CHIRALITY (2013)

Review Article Stereoselective Bromofunctionalization of Alkenes CHONG KIAT TAN, WESLEY ZONGRONG YU, AND YING-YEUNG YEUNG* Department of Chemistry, National University of Singapore, Singapore

ABSTRACT The stereoselective bromofunctionalization of alkenes, particularly the enantioselective format, has been a subject of intense research in recent years. The ground-breaking works are documented in recent reviews. On the other hand, this account will provide an insight into our group’s approach in tackling the challenges in enantioselective bromocyclization of alkenes as well as the development of diastereoselective N-bromosuccinimide-initiated multicomponent reactions. Chirality 00:000–000, 2013. © 2013 Wiley Periodicals, Inc. KEY WORDS: alkenes; asymmetric catalysis; electrophilic addition; multicomponent reactions; organocatalysis The halofunctionalization of alkenes via an electrophilic process has been a widely used organic reaction. The first proposed mechanism involving a halonium intermediate was proposed by Roberts and Kimball.1 The characterization of the stable halonium intermediate was first performed by Olah et al. and supported by later studies.2–10 As the products of halofunctionalization are generally observed with an antirelationship between the halogen and the nucleophile, a widely accepted mechanism is illustrated in Scheme 1. The formation of a 3-membered ring halonium intermediate is followed by a ring-opening by the nucleophile in a stereospecific SN2 fashion to give a diastereoselective product with an anti-relationship between the halogen and the nucleophile. The enantioselective halofunctionalization of alkenes has been a subject of interest over many decades. Reports of a useful level of enantioselectivity in this area have been sporadic in the past few decades.11,12 Nevertheless, several milestones were reached in this field of research in the past few years and these efforts have been documented in several recent reviews.13–18 This field is also a key research area of our laboratory. Our main contributions to the enantioselective bromocyclization of alkenes are the discovery of both aminothiocarbamates and cyclic dialkyl selenide as competent asymmetric organocatalysts. The rationalization of our efforts in this field will be described in the first part of this article, following which we also describe our efforts in developing a catalyst-free, N-bromosuccinimide (NBS) initiated electrophilic multicomponent reactions (MCRs) which are highly stereoselective. CHALLENGES OF DEVELOPING ENANTIOSELECTIVE BROMOCYCLIZATION OF ALKENES

Despite the long history of halofunctionalization of alkenes with electrophilic halogens, the reaction has oddly been absent in the list of organic reactions that has been made into an asymmetric format. Its absence is not due to a lack of effort, as early attempts at solving this problem with a chiral amide auxiliary have been documented.19–21 Early attempts to tackle this problem via reagent control method has led to moderate success.22,23 © 2013 Wiley Periodicals, Inc.

The reasons behind the difficulty of achieving highly enantioselective halofunctionalization were addressed by the detailed mechanistic investigations by both Brown et al. and Denmark et al. With the use of 1H NMR, Brown and co-workers were able to demonstrate the existence of a rapid and degenerate olefin-to-olefin transfer process between free alkenes and bromonium ions (Scheme 2).24–27 The rate of this olefin-to-olefin transfer process was also found to be kinetically competitive with that of the nucleophilic capture of the bromonium ions. Thus, the existence of such a process does not bode well for the design of enantioselective halofunctionalization of alkenes. This is because any enantiopure halonium intermediate may have the potential to racemize via this olefin-to-olefin transfer before it can be captured by a desired nucleophile. In a more recent study, Denmark et al. performed a series of acetolysis experiments providing further plausible explanation to the problem (Scheme 3).28 Tosylate 1a was found to suffer from erosion of its enantiospecificity when it is mixed with the free (E)-4-octene in the highly polar hexafluoroisopropanol solvent. The factors affecting this erosion in enantiospecificity were identified to be the concentration of the free (E)-4-octene as well as the identity of the cation of the acetate salt. In contrast, the analogous chlorotriflate 1b does not suffer from such erosion of enantiospecificity. The result of this study suggests an added difficulty to chemists working on a solution to the enantioselective bromofunctionalization of alkenes. Use of Lewis Basic Sulfur as a Bromine Activator

Taking into account the challenge highlighted independently by Brown et al. and Denmark et al., one can appreciate that the development of an enantioselective halofunctionalization of alkenes is not straightforward. Our considerations in the catalyst design were motivated by two pieces of work: 1) Brown’s *Correspondence to: Y.-Y, Yeung, Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore. E-mail: [email protected] Received for publication 30 June 2013; Accepted 10 October 2013 DOI: 10.1002/chir.22272 Published online in Wiley Online Library (wileyonlinelibrary.com).

