Gold‐Catalyzed Oxidative Ring Expansions and Ring Cleavages of Alkynylcyclopropanes by Intermolecular Reactions Oxidized by Diphenylsulfoxide

Abstract

A golden opportunity: A novel gold-catalyzed oxidative ring-expansion of unactivated cyclopropylalkynes using Ph2SO has been developed (see scheme). For substrates bearing a donor group at the cyclopropane ring, preliminary results reveal a distinct cleavage of the cyclopropane unit; such a ring cleavage is further applicable to the synthesis of 2H-pyrans. L=P(tBu)2(o-biphenyl), Tf=triflate. Cyclobutane derivatives are important structural units in many natural products,1, 2 but efficient methods for their synthesis are few compared to those for the preparation of other carbocyclic systems.3, 4 An advance in the synthesis of cyclobutane derivatives involves metal-catalyzed ring-expansions of cyclopropane derivatives, including alkylidenecyclopropanes,5 allenylcyclopropanols6 or alkynylcyclopropanols,7 with selected examples depicted in Scheme 1. Such reported reactions should be classified as isomerization reactions, without introduction of a new functionality.8 Herein, we report a gold-catalyzed oxidative ring-expansion of alkynylcyclopropanes A via hypothetic carbenoids C (Scheme 2); this approach introduces a new ketone functionality in a regioselective manner using an external oxygen donor such as X+O−. Related to this work is a report by Tang and co-workers9 on the synthesis of cyclobutenyl esters F via silver(I)-catalyzed decomposition of diazocarbonyl precursors D (Scheme 2). Our new method is advantageous because substrate preparation is much easier for alkynylcyclopropane derivatives A than for cyclopropyl diazocarbonyl species D. Besides ring-expansions, we have also developed an oxidative ring-cleavage of cyclopropylalkynes using Ph2SO. Metal-catalyzed ring-expansions of certain cyclopropane derivatives. Approach for ring-expansions of certain cyclopropane derivatives. The generation of hypothetic gold α-carbonylcarbenoids from tethered sulfur, amine, imine, and pyridine oxides was reported by the research groups of Toste, Zhang, and Shin, respectively.10–12 These oxidation reactions were performed exclusively with cationic gold catalysts [PR3AuCl]/AgX. Despite their elegant work, these oxygen donors were commonly used to generate gold α-carbonylcarbenoids12 by intramolecular activation of alkynes.13, 14 An intermolecular process is likely perturbed by secondary oxidation of α-carbonylcarbenoid intermediates with these oxides.7b, 15 In Table 1, we selected Ph2SO as the oxygen donor because amine oxide, pyridine oxide,16 and imine oxide were inactive for the oxidation of alkynylcyclopropane 1 a when using [PPh3Au]SbF6. With this sulfoxide (1.0 equiv) and [PPh3Au]SbF6 (5 mol %) in hot 1,2-dichloroethane (DCE, 80 °C, 24 h) we observed an oxidation of species 1 a to give the desired cyclobutenyl ketone 2 a (40 %), diketone 3 a (20 %), and starting material 1 a (35 %; Table 1, entry 1). Poor activity and chemoselectivity were also observed for [IPrAuCl]/AgSbF6 under the same reaction conditions (Table 1, entry 2). Although [P(tBu)2(o-biphenyl)AuCl]/AgSbF6 showed an improved selectivity toward the desired 2 a (48 %) with negligible formation of diketone 3 a, the extent of conversion was moderate (52 %; Table 1, entry 3). We selected AgNTf2 to generate [P(tBu)2(o-biphenyl)Au]NTf2 which improved the yield (52 %) of desired 2 a (Table 1, entry 4). Enhanced yields were obtained with three- and fivefold excess of Ph2SO and afforded 2 a in 70 % and 83 % yields, respectively (Table 1, entries 5 and 6). We speculate that Ph2SO tends to stabilize the AuI complex from