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Thiyl-Radical-Catalyzed Photoreductive Hydrodifluoroacetamidation of Alkenes with Hantzsch Ester as Multifunctional Reagent Wenhao Huang, Wenxin Chen, Guoqiang Wang, Jin Li, Xu Cheng, and Guigen Li ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b02420 • Publication Date (Web): 04 Oct 2016 Downloaded from http://pubs.acs.org on October 6, 2016
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Thiyl-Radical-Catalyzed Photoreductive Hydrodifluoroacetamidation of Alkenes with Hantzsch Ester as Multifunctional Reagent Wenhao Huang,a Wenxin Chen,a Guoqiang Wang,b Jin Li,a Xu Cheng,a* and Guigen Lia,c a
Institute of Chemistry and Biomedical Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China
b
Institute of Theoretical and Computational Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China c
Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas, United States
ABSTRACT: Hydrodifluoroacetamidation of alkenes with readily available α-bromodifluoroacetamides was achieved by means of a photoreductive reaction catalyzed by phenyl thiyl radical. A Hantzsch ester was used as the hydrogen donor and electron donor. This photoreductive pathway did not involve the oxidation of a carbon radical intermediate to a carbocation species.
Keywords: Hnatzsch ester, difluoroacetamidation, thiyl radical, photoreductive, visible light Incorporation of a gem-difluoro group can significantly change a molecule’s physicochemical properties and activities, and this strategy has been used for compounds with medical,1 agricultural,2 imaging,3 and materials science applications.4 Various strategies for incorporation of this moiety have been developed in recent years, and a broad range of gem-difluoro compounds have been synthesized.5 In particular, the α-difluoroacetyl group is a highly functionalized moiety that has been widely used in medicinal chemistry.6 Hydrodifluoroacetylation with an inexpensive difluoro reagent is a straightforward strategy for building difluoroacetyl compounds. Visible-lightinduced photoredox alkylation is also an efficient, economical method for introducing the difluoroacetyl functionality and a second functional group.7 However, in the current methods as shown in Scheme 1-I, the catalytic cycle starts with oxidative quenching of a photocatalyst to generate a highly reactive α-carbonyl radical, which is instantly captured by another molecule, such as an alkene, to yield a carbon radical that is then oxidized by the photoredox catalyst. Addition of a nucleophile, such as a bromide anion, to the resulting cation, or loss of a proton, then gives the product. Because this catalytic cycle involves the oxidation of a carbon radical intermediate to a carbocation species, achieving chemoselectivity toward hydrodifluoroacetylation is challenging to exclude side products such β-bromo adduct A and elimination product B. In a related example, Qing and colleagues reported a hydrodifluoromethylation reaction in which a carbon radical intermediate abstracted a hydrogen from THF rather than being oxidized.8 We speculated that a mechanism that precludes reductive regeneration of the photoredox catalyst is important for achieving hydrodifluoroa-
cetylation reactions that do not involve a carbocation species. Recently, we and other groups have reported that inexpensive Hantzsch esters can act as highly efficient, electron donors, and hydride donors under irradiation of visible light in several reactions.9 These reactions do not require costly complexes of transition metal, the presence of which must be limited in pharmaceuticals.10 In addition, these Hantzsch ester protocols do not involve either oxidative regeneration of a photoredox catalyst or a carbocation species. Here, we report the application of a Hantzsch ester in photoreductive hydrodifluoroacetamidation reactions
Scheme 1. Visible-Light-Induced Hydrodifluoroacetylation Pathways catalyzed by a thiyl radical.11 (Scheme 1-II) In our initial screening reactions, we used 2-bromo-2,2difluoro-N-phenylacetamide (1a) and alkene 2a (2 equiv) as standard substrates (Table 1). Irradiation of these substrates with blue LEDs in the presence of a Hantzsch ester in acetonitrile afforded desired hydrodifluoroacetam-
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idation product 3a in 9% yield by GC (entry 1), without any bromo transfer product or elimination product. The yield increased dramatically (88% GC yield, 70% isolated yield) when 10 mol% PhSSPh was added. Wet analysis indicated that the system pH reached 3–4 by the end of the reaction, owing to the formation of HBr as a side product. Reducing the amount of Hantzsch ester to 1.2 equiv decreased the yield (entry 3). Screening of various solvents showed that acetonitrile was the optimal choice (entries 4–7). Next, Hantzsch esters with a diethyl group or a di-t-butyl group were evaluated and shown to decrease the yield (entries 8 and 9). Control reactions demonstrated that a Hantzsch ester and light were essential to the reaction (entries 10 and 11). When 1.0 equiv of K2CO3 was present in the reaction mixture, the desired product was not detected (entry 12).
