Cu-Catalyzed Synthesis of Fluoroalkylated Isoxazoles from

Letter pubs.acs.org/OrgLett

Cite This: Org. Lett. XXXX, XXX, XXX−XXX

Cu-Catalyzed Synthesis of Fluoroalkylated Isoxazoles from Commercially Available Amines and Alkynes Xiao-Wei Zhang, Wen-Li Hu, Suo Chen, and Xiang-Guo Hu* National Engineering Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang, 330022, China S Supporting Information *

ABSTRACT: A one-pot protocol for the construction of fluoroalkylated isoxazoles directly from commercially available amines and alkynes is described. The reaction is scalable, operationally simple, regioselective, mild, and tolerant of a broad range of functional groups. As such, it could be viewed as a “click synthesis” of fluoroalkylated isoxazoles. Preliminary mechanistic investigations reveal that the transformation involves an unprecedented Cu-catalyzed cascade sequence involving RfCHN2. expanded the utility of fluorinated diazoalkanes for the synthesis of various fluorinated compounds. Unsurprisingly, fluorinated diazoalkanes have found applications in the synthesis of FSAs. For example, in 2013, Ma and co-workers developed a silvermediated [3 + 2] cycloaddition of CF3CHN2 for the synthesis CF3-substituted pyrazoles (Figure 1b).7a In 2015, Mykhailiuk solved the long-standing synthetic problem of difluoromethyl diazomethane (HCF2CHN2) and applied it for the construction of CF2-substituted pyrazoles (Figure 1b).9d In 2017, Jamison and co-workers developed an unified synthesis of CF3- and CF2substituted pyrazoles under continuous flow conditions. However, in all these elegant examples, fluorinated diazoalkanes are used as three-atom components and therefore are only suitable for the synthesis of FSAs with two or more nitrogens.7,9a−e,10b,11f We report herein the successful utilization of RfCHN2 for the synthesis of fluoroalkylated isoxazole (FIO), one important FSA containing one nitrogen in the ring.12 Generally, FIOs are prepared by condensation of 1,3dicarbonyl compounds or their equivalents; intramolecular cyclization of alkynyl oximes; or 1,3-cycloaddion of nitrile oxide with alkynes.13 Unfortunately, however, all of the reported methods suffer from at least one of the following problems: narrow substrate scope; forcing reaction conditions; requirement for the handling of unstable intermediates; low efficiency; and lack of regioselectivity. More importantly, poor step- or poteconomy14 is a common roadblock for easy access to FIOs because the requisite starting materials such as nitrile oxides usually need to be synthesized in a multistep fashion.15 In order to address the aforementioned limitations, we aimed to develop a mild, efficient, and pot-economical reaction for the synthesis of FIOs. Based on our understanding of the chemistry of RfCHN211e and inspired by the recent successful transitionmetal-catalyzed couplings of alkynes with diazo-compounds,16 we envisioned that a one-pot approach could be developed via the cascade sequence shown in Figure 1c. Although the research

N

itrogen heterocycles are core structures of numerous bioactive natural and unnatural compounds. A recent analysis showed that nearly 60% of small-molecule drugs approved by the US FDA contain at least one N-heterocycle.1 On the other hand, fluoroalkyl groups, CF3 and CF2 in particular, often impart desirable physical and biological properties when incorporated into organic molecules.2 The combination of these two features has thus generated a great number of pharmaceuticals, agrochemicals, and related candidates,3 with fluoroalkyl-substituted azoles (FSAs) being particularly notable (Figure 1a). Fluorinated diazoalkanes (RfCHN2)4 have emerged as useful building blocks largely owing to the pioneering work from Carreira and co-workers, who in 2010 reported a convenient protocol for in situ generation and application of CF3CHN2.5 Since then, contributions from the groups of Carreira,6 Ma,7 Molander,8 Mykhailiuk,9 Koenigs,10 and others11 have greatly

Figure 1. FSA-containing bioactive compounds and syntheses of FSAs from alkynes and RfCHN2. © XXXX American Chemical Society

