Catalysis of 6π Electrocyclizations

Abstract

The synthetic power of pericyclic reactions has greatly increased with the emergence of catalytic variants. Indeed, catalysis in cycloadditions [1] and sigmatropic rearrangements [2] is now well established. General methods for the catalysis of electrocyclizations, however, have remained elusive, with the notable exception of the Nazarov cyclization.[3] The development of such methods would enable electrocyclizations to occur under milder conditions and create the possibility of catalytic asymmetric variants. Herein, we report the first examples of catalytic 6p electrocyclizations and provide a detailed investigation into the mechanism of these reactions.Experimental and computational studies have shown that the rate of 6p electrocyclizations can be influenced by varying the electronics of the substituents on the triene. [4][5][6][7] Electronwithdrawing groups located in the 2-position of hexatriene systems have been observed to lower their electrocyclization energy barriers, [6,7] sometimes by as much as 10 kcal mol À1 . [7,8] We envisioned exploiting this effect to catalyze 6p electrocyclizations by the coordination of a Lewis acid to a Lewis basic electron-withdrawing group located in the 2-position of a hexatriene system. This coordination should increase the electron-withdrawing effect of the substituent, thereby decreasing the electrocyclization energy barrier. We began our investigations by computationally assessing the viability of this approach in the catalysis of 6p electrocyclizations. Hexatriene systems with methyl ester substituents at all possible positions and orientations were modeled by density functional theory (Figure 1). A proton, serving as the simplest Lewis acid, was bonded to the carbonyl oxygen atom at the lone pair anti to the hexatriene.[9] As seen in Figure 1, these calculations predict a slight increase and decrease of the electrocyclization energy barrier for the (E,Z)-and (Z,Z)-1-carbomethoxy-substituted hexatriene systems (Figure 1 A and B), respectively. Calculations additionally predict a small decrease of the electrocyclization energy barrier for the 3-substituted system (Figure 1 D). However, we found that the electrocyclization energy barrier is predicted to decrease by 10 kcal mol À1 upon protonation of the 2-carbomethoxy-substituted triene system (Figure 1 C). An intrinsic reaction coordinate search in both directions from the protonated electrocyclization transition state of this system suggests that the catalyzed pathway is a concerted process, as no stationary points other than the transition state were located between the protonated triene and protonated cyclohexadiene.

On the Development of Catalytic Carba-6π Electrocyclizations

“…4 A 55-fold rate acceleration was observed for this substrate in the presence of one equivalent of Me 2 AlCl at 28°C. This rate acceleration is significantly larger than the 13-fold rate acceleration observed for hexatriene 1.…”

“…1,1,2,2-Tetrachloroethane, obtained from Sigma-Aldrich, was sparged with N 2 and stored over activated 4 Å molecular sieve pellets overnight prior to use. Sc(OTf) 3 was obtained from Sigma-Aldrich and was dried under vacuum at 150°C for 12 h. Pd(PPh 3 ) 4 and B(C 6 F 5 ) 3 were obtained from Strem Chemicals; Bu 3 SnCl, CsF, DIBAL-H, nBuLi, NaHMDS, trans-cinnamaldehyde, 2,6-di-tert-butyl-4-methylpyridine, Cu(OTf) 2 , Me 3 Al, Me 2 AlCl, BF 3 ·OEt 2 , AlI 3 , TfOH, and 2,6-bis[(4R)-4-phenyl-2-oxazolinyl]pyridine were obtained from Sigma-Aldrich; these reagents were used without further purification. Copper(I) thiophene-2-carboxylate, 6 (iodomethyl)triphenylphosphonium iodide, 16 a-iodocinnamaldehyde (6), 17 abromocinnamaldehyde (9), 18 ethyl 2-tributylstannyl-2-butenoate (15), 4 4-iodo-2-methyl-1-phenyl-1,3-butadiene (18), 4 manganese dioxide, 19 phenylaluminum dichloride, 20 2-tributylstannylpropenol (22), 21 2-tributylstannyl-2-cyclopentenone (33), 4 hexatriene 2, 4 and cyclohexadiene 36, 4 were synthesized according to literature proce- dures.…”

“…A Schlenk flask was charged with 4-tributylstannyl-1-phenyl-1,3-butadiene (5; 6.4 g, 15.3 mmol), a-iodocinnamaldehyde (6; 2.6 g, 10.2 mmol), DMF (300 mL), and Pd(PPh 3 ) 4 (590 mg, 0.51 mmol). To this solution was added copper(I) thiophene-2-carboxylate (2.9 g, 15.3 mmol), after which the reaction mixture was stirred for 10 min, and CsF (3.1 g, 20.4 mmol) was added.…”

“…Synthesized in a fashion analogous to that of hexatriene 7, using 2-tributylstannyl-but-2-enal (17; 50 mg, 0.14 mmol), 4-iodo-2-methyl-1-phenyl-1,3-butadiene (18; 38 mg, 0.14 mmol), DMF (2 mL), Pd(PPh 3 ) 4 …”

“…3 Prior to this, we demonstrated that carba-6π electrocyclizations could be catalyzed with Lewis acids (Scheme 1). 4,5 Using esters (e.g., 1) and ketones (e.g., 2) as Lewis bases and Me 2 AlCl as a Lewis acid, we showed that rate accelerations up to 55-fold could be achieved. Our experimental results were accompanied by theoretical calculations on simple aldehydes, such as 3, which indeed showed that placement of a formyl group in the 2-position should result in significant rate accelerations upon binding of a Lewis acid or a proton.…”