Methyleneaziridines: Unusual Vehicles for Organic Synthesis

Abstract

This account describes the development of methylene­aziridines as heterocyclic building blocks for a variety of useful synthetic transformations including multicomponent reactions, ­cycloadditions and radical cascades.

1 Introduction

2 Preparation of Methyleneaziridines

2.1 Ring Closure to Methyleneaziridines

2.2 Functionalization of Methyleneaziridines

3 Multicomponent Reactions

3.1 Ketone-Forming MCRs

3.2 Amine- and Heterocycle-Forming MCRs

3.3 α-Amino Nitrile Forming MCRs

4 [4+3] Cycloadditions

5 Radical Rearrangements

6 Conclusions

Key words

aziridines - strained heterocycles - ring opening

References and Notes

• 1a Hu XE. Tetrahedron  2004,  60:  2701 
• 1b Dahanukar VH. Zavialov IA. Curr. Opin. Drug Discovery Dev.  2002,  5:  918 
• 1c Sweeney JB. Chem. Soc. Rev.  2002,  31:  247 
• 1d McCoull W. Davis FA. Synthesis  2000,  1347 
• 1e Osborn HMI. Sweeney J. Tetrahedron: Asymmetry  1997,  8:  1693 
• 1f Tanner D. Angew. Chem., Int. Ed. Engl.  1994,  33:  599 
• 2 Bachrach SM. J. Phys. Chem.  1993,  97:  4996 
• 3 Lwowski W. In Comprehensive Heterocyclic Chemistry   Vol. 7:  Katritzky AR. Rees CW. Pergamon; Oxford: 1984.  p.1-16  
• 4 Bottini AT. Roberts JD. J. Am. Chem. Soc.  1957,  79:  1462 
• 5 Quast H. Jakob R. Peters K. Peters E.-M. von Schnering HG. Chem. Ber.  1984,  117:  840 
• 6 Ince J. Ross TM. Shipman M. Slawin AMZ. Ennis DS. Tetrahedron  1996,  52:  7037 
• 7 Hayes JF. Prévost N. Prokes I. Shipman M. Slawin AMZ. Twin H. Chem. Commun.  2003,  1344 
• 8 Shiers JJ. Shipman M. Hayes JF. Slawin AMZ. J. Am. Chem. Soc.  2004,  126:  6868 
• 9 Bottini AT. Roberts JD. J. Am. Chem. Soc.  1958,  80:  5203 
• 10 Quast H. Risler W. Angew. Chem., Int. Ed. Engl.  1973,  12:  414 
• For related thermal rearrangements of methyleneaziridinium cations, see:
• 11a Jongejan E. Steinberg H. De Boer TJ. Recl. Trav. Chim. Pays-Bas  1978,  97:  145 
• 11b Jongejan E. Steinberg H. De Boer TJ. Recl. Trav. Chim. Pays-Bas  1979,  98:  66 
• 12a Bingham EM. Gilbert JC. J. Org. Chem.  1975,  40:  224 
• 12b See also: Bleiholder RF. Shechter H. J. Am. Chem. Soc.  1968,  90:  2131 
• 14 Pollard CB. Parcell RF. J. Am. Chem. Soc.  1951,  73:  2925 
• 15 Ettlinger MG. Kennedy F. Chem. Ind.  1956,  166 
• 16 Wijnberg JBPA. Wiering PG. Steinberg H. Synthesis  1981,  901 
• 17 De Kimpe N. De Smaele D. Sakonyi Z. J. Org. Chem.  1997,  62:  2448 
• 18 Tehrani KA. De Kimpe N. Tetrahedron Lett.  2000,  41:  1975 
• 19 It is suggested that the synthesis of 1,4-diazaspiro-[2.2]pentanes by nitrene addition to allenes proceeds via the corresponding methyleneaziridine. See: Atkinson RS. Malpass JR. Tetrahedron Lett.  1975,  16:  4305 
• 20 Ennis DS. Ince J. Rahman S. Shipman M. J. Chem. Soc., Perkin Trans. 1  2000,  2047 
• 21 Shiers JJ. PhD Thesis   University of Warwick; UK: 2006. 
• 22 Prévost N. Shipman M. Tetrahedron  2002,  58:  7165 
• 24 Twin H. PhD Thesis   University of Exeter; UK: 2002. 
• 25 Hayes JF. Shipman M. Slawin AMZ. Twin H. Heterocycles  2002,  58:  243 
• 26 Ince J. Ross TM. Shipman M. Ennis DS. Tetrahedron: Asymmetry  1996,  7:  3397 