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Scheme 1. Generally accepted proposed mechanism of halofunctionalization.

proposal that the chiral elements of the catalyst or reagent should encapsulate the Br+ to form a pocket into which the alkene is coordinated in order to achieve high enantioselectivity29; 2) the concept of forming a tight ion pair between the bromonium ion and a chiral element proposed by Denmark and Burk.30 When we initiated this project we recognized the need to search for a new way to activate bromine and use it as a platform to develop a chiral catalyst. In terms of activating N-bromoamide reagent, two plausible activation pathways can be conceived (Scheme 4). First, the carbonyl oxygen of the N-bromoamide reagent may be coordinated to a Lewis acid (path A, Scheme 4), which enhances the electrophilicity of the bromine atom on the reagent. Another plausible approach is the Lewis base activation of the bromine atom (path B, Scheme 4). When we first examined these two approaches, we postulated that a Lewis base activation approach may provide a better solution to tackle the enantioselective bromofunctionalization of alkene due to the proximity of the Lewis base and the bromine atom on the N-bromoamide reagent. Second, the potential for racemization with olefin-toolefin transfer may be arrested if the Lewis base can stay coordinated to the bromine atom during the bromination of the desired alkene functionality.29,30 As we began our search for a suitable Lewis base activator of N-bromoamide reagents, for example N-bromosuccinimide (NBS), we were drawn to Denmark and Collins’ work on using triphenylphosphine sulfide as a catalyst for the selenolactonization of alkenoic acids.31 In their report, they proposed that N-phenylselenylsuccinimide is possibly activated by the Lewis basic triphenylphosphine sulfide based on a concept termed as Lewis base activation of Lewis acid (Scheme 5).32–34 Combining this concept with reports by other research group on the X-ray structures of 1:1 molecular complexes between sulfur containing molecules and bromine,35,36 we began our initial search for catalysts with organosulfur compounds. This approach stands in contrast to the recent success in enantioselective chlorocyclization,37–39 bromocyclization,40–45 iodocyclizaton,46–49 and intermolecular halofunctionalization of alkenes.50–54 In our initial studies we screened a variety of organosulfur compounds and found thiocarbamates with the thione (C = S) functional group to be competent bromolactonization catalysts (Scheme 6).55 As shown in Scheme 6, thiocarbamate 5a (entry 1) was able to accelerate the bromolactonization of alkenoic acid 3, while carbamate 5c (entry 6), which lacks the thione functional group, was unable to do so. In addition,

Scheme 2. Chirality DOI 10.1002/chir

Scheme 3. Demonstration of erosion of enantiospecificity via acetolysis.

Scheme 4. Lewis acid and Lewis base activation of N-haloamide reagents.

Scheme 5. Lewis base activation of N-phenylselenylsuccinimide.

the N-methylated thiocarbamate 5d (entry 7) was found to work as a bromolactonization catalyst, although its performance is less superior compared to thiocarbamate 5a. Further corroborating our proposal to activate NBS (Model A, Scheme 6) with organosulfurs as Lewis base is the elaborate

Scheme 2. Proposed mechanism of olefin-to-olefin transfer of bromonium ion.

