View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by University of Richmond University of Richmond UR Scholarship Repository Chemistry Faculty Publications Chemistry 9-12-2011 Synthesis of N-Acyl-N,O-Acetals from N-Aryl Amides and Acetals in the Presence of TMSOTf C. Wade Downey University of Richmond, [email protected] Alan S. Fleisher James T. Rague Chelsea L. Safran Megan E. Venable See next page for additional authors Follow this and additional works at: http://scholarship.richmond.edu/chemistry-faculty- publications Part of the Organic Chemistry Commons This is a pre-publication author manuscript of the final, published article. Recommended Citation Downey, C. Wade; Fleisher, Alan S.; Rague, James T.; Safran, Chelsea L.; Venable, Megan E.; and Pike, Robert D., "Synthesis of N- Acyl-N,O-Acetals from N-Aryl Amides and Acetals in the Presence of TMSOTf" (2011). Chemistry Faculty Publications. 12. http://scholarship.richmond.edu/chemistry-faculty-publications/12 This Post-print Article is brought to you for free and open access by the Chemistry at UR Scholarship Repository. It has been accepted for inclusion in Chemistry Faculty Publications by an authorized administrator of UR Scholarship Repository. For more information, please contact [email protected]. Authors C. Wade Downey, Alan S. Fleisher, James T. Rague, Chelsea L. Safran, Megan E. Venable, and Robert D. Pike This post-print article is available at UR Scholarship Repository: http://scholarship.richmond.edu/chemistry-faculty-publications/12 Synthesis of N-Acyl-N,O-Acetals from N-Aryl Amides and Acetals in the Presence of TMSOTf C. Wade Downey,a, * Alan S. Fleisher, a James T. Rague, a Chelsea L. Safran, a Megan E. Venable, a and Robert D. Pike b aDepartment of Chemistry, University of Richmond, Richmond, VA 23173, USA bDepartment of Chemistry, The College of William & Mary, Williamsburg, VA 23187, USA R R MeO OMe TMSOTf (1.45 equiv) OMe R" N R" H R3N (1.4 equiv) CH2Cl2, 0 °C R' N(H)R' Abstract Secondary amides undergo in situ silyl imidate formation mediated by TMSOTf and an amine base, followed by addition to acetal acceptors to provide N-acyl-N,O-acetals in good yields. An analogous, high-yielding reaction is observed with 2-mercaptothiazoline as the silyl imidate precursor. Competing reduction of the acetal to the corresponding methyl ether via transfer hydrogenation can be circumvented by the replacement of i-Pr 2NEt with 2,6-lutidine under otherwise identical reaction conditions. Keywords : N,O-acetal; silyl triflate; silyl trifluoromethanesulfonate; silyl imidate. * Corresponding author. Fax: +1 804 287 1897; email: [email protected] Addition of nucleophiles to N-acyliminium ions is a Given the importance of N-acyliminium ions, we chose proven method for the construction of substituted amines. 1 to pursue optimization of this N,O-acetal formation Iminium ions derived in situ from N,O-acetals are popular reaction. Replacement of i-Pr 2NEt with Cy 2NMe provided electrophiles, and are often used in conjunction with improved and more reproducible product yields. A slight Mannich reactions to yield β-amino carbonyl compounds 2 excess of TMSOTf (1.45 equiv) relative to acetal (1.4 and organometallic additions to yield substituted alkyl equiv) was used to ensure that a catalytic amount of amines, 3 among other reactions. 4 The N-acyl-N,O-acetal silylating agent remained in solution even after full functionality is also a key component of important natural conversion of the acetal to the oxocarbenium ion. After products like zampanolide 5 and psymberin. 6 Accordingly, a conversion to products was complete, the unpurified convenient synthesis of N-acyl-N,O-acetals from readily reaction mixture was quenched with pyridine in order to available starting materials would provide access to a class sequester any remaining TMSOTf, which otherwise of compounds that may easily act as acyliminium ion facilitated product decomposition during purification on precursors. 7 We now report that N-aryl amides can be silica gel. N-alkoxyalkylated with acetals in the presence of A reasonable mechanism for this one-pot silyl imidate trimethylsilyl trifluoromethanesulfonate (TMSOTf) and a formation-N,O-acetal formation reaction appears in Figure trialkylamine base, providing N-acyl-N,O-acetals in good 1. Deprotonation of the TMSOTf-activated secondary yield. amide with a trialkylamine rapidly generates a silyl In the course of our study of the Mukaiyama aldol imidate, a process that appears to be rapid and quantitative reaction, 8 we examined the addition of in situ-generated by 1H NMR spectroscopy. Reaction of the acetal substrate silyl ketene acetals to dimethyl acetals, including with TMSOTf provides the oxocarbenium electrophile, nucleophiles derived from tertiary amides (eq 1). 