Preparation of Chiral Enantioenriched Densely Substituted Cyclopropyl Azoles, Amines, and Ethers via Formal SN2′ Substitution of Bromocylopropanes

Enantiomerically enriched cyclopropyl ethers, amines, and cyclopropylazole derivatives possessing three stereogenic carbon atoms in a small cycle are obtained via the diastereoselective, formal nucleophilic substitution of chiral, non-racemic bromocyclopropanes. The key feature of this methodology is the utilization of the chiral center of the cyclopropene intermediate, which governs the configuration of the two adjacent stereocenters that are successively installed via 1,4-addition/epimerization sequence.


Results and Discussion
This section may be divided by subheadings. It should provide a concise and precise description of the experimental results, their interpretation, and the experimental conclusions that can be drawn. In our earlier studies of the formal nucleophilic substitution of bromocyclopropanes, we have demonstrated several reaction modes that allow for efficient control of the diastereoselectivity of this transformation (Scheme 1). Thus, it was shown that the derivatives of 2-bromocyclopropylcarboxylic acid 4 produced achiral cyclopropene 5 upon treatment with base. The latter underwent in situ addition of nucleophiles to afford trans-cyclopropane 6. The high diastereoselectivity of the addition was attributed to a base-assisted, thermodynamically driven epimerization of the tertiary carbon atom (C-1, mode A, Scheme 1) [ [59][60][61][62][63]. Alternative approaches to control the diastereoselectivity of the intermolecular nucleophilic substitution were also developed by utilizing 1,2,2-trisubstituted cyclopropanes as the starting materials. The first approach employs substrates bearing two substituents with significantly different steric demands (7, small RS, and large RL). The in situ generated achiral cyclopropene 8 undergoes nucleophilic attack at the least hindered face, resulting in selective formation of product 9 (Scheme 1, mode B) [62,63]. The second approach takes advantage of bromocyclopropane 10, bearing a directing functionality (DG, typically carboxamide or carboxylic acid group) capable of efficient coordination to the potassium cation, which serves as a delivery vehicle for the nucleophilic counter-anion. Overall, the addition to the double bond of cyclopropene 11 proceeds in cis fashion, with respect to the directing functional group furnishing 12 with high diastereoselectivity (Scheme 1, mode C) [62,63]. The addition of a tethered alkoxide entity was also investigated; both exo-trig (Scheme 1, mode D) [64,65]