STEREOSELECTIVE BROMOFUNCTIONALIZATION OF ALKENES

Scheme 6. Initial investigation of thiocarbamates as bromolactonization catalysts.

report by Denmark and Burk that triphenylphosphine sulfide is a catalyst for bromolactonization as well as bromoetherification.56 After confirming the competence of thiocarbamates as bromolactonization catalysts, the next logical step was to examine if chiral thiocarbamates can serve as an asymmetric bromolactonization catalyst. The menthol derived thiocarbamate 5b was thus synthesized for this investigation. To our disappointment, no enantioselectivity was detected when catalyst 5b was used even at low temperature. Amino-thiocarbamates as Asymmetric Bromolactonization Catalysts

The failure of obtaining any enantioselective bromolactonization with chiral and monofunctional thiocarbamates led us to reexamine the validity of model A in Scheme 6. Learning from the failure to achieve enantioselective bromolactonization with monofunctional chiral thiocarbamates, we decided to redesign the catalyst from model A to model B (Fig. 1) by incorporating an amine functionality in addition to a thiocarbamate. By doing so, we hoped that the amine would be able to capture the carboxylate anion of the alkenoic acid via ion pairing while the thiocarbamate could activate the bromine source. Such a bifunctional system might also encapsulate the olefinic substrate, which could alleviate the racemization due to olefin-to-olefin degeneration.29 To test our hypothesis, we decided to incorporate a thiocarbamate into the proline and the cinchona alkaloid systems (Fig. 1). With this redesign we were able to achieve our first breakthrough in achieving enantioselective bromolactonization of alkenoic acid 3b (Table 1). Crucially, it was discovered that both the thiocarbamate and the amino functional group were required in the catalyst in order to obtain high enantioselectivity (catalysts 7c and 7d). The use of cinchonine (7a) resulted in no enantioselectivity. Likewise,

Fig. 1. Redesign of monofunctional thiocarbamate into bifunctional aminothiocarbamate.

carbamate 7e, thiocarbonate 7f, and thiourea 7h were unable to induce enantioselectivity in the reaction. The N-methylated thiocarbamate 7g resulted in significantly reduced enantioselectivity. In addition, we discovered the requirement for an electron-rich aryl substituent to the nitrogen of the thiocarbamate functional group and the 2,4-dimethoxyphenyl substituted thiocarbamate 7d gave the highest enantioselectivity during our preliminary screening in dichloromethane. Another important point is that both 6a and 6c were able to induce appreciable enantioselectivity, further proving that amino-thiocarbamates can work as asymmetric bromolactonization catalysts. In fact, the proline derived 6a was eventually developed into a competent asymmetric bromolactonization catalyst and will be described in a later section. Another factor influencing the enantioselectivity is the halogen source (Table 2). Under the optimized condition, we were unable to attain any reaction when N-chlorosuccinimide (NCS) was used. While the reaction was able to proceed with N-iodosuccinimide (NIS), the enantioselectivity obtained was significantly reduced. For reasons that we have yet to determine the amino-thiocarbamate catalyst system appears to be well positioned for the asymmetric bromolactonization of alkenes but not for the corresponding chloro- and iodolactonization. In terms of the type of bromine reagent, NBS was determined to give the best enantioselectivity but other sources like N-bromophthalimide are good sources and are in fact the most suitable in some of the reactions that we will describe. The substituents adjacent to the alkene were also found to affect the enantioselectivity (Scheme 7). Generally, an aryl group is necessary for attaining high enantioselectivity with the electron-deficient aryl group giving better enantiomeric excess (ee). While other electron-rich aryl groups were well tolerated, the 4-methoxyphenyl substituent resulted in a drastically reduced 28% ee. Nonetheless, the alkyl group like the cyclohexyl substituent could result in a moderately high 82% ee and the tert-butyl substrate returned with 93% ee. Chirality DOI 10.1002/chir

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TABLE 1. Enantioselective bromolactonization with amino-thiocarbamates

TABLE 2. Effect of halogen sources on enantioselectivity

thiocarbamate could lead to the highly enantioselective bromolactonization of both E and Z-pentenoic acids as well as the styrene-type carboxylic acid.57–59 Another noteworthy point to raise is the optimal solvent blend for each type of alkenoic is different. S-Alkyl Amino-thiocarbamates as Asymmetric Bromolactonization Catalysts

