Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Controllable Intramolecular Unactivated C(sp3)‑H Amination and Oxygenation of Carbamates Qihang Guo, Xiang Ren, and Zhan Lu* Department of Chemistry, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China
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S Supporting Information *
ABSTRACT: Dual catalyst-controlled intramolecular unactivated C(sp3)-H amination and oxygenation of carbamates merging visible-light photocatalysis and earth-abundant transition metal catalysis have been reported. Useful amino alcohol and diol derivatives could be selectively obtained from readily available tertiary alcohol derivatives. The possible mechanisms have been proposed via a 1,5-HAT process followed by Lewis acid-controlled cyclization. The nickel and zinc catalysts inhibit the formation of oxygenation and amination products, respectively. An interesting phenomenon of chirality transfer is also observed.
T
Scheme 1. Controllable Unactivated C(sp3)-H Functionalization of Alcohol Derivatives
he vicinal amino alcohols and diols are extremely useful building blocks for synthetic chemistry, agriculture, pharmaceuticals, biology, and materials science.1 Various methods have been explored for the synthesis of vicinal amino alcohols and diols, such as alkene difunctionalizations, ring-opening of corresponding epoxides or aziridines, and so on.2 However, the development of alternative methods for the construction of these useful compounds from simple starting materials is still highly desirable. The β-C(sp3)-H functionalization of readily available alcohols is an alternative strategy to control the site-selectivity.3 It would be ideal to afford C−H bond amination and oxygenation products selectively from the same starting materials which containing both O- and Nsources. In 2013, White and co-workers reported catalystcontrolled allylic C−H bond amination and oxygenation reactions of ureas by using palladium catalysts with silver salt and B(C6F5)3 as cocatalysts, respectively.4 To the best of our knowledge, the controllable amination and oxygenation of unactivated C(sp3)-H bond from same substrate have not been reported yet. In our previous work,5 we developed the visible light promoted diastereodivergent intramolecular oxyamination of alkenes with functionalized hydroxylamines via a primary amidyl radical intermediate. We hypothesized that this primary amidyl radical might enable Hofmann-Löffler-Freytag (HLF) type 1,5-HAT6 to generate a carbon-centered radical. The generated carbon radical might be oxidized to deliver a carbon cation which could undergo an intramolecular cyclization to afford a formal C−H amination product. However, the intramolecular cyclizations of neutral amides often afford a mixture of amination and oxygenation products.7 Here, we reported dual catalyst-controlled intramolecular unactivated C(sp3)-H amination and oxygenation reactions of carbamates merging visible light photocatalysis and earth-abundant transition metal catalysis (Scheme 1). © XXXX American Chemical Society
