Stereo- and Regioselective 1,3-Dipolar Cycloaddition of the Stable

Article Cite This: J. Org. Chem. 2019, 84, 7017−7036

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Stereo- and Regioselective 1,3-Dipolar Cycloaddition of the Stable Ninhydrin-Derived Azomethine Ylide to Cyclopropenes: Trapping of Unstable Cyclopropene Dipolarophiles Alexander S. Filatov,† Siqi Wang,† Olesya V. Khoroshilova,† Stanislav V. Lozovskiy,† Anna G. Larina,† Vitali M. Boitsov,‡,§ and Alexander V. Stepakov*,†,∥ †

Institute of Chemistry, Saint Petersburg State University, Universitetsky pr. 26, 198504 St. Petersburg, Russian Federation Saint Petersburg Academic University, ul. Khlopina 8/3, 194021 St. Petersburg, Russian Federation § Pavlov First Saint Petersburg State Medical University, ul. L’va Tolstogo 6/8, 197022 St. Petersburg, Russian Federation ∥ Saint Petersburg State Institute of Technology, Moskovskii pr. 26, 190013 St. Petersburg, Russian Federation

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‡

S Supporting Information *

ABSTRACT: A stereo- and regioselective 1,3-dipolar cycloaddition of the stable ninhydrin-derived azomethine ylide [2(3,4-dihydro-2H-pyrrolium-1-yl)-1-oxo-1H-inden-3-olate, DHPO] to differently substituted cyclopropenes has been established. As a result, an efficient synthetic protocol was developed for the preparation of biologically relevant spiro[cyclopropa[a]pyrrolizine-2,2′-indene] derivatives. DHPO has proved to be an effective trap for such highly reactive and unstable substrates as parent cyclopropene, 1-methylcyclopropene, 1-phenylcyclopropene, and 1-halo-2-phenylcyclopropenes. It has also been found that 3-nitro-1,2-diphenylcyclopropene undergoes a nucleophilic substitution reaction in alcohols and thiols to afford 3-alkoxy- and 3-arylthiosubstituted 1,2-diphenylcyclopropenes, which can be captured as corresponding 1,3-dipolar cycloadducts in the presence of DHPO. These new approaches provide a straightforward strategy for the synthesis of functionally substituted cyclopropa[a]pyrrolizine derivatives. The factors governing regio- and stereoselectivity have been revealed by means of quantum mechanical calculations (M11 density functional theory), including previously unreported Nylide−Hcyclopropene secondorbital interactions. The outcome of this work contributes to the study of 1,3-dipolar cycloaddition, as well as enriches chemistry of cyclopropenes and methods for the construction of polycyclic compounds with cyclopropane fragments.

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INTRODUCTION

ene) and azomethine ylides generated from aziridines were disclosed by Lown and Uchida.5 Recently, we have investigated 1,3-dipolar cycloadditions of cyclopropenes with azomethine ylides generated in situ by decarboxylative condensation of isatins,6 11H-indeno[1,2-b]quinoxaline-11-ones,7 and tryptanthrines8 with α-amino acids. These cycloadditions were found to be fruitful approaches for the diastereoselective synthesis of cyclopropa[a]pyrrolizine and 3-azabicyclo[3.1.0]hexane frameworks. Asymmetric construction of 3azabicyclo[3.1.0]hexanes was successfully implemented by copper-catalyzed 1,3-dipolar cycloaddition of cyclopropenes with azomethine ylides, generated from glycine aldiminoesters.9 However, cyclopropenes as a unique type of unsaturated compounds have rarely been employed as dipolarophiles in reactions with stable azomethine ylides. A survey of the literature revealed that only two cyclopropenes (1,2,3-

1,3-Dipolar cycloaddition of azomethine ylides with alkenes is a universal synthetic tool for creating five-membered nitrogencontaining heterocyclic fragments,1 which are part of many natural alkaloids, as well as pharmacologically and biologically important compounds.2 The chemistry of azomethine ylides has attracted considerable attention of synthetic chemists. Remarkable results have been achieved in this area, such as the discovery of metal catalysts that make it possible to use unactivated and electron-rich olefins as dipolarophiles in the [3 + 2] cycloaddition reactions.3 Cyclopropenes occupy a special place among alkenes. Their unique reactivity due to high ring strain and low distortion energy makes them valuable synthetic intermediates.4 Owing to the concert nature of 1,3-dipolar cycloadditions, cyclopropene dipolarophiles are intensively used for the highly stereoselective synthesis of many significant polycyclic heterocycles containing a cyclopropane fragment. The first examples of reactions between cyclopropenes (2,3diphenylcycloprop-2-en-1-one and 1,2,3-triphenylcycloprop-1© 2019 American Chemical Society

Received: March 16, 2019 Published: May 8, 2019 7017

DOI: 10.1021/acs.joc.9b00753 J. Org. Chem. 2019, 84, 7017−7036

Article

The Journal of Organic Chemistry

delocalization of the negative charge with a neighboring electron-withdrawing group. In this paper, we set to work questioning whether the addition of a second strong electronwithdrawing group to an azomethine ylide would affect its reactivity in cycloaddition reactions with cyclopropenes (Scheme 1). On the other hand, the cyclopropa[a]pyrrolizine skeleton combines the structural fragments of pyrrolizine and 3azabicyclo[3.1.0]hexane. Pyrrolizine derivatives (Figure 1, I and II) demonstrate promising pharmaceutical activities such as antileukemic,11 anti-inflammatory,12 and antimycobacterial,13 and as inhibitors for the microsomal prostaglandin E2 synthase-1.14 3-Azabicyclo[3.1.0]hexanes (Figure 1, III−V) are a pharmaceutically important class of bicyclic compounds with a broad spectrum of biological activities, for example, antibacterial,15 antiviral,16 antitumor,17 as well as perspective compounds for treating neuroinflammations.18 Thus, the development of cyclopropa[a]pyrrolizine synthesis, particularly with high stereoselectivity, is an important area of synthetic organic chemistry. Herein, we report 1,3-dipolar cycloadditions of stable ninhydrin-derived azomethine ylide [2-(3,4-dihydro2H-pyrrolium-1-yl)-1-oxo-1H-inden-3-olate, DHPO] with various cyclopropenes, including gaseous and unstable substrates, to obtain biologically relevant spiro[cyclopropa[a]pyrrolizine2,2′-indene] framework with complete regio- and diastereoselectivity. The presumed wealth of DHPO in cycloaddition reactions has not yet been exploited to the full. A number of symmetrically (1a−o) and unsymmetrically (2a−i) substituted cyclopropenes, as well as unsubstituted at the double-bond cyclopropenes (3a−c) were chosen for this study (Figure 2).

triphenylcyclopropene and methyl 2-(tert-butyldimethylsilyl)oxy-cycloprop-1-enecarboxylate) were used as dipolarophiles in the reactions with stable pyridazinium, phthalazinium, pyridinium, isoquinolinium dicyanomethylides, and bis(methoxycarbonyl)methylide (Scheme 1).10 In spite of these Scheme 1. 1,3-Dipolar Cycloaddition of Stable Azomethine Ylides with Cyclopropenes

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pioneering works, the reactions of cyclopropenes with stable nitrogen ylides are still rather limited and therefore full of possibilities. In view of the importance of the use of cyclopropenes as dipolarophiles and as a continuation of our efforts in the construction of cyclopropa[a]pyrrolizine scaffolds via azomethine ylide-involved reactions, we explored the 1,3dipolar cycloaddition of differently substituted cyclopropenes with the stable azomethine ylide derived from condensation of ninhydrin and L-proline (Scheme 1). In our recent studies,6−8 we have considered reactions involving stabilized azomethine ylides in situ generated either from 1,2-dicarbonyl compounds (isatins) or from compounds containing the OC−CN fragment (11H-indeno[1,2-b]quinoxalin-11-ones and tryptanthrines). In these cases, the stabilization of azomethine ylides is achieved by the

RESULTS AND DISCUSSION

The condensation reaction of ninhydrin (4) with L-proline (5a) either in lower aliphatic alcohols (MeOH, EtOH) or in the solid state resulted in the formation of DHPO (6) in a high yield (>90%) (Scheme 2). As a rule, DHPO (6) is not isolated in its pure form when studying cycloaddition reactions; it is generated in situ in a solution in the presence of dipolarophiles.19 We considered the cycloaddition of DHPO (6) to 1,2,3-triphenylcyclopropene (1a) to optimize the reaction conditions. Initially, the one-pot three-component 1,3-dipolar cycloaddition of ninhydrin (4), L-proline (5a), and cyclopropene (1a) was performed in MeOH (Table 1). 1,2,3Triphenylcyclopropene (1a) was chosen as a preferred

Figure 1. Selected bioactive pyrrolizine and 3-azabicyclo[3.1.0]hexane derivatives. 7018


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Table 1. Optimization of the Reaction Conditionsa,b,c,d

entry

method

solvent

T

time

yield (%)d

1 2 3 4 5 6 7 8 9 10 11 12 13 14

A B A B A B A B A B A B A B

MeOH MeOH MeOH MeOH THF THF 1,4-dioxane 1,4-dioxane acetonitrile acetonitrile CH2Cl2 CH2Cl2 solvent-free solvent-free

reflux reflux 25 °C 25 °C 25 °C 25 °C 25 °C 25 °C 25 °C 25 °C 25 °C 25 °C 25 °C 25 °C

4h 6h 10 h 10 h 5h 8h 5h 6h 6h 9h 8h 12 h 5 min 10 min

85 72 95 84 82 69 79 72 63 54 57 19 87 62

a

Reactions of 1a (0.4 mmol) and 6 (0.4 mmol) were carried out in 10 mL of solvent. bReactions of 1a (0.4 mmol), 4 (0.4 mmol), and 5a (0.6 mmol) were carried out in 10 mL of solvent. cThe reactants were carefully ground in a porcelain mortar under solid-state conditions. d Isolated yield.

yields (Table 1, entries 5 and 6). The reactions which were performed in other media such as 1,4-dioxane, acetonitrile, and dichloromethane provided the product 7a in moderate to good yields (Table 1, entries 7−11). The use of dichloromethane as a solvent was found to be ineffective for the three-component reaction (Table 1, entry 12). The modest yield of DHPO (6) indicates that the reaction rate in a nonpolar solvent is a much lower than in polar ones. Finally, the solid-state reaction between DHPO (6) and 1,2,3-triphenylcyclopropene (1a) was also investigated. Manual grinding of an equimolar mixture of 1a and DHPO (6) for 5 min in a porcelain mortar gave the desired product 7a in 87% yield (Table 1, entry 13). Carrying out a one-pot three-component reaction under similar conditions led to a decrease in a yield to 62% (Table 1, entry 14). Accordingly, the optimal conditions for further assessment of the reaction scope were set as illustrated in Table 1 (entries 3 and 13). Next, the effect of C3-substituents (R2 groups) of cyclopropenes on the reaction was studied. Under optimized reaction conditions, we explored the scope of symmetrically substituted cyclopropenes 1 (Table 2). Cyclopropenes 1 containing phenyl and methyl substituents at the double bond were used as substrates. As shown in Table 2, the reaction in MeOH tolerates a wide range of cyclopropenes bearing various R2 groups to furnish cycloadducts 7 in moderate to high yields with excellent diastereoselectivities. Regardless of the electronic nature (electron-donating or electron-withdrawing) of the substituent at the C3 position of a cyclopropene ring, the corresponding products 7a−j were obtained in good yields (69−95%). As seen from Table 2, cyclopropenes containing phenyl (1a), ethyl (1b), vinyl (1c), phenylethynyl (1d) substituents, as well as CO2Me (1e), CO2H (1f), CONHi-Pr

Figure 2. Cyclopropenes 1−3 used in the present study.

Scheme 2. Synthesis of Stable Azomethine Ylide 6 from Ninhydrin (4) and L-Proline (5a)

substrate since it had demonstrated high reactivity toward various azomethine ylides in previous studies. When the reaction between cyclopropene 1a and DHPO (6) (method A) was performed using MeOH as the solvent at reflux for 4 h, cycloadduct 7a was obtained in 85% yield as a single diastereomer (Table 1, entry 1). Other possible diastereomers were not detected by 1H NMR analysis of the crude reaction mixture. The structure and the relative endoconfiguration of 7a were determined by spectroscopy and Xray analyses (see Figure S88, Supporting Information). This means that the reaction has been proceeded with complete diastereoselectivity with the approach of azomethine ylide 6 from less-hindered face of 1,2,3-triphenylcyclopropene (1a). The one-pot three-component reaction (method B) afforded a lower yield in MeOH at reflux for 6 h (Table 1, entry 2). When the reaction temperature was lowered to 25 °C, the yield was increased to 95% (method A) and 84% (method B) (Table 1, entries 3 and 4). The reactions could be carried out in tetrahydrofuran (THF) at 25 °C within 5−8 h, affording the target product 7a in 82% (method A) and 69% (method B) 7019


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The Journal of Organic Chemistry Table 2. Reaction of DHPO (6) with Symmetrically Substituted Cyclopropenes 1a−ma,b,c,d

Reactions of 1 (0.4 mmol) and 6 (0.4 mmol) were carried out in 10 mL of MeOH at 25 °C for 10 h. bReaction time for 7l and 7m is 30 h. Isolated yield. dPreparative yields for the solid-state reactions are given in parentheses.

a c

(1g), CONMe2 (1h), CONH2 (1i), and CN (1j) functional groups at the C3 position react actively with DHPO (6). In the case of 1,2-diphenyl-3-vinylcyclopropene (1c) and 1,2diphenyl-3-phenylethynylcyclopropene (1d), the cyclopropene double bond was more susceptible to cycloaddition reactions to form cyclopropa[a]pyrrolizines 7c and 7d in 91 and 92% yields, respectively. When using 1,2-diphenylcyclopropene (1k) as a dipolarophile, the desired endo-cycloadduct 7k was obtained in 87% yield. However, cyclopropenes 1l,m bearing methyl substituents at the double bond showed relative sluggish reactivities, resulting in the formation of corresponding products 7l and 7m in modest yields (42 and 33%, respectively). Based on the relative endo-stereochemistry of 7a, we similarly assigned the relative configurations of other cycloadducts 7b−k, as depicted in Table 2. The exoarrangement of substituents attached to a cyclopropane ring of cycloadducts 7l,m was confirmed by analysis of twodimensional (2D) NMR spectrum (1H−1H nuclear Overhauser effect spectroscopy (NOESY)) of cycloadduct 7m (Figure S27). Thus, the considered approach is applicable to a large number of cyclopropenes with various R2 groups to provide structurally diverse spiro[cyclopropa[a]pyrrolizine2,2′-indene] derivatives 7 in acceptable yields and complete diastereoselectivity. The ability to scale up this method was demonstrated by the preparation of cycloadduct 7a on a gram scale. The reaction of 1a with DHPO (6) proceeded readily to furnish the desired product 7a in 96% yield (Scheme 3).

