Notably, the chemoselectivity of this reaction is complementary to previous studies in which alkoxy-substituted donor-acceptor cyclopropanes are converted to thioamides.3,6. We prepared the enantio-enriched cyclopropane (S)-446 according to literature methods and subjected it to our standard reaction conditions (Scheme 5.6.1).12 Although treatment of this substrate with an isocyanate in the presence of iron(III) chloride resulted in complete racemization. of the benzylic stereocenter (Scheme 5.6.1.A),13 we observed a chirality transfer in the case of (3 + 2) cycloadditions mediated by tin(II) triflate (Schemes 5.6.1.B and 5.6.1.C ). We propose that the mechanism of isothiocyanate and carbodiimide reactions with tin(II) triflate involves a stereospecific intimate ion pair mechanism analogous to that invoked by Johnson and co-workers for the (3 + 2) cycloadditions of aldehydes and donor-acceptor cyclopropanes developed in their laboratories (Scheme 5.6.2).4c,d,16 Our observations including stereochemical inversion at the benzylic position, together with.
We have described an efficient method for the formation of pyrrolidinones, thioimidates and amidines from donor-acceptor cyclopropanes. Efforts to develop Lewis acid catalytic conditions as well as conditions for the enantioselective reactions of isocyanates with donor-acceptor cyclopropanes are currently underway.
Experimental Methods and Analytical Data
Materials and Methods
General Experimental Procedures
The appropriate styrene (469, 5.0 mmol) and anhydrous dichloromethane (5 mL) were added and the solution was stirred under nitrogen and cooled in an ice bath. To a separate, oven-dried 1 dram vial was added the appropriate cyclopropane (430, 0.4 mmol) and isothiocyanate (0.8 mmol). To a separate, oven-dried 1 dram vial was added the appropriate cyclopropane (430, 0.4 mmol) and carbodiimide (0.44 mmol).
The appropriate cyclopropane (430, 0.4 mmol) and isocyanate (1.2 mmol) were added to an oven-dried 1-dram vial. To another oven-dried 1-dram vial, the appropriate cyclopropane (0.4 mmol) and isocyanate (1.2 mmol) were added.
Cyclopropane Characterization Data
S)-dimethyl 2-phenylcyclopropane-1,1-dicarboxylate ((S)-446)
Thioimidate Characterization Data
Amidine Characterization Data
Lactam Characterization Data
Notes and References
Stereoselective (3 + 2) reactions of donor–acceptor cyclopropanes with aldimines
Additional examples of stereoselective cycloadditions of donor–acceptor cyclopropanes can be found in the review articles in reference 1
Chemoselectivity comparable to that observed in our studies has been shown in a palladium-catalyzed (3 + 2) cycloaddition of isothiocyanates with aziridines, see
Two methods were used to set up reactions with dry iron(III) chloride: (a) iron(III) chloride stored in a nitrogen-filled glovebox was dispensed into a flame-
Prolonged exposure of cyclopropane (R)-446 to Sn(OTf) 2 results in racemization
Methyl and phenyl hydrogen atoms and the bromide counterion are omitted for clarity
Ray Crystallography Reports Relevant to Chapter 5
Introduction
Aziridines are versatile intermediates and reaction partners for the preparation of a structurally diverse assortment of nitrogen-containing architectures.1 These heterocyclic compounds are characterized by a unique reactivity profile, due in part to the large strain energy (27 kcal mol-1) contained in their three-membered ring structure,2 making them susceptible to nucleophilic ring opening,3 carbonylation,4 and ring expansion.5 Previous work has demonstrated the utility of 2-arylaziridines in transition metal-mediated and -catalyzed (3 + 2) cycloadditions with heterocumulenes to form imidazolines, 6 a–e oxazolidines, 6d–e iminoazolidinones, 6f–i iminothiazolidines, 6i–k and iminoimidazolidines.6f,I Iminothiazolidines and iminoimidazolidines have been widely used as effective. The critical limitation for the majority of the existing (3 + 2) cycloaddition manifolds is the requirement that aziridine starting materials bear either alkyl or aryl N-substitution. The harsh conditions required to remove such robust groups greatly limit the potential for derivatization and thus the utility of the products.
Nevertheless, the use of N-sulfonyl-protected aziridines in (3 + 2) cycloadditions has been minimally investigated.6a–e,k Prior to our studies, the work of Nadir and co-workers was the only previous study of the (3 + 2) cycloaddition of N-sulfonyl- of 2-arylaziridines with heterocumulenes.6k,9 Their reaction system has a narrow scope and can accommodate only aryl isocyanates and aryl isothiocyanates, resulting in similarly limited possibilities for product derivatization. This transformation depends on the use of alkali metal iodide as a harmless reaction partner; Nadir and co-workers explicitly show the formation of a ring-opened iodide intermediate prior to product formation. Furthermore, only one example is known for the synthesis of enantioenriched iminothiazolidines by stereoselective (3 + 2) cycloaddition6i despite readily available enantioenriched aziridine starting materials. 1,2,6h This method, however, has an extremely narrow substrate scope, requiring the use of N-alkyl- or N-arylaziridines and aryl heterocumulenes.
