Intramolecular Schmidt reactions can be reliably steered toward bridged heterocycles containing orthoamides in high yields. The ketal tether enhances the control of regioselectivity in the migration of the bond distal to the reactive azide nucleophile, thus providing the first examples of the intramolecular Schmidt reaction proceeding with a complete regioselectivity en route to bridged products. The method is broad in scope and allows for systematic study of compounds that are analogous to elusive tetrahedral intermediates of amide addition reactions. Some initial reactivity and structural profiling of these compounds are also reported

Aubé, J.

Szostak, M.

PubMed

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Synthesis, Structural Analysis, and Reactivity of BridgedOrthoamides by Intramolecular Schmidt ReactionMichal Szostak and Jeffrey Aubé*Department of Medicinal Chemistry, University of Kansas, Structural Biology Center, 2121 SimonsDrive, West Campus, Lawrence, KS 66047The intramolecular Schmidt reaction is a useful method for the synthesis of lactams.1 Mostcommonly, this reaction affords fused lactams bearing a nitrogen atom at a ring fusion positionby preferential migration of the carbon bearing the azide-containing side chain. We haverecently shown that certain substitution types lead to the alternative regioisomeric productcontaining a bridged ring system incorporating nitrogen at a bridgehead position (Scheme 1).2 Such compounds are noteworthy since they contain distorted amide bond linkages, whichare of interest from theoretical, mechanistic, and reactivity perspectives.3 However, thesemethods are substrate dependent and provide mixtures of bridged and fused lactams, even inthe most favorable cases. We now show that intramolecular Schmidt reactions can be reliablysteered toward bridged heterocycles containing orthoamides in high yields. The method isbroad in scope and allows for systematic study of compounds that are analogous to elusivetetrahedral intermediates of amide addition reactions.4We hypothesized that (1) the formation of bridged lactams using the Schmidt reaction ofketones and azides was hampered by the necessity of forming a strained non-planar amide, (2)that this could be mitigated by relying instead on formation of a relatively stable iminium etherintermediate, and (3) that intramolecular capture would provide an easy road to a stable – andunusual – orthoamide product. That we had previously demonstrated that ketals also participatein azido-Schmidt chemistry5a combined with a single report of a bridged ring system formedin this way5b suggested that reactions of these species might favor bridged products to a greaterdegree.To maximize the chance for success, we focused first on alkyl azides that had already beenshown to react preferentially by path b (Scheme 1).2 Thus, Lewis or protic acid treatment of aseries of ketals derived from 1,3-dioxolane afforded bridged orthoamides in excellent yield(Table 1). The products were stable to the reaction and chromatographic isolation conditions.As hypothesized, the transformation proceeded with efficient control of regiochemistry, whilethe ketones corresponding to 1a–f provided a ca. 5:2 mixture of bridged and fused lactams.2aThese results demonstrate that this approach accommodates a variety of ketal types. In contrast,the behavior of enol ether 1f shows that success depends upon intramolecular capture of theintermediate oxonium ion and that the [4.3.1] ring system containing a hemiaminal is unstable.Subsequent work showed that a range of conformationally locked azido alkyl 1,3-dioxolanessubstituted with aromatic rings in the 2 position could easily be transformed into analogousproducts (Table 2, entries 1–4). Throughout, these reactions proceeded with complete controlof regiochemistry.6 Even the conformationally flexible azide 1k (entry 5) gave exclusively*jaube@ku.edu.Supporting Information Available: Experimental details characterization data for new compounds, and the .cif file for 2n. This materialis available free of charge via the Internet at http://pubs.acs.org.NIH Public AccessAuthor ManuscriptJ Am Chem Soc. Author manuscript; available in PMC 2011 March 3.Published in final edited form as:J Am Chem Soc. 2010 March 3; 132(8): 2530–2531. doi:10.1021/ja910654t.