Subsequently, we studied the reactions of 1,2-diphenylcyclopropenes 1a−e, 1h, 1j, and 1k in solid-state conditions. The solid-state reactions of cyclopropenes 1a−d, 1j, and 1k with DHPO (6) led to the formation of products 7a−d, 7j, and 7k in 75−87% yields (preparative yields are given in parentheses in Table 2). However, the solid-state reactions of cyclopropenes 1e and 1h containing the electron-withdrawing CO2Me and CONMe2 groups at C3 position are accompanied by a decrease in the yield of target compounds 7e (31%) and 7h (54%), respectively. In contrast to the cycloaddition reaction with cyclopropenes 1a−m monosubstituted and unsubstituted at the C3 position, no cycloadduct was isolated from the reaction of tetrasubstituted cyclopropene 1o and DHPO (6). This fact could be explained by a diminished reactivity of the double bond of such cyclopropene toward 1,3-dipolar cycloaddition due to steric hindrance. The reactions involving 3-nitro-1,2-diphenylcyclopropene (1n) are considered separately since they are accompanied by substitution processes at a cyclopropene ring (vide infra). Unfortunately, we failed to obtain stable azomethine ylides from ninhydrin and such secondary α-amino acids as L-4thiazolidinecarboxylic acid (5b), pipecolic acid (5c), and azetidine-2-carboxylic acid (5d). However, the synthesis of cycloadducts 8 and 9 was successfully implemented through three-component reactions (Scheme 4). The three-component reaction between 1,2,3-triphenylcyclopropene (1a), ninhydrin (4), and L-4-thiazolidinecarboxylic acid (5b) in EtOH at reflux resulted in the diastereoselective formation of 8 in acceptable yield (74%). Further, we found that the one-pot 1,3-dipolar cycloaddition reaction of cyclopropene 1a with the azomethine ylide derived from ninhydrin and pipecolic acid (5c) proceeded in ethanol at reflux. Under these conditions, spiro[cyclopropa[a]indolizine] 9 formed diastereoselectively, albeit in a modest yield (36% isolated). The presence of a nonplanar dihydropiperidinium fragment in the intermediate

Scheme 3. Gram-Scale Synthesis of 7a

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adjacent to the spiro-atom (1,5-orientation) (see Figures S36 and S89, Supporting Information). After that, we carried out our investigation with 1phenylcyclopropene (2b). As previously reported by Lee, 1phenylcyclopropene is a highly unstable compound that undergoes ene dimerization and trimerization, as well as [2 + 2]-dimerization. At the same time, cyclopropene 2b can be trapped in solution as a Diels−Alder adduct with cyclopentadiene.21 In this study, we have made an effort to use the 1,3-dipole 6 as a trap for unstable cyclopropene 2b (Scheme 5). 1-Lithio-2-phenylcyclopropene served as a precursor for the generation of 1-phenylcyclopropene. This salt was readily prepared by treatment of 1,1,2-tribromo-2-phenylcyclopropane with 2.5 equiv of methyllithium. Subsequently, the ether solution of 1-lithio-2-phenylcyclopropene was carefully added to the mixture of DHPO (6) and acetic acid in THF. 1Phenylcyclopropene (2b) that formed during the protonation of 1-lithio-2-phenylcyclopropene with acetic acid reacted smoothly with DHPO (6) to give the corresponding endocycloadduct 11b (88% isolated) in a totally 1,5-regio- and diastereoselective fashion. Then, we examined the reactions of cyclopropenes 2c−i with different substituents at the double bond with DHPO (6) under the optimal conditions (THF or methanol at 25 °C). The results are summarized in Table 3. As it turned out, 1-

Scheme 4. One-Pot Three-Component 1,3-Dipolar Cycloaddition Reactions of Ninhydrin (4), α-Amino Acids 5b−d, and Cyclopropene 1a

azomethine ylide probably hampers the approach of cyclopropene dipolarophile. The relative endo-configurations of resulting cycloadducts 8 and 9 were deduced based on 1H−1H NOESY spectra (see Figures S30 and S33, Supporting Information, respectively). All attempts to carry out threecomponent reactions involving azetidine-2-carboxylic acid have failed. To evaluate the regioselectivity of 1,3-dipolar cycloaddition reaction involving cyclopropenes and DHPO, we further extended the scope of this reaction with unsymmetrically substituted at the double-bond cyclopropenes 2a−i. Initially, we considered the reactions of 1-methylcyclopropene (2a) and 1-phenylcyclopropene (2b) with DHPO (6). To the best of our knowledge, the 1,3-dipolar cycloadditions of monosubstituted cyclopropenes 2a and 2b have never been investigated. Cyclopropene 2a was generated from 1-lithio-2-methylcyclopropene by slow addition of MeOH to its ether solution20 and introduced with a stream of argon to a suspension of DHPO (6) in THF over 5 min at −30 °C. Complete dissolution of ylide 6 was reached by gradually increasing the temperature of the reaction mixture to 0 °C (Scheme 5). Evaporation of the

Table 3. Reaction of DHPO (6) with Unsymmetrically Substituted Cyclopropenes 2c−ia,b,c

Scheme 5. Trapping of Monosubstituted Cyclopropenes 2a,b with DHPO (6) a

Reactions of cyclopropenes 2c−f (1.5 mmol) with 6 (1.0 mmol) were carried out in 5 mL of THF at 25 °C for 5 min. bReactions of cyclopropenes 2g−i (0.4 mmol), 6 (0.4 mmol) were performed in 5 mL of MeOH at 25 °C for 48 h. cIsolated yield.

methyl-2-phenylcyclopropene (2c) proved to be a suitable reactant that successfully participated in 1,3-dipolar cycloaddition with DHPO (6), affording the endo-adduct 11c in 96% yield with full 1,5-regioselectivity. Furthermore, when cyclopropenes with a heteroatom substituent at the double bond 2d−f were tested, it was found that the cycloaddition process proceeded easily for 5 min by employing THF as a solvent. The desired adducts 11d−f were obtained in high yields with excellent regio- and diastereoselectivities. 2-Aryl-3methylcycloprop-2-enecarboxylic acids 2g−i also reacted in a highly regio- and stereoselective manner. However, it needed more time (48 h) to achieve complete conversion of reactants into products. The structures and relative configurations of

solvent followed by purification using preparative thin-layer chromatography (PTLC) gave pure product 11a with total regio- and diastereoselectivity in 92% yield. The 2D NMR spectroscopy (NOESY) and X-ray analysis of cycloadduct 11a have disclosed that the compound 11a has a relative endoconfiguration, and the methyl group of the cyclopropane ring is 7021


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The Journal of Organic Chemistry spirocyclic compounds 11b−f and 11h were ambiguously corroborated by 2D NMR spectra of 11b−f and X-ray analysis of 11h (see Figures S39, S42, S45, S48, S51, and S90, Supporting Information). Parent cyclopropene (3a) is a very active dienophile in the Diels−Alder reaction.22 Nevertheless, less attention has been paid to its activity as a dipolarophile in 1,3-dipolar cycloaddition reactions. This highly reactive cycloalkene has been explored only with 1,3-dipoles of the propargyl/allenyl anion typenitrile oxides and nitrilimines.23 We have suggested that azomethine ylide 6 may act as an effective trap for cyclopropene 3a (Scheme 6). To validate this hypothesis, we

Table 4. Three-Component Reactions of Cyclopropene 1n, DHPO (6), and RXH (X = O, S)a,b,c,d

Scheme 6. Generation of Parent Cyclopropene (3a) and Its Reaction with DHPO (6)

obtained parent cyclopropene (3a) from allyl chloride and sodium bis(trimethylsilyl)amide (NaHMDS) in anhydrous toluene and introduced with a slow stream of dry argon into a suspension of DHPO (6) in THF at −78 °C for 10 min. A gradual increase in the temperature of the reaction mixture to 0 °C led to the complete dissolution of the ylide 6. Subsequent purification by PTLC afforded exclusively endo-cycloadduct 12a in 89% yield. The relative configuration of cycloadduct 12a was established by considering its 2D NMR spectrum (see Figure S61, Supporting Information). The 1,3-dipolar cycloaddition reaction of parent cyclopropene (3a) with DHPO (6) provides a good opportunity for the synthesis of parent spiro[cyclopropa[a]pyrrolizine] derivative. Contrary to parent cyclopropene (3a), 3,3-disubstituted cyclopropenes 3b,c reacted with poor diastereoselectivity to furnish cycloadducts 12b,c as inseparable mixtures of two diastereomers approximately in ratios 1.9:1 and 1.6:1 (the original diastereomeric ratio was examined by analysis of 1H NMR spectra of crude mixtures), respectively (Scheme 7).

a

All reactions in alcohol medium were carried out with 1n (0.4 mmol), 6 (0.4 mmol), and ROH (10 mL) at 25 °C for 24 h. bThe reaction in t-BuOH was conducted at 40 °C for 24 h. cAll reactions in a thiol medium were carried out with 1n (0.4 mmol), 6 (0.4 mmol), and RXH (10 mL) at 140 °C for 5 min. dIsolated yield.

yield (15%) by carrying out the reaction in MeOH−THF mixture. Next, we considered the possibility of using other primary and secondary alcohols under similar conditions [6 (0.4 mmol), 1n (0.4 mmol), 10 mL of ROH at 25 °C], as shown in Table 4. For example, the reaction in ethanol proceeded smoothly to give ethoxy-substituted spiro[cyclopropa[a]pyrrolizine] 13b in a fully diastereoselective fashion. The relative configuration of cycloadduct 13b was unequivocally ascertained by single-crystal X-ray diffraction (see Figure S91, Supporting Information). When we performed reactions in other primary alcohols such as 1propanol and 2-methoxyethanol, the resulting cycloadducts 13c and 13d were obtained in moderate yields (55 and 41%, respectively). The reaction in isopropanol furnished the adduct 13e in 49% yield. Treatment of a mixture of 3-nitro-1,2diphenylcyclopropene (1n) and DHPO (6) by t-BuOH at 40 °C for 24 h resulted in the diastereoselective formation of spirocyclic product 13f containing a tert-butoxy group. Some thiols were also utilized as nucleophilic medium to expand the synthetic usability of this methodology. Thiophenol, p-thiocresol, and 1-hexanethiol were chosen for these reactions (Table 4). The first experiments revealed that the reaction involving DHPO (6), cyclopropene 1n, and thiophenol did not take place in THF. Nevertheless, the reaction proceeded slowly in the thiophenol medium at 25 °C. To reach the full conversion within a short period of time, the mixture of 1n, 6, and thiophenol under an argon atmosphere was heated to 140 °C and kept at this temperature for 5 min. After purification of the crude mixture by PLTC, the phenylthio-substituted product 13g was obtained in a moderate yield (65%). The transformation also worked efficiently under similar conditions by employing 4-methylbenzenethiol as a reactant. The corresponding cycloadduct 13h was obtained in 67% yield with high diastereoselectivity.

Scheme 7. Reactions of DHPO (6) with 3,3-Disubstituted Cyclopropenes 3b,c

After work-up procedure, the mixtures were obtained in 61 and 47% isolated yields, respectively, and characterized by increase in diastereomeric ratio, 3:1 for 12b and 2:1 for 12c (see Figures S62 and S65, Supporting Information). The next phase of the study focused on the reaction involving DHPO (6) and 3-nitro-1,2-diphenylcyclopropene (1n). As it turned out, this reaction did not proceed in aprotic polar solvents (such as THF or 1,4-dioxane), whereas the reaction in MeOH at 25 °C gave a methoxy derivative 13a in 57% yield (Table 4). The compound 13a was isolated in a low 7022


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the first stage of the study, global electrophilicity indexes (ω) were obtained for DHPO (6) and starting cyclopropenes 1−3 using the equations recommended by Parr25 and Domingo.26 These global descriptors were applied to further use within the framework of frontier molecular orbital (FMO) theory (Table 5). The index (ω) increases with the number of substituents attached to a cyclopropene ring, starting from 0.27 eV for parent cyclopropene (3a) (Table 5, entry 2) and ending with diphenylcyclopropenes 1 bearing an electron-withdrawing group such as 2,3-diphenylcyclopropene-1-carboxylate (1e, 0.54 eV), 2,3-diphenylcyclopropene-1-carbonitrile (1j, 0.59 eV), and 3-nitro-1,2-diphenylcyclopropene (1n, 0.62 eV) (Table 5, entries 16, 17, and 19). Thus, the main observed trend is an energetically more favorable interaction between the lowest unoccupied molecular orbital (LUMO) of DHPO (6) (ω = 0.50 eV, Table 5, entry 1) and the highest occupied molecular orbital (HOMO) of cyclopropenes 1−3. The 1,3dipolar cycloadditions should strictly occur under inverse electron demand (IED). That being said, 3-nitro-1,2diphenylcyclopropene (1n) cannot interact with the DHPO (6) along the IED channel due to a sufficiently large value of its ω in comparison to the index of DHPO (Δω = 0.12 eV). The presence of the strong electron-withdrawing nitro group considerably suppresses the nucleophilic power of 1n and dramatically affects the reactivity of 3-nitro-1,2-diphenylcyclopropene toward DHPO under aprotic conditions (Table 4). However, 3-nitro-1,2-diphenylcyclopropene can undergo a nucleophilic substitution reaction in alcohols and thiols via the first-order nucleophilic substitution (SN1) mechanism to give less electrophilic XR-substituted cyclopropenes 15 (Scheme 8). The latter readily cycloadd to DHPO (6) under IED (Scheme 8 and Table 5, entry 19). The complete regioselectivity (exclusive formation of 1,5regioisomers) in the cyclopropene cycloadditions to DHPO (6) was accounted for by considering the theoretically calculated natural bond orbital (NBO) charges, FMO coefficients, and Fukui functions for cyclopropenes 2a−g and DHPO (6) (Table 6). The LUMO coefficients corresponding to C1 and C3 carbon atoms of DHPO (6) and HOMO coefficients corresponding to C4 and C5 carbon atoms of cyclopropenes 2a−g are listed in Table 6. The carbon atom of DHPO (6) referred to as C3 dominates over C1 in terms of energy contributions for the LUMO (Table 6, entry 1, columns 5−7). In turn, the C4 carbon atom provides a major contribution to the HOMO of cyclopropenes 2 (Table 6, entries 2−8, columns 5−7). According to the FMO theory, the preferred orientation is the result of the interaction of the atoms with the largest coefficients. Thus, the more favorable interaction between C3 and C4 atoms providing major contributions to FMO of the DHPO (6) and cyclopropenes 2, respectively, should result in the formation of 1,5regioisomers 11, which is in full agreement with the experimental data. As further confirmation of the above, the condensed Fukui functions for the electrophilic (f−) and the nucleophilic (f+) attacks for cyclopropenes 2a−g and DHPO (6), respectively, were considered closely. The C3 carbon atom of DHPO (6) presents a large f+ value than the C1 site, 0.042 and 0.015, respectively (Table 6, entry 1, columns 10 and 11). Consequently, the C3 position of DHPO (6) should be a preferred position for a nucleophilic attack by cyclopropenes 2. Simultaneously, values of condensed Fukui functions for electrophilic attack (f−) of cyclopropenes 2 demonstrate that the strongest nucleophilic reaction center is always the C4

As illustrated in Table 4, 1-hexanethiol proved to be an ineffective reactant, which reacted with cyclopropene 1n followed by cycloaddition with DHPO (6) to give the product 13i in a modest yield (27%). We assume that these reactions proceed through the formation of the 2,3-diphenylcycloprop-2-en-1-ylium cation (14) due to the heterolytic C−N bond cleavage of the starting 3-nitro-1,2-diphenylcyclopropene (1n) (Scheme 8). The Scheme 8. Proposed Mechanism for the Three-Component Reaction of 3-Nitro-1,2-diphenylcyclopropene (1n), DHPO (6), and RXH

aromatic cation 14 reacts with a nucleophile RXH to give the cyclopropene 15. The latter cycloadds to azomethine ylide 6 to form products 13. To confirm this mechanism, we kept 3nitro-1,2-diphenylcyclopropene (1n) in absolute methanol at 25 °C for 24 h (thin-layer chromatography (TLC) control). After evaporation of the solvent, 3-methoxy-1,2-diphenylcyclopropene (15a, XR = OMe) was obtained as a yellow oil (see Figures S86 and S87, Supporting Information).24 The reaction of cyclopropene 15a with 6 in MeOH (or THF) resulted in the formation of cycloadduct 13a (44% yield, two steps). It is noteworthy that (E)-2,3-diphenylacrylaldehyde (16) was detected as a byproduct (yield up to 10%) in these reactions. The aldehyde presumably formed as a result of oxidation of the intermediate 2,3-diphenylcycloprop-2-en-1-ylium cation (14) under the reaction conditions.6 A comprehensive density functional theory (DFT) computational study was perfomed to reveal factors controlling regioand stereoselectivity in the observed reactions (Scheme 9). At Scheme 9. General Route of DFT Study on Regio- and Stereoselectivity in the Observed Reactions (NEDnormal electron demand; IEDinverse electron demand)

7023


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Table 5. FMO Energies (a.u.), Electronic Chemical Potential (μ, eV), Chemical Hardness (η, eV), and Global Electrophilicity Index (ω, eV) for DHPO (6) and Starting Cyclopropenes 1−3a,b entry

reactant

HOMO

LUMO

μ

η

ω

NED

IED

channel

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

6 3a 3b 3c 2a 2b 2c 2d 2e 2f 2g 1a 1b 1c 1d 1e 1j 1k 1n 15a

−0.28783 −0.35735 −0.31788 −0.38046 −0.34216 −0.3075 −0.29723 −0.30187 −0.30823 −0.3107 −0.31353 −0.28655 −0.28024 −0.28063 −0.29102 −0.29346 −0.29962 −0.28152 −0.30857 −0.29283

0.06166 0.15559 0.12124 0.135 0.15959 0.08764 0.09444 0.08237 0.08115 0.08197 0.087 0.06138 0.065 0.06115 0.05907 0.05805 0.05263 0.06369 0.05185 0.06342

−3.08 −2.74 −2.67 −3.34 −2.48 −2.99 −2.76 −2.99 −3.09 −3.11 −3.08 −3.06 −2.93 −3.06 −3.16 −3.20 −3.36 −2.96 −3.49 −3.12

9.51 13.96 11.95 14.03 13.65 10.75 10.66 10.45 10.59 10.68 10.90 9.47 9.39 9.45 9.53 9.56 9.58 9.39 9.81 9.69

0.50 0.27 0.30 0.40 0.23 0.42 0.36 0.43 0.45 0.45 0.44 0.50 0.46 0.49 0.52 0.54 0.59 0.47 0.62 0.50

12.07 11.13 11.51 12.17 10.22 10.40 10.07 10.04 10.06 10.20 9.50 9.60 9.49 9.43 9.41 9.26 9.56 9.24 9.56

11.40 10.33 12.03 10.99 10.04 9.77 9.89 10.06 10.13 10.21 9.47 9.30 9.46 9.60 9.66 9.83 9.34 10.07 9.65

IED IED IED IED IED IED IED IED IED IED IED/NED IED IED/NED IED/NED IED/NED IED/NED IED NED IED/NED

a

FMO energy (eV) were computed by using the Hartree−Fock (HF)/6-311g single-point calculation on the M11/cc-pVDZ optimized geometries. Energy gaps for both possible HOMO−LUMO interactions between DHPO (6) and cyclopropenes 1−3 are given in electonvolt.