9 When which is attacked by the silyl imidate through a the tertiary amide was replaced with a secondary amide, Mukaiyama aldol-like addition. Silyl transfer to another however, methoxyalkylation was observed at the amide acetal provides the final product and generates another nitrogen rather than at the α carbon (eq 2). High oxocarbenium ion, completing the reaction cycle. conversion to the N,O-acetal occurred with only a trace of aldol-type adduct formation. TMSOTf O O OMe MeO OMe i-Pr NEt 2 (1) Ph2N Me H Ph Ph2N Ph CH2Cl2 80% yield O TMSOTf O MeO OMe i-Pr2NEt PhN Me PhN Me (2) H Me CH Cl H 2 2 MeO Me 77% conv O aStandard reaction conditions: amide (1.00 mmol), acetal (1.40 mmol), MeO OMe TMSOTf (1.45 mmol), Cy 2NMe (1.40 mmol), CH 2Cl 2 (5 mL), 0 °C, 2 h. Me NAr bIsolated yield after chromatography. H R H TMSOTf Similar or better reactivity was observed when R3N benzaldehyde dimethyl acetal was employed as the TMSOTf TMSOMe electrophile (Table 2). Whereas the oxocarbenium ion Me derived in situ from acetaldehyde dimethyl acetal was OTMS O O OMe R3NH potentially susceptible to deprotonation to yield an enol TfO Me NAr H R Me N R ether, potentially instigating byproduct formation and loss Ar in yield, the benzaldehyde derivative is not acidic. This TMSOMe observation may explain why acetaldehyde dimethyl acetal was an inferior reaction partner with acetanilide (Table 1, entry 1), but benzaldehyde dimethyl acetal reacted quite MeO OMe efficiently, providing an isolated yield of 74% (Table 2, TMS H R entry 1). Propionanilide displayed a similar increase in O OMe yield with benzaldehyde dimethyl acetal (89% vs. 65%, Me N R entry 2). The other anilides investigated reacted similarly Ar well (entries 3-6). Figure 1. Proposed Mechanistic Scheme Table 2. Addition of various anilides to benzaldehyde dimethyl The scope of the secondary amide reaction partner was acetal a determined through reaction with two representative R acetals. A survey of condensations with acetaldehyde R dimethyl acetal is summarized in Table 1. Various anilides MeO OMe TMSOTf (1.45 equiv) OMe performed well, including both electron-rich and electron- H Ph N Ph poor secondary amides. The poor reactivity displayed by Cy2NMe (1.4 equiv) CH Cl , 0 °C R' acetanilide itself (entry 1) remains unexplained, but N(H)R' 2 2 replacement of the acetyl group with other acyl groups b (propionyl, benzoyl, cinnamoyl) provided good yields of entry amide product yield (%) the N,O-acetal. To date, amide nucleophiles appear to be 1 X X = H 7 74 limited to N-aryl secondary amides. Other silyl imidate O precursors displayed no reactivity ( N-alkyl) or provided 2 X = OMe 8 73 N Me complex mixtures of unidentified products ( N-allyl, H 9 3 X = NO2 69 N-benzyl). O 4 Ph 10 89 Table 1. Condensation of various anilides with acetaldehyde N Et a H dimethyl acetal O 5 Ph 11 76 R N Ph R H TMSOTf (1.45 equiv) OMe MeO OMe O 12 93 N Me 6 Ph H Me Cy2NMe (1.4 equiv) N Ph R' H R' CH2Cl2, 0 °C N(H) aStandard reaction conditions: amide (1.00 mmol), acetal (1.40 mmol), b TMSOTf (1.45 mmol), Cy 2NMe (1.40 mmol), CH 2Cl 2 (5 mL), 0 °C, 2 h. entry amide product yield (%) bIsolated yield after chromatography. 1 X X = H 1 41 The representative N-aryl amide p-methoxyacetanilide O was chosen for a survey of various acetals under our 2 X = OMe 2 68 N Me optimized reaction conditions (Table 3). For some H 3 3 X = NO2 65 substrates, the use of Cy 2NMe resulted in the competitive O reduction of the acetals to the corresponding aryl methyl 4 Ph 4 65 N Et ethers (vide infra), so 2,6-lutidine was employed as a H surrogate. Under the appropriate reaction conditions, O acetals derived from aromatic or heteroaromatic aldehydes 5 Ph 5 88 N Ph generally performed well (entries 3-7). Yields were lower H for aliphatic acceptors (entries 1-2), presumably because of O 6 competing enol ether formation via deprotonation of the 6 Ph 93 N Ph oxocarbenium ion. H Table 3. Condensation of p-methoxyacetanilide with various hydride donor, similar reduction to the methyl ether was a dimethyl acetals observed. OMe MeO Me O MeO OMe TMSOTf (1.45 equiv) OMe H R N R H R Me Me Cy2NMe (1.4 equiv) O Ac H Et N(H)Ac CH2Cl2, 0 °C N Me Et H R N Me H i-Pr Me entry R product yield (%)b i-Pr Figure 2. Reduction of oxocarbenium ion by i-Pr 2NEt 1 Me 2 68 Noyori has reported that TMSOTf catalyzes the Et 13 52 10 2 reduction of dimethyl acetals with silanes. We attempted 3 X = H 8 73 X to optimize a similar reaction with i-Pr 2NEt as the hydride 4 X = Br 14 99c source, as summarized in Table 4.