While we were able to attain high enantioselectivity for the 1,1-disubstituted alkenoic acid 3, we soon realized that the optimized conditions in Scheme 7 were not suitable for alkenoic acids of other alkene substitution patterns (Scheme 8). As shown in scheme 8, the tuning of the substituents at R1 and R2 position of the cinchona alkaloid derived amino-

While we were able to achieve a reasonably broad substrate scope with the cinchona alkaloid-derived aminothiocarbamate catalysts, we still faced certain limitations. The cinchona alkaloids exist as pseudo-enantiomeric pairs and in some cases an equally high opposite enantioselectivity was not achievable with the pseudo-enantiomeric cinchona alkaloid-derived amino-thiocarbamate. In order to resolve this problem, we decided to look again into the feasibility of using proline scaffold for catalyst development. In the midst of synthesizing such proline-derived aminothiocarbamates, we chanced upon an unexpected rearrangement and obtained the S-alkyl thiocarbamate catalyst 10

Scheme 7. Scope of the asymmetric bromolactonization. Chirality DOI 10.1002/chir

STEREOSELECTIVE BROMOFUNCTIONALIZATION OF ALKENES

would be synthetically inconvenient. In contrast, the prolinederived amino-thiocarbamate has a total of four modifiable handles, which is more conveniently accessible via conventional synthesis (Fig. 2). Amino-thiocarbamates as Asymmetric Bromoaminocyclization Catalysts

The scope of the amino-thiocarbamate catalyst was found not to be limited to enantioselective bromolactonization. In another series of studies, we found that alkenoic amides 13, 15, and 17 were amenable to asymmetric bromoaminocyclization with the cinchona alkaloid-derived aminothiocarbamate catalysts (Scheme 10).61–63 Crucial to the success of the reaction was the need for the 4-nosyl substituent over at the amide end of the substrate. This is presumably to make the amide proton reasonably acidic enough to be captured by the quinuclidine nitrogen of the catalyst. Similar to the results from asymmetric bromolactonization, we found that the tuning of substituents at both R1 and R2 sites of catalyst 12 as well as changes in solvent and brominating agent could lead to enhanced enantioselectivity. More important, the products of this bromoaminocyclization are interesting pyrrolidine and piperidine scaffolds. Chiral Cyclic Selenides as Asymmetric Bromoaminocyclization Catalysts Scheme 8. Enantioselective bromolactonization of other olefinic acid substrates.

(Scheme 9).60 Interestingly, 10 proved to be a very competent asymmetric bromolactonization catalyst for that of 1,1disubstituted hexenoic acid. Equally interesting is the observation that the O-alkyl variant of proline derived thiocarbamate 11 was needed again for the highly enantioselective bromolactonization of 1,1-disubstituted pentenoic acids. In addition to the availability of both (R) and (S) enantiomers of proline, another important advantage of using the proline scaffold to develop a competent asymmetric bromofunctionalization catalyst is the increased number of modifiable handles. While we were able to demonstrate the tunability of the cinchona alkaloid-derived amino-thiocarbamates, further modification beyond the two mentioned sites (cf. catalysts 8 and 9, Scheme 8)

Scheme 9. S-alkyl and O-alkyl thiocarbamate.

Despite the success that we obtained with the aminothiocarbamate scaffold, we were still interested to find a more reactive catalyst. Eventually, we noticed that the analog of thiocarbamate, a selenocarbamate catalyst, could catalyze the reaction with a higher efficiency. However, the selenocarbamate proved to be unstable and later we synthesized the more stable di-alkyl selenides instead.64 Mannitol, an inexpensive and commercially available natural product, was used to construct the catalyst. In addition, from a synthetic point of view, the hydroxyl groups provide convenient handles to attach various substituents for tuning the catalyst’s steric and electronic properties. The ability of selenides as Lewis base activators was also demonstrated by Denmark and Burk in their previous studies on the bromo- and iodolactonization as well as the cycloetherification reactions.56 Having screened a series of mannitol-derived cyclic selenides, we determined selenide 19 to be especially good at providing enantioenriched pyrrolidines 21 from a bromoaminocyclization (Scheme 11). Interestingly, the reaction requires a 3-nosyl substituent at the amide end in contrast to the 4-nosyl substituent for the amino-thiocarbamate catalyzed reaction (Scheme 10). In addition, trisubstituted alkenoic amides 20 were amenable to this asymmetric bromoaminocyclization reaction. This is a substrate that did not work particularly well with the cinchona alkaloid derived amino-thiocarbamates. Unlike the bifunctional amino-thiocarbamates, it appears that the mannitol-derived selenide does not possess the other

