad functional-group tolerance. Versatile synthetic handles such as ester, enolizable ketone, and amide groups were compatible with the reaction conditions (4e–h). Importantly, 1-chloro- and 1-bromo-4-iodobenzenes reacted with high efficiency (4i and 4j). In the latter case, a high chemoselectivity toward the aryl iodide as the primary reaction site (4j/4j′ = 12.8:1) was obtained, demonstrating the high reactivity of aryl iodides. The resulting intact aryl halides provide a good platform for downstream transformations. Additionally, 6-iodoquinoline was a suitable substrate, providing 4k in 50% yield.

To highlight the utility of this nickel-catalyzed reductive process, we examined the reactions of several amino acid and carbohydrate-containing aryl iodides (4l–n). Phenylalanine and serine derivatives gave the corresponding products 4l and 4m in yields of 47 and 58%, respectively. A carbohydrate substrate was also amenable to the reaction, giving 4n in 55% yield. Compared with our previous method,[6] the current method is simpler in that it provides access to complex molecules without the need to prepare arylboronic acids.

Remarkably, the resulting protected α,α-difluoro-γ-amino acids can serve as building blocks for peptide synthesis. A gram-scale synthesis of 4i proceeded smoothly with a 78% yield (Scheme [3]). Subsequent condensation of 4i with alanine gave dipeptide 7 in a synthetically useful 40% yield. Because the introduction of a fluorinated group into peptides can cause unexpected effects,[1] [2] [3] the current method might have potential applications in medicinal chemistry and chemical biology.

On the basis of our previous research[6] and earlier reports,[7] [9] [12] a plausible mechanism was proposed (Scheme [4]; Path I). The reaction begins with bimolecular oxidative addition of [Ni^I(L _n )X] (B) to Ar–I to provide the arylnickel complex [X–Ni^II(L _n )–Ar] (C) together with [Ni^II(L _n )X₂] (A); the nickel(I) species B is then generated by reduction of A with Zn.[12] This bimolecular oxidative addition process is supported by previous control experiments[12] in which the nickel(I) complex B reacted preferentially with an aryl halide rather than an alkyl halide to generate complexes A and C, whereas the electron-rich arylnickel(I) complex D selectively reacted with alkyl halide to provide complex C and an alkyl radical. However, a detailed reaction mechanism remained elusive at this stage.

Complex C is subsequently reduced by Zn to give the arylnickel(I) complex [Ni^I(L _n )–Ar] (D), which reacts with ClCF₂CO₂Et by a single-electron-transfer (SET) pathway to provide C and a difluoroacetyl radical. The radical is trapped by enamide 1 to form a new alkyl radical. With the aid of the chelating amide carbonyl group,[6] recombination of the newly formed radical with C produces the key intermediate Ni(III) complex F. This undergoes reductive elimination to give the final product 4 with simultaneous release of B.

However, a reaction initiated by Ni(I) involving a Ni(0/I/II/III) catalytic cycle cannot be excluded (Scheme [4]; Path II). In this pathway, the reaction begins with the generation of the nickel(I) species B through comproportionation of [Ni⁰] and [Ni^II] generated in situ.[13] B reacts with ClCF₂CO₂Et by a SET pathway to provide a difluoroacetyl radical and nickel(II) species A. The fluoroalkyl radical is subsequently trapped by enamide 1 to afford the new alkyl radical G. Meanwhile, oxidative addition of Ar–I to [Ni⁰], generated by reduction of A by Zn, provides the arylnickel(II) complex C. This reacts with G with the aid of the chelating amide carbonyl group to produce the key intermediate F. Finally, reductive elimination of F delivers the final product 4 with simultaneous release of the nickel(I) complex B.

In conclusion, we have developed an efficient method for preparing α,α-difluoro-γ-amino acids through nickel-catalyzed reductive aryldifluoroacetylation of enamides.[14] [15] The reaction proceeds under mild conditions and tolerates a variety of aryl iodides, providing a complementary approach to our previous method. The principal advantage of this protocol is its synthetic simplicity, and it may have potential applications in peptide chemistry and protein engineering.

Acknowledgment

We thank Mr. Xing Gao for helpful discussions.