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscriptbridged product, in sharp contrast to the corresponding ketone, which only afforded fusedlactam. A number of substrates with heteroatoms in the 2-position underwent the reaction ingood to excellent yields (entries 6–8). Finally, a conformationally flexible azide with a shorterazide chain cleanly furnished the [4.2.1] bridged scaffold (entry 9). It is likely that in this casethe fused product did not form due to strain developing en route to the corresponding a four-membered-lactam containing fused product.We have proposed that chairlike cyclohexanones afford bridged products only when the azide-containing side chain and the diazonium cation are both pseudoaxial (Scheme 2, intermediateC).5c Here, the N2+ leaving group is axial, leading to migration of the antiperiplanar alkylgroup. We propose that the enhanced regioselectivity observed with ketal-containing vs.ketone-containing azides results from steric and electronic repulsion between the diazoniumcation in the D conformation relative to C. In both cases, the most stable conformation of theO-alkyl side chain is likely to be as drawn; the N2+ leaving group in D experiences adisfavorable syn-1,5 interaction with the O-alkyl group that is absent in C. In the analogousreactions of ketones, where the OR group is replaced by either a proton or a Lewis acid, sucheffects are minimized relative to the present case (and the role of attractive non-bondedstabilization between N2+ and R2 is even more important). Interestingly, the Deslongchampsprinciple of maximal overlap could also come into play here. Thus, if the side chain orientationproposed predominates in the transition state leading to product, it is only possible for anoxygen electron lone pair to be antiperiplanar to the migrating bond in C but not in D (wherethe O-alkyl group is instead antiperiplanar to the darkened bond in D).4b Finally, the successof cases lacking an alkyl group at R2 indicates that the reactive conformation in these examplesis exclusively B and not A.The α-amino ketal functionality is stabilized by a non-planar arrangement of atoms. The X-ray crystal structure of 2n reveals that the N1–C1 bond (1.448 Å) as well as the C1-O1 (1.405Å) and C1–O2 (1.416 Å) bonds are shorter than typical N–Csp3 (1.469 Å) and Csp3–O (1.432Å) bonds (Figure 1).4a The C1-C2 bond length of 1.543 Å is slightly longer than the averageCsp3-Csp3 bond (1.530 Å).4a The torsion angles between Nlp and C1-O1 of 69.5° and betweenNlp and C1-O2 of 46.1° are consistent with the absence of that Nlp→σ*C-O interactions in thissystem. By contrast, there exists a reasonably good arrangement between O1lp and N1-C1 bond(~148°) and between O2lp and N1-C1 bond (~158°). While the lengths of C1-O1, C1-O2 andC1-C2 bonds are in agreement with an anomeric effect resulting from Olp→σ*C1-N1 andOlp→σ*C1-C2 interactions, the shortened N1-C1 bond seems to be characteristic to thetetrahedral intermediate stabilized by scaffolding effects of a medium-sized ring.4We begun to examine the reactivity of these α-amino ketals, (Scheme 3). For example, wefound that acid hydrolysis affords 9-membered ring amino esters (these can be converted intothe bridged lactams by treatment with base; see SI). In contrast, chromatography-stablehemiaminal ethers are formed following reduction (DIBAL-H), while reaction with Me3Aldelivers a “twisted enamine”. As expected, α-amino ketals also undergo reactions at nitrogen.In summary, we have established a direct synthesis of orthoamides, which are analogs oftetrahedral intermediates derived from amide addition reactions. Continuing efforts to studythis class of compounds are underway.Supplementary MaterialRefer to Web version on PubMed Central for supplementary material.Szostak and Aubé Page 2J Am Chem Soc. Author manuscript; available in PMC 2011 March 3.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptAcknowledgmentsThis work was supported by the National Institute of General Medical Sciences (GM-49093). We thank Victor Dayfor X-ray crystallography, Ruzhang Liu and Angelica Meyer for helpful discussions.References(1). For recent reviews, see: (a) Nyfeler E, Renaud P. Chimia 2006;60:276–284. (b) Lang S, Murphy JA.Chem. Soc. Rev 2006;35:146–156. [PubMed: 16444296] (c) Grecian, S.; Aubé, J. Organic Azides:Syntheses and Applications. Bräse, S.; Banert, K., editors. John Wiley and Sons; 2009.