A zinc-catalyzed oxidative reaction of ynamides with phenols and thiophenols: highly site-selective synthesis of versatile α-aryloxy amides and α-arylthio amides

Abstract

A zinc-catalyzed oxidative reaction of ynamides with phenols and thiophenols under mild reaction conditions has been developed, which provides various α-aryloxy amides and α-arylthio amides in moderate to good yields, respectively. Importantly, high chemoselectivity is achieved by such a non-noble metal-catalyzed alkyne oxidation.

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α-Aryloxy carbonyls are highly valuable compounds that can be found in a large number of biologically active molecules (Fig. 1).¹ As a result, a range of synthetic methods have been developed mainly by transition metal-catalyzed insertion of α-diazo carbonyls into the O–H bonds of phenols.^2,3 However, the use of hazardous, not easily accessible and potentially explosive α-diazo carbonyls has severely hampered the further synthetic applications of this methodology. Moreover, it remains challenging to control the chemoselectivity of phenols because of the competitive C–H bond insertion (Scheme 1).^2,4 Therefore, the development of an alternative approach is still highly desirable.

Fig. 1 Selected examples of bioactive α-aryloxy carbonyls.

Scheme 1 Transition metal-catalyzed reaction of phenols with α-diazo carbonyls or ynamides.

In the last few years, gold-catalyzed intermolecular alkyne oxidation by an N–O bond oxidant, presumably involving an α-oxo gold carbenoid intermediate,⁵ has attracted considerable attention because this protocol makes alkynes surrogates of hazardous α-diazo carbonyls in accessing α-oxo metal carbenes.⁶ As a result, this strategy has evolved into a robust and reliable method for the construction of C–C and C–X bonds in a highly stereoselective manner.⁷ Despite these significant achievements, intermolecular alkyne oxidation with external nucleophiles is still rare⁸ and challenging mainly due to the competing background reaction of external nucleophiles with the activated alkynes and the overoxidation of the highly electrophilic carbene center by the very oxidant,⁹ thus generating the unwanted olefin and diketone byproducts, respectively. In our continuing effort on studies of ynamides in organic synthesis,^10,11 we recently disclosed that zinc could also catalyze such an intermolecular alkyne oxidation and, importantly, the undesired over-oxidation could be substantially suppressed in such an oxidative zinc catalysis.¹² Inspired by these results, we envisioned that the synthesis of α-aryloxy amides might be accessed directly through such a Lewis acid-catalyzed reaction of ynamides with phenols (Scheme 1). Herein, we describe the realization of the zinc-catalyzed oxidative reaction of ynamides with phenols with high chemoselectivity, which constitutes a very practical approach to the generation of various α-aryloxy amides. In addition, this zinc-catalyzed ynamide oxidation could also be extended to the highly site-selective synthesis of synthetically useful α-arylthio amides.

Ynamide 1a was employed as the model substrate for our initial study (Table 1). To our delight, the reaction of 1a with PhOH by the use of Zn(OTf)₂ as the catalyst and 2,6-dibromopyridine N-oxide 3a as the oxidant in DCE at 80 °C could afford the desired α-phenoxy amide 2a in 61% yield albeit with a small amount of hydration by-product 2ab (entry 1). Importantly, neither C–H functionalization of phenol nor a direct background reaction of PhOH with 1a was observed. The subsequent screening of other N-oxides such as 2,6-lutidine N-oxide 3b and 3,5-dichloropyridine N-oxide 3c only led to diketone 2aa as the main product (entries 2 and 3). In addition, the influence of different Lewis acids was also investigated but it failed to improve the yield (entries 4–6). Finally, it was found that a slightly better result could be obtained at 40 °C (entries 7 and 8), and the desired 2a was formed in 69% yield in the presence of 20 mol% Zn(OTf)₂ (entry 8). Notably, diketone 2aa was formed as the major product if catalyzed by typical gold catalysts such as Ph₃PAuNTf₂ and Cy-JohnPhosAuNTf₂ (entries 9 and 10), and no 2a formation was observed in the absence of the catalyst (>95% of 1a remained unreacted). It should be mentioned that the use of 1.0 equiv. of PhOH led to significant formation of 2ab (entry 11).

Table 1 Optimization of reaction conditions^a

Entry	Catalyst	Oxidant (R)	Yield^b (%)
			2a	2aa	2ab
a Reaction conditions: [1a] = 0.10 M; DCE: 1,2-dichloroethane. b Estimated by ^1H NMR using diethylphthalate as an internal reference. c DCM, 40 °C, 7 h. d 20 mol% Zn(OTf)2 was used, DCM, 40 °C, 4 h. e 5 mol% gold catalyst was used. f 1.0 equiv. of PhOH was used.
1	Zn(OTf)2	3a (2,6-Br2)	61	<1	9
2	Zn(OTf)2	3b (2,6-Me2)	23	35	10
3	Zn(OTf)2	3c (3,5-Cl2)	20	75	<1
4	Yb(OTf)3	3a (2,6-Br2)	56	<1	12
5	Sm(OTf)3	3a (2,6-Br2)	55	<1	14
6	Y(OTf)3	3a (2,6-Br2)	50	<1	15
7^c	Zn(OTf)2	3a (2,6-Br2)	66	<1	<5
8^d	Zn(OTf)2	3a (2,6-Br2)	69	<1	<5
9^e	Ph3PAuNTf2	3a (2,6-Br2)	<1	85	9
10^e	CyJohnPhosAuNTf2	3a (2,6-Br2)	<1	75	13
11^d^,^f	Zn(OTf)2	3a (2,6-Br2)	50	<1	15