Received: December 27, 2017

A

DOI: 10.1021/acs.orglett.7b04028 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters groups of Fu,17a Fox,17b and Wang17c−e reported the coupling of alkynes with nonfluorinated diazo-compounds, and Ma18 documented the reaction of alkynes with CF3CHN2, there remain significant challenges associated with our hypothetical cascade reaction. For example, the trapping of alkyne-derived carbenoid 2 with nitrosonium ion (NO+) is unprecedented even for nonfluorinated diazo-compounds.19 Further, the reaction could entail competing pathways such as β-F elimination20 and protodemetalation.17d Finally, identifying appropriate conditions to integrate all of the individual steps into a one-pot reaction could be viewed as a daunting task. Our first objective was to realize the reaction in a stepwise fashion. We initiated our studies by preparing a solution of HCF2CHN2 in either CHCl3 or CH3CN according to the method of Mykhailiuk.9d Based on the known reactivity of alkynes with diazo-compounds,17,18 we evaluated a variety of CuI and PdII species as the catalyst. Different Lewis acid additives along with tert-butyl nitrite (TBN) for the generation nitrosonium ion were also screened (Table S1).21 After extensive experimentation, we discovered that the desired FIO 5a could be obtained in 28% yield with ZnCl2 as the acid additive and CuI as the catalyst (Scheme 1), thus verifying the feasibility of our reaction design.

(entries 4−7). Other metal additives gave no product under otherwise identical conditions (entries 1−3). The reaction with ZnBr2 showed a strong dependence on the solvent, with CHCl3 affording the best result (entries 8−10). Increasing the amounts of HCF2CH2NH2 (6a) and TBN to 3 molar equiv each gave the desired product in an optimized yield of 87% (entry 11). Control experiments showed that both CuI and ZnBr2 were indispensable (entries 12−15). It is noteworthy that neither of the possible side products 77a,9d,11f or 818 was observed under the optimized conditions. With the optimized conditions in hand (entry 11, Table 1), we proceeded to test the scope of the reaction with respect to both the alkyne and amine components (Scheme 2). Initially, the alkyne component was varied while keeping the amine component constant (6a). The reaction tolerates a variety of Scheme 2. Substrate Scope

Scheme 1. Optimized Condition for the Synthesis of Isoxazole with Prior Formation of HCF2CHN2

Encouraged by this preliminary result, we next investigated whether the reaction could still occur if the HCF2CHN2 was generated in situ rather than being formed in a discrete operation (Table 1 and Tables S2−S3). To our delight, we found the reaction proceeded successfully if certain zinc salts were included within the mixture, with ZnBr2 providing the best outcome Table 1. Optimized Conditions for Synthesis of Isoxazole 5a without Prior Formation of HCF2CHN2

a

entry

additives (equiv)

solvents

yield (%)a

1 2 3 4 5 6 7 8 9 10 11b 12b 13b 14b 15b

LiCl (2.0) AlCl3 (2.0) AgNO3 (2.0) ZnI2 (2.0) Zn(OTf)2 (2.0) ZnCl2 (2.0) ZnBr2 (2.0) ZnBr2 (2.0) ZnBr2 (2.0) ZnBr2 (2.0) ZnBr2 (2.0) no CuI no ZnBr2 ZnBr2 (1 equiv) CuI (5 mol %)

CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CH2Cl2 THF toluene CHCl3 CHCl3 CHCl3 CHCl3 CHCl3

0 0 0 0 0 43 66 52 3 48 87 0 0 42 73

Isolated yield. b3 equiv of HCF2CHNH2 and TBN were used.

a

B

Yield on gram-scale; R1 = 4-MeO-Bz; R2 = 4-NO2-Bz. DOI: 10.1021/acs.orglett.7b04028 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

acetylide (17) failed to afford 5a under the standard conditions (Scheme 3d), suggesting that 17 is not an intermediate. In contrast, an independently prepared zinc acetylide (18) did afford the product 5a under the same conditions (Scheme 3e), indicating that 18 could be a true intermediate. (Organozinc reagents are known to be formed by reaction of alkynes with zinc salt in the presence of an organic base.)27 This is also supported by the observation of gradual dissolution of ZnBr2 during the course of the reaction. Successful reaction of 18 with a stock solution of CF3CHN225 (Scheme 3f) further indicated that the zinc acetylide may be the intermediate, as well as the involvement of fluorinated diazoalkane. Finally, although the presumed oxime intermediate 4a could not be isolated, an independently prepared sample of 4a did cyclize readily under the standard conditions (Scheme 3g). A possible mechanism is proposed based on the control experiments conducted in this work (Scheme 4). The reaction is

