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Aubé, Jeffrey

Forsee, Jennifer E.

Frank, Kristine E.

Smith, Brent T.

English

KU ScholarWorks

1258 LETTERS SYNLETTReactions of Oxazolinium and Dihydrooxazinium Salts Prepared by an Azide InsertionSequence: pH Control of Product DistributionJennifer E. Forsee, Brent T. Smith, Kristine E. Frank, and Jeffrey Aubé*Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66045-2506, USAFax 1.785.864.4496; e-mail: jaube@ukans.eduReceived 6 August 1998Abstract: The Lewis acid-promoted reaction between a ketone and anazido alcohol is an efficient route to imidate salts. The hydrolysis ofthese salts is shown to generate medium to large-ring lactams andlactones in good to excellent yield. The reaction products differaccording to the pH of the medium used for hydrolysis of the imidatesalts.Imidate salts (iminium ethers) are ambident electrophiles that can behydrolytically converted into a variety of useful products.1 Classically,these compounds have been prepared from the corresponding N-hydroxylalkyl amide through a formal dehydration procedure (Scheme1). More recently, we have demonstrated that imidate salts can also begenerated in situ by the Lewis acid-promoted reactions of hydroxyazides with ketones.2-4 The addition of nucleophiles to these imidatesalts affords a range of products that includes amines, enamines and ω-substituted alkyl amides.3 Globally, this mechanistically complexprocess can involve kinetic addition to the cationic center and proceeddirectly to product (path A) or involve displacement at the terminalcarbon of the azido alcohol (starred, path B).1,3 In this paper, we showthat lactones are also available from iminium ether hydrolysis anddemonstrate that a measure of control can be imposed upon the reactionpath (A1 vs. A2/B), resulting in enhanced utility of these heterocyclicintermediates in synthesis. In the special case of an α-bromo substitutedketone, an interesting α-amino ester synthesis is also described.Scheme 1Initial studies using cycloheptanone, 1a or 1b,5 and BF3·OEt2 resultedin exclusive amide 2 formation when KOH was employed for imidatesalt hydrolysis (Scheme 2). Alternatively, the use of NaHCO3 resultedin the formation of lactone 3 as the major product, in addition to theexpected amide 2.6 Only amide formation was observed in our previousstudies with four- to six-membered ring ketones, using either base in thework-up.2-4 The difference in transannular strain associated with thelactams (standard rings, 5-7 members) vs. lactones (medium rings, 8-11members) formed in these cases most likely accounts for the absence oflactone production. In contrast, both products from the ring expansionof cycloheptanone contain medium-to-large rings and therefore, ringstrain is likely to play a less dominant role in product selection.Scheme 2Experiments with 5-nonanone and 1a (Scheme 3) illustrated similarbehavior with respect to each work-up procedure, except that some esterwas formed under both protocols.6 Although previously disclosedstudies with acetone and 1b showed solely amide product in 86% yieldwhen NaHCO3 was used,2 we have had difficulty in repeating thisresult. Current work to elucidate the effect of ketone and azidestructures on the distribution of acyclic products is underway.Scheme 3We decided to explore the reactivity and regiochemistry of the reactionwith α-bromocyclohexanone as substrate (Scheme 4). Amide (6) wasproduced under KOH or NaOH work-up, along with some alkene (7)resulting from elimination of HBr. In this case, work-up with NaHCO3RNR'ONORR'OHN3R"R' ON OR'OHN OONHR" OR'n = 1,2BF41a, n = 11b, n = 2OHnOHnR'n*nnnPathA1PathA2Path A Path BR"R"O+ N3OHn1. BF3•OEt22. Base1a, n = 11b, n = 2NOOHn +ONHnn      base        yield (%) 2     yield (%) 3682762210430701122KOHNaHCO3KOHNaHCO32a, n = 12b, n = 23a, n = 13b, n = 2On-BuO+ N3OH 1. BF3•OEt22. Basen-Bu Nn-BuOOHNn-BuO+5      base       yield (%) 4     yield (%) 55562892KOHNaHCO3OH1a4n-Bun-BuDownloaded by: IP-Proxy University of Kansas Libraries - Watson Library, University of Kansas Libraries. Copyrighted material.November 1998 SYNLETT 1259resulted in the formation of a new product type, an α-amino lactone (8).This latter product is explained by the mechanism outlined in Scheme 6.In all cases, it is noteworthy that the less substituted methylene groupundergoes predominant migration during the azido alcohol additionstep.Scheme 4We propose that the product distribution depends on the protonationstate of intermediate B (Schemes 5 and 6).1,3 Two indistinguishablemechanisms are possible when the reaction is carried out in KOH orNaOH (pH ca. 14). Distal attack of hydroxide ion on the linker carbonof A leads directly to amide. Alternatively, the reversible formation ofintermediate B might also lead to amide by deprotonation in the stronglybasic medium and collapse as shown (RO– being a better leaving