Results and Discussion
This section may be divided by subheadings. It should provide a concise and precise description of the experimental results, their interpretation, and the experimental conclusions that can be drawn. In our earlier studies of the formal nucleophilic substitution of bromocyclopropanes, we have demonstrated several reaction modes that allow for efficient control of the diastereoselectivity of this transformation (Scheme 1). Thus, it was shown that the derivatives of 2-bromocyclopropylcarboxylic acid 4 produced achiral cyclopropene 5 upon treatment with base. The latter underwent in situ addition of nucleophiles to afford trans-cyclopropane 6. The high diastereoselectivity of the addition was attributed to a base-assisted, thermodynamically driven epimerization of the tertiary carbon atom (C-1, mode A, Scheme 1) [59][60][61][62][63]. Alternative approaches to control the diastereoselectivity of the intermolecular nucleophilic substitution were also developed by utilizing 1,2,2-trisubstituted cyclopropanes as the starting materials. The first approach employs substrates bearing two substituents with significantly different steric demands (7, small R S , and large R L ). The in situ generated achiral cyclopropene 8 undergoes nucleophilic attack at the least hindered face, resulting in selective formation of product 9 (Scheme 1, mode B) [62,63]. The second approach takes advantage of bromocyclopropane 10, bearing a directing functionality (DG, typically carboxamide or carboxylic acid group) capable of efficient coordination to the potassium cation, which serves as a delivery vehicle for the nucleophilic counter-anion. Overall, the addition to the double bond of cyclopropene 11 proceeds in cis fashion, with respect to the directing functional group furnishing 12 with high diastereoselectivity (Scheme 1, mode C) [62,63]. The addition of a tethered alkoxide entity was also investigated; both exo-trig (Scheme 1, mode D) [64,65] and endo-trig (mode E) [66] modes efficiently provided the corresponding medium-size heterocycles 15 and 18. endo-trig (mode E) [66] modes efficiently provided the corresponding medium-size heter ocycles 15 and 18.
Attempts to extend this methodology beyond the trisubstituted cyclopropane sub strates greatly amplify the challenge of controlling the stereoselectivity of the addition Indeed, all the modes discussed above require the control of a single center only, since the two forming chiral centers are linked to each other. In 2013, we communicated on the realization of a more advanced strategy, involving two modes of diastereoselctivity con trol providing tetrasubstituted cyclopropyl ethers 23 (mode F, Scheme 2) [67]. The proo of concept of such a strategy was showcased on racemic bromocyclorporpanes 20. We also demonstrated employing racemic substrates, i.e., that the relative configuration of the cen ter at C-3 can be efficiently controlled by steric environment employing appropriate sub stituents RS, RL; thus, control of this step is related to mode B. Finally, relative configura tion at C-1 was installed via the base-assisted epimerization of this center, in a process identical to the one, previously used in mode A (Scheme 2) [66,67]. We reasoned that the absolute configuration of the quaternary stereogenic center at C-2 in chiral non-racemic amide 20 would be preserved during the dehydrohalogenation/nucleophilic addition se quence, which can be used to access to enantiomerically enriched compounds 23. Scheme 2. "Dual" control of diastereoselectivity-a new mode of formal nucleophilic substitution of bromocyclopropanes.
In order to access the densely substituted enantiopure cyclopropanes, we have de veloped a very facile protocol for the chiral resolution of carboxylic acids 19, utilizing the re-crystallization of racemic acids with cinchona alkaloids [68]. It was shown that a variety of enantiomerically enriched acids 19 with ee > 95% were available in multi-gram scale, in both enantiomeric forms after single crystallization of either cinchonine or cinchonidine salts. Enantiopure acids can easily be converted into amides 20, as a precursor for enanti oenriched cyclopropenes (Scheme 3).  In order to access the densely substituted enantiopure cyclopropanes, we have developed a very facile protocol for the chiral resolution of carboxylic acids 19, utilizing the re-crystallization of racemic acids with cinchona alkaloids [68]. It was shown that a variety of enantiomerically enriched acids 19 with ee > 95% were available in multi-gram scale, in both enantiomeric forms after single crystallization of either cinchonine or cinchonidine salts. Enantiopure acids can easily be converted into amides 20, as a precursor for enantioenriched cyclopropenes (Scheme 3).  [66] modes efficiently provided the corresponding medium-size heterocycles 15 and 18. Attempts to extend this methodology beyond the trisubstituted cyclopropane substrates greatly amplify the challenge of controlling the stereoselectivity of the addition. Indeed, all the modes discussed above require the control of a single center only, since the two forming chiral centers are linked to each other. In 2013, we communicated on the realization of a more advanced strategy, involving two modes of diastereoselctivity control providing tetrasubstituted cyclopropyl ethers 23 (mode F, Scheme 2) [67]. The proof of concept of such a strategy was showcased on racemic bromocyclorporpanes 20. We also demonstrated employing racemic substrates, i.e., that the relative configuration of the center at C-3 can be efficiently controlled by steric environment employing appropriate substituents RS, RL; thus, control of this step is related to mode B. Finally, relative configuration at C-1 was installed via the base-assisted epimerization of this center, in a process identical to the one, previously used in mode A (Scheme 2) [66,67]. We reasoned that the absolute configuration of the quaternary stereogenic center at C-2 in chiral non-racemic amide 20 would be preserved during the dehydrohalogenation/nucleophilic addition sequence, which can be used to access to enantiomerically enriched compounds 23. Scheme 2. "Dual" control of diastereoselectivity-a new mode of formal nucleophilic substitution of bromocyclopropanes.
In order to access the densely substituted enantiopure cyclopropanes, we have developed a very facile protocol for the chiral resolution of carboxylic acids 19, utilizing the re-crystallization of racemic acids with cinchona alkaloids [68]. It was shown that a variety of enantiomerically enriched acids 19 with ee > 95% were available in multi-gram scale, in both enantiomeric forms after single crystallization of either cinchonine or cinchonidine salts. Enantiopure acids can easily be converted into amides 20, as a precursor for enantioenriched cyclopropenes (Scheme 3).

Alcohol Nucleophiles
With enantiomerically pure amides in hand, we have utilized the "dual control" mode of the formal nucleophilic substitution of bromide with various alkoxides (Scheme 4). At 40 • C in DMSO, bromocyclopropanes 20 were converted to the corresponding cyclopropanes 23. Primary alcohols served as excellent nucleophiles for the title reaction, with diastereoselectivity greater than 25:1 in all cases. We demonstrated that this methodology is complementary to our previous report, providing an easy access to the enantiopure cyclopropyl ethers.
Molecules 2022, 27, x FOR PEER REVIEW 4 of 16 Scheme 3. Preparation of homochiral 1-bromocyclopropylcarboxamides employed as starting materials in these studies.

Alcohol Nucleophiles
With enantiomerically pure amides in hand, we have utilized the "dual control" mode of the formal nucleophilic substitution of bromide with various alkoxides (Scheme 4). At 40 °C in DMSO, bromocyclopropanes 20 were converted to the corresponding cyclopropanes 23. Primary alcohols served as excellent nucleophiles for the title reaction, with diastereoselectivity greater than 25:1 in all cases. We demonstrated that this methodology is complementary to our previous report, providing an easy access to the enantiopure cyclopropyl ethers.