b

Table 6. NBO Charges, Orbital Coefficients of the LUMO of DHPO (6), and the HOMO of Cyclopropenes 2a−g and Condensed Fukui Functions for the Electrophilic (f−) and Nucleophilic (f+) Attacks (M11/cc-pVDZ)a,b

entry 1 entry 2 3 4 5 6 7 8

ylide

q (C1)

6 −0.157 cyclopropenes q (C4) 2a 2b 2c 2d 2e 2f 2g

−0.218 −0.176 0.048 −0.455 −0.129 −0.050 0.082

C1

q (C3)

FMO

0.170

LUMO

f− (C1)

C3

0.0146

f− (C3)

0.6423

q (C5)

FMO

C4

C5

f− (C4)

f− (C5)

0.012 −0.019 −0.027 0.002 0.002 −0.005 0.015

HOMO HOMO HOMO HOMO HOMO HOMO HOMO

0.6247 0.5354 0.5054 0.5345 0.4499 0.4627 0.4848

0.5560 0.3764 0.4213 0.3885 0.3895 0.3922 0.3772

0.244 0.181 0.143 0.148 0.113 0.123 0.126

0.188 0.097 0.109 0.097 0.088 0.092 0.079

f+ (C1) 0.015 f+ (C4)

f+ (C3) 0.042 f+ (C5)

a The values of the pz coefficient. bCondensed Fukui functions for the electrophilic (f−) and nucleophilic (f+) attacks were calculated for cyclopropenes 2a−g and DHPO (6), respectively, using Hirshfeld’s population scheme.

optimal geometries of transition states (TSs) for the reactions of cyclopropenes 2b−e with DHPO (6). An analysis of the potential energy surface (PES) indicates that the studied 1,3dipolar cycloadditions proceed by a one-step mechanism. Eight TSs TS-(11b−e)-1,4-endo and TS-(11b−e)-1,5-endo associated with the two regioisomeric channels were successfully found and characterized. As depicted in Scheme 10, free energies of activation (ΔG#) clearly identify that the 1,5regiopathway is kinetically favored for all investigated reactions, i.e., the 1,5-regioisomers are preferred products of these reactions. When considering geometries of TSs, we have observed that these regioselective cycloadditions are of course asynchronous processes taking place through a dipolaroid-like transition

carbon atom (Table 6, entries 2−8, columns 8 and 9). For instance, the C4 carbon atom of 1-phenylcyclopropene (2b) has a larger f− value than the C5 one, 0.181 and 0.097, respectively (Table 6, entry 3, columns 8 and 9). In this context, the 1,3-dipolar cycloadditions should proceed via the C3−C4 bond formation by the nucleophilic attack of the C4 carbon atom of cyclopropenes 2 to the more electrophilic C3 site of DHPO (6). Moreover, it is worth mentioning that NBO atomic charges are also consistent with regioselectivity of cycloaddition for most of reactant pairs (Table 6, entries 1−3 and 5−7, columns 3 and 4). At the next stage of our theoretical study, we estimated Gibbs energies of activation corresponding to the two alternative regiopathways (1,4-endo and 1,5-endo) and the 7024


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Scheme 10. Schematic Representation of Potential Energy Surfaces (PESs) Corresponding to the Studied 1,3-Dipolar Cycloadditions of DHPO (6) with Cyclopropenes 2b−e in Two Pathways (1,5-endo and 1,4-endo)

Table 7. Values of the Asynchronicity in TS-1,5-endo and TS-1,4-endo for the Reactions of DHPO (6) with Cyclopropenes 2b− e entry

TS

d1 (C1−C5) (Å)

d2 (C3−C4) (Å)

Δd = d1 − d2 (Å)

1 2 3 4 entry

TS-11b-1,5-endo TS-11c-1,5-endo TS-11d-1,5-endo TS-11e-1,5-endo TS

2.73 2.67 2.69 2.66 d1 (C1−C4) (Å)

2.15 2.18 2.19 2.23 d2 (C3−C5) (Å)

0.58 0.49 0.50 0.43 Δd = d1 − d2 (Å)

5 6 7 8

TS-11b-1,4-endo TS-11c-1,4-endo TS-11d-1,4-endo TS-11e-1,4-endo

2.40 2.55 2.57 2.52

2.25 2.18 2.20 2.26

0.15 0.37 0.37 0.26

atom C 4 is the strongest nucleophilic center that is subsequently subjected to electrophilic attack of the C3 site of DHPO (6), resulting in the formation of cycloadducts with full 1,5-regioselectivity. To rationalize the origins of the endo and exo stereoselectivity in reactions of cyclopropenes 1−3 with DHPO (6), full geometry optimization of the four possible transition states TS-11a-1,5-endo, TS-11a-1,5-exo, TS-11a-1,4-endo, and TS11a-1,4-exo for the reaction between 1-methylcyclopropene (2a) and DHPO (6) was performed using M11/cc-pVDZ (Figure 3). The Gibbs energies of activation corresponding to the two endo and two exo approaches were also evaluated at 298.15 K and 1.0 atm (Figure 4). According to Figure 4, the 1,5-endo-regioisomer 11a is ca. 2.5 kcal/mol more kinetically favorable than its opposite endo-regioisomer due to nucleophilic activation of unsubstituted carbon atom (C4) of MCP (2a) induced by the neighboring electron-releasing methyl group. Together with this, TS-11a-1,5-endo and TS11a-1,4-endo are energetically more stable than their corresponding TS-11a-1,5-exo and TS-11a-1,4-exo (ca. 1.8 and 3.0 kcal/mol, respectively), which in combination with a preference for the 1,5-regiopath is in good accordance with experimental results. Moreover, with parent cyclopropene (3a), the endo cycloaddition is favored by 1.8 kcal/mol (see Figures S92 and Table S6, Supporting Information). A closer look at the geometries of the endo TSs reveals that there is a crucial interaction between nitrogen atom of ylide 6 (NDHPO) and syn-hydrogen (Hcyclopropene) attached to the saturated carbon atom of cyclopropene ring of 2a, contributing to stabilization of the endo transition state. The s-orbital coefficients of endo-hydrogen corresponding to cyclopropenes 2a−e, 3a, LUMO pz coefficient of NDHPO, NBO charges for the

state. For instance, the geometry of the TS-11b-1,5-endo (leading to the experimentally observed regioisomer 11b) displays that the σ bond between C4 carbon atom of 1phenylcyclopropene (2b) and C3 carbon atom of DHPO (6) is more advanced (2.15 Å) than that between C5 carbon atom of 2b and C1 of ylide 6 (2.73 Å), as suggested by the atom distances measured between these reaction centers (Table 7, entry 1). Similar high asynchronicities were identified for other TSs-1,5-endo corresponding to reactions of 2c−e with DHPO (6) (Table 7, entries 2−4). It is essential to note that asynchronicities shown at all of the 1,5-TSs are in full agreement with the results based on DFT reactivity indexes. Actually, the σ bonds formed at 1,5-TSs between the most electrophilic center of DHPO (6)C3 carbon atom and the most nucleophilic site of cyclopropenes 2C4 carbon atom are shorter and more advanced than the C1−C5 ones. In contrast to the head-to-head orientations, 1,4-regiopathways are characterized by less asynchronicity, although σ bonds between C5 carbon atoms of cyclopropenes 11c−e and C3 carbon atom of DHPO (6) are a little more developed (Table 7, entries 5−8). This indicates that the azomethine ylide DHPO (6) controls the asynchronicity of the cycloaddition by a larger bond-formation process at the most electrophilic center of the ylide 6. In other words, DHPO (6) partially acts as an iminium cation in the 1,3-dipolar cycloadditions with cyclopropenes. It can be concluded that regioselectivity of cyclopropene cycloadditions to DHPO (6) is governed by the electronic effects of the substituents at the cyclopropene double bond. In the case of cyclopropenes 2b−e, the presence of the electron-donating phenyl group at C1 position (referred as the C5 one in this discussion) polarizes the HOMOcyclopropene through the C4 carbon atom. As a consequence, the β-carbon 7025


Article


and endo-hydrogen of cyclopropenes 2a−e, 3a notably shorter than the N−H van der Waals radius (rw = 2.65 Å) (Table 8, entries 1−6, column 7). All of this suggests that the observed endo stereoselectivity in the 1,3-dipolar cycloadditions of cyclopropenes with DHPO results from favorable secondary orbital overlap of the endo-hydrogen s-orbital in the HOMO of cyclopropene with the nitrogen π-orbital of the ylide LUMO (see Figure 3). Previously, second-orbital interactions (SOIs) providing stabilization of endo transition states in the Diels− Alder reaction of butadiene with cyclopropenes were comprehensively explored in the works of Apeloig,27 Jursic,28 and Houk.29

■

CONCLUSIONS In summary, the construction of the biologically interesting spiro[cyclopropa[a]pyrrolizine-2,2′-indene] scaffold with quaternary stereogenic centers with complete regio- and diastereoselectivities has been established by using the 1,3dipolar cycloaddition of the stable ninhydrin-derived azomethine ylide (DHPO) to various cyclopropenes. Importantly, the [3 + 2]-cycloaddition reactions proceed smoothly under mild conditions and allow highly reactive and unstable cyclopropene substrates to be introduced into the reaction process. Moreover, unusual cascade substitution−cycloaddition reaction for 3-nitro-1,2-diphenylcyclopropene has been described for the first time. The 1,5-regio- and endostereoselective product formation in the observed reactions arises from charge and orbital control along with secondorbital interactions, as shown by DFT calculations. We also expect that this work will inspire the search for new 1,3dipoleseffective traps for cyclopropenes.

Figure 3. Transition states of the four possible approaches for the cycloaddition between 1-methylcyclopropene (2a) and DHPO (6). The bond lengths for primary interactions and second-orbital interactions (SOIs) are given in angstroms.

■

EXPERIMENTAL SECTION

General Information. Melting points were measured on a melting point apparatus and are uncorrected. 1H (400 MHz) and 13 C (100 MHz) spectra were recorded on an NMR spectrometer in CDCl3 or dimethyl sulfoxide (DMSO)-d6 at ambient temperature. 13 C NMR spectra were registered with broad-band proton decoupling. Chemical shifts (δ) in ppm are reported relative to residual undeuterated solvent in CDCl3 (7.26 ppm for 1H and 77.2 ppm for 13 C) and DMSO-d6 (2.50 ppm for 1H and 39.5 ppm for 13C). The signal patterns are indicated as follows: s = singlet, d = doublet, dd = doublet of doublets, t = triplet, m = multiplet, br = broad. Integrals are given in accordance with assignments; coupling constants are reported in hertz. IR spectra were recorded in KBr pellets and reported in wavenumber (cm−1). Electrospray ionization (ESI) mass spectra were recorded using mass spectrometry, high-resolution mass spectrometry (HRMS)-ESI-quadrupole time-of-flight, electrospray ionization in positive mode. Single-crystal X-ray diffraction experiments were conducted on a diffractometer at 100 K using monochromated Mo Kα and Cu Kα radiation. The progress of reactions was monitored by thin-layer chromatography (TLC) on

Figure 4. Free-energy profile for the 1,3-dipolar cycloaddition reaction of 1-methylcyclopropene (2a) to DHPO (6).

hydrogen of cyclopropenes 2a−e, 3a and for NDHPO of DHPO (6), and the distances between these atoms in endo-1,5-TSs were considered to validate the proposed idea (Table 8). First, such interactions may occur because hydrogen atom provides considerable contribution to HOMO of cyclopropenes 2a−e, 3a as nitrogen atom to LUMO of DHPO (6) (Table 8, entries 1−6, columns 3 and 4). Electrostatic interactions between these atoms in the endo transition states are also supported by examining NBO charges (Table 8, entries 1−6, columns 5 and 6). In addition to this, all endo-1,5-TS were found to have distances (ranging from 2.38 to 2.44 Å) between NDHPO (6)

Table 8. s-Orbital Coefficients in the HOMO of Cyclopropenes 2a−e, 3a for the syn-Hydrogen and the pz-Orbital Coefficient in the LUMO of DHPO (6) for the Nitrogen Atom in the Ground State, Natural Charges at the syn-Hydrogen of Cyclopropenes 2a−e, 3a, the Charge at Nitrogen of DHPO (6), and N−H Distance in the Endo Transition States entry

TS

1 2 3 4 5 6

TS-12a-1,5-endo TS-11a-1,5-endo TS-11b-1,5-endo TS-11c-1,5-endo TS-11d-1,5-endo TS-11e-1,5-endo

H s-orbital coefficient (HOMO) N pz-orbital coefficient (LUMO) q (syn-H), cyclopropene q (N), DHPO N−H distance (Å) −0.3038 −0.2906 −0.2121 −0.2165 −0.2101 −0.1961

−0.4223

7026

0.199 0.206 0.208 0.210 0.214 0.216

−0.368 −0.375 −0.365 −0.367 −0.369 −0.360

2.43 2.39 2.38 2.38 2.38 2.44


Article


1038, 764, 706 cm−1. HRMS (ESI): m/z [M + H]+ calcd for C34H28NO2+: 482.2115; found: 482.2124. (±)-(1R,1aR,6aR,6bS)-1-Ethyl-1a,6b-diphenyl-1a,4,5,6,6a,6b-hexahydro-1H-spiro[cyclopropa[a]pyrrolizine-2,2′-indene]-1′,3′-dione (7b). The reaction was performed according to General Procedure A employing cyclopropene 1b (88 mg, 0.4 mmol) and DHPO (6, 85 mg, 0.4 mmol). Purification by PTLC on silica gel (hexane−EtOAc, 3:1) followed by crystallization from a mixture of MeOH−H2O (2:1) afforded 7b (153 mg, 88%) as a single diastereomer. Following General Procedure C, the solid-state reaction of cyclopropene 1b with DHPO (6) also led to the desired cycloadduct 7b (137 mg, 79%). Yellow solid; mp 147−148 °C (MeOH−H2O, 2:1); Rf 0.46 (SiO2, hexane−EtOAc, 3:1). 1H NMR (400 MHz, CDCl3): δ = 7.92 (d, J = 7.3 Hz, 1H), 7.73−7.62 (m, 3H), 7.50−7.44 (m, 2H), 7.33−7.25 (m, 2H), 7.24−7.19 (m, 1H), 7.00−6.94 (m, 2H), 6.92−6.85 (m, 3H), 4.70 (t, J = 7.1 Hz, 1H), 3.61−3.47 (m, 1H), 2.80−2.62 (m, 1H), 2.18−2.05 (m, 2H), 2.03−1.91 (m, 2H), 1.90−1.79 (m, 1H), 1.55− 1.42 (m, 1H), 1.38−1.25 (m, 1H), 0.99 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ = 201.5, 199.3, 142.4, 141.8, 137.4, 136.0, 135.4, 133.4, 131.7 (2C), 130.4 (2C), 128.1 (2C), 127.7 (2C), 126.9, 126.4, 123.5, 123.0, 75.9, 75.5, 52.5, 49.4, 46.5, 29.8, 28.8, 27.7, 19.7, 14.2. IR (KBr): 3057, 3025, 2968, 2933, 2894, 2873, 1737, 1702, 1596, 1498, 1445, 1268, 1198, 1156, 1079, 769, 706 cm−1. HRMS (ESI): m/z [M + H]+ calcd for C30H28NO2+: 434.2115; found: 434.2129. (±)-(1R,1aR,6aR,6bS)-1a,6b-Diphenyl-1-vinyl-1a,4,5,6,6a,6b-hexahydro-1H-spiro[cyclopropa[a]pyrrolizine-2,2′-indene]-1′,3′-dione (7c). The reaction was performed according to General Procedure A employing cyclopropene 1c (87 mg, 0.4 mmol) and DHPO (6, 85 mg, 0.4 mmol). Purification by PTLC on silica gel (hexane−EtOAc, 3:1) followed by crystallization from a mixture of MeOH−H2O (2:1) afforded 7c (157 mg, 91%) as a single diastereomer. Following General Procedure C, the solid-state reaction of cyclopropene 1c with DHPO (6) also led to the desired cycloadduct 7c (147 mg, 85%). Yellow solid; mp 232−233 °C (MeOH−H2O, 2:1); Rf 0.48 (SiO2, hexane−EtOAc, 3:1). 1H NMR (400 MHz, CDCl3): δ = 7.86 (d, J = 6.6 Hz, 1H), 7.70−7.60 (m, 5H), 7.35−7.29 (m, 2H), 7.23−7.18 (m, 1H), 6.99−6.91 (m, 2H), 6.90−6.81 (m, 3H), 5.50−5.40 (m, 1H), 5.04−4.93 (m, 2H), 4.64 (t, J = 7.1 Hz, 1H), 3.68−3.58 (m, 1H), 2.87 (d, J = 9.7 Hz, 1H), 2.75−2.67 (m, 1H), 2.16−2.03 (m, 1H), 1.98−1.80 (m, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ = 202.5, 198.8, 142.4, 141.7, 137.3, 136.5, 135.9, 135.5, 133.0, 132.6 (2C), 131.7 (2C), 128.3 (2C), 127.7 (2C), 127.0, 126.9, 123.3, 123.0, 114.5, 77.5 (overlapping with CDCl3), 76.5, 54.3, 49.2, 49.0, 30.9, 27.6, 27.5. IR (KBr): 3059, 3023, 2954, 2876, 1738, 1706, 1592, 1497, 1272, 1176, 1158, 980, 904, 741, 725, 703 cm−1. HRMS (ESI): m/z [M + H]+ calcd for C30H26NO2+: 432.1958; found: 432.1973. (±)-(1R,1aR,6aR,6bS)-1a,6b-Diphenyl-1-(phenylethynyl)1a,4,5,6,6a,6b-hexahydro-1H-spiro[cyclopropa[a]pyrrolizine-2,2′indene]-1′,3′-dione (7d). The reaction was performed according to General Procedure A employing cyclopropene 1d (117 mg, 0.4 mmol) and DHPO (6, 85 mg, 0.4 mmol). Purification by PTLC on silica gel (hexane−EtOAc, 2:1) followed by crystallization from a mixture of MeOH−H2O (2:1) afforded 7d (186 mg, 92%) as a single diastereomer. Following General Procedure C, the solid-state reaction of cyclopropene 1d with DHPO (6) also led to the desired cycloadduct 7d (162 mg, 80%). Yellow solid; mp 210−211 °C (MeOH−H2O, 2:1); Rf 0.52 (SiO2, hexane−EtOAc, 2:1). 1H NMR (400 MHz, CDCl3): δ = 7.90 (d, J = 7.4 Hz, 1H), 7.76−7.60 (m, 5H), 7.34−7.27 (m, 2H), 7.25−7.11 (m, 6H), 7.09−7.03 (m, 2H), 6.96− 6.87 (m, 3H), 4.86 (t, J = 7.4 Hz, 1H), 3.65−3.54 (m, 1H), 3.10 (s, 1H), 2.82−2.70 (m, 1H), 2.20−2.07 (m, 2H), 2.06−1.87 (m, 2H). 13 C{1H} NMR (101 MHz, CDCl3): δ = 201.5, 198.0, 142.1, 141.5, 136.1, 135.6, 135.3, 132.6 (2C), 131.5, 131.3 (2C), 130.7 (2C), 128.1 (2C), 127.9 (2C), 127.7, 127.5 (2C), 127.4, 126.9, 123.9, 123.4, 123.1, 87.3, 87.1, 75.8, 75.1, 55.6, 49.0, 48.6, 27.9, 27.6, 18.9. IR (KBr): 3051, 2973, 2940, 2870, 2228, 1743, 1708, 1596, 1491, 1443, 1209, 1152, 751, 701, 692 cm−1. HRMS (ESI): m/z [M + H]+ calcd for C36H28NO2+: 506.2115; found: 506.2134.

