Intramolecular Imino-ene Reaction of 2H-azirines with Alkenes: Rapid

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

pubs.acs.org/OrgLett

Intramolecular Imino-ene Reaction of 2H-azirines with Alkenes: Rapid Construction of Spiro NH Aziridines from Vinyl Azides Tai-Shang Liu, Hao Zhou, Peng Chen, Xiu-Rong Huang, Lin-Qing Bao, Chen-Lu Zhuang, Qing-Song Xu, Mei-Hua Shen,* and Hua-Dong Xu* Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology, School of Pharmaceutical Engineering & Life Science, Changzhou University, Changzhou 213164, People’s Republic of China S Supporting Information *

ABSTRACT: A range of novel (poly)cyclic alkaloids incorporating an unprecedented 1,5-diazaspiro[2.4]heptane core that carry a spiro NH aziridine moiety and a 7-vinyl group are constructed from the thermal reaction of vinyl azides with tethered alkenes. Vinyl azides are converted to 2H-azirines in situ, which serve as enophiles for intramolecular imino-ene reactions with suitable alkenes. High stereoselectivity and specificity have been achieved for this novel intramolecular imino-ene reaction of azirines.

T

construction of a range of novel (poly)cyclic alkaloids that incorporate an unprecedented 1,5-diazaspiro[2.4]heptane core I (X = N) carrying a NH azididine moiety and a 7-vinyl group. Notwithstanding a plethora of protocols available for the synthesis of N-SO2R/N-COR or N-aryl/alkyl aziridines,7 the removal of these N-protecting groups to afford NH aziridines is often problematic. In this regard, practical methods for direct construction of NH aziridines remain limited,8 although significant progress has been made in the groups of Ess, Kurti, and Falck.9 Considering that the NH aziridine moiety not only serves as a flexible handle for derivatizations, but also occurs in many biologically important products,10 methods that can achieve direct NH azidridine constructions are highly desirable. In the course of our research on the chemistry of vinyl azides and azirines,11 we were encouraged to envision that the activated imine group in a strained azirine could be a capable ene-type reaction partner (enophile) to couple with suitable alkenes (ene) to give 2-allyl functionalized NH aziridines (see Scheme 1).12 To test this proposal, intermolecular reactions were explored initially. Thus, mixtures of phenyl vinyl azide 1 and several alkenes 2 were heated to 100 °C in dry toluene overnight, with the hope that the 2H-azirine, formed in situ, would couple with

he pursuit of compounds with novel scaffold constitutes one central theme of chemistry, because new structure means new functionality and, therefore, new opportunity for challenging issues. Nature continues to be a rich source of molecules with fascinating structures.1 Synthesis provides another important and indispensable origin.2 In this respect, reactions involving a new mechanism and/or new reactivity are highly appreciated, because, very frequently, they rendered effective access to novel structures that are difficult or even impossible by conventional methods.3 N-spirocycles are privileged scaffolds found in numerous bioactive molecules, and diverse methods for the construction of a range of azaspiro[m,n]alkane skeletons have been developed.4 (See Figure 1.) However, the synthesis and biological properties of

Figure 1. Aza-spiro[2.4]heptane core in bioactive agents.

Scheme 1. NH Aziridine Synthesis from Hypothesized Iminoene Reaction of 2H-azirines with Alkenes

compounds with a 1-aza-spiro[2.4]heptane core I is largely neglected and only sporadic examples have been reported.5 Very recently, two classes of intriguing molecules ridonin derived II and nucleotide analogues III were patented for their antitumor and anti-HCV activities respectively, indicating the immense potentials of spiro NH aziridine in pharmaceutic and medicinal research.6 Herein, we would like to report an intramolecular imino-ene reaction of 2H-azirines with alkenes rendering rapid © XXXX American Chemical Society

Received: March 13, 2018

A

DOI: 10.1021/acs.orglett.8b00821 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters ene donors 2.13 However, in all cases, only 3-pheny-2H-azirine 3 was isolated and the desired ene-type product 4 was not detected, indicating that no ene-reaction was occurring between 3 and alkenes 2 (see Scheme 2).

attempt to isolate this azirine intermediate in pure form failed, we have managed to detect its formation by monitoring the reaction with NMR. As shown in Figure 2, upon heating 5a at 80 °C for 5 h in toluene-d8, 1H NMR signals corresponding to 6a clearly appeared, indicating that a significant amount of azirine was formed.

Scheme 2. Attempted Intermolecular Imino-ene Reaction of Phenylvinyl Azide with Alkenes

Then, we turned to intramolecular versions of the target reaction on the assumption that both kinetic and entropic advantages stemming from intramolecularity would facilitate the ene process.14 For this purpose, vinyl azide 5a with a 3methylbut-2-enyl group linked through a benzyl amine unit was prepared15 and subjected to thermal conditions in toluene for 8 h in a sealed tube. To our delight, a clean reaction was obtained and a sole product, the spiro cis-aziridine 7a was isolated in 74% yield (see Table 1, entry 1). The reaction proceeded equally well in dry Figure 2. 1H NMR spectra of reaction mixtures and product.

