Metal‐Catalyzed [2+2+1] Cycloadditions of 1,3‐Dienes, Allenes, and CO (2006)

Closing the circle: RhI-catalyzed [2+2+1] cycloadditions are achieved under mild reaction conditions and in good to excellent yields with catalyst loading as low as 0.1 mol %. The diene–allenes react selectively with the proximal double bonds of the allene and diene units, thus allowing for a variety of substitutions. DCE=1,2-dichloroethane, TFE=2,2,2-trifluoroethanol, Ts=tosyl. Step economy is a preeminent goal of synthesis.1 It influences the length, efficiency, cost, time, separation, and environmental impact of a synthesis. Step economy is favored by the use of single, serial, or multicomponent reactions that proceed in one operation with a great increase in target revelant complexity. The design or discovery of such reactions is thus critical to extending the practical reach of organic synthesis. Toward this end, we have directed effort at the identification of new metal-catalyzed reactions, especially those which are forbidden or difficult to achieve in the absence of a catalyst. This program has thus far produced several new two-, three-, and four-component reactions, including [4+4],2 [4+2],3 [5+2],4 [6+2],5 [5+2+1],6 [2+2+1],7 [4+2+1],7a and [5+1+2+1]8 cycloadditions. Herein, we report the first examples of the [2+2+1] cycloaddition reaction of diene–allenes and CO and preliminary examples of acceleration of this process by Brønsted acids. RhI-catalyzed cycloisomerization reaction of alkene–allenes. Ts=tosyl. Under the optimal conditions found for the analogous [2+2+1] cycloaddition reaction of diene-enes,7c diene–allene 1 provides the [2+2+1] and the [4+2] cycloadducts 2 and 3 upon treatment with a catalytic amount of a RhI complex in 1,2-dichloroethane (DCE) at 80 °C under one atmosphere of CO (Scheme 2). It is noteworthy that diene–allenes give high yields of the [4+2] product in the absence of CO.15 Exploration of the reaction conditions revealed that a decrease in reaction temperature from 80 °C to room temperature led to the exclusive formation of the [2+2+1] product 2, which was structurally assigned by X-ray crystallographic analysis. Initial results and temperature effects for the competing [2+2+1] and [4+2] cycloaddition reactions. A brief survey of different RhI complexes indicated that [{RhCl(CO)2}2] is the best catalyst of those examined (Table 1, entries 1–3). The nature of the solvent had a substantial effect on the efficiency of the reaction. Poor-to-moderate yields were obtained and long reaction times were required when toluene, dioxane, and acetonitrile were used, whereas excellent yields were obtained when the reaction was carried out in either DCE, methanol, or 2,2,2-trifluoroethanol (TFE; entries 1, 4–8). Significantly, a dramatic increase in the reaction rate was observed with TFE.16 Gratifyingly, when the catalyst loading was lowered to 0.1 mol % and the concentration in TFE was increased to 0.5 M, an excellent yield of 2 was obtained (entry 9). Entry Catalyst Solvent t [h] Yield of 2 [%][b] 1 [{RhCl(CO)2}2] DCE 7 99 2 [Rh(naph)(cod)]SbF6 DCE 1.5 32 3 [{RhCl(dppb)}2] DCE 32 80 4 [{RhCl(CO)2}2] toluene 24.5 38 5 [{RhCl(CO)2}2] dioxane 21.5 64 6 [{RhCl(CO)2}2] CH3CN 45 77 7 [{RhCl(CO)2}2] MeOH 12 96 8 [{RhCl(CO)2}2] TFE 0.25 92 9 [{RhCl(CO)2}2] TFE[c] 8 97 Intrigued by the rate enhancement observed with TFE, we wondered whether this effect could be due to the acidity of the solvent, as the observed trend correlates poorly with the corresponding dielectric constants or dipole moments of the solvents used. To test this hypothesis, the effect of adding acids to the [2+2+1] cycloaddition reaction of 1 was investigated (Table 2).17 This study revealed that the addition of acid provides a rate enhancement and, with the exception of para-toluenesulfonic acid (TsOH; the most acidic of the acids surveyed), has a negligible effect on the yield of the [2+2+1] cycloaddition reaction. The fastest reactions were obtained when the reaction was carried out in DCE in the presence of 14 equivalents of phenol (entry 7) or in TFE (entry 2). For practical