decomposition to Au0. AgNTf2 alone failed to catalyze the reaction at all (Table 1, entry 7). When we examined the solvent effects (Table 1, entries 8–10), we found that nitromethane gave the best yield of 2 a (90 %) over a moderate period (12 h) at 80 °C. Brønsted acid TfOH was inactive as a catalysis in this reaction (Table 1, entry 11). Entry Catalyst (5 mol %) Ph2SO [equiv] Solvent t [h] Products (yield [%])[b] 1 a 2 a 3 a 1 [PPh3AuCl]/AgSbF6 1 DCE 24 35 40 20 2 [IPrAuCl]/AgSbF6 1 DCE 24 50 19 29 3 [LAuCl]/AgSbF6 1 DCE 24 48 42 – 4 [LAuCl]/AgNTf2 1 DCE 24 43 52 – 5 [LAuCl]/AgNTf2 3 DCE 24 23 70 – 6 [LAuCl]/AgNTf2 5 DCE 24 – 83 – 7 AgNTf2 5 DCE 24 96 – – 8 [LAuCl]/AgNTf2 5 MeNO2 12 – 90 – 9 [LAuCl]/AgNTf2 5 1,4-dioxane 12 – 62 – 10 [LAuCl]/AgNTf2 5 MeCN 12 98 – – 11 TfOH 5 DCE 24 94 – – Table 2 includes various alkynylcyclopropane derivatives 1 b–1 q bearing either an aryl or an amino group to ensure that attack of Ph2SO occurs only at the Cβ carbon atom. Under optimized conditions, the gold-catalyzed ring-expansions occurred smoothly, without formation of diketone by-products. Entries 1–6 of Table 2 show the effects of para-substituted phenyl substituents; we obtained excellent yields (92–95 %) of resulting cyclobutenyl ketones 2 b–2 c bearing electron-donating groups such as methyl and methoxy. Notably, the catalytic reactions maintained satisfactory efficiency with substrates 1 d–1 g containing electron-withdrawing groups including fluoro, chloro, bromo, and ethoxycarbonyl; the corresponding products 2 d–2 g were obtained in 61–86 % yields after longer reaction times. Such oxidative ring-expansions worked well with phenylalkynylcyclopropanes 1 h–1 m bearing altered meta-substituents comprising methoxy, fluoro, chloro, 2,4-dimethoxy, 2,3-methylenedioxy, and 2-naphthyl groups; their resulting products 2 h–2 m were obtained in 72–95 % yields (Table 2, entries 7–12). This gold catalysis is particularly suitable for aminoalkynylcyclopropanes 1 n–1 q; the reactions were completed within 2–5 hours, and gave desired cyclobutenyl amides in 91–95 % yields (Table 2, entries 13–16). Entry Substrate t [h] Product (yield [%])[b] 1 R=4-MeC6H4 (1 b) 10 2 b (92) 2 R=4-MeOC6H4 (1 c) 8 2 c (95) 3 R=4-FC6H4 (1 d) 15 2 d (86) 4 R=4-ClC6H4 (1 e) 24 2 e (77) 5 R=4-BrC6H4 (1 f) 20 2 f (69) 6 R=4-MeO2CC6H4 (1 g) 24 2 g (61) 7 R=3-MeOC6H4 (1 h) 8 2 h (85) 8 R=3-FC6H4 (1 i) 12 2 i (72) 9 R=3-ClC6H4 (1 j) 15 2 j (72) 10 R=3,5-(MeO)2C6H3 (1 k) 12 2 k (72) 11 R=3,4-(OCH2O)C6H3 (1 l) 8 2 l (95) 12 R=2-naphthyl (1 m) 12 2 m (92) 13 R=TsNMe (1 n) 5 2 n (94) 14 R=TsN(nPr) (1 o) 2 2 o (91) 15 R=MsNMe (1 p) 5 2 p (95) 16 R=MsNBn (1 q) 5 2 q (93) Table 3 shows the applicability of this catalysis to substituted cyclopropylalkynes 4 a and 4 b, which delivered cyclobutenyl ketones 6 a and 6 b in 71 and 76 % yields, respectively. Substrate 4 c underwent smooth reaction with PhArSO (1.0 equiv, Ar=2-MeC6H4) and gave the desired ketone 6 c in 84 % yield. In the case of substituted cyclopropylalkynes 4 d and 4 e, the desired products 6 d and 6 e were obtained in 56 and 61 % yields, respectively. These reaction outcomes resulted from a selective migration of the more substituted CC cyclopropyl bond. Entry Cyclopropane Conditions[a] Product (yield [%])[b] 1 Ar=4-MeOC6H4 (4 a) MeNO2, 8 h 6 a (71) 2 Ar=3,4-(MeO)2C6H3 (4 b) MeNO2, 8 h 6 b (76) 3 Ar=4-MeOC6H4 (4 c) MeNO2, 5 h 6 c (84)[c] 4 R=C6H4CH2 (4 d)[d] MeNO2/DCE[e] 6 d (56) 5 R=n-C6H13 (4 e)[d] MeNO2, 7 h 6 e (61) For curiosity, we extended the use of this catalysis to other arylalkyne derivatives 5 a,b; these oxidation reactions proceeded smoothly using Ph2SO (1.2 equiv), but gave compounds 7 a,b arising from