Letter Cite This: Org. Lett. 2017, 19, 5653-5656
pubs.acs.org/OrgLett
Photoredox-Catalyzed Cross-Coupling of Enamides for the Assembly of β‑Difluoroimine Synthons Jicheng Wu, Ming Lang, and Jian Wang* School of Pharmaceutical Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Key Laboratory of Bioorganic Phosphorous Chemistry & Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, China S Supporting Information *
ABSTRACT: A photoredox-catalyzed formal Csp3−Csp3 crosscoupling reaction of enamides with bromodifluoro compounds is established. The resulting gem-difluoromethylenated γ-imines indicated high stability, excellent E/Z control, and broad functional group tolerance. These synthetic intermediates can efficiently transfer to difluoromethylenated γ-amino acids or δamino alcohols. Mechanistic analysis indicates that a radical/ SET mechanism proceeding via a difluoroalkyl radical may be involved in the catalytic cycle.
O
Scheme 1. Addition of Difluoro Radicals to CN Bonds and Our Synthetic Strategy
wing to their unique biological and physical properties, fluorinated organic molecules are commonly found in pharmaceuticals and agrochemicals.1 It is well-known that fluorinated subunits can remarkably enhance the lipophilicity, metabolic stability, and bioavailability of the parent molecules.2 As one of the most promising members of the “F” family, the difluoromethylene group (CF2) has shown particular value. In principle, the CF2 group can serve as a bioisostere for the oxygen or carbonyl group,3 resulting in an improved biological activity.4 Therefore, considerable and persistent efforts, both from an academic and an industrial perspective, have been made to seek efficient protocols for the assembly of CF2-contained organic molecules.5 In recent years, radical reactions via visible-light-induced photoredox catalysis have attracted much attention because of their mild reaction conditions and green features.6 Inspired by this fascinating progress, we questioned whether the CF2contained organic molecules can make it through such a photoredox process. Literature showed that the addition of CF2 radical to hydrazones (Scheme 1a),7 as well as isocyanides, alkenes, arenes, alkynes, etc.,8 resulting in a variety of CF2contained frameworks, has been intensively investigated. Surprisingly, enamides or enecarbamates, which commonly served as versatile building blocks (electron-rich CC equivalence) for the synthesis of fine chemicals,9 have rarely been reported to assemble CF2-contained molecules.10 For example, the Zhang group reported an elegant nickel-catalyzed tandem difuoroalkylation−arylation reaction of enamides.8f Herein, we report a visible-light-induced photoredox-catalyzed difluoroalkylation of enamides or enecarbamates, resulting in the corresponding β-difluoromethylenated imines (Scheme 1b). In sharp contrast, the synthesis of α-difluoromethylenated imines by the addition of CF2 radical to imines or hydrozones has been reported broadly (Scheme 1a).7 To our knowledge, the rapid and green synthesis of β-difluoromethylenated imines still remains a © 2017 American Chemical Society
challenge. This protocol, joined as a special complementary method, will enrich the family of enamide chemistry.9 In addition, these β-difluoromethylenated imines could easily transfer to a few valuable feedstocks, such as gem-difluoromeReceived: September 8, 2017 Published: October 12, 2017 5653
DOI: 10.1021/acs.orglett.7b02809 Org. Lett. 2017, 19, 5653−5656
Letter
Organic Letters thylenated γ-amino acids, δ-amino alcohols, or γ-ketoesters, with the potential to be used in drug synthesis and drug discovery.11 The key results are summarized in Table 1 (see the Supporting Information for details). We began our study by investigating the
Scheme 2, a variety of enamines (1c−z) were successfully converted to the corresponding difluoromethylenated imines Scheme 2. Scope of Enamidea,b
Table 1. Optimization of the Reaction Conditionsa
entry
photocatalyst
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
fac-[Ir(ppy)3] [Ir(ppy)2(dtbbpy)]PF6 [Ru(bpy)3](PF6)2 EosinY fac-[Ir(ppy)3] fac-[Ir(ppy)3] fac-[Ir(ppy)3] fac-[Ir(ppy)3] fac-[Ir(ppy)3] fac-[Ir(ppy)3] fac-[Ir(ppy)3] fac-[Ir(ppy)3] fac-[Ir(ppy)3] fac-[Ir(ppy)3] fac-[Ir(ppy)3] fac-[Ir(ppy)3]
base Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2HPO4 NaOAc KOAc KOAc KOAc KOAc KOAc
solvent
yieldb (%)
MeCN MeCN MeCN MeCN MeCN MeCN DMF THF Et2O MTBE Et2O Et2O Et2O Et2O Et2O Et2O Et2O
NR 65 34 6 trace trace 72 46 83 40 20 65 88 (91)c 89c,d NRe 76f 58g
a Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol, 1.5 equiv), photocatalyst (0.004 mmol), base (0.4 mmol, 2.0 equiv), solvent (1.5 mL), 36 W blue LEDs, room temperature, argon atmosphere, 24 h. b Yield of isolated products after column chromatography. c80 mg of 4 Å MS was added. d(E)-N-(1-phenylprop-1-en-1-yl)acetamide 1a′ as substrate. eIn the dark; NR = no reaction. f25 W white LEDs. gUnder air.