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With the optimized reaction conditions in hand, the scope of this oxidative zinc catalysis was explored (Table 2). Ynamides with different protecting groups were first examined (entries 1–3), and the Bs-substituted ynamide gave the best result (entry 3). Meanwhile, different aryl-substituted ynamides (R² = aryl) also worked well to yield the desired α-aryloxy amides 2f–2j smoothly (entries 6–10). In the case of styryl-substituted ynamide, the reaction afforded α,β-unsaturated amide 2k as a single isomer in 68% yield (entry 11). In addition, various substituted phenols with both electron-donating and -withdrawing substituents are applicable to the present reaction, thus delivering the corresponding 2l–2o in 77–81% yields (entries 12–15). Importantly, no diketone formation was detected in all the cases. Moreover, all these reactions are chemospecific, leading to the α-aryloxy amides as the sole product. Attempts to extend the reaction to aliphatic-substituted ynamides only resulted in the formation of α,β-unsaturated amides.¹³ It is to be noted that the reaction proceeded with a low efficiency (<10% yield) on employing ethyl phenylethynyl ether instead of ynamides under the optimal reaction conditions. To test the practicality of the current catalytic system, a gram-scale reaction of 1c and PhOH was carried out in the presence of 10 mol% Zn(OTf)₂, and the desired 2c was obtained in 72% yield (entry 3).

Table 2 Reaction scope with different phenols and ynamides 1^a

a Reactions run in vials; [1] = 0.10 M; isolated yields are reported. b 5.0 mmol scale, 10 mol% Zn(OTf)₂ was used, 9 h.

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We then wondered whether this oxidative zinc catalysis is applicable to thiophenols. As outlined in Table 3, the reaction proceeded smoothly with various thiophenols and ynamides under the optimal reaction conditions (2 equiv. of ArSH, 2 equiv. of 3b, 10 mol% of Zn(OTf)₂, 4 ÅMS, DCE, 80 °C, 3 h).¹⁴ Besides the tosyl group, Ms and Bs protected ynamides were also suitable substrates for this transformation, thus delivering the corresponding α-arylthio amides 4b (66%) and 4c (62%), respectively (entries 2 and 3). The reaction also worked satisfactorily with various substituted ynamides, providing the desired 4d–4g in good yields (entries 4–7). In addition, thiophenols bearing both electron-donating and -withdrawing substituents turned out to be suitable substrates as well, leading to the desired 4h–4l in moderate to good yields (entries 8–12). Finally, a gram scale synthesis was also feasible (entry 1). Again, neither C–H functionalization of thiophenols nor overoxidation of ynamides was observed in all the cases. Thus, this protocol provides a highly efficient and practical route for the construction of the valuable α-arylthio carbonyl compounds.¹⁵ Notably, the use of ethyl phenylethynyl ether instead of ynamides under the optimal reaction conditions only resulted in the formation of the hydration product (85% yield).

Table 3 Reaction scope with different thiophenols and ynamides 1^a

a Reactions run in vials; [1] = 0.10 M; isolated yields are reported. b 5.0 mmol scale, 5 mol% Zn(OTf)₂ was used, 9 h.

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Attempts to expand this chemistry to aliphatic alcohols or thiols only led to the formation of the corresponding amides in low yield (<50% yield), and further studies in this direction are currently ongoing. Besides phenols and thiophenols, this oxidative zinc catalysis could also be extended to anilines by the employment of 2-bromopyridine N-oxide as the oxidant, leading to the corresponding α-amino amide 5 with serviceable yield (eqn (1)).

The synthetic utility of this protocol was demonstrated by the transformation of the above α-phenoxy amide 2c. As depicted in eqn (2), the amide 2c could be readily transformed into the corresponding β-phenoxy alcohol 6a in 76% yield by NaBH₄ reduction. In addition, treatment of amide 2c with NaOMe could afford the synthetically useful α-phenoxy ester 6b in 80% yield.

Based on the above results and our previous work^12,13 on the oxidative zinc catalysis, a tentative mechanism is proposed in Scheme 2. The pyridine N-oxide first attacked the Zn-activated alkyne leading to the generation of the Zn-substituted alkene A, which could then be converted into B through an S_N2′ pathway.^7e,g Finally, the intermediate B would undergo protodemetalation to furnish the final product 2a along with the regeneration of the zinc catalyst. The formation of by-product 2aa might be rationalized by an intermolecular secondary oxidation through a similar S_N2′ pathway.

Scheme 2 Plausible mechanism of the formation of 2a.

In summary, we have developed a novel zinc-catalyzed oxidative reaction of ynamides with phenols and thiophenols, allowing the efficient synthesis of various α-aryloxy amides and α-arylthio amides, respectively. Importantly, high chemoselectivity is achieved by such a non-noble metal-catalyzed alkyne oxidation. Besides, the use of readily available substrates, a simple procedure, and mild reaction conditions makes this method potentially useful in organic synthesis. Further investigations into the asymmetric version of the current protocol are in progress in our laboratory.

We are grateful for financial support from the National Natural Science Foundation of China (21272191 and 21572186), the Natural Science Foundation of Fujian Province for Distinguished Young Scholars (2015J06003), the President Research Funds from Xiamen University (20720150045), NFFTBS (J1310024), and XMU Undergraduate Innovation and Entrepreneurship Training Programs (201510384008).

Notes and references

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14. For details, please see the ESI.†.
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Footnotes

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6qo00169f

‡ These authors contributed equally to this work.

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