aluminum sheets with 0.2 mm silica gel with fluorescent indicator using UV light and iodine for visualization. Preparative thin-layer chromatography (PTLC) was performed on silica gel (5−40 mesh). All air- or moisture-sensitive reactions were carried out under an argon atmosphere in oven-dried glassware. Unless otherwise stated, all reagents were purchased from commercial suppliers and used as received. Solvents were dried by standard procedures and freshly distilled prior to use: tetrahydrofuran, diethyl ether, and benzene were distilled from sodium; benzophenone ketyl, dichloromethane, and dimethyl sulfoxide from calcium hydride; and acetonitrile and acetone from phosphorus pentoxide. Technical grade hexane and ethyl acetate used for PTLC were distilled prior to use. Commercial methanol of high-performance liquid chromatography grade was used without purification. Preparation of Reactants. Cyclopropenes 1a,30 1b, 1c, 1o,31 1d,32 1e, 1f, 1l, 1m,33 1g−j,34 1k,35 1n,36 2a,20 2b,21 2c,37 2d,38 2e,39 2f,40 2g−i,41 3b,42 and 3c43 were prepared according to the literature data. Parent cyclopropene (3a) was obtained according to a literature procedure with slight modifications.44 2-(3,4-Dihydro-2H-pyrrol-1ium-1-yl)-1-oxo-1H-inden-3-olate (DHPO, 6) was synthesized by the method of Grassmann and Arnim.45 General Procedure A for the 1,3-Dipolar Cycloaddition Reaction of Cyclopropenes to DHPO. A 50 mL round-bottom flask was charged with cyclopropene 1−3 (0.4 mmol), DHPO (6, 85 mg, 0.4 mmol), and MeOH (5 mL). The reaction mixture was stirred at 25 °C for 10 h. Full consumption of reagents was monitored by TLC. All volatiles were evaporated under reduced pressure. The residue was purified by PTLC on silica gel using an appropriate eluent followed by crystallization from a mixture of MeOH−H2O (2:1) to furnish the target 1,3-dipolar cycloadduct 7, 11, and 12. General Procedure B for the One-Pot Three-Component Reaction of 1,2,3-Triphenylcyclopropene, Ninhydrin, and Cyclic α-Amino Acids. A mixture of 1,2,3-triphenylcyclopropene (1a, 107 mg, 0.4 mmol), ninhydrin (4, 71 mg, 0.4 mmol), and α-amino acid 5b,c (0.6 mmol) was refluxed in EtOH (5 mL) for 6 h. After completion of the reaction as monitored by TLC, the solvent was evaporated in vacuo. The residue was chromatographed on silica gel using a mixture of hexane−EtOAc (3:1) followed by crystallization from a mixture of MeOH−H2O (2:1) to give the title 1,3-dipolar cycloadduct 8, 9. General Procedure C for the Solid-State 1,3-Dipolar Cycloaddition Reaction of 3-(R)-1,2-Diphenylcyclopropenes to DHPO. DHPO (6, 85 mg, 0.4 mmol) and cyclopropene 1a−e, 1h, 1j, and 1k (0.4 mmol) were placed in a porcelain mortar and manually ground with a pestle and mortar for 5 min at ambient temperature. The resulting crude product was chromatographed on silica gel using a mixture of hexane−EtOAc (3:1 or 2:1) followed by crystallization from a mixture of MeOH−H2O to afford the pure 1,3-dipolar cycloadduct 7. (±)-(1R,1aR,6aR,6bS)-1,1a,6b-Triphenyl-1a,4,5,6,6a,6b-hexahydro-1H-spiro[cyclopropa[a]pyrrolizine-2,2′-indene]-1′,3′-dione (7a). The reaction was performed according to General Procedure A employing cyclopropene 1a (107 mg, 0.4 mmol) and DHPO (6, 85 mg, 0.4 mmol). Purification by PTLC on silica gel (hexane−EtOAc, 3:1) followed by crystallization from a mixture of MeOH−H2O (2:1) afforded 7a (183 mg, 95%) as a single diastereomer. Following General Procedure C, the solid-state reaction of cyclopropene 1a with DHPO (6) also led to the desired cycloadduct 7a (168 mg, 87%). Yellow solid; mp 254−255 °C (MeOH−H2O, 2:1); Rf 0.49 (SiO2, hexane−EtOAc, 3:1). 1H NMR (400 MHz, CDCl3): δ = 7.85−7.79 (m, 1H), 7.71−7.59 (m, 3H), 7.46−7.39 (m, 2H), 7.30−7.16 (m, 3H), 7.02−6.84 (m, 5H), 6.82−6.71 (m, 3H), 6.47−6.37 (m, 2H), 4.70 (t, J = 6.8 Hz, 1H), 3.85−3.75 (m, 1H), 3.30 (s, 1H), 2.85−2.74 (m, 1H), 2.22−2.10 (m, 1H), 2.02−1.87 (m, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ = 202.3, 198.8, 142.5, 141.7, 136.7, 135.9, 135.4, 134.7, 133.0 (2C), 132.5 (2C), 131.9, 131.2 (2C), 128.0 (2C), 127.6 (2C), 127.0, 126.9, 126.6 (2C), 125.4, 123.3, 122.9, 78.9, 77.1, 56.6, 50.4, 49.4, 31.7, 27.6, 27.5. IR (KBr): 3058, 3031, 2940, 2889, 2857 1737, 1703, 1598, 1497, 1447, 1344, 1322, 1263, 1208, 1152, 7027


Article

The Journal of Organic Chemistry Methyl (±)-(1R,1aR,6aR,6bS)-1′,3′-Dioxo-1a,6b-diphenyl1a,1′,3′,4,5,6,6a,6b-octahydro-1H-spiro[cyclopropa[a]pyrrolizine2,2′-indene]-1-carboxylate (7e). The reaction was performed according to General Procedure A employing cyclopropene 1e (100 mg, 0.4 mmol) and DHPO (6, 85 mg, 0.4 mmol). Purification by PTLC on silica gel (hexane−EtOAc, 2:1) followed by crystallization from a mixture of MeOH−H2O (2:1) afforded 7e (167 mg, 90%) as a single diastereomer. Following General Procedure C, the solid-state reaction of cyclopropene 1e with DHPO (6) also led to the desired cycloadduct 7e (57 mg, 31%). Yellow solid; mp 186−187 °C (MeOH−H2O, 2:1); Rf 0.40 (SiO2, hexane−EtOAc, 2:1). 1H NMR (400 MHz, CDCl3): δ = 7.89 (d, J = 7.0 Hz, 1H), 7.72−7.63 (m, 3H), 7.55−7.48 (m, 2H), 7.37−7.29 (m, 2H), 7.27−7.20 (m, 1H), 7.15− 7.05 (m, 2H), 6.93−6.81 (m, 3H), 4.66 (t, J = 6.6 Hz, 1H), 3.61− 3.51 (m, 1H), 3.45 (s, 3H), 3.02 (s, 1H), 2.73−2.63 (m, 1H), 2.14− 2.01 (m, 1H), 1.99−1.78 (m, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ = 201.2, 198.0, 169.4, 142.4, 141.7, 136.2, 135.6, 134.4, 132.3, 131.2 (2C), 130.8 (2C), 128.2 (2C), 127.7 (2C), 127.3 (2C), 123.5, 123.1, 77.8, 76.2, 56.3, 52.0, 51.5, 49.1, 28.6, 27.5, 27.4. IR (KBr): 3067, 3031, 2998, 2975, 2948, 2906, 1742, 1704, 1590, 1498, 1441, 1363, 1270, 1207, 1168, 771, 703 cm−1. HRMS (ESI): m/z [M + H]+ calcd for C30H26NO4+: 464.1856; found: 464.1865. (±)-(1R,1aR,6aR,6bS)-1′,3′-Dioxo-1a,6b-diphenyl1a,1′,3′,4,5,6,6a,6b-octahydro-1H-spiro[cyclopropa[a]pyrro-lizine2,2′-indene]-1-carboxylic Acid (7f). The reaction was performed according to General Procedure A employing cyclopropene 1f (95 mg, 0.4 mmol) and DHPO (6, 85 mg, 0.4 mmol). Purification by PTLC on silica gel (CH2Cl2−MeOH, 40:1) followed by crystallization from a mixture of MeOH−H2O (2:1) afforded 7f (128 mg, 71%) as a single diastereomer. Light yellow solid; mp > 260 °C (MeOH−H2O, 2:1); Rf 0.42 (SiO2, hexane−EtOAc, 1:1). 1H NMR (400 MHz, DMSO-d6): δ = 12.20 (s, 1H), 7.96−7.91 (m, 1H), 7.90− 7.81 (m, 2H), 7.77−7.70 (m, 1H), 7.53−7.45 (m, 2H), 7.40−7.32 (m, 2H), 7.28−7.21 (m, 1H), 7.06−6.98 (m, 2H), 6.95−6.95 (m, 3H), 4.39 (t, J = 6.6 Hz, 1H), 3.46−3.36 (m, 1H), 2.81 (s, 1H), 2.63−2.53 (m, 1H), 2.10−1.96 (m, 1H), 1.89−1.66 (m, 3H). 13 C{1H} NMR (101 MHz, DMSO-d6): δ = 199.8, 197.3, 169.5, 141.4, 140.7, 137.0, 136.5, 134.4, 132.2, 130.8 (2C), 130.4 (2C), 127.9 (2C), 127.2 (2C), 126.8 (2C), 123.1, 123.0, 77.2, 75.4, 55.3, 51.1, 48.5, 27.6, 26.8, 26.6. IR (KBr): 3429, 3064, 3029, 2983, 2967, 2951, 2881, 1740, 1710, 1674, 1591, 1501, 1425, 1275, 1211, 1184, 976, 746, 703 cm−1. HRMS (ESI): m/z [M + Na]+ calcd for C29H23NNaO4+: 472.1519; found: 472.1544. (±)-(1R,1aR,6aR,6bS)-N-Isopropyl-1′,3′-dioxo-1a,6b-diphenyl1a,1′,3′,4,5,6,6a,6b-octahydro-1H-spiro[cyclopropa[a]pyrrolizine2,2′-indene]-1-carboxamide (7g). The reaction was performed according to General Procedure A employing cyclopropene 1g (111 mg, 0.4 mmol) and DHPO (6, 85 mg, 0.4 mmol). Purification by PTLC on silica gel (hexane−EtOAc, 1:1) followed by crystallization from a mixture of MeOH−H2O (2:1) afforded 7g (153 mg, 78%) as a single diastereomer. Yellow solid; mp 206−207 °C (MeOH−H2O, 2:1); Rf 0.44 (SiO2, hexane−EtOAc, 1:1). 1H NMR (400 MHz, CDCl3): δ = 7.91 (d, J = 7.3 Hz, 1H), 7.78−7.63 (m, 5H), 7.40−7.31 (m, 2H), 7.30−7.23 (m, 1H), 7.22−7.15 (m, 2H), 7.00−6.84 (m, 3H), 4.67−4.51 (m, 1H), 4.03 (d, J = 7.7 Hz, 1H), 3.80−3.67 (m, 1H), 3.65−3.51 (m, 1H), 2.86 (s, 1H), 2.79−2.62 (m, 1H), 2.14− 2.02 (m, 1H), 2.00−1.79 (m, 3H), 0.60 (d, J = 6.5 Hz, 3H), 0.52 (d, J = 6.5 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ = 200.5, 197.7, 167.1, 142.4, 141.7, 136.2, 135.7, 134.0, 131.9, 131.7 (4C), 128.3 (2C), 128.2 (2C), 127.8, 127.6, 123.6, 123.3, 78.0, 76.0, 53.5, 50.1, 49.5, 41.1, 31.3, 27.5, 27.3, 22.0 (2C). IR (KBr): 3421, 3053, 3023, 2966, 2930, 2905, 2862, 1737, 1705, 1645, 1527, 1445, 1265, 1155, 774, 709 cm−1. HRMS (ESI): m/z [M + H]+ calcd for C32H31N2O3+: 491.2329; found: 491.2323. (±)-(1R,1aR,6aR,6bS)-N,N-Dimethyl-1′,3′-dioxo-1a,6b-diphenyl1a,1′,3′,4,5,6,6a,6b-octahydro-1H-spiro[cyclopropa[a]pyrrolizine2,2′-indene]-1-carboxamide (7h). The reaction was performed according to General Procedure A employing cyclopropene 1h (105 mg, 0.4 mmol) and DHPO (6, 85 mg, 0.4 mmol). Purification by PTLC on silica gel (hexane−EtOAc, 1:1) followed by crystallization from a mixture of MeOH−H2O (2:1) afforded 7h (162 mg, 85%) as a

