Palladium/Xu-Phos-catalyzed asymmetric carboamination towards isoxazolidines and pyrrolidines†

An efficient palladium-catalyzed enantioselective carboamination reaction of N-Boc-O-homoallyl-hydroxylamines and N-Boc-pent-4-enylamines with aryl or alkenyl bromides was developed, delivering various substituted isoxazolidines and pyrrolidines in good yields with up to 97% ee. The reaction features mild conditions, general substrate scope and scalability. The obtained products can be transformed into chiral 1,3-aminoalcohol derivatives without erosion of chirality. The newly identified Xu-Phos ligand bearing an ortho-OiPr group is responsible for the good yield and high enantioselectivity.


Introduction
Five-membered N-heterocyclic skeletons are commonly found in biological and pharmaceutical molecules (Fig. 1). 1 For example, pyrrolidine-based compounds can act as receptor antagonists, and their diverse activities are determined by the different congurations (eg 2 and 3). 2 Isoxazolidine is a versatile precursor for the synthesis of 1,3-amino alcohols, taking sitagliptin as a typical case (eg 5). 3 Therefore, it is highly desirable to develop synthetic methods towards isoxazolidine and pyrrolidine compounds, especially for efficient construction of enantioenriched molecules.
Isoxazolidines could be furnished by 1,3-dipolar cycloaddition reactions or cyclization of unsaturated hydroxylamines proceeding through electrophilic or free radical pathways, Michael addition reactions etc. 4 Transition metal catalyzed cyclization strategies have also been showcased in recent years using palladium or gold as common catalysts. 5In 2010, Toste 6a reported the Au(I)-catalyzed enantioselective synthesis of isoxazolidines from allenic hydroxylamines, which could be also extended for the preparation of pyrazolidines and tetrahydroxazines with high enantioselectivity (Scheme 1a).Recently, Gao and co-workers reported a tandem aza-Michael/hemiacetal reaction between (E)-4-phenylbut-2-enal and N-Boc-hydroxylamine for the synthesis of 2-hydroxyl-isoxazolidines (Scheme 1b). 3 The Wolfe group reported an elegant palladium-catalyzed carboamination of alkenes, which provides facile access to enantioenriched pyrrolidines (Scheme 1c). 7Recently, Zhang and co-workers 8 also implemented an enantioselective radical cyclization approach by metalloradical C-H alkylation reactions (Scheme 1d).
Despite the above advances, the development of an efficient methodology for N-heterocyclic skeletons with high enantioselectivity is of great importance and still challenging, especially for the introduction of an alkenyl group.Based on our interests in the asymmetric synthesis of heterocyclic compounds, 9 herein we wish to report our efforts in the development of palladiumcatalyzed intermolecular carboamination of unsaturated hydroxylamines with aryl or alkenyl halides, in which the newly identied (S,Rs)-Xu4 bearing an ortho-O i Pr group ligand showed a unique effect, leading to substituted isoxazolidines in relatively high yield and selectivity.Moreover, pyrrolidines could also be synthesized efficiently starting from corresponding carbamates.

Results and discussion
In our initial study, N-Boc-O-homoallyl-hydroxylamine 1a and 4bromobiphenyl were selected as the model substrates.A series of commercially available chiral ligands were investigated at rst (Fig. 2).Although L1 afforded the desired product 3a with moderate enantioselectivity, other bisphosphine ligands L2-L5 suppressed the reaction, with no or only a small amount of 3a detected.The desired product could be obtained in low yield with poor enantioselectivity when using chiral phosphoramidite ligand L6, but L7 is not effective at all.Josiphos L8 delivered the product 3a with moderate yield but as a close to racemic mixture.The phoxphos derivative L9 is not effective for this reaction.
Inspired by the success of our developed Sadphos ligands in asymmetric catalysis, we turned our attention to evaluate their performance in the present carboamination reaction.Of note, the Sadphos kits are commercially available from Strem Inc. now.As an initial trial, Ming-Phos 9h,10 (S,Rs)-M1 with free NH was inactive, leaving the starting materials untouched.Surprisingly, when the amine moiety was protected by a methyl group ((S,Rs)-M2), 3a was obtained in 75% yield, albeit the enantioselectivity was unsatisfactory, indicating that the NH moiety of Ming-Phos might inhibit carboamination.The dicyclohexyl phosphine ligand Xu-Phos 11 showed a consistent trend, and (S,Rs)-Xu2 bearing a N-methyl group resulted in higher yield and enantioselectivity.Inspired by these notable results, we investigated the modication of Xu-Phos ligand.(S,Rs)-Xu3 bearing a 3,5-di-tert-butyl-4-methoxybenzyl group did not provide a better result.Amazingly, the introduction of O i Pr at the ortho-position of the phosphine moiety dramatically improved the enantioselectivity, delivering 3a in 84% yield and 92% ee. 13 These results unambiguously prove the subtleness and unique efficacy of the Xu-Phos ligands.We attribute this ortho-effect to the repulsion of the iso-propyl group with the cyclohexyl group on the P-atom, which would push the cyclohexyl group close to the catalytic center and affect the enantioselectivity.
Scheme 1 Enantioselective synthesis of isoxazolidines and pyrrolidines.
Fig. 2 Representative chiral ligands tested in this work.factors were also systematically examined consequently.Among the palladium sources tested (Table 1), PdCl 2 , Pd(OAc) 2 , Pd(MeCN) 2 Cl 2 and [Pd(allyl)Cl] 2 were obviously less active, generating 3a in lower yields (Table 1, entries 1-4).Pd 2 (dba) 3 performed similarly to Pd(dmdba) 2 , with slightly reduced yield (Table 1, entry 5).Other bases including NaO t Bu, KO t Bu and K 2 CO 3 led to lower yields (Table 1, entries 7-9).Various solvents were also screened, and MTBE was demonstrated to be the best choice (entries 10-14).To our delight, the enantioselectivity was further improved by lowering the temperature, and the yield could also be promoted with prolonged reaction time (Table 1, entries 15 and 16).Finally, using Pd(dmdba) 2 /(S,Rs)-Xu4 as the catalyst and Cs 2 CO 3 as the base, the reaction proceeds smoothly in MTBE at 30 C to afford the desired product in 88% yield and 95% ee (Table 1, entry 16).