Azole Nucleophiles
The nitrogen-based nucleophiles in our original report have been explored to a lesser extent. Therefore, we became interested in utilizing homochiral amides 20 for the generation of the corresponding cyclopropyl amines. We tested a series of different amines as Npronucleophiles; however, our initial attempts to induce the addition primary and secondary alkyl amines, as well as carboxamides and sulfonamides, were unsuccessful. We were pleased to find that the azoles underwent a facile addition to cyclopropenes to provide substituted hetarylcyclopropanes in an optically pure form (Scheme 5). The reaction in the presence of pyrrole afforded the corresponding tetrasubstituted cyclopropanes (+)-23cag and (+)-23dag in high yields and with excellent diastereoselectivities. We were glad to find that such problematic nucleophiles, such as indoles, known for their susceptibility to Friedel-Crafts alkylation, dimerization, and polymerization, afforded good, isolated yields of the corresponding adducts. Substituted indoles and 7-azaindole proceeded cleanly to afford the corresponding cyclopropanes. Similarly, pyrazole was engaged in a very efficient transformation with enantiomerically pure cyclopropyl bromide, providing (+)-23cah in good, isolated yield, although longer reaction times were reacquired, and the diastereoselectivity was slightly lower. More acidic azoles, including imidazoles, 18-crown-6 (cat)/t-BuOK

Azole Nucleophiles
The nitrogen-based nucleophiles in our original report have been explored to a lesser extent. Therefore, we became interested in utilizing homochiral amides 20 for the generation of the corresponding cyclopropyl amines. We tested a series of different amines as N-pronucleophiles; however, our initial attempts to induce the addition primary and secondary alkyl amines, as well as carboxamides and sulfonamides, were unsuccessful. We were pleased to find that the azoles underwent a facile addition to cyclopropenes to provide substituted hetarylcyclopropanes in an optically pure form (Scheme 5). The reaction in the presence of pyrrole afforded the corresponding tetrasubstituted cyclopropanes (+)-23cag and (+)-23dag in high yields and with excellent diastereoselectivities. We were glad to find that such problematic nucleophiles, such as indoles, known for their susceptibility to Friedel-Crafts alkylation, dimerization, and polymerization, afforded good, isolated yields of the corresponding adducts. Substituted indoles and 7-azaindole proceeded cleanly to afford the corresponding cyclopropanes. Similarly, pyrazole was engaged in a very efficient transformation with enantiomerically pure cyclopropyl bromide, providing (+)-23cah in good, isolated yield, although longer reaction times were reacquired, and the diastereoselectivity was slightly lower. More acidic azoles, including imidazoles, benzimidazoles, and triazoles, did not participate in the title reaction, due to deactivation of the base in the reaction media, thus preventing the generation of the cyclopropane intermediate. The sensitivity of the reaction to sterics can be seen by comparing the reactivity of bromocyclo-propanes possessing a methyl and an ethyl group, respectively, at the β-quaternary center. Compared to methyl-tolyl cyclopropane (+)-23cag, its ethyl/phenyl isomer reacted very sluggishly at 40 • C and required higher temperature to achieve full conversion, which led to a lower, although still respectable, diastereoselectivity of 15:1 for 23aag. To our delight, the carboxamide, possessing a larger naphthyl substituent, also participated in the substitution reaction with pyrrole, giving (+)-23dag as a single enantiomer.
benzimidazoles, and triazoles, did not participate in the title reaction, due to deactivation of the base in the reaction media, thus preventing the generation of the cyclopropane intermediate. The sensitivity of the reaction to sterics can be seen by comparing the reactivity of bromocyclopropanes possessing a methyl and an ethyl group, respectively, at the β-quaternary center. Compared to methyl-tolyl cyclopropane (+)-23cag, its ethyl/phenyl isomer reacted very sluggishly at 40 °C and required higher temperature to achieve full conversion, which led to a lower, although still respectable, diastereoselectivity of 15:1 for 23aag. To our delight, the carboxamide, possessing a larger naphthyl substituent, also participated in the substitution reaction with pyrrole, giving (+)-23dag as a single enantiomer.