single diastereomer. Following General Procedure C, the solid-state reaction of cyclopropene 1h with DHPO (6) also led to the desired cycloadduct 7h (103 mg, 54%). Yellow solid; mp 199−200 °C (MeOH−H2O, 2:1); Rf 0.27 (SiO2, hexane−EtOAc, 1:1). 1H NMR (400 MHz, CDCl3): δ = 7.89 (d, J = 7.4 Hz, 1H), 7.74−7.67 (m, 1H), 7.67−7.63 (m, 2H), 7.49−7.43 (m, 2H), 7.31−7.24 (m, 2H), 7.23− 7.16 (m, 1H), 7.02−6.95 (m, 2H), 6.87−6.79 (m, 3H), 4.68 (t, J = 7.0 Hz, 1H), 3.55−3.45 (m, 1H), 3.36 (s, 3H), 3.19 (s, 1H), 2.80− 2.71 (m, 1H), 2.80 (s, 3H), 2.18−2.07 (m, 1H), 2.07−1.91 (m, 2H), 1.90−1.78 (m, 1H). 13C{1H} NMR (101 MHz, CDCl3): δ = 201.1, 198.7, 167.4, 142.1, 141.7, 136.3, 135.6, 135.0, 132.1, 131.5 (2C), 130.8 (2C), 127.8 (2C), 127.3 (2C), 127.0, 126.8, 123.4, 123.0, 76.6, 76.0, 56.1, 49.4, 48.4, 37.9, 36.0, 27.6, 27.4, 27.2. IR (KBr): 3077, 3060, 3027, 2977, 2944, 2902, 2847, 1739, 1707, 1649, 1497, 1271, 1149, 703 cm−1. HRMS (ESI): m/z [M + H]+ calcd for C31H29N2O3+: 477.2173; found: 477.2188. (±)-(1R,1aR,6aR,6bS)-1′,3′-Dioxo-1a,6b-diphenyl1a,1′,3′,4,5,6,6a,6b-octahydro-1H-spiro[cyclopropa[a]pyrrolizine2,2′-indene]-1-carboxamide (7i). The reaction was performed according to General Procedure A employing cyclopropene 1i (94 mg, 0.4 mmol) and DHPO (6, 85 mg, 0.4 mmol). Purification by PTLC on silica gel (CH2Cl2−MeOH, 20:1) followed by crystallization from a mixture of MeOH−H2O (2:1) afforded 7i (124 mg, 69%) as a single diastereomer. Light yellow solid; mp > 260 °C (MeOH−H2O, 2:1); Rf 0.30 (SiO2, CH2Cl2−MeOH, 20:1). 1H NMR (400 MHz, DMSO-d6): δ = 8.00 (br s, 1H), 7.94−7.88 (m, 1H), 7.87−7.78 (m, 2H), 7.74−7.68 (m, 1H), 7.52−7.43 (m, 2H), 7.36− 7.28 (m, 2H), 7.24−7.16 (m, 1H), 7.05−6.92 (m, 2H), 6.90−6.72 (m, 4H), 4.35 (t, J = 6.8 Hz, 1H), 3.61−3.48 (m, 1H), 2.85 (s, 1H), 2.59−2.50 (m, 1H, overlapping with DMSO), 2.07−1.94 (m, 1H), 1.91−1.64 (m, 3H). 13C{1H} NMR (101 MHz, DMSO-d6): δ = 200.2, 197.6, 168.9, 141.5, 140.7, 136.8, 136.3, 135.5, 133.1, 130.9 (2C), 130.5 (2C), 127.6 (2C), 126.8 (2C), 126.4, 126.2, 123.0, 122.9, 77.3, 75.6, 54.3, 49.9, 48.3, 27.9, 26.8, 26.7. IR (KBr): 3439, 3310, 3196, 3062, 3029, 2978, 2952, 2873, 1734, 1696, 1501, 1448, 1273, 971, 703 cm−1. HRMS (ESI): m/z [M + H]+ calcd for C29H24N2O3+: 449.1860; found: 449.1880. (±)-(1R,1aR,6aR,6bS)-1′,3′-Dioxo-1a,6b-diphenyl1a,1′,3′,4,5,6,6a,6b-octahydro-1H-spiro[cyclopropa[a]pyrrolizine2,2′-indene]-1-carbonitrile (7j). The reaction was performed according to General Procedure A employing cyclopropene 1j (87 mg, 0.4 mmol) and DHPO (6, 85 mg, 0.4 mmol). Purification by PTLC on silica gel (hexane−EtOAc, 2:1) followed by crystallization from a mixture of MeOH−H2O (2:1) afforded 7j (153 mg, 89%) as a single diastereomer. Following General Procedure C, the solid-state reaction of cyclopropene 1j with DHPO (6) also led to the desired cycloadduct 7j (145 mg, 84%). Yellow solid; mp 251−252 °C (MeOH−H2O, 2:1); Rf 0.67 (SiO2, hexane−EtOAc, 1:1). 1H NMR (400 MHz, CDCl3): δ = 7.91 (d, J = 7.6 Hz, 1H), 7.77−7.62 (m, 5H), 7.42−7.33 (m, 2H), 7.32−7.24 (m, 1H), 7.22−7.12 (m, 2H), 7.05− 6.90 (m, 3H), 4.75 (t, J = 7.1 Hz, 1H), 3.50−3.35 (m, 1H), 2.94 (s, 1H), 2.77−2.64 (m, 1H), 2.17−2.01 (m, 2H), 2.00−1.88 (m, 1H), 1.84−1.71 (m, 1H). 13C{1H} NMR (101 MHz, CDCl3): δ = 200.4, 197.1, 141.9, 141.5, 136.6, 136.0, 132.9, 131.8 (2C), 130.1 (2C), 129.8, 128.7 (2C), 128.5, 128.4 (2C), 128.0, 123.6, 123.4, 117.9, 75.1, 74.9, 54.7, 49.1, 48.1, 27.5, 27.4, 14.7. IR (KBr): 3052, 3032, 2975, 2947, 2889, 2234, 1740, 1706, 1593, 1500, 1446, 1352, 1271, 1202, 1156, 772, 704 cm−1. HRMS (ESI): m/z [M + H]+ calcd for C29H23N2O2+: 431.1754; found: 431.1760. (±)-(1aR,6aR,6bS)-1a,6b-Diphenyl-1a,4,5,6,6a,6b-hexahydro1H-spiro[cyclopropa[a]pyrrolizine-2,2′-indene]-1′,3′-dione (7k). The reaction was performed according to General Procedure A employing cyclopropene 1k (77 mg, 0.4 mmol) and DHPO (6, 85 mg, 0.4 mmol). Purification by PTLC on silica gel (hexane−EtOAc, 3:1) afforded 7k (141 mg, 87%) as a single diastereomer. Following General Procedure C, the solid-state reaction of cyclopropene 1k with DHPO (6) also led to the desired cycloadduct 7k (122 mg, 75%). Yellow-orange amorphous powder; Rf 0.41 (SiO2, hexane−EtOAc, 3:1). 1H NMR (400 MHz, CDCl3): δ = 7.89−7.82 (m, 1H), 7.74− 7.60 (m, 3H), 7.43−7.36 (m, 2H), 7.29−7.20 (m, 2H), 7.18−7.11 7028


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(±)-(1R,1aR,7aR,7bS)-1,1a,7b-Triphenyl-1,1a,4,5,6,7,7a,7boctahydrospiro[cyclopropa[a]indolizine-2,2′-indene]-1′,3′-dione (9). The reaction was performed according to General Procedure B employing 1,2,3-triphenylcyclopropene (1a, 107 mg, 0.4 mmol), ninhydrin (4, 71 mg, 0.4 mmol), and DL-pipecolic acid (5c, 77 mg, 0.6 mmol). Purification by PTLC on silica gel (hexane−EtOAc, 3:1) followed by crystallization from a mixture of MeOH−H2O (2:1) afforded 9 (71 mg, 36%) as a single diastereomer. Yellow solid; mp 212−213 °C (MeOH−H2O, 2:1); Rf 0.49 (SiO2, hexane−EtOAc, 3:1). 1H NMR (400 MHz, CDCl3): δ = 7.75 (d, J = 6.6 Hz, 1H, Harom.), 7.65−7.55 (m, 3H, Harom.), 7.42−7.34 (m, 2H, Harom.), 7.29− 7.17 (m, 3H, Harom.), 6.99−6.91 (m, 2H, Harom.), 6.90−6.82 (m, 3H, Harom.), 6.79−6.69 (m, 3H, Harom.), 6.47−6.40 (m, 2H, Harom.), 4.00 (s, 1H, C1H), 3.87 (dd, J = 9.9, 3.3 Hz, 1H, C7aH), 2.65−2.50 (m, 2H, C4H + C4H″), 1.84−1.74 (m, 1H, C6H), 1.72−1.61 (m, 1H, C5H), 1.59−1.50 (m, 1H, C5H″), 1.49−1.37 (m, 2H, C7H + C7H″), 1.29−1.14 (m, 1H, C6H″). 13C{1H} NMR (101 MHz, CDCl3): δ = 205.5, 201.6, 142.6, 141.2, 137.3, 135.8, 135.6, 134.3, 133.1 (3C), 133.0, 131.9, 131.5 (2C), 127.8 (2C), 127.7 (2C), 127.0, 126.9, 126.5 (2C), 125.2, 122.5, 122.1, 79.7, 71.7, 50.7, 47.5, 46.7, 30.1, 26.7, 25.9, 24.1. IR (KBr): 3058, 3029, 2939, 2859, 1737, 1703, 1599, 1498, 1447, 1344, 1325, 1264, 764, 706 cm−1. HRMS (ESI): m/z [M + H]+ calcd for C35H30NO2+: 496.2271; found: 496.2279. Trapping of 1-Methylcyclopropene with DHPO. An ether solution of 1-lithio-2-methylcyclopropene which had been synthesized according to Magid’s method20 using 3-chloro-2-methyl-1-propene (980 μL, 10 mmol) and freshly prepared phenyllithium (1.0 M in ether, 30 mL, 30 mmol) was placed in a 100 mL three-neck roundbottom flask. The latter was provided with a condenser, a 10 mL dropping funnel, a magnetic stir bar, and an inlet tube connected to a 10 mL screw-cap tube containing DHPO (6, 213 mg, 1 mmol), absolute THF (5 mL), and a small magnetic stirrer. Argon flow was introduced from the top of the condenser. To a thoroughly stirred solution of 1-lithio-2-methylcyclopropene at 0 °C was carefully added MeOH (10 mL) over 15 min while a slow stream of argon was swept through the flask and into the tube at −30 °C. Having finished neutralization, the cap was tightly screwed and the tube was allowed to warm to 0 °C with stirring until complete dissolution of DHPO (6). After 5 min, full conversion of starting azomethine ylide 6 into 1,3-dipolar cycloadduct 11a was identified by TLC-control. All volatiles were evaporated in vacuo, and the residue was purified by PTLC on silica gel using a hexane−EtOAc mixture (2:1) as the eluent followed by crystallization from a MeOH−H2O mixture (2:1) to give the title cycloadduct 11a as a single diastereomer. (±)-(1aS,6aR,6bR)-1a-Methyl-1a,4,5,6,6a,6b-hexahydro-1Hspiro[cyclopropa[a]pyrrolizine-2,2′-indene]-1′,3′-dione (11a). Yellow-orange solid; yield: 246 mg (92%); mp 98−99 °C (MeOH−H2O, 2:1); Rf 0.42 (SiO2, hexane−EtOAc, 2:1). 1H NMR (400 MHz, CDCl3): δ = 8.04−8.00 (m, 1H, Harom.), 7.99−7.94 (m, 1H, Harom.), 7.90−7.81 (m, 2H, Harom.), 4.45−4.36 (m, 1H, C6aH), 3.24−3.14 (m, 1H, C4H), 2.62−2.53 (m, 1H, C4H″), 2.02−1.81 (m, 3H, C5H + C5H″ + C6H), 1.66−1.52 (m, 2H, C6H″ + C6bH), 1.27−1.22 (m, 1H, C1H), 0.98 (s, 3H, CH3−C1a), 0.50−0.44 (m, 1H, C1H″). 13C{1H} NMR (101 MHz, CDCl3): δ = 201.9, 198.9, 142.3, 141.4, 136.4, 135.9, 123.7, 123.3, 73.3, 67.6, 48.7, 36.6, 29.9, 28.6, 28.3, 17.4, 13.2. IR (KBr): 2966, 2946, 2897, 2860, 2844, 1736, 1708, 1591, 1445, 1214, 1152, 759 cm−1. HRMS (ESI): m/z [M + H]+ calcd for C17H18NO2+: 268.1332; found: 268.1341. Trapping of 1-Phenylcyclopropene with DHPO. A 100 mL twoneck flask was equipped with a 25 mL dropping funnel, a calcium chloride tube, and a magnetic stirring bar. The flask was charged with DHPO (6, 213 mg, 1 mmol), THF (10 mL), and AcOH (570 μL, 10 mmol). A solution of 1-lithio-2-phenylcyclopropene in ether that had been prepared by the literature procedure21 using 1,1,2-tribromo-2phenylcyclopropane (710 mg, 2 mmol) and methyllithium (1.6 M in ether, 3.1 mL, 5 mmol) was slowly added to the vigorously stirred suspension of the ylide 6 at 25 °C over a period of 5−10 min. Upon completion of addition, the DHPO (6) completely dissolved, whereas a white precipitate of AcOLi was formed. Full consumption of starting material 6 was ascertained by TLC. All volatiles were evaporated in

(m, 1H), 7.02−6.95 (m, 2H), 6.87−6.81 (m, 3H), 4.94 (t, J = 6.7 Hz, 1H), 3.60−3.50 (m, 1H), 2.80−2.67 (m, 1H), 2.13−1.90 (m, 4H), 1.83−1.69 (m, 1H), 1.51 (d, J = 5.3 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3): δ = 202.2, 198.4, 142.1, 141.6, 137.8, 136.1, 135.5, 135.2, 131.9 (2C), 129.3 (2C), 128.3 (2C), 127.7 (2C), 127.2, 126.8, 123.4, 123.0, 75.9, 73.4, 51.8, 48.9, 44.3, 27.8, 27.7, 17.6. IR (KBr): 3056, 3025, 2963, 2904, 2866, 1741, 1705, 1596, 1498, 1447, 1271, 1211, 1153, 768, 701 cm−1. HRMS (ESI): m/z [M + H]+ calcd for C28H24NO2+: 406.1802; found: 406.1800. Methyl (±)-(1R,1aS,6aR,6bR)-1a,6b-Dimethyl-1′,3′-dioxo1a,1′,3′,4,5,6,6a,6b-octahydro-1H-spiro[cyclopropa-[a]pyrrolizine2,2′-indene]-1-carboxylate (7l). The reaction was performed according to General Procedure A employing cyclopropene 1l (50 mg, 0.4 mmol) and DHPO (6, 85 mg, 0.4 mmol). Purification by PTLC on silica gel (hexane−EtOAc, 2:1) followed by crystallization from a mixture of MeOH−H2O (2:1) afforded 7l (57 mg, 42%) as a single diastereomer. Yellow-brown solid; mp 145−146 °C (MeOH− H2O, 2:1); Rf 0.41 (SiO2, hexane−EtOAc, 2:1). 1H NMR (400 MHz, CDCl3): δ = 8.02−7.95 (m, 2H), 7.90−7.81 (m, 2H), 4.09 (t, J = 7.3 Hz, 1H), 3.65 (s, 3H), 3.27−3.18 (m, 1H), 2.52 (t, J = 7.6 Hz, 1H), 2.25 (s, 1H), 2.06−1.96 (m, 2H), 1.93−1.80 (m, 1H), 1.65−1.54 (m, 1H), 1.35 (s, 3H), 1.04 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ = 202.1, 198.5, 171.1, 142.4, 141.6, 136.5, 136.0, 123.7, 123.5, 74.5, 74.3, 51.6, 48.1, 46.8, 41.3, 28.0, 27.6, 26.1, 9.9, 8.1. IR (KBr): 2977, 2948, 2925, 2862, 1730, 1709, 1592, 1436, 1367, 1275, 1206, 1158, 1127, 1077, 773 cm−1. HRMS (ESI): m/z [M + H]+ calcd for C20H22NO4+: 340.1543; found: 340.1549. (±)-(1R,1aS,6aR,6bR)-1a,6b-Dimethyl-1′,3′-dioxo1a,1′,3′,4,5,6,6a,6b-octahydro-1H-spiro[cyclopropa[a]pyrrolizine2,2′-indene]-1-carboxylic Acid (7m). The reaction was performed according to General Procedure A employing cyclopropene 1m (45 mg, 0.4 mmol) and DHPO (6, 85 mg, 0.4 mmol). Purification by PTLC on silica gel (CH2Cl2−MeOH, 40:1) followed by crystallization from a mixture of MeOH−H2O (2:1) afforded 7m (43 mg, 33%) as a single diastereomer. Light yellow solid; mp 218−219 °C (MeOH−H2O, 2:1); Rf 0.38 (SiO2, hexane−EtOAc, 1:1). 1H NMR (400 MHz, DMSO-d6): δ = 12.09 (br s, 1H, CO2H), 8.09−7.98 (m, 4H, Harom.), 3.91 (t, J = 7.2 Hz, 1H, C6aH), 3.12−3.03 (m, 1H, C4H), 2.40 (t, J = 7.5 Hz, 1H, C4H″), 2.04 (s, 1H, C1H), 2.02−1.91 (m, 2H, C6H + C5H), 1.79−1.64 (m, 1H, C6H″), 1.55−1.43 (m, 1H, C5H″), 1.25 (s, 3H, CH3−C6b), 0.94 (s, 3H, CH3−C1a). 13C{1H} NMR (101 MHz, DMSO-d6): δ = 200.6, 197.7, 171.2, 141.5, 140.7, 137.2, 136.7, 123.3 (2C), 73.7, 73.5, 47.4, 45.0, 39.9, 27.3, 26.9, 25.5, 9.6, 7.6. IR (KBr): 3437, 2963, 2930, 2907, 1746, 1712, 1594, 1366, 1273, 1222, 1165, 620 cm−1. HRMS (ESI): m/z [M + H]+ calcd for C19H20NO4+: 326.1387; found: 326.1371. (±)-(5aR,6R,6aS,6bS)-5a,6,6a-Triphenyl-1,3,5a,6,6a,6bhexahydrospiro[cyclopropa[3,4]pyrrolo[1,2-c]thiazole-5,2′-indene]-1′,3′-dione (8). The reaction was performed according to General Procedure B employing 1,2,3-triphenylcyclopropene (1a, 107 mg, 0.4 mmol), ninhydrin (4, 71 mg, 0.4 mmol), and L-4thiazolidinecarboxylic acid (5b, 80 mg, 0.6 mmol). Purification by PTLC on silica gel (hexane−EtOAc, 2:1) followed by crystallization from a mixture of MeOH−H2O (2:1) afforded 8 (148 mg, 74%) as a single diastereomer. Yellow solid; mp 220−221 °C (MeOH−H2O, 2:1); Rf 0.34 (SiO2, hexane−EtOAc, 3:1). 1H NMR (400 MHz, CDCl3): δ = 7.78 (d, J = 7.3 Hz, 1H, Harom.), 7.70−7.57 (m, 3H, Harom.), 7.43−7.36 (m, 2H, Harom.), 7.31−7.18 (m, 3H, Harom.), 7.01− 6.95 (m, 1H, Harom.), 6.93−6.83 (m, 4H, Harom.), 6.82−6.71 (m, 3H, Harom.), 6.43 (d, J = 7.6 Hz, 2H, Harom.), 4.79 (dd, J = 8.4, 5.4 Hz, 1H, C6bH), 4.05 (s, 1H, C6H), 4.03 (d, J = 5.3 Hz, 1H, C3H), 3.81 (d, J = 5.3 Hz, 1H, C3H″), 2.93 (t, J = 8.9 Hz, 1H, C1H), 2.67 (dd, J = 9.5, 5.4 Hz, 1H, C1H″). 13C{1H} NMR (101 MHz, CDCl3): δ = 203.4, 198.3, 142.0, 141.0, 136.1, 136.1, 135.9, 133.8, 132.8 (2C), 132.5 (2C), 131.5 (2C), 131.1, 128.3 (2C), 127.8 (2C), 127.5, 127.4, 126.7 (2C), 125.7, 122.9, 122.7, 78.2, 75.5, 56.4, 46.0, 45.1, 30.1, 30.0. IR (KBr): 3058, 3034, 2949, 2849, 1741, 1706, 1601, 1497, 1445, 1258, 1227, 769, 707 cm−1. HRMS (ESI): m/z [M + Na]+ calcd for C33H25NNaO2S+: 522.1498; found: 522.1497. 7029


