Gold-Catalyzed 1,3-Transposition of Ynones

Abstract

An efficient, regioselective gold-catalyzed 1,3-transposition reaction of ynones and diynones has been developed. It was found that stereoelectronic (interrupted conjugation) and electronic (extended conjugation) factors could efficiently govern the regioselectivity of this thermodynamically controlled transformation. The produced conjugated diynones were efficiently transformed into diverse alkyne-substituted five- and six-membered heterocycles.

Transition-metal-catalyzed transposition reactions are useful tools in organic synthesis. For instance, the metal-catalyzed 1,3-transposition of allylic alcohols is a well-established method (Scheme 1, eq 1) that has been successfully employed in the synthesis of natural products.¹ Likewise, the metallotropic 1,3-shift has been used for assembly of acyclic, cyclic, and polycyclic compounds (Scheme 1, eq 2).² Herein we report an efficient gold-catalyzed 1,3-transposition of ynones (Scheme 1, eq 3).

Scheme 1. Metal-Catalyzed 1,3-Transposition of Functional Groups.

During our ongoing studies of transition-metal-catalyzed cycloisomerization of ynones toward heterocycles,³ we found an interesting transformation: ynone 1, which in the presence of a copper catalyst underwent a selective cycloisomerization reaction into furan A, under palladium catalysis produced detectable amounts of regioisomeric ynone B (Scheme 2, eq 4). In fact, unselective low-yielding transposition reaction of ynones has been reported previously.⁴ Thus, in the presence of a Pt catalyst, ynone 2 was transformed into a mixture of transposed ynone C and isomeric hydrochlorinated products D and E (Scheme 2, eq 5). The low efficiency of this reaction was attributed to an equilibrium between 2 and C.⁴ We thought that the development of regioselective and efficient 1,3-transposition of ynones would be worthwhile⁵ since this moiety is widely used as an intermediate in the total synthesis of natural products⁶ and in the construction of a variety of heterocyclic scaffolds.⁷ First, in order to identify the factors that would allow control of the position of the thermodynamic equilibrium between differently substituted ynones, we computed the ground-state energies of 3 and 4 (Scheme 3).⁸ It was found that 3, in which the phenyl ring is conjugated with the carbonyl group, is nearly as stable as the transposed product 4 (0.1 kcal/mol;⁹ Scheme 3), thus predicting a 44:56 product ratio.¹⁰ We also found that steric (small vs big groups) and electronic (electron-withdrawing vs electron-releasing groups) factors at R¹ and R² of ynone F do not have significant effects on the stability of the isomers and consequently would not control the regioselectivity of this reaction (Scheme 3).¹⁰ Next, we thought that incorporation of an o-tolyl group (5a, R = Me) would force the carbonyl group out of plane, thus preventing its conjugation with the phenyl moiety and hence destabilizing 5a. In contrast, there would be conjugation between the phenyl ring and the triple bond in regioisomer 6a. Therefore, shifting the equilibrium toward the more stable isomer 6a by engaging this stereoelectronic handle seemed feasible. Indeed, computations validated this hypothesis, showing a dihedral angle of 25° in 5a and thus predicting the release of ca. 5 kcal/mol upon transposition, which would ensure the full conversion of ynone 5a to thermodynamically more stable isomer 6a (Scheme 3).

Scheme 2. Non-regioselective 1,3-Transposition of Ynones.

Conditions: (a) CuI (5 mol %), DMA/Et₃N (7:1), 100 °C. (b) Pd₂(dba)₃ (5 mol %), TDMPP (20 mol %), PTSA (50 mol %), DMF, 80 °C. (c) PtCl₄ (10 mol %), EtOAc, reflux. TDMPP = Tris(2,5-dimethoxyphenyl)phosphine, PTSA = p-toluenesulfonic acid.

Scheme 3. Computational Predictions of Regioselectivity in the 1,3-Transposition Reaction of Ynones.

Inspired by computational predictions, we examined the transposition reaction of 5a in the presence of different metals. Our optimization study⁸ indicated that the use of a cationic gold catalyst such as chloro[tris(2,4-di-tert-butylphenyl)phosphite]gold with tetrafluoroborate as the counterion¹¹ was the best choice for efficient transformation of 5a into the transposed isomer 6a. With the optimized conditions in hand, we examined the scope of the o-tolyl-type stereoelectronic handle on the transposition of differently substituted 1,3-ynones (Table 1). Thus, ynones 5a–c bearing acyclic substituents reacted smoothly to produce the rearranged products 6a–c (entries 1–3). As expected (vide supra),¹⁰ the reaction of ynone 5d (R = H) was not regioselective, producing a 36:64 mixture of isomers 6d and 5d (entry 4). However, the analogous substrate 5d′ (R = Me) afforded transposed isomer 6d′ exclusively in 91% yield. Likewise, substrates 5e and 5f bearing three- and six-membered carbocycles afforded the transposed products in good to excellent yields (entries 5 and 6). Phenyl- and thiophenyl-substituted ynones 5g and 5h were also competent reactants in this transformation (entries 7 and 8). As expected, the methyl substituent at the ortho position of the phenyl ring of 5i governed the regioselectivity of the transposition reaction over the meta-substituted phenyl to produce product 6i in excellent yield (entry 9). Transposition of F- and OMe-containing ynones proceeded uneventfully as well (entries 10 and 11). As expected, not only a methyl substituent but also a variety of other groups at the ortho position of the ynone phenyl group were effective in imposing the controlling stereoelectronic effect. Thus, aryl ynones 5l–q bearing phenyl (entry 12), trimethylsilyl (entry 13),¹² halogen (entries 14–16), and naphthyl (entry 17) groups showed excellent regioselectivity, affording the rearranged products 6l–q exclusively in high to excellent yields. Notably, 3-methylated indole 5r could also be efficiently employed in this reaction to produce 6r (entry 18).¹³

Table 1. Substrate Scope in the Gold-Catalyzed 1,3-Transposition of Ynones.

