With our desired starting material in hand, we then began to explore the stereoconvergent Michael addition of nitroalkanes to −halo alkylidene malonates 1.23. We were pleased to discover that
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using a variety of catalysts, we could indeed add nitroalkanes to −haloalkylidene malonates 1.23 to afford the Michael addition products 1.27 with varying levels of success (Table 1-1). By employing Dixon-type iminophosphorane catalyst 1.19a, we could generate the desired product in full conversion. Unfortunately, we saw a 1:1 mixture of diastereomers when using the Ph-substituted substrate 1.23a (Table 1-1, entry 1).
By switching to the methyl-substituted substrate 1.23b, we could improve the diastereoselectivity to 5:1, while still maintaining full conversion (Table 1-1, entry 2). In the case of both substrates, switching the nitroalkane to nitroethane significantly reduced conversion without any improvement in diastereoselectivity (Table 1-1, entry 3-4). Based on these initial findings, we decided to continue our reaction exploration by screening other catalysts using nitromethane as our nitroalkane. Table 1-1. Initial Results for the Addition of Nitroalkanes to −Chloro Alkylidene Malonates
entry substrate R2 cat solvent temp.
(℃) conversion dr
1 1.23a Ha 1.19a Et2O -60 100% 1:1
2 1.23b Ha 1.19a Et2O -60 100% 5:1
3 1.23a Mea 1.19a Et2O -60 62% 2.4:1.4:1
4 1.23b Mea 1.19a Et2O -60 51% 2.5:1
5 1.23a H 1.28 neatb 23 trace nd
6 1.23b H 1.28 neatb 23 61% 3:1
7 1.23b H 1.29 neatb 23 26% 3:1
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Cinchona alkaloid-derived thiourea 1.28 catalyst gave only trace amounts of the desired product when employing Ph-substrate 1.23a (Table 1-1, entry 5), but gave 61% conversion in the case of Me-substrate 1.23b (Table 1-1, entry 6). There was a slight increase in diastereoselectivity with catalyst 1.28, affording the desired product in 3:1 dr. Quinidine 1.29 can catalyze the reaction as well, though in poor conversion (Table 1-1, entry 7).
Based on these preliminary results, we began to screen the reaction for enantioselectivity. We screened a small library of chiral catalysts, including Dixon-type iminophosphoranes 1.19 (both 1st and 2nd generation 1.30), Ooi phosphazene 1.31,45 and Cinchona-derived thiourea catalyst 1.28. By using tBu-substituted catalyst 1.19b, we could achieve the desired reaction in 61% conversion and modest diastereoselectivity; however, poor enantioselectivity was observed (Table 1-2, entry 1). Cooling the reaction significantly decreased the conversion and did not improve the diastereoselectivity (Table 1- 2, entry 2). By changing the aryl group on the iminophosphorane moiety 1.19c, we completely shut down the reaction (Table 1-2, entry 3). By changing the catalyst substituent to a benzyl group 1.19d, we saw full conversion to the desired product, but it was nearly racemic (Table 1-2, entry 4). The Ph- substituted catalyst 1.19a gave full conversion to the desired product and modest diastereoselectivity, however, no appreciable enantioselectivity was observed (Table 1-2, entry 5). In both cases, the minor enantiomer was isolated with good enantioselectivity; the root cause for this peculiar trend remains unclear. By switching to the 2nd generation catalyst 1.30, we observed only modest conversion, but the diastereoselectivity improved dramatically (Table 1-2, entry 6). Cooling the reaction reduced the conversion significantly but afforded the product with modest enantioselectivity (Table 1-2, entry 7).
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Warming the reaction did not improve conversion and actually proved to be deleterious for conversion and diastereoselectivity (Table 1-2, entry 8-10). The Ooi phosphazene catalyst 1.31 gave excellent diastereoselectivity, but no appreciable levels of enantioselectivity were observed (Table 1- 2, entry 11). Even at room temperature, the cinchona thiourea catalyst 1.28 only gave modest conversion, poor diastereoselectivity, and racemic product (Table 1-2, entry 12).