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1.86 (m, 3H, C5H + C5H″ + C6H), 1.64−1.55 (m, 1H, C6H″), 1.62 (d, J = 5.0 Hz, 1H, C1H), 0.85 (d, J = 5.0 Hz, 1H, C1H″), −0.15 (s, 9H, tetramethylsilane). 13C{1H} NMR (101 MHz, CDCl3): δ = 203.0, 198.9, 142.1, 141.6, 137.2, 135.9, 135.3, 131.9 (2C), 127.8 (2C), 127.3, 123.1, 122.8, 76.4, 71.0, 52.3, 48.7, 30.0, 28.5, 28.4, 14.6, −2.1 (3C). IR (KBr): 3056, 3005, 2961, 2903, 2876, 2847, 1742, 1709, 1599, 1492, 1444, 1348, 1326, 1278, 1251, 954, 847, 836, 708 cm−1. HRMS (ESI): m/z [M + Na]+ calcd for C25H27NNaO2Si+: 424.1703; found: 424.1709. (±)-(1aS,6aR,6bS)-6b-Bromo-1a-phenyl-1a,4,5,6,6a,6b-hexahydro-1H-spiro[cyclopropa[a]pyrrolizine-2,2′-indene]-1′,3′-dione (11e). Yellow-green solid; yield: 334 mg (82%); mp 173−174 °C (MeOH−H2O, 3:1); Rf 0.45 (SiO2, hexane−EtOAc, 3:1). 1H NMR (400 MHz, CDCl3): δ = 7.87−7.82 (m, 1H, Harom.), 7.71−7.61 (m, 3H, Harom.), 7.22−7.16 (m, 2H, Harom.), 7.10−6.99 (m, 3H, Harom.), 4.73 (t, J = 6.9 Hz, 1H, C6aH), 3.47−3.38 (m, 1H, C4H), 2.71−2.66 (m, 1H, C4H″), 2.26 (d, J = 6.9 Hz, 1H, C1H), 2.25−2.18 (m, 1H, C6H), 2.09−2.00 (m, 1H, C5H), 1.99−1.90 (m, 1H, C5H″), 1.89− 1.79 (m, 1H, C6H″), 1.39 (dd, J = 6.9, 1.6 Hz, 1H, C1H″). 13C{1H} NMR (101 MHz, CDCl3): δ = 200.8, 197.7, 141.7, 141.3, 136.2, 135.6, 134.4, 132.0 (2C), 128.0 (3C), 123.4, 123.0, 74.6, 74.3, 49.0, 48.6, 45.4, 27.3, 27.2, 22.7. IR (KBr): 3063, 2979, 2956, 2919, 2880, 2858, 1741, 1705, 1588, 1447, 1351, 1276, 1208, 1142, 1073, 1024, 762, 701 cm −1 . HRMS (ESI): m/z [M + H] + calcd for C22H1979BrNO2+: 408.0594; found: 408.0595; m/z [M + H]+ calcd for C22H1981BrNO2+: 410.0574; found: 410.0578. (±)-(1aS,6aR,6bS)-6b-Chloro-1a-phenyl-1a,4,5,6,6a,6b-hexahydro-1H-spiro[cyclopropa[a]pyrrolizine-2,2′-indene]-1′,3′-dione (11f). The cycloadduct 11f was obtained from a solution of 1-chloro2-phenylcyclopropene (2f, 212 mg, 1.5 mmol) in a mixture of THF and CCl4 (5 mL) and DHPO (6, 213 mg, 1 mmol). Yellow solid; yield: 256 mg (75%); mp 167−168 °C (MeOH−H2O, 2:1); Rf 0.36 (SiO2, hexane−EtOAc, 3:1). 1H NMR (400 MHz, CDCl3): δ = 7.85 (d, J = 7.3 Hz, 1H, Harom.), 7.72−7.60 (m, 3H, Harom.), 7.21−7.15 (m, 2H, Harom.), 7.11−7.01 (m, 3H, Harom.), 4.67 (t, J = 6.9 Hz, 1H, C6aH), 3.49−3.39 (m, 1H, C4H), 2.74−2.64 (m, 1H, C4H″), 2.28− 2.19 (m, 1H, C6H), 2.21 (d, J = 6.8 Hz, 1H, C1H), 2.11−2.02 (m, 1H, C5H), 2.01−1.93 (m, 1H, C5H″), 1.93−1.82 (m, 1H, C6H″), 1.39 (dd, J = 6.8, 1.7 Hz, 1H, C1H″). 13C{1H} NMR (101 MHz, CDCl3): δ = 200.6, 197.5, 141.6, 141.3, 136.3, 135.7, 133.7, 132.1 (2C), 128.1 (2C), 128.0, 123.5, 123.1, 74.5, 73.4, 54.7, 49.0, 48.4, 27.4, 27.1, 22.3. IR (KBr): 3067, 3026, 2977, 2880, 2857, 1741, 1704, 1589, 1447, 1279, 1209, 764, 703 cm−1. HRMS (ESI): m/z [M + H]+ calcd for C22H19ClNO2+: 364.1099; found: 364.1103. (±)-(1R,1aR,6aR,6bR)-6b-Methyl-1′,3′-dioxo-1a-phenyl1a,1′,3′,4,5,6,6a,6b-octahydro-1H-spiro[cyclopropa[a]pyrrolizine2,2′-indene]-1-carboxylic Acid (11g). The reaction was performed according to General Procedure A employing cyclopropene 2g (70 mg, 0.4 mmol) and DHPO (6, 85 mg, 0.4 mmol). Purification by PTLC on silica gel (CH2Cl2−MeOH, 40:1) followed by crystallization from a mixture of MeOH−H2O (2:1) afforded 11g (98 mg, 63%) as a single diastereomer. Light yellow solid; mp 246−247 °C (MeOH−H2O, 2:1); Rf 0.53 (SiO2, hexane−EtOAc, 1:1). 1H NMR (400 MHz, DMSO-d6): δ = 11.99 (br s, 1H), 7.94−7.90 (m, 1H), 7.88−7.83 (m, 1H), 7.81−7.75 (m, 1H), 7.56 (d, J = 7.5 Hz, 1H), 7.04−6.94 (m, 3H), 6.86−6.76 (m, 2H), 4.19 (t, J = 7.2 Hz, 1H), 3.36−3.26 (m, 1H, overlapping with H2O), 2.56−2.50 (m, 1H, overlapping with DMSO), 2.48 (s, 1H), 2.12−1.97 (m, 2H), 1.86− 1.72 (m, 1H), 1.66−1.54 (m, 1H), 1.43 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6): δ = 200.1, 197.6, 170.1, 141.2, 140.4, 136.8, 136.3, 132.1, 130.8 (2C), 127.5 (2C), 127.0, 122.8, 122.7, 75.4, 74.0, 54.5, 47.6, 40.9, 27.3 (2C), 27.1, 11.4. IR (KBr): 3058, 3026, 2961, 2875, 1743, 1706, 1431, 1324, 1279, 1232, 1145, 959, 769, 702 cm−1. HRMS (ESI): m/z [M + H]+ calcd for C24H22NO4+: 388.1543; found: 388.1542. (±)-(1R,1aR,6aR,6bR)-6b-Methyl-1′,3′-dioxo-1a-(p-tolyl)1a,1′,3′,4,5,6,6a,6b-octahydro-1H-spiro[cyclopropa[a]pyrrolizine2,2′-indene]-1-carboxylic Acid (11h). The reaction was performed according to General Procedure A employing cyclopropene 2h (75 mg, 0.4 mmol) and DHPO (6, 85 mg, 0.4 mmol). Purification by PTLC on silica gel (CH2Cl2−MeOH, 40:1) followed by crystal-

vacuo. To the crude mixture was added 10 mL of Et2O and aqueous saturated sodium bicarbonate (10 mL), and the resulting mixture was transferred into a separatory funnel. The organic phase was washed twice with saturated NaHCO3 and brine. The washed organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by PTLC on silica gel using a mixture of hexane−EtOAc (3:1) as the eluent followed by crystallization from a MeOH−H2O mixture (2:1) to afford the title cycloadduct 11b as a sole diastereomer. (±)-(1aS,6aR,6bR)-1a-Phenyl-1a,4,5,6,6a,6b-hexahydro-1Hspiro[cyclopropa[a]pyrrolizine-2,2′-indene]-1′,3′-dione (11b). Yellow-orange solid; yield: 290 mg (88%); mp 94−95 °C (MeOH−H2O, 2:1); Rf 0.49 (SiO2, hexane−EtOAc, 3:1). 1H NMR (400 MHz, CDCl3): δ = 7.92 (d, J = 7.5 Hz, 1H, Harom.), 7.75−7.68 (m, 1H, Harom.), 7.67−7.60 (m, 2H, Harom.), 7.13−7.05 (m, 2H, Harom.), 7.03− 6.94 (m, 3H, Harom.), 4.65−4.52 (m, 1H, C6aH), 3.37−3.26 (m, 1H, C4H), 2.64−2.52 (m, 1H, C4H″), 2.13−1.97 (m, 3H, C6bH + C5H + C5H″), 1.96−1.85 (m, 1H, C6H), 1.74−1.65 (m, 1H, C6H″), 1.63 (t, J = 5.2 Hz, 1H, C1H), 0.85 (dd, J = 8.2, 5.6 Hz, 1H, C1H″). 13C{1H} NMR (101 MHz, CDCl3): δ = 201.5, 199.1, 142.1, 141.5, 138.0, 136.0, 135.4, 130.6 (2C), 128.1 (2C), 127.2, 123.4, 123.0, 74.6, 67.5, 48.6, 46.3, 29.4, 28.8, 28.4, 13.8. IR (KBr): 3063, 2991, 2972, 2936, 2879, 1740, 1705, 1591, 1495, 1446, 1356, 1216, 1157, 1077, 1001, 772, 697 cm−1. HRMS (ESI): m/z [M + H]+ calcd for C22H20NO2+: 330.1489; found: 330.1489. Trapping of Unsymmetrically 1,2-Substituted Cyclopropenes with DHPO. DHPO (6, 213 mg, 1 mmol) was suspended in THF (5 mL) and treated with the freshly prepared ether solution (∼10 mL) containing 1-bromo-2-phenylcyclopropene (2e, 292 mg, 1.5 mmol). The reaction mixture was stirred at ambient temperature for 5 min until the complete dissolution of DHPO (6). The starting azomethine ylide 6 was fully consumed according to TLC. After removing the volatile fraction using a rotary evaporator, the residue was subjected to recrystallization from a mixture of MeOH−H2O (3:1) to afford the desired cycloadduct 11e as a single diastereomer. Similarly, freshly prepared 1-methyl-2-phenylcyclopropene (2c), 1-phenyl-2-trimethylsilylcyclopropene (2d), and 1-chloro-2-phenylcyclopropene (2f) were trapped by stirring the reaction mixture containing DHPO (6, 213 mg, 1 mmol) and cyclopropenes 2c, 2d, and 2f (1.5 mmol) in anhydrous THF (5 mL) at 25 °C for 5 min. The crude products 11c, 11d, and 11f were purified by PTLC on silica gel using a mixture of hexane−EtOAc (3:1) as the eluent. (±)-(1aS,6aR,6bS)-6b-Methyl-1a-phenyl-1a,4,5,6,6a,6b-hexahydro-1H-spiro[cyclopropa[a]pyrrolizine-2,2′-indene]-1′,3′-dione (11c). The cycloadduct 11c was obtained from crude 1-methyl-2phenylcyclopropene (2c, 195 mg, 1.5 mmol) and DHPO (6, 213 mg, 1 mmol). Yellow-orange amorphous powder; yield: 330 mg (96%); Rf 0.52 (SiO2, hexane−EtOAc, 3:1). 1H NMR (400 MHz, CDCl3): δ = 7.84−7.79 (m, 1H, Harom.), 7.66−7.54 (m, 3H, Harom.), 7.10−7.03 (m, 2H, Harom.), 7.02−6.93 (m, 3H, Harom.), 4.30 (t, J = 7.1 Hz, 1H, C6aH), 3.44−3.36 (m, 1H, C4H), 2.64−2.57 (m, 1H, C4H″), 2.09− 1.98 (m, 2H, C5H + C6H), 1.97−1.86 (m, 1H, C5H″), 1.71 (d, J = 5.5 Hz, 1H, C1H), 1.70−1.60 (m, 1H, C6H″), 1.17 (s, 3H, CH3−C6b), 0.63 (dd, J = 5.5, 1.4 Hz, 1H, C1H″). 13C{1H} NMR (101 MHz, CDCl3): δ = 202.7, 199.0, 141.9, 141.3, 136.2, 135.8, 135.3, 132.1 (2C), 127.9 (2C), 127.1, 123.1, 122.7, 76.4, 73.0, 49.9, 48.1, 35.2, 28.0, 27.7, 18.8, 17.3. IR (KBr): 3058, 3025, 2963, 2866, 1742, 1706, 1595, 1448, 1273, 1210, 1153, 1074, 1026, 750, 702 cm−1. HRMS (ESI): m/z [M + H]+ calcd for C23H22NO2+: 344.1645; found: 344.1640. (±)-(1aS,6aR,6bS)-1a-Phenyl-6b-(trimethylsilyl)-1a,4,5,6,6a,6bhexahydro-1H-spiro[cyclopropa[a]pyrrolizine-2,2′-indene]-1′,3′dione (11d). The cycloadduct 11d was obtained from 1-phenyl-2trimethylsilylcyclopropene (2d, 282 mg, 1.5 mmol) and DHPO (6, 213 mg, 1 mmol). Yellow-orange solid; yield: 349 mg (87%); mp 119−120 °C (MeOH−H2O, 2:1); Rf 0.43 (SiO2, hexane−EtOAc, 2:1). 1H NMR (400 MHz, CDCl3): δ = 7.82−7.76 (m, 1H, Harom.), 7.68−7.64 (m, 1H, Harom.), 7.63−7.58 (m, 2H, Harom.), 7.19−7.13 (m, 2H, Harom.), 7.00−6.91 (m, 3H, Harom.), 4.56 (t, J = 7.3 Hz, 1H, C6aH), 3.42−3.32 (m, 1H, C4H), 2.67−2.58 (m, 1H, C4H″), 2.08− 7030