Fig. 2. Modifiable handles of the proline derived amino-thiocarbamate. Chirality DOI 10.1002/chir

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racemization via an olefin-to-olefin transfer while the amide nucleophile could attack the bromonium intermediate D to give the desired product. The products of bromolactonization are useful for transformation into higher-value intermediates. For example, γ-lactone 4b could be subjected into a three-step transformation into 24, which is a precursor of the VLA-4 antagonist (Scheme 13).65 Also, debromination of γ-lactone 4c with nBu3SnH and AIBN led to (R)-(+)-Boivinianin A in one step (Scheme 14).66,67 The product of the bromoaminocyclization could also be converted into useful synthetic intermediates. For example, piperidine 16a could undergo a silver salt-mediated rearrangement to give the 3-aryl piperidine 25. Subsequent dehydroxylation followed by deprotection furnished piperidine 27, a precursor of ( )-3-PPP Preclamol.68(Scheme 15) NBS-INITIATED MULTICOMPONENT REACTIONS (MCRS)

Scheme 10. Scope of enantioselective bromoaminocyclization.

Multicomponent reactions (MCRs) allow the assembly of several simple reactants into a complex structure in one-pot. Typically, multicomponent products are assembled by a cascade of nucleophilic and/or electrophilic reactions. The unifying objectives of these one-pot reactions are to achieve atom economy and selectivity in a single reaction under mild conditions to produce myriad different products. Several reviews documented MCRs as a useful strategy in many applications ranging from organic synthesis to chemical biology. 69–72 Some examples of MCRs such as Strecker synthesis,73,74 Hantzsch reaction,75 Biginelli reaction,76,77 Mannich reaction,78 and Ugi reaction79,80 are well documented. In comparison, electrophilic MCRs have been less reported.81–88 A likely reason might be due to the common incompatibility of electrophiles with the other components. Nonetheless, one of the key interests in our laboratory is the development of NBS-initiated multicomponent reactions.89–94 In these MCRs, we postulated that the olefinic substrate could react with NBS to form the three-member bromonium ion system E, followed by the nucleophilic attack by the primary (the first attack) and the secondary (the second attack) nucleophiles in a cascade manner (E → F → G) to yield product G (Scheme 16). Development of Aminoalkoxylation MCR

Scheme 11. Cyclic selenide catalyzed asymmetric bromoaminocyclization.

functional group that may activate either the bromine source or the substrate. We thus proposed a preliminary mechanism involving the activation of bromine by the chiral selenide to generate intermediate C (Scheme 12). The selenide could possibly remain attached to the bromonium to avoid potential

Based on the knowledge on the formation of bromonium cation ring1–10,24–28 and the cascade reactions, 95–100 and after an initial search for appropriate nucleophilic partners, we eventually developed an electrophilic aminoalkoxylation reaction using cyclic ether and sulfonamide. In this cascade, we speculated that a cyclic ether could act as the primary nucleophile in the opening of the bromonium cation ring to form an oxonium cation which could then be captured by an amine

Scheme 12. Proposed mechanism of dialkyl cyclic selenide catalyzed asymmetric bromoaminocyclization. Chirality DOI 10.1002/chir

STEREOSELECTIVE BROMOFUNCTIONALIZATION OF ALKENES

Scheme 13. Synthesis of VLA-4 antagonist precursor 24 from 4b.

Scheme 14. Synthesis of (R)-(+)-Boivinianin A.

Scheme 15. Synthesis of ( )-3-PPP Preclamol intermediate 27.