Enantioselective synthesis of substituted isoxazolidines
With the optimized reaction conditions in hand, a variety of aryl bromides were reacted with N-Boc-O-homoallyl-hydroxylamine 1a to verify the generality of the reaction system (Scheme 2).Both electron-donating and electron-withdrawing groups at the para-position of the aryl bromides are compatible, providing isoxazolidines 3a-3h with 91-96% ee.When 4-biphenylyl tri-uoromethanesulfonate is used instead of p-bromobiphenyl at 75 C, 3a can be prepared with 81% yield and 91% ee.In addition to halogens, electron-withdrawing groups at the paraposition of the benzene ring such as an aldehyde group, ester group, cyano group, and triuoromethyl group are all tolerated, delivering products 3i-3l in good yields with 91-95% ee.Aryl bromides bearing different substituents such as OMe, F, Cl, CHO, or COCH 3 at the meta-position could also efficiently give the desired products 3m, 3o, 3r, 3s and 3u with up to 97% ee.The absolute conguration of 3r was conrmed by X-ray crystallography analysis. 13Moreover, when a methoxy or uorine substituent was located at the ortho-position of the phenyl bromide, the products 3n and 3p were obtained with 93% and 88% ee, respectively in moderate yields.Disubstituted phenyl bromides could also be transformed smoothly, and the corresponding products 3t, 3v and 3w were furnished in 78-91% yields with up to 97% ee.The trisubstituted compound 3q on the phenyl ring can also be obtained in 64% yield and 84% ee.Naphthyl and phenanthryl isoxazolidines were furnished in notably high yields and enantioselectivity (3x-3aa).Moreover, heteroaromatic rings including quinolinyl and thienyl could also be well tolerated, affording 3ab and 3ac with no inferior effects.The introduction of an alkenyl group to the molecule could increase the diversity of the compounds due to the alkenyl group having abundant functional group transformations.To our delight, the alkenyl group could also be transferred into the nal products from the corresponding alkenyl bromides by slight adjustment of the catalyst loading.Both cyclic and linear precursors performed gratifyingly, delivering the desired products 4a-4c in good yields with up to 91% ee.A preliminary and promising result showed that the present method is also promising for the synthesis of isoxazolidine 4d with an azaquaternary carbon stereocenter, albeit the efficiency and enantioselectivity are not satisfactory yet and further modication of the chiral ligand is necessary.
To demonstrate the practicability of our protocol, a 6 mmol scale reaction was carried out under standard conditions, delivering 1.7 g of naphthyl isoxazolidine 3x in 90% yield with 96% ee.Further treatment with NaBH 4 furnished chiral aminoalcohol 9a in 88% yield with 94% ee (Scheme 4). 12 catalytic cycle and asymmetric induction model were proposed in Scheme 5.The oxidative addition of aryl bromides to the (S,Rs)-Xu4/Pd(0) complex would generate Pd(II) species II.
In the presence of a base, species II would form a Pd-N bond to deliver the intermediate III, which undergoes insertion or aminopalladation of the alkene to produce the intermediate IV.
The nal product was obtained via reductive elimination, and the catalytic species were also regenerated.Xu-Phos and Pd coordinate through P on the ligand and O on the sulnamide to form the corresponding catalytic center.The cyclohexyl group is in the sensitive area of metal active species.The introduction of O i Pr as a side arm group may push the cyclohexyl group closer to the catalytic center and produce a key dynamic steric hindrance effect.

Conclusions
In summary, we have successfully developed a palladium-catalyzed asymmetric carboamination reaction of N-Boc-O-homoallyl-hydroxylamine and N-Boc-pent-4-enylamine with either aryl or alkenyl bromides under mild reaction conditions, furnishing various substituted isoxazolidines and pyrrolidines in moderate to high yields with high enantioselectivity.The newly identied ligand of (S,Rs)-Xu4 with O i Pr at the orthoposition, which is easily prepared from commercially available starting materials, is responsible for the general substrate scope, good yield and high enantioselectivity.The application of this chiral ligand in other transition metal asymmetric reactions is ongoing in our lab.

Table 1
Optimization of the reaction conditions a