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1H, C1H″). 13C{1H} NMR (101 MHz, CDCl3): δ = 203.0, 197.5, 141.6, 140.5, 136.6, 136.2, 124.3, 123.7, 70.4, 68.6, 49.5, 29.6, 28.8, 28.6, 22.9, 6.4. IR (KBr): 2962, 2927, 2892, 2863, 1741, 1711, 1590, 1443, 1353, 1264, 945, 769 cm−1. HRMS (ESI): m/z [M + H]+ calcd for C16H16NO2+: 254.1176; found: 254.1173. (±)-(1R,1aR,6aR,6bS)-1-Methyl-1-phenyl-1a,4,5,6,6a,6b-hexahydro-1H-spiro[cyclopropa[a]pyrrolizine-2,2′-indene]-1′,3′-dione (12b-endo-Me) and (±)-(1S,1aR,6aR,6bS)-1-Methyl-1-phenyl1a,4,5,6,6a,6b-hexahydro-1H-spiro[cyclopropa[a]pyrrolizine-2,2′indene]-1′,3′-dione (12b-endo-Ph). The reaction was performed according to General Procedure A (reaction temperature, 25−60 °C; reaction time, 24 h) employing cyclopropene 3b (52 mg, 0.4 mmol) and DHPO (6, 85 mg, 0.4 mmol). 1H NMR analysis of the crude reaction mixture revealed that the reaction led to the formation of two diastereomers 12b-endo-Me and 12b-endo-Ph in ratio 1.9:1 (79% NMR overall yield), respectively. Purification by PTLC on silica gel (hexane−EtOAc, 3:1) followed by crystallization from a mixture of MeOH−H2O (2:1) afforded 12b (84 mg, 61% isolated yield) as an inseparable mixture of two diastereomers 12b-endo-Me and 12bendo-Ph in ratio 3:1, respectively. Data for the diastereomeric mixture 12b: yellow solid. IR (KBr): 3065, 3027, 2953, 2931, 2872, 1743, 1709, 1593, 1497, 1447, 1352, 1263, 1224, 1200, 1148, 948, 749, 695 cm−1. HRMS (ESI): m/z [M + H]+ calcd for C23H22NO2+: 344.1645; found: 344.1651. NMR data for major diastereomer 12b-endo-Me: 1 H NMR (400 MHz, CDCl3): δ = 8.04−8.01 (m, 1H, Harom.), 7.98− 7.92 (m, 1H, Harom.), 7.91−7.84 (m, 2H, Harom.), 7.24−7.16 (m, 3H, Harom.), 7.15−7.07 (m, 2H, Harom.), 3.86−3.68 (m, 1H, C6aH), 3.10− 2.94 (m, 1H, C4H), 2.64−2.52 (m, 1H, C4H″), 2.26−2.10 (m, 3H, C6H + C5H + C5H″), 2.08−1.99 (m, 1H, C6H″), 1.95−1.74 (m, 2H, C6bH + C1aH, overlapping with CH3), 1.92 (s, 3H, CH3, overlapping with C6bH). 13C{1H} NMR (101 MHz, CDCl3): δ = 203.5, 201.9, 147.1, 141.5, 139.7, 136.3, 136.0, 128.4 (2C), 126.7 (2C), 126.1, 123.7, 123.1, 79.3, 68.4, 48.8, 42.0, 33.2, 32.1, 31.0, 28.2, 17.3. NMR data for minor diastereomer 12b-endo-Ph: 1H NMR (400 MHz, CDCl3): δ = 8.04−8.01 (m, 1H, Harom.), 7.98−7.92 (m, 1H, Harom.), 7.91−7.84 (m, 2H, Harom.), 7.24−7.16 (m, 2H, Harom.), 7.15−7.07 (m, 3H, Harom.), 4.54−4.44 (m, 1H, C6aH), 3.21−3.15 (m, 1H, C4H), 2.64−2.52 (m, 1H, C4H″), 2.26−2.10 (m, 3H, C6H + C5H + C5H″), 2.08−1.99 (m, 1H, C6H″), 1.87 (s, 3H, CH3), 1.86−1.74 (m, 2H, C6bH + C1aH). Methyl (±)-(1R,1aR,6aR,6bS)-1-Methyl-1′,3′-dioxo1a,1′,3′,4,5,6,6a,6b-octahydro-1H-spiro[cyclopropa[a]pyrrolizine2,2′-indene]-1-carboxylate (12c-endo-Me) and Methyl (±)-(1S,1aR,6aR,6bS)-1-Methyl-1′,3′-dioxo-1a,1′,3′,4,5,6,6a,6b-octahydro-1H-spiro[cyclopropa[a]pyrrolizine-2,2′-indene]-1-carboxylate (12c-endo-CO2Me). The reaction was performed according to General Procedure A (reaction temperature, 25−60 °C; reaction time, 24 h) employing cyclopropene 3c (45 mg, 0.4 mmol) and DHPO (6, 85 mg, 0.4 mmol). 1H NMR analysis of the crude reaction mixture revealed that the reaction led to the formation of two diastereomers 12c-endo-Me and 12c-endo-CO2Me in a 1.6:1 ratio (73% NMR overall yield). Purification by PTLC on silica gel (hexane−EtOAc, 2:1) followed by crystallization from a mixture of MeOH−H2O (2:1) afforded 12c (61 mg, 47% isolated yield) as an inseparable mixture of two diastereomers 12c-endo-Me and 12c-endo-CO2Me in a 2:1 ratio. Data for the diastereomeric mixture 12c: yellow solid. IR (KBr): 2982, 2963, 2926, 2868, 1732, 1712, 1595, 1451, 1299, 1245, 1133, 1094, 1021, 766 cm−1. HRMS (ESI): m/z [M + H]+ calcd for C19H20NO4+: 326.1387; found: 326.1398. NMR data for major diastereomer 12c-endo-Me: 1H NMR (400 MHz, CDCl3): δ = 8.00− 7.92 (m, 2H, Harom.), 7.89−7.82 (m, 2H, Harom.), 4.49−4.40 (m, 1H, C6aH), 3.59 (s, 3H, CO2CH3) 3.12−3.04 (m, 1H, C4H), 2.57−2.48 (m, 1H, C4H″), 2.26−1.93 (m, 4H, C5H + C5H″ + C6H + C6H″), 1.77 (s, 3H, CH3), 1.75−1.68 (m, 2H, C6bH + C1aH). 13C{1H} NMR (101 MHz, CDCl3): δ = 202.2, 198.3, 174.5, 142.0, 139.8, 136.3, 136.1, 123.6 (2C), 70.7, 67.9, 52.4, 42.4, 42.1, 30.6, 30.4, 28.9, 24.4, 13.0. NMR data for minor diastereomer 12c-endo-CO2Me: 1H NMR (400 MHz, CDCl3): δ = 8.00−7.92 (m, 2H, Harom.), 7.89−7.82 (m, 2H, Harom.), 3.62−3.55 (m, 1H, C6aH, overlapping with ester groups), 3.57 (s, 3H, CO2CH3), 3.00−2.90 (m, 1H, C4H), 2.56−2.48 (m, 1H,

lization from a mixture of MeOH−H2O (2:1) afforded 11h (116 mg, 72%) as a single diastereomer. Light yellow solid; mp 249−250 °C (MeOH−H2O, 2:1); Rf 0.51 (SiO2, hexane−EtOAc, 1:1). 1H NMR (400 MHz, DMSO-d6): δ = 11.95 (br s, 1H, CO2H), 7.94−7.91 (m, 1H, Harom.), 7.89−7.84 (m, 1H, Harom.), 7.83−7.77 (m, 1H, Harom.), 7.60 (d, J = 7.5 Hz, 1H, Harom.), 6.85−6.79 (m, 2H, Harom.), 6.75−6.69 (m, 2H, Harom.), 4.17 (t, J = 7.2 Hz, 1H, C6aH), 3.31−3.23 (m, 1H, C4H, overlapping with H2O), 2.53−2.47 (m, 1H, C4H″, overlapping with DMSO), 2.45 (s, 1H, C1H), 2.10−1.97 (m, 2H, C6H + C5H), 2.06 (s, 3H, p-tol-CH3), 1.84−1.72 (m, 1H, C5H″), 1.64−1.54 (m, 1H, C6H″), 1.42 (s, 3H, CH3−C6b). 13C{1H} NMR (101 MHz, DMSO-d6): δ = 199.9, 197.6, 170.1, 141.2, 140.5, 136.8, 136.3, 136.1, 130.7 (2C), 129.0, 128.2 (2C), 122.8 (2C), 75.2, 73.9, 54.0, 47.6, 40.8, 27.3, 27.2, 27.1, 20.5, 11.5. IR (KBr): 3066, 2972, 2923, 1743, 1711, 1599, 1452, 1326, 1273, 1221, 1176, 964, 775, 754 cm−1. HRMS (ESI): m/z [M + H]+ calcd for C25H24NO4+: 402.1700; found: 402.1700. (±)-(1R,1aR,6aR,6bR)-1a-(4-Methoxyphenyl)-6b-methyl-1′,3′dioxo-1a,1′,3′,4,5,6,6a,6b-octahydro-1H-spiro[cyclopropa[a]pyrrolizine-2,2′-indene]-1-carboxylic Acid (11i). The reaction was performed according to General Procedure A employing cyclopropene 2i (82 mg, 0.4 mmol) and DHPO (6, 85 mg, 0.4 mmol). Purification by PTLC on silica gel (CH2Cl2−MeOH, 35:1) followed by crystallization from a mixture of MeOH−H2O (2:1) afforded 11i (85 mg, 51%) as a single diastereomer. Light yellow solid; mp 233− 234 °C (MeOH−H2O, 2:1); Rf 0.32 (SiO2, hexane−EtOAc, 1:1). 1H NMR (400 MHz, DMSO-d6): δ = 11.94 (br s, 1H), 7.95−7.91 (m, 1H), 7.89−7.85 (m, 1H), 7.84−7.78 (m, 1H), 7.60 (d, J = 7.4 Hz, 1H), 6.77−6.68 (m, 2H), 6.61−6.53 (m, 2H), 4.16 (t, J = 7.2 Hz, 1H), 3.56 (s, 3H), 3.36−3.24 (m, 1H, overlapping with H2O), 2.55− 2.47 (m, 1H, overlapping with DMSO), 2.43 (s, 1H), 2.10−1.96 (m, 2H), 1.85−1.71 (m, 1H), 1.64−1.52 (m, 1H), 1.41 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6): δ = 200.2, 197.7, 170.1, 158.0, 141.2, 140.5, 136.8, 136.3, 132.0 (2C), 123.8, 122.8 (2C), 113.0 (2C), 75.4, 73.9, 54.8, 53.8, 47.6, 40.9, 27.4, 27.2, 27.1, 11.5. IR (KBr): 3069, 3033, 2959, 2927, 2900, 2837, 1743, 1710, 1609, 1515, 1454, 1249, 1222, 1176, 963, 755 cm−1. HRMS (ESI): m/z [M + H]+ calcd for C25H24NO5+: 418.1649; found: 418.1651. Trapping of Parent Cyclopropene with DHPO. A 50 mL threeneck round-bottom flask was equipped with a Dimroth-type reflux condenser, a 10 mL dropping funnel, a magnetic stir bar, and a silicon oil gas bubbler with a short connection to a 10 mL screw-cap tube. Argon flow was introduced from the top of the condenser. The flask was charged with NaHMDS (1.05 g, 5.75 mmol) and anhydrous toluene (5 mL), while DHPO (6, 213 mg, 1 mmol), THF (5 mL), and a small stirrer were added to the screw-cap tube. The flask was placed in a preheated oil bath at 140 °C under an argon atmosphere until the salt dissolved completely. The resulting solution is brought to a vigorous reflux, after which a solution of allyl chloride (0.41 mL, 5 mmol) in toluene (3 mL) was added from the dropping funnel for 10 min. A slow stream of argon was swept through the condenser during this period. The emerged cyclopropene 3a was driven into the tube at −80 °C. Upon completion of addition, the reaction vessel was heated within 10 min. The cap was tightly screwed, and the tube was allowed to warm to 0 °C with stirring until complete dissolution of DHPO (6). After 10 min, TLC analysis revealed the full consumption of the starting azomethine ylide 6. The solvent was evaporated under reduced pressure. The crude product was purified by PTLC on silica gel using a hexane−EtOAc mixture (3:1) as the eluent followed by crystallization from a mixture of MeOH−H2O (2:1) to furnish the title cycloadduct 12a as a single diastereomer. (±)-(1aS,6aR,6bR)-1a,4,5,6,6a,6b-Hexahydro-1H-spiro[cyclopropa[a]pyrrolizine-2,2′-indene]-1′,3′-dione (12a). Yelloworange solid; yield: 225 mg (89%); mp 86−87 °C (MeOH−H2O, 2:1); Rf 0.33 (SiO2, hexane−EtOAc, 2:1). 1H NMR (400 MHz, CDCl3): δ = 8.05−8.01 (m, 1H, Harom.), 7.99−7.95 (m, 1H, Harom.), 7.91−7.82 (m, 2H, Harom.), 4.55−4.44 (m, 1H, C6aH), 3.32−3.22 (m, 1H, C4H), 2.79−2.67 (m, 1H, C4H″), 2.12−1.94 (m, 3H, C5H + C5H″ + C6H), 1.92−1.84 (m, 1H, C6bH), 1.81−1.74 (m, 1H, C1aH), 1.73−1.64 (m, 1H, C6H″), 1.13−1.06 (m, 1H, C1H), 0.72−0.63 (m, 7031


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The Journal of Organic Chemistry C4H″), 2.26−2.20 (m, 1H, C6bH), 2.19−2.02 (m, 4H, C5H + C5H″ + C6H + C1aH), 2.01−1.93 (m, 1H, C6H″), 1.79 (s, 3H, CH3). General Procedure D for the in Situ Generation of 3-Alkoxy-1,2diphenylcyclopropenes and 3-Arylthio-1,2-diphenylcyclopropenes Followed by the Cycloaddition Reaction to DHPO. A mixture containing 3-nitro-1,2-diphenylcyclopropene (1n, 100 mg, 0.42 mmol) and DHPO (6, 90 mg, 0.42 mmol) in 10 mL of the appropriate absolute alcohol was allowed to stir at 25 °C for 24 h until complete consumption of 1n as monitored by TLC. The analogous reaction with a thiol (10 mL) was conducted at 140 °C for 5 min. The solvent was evaporated under reduced pressure to dryness. The crude residue was subjected to PTLC using a suitable eluent to furnish pure cycloadduct 13. (±)-(1R,1aS,6aR,6bR)-1-Methoxy-1a,6b-diphenyl-1a,4,5,6,6a,6bhexahydro-1H-spiro[cyclopropa[a]pyrrolizine-2,2′-indene]-1′,3′dione (13a). The reaction was performed according to General Procedure D employing 3-nitro-1,2-diphenylcyclopropene (1n) (111 mg, 0.4 mmol), DHPO (6) (85 mg, 0.4 mmol), and anhydrous MeOH (10 mL). Purification by PTLC on silica gel (hexane−EtOAc, 2:1) followed by crystallization from a mixture of MeOH−H2O (2:1) afforded 13a (99 mg, 57%) as a single diastereomer. Yellow solid; mp 140−141 °C (MeOH−H2O, 2:1); Rf 0.32 (SiO2, hexane−EtOAc, 3:1). 1H NMR (400 MHz, CDCl3): δ = 7.92 (d, J = 7.3 Hz, 1H), 7.74−7.69 (m, 1H), 7.68−7.64 (m, 2H), 7.28−7.16 (m, 5H), 6.96− 6.88 (m, 3H), 6.84−6.79 (m, 2H), 4.82 (t, J = 7.3 Hz, 1H), 4.22 (s, 1H), 3.41−3.33 (m, 1H), 3.16 (s, 3H), 2.66−2.59 (m, 1H), 2.29− 2.20 (m, 1H), 2.18−2.08 (m, 1H), 2.06−1.95 (m, 1H), 1.93−1.82 (m, 1H). 13C{1H} NMR (101 MHz, CDCl3): δ = 200.7, 199.0, 142.0, 141.6, 136.1, 135.4, 135.2, 132.0 (2C), 130.7, 129.6 (2C), 127.8 (2C), 127.6 (2C), 127.0, 126.1, 123.5, 123.0, 75.4, 72.6, 66.4, 58.6, 53.5, 47.7, 45.0, 28.1, 27.8. IR (KBr): 3057, 3028, 2967, 2939, 2875, 2829, 1736, 1701, 1590, 1498, 1444, 1269, 1214, 1156, 972, 771, 703 cm−1. HRMS (ESI): m/z [M + H]+ calcd for C29H26NO3+: 436.1907; found: 436.1918. (±)-(1R,1aS,6aR,6bR)-1-Ethoxy-1a,6b-diphenyl-1a,4,5,6,6a,6bhexahydro-1H-spiro[cyclopropa[a]pyrrolizine-2,2′-indene]-1′,3′dione (13b). The reaction was performed according to General Procedure D employing 3-nitro-1,2-diphenylcyclopropene (1n, 111 mg, 0.4 mmol), DHPO (6, 85 mg, 0.4 mmol), and anhydrous EtOH (10 mL). Purification by PTLC on silica gel (hexane−EtOAc, 2:1) followed by crystallization from a mixture of MeOH−H2O (2:1) afforded 13b (77 mg, 43%) as a single diastereomer. Yellow solid; mp 116−117 °C (MeOH−H2O, 2:1); Rf 0.34 (SiO2, hexane−EtOAc, 3:1). 1H NMR (400 MHz, CDCl3): δ = 7.91 (d, J = 7.4 Hz, 1H), 7.74−7.69 (m, 1H), 7.68−7.61 (m, 2H), 7.29−7.15 (m, 5H), 6.96− 6.86 (m, 3H), 6.84−6.76 (m, 2H), 4.82 (t, J = 7.3 Hz, 1H), 4.28 (s, 1H), 3.46−3.33 (m, 2H), 3.31−3.21 (m, 1H), 2.67−2.57 (m, 1H), 2.28−2.18 (m, 1H), 2.17−2.08 (m, 1H), 2.06−1.95 (m, 1H), 1.93− 1.82 (m, 1H), 0.99 (t, J = 7.0 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ = 200.8, 199.0, 141.9, 141.6, 136.1, 135.5, 135.4, 132.1 (2C), 130.9, 129.7 (2C), 127.6 (2C), 127.5 (2C), 126.8, 126.0, 123.5, 123.0, 75.5, 72.6, 66.6, 64.8, 53.5, 47.7, 45.0, 28.0, 27.8, 14.9. IR (KBr): 3053, 2971, 2906, 2875, 2856, 1738, 1705, 1597, 1498, 1267, 1199, 1153, 1114, 1041, 741, 701 cm−1. HRMS (ESI): m/z [M + H]+ calcd for C30H28NO3+: 450.2064; found: 450.2066. (±)-(1R,1aS,6aR,6bR)-1a,6b-Diphenyl-1-propoxy-1a,4,5,6,6a,6bhexahydro-1H-spiro[cyclopropa[a]pyrrolizine-2,2′-indene]-1′,3′dione (13c). The reaction was performed according to General Procedure D employing 3-nitro-1,2-diphenylcyclopropene (1n, 111 mg, 0.4 mmol), DHPO (6, 85 mg, 0.4 mmol), and anhydrous PrOH (10 mL). Purification by PTLC on silica gel (hexane−EtOAc, 3:1) afforded 13c (102 mg, 55%) as a single diastereomer. Yellow-orange amorphous powder; Rf 0.45 (SiO2, hexane−EtOAc, 3:1). 1H NMR (400 MHz, CDCl3): δ = 7.93−7.89 (m, 1H), 7.73−7.64 (m, 3H), 7.29−7.25 (m, 2H), 7.24−7.16 (m, 3H), 6.93−6.86 (m, 3H), 6.84− 6.79 (m, 2H), 4.86 (t, J = 7.4 Hz, 1H), 4.27 (s, 1H), 3.46−3.36 (m, 1H), 3.34−3.28 (m, 1H), 3.23−3.16 (m, 1H), 2.75−2.64 (m, 1H), 2.29−2.20 (m, 1H), 2.18−2.09 (m, 1H), 2.07−1.97 (m, 1H), 1.94− 1.83 (m, 1H), 1.46−1.35 (m, 2H), 0.75 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ = 200.2, 198.7, 141.9, 141.6, 136.2, 135.4, 135.2, 132.2 (2C), 130.6, 129.7 (2C), 127.7 (2C), 127.5 (2C),

