Neutral Nazarov‐Type Cyclization Catalyzed by Palladium(0)

Abstract

Joining the circle: The first Pd0 catalyzed Nazarov-type cyclization of diketoesters (see scheme) proceeds in 70 % to 95 % yield under strictly neutral pH conditions. Aryl substitution of the diketoesters is not required, so the reaction shows great versatility and can also proceed with aliphatic substrates. In earlier work we described PdII-catalyzed Nazarov-type cyclizations of α-ethoxy dienones, which proceed through a palladium enolate intermediate.8 These PdII-catalyzed cyclization reactions are initiated through an electrophilic interaction with the metal and are suppressed in the presence of basic ligands, for example, PPh3. We postulated that silyl enol ether 4 b, which was prepared from 4 a (Scheme 1), would also undergo cyclization under PdII catalysis. The complementary polarization of carbon atoms 2 and 6 in 4 a greatly increases the reactivity, so we hoped that cyclization would not be suppressed in the presence of phosphines. This would enable the use of chiral phosphine ligands for an asymmetric catalytic cyclization. The starting materials for this study were prepared according to our published method.7 The Nazarov product 5 was obtained in 65 % or 80 % yield from the treatment of 4 b with PdCl2 or Pd(OAc)2, respectively. However, this cyclization did not take place in the presence of [PdCl2(PPh3)2], thereby precluding our approach to an asymmetric catalytic process. Much to our surprise, exposure of 4 a to 20 mol % [Pd(PPh3)4] in dichloromethane at room temperature led to Nazarov product 5 in 80 % yield. This Pd0-catalyzed reaction proceeds under strictly neutral pH conditions and is the first Nazarov-type cyclization that is catalyzed by a zero-valent metal. The success of [Pd(PPh3)4] as a catalyst indicates a mechanism that is distinct from the PdII catalyzed reaction and suggests the possibility of asymmetric catalysis through the use of chiral phosphine ligands. Palladium-catalyzed cyclizations. Conditions: A: (4 a) 20 mol % [Pd(PPh3)4], 0.1 M CH2Cl2, room temperature, <24 h; 80 % yield. B: (4 b) 20 mol % [PdCl2(MeCN)2], 0.1 M wet acetone, room temperature, approximately 3 d; 65 % yield. C : (4 b) 20 mol % [Pd(OAc)2], 0.1 M DMSO, room temperature, approximately 5 d; 80 % yield. First, we defined the scope of the cyclization leading to racemic products. The reaction was optimized with respect to solvent, concentration, temperature, catalyst, and catalyst load (Table 1). The cyclization was most efficient in DMF and DMSO. In the absence of added PPh3, no reaction took place. Our initial experiments utilized a 1:4 ratio of palladium to phosphine. Decreasing the ratio to 1:2 had no effect on the yield (entries 6, 7 versus 8, 9). In DMSO, we were able to reduce the catalyst load to 0.5 mol % [Pd2(dba)3] (1 mol % Pd atoms) without an appreciable decrease in the rate or yield (entry 11). For less reactive substrates that lack a C6 aryl group, the use of 2 mol % Pd atoms led to a better reaction, so we settled on the conditions that appear in entry 10 of Table 1. No reaction took place in the absence of palladium (entry 14) and only traces of product were observed in the absence of PPh3 (entry 13). Entry Solvent Pd/P t [h] Yield [%] 1[a] CH2Cl2 1:4 120 69 2 (CH2Cl)2 1:4 16 82 3 PhMe 1:4 16 85 4 THF 1:4 9 85 5 MeCN 1:4 9 86 6 DMF 1:4 7 90 7 DMSO 1:4 4 92 8 DMF 1:2 7 91 9 DMSO 1:2 4 92 10[b] DMSO 1:2 4.5 91 11[c] DMSO 1:2 5 91 12[a] DMSO 1:2 40 72 13[b] DMSO 1:0 24 trace 14 DMSO 0:1[d] 24 No rxn 15 DMSO 0:0[e] 24 No rxn Examples of the Pd0-catalyzed Nazarov cyclization with yields. In conclusion, we have described the first Pd0-catalyzed Nazarov-type cyclization of diketoesters. The reaction proceeds in good to excellent yields for a variety of substrates under strictly neutral pH conditions and has a much broader scope than the organocatalyzed process of Equation (1). Aryl substitution at C6 is not required, so the reaction succeeds with aliphatic substrates, including those that fail to cyclize in the presence of organocatalyst 2 (e.g. 8, and 16–20). The mechanism may not involve a pentadienyl cation intermediate, even though the reaction leads to the same products as a Nazarov cyclization. Early indications suggest that the asymmetric version of this process will also be successful. A solution of diketoester 6 (58 mg, 0.20 mmol), [Pd2(dba)3]⋅CHCl3 (2 mg, 2.0 μmol, 1 mol %), and PPh3 (2 mg, 8.0 μmol, 4 mol %) in dry DMSO (1.0 mL, 0.2 M) was stirred at 60 °C. After 4.5 h, the reaction mixture was poured into water (5 mL) and extracted with ether (3×10 mL). The combined ether extracts were washed with water, brine, and dried (anh. Na2SO4). Evaporation and column chromatography (silica gel, 15 % EtOAc in hexanes) produced 7 as a clear oil (53 mg, 91 % yield): 1H NMR (300 MHz, CDCl3): δ=7.26–7.27 (m, 3 H), 7.08–7.11 (m, 2 H), 3.73 (s, 1 H), 3.53 (dq, J=10.8, 7.2 Hz, 1 H), 3.42 (dq, J=10.8, 7.2 Hz, 1 H), 2.23 (dq, J=14.8, 7.4 Hz, 1 H), 2.20 (dq, J=14.8, 7.4 Hz, 1 H), 1.90 (s, 3 H), 0.92 (t, J=7.4 Hz, 3 H), 0.85 ppm (t, J=7.2 Hz, 3 H); 13C NMR (75 MHz, CDCl3): δ=199.8, 169.8, 149.6, 142.8, 136.9, 129.3, 128.1, 127.6, 62.4, 60.8, 55.7, 28.4, 13.4, 12.8, 8.3 ppm; IR (neat): =3342, 1731, 1713, 1660, 1242, 1079 cm−1; MS (EI+): m/z (%): 288 [M+, 100], 242 (23), 215 (35), 145 (61), 143 (75), 115 (54); HRMS (EI+): m/z calcd for C17H20O4: 288.1362 [M+]; found 288.1364. 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. 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