There are no examples of this transformation with N-sulfonyl-protected aziridines or more synthetically versatile heterocumules.
Initial Reaction Development
Exploration of 2-Aziridine and Heterocumulene Substitution
In contrast to C-aryl-substituted aziridines, C-alkyl-substituted aziridine 517 reacted with allyl isothiocyanates under the reaction conditions to give two isomeric (3 + 2) adducts (Scheme 6.3.2). Formation of the 5-alkyl-substituted iminothiazolidine 518 was accomplished in only 18% yield, while the 4-alkyl-substituted product 519 was provided in 56% yield. While aziridines substituted with C-alkyl are suitable reaction partners in cycloaddition (3 + 2) and heterocyclic products are formed with it.
Effect of Aziridine N-Substitution
Extension of Heterocumulene Scope
Cycloaddition of Disubstituted N-Sulfonylaziridines
- Development of a Stereoselective (3 + 2) Cycloaddition
- Isothiocyanate Substitution in Stereoselective (3 + 2) Cycloaddition
- Effect of Aziridine N-Substitution on Transfer of Chiral Information
- Proposed Mechanism of Stereoselective (3 + 2) Cycloaddition
- Cycloaddition of a Diester Aziridine
The formation of cis -thiazolidines 538 and 541 with excellent chemo-, regio- and diastereoselectivity intimated the potential to develop a multiplicity of stereoselective reactions. Inspired by this result, we were pleased to find that the increase in isothiocyanate equivalents in the presence of Finally, the use of 1.25 equivalents of zinc(II) chloride and 10.0 equivalents of allyl isothiocyanate in dichloromethane at ambient temperature proved optimal, providing (S)-499 in 99% yield and with 94% ee (entry 8).
With optimal conditions identified, we investigated the extent of heterocumulene substitution in the reaction.23 We found that, along with allyl isothiocyanate, primary and secondary alkyl isothiocyanates were all highly compatible under the reaction conditions, affording the desired enantioenriched iminothiazolidines (S) -49 provided, (S)-512, and (S)-513 in uniformly excellent yields and ee (Scheme 6.8.1).13 However, the use of a tertiary isothiocyanate prolonged the reaction time and thiazolidine (S)-546 in reduced yield provided and ee. We hypothesize that the mechanism of the (3 + 2) cycloadditions presented herein proceeds through a stereoselective intimate ion-pair mechanism similar to that reported in our previous work10 and by Johnson24 and Kerr25 in related work on the cycloadditions of donor-acceptor cyclopropanes have been invoked (Scheme 6.10.1). Our observations, including lack of reactivity in the absence of Lewis acid, 11,26-inversion at the benzyl position, greater reactivity of aziridines with electron-rich aryl substituents, and shorter reaction times of N-substituted aziridines with more electron-withdrawing groups are all consistent with.
The formation of (R)-499 under lithium bromide-mediated conditions strongly suggests that we have evolved a Lewis acid-mediated process in contrast to the related alkali metal halide-mediated system reported by Nadir and co-workers, who observe general stereoretention as a result of a double inversion pathway , which proceeds via an iodinated intermediate, and the palladium(II)-catalyzed reaction conditions of Alper and co-workers who also observe the stereoretentive product as the major enantiomer. Given the apparent mechanistic similarities to our previous work, we synthesized diester aziridine 549 to assess the potential for selective activation of the C–. C or C-N bond under our tin(II) or zinc(II) mediated conditions, respectively.27 Unfortunately, Sn(OTf)2 failed to yield any cycloaddition product.28 Alternatively, the use of ZnBr2 yielded thiolactam 550 as the only (3 + 2) adduct (scheme 6.11.1.A).
This is the only thiolactam (3 + 2) cycloaddition product observed during our studies.13 The ability of the malonate group to stabilize the negative charge and. The secondary iminothiazolidine (S)-525 could be rapidly accessed in excellent 91% yield without any loss of enantiomeric excess by detosylation of thiazolidine (S)-499 (Scheme 6.12.1.A)30 or by desulfonylation of the p-nosyl-protected thiazolidine (S)-522 in slightly increased yield (Scheme 6.12.1.B), providing thiazolidine (S)-525 in 87% yield and 94% ee in two steps from (R)-N-(p -nitrobenzenesulfonyl )-2-phenylaziridine.31. Alternatively, cleavage of the allylimine C–N bond of heterocycle (S)-499 in the presence of palladium(0) afforded access to the secondary iminothiazolidine (S)-552 with some loss of enantiomeric excess (Scheme 6.12.1.C).