126.9, 126.1, 123.5, 123.0, 75.4, 72.9, 72.7, 64.8, 53.4, 48.1, 45.0, 28.1, 27.7, 22.8, 10.7. IR (KBr): 3056, 2963, 2935, 2872, 1743, 1709, 1598, 1499, 1269, 1206, 1073, 709 cm−1. HRMS (ESI): m/z [M + H]+ calcd for C31H30NO3+: 464.2220; found: 464.2229. (±)-(1R,1aS,6aR,6bR)-1-(2-Methoxyethoxy)-1a,6b-diphenyl1a,4,5,6,6a,6b-hexahydro-1H-spiro[cyclopropa[a]pyrrolizine-2,2′indene]-1′,3′-dione (13d). The reaction was performed according to General Procedure D employing 3-nitro-1,2-diphenylcyclopropene (1n, 111 mg, 0.4 mmol), DHPO (6, 85 mg, 0.4 mmol), and anhydrous 2-methoxyethanol (10 mL). Purification by PTLC on silica gel (hexane−EtOAc, 2:1) afforded 13d (79 mg, 41%) as a single diastereomer. Yellow-orange amorphous powder; Rf 0.43 (SiO2, hexane−EtOAc, 2:1). 1H NMR (400 MHz, CDCl3): δ = 7.91 (d, J = 7.5 Hz, 1H), 7.75−7.64 (m, 3H), 7.32−7.27 (m, 2H), 7.25−7.15 (m, 3H), 6.95−6.86 (m, 3H), 6.83−6.79 (m, 2H), 4.80 (t, J = 7.0 Hz, 1H), 4.37 (s, 1H), 3.51−3.41 (m, 2H), 3.40−3.29 (m, 3H), 3.25 (s, 3H), 2.68−2.60 (m, 1H), 2.26−2.16 (m, 1H), 2.15−2.07 (m, 1H), 2.05−1.85 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3): δ = 200.2, 198.7, 141.9, 141.6, 136.1, 135.4, 135.1, 132.0 (2C), 130.8, 129.8 (2C), 127.8 (2C), 127.5 (2C), 126.9, 126.2, 123.6, 123.0, 75.4, 73.0, 71.7, 70.4, 65.3, 59.1, 53.1, 48.0, 45.2, 27.9, 27.7. IR (KBr): 3056, 2963, 2927, 2871, 1743, 1709, 1598, 1499, 1328, 1270, 1207, 1155, 1125, 1072, 1033, 770, 741, 701 cm−1. HRMS (ESI): m/z [M + H]+ calcd for C31H30NO4+: 480.2169; found: 480.2186. (±)-(1R,1aS,6aR,6bR)-1-Isopropoxy-1a,6b-diphenyl1a,4,5,6,6a,6b-hexahydro-1H-spiro[cyclopropa[a]pyrrolizine-2,2′indene]-1′,3′-dione (13e). The reaction was performed according to General Procedure D employing 3-nitro-1,2-diphenylcyclopropene (1n, 111 mg, 0.4 mmol), DHPO (6, 85 mg, 0.4 mmol), and anhydrous i-PrOH (10 mL). Purification by PTLC on silica gel (hexane−EtOAc, 2:1) followed by crystallization from a mixture of MeOH−H2O (3:1) afforded 13e (91 mg, 49%) as a single diastereomer. Yellow solid; mp 139−140 °C (MeOH−H2O, 2:1); Rf 0.45 (SiO2, hexane−EtOAc, 3:1). 1H NMR (400 MHz, CDCl3): δ = 7.91 (d, J = 7.3 Hz, 1H), 7.77−7.63 (m, 3H), 7.32−7.25 (m, 2H), 7.24−7.14 (m, 3H), 6.98−6.84 (m, 3H), 6.82−6.75 (m, 2H), 4.79 (t, J = 7.2 Hz, 1H), 4.38 (s, 1H), 3.51−3.43 (m, 1H), 3.42−3.33 (m, 1H), 2.70−2.60 (m, 1H), 2.26−2.17 (m, 1H), 2.16−2.08 (m, 1H), 2.07−1.95 (m, 1H), 1.94−1.82 (m, 1H), 1.05 (d, J = 6.0 Hz, 3H), 1.01 (d, J = 6.0 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ = 200.2, 198.7, 141.7, 141.4, 136.0, 135.4, 135.2, 132.0 (2C), 130.9, 129.9 (2C), 127.4 (2C), 127.2 (2C), 126.6, 125.9, 123.4, 122.8, 75.3, 73.0, 72.4, 62.4, 52.9, 47.8, 44.8, 27.8, 27.6, 21.8, 21.7. IR (KBr): 3061, 3029, 2965, 2935, 2893, 2850, 1741, 1706, 1598, 1500, 1328, 1220, 1201, 1115, 941, 703 cm−1. HRMS (ESI): m/z [M + H]+ calcd for C31H30NO3+: 464.2220; found: 464.2238. (±)-(1R,1aS,6aR,6bR)-1-(tert-Butoxy)-1a,6b-diphenyl1a,4,5,6,6a,6b-hexahydro-1H-spiro[cyclopropa[a]pyrrolizine-2,2′indene]-1′,3′-dione (13f). The reaction was performed according to General Procedure D employing 3-nitro-1,2-diphenylcyclopropene (1n, 111 mg, 0.4 mmol), DHPO (6, 85 mg, 0.4 mmol), and anhydrous t-BuOH (10 mL). Purification by PTLC on silica gel (hexane−EtOAc, 4:1) followed by crystallization from a mixture of MeOH−H2O (3:1) afforded 13f (71 mg, 37%) as a single diastereomer. Yellow solid; mp 160−163 °C (MeOH−H2O, 2:1); Rf 0.48 (SiO2, hexane−EtOAc, 3:1). 1H NMR (400 MHz, CDCl3): δ = 7.90 (d, J = 7.6 Hz, 1H), 7.73−7.67 (m, 1H), 7.66−7.62 (m, 2H), 7.25−7.12 (m, 5H), 6.93−6.84 (m, 3H), 6.77−6.72 (m, 2H), 4.84 (t, J = 7.0 Hz, 1H), 4.46 (s, 1H), 3.43−3.34 (m, 1H), 2.71−2.62 (m, 1H), 2.26−2.18 (m, 1H), 2.17−2.10 (m, 1H), 2.09−1.89 (m, 2H), 1.09 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3): δ = 200.9, 199.0, 141.8, 141.6, 136.0 (2C), 135.3, 132.5 (2C), 131.2, 130.1 (2C), 127.3 (2C), 127.2 (2C), 126.5, 125.7, 123.4, 122.9, 75.6 (2C), 72.8, 58.5, 52.0, 47.5, 43.9, 28.0 (3C), 27.7, 27.5. IR (KBr): 3054, 2971, 2902, 2865, 1742, 1708, 1599, 1498, 1365, 1266, 1218, 1174, 894, 763, 704 cm−1. HRMS (ESI): m/z [M + H]+ calcd for C32H32NO3+: 478.2377; found: 478.2375. (±)-(1R,1aS,6aR,6bR)-1a,6b-Diphenyl-1-(phenylthio)1a,4,5,6,6a,6b-hexahydro-1H-spiro[cyclopropa[a]pyrrolizine-2,2′indene]-1′,3′-dione (13g). The reaction was performed according to General Procedure D employing 3-nitro-1,2-diphenylcyclopropene 7032


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The Journal of Organic Chemistry (1n, 111 mg, 0.4 mmol), DHPO (6, 85 mg, 0.4 mmol), and freshly distilled thiophenol (10 mL). Purification by PTLC on silica gel (hexane−EtOAc, 3:1) afforded 13g (134 mg, 65%) as a single diastereomer. Yellow amorphous powder; Rf 0.44 (SiO2, hexane− EtOAc, 3:1). 1H NMR (400 MHz, CDCl3): δ = 7.93 (d, J = 7.2 Hz, 1H), 7.75−7.65 (m, 3H), 7.65−7.59 (m, 2H), 7.46−7.40 (m, 2H), 7.36−7.28 (m, 4H), 7.27−7.21 (m, 1H), 7.20−7.13 (m, 1H), 7.03− 6.97 (m, 2H), 6.94−6.83 (m, 3H), 4.83 (t, J = 6.8 Hz, 1H), 3.68 (s, 1H), 3.64−3.54 (m, 1H), 2.84−2.70 (m, 1H), 2.20−2.06 (m, 2H), 2.04−1.86 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3): δ = 200.5, 198.2, 142.2, 141.6, 137.4, 136.3, 135.6, 135.1, 132.0 (2C), 131.5, 130.8 (2C), 129.0 (2C), 128.1 (2C), 128.0 (2C), 127.7 (2C), 127.6, 127.2, 125.7, 123.6, 123.2, 75.9, 75.7, 54.3, 49.1, 47.3, 31.0, 27.9, 27.4. IR (KBr): 3056, 2964, 2869, 1742, 1706, 1597, 1442, 1267, 1155, 767, 739, 702 cm−1. HRMS (ESI): m/z [M + H]+ calcd for C34H28NO2S+: 514.1835; found: 514.1822. (±)-(1R,1aS,6aR,6bR)-1a,6b-Diphenyl-1-(p-tolylthio)1a,4,5,6,6a,6b-hexahydro-1H-spiro[cyclopropa[a]pyrrolizine-2,2′indene]-1′,3′-dione (13h). The reaction was performed according to General Procedure D employing 3-nitro-1,2-diphenylcyclopropene (1n, 111 mg, 0.4 mmol), DHPO (6, 85 mg, 0.4 mmol), and 4methylbenzenethiol (10 mL). Purification by PTLC on silica gel (hexane−EtOAc, 3:1) afforded 13h (141 mg, 67%) as a single diastereomer. Yellow amorphous powder; Rf 0.46 (SiO2, hexane− EtOAc, 3:1). 1H NMR (400 MHz, CDCl3): δ = 7.91 (d, J = 7.3 Hz, 1H), 7.74−7.64 (m, 3H), 7.63−7.58 (m, 2H), 7.34−7.22 (m, 5H), 7.16−7.08 (m, 2H), 7.04−6.97 (m, 2H), 6.94−6.83 (m, 3H), 4.84 (t, J = 7.1 Hz, 1H), 3.65 (s, 1H), 3.64−3.53 (m, 1H), 2.81−2.71 (m, 1H), 2.33 (s, 3H), 2.20−2.07 (m, 2H), 2.05−1.83 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3): δ = 200.8, 198.4, 142.2, 141.6, 136.2, 135.6 (2C), 135.3, 133.7, 132.1 (2C), 131.6, 130.7 (2C), 129.8 (2C), 128.4 (2C), 128.0 (2C), 127.6 (2C), 127.3, 127.0, 123.5, 123.2, 76.0, 75.6, 54.4, 48.9, 47.3, 31.6, 28.0, 27.5, 21.2. IR (KBr): 3055, 3023, 2967, 2919, 2867, 1742, 1706, 1597, 1493, 1267, 1155, 767, 701 cm−1. HRMS (ESI): m/z [M + H]+ calcd for C35H30NO2S+: 528.1992; found: 528.2013. (±)-(1R,1aS,6aR,6bR)-1-(Hexylthio)-1a,6b-diphenyl1a,4,5,6,6a,6b-hexahydro-1H-spiro[cyclopropa[a]pyrrolizine-2,2′indene]-1′,3′-dione (13i). The reaction was performed according to General Procedure D employing 3-nitro-1,2-diphenylcyclopropene (1n, 111 mg, 0.4 mmol), DHPO (6, 85 mg, 0.4 mmol), and freshly distilled 1-hexanethiol (10 mL). Purification by PTLC on silica gel (hexane−EtOAc, 3:1) afforded 13i (56 mg, 27%) as a single diastereomer. Yellow oil; Rf 0.52 (SiO2, hexane−EtOAc, 3:1). 1H NMR (400 MHz, CDCl3): δ = 7.96−7.92 (m, 1H), 7.77−7.65 (m, 3H), 7.48−7.42 (m, 2H), 7.31−7.20 (m, 4H), 6.97−6.85 (m, 4H), 4.78 (t, J = 6.9 Hz, 1H), 3.54−3.42 (m, 1H), 3.26 (s, 1H), 2.76−2.65 (m, 1H), 2.44−2.33 (m, 2H), 2.24−2.16 (m, 1H), 2.15−2.07 (m, 1H), 2.06−1.94 (m, 1H), 1.93−1.81 (m, 1H), 1.52−1.38 (m, 2H), 1.35−1.07 (m, 6H), 0.85 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ = 200.4, 198.5, 142.1, 141.7, 136.2, 135.5, 132.0, 131.8 (2C), 130.4 (3C), 127.8 (2C), 127.5 (2C), 127.2, 126.7, 123.7, 123.1, 75.8, 74.7, 54.3, 49.0, 47.2, 33.8, 32.1, 31.5, 29.2, 28.7, 28.5, 27.6, 22.7, 14.2. IR (KBr): 3056, 2954, 2925, 2853, 1743, 1707, 1598, 1497, 1445, 1266, 1155, 766, 736, 699 cm−1. HRMS (ESI): m/z [M + H]+ calcd for C34H36NO2S+: 522.2461; found: 522.2450. Computational Methodology. The full geometry optimization of reactants, products, and transition state (TS) structures were carried out at the DFT/HF level of theory using M11 hybrid exchange-correlation functional46 and cc-pVDZ basis set.47 The polarizable continuum model was applied to calculate solvent effects of tetrahydrofuran.48 The optimizations were carried out using the Berny analytical gradient optimization method.49 All stationary points were characterized by harmonic vibrational frequency calculations to prove the location of correct minima (only real frequencies) and transition states (only one imaginary frequency). For the transition states, the normal modes corresponding to the imaginary frequencies were related to the vibrations of new developing bonds. IRC calculations were carried out to check the energy profiles connecting each TS to the two associated minima of the proposed mechanism.50

Due to the poor estimation of the Kohn−Sham orbitals for FMO energy values, HOMO and LUMO energies and the corresponding global descriptors for reactants were computed by using HF/6-311-g single-point calculation based on the M11/cc-pVDZ optimized geometries. The atomic charges and orbital coefficients were calculated by using the natural bond orbital (NBO) partitioning scheme.51 Electrophilic and nucleophilic Fukui functions condensed to atoms were estimated from single-point calculations at M11/ccpVDZ by applying Hirshfeld’s population scheme. Thermal corrections to enthalpy and entropy values were evaluated at 298.15 K and 1.0 atm. All calculations were performed using Gaussian 09 computational program package.52

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.9b00753. Calculation details with energies of the reactants, transition states, their Cartesian coordinates, and tube representation of the calculated molecules; 1H and 13C NMR spectra for all new products (PDF) X-ray crystallography data for compound 7a (CCDC 1841118) (CIF) X-ray crystallography data for compound 11a (CCDC 1897279) (CIF) X-ray crystallography data for compound 11h (CCDC 1843132) (CIF) X-ray crystallography data for compound 13b (CCDC 1843131) (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Vitali M. Boitsov: 0000-0002-4857-2046 Alexander V. Stepakov: 0000-0001-9470-1710 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This paper is dedicated to the memory of Prof. Rafael R. Kostikov. A.S.F., V.M.B., and A.V.S. gratefully acknowledge the financial support from Russian Foundation for Basic Research (Projects nos. 18-33-00464 and 18-015-00443). V.M.B. acknowledges financial support provided by SPbAU RAS state order (Project 16.9790.2017/BCh). S.W. is grateful for the support and funding received from China Scholarship Council as well as for training from Heilongjiang University. This research was performed by using the equipment of the SPbU resource centers: Magnetic Resonance Research Centre, Centre for X-ray Diffraction Studies, Chemical Analysis and Materials Research Centre, Chemistry Educational Centre, and Computing Centre.

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REFERENCES

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