Chapter II: Development of an Ene-Allene and Allene [2+2+2] Cycloaddition
B. Catalyst Optimization
All aspects of the catalyst system were analyzed to optimize the reaction. Initial experiments evaluated numerous solvents, reaction temperatures, silver salt additives, ligands, and reaction stoichiometries. These optimization efforts are summarized in Table 1. Reactions with phenyl allene are very difficult to monitor accurately, but, cycloadducts derived from ethyl allenoate produce large differences in Rf. Therefore, optimization reactions were performed with ethyl allenoate.
The initially used conditions of 5 eq of allenoate with respect to substrate were used because ethyl allenoate undergoes competitive side reactions to form a mix of uncharacterized side products.107 Thus, using an excess was necessary to ensure complete consumption of the substrate. Slow addition of the either component leads to lower conversions and significant amounts of substrate dimer (Entries 2 and 3). Dimerization occurs when the concentration of substrate is significantly higher than that of the added allene. By design, the concentration of allenoate is always low when it is added slowly. A low concentration of allenoate also occurs when the ene-allene is added slowly because the decomposition of allenoate is rapid in the absence of ene-allene. Thus, slow addition of either reaction component results in a decrease in yield. The concentration of the reaction is also important (not shown in the table). Reactions are run with an initial ene-allene concentration of 0.04 M. At lower concentration the reactions require much more time and at higher concentrations substrate dimerization becomes problematic. All subsequent reactions were performed at 0.04M by adding a solution of substrate and allenoate to the catalyst immediately prior to heating.
When the reaction is performed at higher temperature in toluene a better yield is obtained (Entry 2). Decreasing the equivalents of allene from five to 1.25 equivalents provided a decrease in both yield and reaction time. Despite the decrease in yield, subsequent reactions were conducted with 1.25 equivalents due to the shorter reaction times and better atom economy. Substituting AgBF4 for AgOTf
Table 1. Representative Optimization Experiments.
Entry [Rh], mol % [Ag], mol % Ligand, mol % eq Allene Solvent Temp
(°C) Time (h)
Isolated Yield (%)
1 [Rh(COD)Cl]2, 5 AgBF4, 20 BINAP, 12 5 THF 60 2 35
2 [Rh(COD)Cl]2, 5 AgBF4, 20 BINAP, 12 5a Toluene 80 6 25
3 [Rh(COD)Cl]2, 5 AgBF4, 20 BINAP, 12 5b Toluene 80 24 Trace
4 [Rh(COD)Cl]2, 5 AgBF4, 20 BINAP, 12 5 Toluene 100 2 50
5 [Rh(COD)Cl]2, 5 AgBF4, 20 BINAP, 12 1.25 Toluene 100 1.5 31
6 [Rh(COD)Cl]2, 5 AgOTf, 20 BINAP, 12 1.25 Toluene 100 1.5 43
7 [Rh(COD)Cl]2, 5 None BINAP, 12 1.25 Toluene 100 3 37c
8 [Rh(COD)Cl]2, 5 AgOTf, 20 BINAP, 12 5 Toluene 60 1.5 30c
9 [Rh(COD)Cl]2, 5 AgOTf, 20 BINAP, 12 1.25 DCE 80 3.5 27c
10 [Rh(COD)Cl]2, 2.5 AgOTf, 10 BINAP, 6 1.25 Toluene 100 1.5 48
11 [Rh(COD)Cl]2, 1 AgOTf, 4 BINAP, 2.4 1.25 Toluene 100 12 36 c
12 [Ir(COD)Cl]2, 2.5 AgOTf, 10 BINAP, 6 1.25 Toluene 100 1.5 0
13 [Rh(COD)Cl]2, 2.5 AgSbF6, 10 BINAP, 6 1.25 Toluene 100 1.5 40
14 [Rh(COD)Cl]2, 2.5 AgPF6, 10 BINAP, 6 1.25 Toluene 100 1.5 46
15 [Rh(COD)Cl]2, 2.5 AgOTf, 5 BINAP, 6 1.25 Toluene 100 1.5 57
16 [Rh(COD)Cl]2, 2.5 NaBArF,5 BINAP, 6 1.25 Toluene 100 1.5 34
17 [Rh(COD)Cl]2, 2.5 AgNTf2, 5 BINAP, 6 1.25 Toluene 100 1.5 40
18 [Rh(COD)Cl]2, 2.5 AgOTs, 5 BINAP, 6 1.25 Toluene 100 1.5 38
19 [Rh(COD)Cl]2, 2.5 AgTFA, 5 BINAP, 6 1.25 Toluene 100 1.5 NDd
20 [Rh(COD)Cl]2, 2.5 AgClO4, 5 BINAP, 6 1.25 Toluene 100 1.5 NDd
21 [Rh(COD)Cl]2, 2.5 AgAsF6, 5 BINAP, 6 1.25 Toluene 100 1.5 NDd
22 [Rh(COD)Cl]2, 2.5 AgOTf, 5 BINAP, 10 1.25 Toluene 100 1.5 52
23 [Rh(COD)Cl]2, 2.5 AgOTf, 5 BINAP, 6 1.25 Trifluorotoluene 100 12 43
24 [Rh(COD)Cl]2, 2.5 AgOTf, 5 BINAP, 6 1.25 DCE 100 3 41
25 [Rh(COD)Cl]2, 2.5 AgOTf, 5 BINAP, 6 1.25 9:1 Toluene/DCE 100 3 51
26 [Rh(COD)Cl]2, 2.5 AgOTf, 5 BINAP, 6 1.25 Mesitylene 100 3 59
27 Rh(PPh3)3Cl, 5 None None 1.25 Toluene 100 12 0
28 [Rh(CO)2Cl]2, 2.5 None PPh3, 11 1.25 Toluene 100 12 0
29 [Rh(COD)Cl]2, 2.5 AgOTf, 5 Segphos, 6 1.25 Toluene 100 12 23
30 [Rh(COD)Cl]2, 2.5 AgOTf, 10 o-tolyl-BINAP, 6 1.25 Toluene 100 12 39
31 [Rh(COD)Cl]2, 2.5 AgOTf, 10 MONOPHOS, 12 1.25 Toluene 100 12 0
32 [Rh(COD)Cl]2, 2.5 AgOTf, 5 P-Phos, 6 1.25 Toluene 100 12 41
33 [Rh(COD)Cl]2, 2.5 AgOTf, 5 MeDUPHOS, 6 1.25 Toluene 100 12 NR
