Tetrahedron Letters 54 (2013) 5461–5463

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Tetrahedron Letters

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A solvent-free amidation of vinylogous esters via direct aziridination

0040-4039/$ - see front matter � 2013 Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.tetlet.2013.07.135

⇑ Corresponding author. Tel.: +1 845 752 2355; fax: +1 845 752 2339.E-mail address: mclaughl@bard.edu (E.C. McLaughlin).

Emily C. McLaughlin ⇑, Anuska Shrestha, Madison H. Fletcher, Nathaniel S. Steinauer, Min Kyung Shinn,Sabrina M. ShahidBard College, 30 Campus Road, Annandale-on-Hudson, NY 12504, United States

a r t i c l e i n f o a b s t r a c t

Article history:Received 5 July 2013Revised 22 July 2013Accepted 25 July 2013Available online 2 August 2013

Keywords:AziridinationEthyl azidoformateMicrowave-mediated synthesisVinylogous esterAmidation

A microwave-mediated aziridination of a,b-unsaturated ketones and esters through the decomposition ofethyl azidoformate has been developed. When the same atom-economical reaction conditions are appliedto cyclic vinylogous esters, N-functionalization at the a-position occurs. Based on NMR analysis, theseamidation products appear to be formed from the desired aziridine in moderate to good yields.

� 2013 Elsevier Ltd. All rights reserved.

The direct aziridination of olefins is a powerful tool that iswidely utilized in organic synthesis to introduce nitrogen function-ality onto hydrocarbon scaffolds.1 These electrophilic ring systemsare important building blocks in the preparation of a diverse arrayof bioactive organic compounds.2 The chemical literature is repletewith examples of olefin aziridination, however there are few re-ports concerning aziridination of enol ethers,3 a,b-unsaturatedesters,4 and even fewer examples involving both the enol and esterfunctionalities in the same substrate, such as the vinylogous ester.5

Our work in this area has focused on N-insertion onto the al-kene of substituted vinylogous esters like dioxenone 1. The vinyl-ogous ester is a hybrid of the enone and ester functionality andprovides a unique electronic environment in which the b-positionis less electrophilic than that of an a,b-unsaturated carbonyl. Weenvisioned that the direct aziridination of 1,3-dioxen-4-ones couldprovide access to an array of variably substituted non-proteino-genic amino acids (Scheme 1). Starting with a variety of substi-tuted b-ketoesters, their respective enol tautomers could betrapped as a stable, yet temporary, cyclic vinylogous ester 1, set-ting up the alkene for aziridination. Once formed, the bicyclic prod-uct 2 could be released and hence afford a range of b-keto aminoacid derivatives such as compound 3.

One significant challenge in the manipulation of dioxenones istheir sensitivity to cycloreversion (or retro-aldol decomposition)under acidic, basic, or thermal conditions.6 In this light, our preli-minary investigation of N-functionalization explored the direct

aziridination of the more stable, electron deficient alkenes of cyclicand acyclic a,b-unsaturated ketones and esters.

Just as cyclopropanation is accomplished through carbeneinsertion into alkenes, aziridination can be achieved in a similarfashion with nitrenes.7 The short-lived and reactive nitrene speciesis most commonly generated through the oxidation of amides orsulfonamides (chemically or electrochemically),8 or by thermal orphotochemical decomposition of acyl azides9 and alkyl azidofor-mates.3,10 We found the latter to be the most attractive methodfor nitrogen incorporation into our targeted substrates based onthe previously reported aziridination of a,b-unsaturated ketonesemploying ethyl azidoformate (EAF).4

Lwowski has reported evidence of a reactive carbethoxynitrenespecies produced through the decomposition of ethyl azidofor-mate.10b For our experiments, we prepared EAF according toLwowski’s procedure11 and employed the nitrene precursor forthe aziridination reactions of alkenes 4 through 8, (Table 1, entries1–5). Upon heating each substrate in a solution of dichloromethane(2 mmol scale; 4 equiv of EAF; 3–8 h; 115–130 �C in an oil bath)aziridines 13–17 were identified and isolated in low to moderateyields. In an effort to develop milder reaction conditions and amore environmentally benign and efficient method of aziridin-ation, we removed the solvent (dichloromethane) from the proto-col and utilized microwave irradiation as our source of thermalenergy for the nitrene transfer from EAF to the olefin substrates.To our satisfaction, we found these changes to be effective inreducing the reaction time for aziridine formation (1–4 h com-pared to 3–8 h) and to be high-yielding (79–97%).12 Aziridine prod-ucts were easily isolated from both cis and trans disubstituted

Scheme 2. Proposed mechanism for the N-functionalization of methyl dioxenone.Scheme 1. Aziridination of cyclic vinylogous esters.