At the beginning of our study by using 2-methyl-4phenylbutan-2-yl benzoyloxycarbamate 1a as a model substrate, Et3N as an electron sacrificial donor and 1,4-dioxane as a solvent at 30 °C under the irradiation of 18 W cold fluorescent light (CFL), a variety of photocatalysts were screened (Table S1 in SI). The Ir(dFCF3ppy)2(bpy)(PF6) led to intramolecular amination (2a) and oxygenation (3a and 4a) products in total 62% yield with a ratio of 1/1 (Table 1, entry 1). Various additives were applied to improve the chemoselectivity (Table S2 in SI). When nickel chloride was employed, the combined oxygenation products were dramatically inhibited (entry 2). After the optimization of solvents, electron sacrificial donors, and ligands (Tables S3 and S4 in SI), the reaction using acetonitrile as a solvent and iPr2NEt as an electron sacrificial donor could give 2a in 44% yield (entry 4). When bidentate ligand L1 ((4S,4′S)-2,2′-(propane-2,2diyl)bis(4-benzyl-4,5-dihydrooxazole))8 was employed, the reaction afforded 2a in 68% yield with excellent chemoselectivity (>20/1) (entry 5). It should be noted that no enantioselectivity was observed using this chiral ligand (Table Received: November 21, 2018
A
DOI: 10.1021/acs.orglett.8b03299 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Optimization of Reaction Conditionsa
entry
solvent
base
1 2 3 4 5b 6b 7b,d 8b,e 9 10
dioxane dioxane MeCN MeCN MeCN MeCN MeCN MeCN dioxane dioxane
Et3N Et3N Et3N iPr2NEt iPr2NEt / iPr2NEt iPr2NEt Et3N Et3N
11f
dioxane/ DME dioxane/ DME dioxane/ DME dioxane/ DME
iPr2NEt
f ,g
12
13f,g 14f,e,g
iPr2NEt iPr2NEt iPr2NEt
additives (mol %)
yield of 2a (%)
/ NiCl2 (10) NiCl2 (10) NiCl2 (10) NiCl2 (5) NiCl2 (5) NiCl2 (5) NiCl2 (5) ZnCl2 (10) Zn(OTf)2 (10) Zn(OTf)2 (10) Zn(OTf)2 (10) Zn(OTf)2 (15) Zn(OTf)2 (10)
31 27 35 44 68 (66c) / / / 26 21 10
Scheme 2. Intramolecular C(sp3)-H Aminationa
yield of 3a + 4a (%) 31 trace 7 3 3 / / / 53 55 66
6
69(64c)
3
61
/
/
a Yields of 2a, 3a, and 4a were determined by 1H NMR using TMSPh as an internal standard. b6 mol % of L1 was used. cIsolated yield. d Without photocatalyst. eWithout light. f0.025 M, dioxane/DME = 1/ 1, 80 °C. After 4 h, the reaction mixture was added by 1 M HCl (1 mL) followed by stirred for another 15 min. g5 W Blue LEDs instead of 18 CFL.
a
Standard conditions A: alkyl benzoyloxycarbamate (1.0 equiv), NiCl2 (0.05 equiv), L1 (0.06 equiv), Ir(dFCF3ppy)2(bpy)(PF6) (0.02 equiv), iPr2NEt (1 equiv) in a solution of MeCN (0.05 M) under the irradiation of 18 W CFL for 5 h at room temperature; the yields of amination products were in the scheme. bc.r. = 10/1. cWithout NiCl2 and L1. dc.r. = 17/1, 10 h. eThe combined yield of two diastereoisomers. fc.r. = 3/1. gc.r. = 7/1.
S4). Control experiments demonstrated that photocatalyst, light, and base were all essential for this transformation (entries 6−8). On the other hand, when zinc chloride was used instead of nickel chloride, the reaction afforded 2a in 26% yield and the oxygenation products 3a and 4a in 53% combined yield (entry 9). After optimizing reaction conditions (Table S5), the reaction using iPr2NEt as an electron sacrificial donor, zinc trifluoromethylsulfonate as a cocatalyst and 1,4-dioxane/DME (1/1) as cosolvent afforded 4a in 66% yield with 6.6/1 chemoselective ratio (c.r.) after hydrolysis (entry 11). When blue LEDs were used, the ratio of chemoselectivity was improved to 11/1 (entry 12).9 Using 15 mol % of zinc trifluoromethylsulfonate, the reaction afforded the oxygenation products with 20/1 c.r. (entry 13). Light was also essential for this reaction (entry 14). Then we investigated the scope of C−H bond amination under standard conditions A (Scheme 2). The ratios of chemoselectivity for most reactions were better than 20/1 unless specially noted. The reactions of both electron-donating and withdrawing aryl derivatives gave 2b−f in 67−73% yields. Simple alkyl substrates were suitable to deliver 2g−k in 62− 