addition of Ph2S to the alkynyl carbon atom adjacent to the aryl group. Similar results were reported by Ujaque, Asensio, and co-workers,10e who proposed a [3,3]-sigmatropic rearrangement rather than carbenoid intermediates to give these addition products. Accordingly, we performed crossover experiments (Scheme 3), which clearly indicate that external sulfides are not the reaction sources for compounds 7 c and 7 c′, thus excluding the intermediacy of α-carbonylcarbeniods C that were hypothesized in Scheme 2. Crossover experiments. For the Ph2SO-oxidation of cyclobutylalkyne species 5 c (Scheme 4), we speculate that initial intermediate G proceeds through a reported [3,3]-sigmatropic rearrangement; this mechanism was supported by computational results.10e We did not observe this rearrangement for tested cyclopropylalkyne substrates including 1 c; we hypothesize that the absence of rearrangement is attributed to a competitive 1,2-cyclopropyl expansion that facilitates cleavage of the OS+ bond to generate cyclobutyl cationic intermediate J and the observed product 2 c. Mechanism for Ph2SO-oxidation of cyclopropylalkyne and cyclobutylalkyne. Cyclopropane compounds are prone to ring-cleavage when the donor and acceptor groups are present as vicinal substituents at the cyclopropane ring.16 As shown in Scheme 5, we observed a new catalysis involving the oxidative ring-cleavage of cyclopropylalkynes 8 using Ph2SO and the gold catalyst that gave 2,4-dien-1-one 9 in 74 % yield. We envisage that this ring-cleavage follows a typical push-pull model,16 as exemplified by species K, giving benzyl cation L with an E configuration that ultimately gave 9 through a retro-6π electrocyclization of 2H-pyran species M. Oxidative ring-cleavage of cyclopropylalkynes 8. Table 4 depicts the use of this oxidative cleavage reaction for an efficient synthesis of 2H-pyrans; we were pleased to find that the same gold catalysis on the functionalized cyclopropylalkynes 10 a–10 g gave the desired 2H-pyrans 11 a–11 g in up to 72 % yield, without a retro-6π ring-opening. For cyclopropylalkyne 10 a, [IPrAuCl]/AgNTf2 gave 2H-pyran 11 a in a better yield (55 %; Table 4, entry 1) than that obtained when [P(tBu)2(o-biphenyl)AuCl]/AgNTf2 was used (19 %; Table 1, entry 2). Such syntheses of 2H-pyran are suitable for substrates 10 b–10 f bearing electron-donating groups including methyl, tert-butyl, and methoxy at the various positions on the phenyl ring, and gave the resulting products 11 b–11 g in 60–72 % yields (Table 4, entries 2–6). The fluoro analogue 10 g gave the desired product 11 g in 65 % yield (Table 4, entry 7). Entry Cyclopropane t [h] Product (yield [%])[b] R R1 1 10 a C6H5 Me 32 (48)[c] 11 a (55, 19[d]) 2 10 b 4-MeC6H4 Me 40 11 b (72) 3 10 c 4-tBuC6H4 Me 40 11 c (62) 4 10 d 4-MeOC6H4 Et 40 11 d (70) 5 10 e 3,4-(MeO)2C6H3 Me 30 11 e (65) 6 10 f 3,5-(MeO)2C6H3 Me 30 11 f (60) 7 10 g 4-FC6H4 Et 35 11 g (65) In summary, we have reported a novel gold-catalyzed oxidative ring-expansion of unactivated cyclopropylalkynes using Ph2SO as an oxidant. This catalysis enables the generation of a ketone group at the alkynyl carbon atom in a regioselective manner, accompanied by expansion of a cyclopropyl ring. Crossover experiments exclude the participation of gold α-carbonylcarbenoid intermediates. For substrates bearing an electron-donor group at the cyclopropane ring, our preliminary results reveal a distinct cyclopropane cleavage arising from the Ph2SO oxidation of the alkyne functionality. Such a ring-cleavage is further applicable to the synthesis of 2H-pyrans, further manifesting the use of this method. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.