Gold(I)‐Catalyzed Enantioselective Synthesis of Pyrazolidines, Isoxazolidines, and Tetrahydrooxazines

Abstract

Au-ff on a trip: Chiral ligands (L*) and chiral anions [(S)-TriPAg] are employed in the gold(I)-catalyzed enantioselective intramolecular additions of hydrazines and hydroxylamines to allenes. These complementary methods allow access to chiral vinyl isoxazolidines, oxazines, and differentially protected pyrazolidines. PNB=para-nitrobenzoyl. We began our studies with a mono-Boc-protected homoallenic hydrazine, easily synthesized in four steps from the homoallenic alcohol. Whereas unprotected amines are usually considered incompatible with cationic gold complexes, we hypothesized that the reduced Lewis basicity of the hydrazine would allow the use of an unprotected terminal amine. Indeed, upon treatment of 1 a with [(R)-xylyl-binap(AuOPNB)2] (I) in nitromethane at 50 °C the desired product 2 a was formed, although in modest yield and low enantioselectivity (Table 1, entry 1). By simply adding a second protecting group, both the yield and enantiomeric excess of 2 b were improved (Table 1, entry 2). This result led us to theorize that sterically differentiating the protecting groups would be necessary to additionally improve the enantioselectivity. Indeed, utilizing a mesitylenesulfonyl protecting group on the terminal nitrogen atom raised the observed enantioselectivity to 80 % ee (Table 1, entry 3). A brief examination of chiral ligands revealed that (R)-DTBM-Segphos was optimal, yielding pyrazolidine 2 c in 97 % ee (Table 1, entry 4). Similar to hydroamination with hydrazines, we found that although unprotected hydroxylamines were transformed into the isoxazolidines in excellent conversion (>92 %), low enantioselectivity (10 % ee) was observed (Table 1, entry 5). Upon treating N-Boc-protected hydroxylamine 1 f with catalyst I the isoxazolidine 2 f was formed in 93 % yield and 93 % ee (Table 1, entry 7). Other protecting groups, such as Cbz, significantly reduced the conversion to 8 % (Table 1, entry 6). Additionally, a polar, noncoordinating solvent such as nitromethane was effective, producing 2 f in 98 % conversion and 87 % ee. However, nonpolar solvents (benzene) and coordinating solvents (dioxane) completely eliminated catalyst activity. Entry 1; X R Cond.[a] 2; Yield[b] [%] ee[c] [%] 1 1 a; NBoc H A 2 a; 46 5 2 1 b; NBoc Boc A 2 b;>98[d] 70 3 1 c; NBoc Mts A 2 c;>98[d] 80 4 1 c; NBoc Mts A[e] 2 c; 78 97 5 1 d; O H B[f] 2 d; 92 10 6 1 e; O Cbz B 2 e; 8[d] – 7 1 f; O Boc B 2 f; 93 93 Whereas gold(I)/bis(p-nitrobenzoate) complexes proved to be ineffective catalysts for the hydroalkoxylation of allenes (Table 2, entry 1), we hypothesized that employing a more noncoordinating counterion with a lower pKa value would improve catalysis. Chiral silver sulfonate (S)-(5)Ag (IV) was synthesized in seven steps from (S)-binol (binol=2,2-dihydroxy-1,1-binaphthyl).9 Gratifyingly, upon treatment with 3 mol % [dppm(AuCl)2] and 3 mol % IV, isoxazolidine 4 was formed in quantitative conversion and 65 % ee (Table 2, entry 2). However, attempts to improve the enantioselectvity by matching the chiral counterion with chiral gold/binap complexes were unsuccessful (Table 2, entries 3 and 4). Both the matched and mismatched mixtures produced 4 with lower enantioselectivity (42 % and 8 % ee, respectively). Chiral silver phosphate (S)-TriPAg (III) proved to be the key to enhancing the enantioselectivity to 97 % ee (Table 2, entry 5). Entry Catalyst[a] Yield [%][b] ee [%][c] 1 I 0 – 2 3 mol % [dppm(AuCl)2] 98[d] 65 3 mol % IV 3 3 mol % [(R)-binap(AuCl)2] 98[d] 8 3 mol % IV 4 3 mol % [(S)-binap(AuCl)2] 98 42 3 mol % IV 5 3 mol % [dppm(AuCl)2] 98 98 6 mol % III