cross-coupling of (Z)-N-(1-phenylprop-1-en-1-yl)acetamide 1a with BrCF2CO2Et 2a as the model reaction (Table 1). Pleasingly, the desired product 3a was achieved in a moderate yield in the presence of blue LEDs as visible light source, fac-[Ir(ppy)3] as photoredox catalyst, Na2CO3 as base, and CH3CN as medium (Table 1, entry 2). After testing several commonly used photocatalysts (Table 1, entries 2−5), fac-[Ir(ppy)3] was proven to be the best due to its high catalytic efficiency. Encouragingly, solvent screening disclosed that diethyl ether was the most suitable medium for this reaction (entries 7−10). We also found that the base is essential for this reaction and can potentially neutralize the byproduct HBr (entry 6). Further screening showed a higher yield of 3a (88%) was obtained when the system used KOAc instead of Na2CO3 (entry 13). Meanwhile, 4 Å molecular sieves used to suppress the hydrolysis of 3a (91%). Notably, we found that the E/Z isomers of substrates 1 did not have a significant impact on the reaction yields (entry 14, 3a, 89%). Finally, the optimization of reaction parameters, including visible-light source and catalyst loadings (entries 15−17), revealed that product 3a could be obtained in the highest yield when 1a conducted with 1.5 equiv of 2a under visible-light irradiation, 2 mol % of fac-[Ir(ppy)3], 2.0 equiv of KOAc, and Et2O as medium at room temperature for 12 h (entry 13). With the optimized reaction conditions in hand, we then turned our attention to investigate the scope. As shown in
a
Reaction conditions: 1 (0.2 mmol), 2a (1.5 equiv), fac-[Ir(ppy)3] (2 mol %), KOAc (2.0 equiv), Et2O (1.5 mL), 80 mg of 4 Å MS, 36 W blue LEDs, room temperature, argon atmosphere, 12−48 h. bIsolated yields. cN-(1-Phenylvinyl)acetamide (0.2 mmol), 2a (1.5 equiv), fac[Ir(ppy)3] (2 mol %), Na2CO3 (2.0 equiv), Et2O (1.5 mL), 36 W blue LEDs, stirred at room temperature under argon atmosphere for 24 h, then addition of NaHB(OAc)3 (5.0 equiv) in DCE for 2 h. dNa2CO3 (2.0 equiv).
(3c−z) with moderate to excellent yields. For starting material 1b (R2 = H), because of its instability, a subsequent reduction after the cross-coupling assisted the formation of stable gemdifluoromethylenated γ-amino acid ester 3b in 80% yield. Further scope examination indicated that substituents on the aryl ring (R1 = Ar), both electron-donating and electron-withdrawing, have almost no effect on reaction efficiency (3c−k). Substrates 1l−m (R1 = heterocycles) were also good substrates and gave the corresponding products 3l−m in moderate yields. Enamides with alkyl or aryl group on R2 position (1n−y) can also 5654
DOI: 10.1021/acs.orglett.7b02809 Org. Lett. 2017, 19, 5653−5656
Letter
Organic Letters Scheme 4. Scope of α-Carbonyl Alkyl Bromidesa,b
participated in the reaction to afford their corresponding products (3n−y) in good chemical yields. It should be noted that enamides 1u−y, bearing an ester group, sulfonyl group, alkynyl group, or alkenyl group, also furnished the corresponding products 3u−y with good yields (Scheme 2). Additionally, enamide 1z bearing alkyl groups on both R1 and R2 positions also underwent radical addition to provide the gemdifluoromethylenated imine 3z. Further investigation of the scope of enamides was conducted (Scheme 3). When R3 = alkyl group, reactions proceeded well to Scheme 3. Scope of Other Enamidesa,b
a
Reaction conditions: 1 (0.2 mmol), 2 (1.5 equiv), fac-[Ir(ppy)3] (2 mol %), KOAc (2.0 equiv), Et2O (1.5 mL), 80 mg of 4 Å MS, 36 W blue LEDs, room temperature, argon atmosphere, 18−32 h. bIsolated yield. cNa2CO3 (2.0 equiv) and MeCN (1.5 mL) were used.