(the secondary nucleophile) to form the corresponding amino ether derivative (Scheme 17). We began by examining the cascade reaction using cyclohexene, NBS, tetrahydrofuran (THF), and primary amines 28 (Table 3). It was found that the relatively electron-rich amines such as isopropyl amine (28a) and p-nitroaniline (28b) did not return with any product. In comparison, the weakly nucleophilic sulfonamides 28c to 28f gave good to excellent yield of the desired products. The highest yield of

all the amines screening was 4-nosyl sulfonamide, which resulted in 95% of the desired bromo aminoether (Table 3, 28f). After a systematic investigation, we found that this new reaction protocol is applicable to a wide range of olefins. Some examples are shown in Table 4, which include the bromoaminoether derivatives derived from trisubstituted (Table 4, 29a and 29d), acyclic and benzylic olefins (Table 4, 29b and 29c). The chemoselectivity of these olefinic substrates are depicted by 29a and 29d, where in both cases the reaction took place at the electron-rich alkenes and only the Markovikov-type products were isolated. It is also worth noting that 29e and 29f were the only stereoisomers isolated from their corresponding allylic substituted olefins. In addition, it was found that, other than THF, various sizes of cyclic ethers could be utilized to offer the corresponding amino ether derivatives (Table 4, 29g and 29h). Among various brominating sources such as Et2SBr · SbCl5Br,100 PyHBr3, nBu4NBr3, and 2,4,4,6-tetrabromo-2,5-cyclohexadienone (TBCO), NBS was found to be the most effective. It is worth mentioning several unique features in the above novel electrophilic aminoalkoxylation reaction: 1) The addition of an external NBS activator was not necessary. In fact, adding Lewis acid catalyst [e.g. BF3 · Et2O or Cu(OTf)2] led to a decrease in reaction yield101–105; 2) NBS was found to be superior to other similar halogen sources such as NCS and NIS; 3) the reaction proceeded equally smoothly when 10 equivalent of THF in CH2Cl2 was used; 4) increasing the reaction scale to 1.0 g had no detrimental effect in efficiency. In 2011, Braddock and co-workers reported an intramolecular bromonium ion-assisted epoxide ring opening reaction.87 We then applied this methodology in the synthesis of pharmaceutically important morpholines.106 For instance, a norepinephrine-dopamine releasing agent phenmetrazine107 and an anorexigenic drug Bontril108 could be prepared efficiently by using β-methylstyrene and ethylene oxide as the starting materials.(Scheme 18)

Scheme 16. Design of NBS-initiated MCR. Chirality DOI 10.1002/chir

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Scheme 17. NBS-initiated electrophilic aminoalkoxylation cascade.

TABLE 3. Scope of amines in the electrophilic aminoalkoxylation of cyclohexene

TABLE 4. Scope of electrophilic NBS initiated aminoalkoxylation

2,2,6-Trisubstituted Morpholine Derivatives From NBS-Initiated MCR

After the development of the above-mentioned aminoalkoxylation methodology, we further applied it to the synthesis of other morpholine systems. However, a challenging task was encountered. When a monosubstituted epoxide 33 was used as the counter nucleophilic partner, the corresponding oxonium intermediate could be opened in an anti-Markovnikov Chirality DOI 10.1002/chir

(path A) or a Markovnikov (path B) fashion (Scheme 19). After extensive studies, it was interesting to find that the use of epichlorohydrin, a relatively electron-deficient epoxide, resulted in a high anti-Markovnikov selectivity while other monosubstituted epoxides (e.g., propylene oxide) gave very low positional selectivity (1:1 for propylene oxide). The resulting MCR product 34a could easily be converted into 2,2,6-trisubstituted morpholine, which is an important pharmacophore.109–112

STEREOSELECTIVE BROMOFUNCTIONALIZATION OF ALKENES

Scheme 18. Synthesis of pharmaceutically important morpholines.

Scheme 19. Reaction pathways of aminoalkoxylation using monosubstituted epoxide.