93% yields. Protected alcohols could be tolerated to give 2l and 2m in 78% and 60% yield, respectively. The reactions of cyclic derivatives 1n−p, 1r, and 1s could afford syn-products in 79− 95% yields. Cyclooctanol derivatives could be transferred to 2q in 49% yield without nickel salt and ligand. The reactivity of this C−H bond amination could be formulated as follows: 3° > 2° > 1° based on the reaction of 1t. 3-Ethylpentan-3-ol derivatives could be transferred to 2u in 98% yield without nickel salt and ligand. The more sterically bulky diethyl group
is favorable for the cyclization. The detail for high chemoselectivity is not clear. The reaction of racemic alcohol derivatives could afford 2v−x in 46−88% yields, and excellent diastereoselectivity could be achieved when 1x containing a tertiary butyl group was used as a substrate. The diastereochemical outcomes of 2x were determined by NOESY analysis. The bioactive molecule derivatives, such as menthone, estrone, and epiandrosterone derivatives could be converted to 2y-2aa in 35−73% yields. The scope of C−H oxygenation was also investigated under standard conditions B (Scheme 3). The ratios of chemoselectivity for most reactions were better than 10/1 unless specially noted. The reactions of electron-donating and withdrawing aryl derivatives gave 4b−d in 61−64% yields with good chemoselectivities. Due to the generation of the debenzoyl byproducts, the yield of all reactions were slightly low. Substrates with 1-naphthyl and 2-naphthyl could be converted to 4e and 4f with 59% and 62% yield, respectively. Neutral red was found to be a better photocatalyst for some reactions. Simple alkyl substrates also provided the corresponding 4h−j in 52−72% yields. The reactions of cyclic derivatives 1n−p gave syn-products in 60−75% yields. 3Ethylpentan-3-ol derivatives could be transferred to 4u in 84% yield. Racemic alcohol derivatives could be transformed to 4v and 4x in 73% and 79% yield, respectively. The diastereochemical outcomes of 4x were determined by NOESY analysis. The more bulky substituent was used, the higher diastereoselectivity was observed. Estrone and epiandrosterone B
DOI: 10.1021/acs.orglett.8b03299 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 3. Intramolecular C(sp3)-H Oxygenationa
determined by X-ray diffraction analysis,11 which illustrated that the stereochemical outcome maintained. This interesting phenomenon might come from the intramolecular hydrogen bonding effect between oxygen on methoxyl group and hydrogen on carbamate (see SI). To demonstrate the utility of these transformations, the amination product 2y and estrone derivative 4z could be converted to the vicinal amino alcohol 7 in 99% yield, and vicinal diol 8 in 88% yield,12 which was an analogue of pulmicort (Scheme 4b). To illustrate the possible mechanisms, a series of control experiments were carried out (Scheme 5). The reaction of a Scheme 5. Mechanistic Studies
a
Standard conditions B: alkyl benzoyloxycarbamate (1.0 equiv), Zn(OTf)2 (0.15 equiv), Ir(dFCF3ppy)2(bpy)(PF6) (0.02 equiv), iPr2NEt (1 equiv) in a solution of dioxane/DME (1:1, 0.025 M) under the irradiation of 5 W blue LEDs for 4 h at 80 °C. Then 1 M HCl (1 mL) was added and the mixture stirred for more than 15 min. The yields of oxygenation products are in the scheme. bc.r. = 9/1. c Zn(OTf)2 (0.10 equiv). dc.r. = 4/1. eNeutral red (2 mol %) was used instead of Ir(dFCF3ppy)2(bpy)(PF6), 50 °C, DME (0.025 M). fc.r. = 6/1. gCombined yield of two diastereoisomers.
