Highly Stereoselective Intermolecular Haloetherification and Haloesterification of Allyl Amides

Abstract

An organocatalytic and highly regio-, diastereo-, and enantioselective intermolecular haloetherification and haloesterification reaction of allyl amides is reported. A variety of alkene substituents and substitution patterns are compatible with this chemistry. Notably, electronically unbiased alkene substrates exhibit exquisite regio-and diastereoselectivity for the title transformation. We also demonstrate that the same catalytic system can be used in both chlorination and bromination reactions of allyl amides with a variety of nucleophiles with little or no modification. Keywords chloroetherification; enantioselectivity; halogenation; organocatalysis; regioselectivity The field of catalytic asymmetric alkene halogenation has witnessed an explosive growth in recent years, with tremendous advances being made both in terms of new reaction discovery as well as mechanistic understanding. Two of the major issues that have thwarted the development of asymmetric alkene halogenations are the rapid stereochemical degradation of chiral halonium ions by olefin-to-olefin halenium transfer, [1] and isomerization of halonium ions to the open β-halocarbenium ions. [2] Not surprisingly, most early examples have reported on the intramolecular capture of halonium ions via tethered nucleophiles; [3] the proximity-driven rate enhancement of the cyclization step presumably outcompetes any Correspondence to: Babak Borhan, babak@chemistry.msu.edu. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.201502341. More recently, the development of enantioselective intermolecular alkene halofunctionalization reactions has come into focus. [4] A number of excellent reports have shown a great deal of progress in this area. [4a, 5] Intermolecular aminohalogenation, [5b-e] haloesterifications, [5g,h,k] halohydrin [5l, 6] synthesis, and dihalogenation [5i,m] have all been reported. HHS Public AccessDespite this progress, numerous shortcomings are apparent. First, alcohols are yet to be demonstrated as viable nucleophiles in this chemistry despite the success seen in halocycloetherification reactions ( Figure 1A and B). [7] Second, substrates with alkyl substituents on the alkene are known to afford poor or moderate levels of enantioselectivity at best. [8] Third, substrate scope studies have been limited to electronically biased alkenes and hence possible regioselectivity issues have remained unaddressed. [9] Finally, none of the catalytic systems were demonstrated to be promiscuous enough to allow for the use of different halenium sources and nucleophiles with the same substrates.We sought to develop an enantioselective intermolecular haloetherification reaction with the intention of both demonstrating the feasibility of this unprecedented transformation as well as to address some of the limitations detailed above. We report herein the enantio-, diastereo-, and regioselective intermolecular haloetherification, haloesterification and halohydrin synthesis of a variety of alkene...

Oxoammonium salts are catalysing efficient and selective halogenation of olefins, alkynes and aromatics

“…Inspired by the above success, the dibromination of alkynes was tested with present TEMPO/DBDMH system to realize the efficient synthesis of (E)-dibromoolefins. Aliphatic or aromatic alkynes, internal or terminal alkynes were all dibrominated to afford (E)-dibromoolefins in good yields (43)(44)(45)(46)(47).…”

“…Encouraged by Denmark's work [36][37][38][39] , Lewis bases, which always bear a donor heteroatom, have been widely employed in activation of haleniums. Up to date, N-centered [40][41][42][43][44][45][46][47][48][49][50][51][52] , S-centered [53][54][55][56][57][58][59][60][61][62][63] , Se-centered [64][65][66][67][68][69][70] , and P-centered 71,72 Lewis bases showed high efficiency in halogenation reactions (Fig. 2a).…”

“…2a). For example, Borhan [44][45][46][47][48] and Nicolaou 49 employed (DHQD) 2 PHAL as an efficient catalyst in enantioselective chlorofunctionalization reactions. Yamamoto et al 50 reported 2,4,6trimethylaniline catalyzed aromatic halogenation.…”

Catalytic Enantioselective Construction of Chiral Benzo-Fused N -Heterocycles through Friedel–Crafts-Type Electrophilic Chlorination

“…[30][31][32][33][34][35][36][37][38][39][40] Particularly, due to the good convertibility of the chlorine atom and its prevalence in natural products and bioactive compounds, as well as the more reactive nature of the chloriranium ion that promotes intriguing transformations compared with other iranium ions such as brom-, iod-, and thiiranium ions, catalytic asymmetric electrophilic chlorination of alkenes has received considerable attention from chemists in the past decade. [41][42][43][44][45][46][47] For instance, Borhan et al [41][42][43][44][45] reported hydroquinidine 1,4-phthalazinediyl diether [(DHQD) 2 PHAL]-catalyzed asymmetric chlorolactonization of olefinic carboxylic acids, and developed intraand intermolecular chlorination of allyl amides with the same catalyst (Figure 1b). In addition, other groups have developed catalytic asymmetric chlorination of allyl alcohols, 33,36 homoallylic alcohols, 46 2-vinylphenylcarbamates, 47 and so on.…”

“…It is possible that this cyclization is very challenging due to the following problems: (1) Known methods for asymmetric chlorination rely on the use of secondary amides with a necessary N-H group that can act as a hydrogen-bonding donor to interact with the chiral catalyst to help control the chiral environment of the reaction. [42][43][44][45][49][50][51][52][53][54] When protected N-allyl secondary anilines, namely tertiary N-allyl anilines, are used as substrates, not only the steric hindrance on the nitrogen increases, but also the hydrogen bonding from the nitrogen-containing group disappears, which theoretically results in hard control of the enantioselectivity of the reaction. (2) Using tertiary N-allyl aniline derivatives as substrates, the electron-rich aromatic ring of the substrates easily undergoes electrophilic substitution, [55][56][57] which can retard the functionalization of the double bond to form the desired products.…”