Table 1. Condition Optimization for Intramolecular Aza-ene Reactiona

a b

entry

temperature (°C)

solvent

cis/transb

yield (%)c

1 2 3 4 5 6 7 8 9

100 100 100 100 100 100 100 80 120

toluene MeCN DCE THF EtOH DMF DMSO toluene toluene

cis only cis only 9.5/1 4/1 cis only cis only

74 75 68 52 40 56

cis only cis only

63d 59

Next, the generality of this reaction was investigated with various alkenyl vinyl azides 5b−5t in dry toluene (see Table 2). Compound 5b with trans-2-butenyl group the ene donor gave solely cis-aziridine 7b in 75% yield. Surprisingly, the cis-spiro aziridine 7c was obtained exclusively in 79% yield from the reaction of 5c, which is a substrate with a cis-allylic methyl group as the hydrogen donor. Thermolysis of vinyl azide 5d in toluene resulted in a more complex reaction mixture from which corresponding spiro aziridine cis-7d was isolated in only 38% yield. The basic and thermally labile vinyl chloride moiety may account for the inferior outcomes with 5d, which is consistent with the reaction of more vulnerable vinyl iodine 5e for which no formation of corresponding spiro aziridine was observed. Vinyl azides 5f−5l carrying cyclic alkylidene groups all underwent this imino-ene reaction, smoothly affording the related NH aziridines cis-7f−7l in good to excellent yields with complete diastereoselectivity. Cyclobutylidene, cyclopentylidene, and cyclohexylidene substrates (5f, 5g, and 5h, respectively) afforded better yields than the cycloheptylidene and cyclooctylidene analogues (5k and 5l, respectively). The reason for this curious trend has yet to be determined. The reaction of 5m proceeded in an exclusive regioselective fashion to give rise to cis-7m solely in 79% yield, suggesting that the α-methyl group outcompeted the α-methylene group as a hydrogen donor in this ene reaction; interestingly, similar complete discrimination again occurred for the unsymmetrical substrate 5n derived from (+)-menthol; this time, the less-hindered cis α-methylene group surpassed the related trans α-methine group to produce enantiomer cis-7n in 55% yield. A 1.7:1 geometric mixture of vinyl azides 5o was transformed to a mixture of regioisomers cis-7o in 75% yield. These data collectively indicate that this intramolecular ene reaction is extremely sensitive to steric effects and is also highly stereospecific, as evidenced by the formation of the single enantiomer cis-7n. Vinyl azides 5p and 5q, with the N-benzyl group replaced by a N-aryl group, were also excellent substrates for this azirine formation/imino-ene reaction sequence affording N-aryl spiroaziridines 7p and 7q in high yields. In contrast to their N-

Reaction conditions: 5a (0.3 mmol), solvent (1 mL), heating, 8 h. Determined by 1H NMR. cIsolated yield. d10 h.

acetonitrile when the same yield was achieved (Table 1, entry 2). Interestingly, upon changing the reaction medium to dichloroethane or THF, the reaction delivered a diastereomeric mixture of cis-7a and trans-7a with 9.5/1 and 4/1 cis/trans ratios, respectively (Table 1, entries 3 and 4). The intramolecular azaene reaction of 5 also occurred in protic solvents such as ethanol, albeit in much lower yield (Table 1, entry 5). In highly polar solvent DMF, 56% cis-7a was obtained; however, in hot DMSO, vinyl azide 5a decomposed to a complex mixture (Table 1, entry 6 vs entry 7). The reason why a tiny amount of trans-isomer was observed with dichloroethane or THF as solvent currently remains elusive. At 80 °C in toluene, the reaction time had to be prolonged to 10 h in order to reach completion and give 63% yield (Table 1, entry 8). A decreased yield was also observed at 120 °C in toluene (Table 1, entry 9). This reaction provides an efficient access to structurally intriguing spiro NH aziridine using a facile linear substrate. It is worth mentioning that an intermediate suspected to be the azirine 6a was observed by TLC during the reaction. While the B

DOI: 10.1021/acs.orglett.8b00821 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Table 2. Substrates with Noncyclic Alkenes or Exocyclic Alkenesa

a

Reaction conditions: 5 (0.3 mmol), toluene (1 mL), 100 °C, 8 h. bIsolated yield. cNMR ratio. dWeight ratio.