Iminothiazolidines (S)-525 and (S)-552 are extremely versatile heterocycles
Conclusion
Experimental Methods and Analytical Data
- Materials and Methods
- General Experimental Procedures
- Aziridine Synthesis and Characterization Data
To a flame-dried round bottom flask with a stir bar was added p-toluenesulfonamide (5.60 mmol, 1.40 equiv), tetrakis(acetonitrile)copper(I). The stirred suspension was cooled to 0 °C (ice/H 2 O bath), at which time iodosobenzene (5.60 mmol, 1.40 equiv) was added as a solid in one portion. The stirred suspension was cooled to 0 °C (ice/H 2 O bath), at which time the appropriate sulfonyl chloride (2.19 mmol, 3.00 equiv) was added in one portion.
To an oven-dried 1-dram vial equipped with a magnetic stir bar was added zinc(II) bromide (113 mg, 0.50 mmol, 1.25 equiv), freshly pulverized with a mortar and pestle, in a glove box with an inert atmosphere. The vial was sealed with a screw cap fitted with a Teflon septum and anhydrous CH 2 Cl 2 (0.60 mL) and isothiocyanate (0.80 mmol, 2.00 equiv) were added. The mixture was transferred to the first vial with a rinse of anhydrous CH 2 Cl 2 (0.20 mL).
After consumption of aziridine (determined by TLC or LCMS analysis), the reaction solution was diluted with CH2Cl2 (3 mL) and CH3OH (1 mL), adsorbed on celite and purified by column chromatography on silica gel (eluent acetone in hexanes). The vial was sealed with a screw cap fitted with a Teflon septum and anhydrous CH2Cl2 (0.60 mL) and carbodiimide (0.41 mmol, 1.02 equiv) were added. After consumption of aziridine (determined by TLC or LCMS analysis), the reaction solution was diluted with CH2Cl2 (3 mL) and CH3OH (1 mL), adsorbed on celite and purified by silica gel column chromatography (acetone in hexanes or CH3OH in CH2Cl2 eluent).
Zinc(II) chloride powder (68 mg, 0.50 mmol, 1.25 equiv) was added to an oven-dried 1-dram vial equipped with a magnetic stir bar under an inert atmosphere. The vial was sealed with a screw cap fitted with a Teflon septum and anhydrous CH2Cl2 (0.60 mL) and isothiocyanate (4.00 mmol, 10.0 equiv) were added. After consumption of aziridine (determined by TLC or LCMS analysis), the reaction solution was diluted with CH2Cl2 (3 mL) and CH3OH (1 mL), adsorbed on Celite and purified by column chromatography on silica gel (acetone in hexanes).
R)-N-tosyl-2-phenylaziridine ((R)-498)
- tosyl-2-mesitylaziridine (558)
- tosyl-2-(p-tolyl)aziridine (560)
- tosyl-2-(p-acetoxyphenyl)aziridine (562)
- tosyl-2-(p-chlorophenyl)aziridine (564)
- tosyl-2-(p-nitrophenyl)aziridine (566)
- tosyl-2-(o-chlorophenyl)aziridine (568): 43
- tosyl-2-(m-chlorophenyl)aziridine (570): 43
- tosyl-2-(o-pyridyl)aziridine (572): 44
- tosyl-2-((E)-styryl)aziridine (574)
- tosyl-2-(n-butyl)aziridine (576)
- mesyl-2-phenylaziridine (577)
Aziridine 558 was prepared according to General Procedure A: 40% yield; Rf EtOAc:Hexanes eluent); characterization data are consistent with those reported in the literature.42. Aziridine 560 was prepared according to General Procedure A: 75% yield; Rf Acetone:Hexanes eluent); characterization data are consistent with those reported in the literature.42. Aziridine 564 was prepared according to General Procedure A: 82% yield; Rf EtOAc:Hexanes eluent); characterization data are consistent with those reported in the literature.42.
Aziridine 566 was prepared according to General Procedure A: 31% yield; Rf Acetone:Hexanes eluent); characterization data are consistent with those reported in the literature.42b. Aziridine 576 was prepared according to General Procedure A: 32% yield; Rf EtOAc:Hexanes eluent); characterization data are consistent with those reported in the literature.42b. Aziridine 577 was prepared according to General Procedure B from 2-phenylglycinol yield; Rf Acetone:Hexanes eluent); characterization data match those reported in the literature.45.
R)-N-mesyl-2-phenylaziridine ((R)-577)
R)-N-(p-methoxybenzenesulfonyl)-2-phenylaziridine ((R)-578)
R)-N-(p-nitrobenzenesulfonyl)-2-phenylaziridine ((R)-579)
2-phenylaziridine (580)
The crude residue was purified by column chromatography (85% EtOAc and 3% Et3N in hexanes → 3% Et3N in EtOAc eluent) to afford aziridine 580 (342 mg, 78% yield) as a clear, colorless oil: R.4 Eluent EtOAc); characterization data match that of a clear, colorless oil: Rf = 0.42 (eluent EtOAc); the characterization data match those reported in the literature.30.
R)-2-phenylaziridine ((R)-580)
After consumption of starting material (determined by TLC analysis, approximately 1 hour), the reaction mixture was concentrated in vacuo to provide a golden oil.