groupthan R2N–).7Scheme 5In NaHCO3 (pH ca. 9), we propose that the reaction proceeds viaprotonated species C (Scheme 6). This is based on the expected pKa ofthe amine (ca. 10-11).7 For this species, preferential carbon-nitrogenbond cleavage occurs to give lactone as the major product. For α-bromocyclohexanone, this explanation is reasonable if we also proposethat the bromine is intramolecularly displaced by the amine once themacrocycle is formed, giving rise to 9. Importantly, the formation oflactones 3a,b require the intermediacy of B.In summary, we have devised a method for the synthesis of ring-expanded esters, amides, and their cyclic equivalents from ketones.Additionally, the choice of work-up conditions (NaHCO3 vs. KOH)permits moderate control of product outcome and reaction pathway.Application of this strategy to larger ring sizes and various α-substitutedketones is under current investigation, as this methodology provides ameans of obtaining products that may serve as possible amino acid andpeptidomimetic precursors.Acknowledgments: This work was supported by the National Instituteof Health (GM-07775). K.E. Frank and J.E. Forsee gratefullyacknowledge the Madison A. and Lila Self Fellowship Program for theirsupport. The authors thank Martha D. Morton for assistance with NMRstudies.References and Notes1. Hünig, S. Angew. Chem., Int. Ed. Engl. 1964, 3, 548-560.2. Gracias, V. J.; Milligan, G. L.; Aubé, J. . Am. Chem. Soc. 1995,117, 8047-8048.3. Gracias, V. J.; Milligan, G. L.; Aubé, J. . Org. Chem. 1996, 61,10-11.4. Gracias, V. J.; Frank, K. E.; Milligan, G. L.; Aubé, J. Tetrahedron1997, 53, 16241-16252.5. For the preparation of 1a and 1b, see: Badiang, J. G.; Aubé, J. J.Org. Chem. 1996, 61, 2484-2487.6. Representative experimental details. (a) Preparation of 2a and3a. Cycloheptanone (0.200 g, 1.78 mmol) and 1a (0.170 g, 1.96mmol) were stirred in CH2Cl2 (20 mL) at 0 °C for 20 min,whereupon 0.53 mL of BF3·OEt2 (0.612 g, 4.30 mmol) was addeddropwise. After stirring for 1 h, the solution was heated to refluxfor 48 h. After cooling, 15% aqueous KOH (10 mL) or saturatedaqueous NaHCO3 (10 mL) was added over 5 min, and theresulting mixture was stirred for 24 h. The reaction mixture wasthen extracted with CH2Cl2 (2x100 mL) and ether (3x100 mL).The organic extracts were combined, dried over MgSO4, andfiltered. Concentration and silica gel chromatography afforded 2aand 3a, respectively.For 2a: 205 mg of a white solid, 67% yield; mp 79-81 °C; 1HNMR (400 MHz, CDCl3) δ 1.56 (m, 4H), 1.68 (m, 2H), 1.81 (m,2H), 2.54 (t, J = 6.3 Hz, 2H), 3.53 (t, J = 5.3 Hz, 4H), 3.79 (m,2H), 3.86 (s, 1H); 13C NMR (75.6 MHz, CDCl3) δ 24.3, 26.2,28.6, 29.3, 34.0, 49.1, 50.0, 62.8, 177.4;  IR (neat) 3330, 2905,2820, 1610 cm-1; MS (EI) m/e  171 (M+), 153, 141, 55; HRMScalcd for C9H18NO2 (M++H): 172.1338, found 172.1325.For 3a: 134 mg of a crystalline solid, 43% yield; mp 81-82 °C; 1HNMR (400 MHz, CDCl3) δ 1.42-1.59 (m, 7H), 1.82 (m, 2H), 2.39N3N1. BF3•OEt22. Base+      base     yield (%) 6    yield (%) 7    yield (%) 8433509120KOHNaOHNaHCO36 7 80067+1bOHOOorOBrNOBrHONOHOOX NOXNOXHONXONOXOBF4mmAmBX = Br, m = 1X = H, m = 2At pH ~ 14m mHOOHHOHO*(attack at     )*H2ONOXHHONOOHBrNOONOXHOAt pH ~ 9mX = BrX = Hm = 2C m = 1mB9NOOHScheme 6Downloaded by: IP-Proxy University of Kansas Libraries - Watson Library, University of Kansas Libraries. Copyrighted material.1260 LETTERS SYNLETT(m, 2H), 2.68 (t, J = 4.4 Hz, 2H), 2.94 (t, J = 4.7 Hz, 2H), 4.22 (t,J = 4.8 Hz, 2H); 13C NMR (100.6 MHz, CDCl3) δ 24.7, 26.6,29.0, 29.8, 34.4, 49.6, 50.6, 63.3, 177.9; IR (CH2Cl2) 3340, 2920,1715 cm-1; MS (CI) m/e 172 (M++H); HRMS calcd forC9H18NO2 (M++H):172.1337 found 172.1348.(b) Compound 8 was prepared as described above (NaHCO3method) except reaction was run at room temperature: 148 mg ofan oil, 67% yield; 1H NMR (100.6 MHz, CDCl3) δ 1.47-1.90 (m,6H), 1.92-2.12 (m, 2H), 2.49 (dt, J = 11.7, 4.5 Hz, 1H), 2.71 (m,1H), 2.97 (ddd, J = 14.4, 11.7, 4.5 Hz, 1H), 3.13 (m, 1H), 3.63 (t,J = 4.2 Hz, 1H), 4.16 (ddd, J = 12.3, 9.3, 1.8 Hz, 1H), 4.49 (qq, J =12.0, 6.3 Hz, 1H); 13C NMR (100.6 MHz, CDCl3) δ 20.6, 25.9,26.7, 28.6, 50.5, 56.6, 62.6, 67.8, 174.9; IR (neat) 2925, 1720 cm-1; MS (CI) m/e 170 (M++H), 142, 124, 97, 83; HRMS calcd forC9H16NO2 (M++H): 170.1175, found 170.1181. 7. Deslongchamps, P. Stereoelectronic Effects in OrganicChemistry; 2 ed.; Pergamon Press: Oxford, 1983; Vol. 1, pp 101-162.Downloaded by: IP-Proxy University of Kansas Libraries - Watson Library, University of Kansas Libraries. Copyrighted material.

Reactions of Oxazolinium and Dihydrooxazinium Salts Prepared by an Azide Insertion Sequence: pH Control of Product Distribution

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Reactions of Oxazolinium and Dihydrooxazinium Salts Prepared by an Azide Insertion Sequence: pH Control of Product Distribution

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