substitution patterns and functional groups on the phenylacetylene moiety. Para- (5a−5p), ortho- (5q−5s), and metasubstituted examples (5t−5bb) all smoothly afforded the desired isoxazoles in good to excellent yields. A wide variety of functional groups are tolerated including methoxy (5e, 5q), halide (5f−5h), trifluoromethyl (5i), cyano (5j), nitro (5k, 5t), ester (5i, 5s), acetyl (5s), sulfinyl (5n), sulfonyl (5o), sufoxyl (5p), alkenyl (5s), protected amino (5x−5bb), and free hydroxyl (5v) groups. The fact that some common protecting groups (5w−5aa) are compatible with the reaction conditions suggests that the method is potentially useful for other functionalized substrates. The reaction exhibits good chemoselectivity, as no ring nitration occurs even for the electron-rich compounds (e.g., 5e, 5q, 5v, 5w).22 Generally, the yields of substrates with electronwithdrawing substituents were slightly lower than those with electron-donating substituents. Besides the phenylacetylenes described thus far, bicylcoaryl (5ee) and heteroaryl (5ff−5ii) substituted acetylenes are also viable substrates. Also, the reaction is not limited to (hetero)aryl substituted acetylenes: styryl and aliphatic alkynes also gave rise to the corresponding products (5jj−5ll), albeit in somewhat lower yields. With respect to the fluorinated amine component, the method is equally efficient with trifluoroethylamine (6b); all of the corresponding CF3-substituted isoxazoles (9a−9qq) were obtained in comparable yields to their CF2 counterparts. Finally, other two fluoroalkylamines (6c−6d) are also suitable for this reaction, giving 10a and 11a in 83% and 86% yields, respectively. It should be pointed out that only one regioisomer was observed for all of the 78 examples tested, and 66 products obtained are unprecedented in the literature. Furthermore, the reaction is also scalable: for example, 9g was obtained in 82% yield on gramscale with a lower catalyst loading (5 mol % CuI). The structures of 5k, 5y, and 9c were confirmed by means of X-ray crystallographic analysis (CCDC 1577898, 1577906, 1577913). Because of the efficiency, generality, regioselectivity, chemoselectivity, and mildness of the reaction conditions, as well as the ready availability of all of the reagents, this method could be viewed as a “click synthesis”23 of fluoroalkylated isoxazoles. To gain an insight into the mechanism of this transformation, a series of control experiments were conducted (Scheme 3). First,

Scheme 4. Mechanistic Proposal

initiated by the formation of Cu-carbene A from diazocompound B, generated in situ via the reaction of amine C with tert-butyl nitrite. Transmetalation of Cu-carbene A with zinc acetylide D, followed by a migratory insertion of the resulted E, yields copper carbenoid F. A nitrosonium ion, generated from tert-butyl nitrite, then captures carbenoid F to afford oxime H after tautomerization. Finally, 5-endo-dig cyclization of oxime H affords the isoxazole product I. In summary, we have developed a one-pot protocol for the construction of fluoroalkylated isoxazoles directly from commercially available amines and alkynes. The reaction is scalable, operationally simple, regioselective, mild, and tolerant of a broad range of functional groups (78 examples tested, 66 products obtained are unprecedented). As such, it could be viewed as a “click synthesis” of fluoroalkylated isoxazoles. Preliminary mechanistic investigations reveal that this transformation involves an unprecedented cascade sequence, featuring trapping of a carbenoid, generated from reaction of an alkyne and RfCHN2, with a nitrosonium ion. An additional salient feature of this reaction is that no prior formation and transfer of potentially dangerous RfCHN2 is required. Developing a new cascade reaction employing RfCHN2 for the synthesis of other types of fluoroalkylated heterocycles is actively being pursued in this laboratory and will be reported in due course.

Scheme 3. Control Experimentsa

a

R = 4-Ph-Phenyl.

simple mixing of CF3CHN224 and CuI in CHCl3 (Scheme 3a) suggested that Cu-carbene formation is facile in this transformation.25 Second, an isotopically labeled substrate suffered significant loss of deuterium (Scheme 3b), indicating that a metalated alkyne is involved and that a possible reaction pathway involving nitrile oxide is less likely;26 the fact that compounds 12−16 failed to react also suggests that the latter pathway is not involved (Scheme 3c). Third, an independently prepared copper

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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.7b04028. Experimental details, analytical data (PDF) C

DOI: 10.1021/acs.orglett.7b04028 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Accession Codes

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CCDC 1577898, 1577906, and 1577913 contain 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.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Xiao-Wei Zhang: 0000-0002-2262-4143 Xiang-Guo Hu: 0000-0002-5909-2582 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank National Natural Science Foundation of China (21502076), Natural Science Foundation of Jiangxi province (20161BAB213068), and Outstanding Young Talents Scheme of Jiangxi Province (20171BCB23039) for funding, and Dr. Luke Hunter at UNSW for proof reading.

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DOI: 10.1021/acs.orglett.7b04028 Org. Lett. XXXX, XXX, XXX−XXX