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the reaction of cyclooctene and 1a was even higher (3h, 71%). Compounds 3i and 3j could be prepared in 76% and 85% yields, respectively, from the corresponding exo alkenes. A substrate bearing a cyclopropyl group was also subjected to this photoreductive reaction, and 3k was produced in 70% yield. A substrate with a free hydroxyl group was compatible with the reaction conditions, affording 3l in 74% yield. Table 2. Reactions of Alkenes 2 with 1aa
Table 1. Optimization of Reaction Conditionsa
entry
Hantzsch ester
solvent
b
yield (%)
c
1
Me-HE
MeCN
9
2
Me-HE
MeCN
88 (70)
d
Me-HE
MeCN
68
d
Me-HE
Acetone
60
d
Me-HE
DCE
56
d
Me-HE
DMF
43
d
7
Me-HE
DMSO
55
8
Et-He
MeCN
85
9
t-Bu-HE
MeCN
61
10
—
MeCN
NR
e
Me-HE
MeCN
NR
f
Me-HE
MeCN
ND
3
4 5
6
11
12
f
a
Reaction conditions, unless otherwise noted: 1a (0.1 mmol), 2a (2 equiv), PhSSPh (10 mol%), Hantzsch ester (1.5 equiv), b blue LEDs, solvent (1 mL), room temperature, 22 h. Determined by GC-MS with dodecane as an internal standard; the yield in parentheses is an isolated yield. NR = no reaction; c ND = not detected. Reaction carried out without PhSSPh. d e Reaction carried out with 1.2 equiv of Me-HE. Reaction carf ried out without light. Reaction carried out with 1.0 equiv of K2CO3.
Using the optimized conditions (Table 1, entry 2), we explored the substrate scope by carrying out reactions with various alkenes (Table 2). Terminal alkenes substrates were readily converted to the desired hydrodifluoroacetamidation products in good yields (3b–3f). Product 3e was obtained in 86% yield when the reaction was carried out on a 1 gram scale. The reaction between cyclohexene and 1a gave a 56% yield of 3g, which has a newly generated secondary carbon center. The yield of
a
Reaction conditions, unless otherwise stated: 1 (0.1 mmol), 2 (2 equiv), PhSSPh (10 mol%), Me-HE (1.5 equiv), blue LEDs, b MeCN (1 mL), rt, 22–32 h. Yields are isolated yields. Reaction c on a 4 mmol scale. Reaction with 1.2 equiv of 2.
A compound with bromo substitution underwent the hydrodifluoroacetamidation reaction to produce 3m in good yield without any side product resulting from debromination. Alkenes with heterocyclic moieties were also tested in this photoreductiveacetamidation reaction. Products with a free indole and a protected indole (3n and 3o, respectively) were obtained in 61% and 80% yields, respectively. Pyridinyl compound 3p was also prepared in good yield. Compounds 3q and 3r, which bear a furyl group and a thiophenyl group, respectively, could be prepared in moderate yields as well. Protecting groups, such as O-silyl, C-TMS, N-benzoyl and N-imide, were well tol-
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erated, and the corresponding difluoroamides (3s–3v, respectively) were obtained in 65%–85% yields. Subsequently, we evaluated several αbromodifluoroacetamides in the photoreductive alkylation reaction (Table 3), and we found that a substrate with a benzyl amide moiety worked satisfactorily, affording 3w in 68% yield. Tertiary amides also reacted with an alkene to give 3x and 3y in good yields. The Weinreb amide (3z), which can serve as an intermediate in the synthesis of various difluoro compounds, was obtained in 73% yield. To our delight, a moderate yield of unsubstituted amide 3aa could also be obtained by means of this protocol.
alkenes, a reaction in which the base activates the Hantzsch ester.9b
Scheme 2. Control Experiments 1.8
Table 3. Reactions of α-Bromodifluoroacetamides 1 with Alkenes 2a
1.6
I0/I
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1.4
1.2
1.0 0
10
20
30
40
50
60
70
[Quencher]/[HE-Me]
Figure 1. Fluorescence quenching of Hantzsch ester.
a
Reaction conditions, unless otherwise stated: 1 (0.1 mmol), 2 (2 equiv), PhSSPh (10 mol%), Me-HE (1.5 equiv), blue LEDs, MeCN (1 mL), rt, 22–32 h. Yields are isolated yields.