5462 E. C. McLaughlin et al. / Tetrahedron Letters 54 (2013) 5461–5463

alkenes (Table 1, entries 2–4) and we attribute the longer reactiontime and increased equivalents of EAF necessary for methyl cinna-mate (5, entry 3) to the attenuated solubility of the solid substrate.The aziridination of (R)-hydrocarvone (8) demonstrates the utilityof this methodology for more sterically hindered trisubstituted al-kenes. The corresponding product, 17, was also formed with mod-erate diastereoselectivity.

With these results in hand, we turned our attention to theaziridination of our targeted cyclic vinylogous ester. The 1,3-dioxe-none substrate (9) was prepared in one step from the correspond-ing ketoester (Scheme 1) employing an acid mediated ketenecyclization developed by Winkler.13 The compound was then sub-jected to both thermal and photochemical conditions with EAF indichloromethane. In both cases, a substantial amount of cyclore-version of 9 was observed. This was indicated by the increasedpresence of acetone in NMR studies performed in dichlorometh-ane-d2. Under milder, microwave-mediated, and solvent-free con-ditions, a product was observed that indicated the incorporation of

Table 1Microwave promoted aziridination/amidation with ethyl azidoformate (EAF) of compound

Entry Alkene Equiv EAF Temp

1 4 4 115 �C

2 5 8 115 �C

3 6 6 115 �C

4 7 6 115 �C

5 8 6 115 �C

6 9 6 100 �Cd

7 10 6 115 �C

8 11 6 115 �C

9 12 6 115 �C

a The reactions were carried out under microwave irradiation varying time, temperatb Yields were determined by GCMS analysis using dodecane as an internal standard.c The aziridine product was formed in 3.2:1 ratio of diastereomers.d A lower temperature was used for dioxenone 9 to prevent appreciable amounts of c

ethyl carbamate onto our substrate. This product was isolated andfound not to be the desired aziridine 22 (Scheme 2). Surprisingly,1H and 13C NMR analysis confirmed the formation of 18 in moder-ate yield. We carefully monitored the transformation with both 1HNMR and GCMS and found evidence for the formation of aziridine22 (singlet at 3.4 ppm, Ha), but we were unable to isolate the inter-mediary product. However, the insertion product 18 was easily iso-lated after flash chromatography on neutral alumina.

Based on the formation of 22 during the course of the reaction,the amidation product (18) appears to be a result of the aziridinering opening, which is promoted by electron donation of the prox-imal oxygen lone pair (Scheme 2). We propose that the oxoniumintermediate allows for facile removal of the acidic a-proton in23, to regenerate the olefin and provide 18.

To support our proposed mechanism and to showcase a trend inthis amidation methodology, we prepared three dioxenoneanalogs, which contain cyclic vinylogous ester functionality.Methyl pyranone 10 was prepared in acceptable yield according

s 4–12a

Time (h) Product Yieldb (%)

1 13 91

4 14 89

2.5 15 95

3 16 79

1 17 97c

1 18 58

1 19 55

2 20 78

1 21 79

ure, and equivalents of ethyl azidoformate.

ycloreversion.

Scheme 3. Microwave-promoted oxazinone formation.

E. C. McLaughlin et al. / Tetrahedron Letters 54 (2013) 5461–5463 5463

to the literature.14 Additionally, oxazinone heterocycles 11 and 12were prepared by cyclization of the corresponding b-ketoesterwith diisopropylcarbodimide, catalytic triethylamine, and micro-wave irradiation (Scheme 3).

Repeating the reaction conditions outlined above with analogs10–12, we obtained the expected amidation products 19–21,respectively (Table 1). The moderate yields for the amidation ofdioxenone 9 and pyranone 10 are presumably due to the instabilityof both starting materials and products at elevated temperatures.Neither aziridination nor amidation products were observed attemperatures lower than 100 �C in any of our trials.

Similar examples for this type of N-functionalization includemultistep nitration/reduction protocols of isoflavonoids,15 hydraz-ination,16 and transition metal catalyzed Buchwald–Hartwigamination17 of chromone derivatives. In each of the aforemen-tioned transformations, the authors took advantage of the aroma-ticity of the flavones through electrophilic aromatic substitutionor aryl-halide coupling. Under our reaction conditions, we havefound an atom-economical, one-pot process to do the sametransformation on substituted alkenyl substrates.

In conclusion, we have developed an environmentally benign,solvent-free microwave aziridination protocol for a,b-unsaturatedcarbonyl compounds. When this methodology is applied to vinylo-gous esters, a formal nitrogen insertion through an aziridinationpathway is observed. We plan to investigate this reactivity withacyclic vinylogous esters as well as substrates containing vinylo-gous amide functionality in an effort to broaden the scope of thiswork.

Acknowledgments

The authors acknowledge financial support from the AmericanChemical Society’s Petroleum Research Fund (ACS-PRF, #49471-UNI1) for this work as well as support from the Research Corpora-tion for Scientific Advancement (RCSA #20215), Bard College, andthe Bard College Summer Research Institute (BSRI).