We next sought to test the substrate scope of our optimized hydroamination conditions (Table 3). Linear and cyclic alkyl substitutions were tolerated at the allene terminus in both the hydrazine and hydroxylamine hydroamination. For instance, methyl-substituted substrates cyclized with excellent enantioselectivity (Table 3, entries 1 and 4). Cyclohexyl-substituted allenes also reacted with high enantioselectivity (Table 3, entries 3 and 6). Cyclopentyl-substituted substrates 8 and 12 also provided pyrazolidine 9 and isoxazolidine 13 in good yield and slightly lower enantioselectivity (Table 3, entries 2 and 5). Furthermore, sterically challenging backbone substitutions were accommodated by heating gently (50 °C) in a polar, noncoordinating solvent (nitromethane). Whereas substitution at the allenic position (Table 3, entry 8) gave enhanced enantioselectivity (99 %) with modest yield (73 %), the homoallenic position showed the reverse trend: modest enantioselectivity (63 %) and excellent yield (94 %). Entry Substrate R1 R2 Cond.[a] Product Yield [%][b] ee [%][c] 1 6 Me – A 7 98 99 2 8 -(CH2)4- – A 9 90 83 3 1 c -(CH2)5- – A 2 c 75 97 4 10 Me – B 11 91 98 5 12 -(CH2)4- – B 13 98 91 6 1 f -(CH2)5- – B 2 f 93 93 7 14 Me H C 15 94 63 8 16 H Me C 17 73 99 9 18 -(CH2)5- H D[d] 19 63 89 10 20 -(CH2)5- Me D 21 85 89 11 22 Me Me D 23 79 89 We also applied our hydroamination conditions to the formation of six-membered ring tetrahydrooxazine heterocycles. Gentle heating in a polar noncoordinating solvent was required to produce tetrahydrooxazines in good yield (63–85 %). Substrates with backbone substitutions (Table 3, entries 10 and 11) have higher yield than those without substitutions, presumably the result of a Thorpe–Ingold effect. Also, both linear and cyclic alkyl substitutions were tolerated at the allene terminus, providing the heterocycles with 89 % ee in all cases. We were pleased to find that chiral silver salts used with gold(I) complexes catalyze the hydroalkoxylation of N-linked hydroxylamines with good to excellent enantioselectivity. Both cyclic and linear alkyl substitutions at the allene terminus were well tolerated, yielding the corresponding isomeric vinyl-isoxazolidines in good yield and high enantiomeric excess (Table 4, entries 1 and 2). Formation of oxazines proved to be more challenging, with the gold(I)-catalyzed reaction affording 31 in modest yield and 50 % ee (Table 4, entry 4).11 However, both the yield and enantioselectivity were greatly improved by combining a chiral ligand with the chiral silver salt (Table 4, entry 5). Additionally, whereas good diasteroselectivity was observed for substituted substrates (Table 4, entry 3), the corresponding enantioselectivities favor the minor diasteromer. Entry Substr. n R1; R2 Cond.[a] Prod. Yield [%][b] ee [%][c] 1 26 1 Me; H A 27 98 98 2 3 1 -(CH2)5-; H A 4 75 99 3 28 1 Me; Me A 29 99[d] 40/97 4 30 2 Me; H A[e] 31 66 50 5 30 2 Me; H B 31 94 87 6 30 2 Me; H C 31 36 45 In conclusion, we have developed a series of enantioselective gold(I)-catalyzed hydroaminations and hydroalkoxylations of allenes with hydroxylamines and hydrazines. Whereas chiral biarylphosphinegold(I) complexes12 are suitable catalysts for the enantioselective addition of nitrogen nucleophiles to allenes, the addition of oxygen nucleophiles requires the use of chiral anions. These complementary methods allow rapid access to chiral vinyl isoxolidines, oxazines, and differentially protected pyrazolidines.13, 14 Studies on the mechanism of enantioinduction in these transformations are ongoing in our laboratories. 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. 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.