• 27 Margathe JF. Shipman M. Smith SC. Org. Lett.  2005,  7:  4987 
• 28 Prie G. Prévost N. Twin H. Fernandes SA. Hayes JF. Shipman M. Angew. Chem. Int. Ed.  2004,  43:  6517 
• 29 Bottini AT. Olsen RE. J. Am. Chem. Soc.  1962,  84:  195 
• 31a Rappoport Z. Acc. Chem. Res.  1981,  14:  7 
• 31b Rappoport Z. Acc. Chem. Res.  1992,  25:  474 
• 32a Clarke TC. Kelsy DR. Bergman RG. J. Am. Chem. Soc.  1972,  94:  3626 
• 32b Summerville RH. Senkler CA. Schleyer P. Dueber TE. Stang PJ. J. Am. Chem. Soc.  1974,  96:  1100 
• 32c Summerville RH. von R. Schleyer P. J. Am. Chem. Soc.  1974,  96:  1110 
• 33a Ochiai M. Oshima K. Masaki Y. J. Am. Chem. Soc.  1991,  113:  7059 
• 33b Okuyama T. Ochiai M. J. Am. Chem. Soc.  1997,  119:  4785 
• 33c Ochiai M. Yamamoto S. Sato K. Chem. Commun.  1999,  1363 
• 33d Ochiai M. Yamamoto S. Chem. Commun.  2002,  2802 
• 34a Bach RD. Baboul AG. Schlegel HB. J. Am. Chem. Soc.  2001,  123:  5787 
• 34b Kim CK. Hyun KH. Kim CK. Lee I. J. Am. Chem. Soc.  2000,  122:  2294 ; and references cited therein
• 35 Quast H. Weise Vélez CA. Angew. Chem., Int. Ed. Engl.  1974,  13:  342 
• 36 For a recent elegant solution to this problem, see: Hodgson DM. Humphreys PG. Ward JG. Org. Lett.  2005,  7:  1153 
• 37 Montagne C. Prévost N. Prie G. Rahman S. Ince J. Hayes JF. Shipman M. Tetrahedron  2006,  62:  8447 
• 38 Quast H. Weise Vélez CA. Angew. Chem., Int. Ed. Engl.  1978,  17:  213 
• 39 For a monograph, see: Multicomponent Reactions   Zhu J. Bienaymé H. Wiley-VCH; Weinheim, Germany: 2005. 
• 40a Strecker A. Justus Liebigs Ann. Chem.  1850,  75:  27 
• For reviews, see:
• 40b Yet L. Angew. Chem. Int. Ed.  2001,  40:  875 
• 40c Ohfune Y. Shinada T. Bull. Chem. Soc. Jpn.  2003,  76:  1115 
• 40d Groger H. Chem. Rev.  2003,  103:  2795 
• 41a Passerini M. Gazz. Chim. Ital.  1921,  51:  126 
• 41b Passerini M. Ragni G. Gazz. Chim. Ital.  1931,  61:  964 
• For recent developments, see:
• 41c Denmark SE. Fan Y. J. Am. Chem. Soc.  2003,  125:  7825 
• 41d Andreana PR. Liu CC. Schreiber SL. Org. Lett.  2004,  6:  4231 ; and cited references therein
• 42a Ugi I. Steinbrückner C. Angew. Chem.  1960,  72:  267 
• 42b Domling A. Ugi I. Angew. Chem. Int. Ed.  2000,  39:  3168 
• 43a Khand IU. Knox GR. Pauson PL. Watts WE. J. Chem. Soc. D  1971,  36 
• 43b Gibson SE. Mainolfi N. Angew. Chem. Int. Ed.  2005,  44:  3022 
• 44a Biginelli P. Gazz. Chim. Ital.  1893,  23:  360 
• 44b Kappe CO. Tetrahedron  1993,  49:  6937 
• 44c Kappe CO. Acc. Chem. Res.  2000,  33:  879 
• 45a Mannich C. Kröschl W. Arch. Pharm.  1912,  250:  647 
• 45b For a recent review, see: Córdova A. Acc. Chem. Res.  2004,  37:  102 
• For examples, see:
• 47a Penkett CS. Simpson ID. Tetrahedron Lett.  2001,  42:  1179 
• 47b Eis MJ. Ganem B. Tetrahedron Lett.  1985,  26:  1153 
• 48 Crandall JK. Crawley LC. Komin JB. J. Org. Chem.  1975,  40:  2045 
• 49 Ince J. Shipman M. Ennis DS. Tetrahedron Lett.  1997,  38:  5887 
• 50 Hayes JF. Shipman M. Twin H. Chem. Commun.  2000,  1791 
• 51 Hayes JF. Shipman M. Twin H. J. Org. Chem.  2002,  67:  935 
• For discussion of the factors influencing regioselectivity in the deprotonation of imines, see:
• 52a Meyers AI. Williams DR. Erickson GW. White S. Druelinger M. J. Am. Chem. Soc.  1981,  103:  3081 
• 52b Hosomi A. Araki Y. Sakurai H. J. Am. Chem. Soc.  1982,  104:  2081 
• 52c Smith JK. Bergbreiter DE. Newcomb M. J. Am. Chem. Soc.  1983,  105:  4396 
• 53 For another regiospecific route to metalloenamines, see: Wender PA. Eissenstat MA. J. Am. Chem. Soc.  1978,  100:  292 
• For reviews, see:
• 54a Bailey PD. Millwood PA. Smith PD. Chem. Commun.  1998,  633 
• 54b Laschat S. Dickner T. Synthesis  2000,  1781 
• 55 Hayes JF. Shipman M. Twin H. Chem. Commun.  2001,  1784 
• 56 Shiers JJ. Clarkson GJ. Shipman M. Hayes JF. Chem. Commun.  2006,  649 
• 57 Cookson RC. Halton B. Stevens IDR. Watts CT. J. Chem. Soc. C  1967,  928 
• 58 Shipman M. Ross TM. Slawin AMZ. Tetrahedron Lett.  1999,  40:  6091 
• 59 Akasaka T. Nomura Y. Ando W. J. Org. Chem.  1988,  53:  1670 
• 60a Schmid R. Schmid H. Helv. Chim. Acta  1974,  57:  1883 
• 60b Ernst B. Ganter C. Helv. Chim. Acta  1978,  61:  1775 
• 60c De Kimpe N. Palamareva M. Verhe R. De Buyck L. Schamp N. J. Chem. Res., Synop.  1986,  190 
• 60d Oh J. Lee J. Jin S.-J. Cha JK. Tetrahedron Lett.  1994,  35:  3449 
• 60e Lee J. Oh J. Jin S.-J. Choi J.-R. Atwood JL. Cha JK. J. Org. Chem.  1994,  59:  6955 
• 60f Kim H. Ziani-Cherif C. Oh J. Cha JK. J. Org. Chem.  1995,  60:  792 
• 60g Jin S.-J. Choi J.-R. Oh J. Lee D. Cha JK. J. Am. Chem. Soc.  1995,  117:  10914 
• 60h Kende AS. Huang H. Tetrahedron Lett.  1997,  38:  3353 
• For reviews, see:
• 61a Noyori R. Hayakawa Y. Org. React.  1983,  29:  163 
• 61b Hoffmann HMR. Angew. Chem., Int. Ed. Engl.  1984,  23:  1 
• 61c Mann J. Tetrahedron  1986,  42:  4611 
• 61d Rigby JH. Pigge FC. Org. React.  1997,  51:  351 
• 61e Harmata M. Acc. Chem. Res.  2001,  34:  595 
• 61f Harmata M. Rashatasakhon P. Tetrahedron  2003,  59:  2371 
• 62a Stamm H. Assithianakis P. Buchholz B. Weib R. Tetrahedron Lett.  1982,  23:  5021 
• 62b Werry J. Stamm H. Lin P.-Y. Falkenstein R. Gries S. Irngartinger H. Tetrahedron  1989,  45:  5015 
• 62c Dickinson JM. Murphy JA. J. Chem. Soc., Chem. Commun.  1990,  434 
• 62d Dickinson JM. Murphy JA. Tetrahedron  1992,  48:  1317 
• 62e De Kimpe N. Jolie R. De Smaele D. J. Chem. Soc., Chem. Commun.  1994,  1221 
• 62f De Kimpe N. De Smaele D. Bogaert P. Synlett  1994,  287 
• 62g De Smaele D. Bogaert P. De Kimpe N. Tetrahedron Lett.  1998,  39:  9797 
• 62h Schwan AL. Refvik MD. Tetrahedron Lett.  1993,  34:  4901 
• 62i Molander GA. Stengel PJ. Tetrahedron  1997,  53:  8887 
• 62j Marples BA. Toon RC. Tetrahedron Lett.  1999,  40:  4873 
• 63 For a review on the use of aminyl radicals in synthesis, see: Fallis AG. Brinza IM. Tetrahedron  1997,  53:  17543 
• 64 Clive DLJ. Chittatu GJ. Farina V. Kiel WA. Menchen SM. Russell CG. Singh A. Wong CK. Curtis NJ. J. Am. Chem. Soc.  1980,  102:  4438 
• 65 Prévost N. Shipman M. Org. Lett.  2001,  3:  2383 
• 66 Oh BH. Nakamura I. Yamamoto Y. Tetrahedron Lett.  2002,  43:  9625 
• 67 Oh BH. Nakamura I. Yamamoto Y. ARKIVOC  2003,  (viii):  67 
• 68 Siriwardana AI. Kathriarachchi KKADS. Nakamura I. Gridnev ID. Yamamoto Y. J. Am. Chem. Soc.  2004,  126:  13898 
• 69 Oh BH. Nakamura I. Yamamoto Y. J. Org. Chem.  2004,  69:  2856 