A number of 2,2,6-trisubstituted morpholines could be prepared using this MCR followed by cyclization. Some selected examples are shown in Scheme 20. Although the role played by the chlorine atom in epichlorohydrin remains elusive,113 it was found that epichlorohydrin could assist to desymmetrize the 4-substituted 1-methylenecyclohexane in the cascade reaction. For example, when enantiopure (R)-epichlorohydrin and olefin 35 were used, enantiopure 36 was isolated as a single diastereomer exclusively (Scheme 20). NBS-Initiated Electrophilic Alkoxyetherification

After demonstrating broad applications through the modification of the primary nucleophile cyclic ether,89 we were also interested to further elaborate this methodology by changing the sulfonamide partner. In 2011, we reported a MCR by the replacement of the sulfonamide with a carboxylic acid in the cascade shown in Scheme 17 which could give the corresponding alkoxyether derivative (Scheme 21).92 In our initial studies using cyclohexene, acetic acid, NBS, and THF, the alkoxyetherification under various concentrations was found to be influential in the reaction yield. For example, at a diluted condition of 0.04 M compared to 0.13 M resulted in a two-fold increase in reaction yield. Various carboxylic acids were then subjected to investigation. It was found that the reaction yield varied with the acidity of the carboxylic acid partner (Table 5). For example, comparing to benzoic acid (37c) (pKa = 4.20), a higher yield were obtained with relatively

more acidic carboxylic acid such as pentafluorobenzoic acid (37a); while less acidic 4-methylbenzoic acid (37d) (pKa = 4.34) and 4-methoxybenzoic acid (37e) (pKa = 4.47) resulted in lower yields. Interestingly, hydroxyl carboxylic acids 37f to 37i exclusively formed the carboxylate-adducts in high reaction yields and the hydroxyl groups remained intact (Table 5). Similar to the aminoalkoxylation reaction, a large substrate scope was achieved and the products were generally obtained with excellent positional-, chemo-, and stereoselectivity. Again, the cyclic ether could be varied to furnish the corresponding alkoxyethers. This methodology has since been documented as one of the new chemistry of four- and fivemembered oxygen-containing heterocycles.114,115 Some selected examples are listed in Figure 3. Having established alkoxyetherification as a useful methodology, we recently reported the use of phenol in place of carboxylic acid in the same MCR cascade. In this reaction, the electron-deficient p-nitrophenol was found to be the most effective counter nucleophile. During the reaction, it was noticed that the phenol unit was brominated in the same pot to offer the 2,6-dibrominated phenyl ether derivative 39.94 Further coupling of 39 with alkynes furnished 40, which is a potential framework for ligand preparation and self-assembly complex in material chemistry.116 The scope of this reaction was equally highly chemo- and regioselective with regard to various olefinic substrates and different ring size of cyclic ether (Scheme 22). Chirality DOI 10.1002/chir

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Scheme 20. Substrate scope and desymmetrization of 35.

Scheme 21. NBS-initiated one-pot alkoxyetherification.

TABLE 5. Alkoxyetherification of cyclohexene using various oxygen nucleophiles

NBS-Initiated One-pot Synthesis of Imidazoline and Guanidine

Other than the modifications described in the above two sections, concurrently we attempted to seek for other partners in place of the cyclic ether. Eventually, we noticed that nitrile could replace cyclic ether in this type of MCR to offer the amidine product.90 Subsequent Chirality DOI 10.1002/chir

cyclization of the bromoamidine gave the imidazoline, which is the fundamental unit of natural products, biologically active molecules, organocatalysts, and metal complexation ligands.117–136 Some examples are shown in Scheme 23. We believed that this Ritter-type reaction proceeded through the mechanism similar to the one illustrated in Scheme 17.

STEREOSELECTIVE BROMOFUNCTIONALIZATION OF ALKENES

Fig. 3. Selected examples of alkoxyetherification products.

Scheme 22. NBS-promoted phenoxyetherification.