benzyl congeners 5a−5o, however, these reactions delivered 1.5/ 1 and 1.2/1 mixtures of cis/trans isomers, respectively. The complete loss in exclusive cis-diastereoselectivity may correlate with the change from the pyramidal benzyl amines to the trigonal planar aryl amines that necessitates a change in geometry of the transition state; however, the detailed explanations must await further studies. Surprisingly, for anilinyl substrate 5r, with only a cis-CH3 group as hydrogen donor, a single diasteroisomer cis-7r was obtained in 78% yield. The N-Boc and N-Cbz vinyl azides 5s and 5t also contain a planar tertiary amide group and comparably low cis/trans selectivities were observed for their imino-ene reactions. When a sulfonyl group was used as an N-protecting group in 5u−5w, the N-center adopts a flattened pyramidal geometry. In these cases, the stereoselectivity was restored almost completely and the ene products 7u−7w were obtained with cis/trans ratios of >10/1. Vinyl azide 5x with a free NH group was not a viable substrate for this reaction, since its thermolysis in toluene led to complete decomposition of the reactant. The configuration of 7a and 7r was established to be cis via intensive NMR experiments including H−H COSY and H−H NOESY analysis (see the Supporting Information (SI)), and that of the other spiro aziridines was assigned by analogy with comparison of their NMR data and polarities with cis-7a and cis7r. The assignments were further supported by X-ray analysis of single crystals of cis-8p and trans-8p, which were prepared from cis-7p and trans-7p, respectively, via N-tosylation followed by ring opening with benzyl amine (see Figure 3). Subsequently, we turned to substrates incorporating cyclic alkenes as the ene-donor (see Table 3). Under standard conditions, the azirine formation/ene reaction cascade proceeded smoothly, converting N-hexenyl vinyl azide 9a into the 6-

Figure 3. X-ray crystal structures for cis-8p and trans-8p.

5-3 tricyclic alkaloid 10a in high yield with exclusive cisselectivity. In contrast to the N-aryl substrates 5p and 5q carrying an acyclic alkenyl moiety, which gave rise to pairs of diastereomers, the N-phenyl analogue 9b with a cyclohexenyl group delivered cis-10b uniquely in 81% yield. The stereochemical outcomes evident in 10a and 10b also revealed the high stereospecificity of these reactions. This efficient reaction was successfully applied to substrates 9c and 9d with bicyclic alkenyl ene-donors when the corresponding 6-6-5-3 tetracyclic Nheterocycles 10c and 10d also were obtained in good yields. Again, exclusive cis-selectivity and stereospecificity was observed. The polycyclic vinyl azide 9e was conveniently made from naturally occurring testosterone and was converted to optically pure hormonal alkaloid 10e. It appears that the ester groups in 9d and 9e impair the domino process slightly as an ∼5% reduction in yield was observed. Substrate 9f, with the incorporation of a ring into the linker connecting the two reacting partners, was transformed efficiently to the 6-5-3 spiro aziridine 10f. Switching the relative positions of vinyl azide and alkene groups in 9f give C

DOI: 10.1021/acs.orglett.8b00821 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Table 3. Substrates with Cyclic Ene-donor or Cyclic Tethera

a

Reaction conditions: 9 (0.3 mmol), toluene (1 mL), 100 °C, 10 h. bIsolated yield.

addition, this reaction also exhibits completely stereospecificity when substrates with stereo genic center are employed. This method provides an efficient way to access otherwise difficult, structurally intriguing NH spiro aziridines of high value. Mechanism studies and synthetic applications are ongoing in our laboratory.

9g, and, after reaction under standard conditions, another type of 6-5-3 spiro aziridine 10g was obtained in high yield with high stereoselectivity and specificity. Similarly, the tricyclic and tetracyclic spiro aziridines 10h−10j were achieved from vinyl azides 9h−9j. Pleasingly, the condensed pentacyclic alkaloid 10k also could be obtained as a single isomer in 82% yield via this protocol. The relative stereochemistry for products in Table 3 was assigned based on the rule of cis-selectivity established in Table 2. To ensure the validity of these assignments, 10d and 10k were tosylated with TsCl, and the nicely crystalline 11d and 11k were examined crystallographically. As shown in Figure 4, their relative configuration is consistent with the prediction and supports the broader assignment of product structure using the rule of cisselectivity.

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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.orglett.8b00821. Experimental procedures, characterization data and NMR spectra for new compounds (PDF) Accession Codes

CCDC 1814239, 1814242, and 1814243 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/ cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (M.-H. Shen). *E-mail: [email protected] (H.-D. Xu). ORCID

Figure 4. X-ray crystal structures for 11d and 11k.

Hua-Dong Xu: 0000-0002-4510-3754

In summary, an intramolecular imino-ene reaction of 2Hazirines has been disclosed using vinyl azides as in situ azirine precursors under thermal conditions. The N-substitution pattern, alkene configuration, and linker skeleton all have important impacts on the reaction, with respect to stereochemical outcomes. In most cases, the cis spiro aziridine is obtained solely, except linear aromatic amine tether was used. In

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors dedicate this paper to Prof. Q.-L. Zhou on the occasion of his 60th birthday and thank him for his constructive D

DOI: 10.1021/acs.orglett.8b00821 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

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advice. The authors also thank the National Natural Science Foundation of China (Nos. NSFC 21672027 and 21402014), QingLan Project of Jiangsu Province (2016) and Six-TalentPeaks Program of Jiangsu (2016) for financial support.

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