• References and Notes

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For nickel-catalyzed reductive cross-coupling reactions with fluoroalkyl halides, see:
• 8a Li X, Feng Z, Jiang Z.-X, Zhang X. Org. Lett. 2015; 17: 5570
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• 14 Ethyl 4-Aryl-4-(acetylamino)-2,2-difluorobutanoates 4a–n; General Procedure A 25 mL Schlenk tube was charged with N-vinylacetamide (1; 34.0 mg, 0.4 mmol, 1.0 equiv), the appropriate aryl iodide 2 (0.6 mmol, 1.5 equiv), NiCl₂·DME (5 mol%), phen (5 mol%), and Zn (2.0 equiv) under an argon atmosphere. DMA (2 mL) was added and the mixture was stirred for 5 min at rt. ClCF₂CO₂Et (3b; 0.6 mmol, 1.5 equiv) and DMA (2 mL) were then added, the tube was screw-capped, and the mixture was stirred at rt for 12 h. The mixture was then diluted with EtOAc and washed with H₂O. The organic phase was dried (Na₂SO₄), filtered, and concentrated, and the residue was purified by chromatography (silica gel).
• 15 Ethyl 4-(Acetylamino)-4-biphenyl-4-yl-2,2-difluorobutanoate (4a) Prepared by the general method and purified by chromatography [silica gel, PE–EtOAc (2:1)] as a white solid; yield: 102 mg (70%); mp 166–168 °C. IR (thin film): 3294, 3084, 2995, 2926, 1766, 1651 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.60–7.51 (m, 4 H), 7.43 (t, J = 7.6 Hz, 2 H), 7.40–7.31 (m, 3 H), 6.26 (d, J = 7.6 Hz, 1 H), 5.41–5.31 (m, 1 H), 4.19 (q, J = 7.0 Hz, 2 H), 2.84–2.55 (m, 2 H), 1.98 (s, 3 H), 1.30 (t, J = 7.2 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 169.2, 163.7 (t, J = 32.4 Hz), 140.9, 140.4, 139.5, 128.8, 127.5, 127.4, 127.0, 126.9, 115.0 (t, J = 255.6 Hz), 63.1, 47.9 (t, J = 4.7 Hz), 40.2 (t, J = 22.8 Hz), 23.2, 13.8. ¹⁹F NMR (376 MHz, CDCl₃): δ = –102.7 (dt, J = 267.8, 15.5 Hz, 1 F), –103.5 (dt, J = 267.8, 15.7 Hz, 1 F).

Corresponding Author

Publication History

Received: 09 September 2020

Accepted after revision: 28 September 2020

Article published online:
02 November 2020

© 2020. Thieme. All rights reserved

Georg Thieme Verlag KG
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• References and Notes

• 1a Smits R, Koksch B. Curr. Top. Med. Chem. (Sharjah, United Arab Emirates) 2006; 6: 1483
  CrossrefPubMedSearch in Google Scholar
• 1b Salwiczek M, Nyakatura EK, Gerling UI. M, Ye S, Koksch B. Chem. Soc. Rev. 2012; 41: 2135
  CrossrefPubMedSearch in Google Scholar
• 1c Moschner J, Stulberg V, Fernandes R, Huhmann S, Leppkes J, Koksch B. Chem. Rev. 2019; 119: 10718
  CrossrefPubMedSearch in Google Scholar
• 2a Müller K, Faeh C, Diederich F. Science 2007; 317: 1881
  CrossrefPubMedSearch in Google Scholar
• 2b Hagmann WK. J. Med. Chem. 2008; 51: 4359
  CrossrefPubMedSearch in Google Scholar
• 2c Meanwell NA. J. Med. Chem. 2011; 54: 2529
  CrossrefPubMedSearch in Google Scholar
• 2d Meanwell NA. J. Med. Chem. 2018; 61: 5822
  CrossrefPubMedSearch in Google Scholar

For selected reviews, see:
• 3a Marsh EN. G. Acc. Chem. Res. 2014; 47: 2878
  CrossrefPubMedSearch in Google Scholar
• 3b Berger AA, Völler J.-S, Budisa N, Koksch B. Acc. Chem. Res. 2017; 50: 2093
  CrossrefPubMedSearch in Google Scholar
• 4 Pace CJ, Gao J. Acc. Chem. Res. 2013; 46: 907
  CrossrefPubMedSearch in Google Scholar
• 5a Luo Y.-C, Xu C, Zhang X. Chin. J. Chem. 2020; 38: 1371
  CrossrefSearch in Google Scholar
• 5b Dhungana RK, Shekar KC, Basnet P, Giri R. Chem. Rec. 2018; 18: 1314
  CrossrefPubMedSearch in Google Scholar
• 5c Derosa J, Apolinar O, Kang T, Tran VT, Engle KM. Chem. Sci. 2020; 11: 4287
  CrossrefPubMedSearch in Google Scholar
• 6a Gu J.-W, Min Q.-Q, Yu L.-C, Zhang X. Angew. Chem. Int. Ed. 2016; 55: 12270
  CrossrefPubMedSearch in Google Scholar
• 6b Xu C, Yang Z.-F, An L, Zhang X. ACS Catal. 2019; 9: 8224
  CrossrefSearch in Google Scholar
• 6c Yang Z.-F, Xu C, Zheng X, Zhang X. Chem. Commun. 2020; 56: 2642
  CrossrefPubMedSearch in Google Scholar