derivatives could be transferred to 4z and 4aa in 75% and 68% yield, respectively. It should be noted that the reaction of primary and secondary alcohol derivatives did not afford cyclization products which was consistent with the ThorpeIngold effect. The reaction of enantioenriched 1ab (99.2% ee) could afford aimination product 2ab in 62% yield with a decreasing ee (28.2% ee, Scheme 4a). Interestingly, the reaction of enantioenriched 1ac (99.7% ee) could deliver the chiral amination product 2ac in 65% yield and 97.4% ee, which could be a key skeleton of potent antiadenoviral pseudonatural polyketides.10 The absolute configuration of 2ac was
1:1 mixture of 1a and deuterated D-1a was conducted under amination and oxygenation conditions, and kinetic isotope effect (KIE) was 1.4 and 3.5, respectively (Scheme 5a). Typical experimental values for normal secondary KIEs are around 1.1−1.2.13 These results illustrated that the 1,5-HAT process should be the rate-determining step in both reactions. Subsequently, a “radical clock” substrate 5 was applied under both the amination and oxygenation reaction conditions to afford the ring-opening product 6 in 43% and 47% yield, respectively (Scheme 5b). The alkyl radical generated from 1,5-HAT might be involved in both reactions. The alkyl radical could be easily oxidized to carbon cation which might undergo nucleophilic substitution to afford the cyclization products. We hypothesized that the chemoselectivity might be controlled by metal salts through nucleophilic substitution of carbon cation. So, a diazonium salt 9 was designed and synthesized as a precursor of carbon cation intermediate. The reaction of 9 with hydrochloric acid and sodium nitrite could afford the diazonium salt A, which would easily decompose to a carbocation B. Intramolecular nucleophilic attack of B could afford a mixture of 2a and 4a (Table 2, entries 1 and 3). When nickel chloride was employed, the yield of 2a was increased to 25% with a decrease yield of 4a (Table 2, entry 2). On the other hand, when zinc trifluoromethanesulfonate was employed, the yield of 4a was increased to 41% with a trace yield of 2a (Table 2, entry 4). These phenomena could be explained by the different coordination situations between carbamates and metal ions. The Zn2+ cation (ionic radius is 74 pm) preferred to coordinate with the slight “softer” nitrogen and decreased its reactivity. On the hand, the Ni2+ cation (ionic radius is 69 pm) preferred to coordinate with the slight “harder” oxygen and decreased its reactivity.
Scheme 4. Synthetic Applications
C
DOI: 10.1021/acs.orglett.8b03299 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
was also observed. The asymmetric transformations are going to be investigated in our laboratory.
Table 2. Carbocation Trapping Experiments
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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.8b03299. Experimental details, characterization data, and NMR spectra of new compounds (PDF) entry
solvent
additive
2a (%)
4a (%)
1 2 3 4
MeCN MeCN DME DME
/ NiCl2 / Zn(OTf)2
15 25 16 trace
14 8 29 41
Accession Codes
CCDC 1814175 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
On the basis of the results above and previously reported literature,5a,14 plausible mechanisms are proposed (Scheme 6).
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Scheme 6. Proposed Mechanism
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Zhan Lu: 0000-0002-3069-079X Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We gratefully acknowledge the financial support from NSFC (21472162, 21772171), the National Basic Research Program of China (2015CB856600), the Zhejiang Provincial Natural Science Foundation of China (LR19B020001) and Zhejiang University.
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The photocatalyst (PC) absorbs the visible light to generate the excited state PC* which can be reduced by the electron sacrifice to produce the reduced photocatalyst PC− and trialkylammonium radical cation. The substrate 1a can be reduced by PC− species to regenerate PC and afford the radical ion intermediate which may undergo N−O bond cleavage to form an amidyl radical C. The primary amidyl radical can undergo the intramolecular 1,5-HAT to afford an alkyl radical D, which is easily oxidized to alkyl carbocation B by PC*.14 Oxidation via trialkylammonium radical cation cannot be ruled out. The nickel(II) complex might coordinate with the slightly “harder” oxygen atom on carbamate which led the nitrogen atom to attack the alkyl carbocation to give 2a. On the other hand, Zn2+ might coordinate with slightly “softer” nitrogen atom on carbamate which led the oxygen atom to attack the alkyl carbocation to give 3a. Experimental and computational studies will be further conducted to gain an accurate understanding of the mechanisms. In summary, we developed dual catalyst-controlled intramolecular unactivated C(sp3)-H amination and oxygenation of carbamates. Amino alcohol and diol derivatives could be easily obtained from readily available alcohol derivatives by merging visible light photocatalyst with nickel and zinc catalysts, respectively. The alternative possible mechanisms were proposed via 1,5-HAT process followed by catalyst-controlled cyclization. An interesting phenomenon of chirality transfer
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DOI: 10.1021/acs.orglett.8b03299 Org. Lett. XXXX, XXX, XXX−XXX