Interestingly, when α-pinene was subjected to the reaction, ring-opening product 41 was isolated exclusively. We postulated that the formation of 41 might undergo a bromonium ion-initiated rearrangement depicted in Scheme 24. Further study on the racemization of this bicycloamidine has since been reported.137 We anticipated that a similar reaction should take place when replacing the nitrile with cyanimide. As expected, the reaction proceeded smoothly, which furnished the desired guanidine compound (Scheme 25).91 The practicality of both imidazoline and guanidine syntheses was demonstrated with a total of 43 examples that afforded up to 99% yield. Again, this

type of MCR was applicable to a variety of olefins. In some cases, bromoamidine and bromoguanidine were isolated without further cyclization. Nevertheless, the desired imidazoline and guanidine cyclized products could be obtained by simply heating the reaction mixtures. By using this methodology, guanidine 42, a precursor of a rTRTVI antagonist,138 could be synthesized in a one-pot fashion (Scheme 26). Mechanistic Insights

For all of the MCRs described in the above four sections, it was found that the reactions proceeded smoothly without any Chirality DOI 10.1002/chir

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Scheme 23. Synthesis of imidazoline using the MCR process.

Scheme 24. Proposed mechanism for the formation of 41.

Scheme 25. NBS-initiated one-pot synthesis of guanidine.

Scheme 26. Synthesis of 42 in one-pot. Chirality DOI 10.1002/chir

STEREOSELECTIVE BROMOFUNCTIONALIZATION OF ALKENES

Fig. 4. Proposed activation modes of NBS.

Scheme 27. Two proposed mechanistic pathways.

additional NBS activator. Typically, catalyst (either Lewis base or acid)138–140 is required to activate NBS in the electrophilic halogenation process. Since we discovered that the reaction efficiency was highly dependent on the acidity of the nucleophilic partners (sulfonamides and carboxylic acids), we speculated that the acidic partners might act as the activator. Two possible activation modes are shown in Figure 4. The first one involves a hydrogen-bond coordination which enhances the electrophilicity of the brominating agents (mode H). The second one involves the generation of a more reactive brominating agent through a halogen exchange process; 1H NMR studies support the existence of NsNHBr (mode I). Taking the alkoxyetherification MCR as an example, a mechanistic proposal is shown in Scheme 27. For the activation mode H, species 45 might react with the olefinic substrate to yield bromonium ion intermediate 48. Subsequent nucleophilic attack of 48 by a molecule of cyclic ether could give an ion pair intermediate 49. Finally, oxonium ring-opening by the attack of the carboxylate anion accompanied by the elimination of a molecule of succinimide could furnish the alkoxyether derivative. On the other hand, species 47, which could be generated by the elimination of a succinimide from species 45, could react with the olefin to give bromonium ion 50. The cyclic ether could then attack 50 to yield an ion pair intermediate 51. Again, the collapse of 51 could offer the desired alkoxyether. This proposal

can also explain why the hydroxyl group did not open the oxonium ion ring as the collapsing of species 49 (or 51) seems to be more favorable by the attack of the more nucleophilic carboxylate anion. CONCLUSION

In this account, we outlined the rational modification of our catalyst design from a simple thiocarbamate to an aminothiocarbamate for the enantioselective bromocyclization reactions. The nuances of the reaction which include appropriate halogen source and optimal solvent were also described. Our eventual discovery of the competence of S-alkyl thiocarbamate as an asymmetric bromolactonization catalyst provided further mechanistic insights. In addition, the concept of using a monofunctional chalcogen as an NBS activator was delineated in the design of the C2-symmetric cyclic selenium catalyst for the enantioselective bromoaminocyclization. In the realm of MCR, we outlined our development of two one-pot NBS-initiated MCRs, electrophilic aminoalkoxylation and alkoxyetherification, which exhibit high chemo- and regioselectivity with only the Markovnikovtype product isolated. Our methodologies provide a practical and efficient alternative to the synthesis of imidazoline, guanidine, morpholine, and phenoxy functionalized ether derivatives under mild reaction conditions. In one of the Chirality DOI 10.1002/chir

TAN ET AL.

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Stereoselective bromofunctionalization of alkenes.

The stereoselective bromofunctionalization of alkenes, particularly the enantioselective format, has been a subject of intense research in recent year...
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