Supplementary data

Supplementary data associated with this article can be found, inthe online version, at http://dx.doi.org/10.1016/j.tetlet.2013.07.135.

References and notes

1. (a) Padwa, A. In Comprehensive Heterocyclic Chemistry III; Katrizky, A. R.,Ramsden, C. A., Scriven, E. F. V., Taylor, R. J. K., Eds.; Elsevier: Oxford, 2008; Vol.1, pp 1–104; (b) McMills, M. C.; Bergmeier, S. C. In Comprehensive HeterocyclicChemistry III; Katrizky, A. R., Ramsden, C. A., Scriven, E. F. V., Taylor, R. J. K., Eds.;Elsevier: Oxford, 2008; pp 105–172.

2. Singh, G. S.; D’hooghe, M.; De Kimpe, N. Chem. Rev. 2007, 107, 2080–2135; (b)Olsen, C. A.; Franzyk, H.; Jaroszewski, J. W. Eur. J. Org. Chem. 2007, 2007, 1717–1724; (c) Padwa, A.; Murphree, S. S. Arkivoc 2006, 3, 6–33; (d) Hu, X. E.Tetrahedron 2004, 60, 2701–2743; (e) Sweeney, J. B. Chem. Soc. Rev. 2002, 31,247–258.

3. Fioravanti, S.; Loreto, M. A.; Pellacani, L.; Tardella, P. A. Tetrahedron 1991, 47,5877–5882.

4. Fioravanti, S.; Pellacani, L.; Tabanella, S.; Tardella, P. Tetrahedron 1998, 54,14105–14112.

5. Xu, X.; Shabashov, D.; Zavalij, P. Y.; Doyle, M. P. J. Org. Chem. 2012, 77, 5313–5317.

6. Wentrup, C.; Heilmayer, W.; Kollenz, G. Synthesis 1994, 1994, 1219–1248.7. Dequirez, G.; Pons, V.; Dauban, P. Angew. Chem., Int. Ed. 2012, 51, 7384–7395.8. Müller, P.; Baud, C.; Jacquier, Y. Can. J. Chem. 1998, 76, 738–750; (b) Siu, T.;

Picard, C. J.; Yudin, A. K. J. Org. Chem. 2005, 70, 932–937; (c) Siu, T.; Yudin, A. K.J. Am. Chem. Soc. 2002, 124, 530–531.

9. Bergmeier, S. C.; Stanchina, D. M. J. Org. Chem. 1997, 62, 4449–4456; (b)Mendlik, M. T.; Tao, P.; Hadad, C. M.; Coleman, R. S.; Lowary, T. L. J. Org. Chem.2006, 71, 8059–8070.

10. (a) Lwowski, W.; Mattingly, T. W., Jr. J. Am. Chem. Soc. 1965, 87, 1947–1958; (b)Lwowski, W.; Maricich, T. J. J. Am. Chem. Soc. 1965, 87, 3630–3637; (c) Dyke, J.M.; Levita, G.; Morris, A.; Ogden, J. S.; Dias, A. A.; Algarra, M.; Santos, J. P.; Costa,M. L.; Rodrigues, P.; Andrade, M. M.; Barros, M. T. Chem. Eur. J. 2005, 11, 1665–1676.

11. Sodium azide (157 mmol) was dissovled in 55 mL of H2O and cooled in an icebath. Ethyl chloroformate (131 mmol) in 15 mL of diethyl ether was thenadded to the aqueous sodium azide. The reaction was stirred vigorouslyovernight, warming to room temperature. The reaction was extracted intodiethyl ether (2 � 40 mL) and the organics were dried over MgSO4 andconcentrated under reduced pressure. EAF was isolated as a transparent oil in80% yield. CAUTION: ethyl azidoformate can decompose explosively attemperatures above 160 �C.

12. The alkenyl substrate (4–12) (2 mmol) and ethyl azidoformate (8–12 mmol)were added to a 10 mL snap-cap microwave vessel. The reaction was subjectedto microwave irradiation for 1–4 h at 100–115 �C. The crude reaction mixturewas directly subjected to chromatography (see Supplementary data).

13. Winkler, J.; Hershberger, P. J. Am. Chem. Soc. 1989, 111, 4852–4856.14. Peterson, J. R.; Winter, T. J.; Miller, C. P. Synth. Commun. 1988, 18, 949–963.15. Gammon, D. W.; Hunter, R.; Wilson, S. A. Tetrahedron 2005, 61, 10683–10688.16. Samanta, R.; Bauer, J. O.; Strohmann, C.; Antonchick, A. P. Org. Lett. 2012, 14,

5518–5521.17. Fitzmaurice, R. J.; Etheridge, Z. C.; Jumel, E.; Woolfson, D. N.; Caddick, S. Chem.

Commun. 2006, 4814.