Table 1-2. Optimization of Nitromethane Addition to Diethyl 2-(2-chloropropylidene)malonate
entry cat temp. (℃) conversion dr er (major) er (minor)
1 1.19b -60 61% 4.6:1 57:43 88:22 2 1.19b -78 18% 4.8:1 nd nd 3 1.19c -60 NR - - - 4 1.19d -60 100% 5:1 51:49 83:17 5 1.19a -60 100% 4.6:1 58:42 90:10 6 1.30 -60 46% 11.5:1 59:41 63:37 7 1.30 -78 10% 5.7:1 79:21 91:9 8 1.30 -40 34% 4:1 67:33 83:17 9 1.30 -20 28% 5.7:1 64:36 75:25 10 1.30 0 13% 4.9:1 64:36 75:25 11 1.31 -60 42% 13.2:1 59:41 63:37 12a 1.28 23 61% 2.8:1 51:49 53:47
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We then decided to explore other substitution patterns on the substrate. By switching the halogen to a bromine (1.23c), we saw only 43% conversion to desired product 1.27c in 1.4:1 dr when employing the Ph-substituted Dixon catalyst 1.19a (Scheme 1-9). The second-generation Dixon catalyst 1.30 did not catalyze the reaction with the brominated substrate 1.23c.
Scheme 1-9. Nitromethane Addition to Diethyl 2-(2-Bromopropylidene)malonate 1.23c
Given the lack of promising results with the brominated substrate, we next moved our focus to the carbon substituent at the −position. Upon switching from a methyl to a phenyl group 1.23a, the reaction proceeds with poor conversion and diastereoselectivity (Table 1-3, entry 1). Additionally, the Ph-substrate 1.23a easily rearranges under basic conditions to afford the constitutional isomer 1.32 (Scheme 1-10).
Scheme 1-10. Base-catalyzed Isomerization of Diethyl 2-(2-chloro-2-phenylethylidene)malonate 1.23a
If we employ bulkier alkyl groups (e.g. cyclohexyl 1.23d), nitromethane is added in >20:1 dr. By employing the Ph-substituted iminophosphorane catalyst 1.19a at -20 ℃, near full conversion to the desired product, in >20:1 dr, but only 52:48 er is observed (Table 1-3, entry 2). If the reaction is
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cooled to -60 ℃, the conversion decreases to 40%, but the enantioselectivity rises to 70:30 (Table 1-3, entry 3).
Table 1-3. Exploration of −Substituents
entry substrate temp. (℃) conversion dr er (major)
1 1.23a -78 25% 1:1 nd
2 1.23d -20 100% >20:1 52:48
3 1.23d -60 40% >20:1 70:30
At this point, we decided to isolate the remaining starting material from the -60 ℃ trial (Table 1-3, entry 3). We were dismayed to discover the remaining starting material 1.23d was isolated in 63:37 er. Enantioenriched starting material indicates the −proton is not sufficiently acidic to racemize rapidly (a requirement of DKR transformations), and a kinetic resolution may be operative (Scheme 1-11). To test this hypothesis, we subjected the enantioenriched starting material 1.23d to various strong bases to see if racemization occurred. Dixon catalyst 1.19a and Dixon 2nd generation 1.30 catalyst were not strong enough bases to epimerize the −stereocenter (Table 1-4, entries 1-2).
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Realizing this could be because both Dixon catalysts are very large, we then subjected the enantioenriched substrate to smaller superbase BEMP, but again isolated the starting material with no change in enantioenrichment (Table 1-4, entry 3). We also tried racemizing with DBU, which resulted in rearrangement of the starting material (Table 1-4, entry 4).
Table 1-4. Attempts to Racemize Enantioenriched Starting Material
entry base starting er final er
1 1.19a (5.0 mg) 37:63 39:61
2 1.30 (5.0 mg) 26:74 26:74
3 BEMP (1 drop) 26:74 27:73
4 DBU (1 drop) 36:61 Mixture of SM
isomersa aIsomers were inseparable; final er could not be determined
We came to the conclusion that −halo alkylidene malonates are not appropriate substrates for the enantioconvergent Michael addition. The −proton of these substrates is not sufficiently kinetically acidic enough to form the dienolate to quickly racemize the starting material, a key requirement to perform a DKR reaction.