^aIsolated yields.

^bOvernight at rt.

^c3 h at 70 °C; 6d:5d = 51:49.

^dIPrAuCl (5 mol %) + AgSbF₆ (5 mol %) was used as the catalyst.

Having established the stereoelectronically controlled transposition of 1,3-ynones, we wondered whether extended conjugation could possibly serve as a regioselectivity-controlling factor in this transformation. If so, then easily accessible skipped diynones 7 could undergo the 1,3-transposition reaction in the presence of a gold catalyst to give valuable conjugated isomers 8 (Table 2). Computations predicted this electronic factor to be overwhelming, as it would release ca. 8 kcal/mol toward the thermodynamically more favored conjugated isomer 8a.¹⁰ To our delight, 7a reacted smoothly under the standard conditions to afford 8a in 88% yield (entry 1). Likewise, diynone 7b possessing a phenyl group was smoothly transposed into 8b (entry 2). Naturally, we were next interested in the development of a 1,3-transposition reaction leading toward synthetically more attractive unsymmetrical conjugated diynones. First, we speculated that when diynone 7c bearing an o-tolyl moiety was employed, the stereoelectronic effect (vide supra) would render a selective transposition toward the phenyl group, thus forming 8c as the sole product (entry 3). However, when this reaction was performed at room temperature, both alkyne moieties of 7c were involved in the transposition reaction to produce a 58:42 mixture of rearranged products 8c and 8c′. Gratifyingly, at elevated temperature the thermodynamically more stable isomer 8c was obtained exclusively. Next, we speculated that employing a skipped diynone possessing a bulky triisopropylsilyl (TIPS) terminus would impose steric hindrance at the proximal triple bond, and as a result, the distal alkyne would selectively be activated by the gold catalyst toward the 1,3-transposition reaction. Indeed, skipped diynones 7d–h efficiently afforded the unsymmetrical conjugated diynones 8d–h bearing a variety of alkyl, aryl, and heteroaryl substituents (entries 4–8).

Table 2. Substrate Scope in the Gold-Catalyzed 1,3-Transposition of Skipped Diynones.

^aIsolated yields.

^bThe yield of the reaction performed at 100 °C is shown.

^cTrimethylsilyl and triethylsilyl analogues of the 1,3-ynone did not work under the optimized conditions, and the substrates were recovered intact.

To determine whether this transformation proceeds with skeletal rearrangement, which is often observed in gold-catalyzed transformations,^11d the C1-labeled ynone 9 was prepared and subjected to the standard reaction conditions (Scheme 4). Thus, the C1-1,3-transposed isomer 10 possessing the labeled carbon at the alkyne moiety was formed. This observation indicates that the ynone transposition reaction does not involve C–C bond disconnection and most likely proceeds through the intermediacy of a four-membered heterocycle i.⁴

Scheme 4. Isotope-Labeling Experiment.

Finally, after developing the regioselective gold-catalyzed 1,3-transposition reaction, we examined the possibility of using the obtained conjugated diynones to synthesize heterocyclic scaffolds bearing an alkyne moiety (Scheme 5). Indeed, the addition of hydrazine to diynone 8e afforded pyrazole 11 in moderate yield,¹⁴ and the cycloaddition reaction of 8f with sodium azide produced triazole 12 in 71% yield;^7b also, the reaction of 8f with benzamidine hydrochloride furnished C4-alkynylated pyrimidine 13,^7c,7d and the condensation reaction of 8f with ethyl acetoacetate and ammonium acetate produced alkynylated pyridine 14 in 78% yield.^7c

Scheme 5. Synthetic Utility of the Obtained Diynones.

Conditions: (i) NH₂NH₂ (3.0 equiv), MeCN, rt. (ii) NaN₃ (1.1 equiv), DMF, rt. (iii) benzamidine hydrochloide (1.2 equiv), Na₂CO₃ (2.4 equiv), MeCN/H₂O = 7:1, 80 °C. (iv) Ethyl acetoacetate (1.7 equiv), NH₄OAc (5.0 equiv), EtOH, reflux.

In summary, we have developed an efficient thermodynamically controlled 1,3-transposition of ynones and diynones. We found that stereoelectronic (interrupted conjugation) and electronic (extended conjugation) effects can efficiently control the regioselectivity of this reaction. The synthetic usefulness of obtained unsymmetrical diynones was demonstrated by efficient synthesis of various five- and six-membered heterocyclic scaffolds possessing an alkyne moiety.

Supporting Information Available

Experimental procedures and compound characterization data. This material is available free of charge via the Internet at http://pubs.acs.org.

The authors declare no competing financial interest.

Funding Statement

National Institutes of Health, United States