butanoate 3a, difluoromethylenated δ-amino alcohol, γ-amino acid, and γ-ketoester could be synthesized smoothly (for details, see the SI). A plausible mechanism is depicted in Scheme 5. Under visiblelight irradiation, the photocatalyst fac-[Ir3+(ppy)3] undergoes a metal-to-ligand charge transfer (MLCT) process to generate a strongly reducing excited state Ir3+* (−1.73 V vs SCE in CH3CN). When Ir3+* meets with 2a, a SET process allows formation of radical precursor 6 and Ir4+ (+0.77 V vs SCE in CH3CN).10 The subsequent radical addition to enamide 1a leads
a
Reaction conditions: 1 (0.2 mmol), 2a (1.5 equiv), fac-[Ir(ppy)3] (2 mol %), KOAc (2.0 equiv), Et2O (1.5 mL), 80 mg of 4 Å MS, 36 W blue LEDs, room temperature, argon atmosphere, 18−32 h. bIsolated yield. cNa2CO3 (2.0 equiv) as base.
afford the corresponding products in good chemical yields (4a− g,n,o). When R3 = phenyl group, the catalytic process smoothly provided 4h in 70% yield. When R3 was an alkenyl group, a moderate yield (50%) of 4i was achieved. Furthermore, ene carbamates and ene ureas were successfully disclosed as suitable partners, affording the corresponding products (4j−m) as expected. We then turned our attention to explore the scope of difluorinating reagents 2. As shown in Scheme 4, bromodifluoroacetamides,12 as difluorinating reagents, had proven to be suitable substrates, thus providing the corresponding difluoromethylenated products with good yields (5a−d). A monofluorinating reagent, ethyl 2-bromo-2-fluoroacetate, also reacted smoothly with 1a to provide the corresponding product 5e in 81%, but albeit with 1:1 dr. To our delight, long-chained, branched, or cyclic 2-bromide ethyl esters were all found to be suitable radical sources, thus producing the corresponding 5f−j in moderated to high yields. In contrast, perfluoroalkyl bromides (e.g., n-C6F13Br and n-C8F17Br) indicated poor reactivities and gave almost no desired products under the standard conditions. To clarify, the products β-difluoromethylenated γ-imines were determined to be E-configured by 1H−1H NOESY (see the SI for details). To indicate the synthetic utility, several transformations have been conducted. Building upon the synthon γ-imino
Scheme 5. Postulated Mechanism
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DOI: 10.1021/acs.orglett.7b02809 Org. Lett. 2017, 19, 5653−5656
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Organic Letters
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to the formation of radical intermediate 7. However, the product 8 is not detected by the crude NMR and LC−MS, which indicated that H atom abstraction of 7 may not be involved in the catalytic cycle (path A). Instead, a key tertiary carbon radical/ polar crossover step proceeds between 7 and Ir4+,6,7,13 thus regenerating the photocatalyst and either the tertiary carbon cation 9 (path B). Further tautomerization and deprotonation of the tertiary carbon cation would deliver the final product 3a with (E)-configuration. In summary, we have successfully developed a visible-light induced photoredox-catalyzed difluoroalkylation of enamides. The synthesized gem-difluoromethylenated γ-imines are excellent substrates and can rapidly transfer to other useful and valuable building blocks, such as gem-difluoromethylenated γamino acid, δ-amino alcohol, and γ-ketoesters. Asymmetric synthesis of such fluorinated molecules is now in progress in our laboratory.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02809. Experimental procedures, characterization data, and NMR spectra of the products (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Jian Wang: 0000-0002-3298-6367 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Generous financial support for this work is provided by the National Natural Science Foundation of China (21672121), the “Thousand Plan” Youth program of China, the Tsinghua University, the Bayer Investigator fellow, and the fellowship of the Tsinghua−Peking Centre for Life Sciences (CLS).
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REFERENCES
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DOI: 10.1021/acs.orglett.7b02809 Org. Lett. 2017, 19, 5653−5656