13

Purification by distillation is preferred over chromatography. Poor mass recovery is observed when methyleneaziridines are subjected to this purification technique. Exceptions include derivatives bearing substituents on the exocyclic double bond wherein high mass recovery and purity can be achieved by chromatography on silica gel pretreated with Et₃N.

23

Margathe, J. F.; Shipman, M.; Smith, S. C. unpublished results.

30

It is unclear why Bottini and Olsen (ref. 29) were unable to detect exchange with the solvent under their experimental conditions. However, we suspect that an insufficient amount of base was added. This conclusion was reached on the basis of the following observations. First, for the exchange experiment, they used just a catalytic quantity (0.26 equiv) of commercial sodium amide, whereas cyclisations were conducted using NaNH₂ made in situ from sodium metal and FeCl₃. In our experience, the activity of commercial material is inferior and often necessitates the use of a large excess of reagent. Second, 28 used in the experiment was contaminated with 7% of the corresponding alkyne which would have consumed a significant proportion of the added base.

46

This process involves the reaction of two reagents together to form an intermediate that is captured by the subsequent addition of further reagents. Hence it is more precisely defined as a sequential component reaction.

70

As far as we are aware, the toxicological effects of methyleneaziridines are unknown. However, since the adverse health effects of aziridines are well established, it is prudent to exercise caution in the handling of methyleneaziridines. Avoid all skin contact and perform all manipulations in a well-vented fume cupboard with adequate personal protection measures.