For nickel-catalyzed reductive dicarbofunctionalization of olefins, see:
• 7a García-Domínguez A, Li Z, Nevado C. J. Am. Chem. Soc. 2017; 139: 6835
  CrossrefPubMedSearch in Google Scholar
• 7b Shu W, García-Domínguez A, Quirós MT, Mondal R, Cárdenas DJ, Nevado C. J. Am. Chem. Soc. 2019; 141: 13812
  CrossrefPubMedSearch in Google Scholar

For nickel-catalyzed reductive cross-coupling reactions with fluoroalkyl halides, see:
• 8a Li X, Feng Z, Jiang Z.-X, Zhang X. Org. Lett. 2015; 17: 5570
  CrossrefPubMedSearch in Google Scholar
• 8b Xu C, Guo W.-H, He X, Guo Y.-L, Zhang X.-Y, Zhang X. Nat. Commun. 2018; 9: 1170
  CrossrefPubMedSearch in Google Scholar
• 8c He X, Gao X, Zhang X. Chin. J. Chem. 2018; 36: 1059
  CrossrefSearch in Google Scholar
• 8d Gao X, He X, Zhang X. Chin. J. Org. Chem. 2019; 39: 215
  CrossrefSearch in Google Scholar

For reviews of nickel-catalyzed cross-coupling, see:
• 9a Weix DJ. Acc. Chem. Res. 2015; 48: 1767
  CrossrefPubMedSearch in Google Scholar
• 9b Gu J, Wang X, Xue W, Gong H. Org. Chem. Front. 2015; 2: 1411
  CrossrefSearch in Google Scholar
• 10a Dolbier WR. Jr. Chem. Rev. 1996; 96: 1557
  CrossrefPubMedSearch in Google Scholar
• 10b Chen Q.-Y, Yang Z.-Y, Zhao C.-X, Qiu Z.-M. J. Chem. Soc., Perkin Trans. 1 1988; 563
• 11 For transition-metal-catalyzed cross-coupling with fluoroalkyl halides, see: Feng Z, Xiao Y.-L, Zhang X. Acc. Chem. Res. 2018; 51: 2264
  CrossrefPubMedSearch in Google Scholar
• 12 Lin Q, Diao T. J. Am. Chem. Soc. 2019; 141: 17937
  CrossrefPubMedSearch in Google Scholar
• 13 Somerville RJ, Hale LV. A, Gómez-Bengoa E, Burés J, Martin R. J. Am. Chem. Soc. 2018; 140: 8771 ; corrigendum: J. Am. Chem. Soc. 2019, 141, 20565
  CrossrefPubMedSearch in Google Scholar
• 14 Ethyl 4-Aryl-4-(acetylamino)-2,2-difluorobutanoates 4a–n; General Procedure A 25 mL Schlenk tube was charged with N-vinylacetamide (1; 34.0 mg, 0.4 mmol, 1.0 equiv), the appropriate aryl iodide 2 (0.6 mmol, 1.5 equiv), NiCl₂·DME (5 mol%), phen (5 mol%), and Zn (2.0 equiv) under an argon atmosphere. DMA (2 mL) was added and the mixture was stirred for 5 min at rt. ClCF₂CO₂Et (3b; 0.6 mmol, 1.5 equiv) and DMA (2 mL) were then added, the tube was screw-capped, and the mixture was stirred at rt for 12 h. The mixture was then diluted with EtOAc and washed with H₂O. The organic phase was dried (Na₂SO₄), filtered, and concentrated, and the residue was purified by chromatography (silica gel).
• 15 Ethyl 4-(Acetylamino)-4-biphenyl-4-yl-2,2-difluorobutanoate (4a) Prepared by the general method and purified by chromatography [silica gel, PE–EtOAc (2:1)] as a white solid; yield: 102 mg (70%); mp 166–168 °C. IR (thin film): 3294, 3084, 2995, 2926, 1766, 1651 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.60–7.51 (m, 4 H), 7.43 (t, J = 7.6 Hz, 2 H), 7.40–7.31 (m, 3 H), 6.26 (d, J = 7.6 Hz, 1 H), 5.41–5.31 (m, 1 H), 4.19 (q, J = 7.0 Hz, 2 H), 2.84–2.55 (m, 2 H), 1.98 (s, 3 H), 1.30 (t, J = 7.2 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 169.2, 163.7 (t, J = 32.4 Hz), 140.9, 140.4, 139.5, 128.8, 127.5, 127.4, 127.0, 126.9, 115.0 (t, J = 255.6 Hz), 63.1, 47.9 (t, J = 4.7 Hz), 40.2 (t, J = 22.8 Hz), 23.2, 13.8. ¹⁹F NMR (376 MHz, CDCl₃): δ = –102.7 (dt, J = 267.8, 15.5 Hz, 1 F), –103.5 (dt, J = 267.8, 15.7 Hz, 1 F).

• Supplementary Material