Aniline Nucleophiles
Anilines were also tested in this reaction, and, to our delight, N-methylaniline gave a cyclopropyl amine (+)-23ack in 55% and dr 3:1. p-Flouro-N-methylaniline can be utilized in the described reaction, providing a tetrasubstituted cyclopropane (+)-23acm with similar diastereoselectivity and yield. It was found that increased steric hindrance at the N- 18-crown-6 (cat)

Aniline Nucleophiles
Anilines were also tested in this reaction, and, to our delight, N-methylaniline gave a cyclopropyl amine (+)-23ack in 55% and dr 3:1. p-Flouro-N-methylaniline can be utilized in the described reaction, providing a tetrasubstituted cyclopropane (+)-23acm with similar diastereoselectivity and yield. It was found that increased steric hindrance at the Ntermini of the pronucleophile had a significant effect on the reaction course. Thus, aniline bearing an ethyl substituent greatly increased the reaction's efficacy; the diastereoselectivity increased to 13:1 for (+)-23acl. The utilization of naphtyl-substituted bromocyclopropane precursor gave exclusive formation of (+)-23dal (Scheme 5). Unfortunately, anilines with the secondary alkyl group at the nitrogen atom did not participate in this reaction, most likely due to the excessive steric demands (compound 23ddl in Scheme 5).

General
NMR spectra (See Supporting Information, Figures S1-S32) were recorded on a Bruker Avance DRX-500 (500 MHz) with a dual carbon/proton cryoprobe (CPDUL). 13 C NMR spectra were registered with broadband decoupling. The (+) and (−) designations represent positive and negative intensities of signals in 13 C DEPT-135 experiments. Numbers of magnetically equivalent carbons for each signal in 13 C NMR spectra (unless it is one) are also reported. IR spectra were recorded on a ThermoFisher Nicolet iS 5 FT-IR Spectrometer. HRMS was carried out on LCT Premier (Micromass Technologies) instrument, employing ESI TOF detection techniques. Glassware used in moisture-free syntheses was flame-dried in vacuum prior to use. Column chromatography was carried out on silica gel (Sorbent Technologies, 40-63 mm). Precoated silica gel plates (Sorbent Technologies Silica XG 200 mm) were used for TLC analyses. Anhydrous dichloromethane was obtained by passing degassed commercially available HPLC-grade inhibitor-free solvent consecutively through two columns filled with activated alumina and stored over molecular sieves under nitrogen. Water was purified by dual stage deionization, followed by dual stage reverse osmosis. Anhydrous THF was obtained by refluxing commercially available solvent over calcium hydride, followed by distillation in a stream of dry nitrogen. All other reagents and solvents were purchased from commercial vendors and used as received. Diastereomeric ratios of products were measured by GC and NMR analyses of crude reaction mixtures. In the event where minor diastereomer was not detected by either of these methods, ratio >100:1 was reported. 33 mmol, 1.00 equiv.), DMF (10 mL), and anhydrous dichloromethane (40 mL). The mixture was treated with oxalyl chloride (563 µL, 6.50 mmol, 1.50 equiv.) at 0 • C, stirred for 15 min, warmed to room temperature, and additionally stirred for 2 h. The solvent was removed in vacuum, and the crude acyl chloride was dissolved in dry THF (20 mL), followed by addition of a solution of tert-butyl amine (24a) (1.35 mL, 12.8 mmol, 2.97 equiv.) in THF (20 mL). The reaction mixture was stirred overnight. After the reaction was complete, the solvent was removed in vacuum, and the residue was partitioned between EtOAc (25 mL) and water (25 mL). The organic phase was separated, and the aqueous layer was extracted with EtOAc (2 × 25 mL). The combined organic phases were dried (MgSO 4 ), filtered, and concentrated. The residual crude oil was purified by column chromatography on silica gel. The titled compound obtained a colorless solid, mp: 83. .0 • C, R ƒ 0.55 (hexanes/EtOAc 6:1), [α] D = +14.0 • (c 0.172, CH 2 Cl 2 ). Yield 1.03 g (3.32 mmol, 77%). Spectral properties of this material were identical to those reported for the racemic amide [67]. . Yield 240 mg (0.700 mmol, 70%). Spectral properties of this material were identical to those reported for the racemic amide [67].

Conclusions
In conclusion, a highly efficient method for the assembly of tetrasubstituted chiral non-racemic cyclopropanes with all three asymmetric carbons in the strained ring was demonstrated. This method utilizes a "dual-control" strategy, which was successfully employed for the highly diastereoselective addition of the nucleophilic species to in situ generated enantiomerically enriched cyclopropenes. The chiral integrity of the starting material was translated to the product via the sequential installation of two stereogenic centers that were efficiently controlled by steric and thermodynamic effects. Alkoxides, as well as nitrogen-based nucleophiles (azoles and anilines), were used to access the homochiral derivatives of cyclopropyl ethers and cyclopropylamines. These reactions proceeded smoothly, affording unusually conformationally constrained amide derivatives of densely substituted enantiomerically enriched β-amino acids possessing three contiguous stereogenic carbon atoms. It should be also pointed out that one of these centers is an all-carbon-substituted quaternary stereocenter, the installation of which, by traditional methods, represents a long-standing challenge.