(2). (a) Yao L, Aubé J. J. Am. Chem. Soc 2007;129:2766–2767. [PubMed: 17302421] (b) Szostak M,Yao L, Aubé J. Org. Lett 2009;11:4386–4389. [PubMed: 19722508](3). For recent reviews, see: (a) Greenberg, A.; Breneman, CM.; Liebman, JF. Amide Linkage: SelectedStructural Aspects in Chemistry, Biochemistry, and Materials Science. Wiley; New York: 2000. .(b) Clayden J, Moran WJ. Angew. Chem., Int. Ed 2006;45:7118–7120. For selected examples, see:(c) Kirby AJ, Komarov IV, Feeder N. J. Chem. Soc., Perkin Trans 2001;2:522–529. (d) Tani K,Stoltz BM. Nature 2006;441:731–734. [PubMed: 16760973] (e) Lei Y, Wrobleski AD, Golden JE,Powell DR, Aubé J. J. Am. Chem. Soc 2005;127:4552–4553. [PubMed: 15796502](4). (a) Adler M, Adler S, Boche G. J. Phys. Org. Chem 2005;18:193–209.(b) Deslongchamps, P.Stereoelectronic Effects in Organic Chemistry. Pergamon Press; 1983. (c) Evans DA, Borg G,Scheidt KA. Angew. Chem., Int. Ed 2002;41:3188–3191. (d) Kirby AJ, Komarov IV, Feeder N. J.Am. Chem. Soc 1998;120:7101–7102. (e) Szostak M, Aubé J. J. Am. Chem. Soc 2009;131:13246–13247. [PubMed: 19715274](5). (a) Mossman CJ, Aubé J. Tetrahedron 1996;52:3403–3408. (b) Iyengar R, Schildknegt K, MortonM, Aubé J. J. Org. Chem 2005;70:10645–10652. [PubMed: 16355981] (c) Milligan GL, MossmanCJ, Aubé J. J. Am. Chem. Soc 1995;117:10449–10459.(6). Only bridged orthoamides were observed in the analysis of the crude reaction mixtures by 1H NMR.See SI for details.(7). Interestingly, 2n was originally reported in Reference 5a as a fused isomer. We now reassign 2n asa bridged orthoamide. See, SI for details.Szostak and Aubé Page 3J Am Chem Soc. Author manuscript; available in PMC 2011 March 3.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptFigure 1.X-ray structure of 2n. Selected bond lengths [Å] and angles [°]: N1-C1 1.448, C1-O1 1.405,C1-O2 1.416, C1-C2 1.543, C6-N1-C1-O1 −38.1, C7-N1-C1-O1 177.0, C7-N1-C1-O2 61.5,C6-N2-C1-O1 −153.7Szostak and Aubé Page 4J Am Chem Soc. Author manuscript; available in PMC 2011 March 3.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptScheme 1.Szostak and Aubé Page 5J Am Chem Soc. Author manuscript; available in PMC 2011 March 3.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptScheme 2.Szostak and Aubé Page 6J Am Chem Soc. Author manuscript; available in PMC 2011 March 3.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptScheme 3.Conditions: (a) 2i, THF, 60 °C, 12 h, 89%.(b) 2c, PhH, 80 °C, 15 h, 67%. (c) 2d, CH2Cl2, 40°C, 15 h, 56%. (d) 2h, rt, 20 h, 96%.Szostak and Aubé Page 7J Am Chem Soc. Author manuscript; available in PMC 2011 March 3.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptSzostak and Aubé Page 8Table 1Formation of bridged orthoamides from ketals.entry azide product conditionsa yield (%)b1 (1a) R, R = H (2a) A 882 (1b) R, R = -(CH2)4- (2b) A 71J Am Chem Soc. Author manuscript; available in PMC 2011 March 3.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptSzostak and Aubé Page 9entry azide product conditionsa yield (%)b3 (1c) n = 1, R, R = H (2c) B 774 (1d) n = 1, R, R = Me (2d) B 755 (1e) n = 2, R, R = H (2e) B 70cJ Am Chem Soc. Author manuscript; available in PMC 2011 March 3.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptSzostak and Aubé Page 10entry azide product conditionsa yield (%)b6 C 63aA: BF3•CH3CN, 5.0 equiv, 0 °C to rt; B: BF3•CH3CN, 3.0 equiv, −78 °C to rt; C: TfOH, 5.0 equiv, 0 °C.bIsolated after chromatographycDetermined by 1H NMR, see SI (Supporting Information) for details.J Am Chem Soc. Author manuscript; available in PMC 2011 March 3.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptSzostak and Aubé Page 11Table 2Azide scope.aentryazideR1R2nketalyield (%)1(1g)t-Bu4-(OMe)C6H41(2g)922(1h)t-Bu3,4,5-(OMe)3C6H21(2h)863(1i)t-Bu3,5-(OMe)2C6H31(2i)864(1j)t-Bu4-(NO2)C6H41(2j)945(1k)HC6H51(2k)596(1l)HOMe1(2l)52b7(1m)HSMe1(2m)508(1n)HSPh1(2n)778b9(1o)HC6H50(2o)91a BF 3•CH3CN, 3.0–5.0 equiv in CH2Cl 2b TMSOTf.J Am Chem Soc. Author manuscript; available in PMC 2011 March 3.

Synthesis, structural analysis, and reactivity of bridged orthoamides by intramolecular schmidt reaction

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