1.3.3 Alkyl Thiol Addition to −Halo Alkylidene Malonates
Concurrent with the nitromethane addition studies, investigated the addition of alkyl thiols using the same catalysts. Though we were able to successfully add isopropyl thiol to these substrates in excellent conversions 1.33, and modest diastereoselectivity (depending on catalyst), this transformation was plagued by two major issues. The first issue is similar to the aforementioned nitromethane addition, in which the −proton is not acidic enough to form the dienolate. The second
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issue is these products are not stable to silica gel and rearrange to −thiol alkylidene malonate 1.34 (Scheme 1-12). We believe this occurs via collapse to the thiiaranium ion 1.35, followed by ring opening. Although this result is intriguing, we elected to explore other substrates for this transformation.
Scheme 1-12. Addition of Isopropyl Thiol to Diethyl 2-(2-chloro-2-cyclohexylethylidene)malonate
1.3.4 Optimization of Nitromethane Addition of γ‒Substituted Alkylidene Malononitriles
Moving away from alkylidene malonates, we next investigated −stereogenic alkylidene malononitriles. We hypothesized that changing the diester to a dimalononitrile would increase the acidity of the −proton and enable more facile racemization of the substrate. For comparison, the pKa of diethyl malonate is 16.4, whereas, the pKa of malononitrile is 11.1 in water.46 We were unable to explore −halo alkylidene malononitriles due to their instability,47 so we began studying 2-(2- phenylpropylidene)malononitrile 1.36, which is synthesized in a single step via a Knoevenagel condensation of 2-phenylpropanal and malononitrile.
With this substrate in hand, we initiated a catalyst screen for the addition of nitromethane to 1.36, similar to that of prior substrates. With the tBu-Dixon catalyst 1.19b, we could achieve full conversion to the desired product 1.37 at room temperature; however, we did not observe any appreciable diastereoselectivity or enantioselectivity (Table 1-5, entry 1). By cooling the reaction to - 20 ℃, we saw a modest increase in diastereoselectivity (Table 1-5, entry 2). Cooling the reaction further
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to -60 and -78 ℃, resulted in a drastic drop in conversion, but good diastereoselectivity and an increase in enantioselectivity (Table 1-5, entry 3-4). We were able to isolate the remaining starting material in 53:47 and 51:49 er respectively, which we believe indicates that under these reaction conditions the substrate is racemizing, albeit perhaps relatively slowly. A brief solvent screen indicated that solvent plays only a small role in controlling the reactivity and stereoselectivity (Table 1-5, entries 5-7). Varying the substitution on the Dixon catalyst did not increase enantioselectivity (Table 1-5, entries 8- 9), and again, changing the aryl groups on the catalyst 1.19c had a negative effect on reactivity (Table 1-5, entry 10). We also investigated various cinchona-derived-thioureas (Table 1-5, entry 11) and squaramides (Table 1-5, entry 12), which also failed to improve enantioselectivity. Finally, we employed optimized conditions for our group’s previously reported enantioconvergent addition of nitromethane to −stereogenic −ketoesters,8 but saw only modest conversion and diastereoselectivity, and poor enantioselectivity (Table 1-5, entry 13).
Table 1-5. Optimization of Nitromethane Addition to 1.36
entry cat temp.
(℃)
solvent conversion dr er (major) er isolated SM 1 1.19b 23 Et2O 100% 1.4:1 51:49 - 2 1.19b -20 Et2O 100% 3.7:1 54:46 - 3 1.19b -60 Et2O 40% 7.3:1 67:33 53:47 4 1.19b -78 Et2O 18% 9.6:1 71:29 51:49 5 1.19b -78 DCM 19% 5:1 67:33 50:50 6 1.19b -78 toluene 20% 8.8:1 79:21 51:49 7 1.19b -78 THF 24% 9.5:1 nd nd 8 1.19a -20 Et2O 100% 5.2:1 55:45 - 9 1.19d -20 Et2O 100% 6.8:1 52:48 - 10 1.19c -20 Et2O 25% 2.5:1 nd nd