To gain some information about the mechanism, we carried out several control reactions using 1a as the difluoroalkylation reagent. First, we observed that the reaction did not proceed in the presence of 4.0 equiv of TEMPO under the standard conditions (Scheme 2a). A fluorescence quenching experiment showed that there was no significant quenching between the excited Hantzsch ester and α-bromodifluoroacetamide 1a (E1/2Red = –1.15 V vs SCE) or the alkenes. We were interested to find that the diphenyldisulfide quenched the fluorescence of the Hantzsch ester (Figure 1). Phenyl thiyl radical has been proposed to be the species generated by homolysis of diphenyldisulfide in the presence of visible light.12 Reaction between the Hantzsch ester and phenyl thiyl radical would be expected to occur via hydrogen transfer to give thiophenol, which was detected in the reaction mixture. We also investigated the reaction between a large excess of thiophenol and 1a in the presence of blue LEDs and did not detect any product (Scheme 2b). These results suggest that phenyl thiyl radical catalytically activates the Hantzsch ester to promote electron transfer between the Hantzsch ester and 1a. A similar phenomenon has been observed in a Hantzsch ester–mediated debromination reaction of dibromo compounds to give
On the basis of these observations, we suggest the mechanism shown in Scheme 3. In the presence of visible light, the diphenyldisulfide undergoes homolysis, giving phenyl thiyl radical (A). Phenyl thiyl radical abstracts a hydrogen from the activated Hantzsch ester. Subsequent single electron transfer (SET) from the excited or ground state Hantzsch ester radical (B) to αbromofluoroacetamide 1 leads to protonated pyridine
Scheme 3. Plausible Mechanism species C, difluoroamide radical D, and bromide by means of mesolysis. Subsequent addition of D to the alkene gives intermediate E. In turn, hydrogen atom transfer (HAT) from the thiophenol to E furnishes the difluoroalkylation product and regenerates phenyl thiyl radical (A). In addition to HAT-initialized path 1, path 2 started from the excited Hantzsch ester with a SET reac-
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tin was also plausible as that suggested by controlled experiment (Table 1, entry 1), 9a giving cationic radical F and amide radical D as intermediates. Subsequently, F and thiyl radical undergo a HAT reaction to yield thiophenol, that donate the hydrogen atom to the intermediate E from D and alkene to furnish the product 3. Other possible pathway are also open for investigation.13 To demonstrate the applications of this protocol, we modified steroid 2ab under the standard conditions (Table 1, entry 2; Scheme 4). Difluoroacetamide derivative 3ab was obtained in 49% yield. Using this method, we prepared autoinducer compound 3ac14 as the sole product (82% yield) after 32 h of reaction.
Scheme 4. Applications of the Hydrodifluoroacetamidation Reaction In summary, we have developed a visible-light-induced hydrodifluoroacetamidation of alkenes with phenyl thiyl radical as the catalyst and readily available αbromodifluoroacetamides as substrates. A Hantzsch ester acted as the hydrogen donor and electron donor in this transformation. Complete chemoselectivity was realized by avoiding oxidative steps, and phenyl thiyl radical played an important role as a hydrogen transfer catalyst.
ASSOCIATED CONTENT Supporting Information. Experiment procedure, compound characterization, and spectra. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION Corresponding Author *
[email protected] Notes The authors declare no competing financial interests.
ACKNOWLEDGMENT We are grateful for grants from the National Science Foundation of China (21572099, 21332005), the Natural Science Foundation of Jiangsu Province (BK20151379).
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(14) Livinghouse, T. Autoinducer Compounds. US20030013755, Mar. 13, 2002..
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