reasons, including avoiding the need to separate phenol from the product at the end of the reaction, TFE was chosen as the solvent in the initial studies on the scope of this new [2+2+1] cycloaddition. Entry Solvent Acid (equiv) t [h] Yield [%] 1 DCE none 7 99 2 TFE none 0.25 92 3 DCE TsOH (0.05) 1.3 81 4 DCE AcOH (6) 4 93 5 DCE AcOH (100) 2.5 96 6 AcOH none 2 93 7 DCE PhOH (14) 0.25 94 8 DCE TFE (14) 2 95 The [2+2+1] cycloaddition reaction of diene–allenes that vary in diene and allene substitution and type of tether was examined next (Table 3). In all cases, reaction at the proximal double bond of the allene was observed. Me, H, and iPr substitution at the 2-position of the diene is well tolerated; however, approximately 10–25 % of the olefin isomer was observed for H substitution.18 Entries 1–3 indicate that the presence of heteroatoms in the tether has no deleterious effect on the efficiency of the reaction. The [2+2+1] cycloaddition reaction of substrate 9, which has a terminally methyl-substituted allene, gave both diastereomers 10 and 11. When this reaction was carried out in TFE, only a 39 % overall yield was obtained (entry 5); however, a much cleaner and higher-yielding process (81 %) was obtained when the reaction was carried out in DCE at a concentration of 0.05 M (entry 6). The [2+2+1] cycloaddition reaction of 12, which is substituted with the larger tBu group, can be carried out in TFE in an excellent overall yield of 94 % (entry 7). Initial attempts to carry out the [2+2+1] cycloaddition reaction of diene–allene 15 in either TFE or DCE were unsuccessful. It was found that when the temperature and CO pressure were increased and the concentration in DCE was decreased, a 43 % yield of the [2+2+1] product and a 19 % yield of the [4+2] product (entry 8) were obtained. Entry Diene–allene Conditions[a] t [h] Product Yield 1 A 8 97 2 B 1.5 97 (2.9:1) 3 C 0.3 92 4 D 1.5 81 5 E 16 39 (4.6:1) 6 F 24 81 (1.2:1) 7 B 24 94 (7.5:1) 8 G 1.5 62 (2.3:1) In conclusion, the first examples of the diene–allene [2+2+1] cycloaddition reaction are reported, thus providing an efficient, selective, and operationally facile route (room temperature, 1 atm CO) to highly substituted alkylidenyl cyclopentanones. The reaction is chemoselective with respect to the allene as the proximal olefin is targeted. The use of the diene leads exclusively to the [2+2+1] cycloadduct instead of the product from the carbocyclization reaction, which has been reported with alkene–allenes (Scheme 1), thus resulting in a process of mechanistic and synthetic utility. An additional point of significance is that the reaction is accelerated in several cases when performed in TFE or in the presence of certain Brønsted acids, thus suggesting co-catalysis possibly involving CO protonation in the migratory-insertion step. Further investigations on this and other [m+n+o] cycloaddition reactions of dienes are ongoing.19 Typical procedure: Preparation of the catalyst solution: [{RhCl(CO)2}2] was weighed into an oven-dried test tube equipped with a magnetic stir bar, and TFE was added by syringe to make a 0.005 M solution. The test tube was capped with a septum, and the solution was stirred under a balloon of CO vented to a bubbler for 45 min. Diene–allene 1 (21 mg, 0.063 mmol) was weighed into an oven-dried test tube equipped with a magnetic stir bar, TFE (0.114 mL) was added by syringe, and the test tube was capped with a rubber septum. The solution was stirred under a balloon of CO vented to a bubbler for 30 min. The catalyst solution ([{RhCl(CO)2}2]; 0.0127 mL, 0.000063 mmol) was added by syringe, and the reaction mixture was stirred under a balloon of CO for 8 h. The solution was concentrated by rotary evaporation, and the residue was purified by column chromatography on silica gel (EtOAc/CH2Cl2 2:98). The product-containing fractions were combined and concentrated to give 2 (20.6 mg, 97 %) as a white solid; the compounds were chromatographically homogeneous. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2006/z600300_s.pdf or from the author. 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.