34 [Rh(COD)Cl]2, 2.5 AgOTf, 5 Xylyl-BINAP, 6 1.25 Toluene 100 2 51
35 [Rh(COD)Cl]2, 2.5 AgOTf, 5 BINAP, 6 2 Toluene 100 2 63
36 [Rh(COD)Cl]2, 2.5 AgOTf, 5 H8-BINAP, 6 2 Toluene 100 2 64
37 [Rh(nbd)Cl]2, 2.5 AgOTf, 5 H8-BINAP, 6 2 Toluene 100 7 61
38 [Rh(coe)2Cl]2, 2.5 AgOTf, 5 H8-BINAP, 6 2 Toluene 100 2 76
39 [Rh(C2H4)2Cl]2, 2.5 AgOTf, 5 H8-BINAP, 6 2 Toluene 100 1.5 79
“Standard Conditions”
40 [Rh(COD)2][BF4], 10 AgBF4, 20 BINAP, 12 1.25 Toluene 100 1.5 32
41 None AgOTf4, 20 BINAP, 12 1.25 Toluene 100 12 0
42 [Rh(COD)Cl]2, 5 AgOTf4, 20 None 1.25 Toluene 100 12 0
aAllene added over the course of 3 h via syringe pump. bSubstrate added to over the course of 24 h via syringe pump. cIncomplete conversion. dCrude NMR indicated that the yield of product was less than 10%.
gives an increase in yield, whereas reactions without silver salts give poorer conversions, require longer times, and elicit a decrease in yield (Entries 6 and 7). Reactions performed at a lower temperature (60 °C) or in an additional solvent (DCE) provided lower yields of the desired cycloadduct (Entries 8 and 9) so experiments were continued in toluene at 100 °C. Decreasing the catalyst loading from 10 mol % total [Rh] to 5 mol % gave a surprisingly large increase in yield, but reactions with lower loadings gave lower conversions and yields (Entries 10 and 11). The origin of the increase in yield is not well understood because control experiments indicate that the product is stable under the reaction conditions.
Because reactions in which AgOTf is used in place of AgBF4 gave higher yields, a more extensive counterion screen was conducted (Entries 16 – 21), but none provided higher yields than what is attained using AgOTf. Increasing the amount of the bidentate ligand slowed the reaction but did not increase the yield. A short solvent screen was also conducted because prior experiments showed a change in solvent typically influenced the yield. However, reactions in trifluorotoluene, DCE, and 9:1 toluene/DCE did not improve the yield (Entries 23 – 25). A marginal improvement in yield occurred by performing the reaction in mesitylene, but the difficulty in removing this solvent prompted the optimization to be continued in toluene.
A ligand screen was also conducted to try to increase the yield. Using CO/PPh3 (the same catalyst system used by the Ma group) and Wilkinson’s catalyst (with or without added silver) suppressed the reaction, which indicated monodentate triarylphosphines did not produce catalytically active complexes (Entries 27 and 28). MeDuPHOS (a dialkyl aryl phosphine) and MONOPHOS (a phosphoramidite) also gave catalytically inactive complexes. This suggests that bidentate triarylphosphines are the ideal ligands for this reaction. A reaction conducted with SEGPHOS gave the product in dramatically lower yield relative to BINAP. Two derivatives of BINAP, o-tolyl and xylyl, also provide lower yields of product relative to the parent ligand BINAP. Surprisingly, using H8BINAP gave the cycloadduct in significantly higher yield when coupled with an increase in allenoate loading to two equivalents. Using BINAP with two equivalents of allenoate also produced the desired product in higher yield, but the increased solubility of the H8BINAP ligand enables facile generation of the complex in situ using stock solutions, and all further reactions were conducted with it.
It was unclear if the identity of the olefin contained in the rhodium precatalyst would have a significant impact on the yield of the reaction. Therefore, the reaction was performed using various olefin-bound rhodium precatalysts (Entries 37 – 39). Using [Rh(nbd)Cl]2, which contains the strongly coordinating bidentate diene norbornadiene, required much longer to consume the starting material. Reactions with cyclooctene and ethylene bound precatalysts gave the product in significantly higher yield and greatly shortened the reaction. This trend suggests that the olefins present on the precatalyst can compete with the substrate for open coordination site on the metal and that precatalysts with bidentate dummy ligands should be avoided. Thus, the following conditions were determined to be optimal for this reaction: 2.5 mol % [Rh(C2H4)2Cl]2, 6 mol % H8BINAP, 5 mol % AgOTf, with 2 equivalents of allenoate in toluene (0.04M), which afford a 79% yield of the desired cycloadduct 6 in the reaction of compound 1 with ethyl allenoate 5.
C. Added Allene Scope