PSEUDOEPHEDRINE 1 Pseudoephedrine product, which is easily removed by crystallization or flash col- umn chromatography. Because intramolecular O→N acyl trans- fer within pseudoephedrine β-amino esters occurs rapidly, and CH3 because the N-acyl form is strongly favored under neutral or ba- H sic conditions,3 products arising from (mono)acylation on oxygen N rather than nitrogen are not observed. OH CH3 Pseudoephedrine amides undergo efficient and highly diastere- oselective alkylation reactions with a wide range of alkyl halides as 1S,2S-(+) substrates (Table 2).2 Alkylation of pseudoephedrine amides is ac- [90-82-4] complished by dianion formation with lithium diisopropylamide InChI = 1/C10H15NO/c1-8(11-2)10(12)9-6-4-3-5-7-9/h3-8,10- (LDA) in tetrahydrofuran (THF) in the presence of lithium chlo- 12H,1-2H3/t8-,10+/m0/s1 ride (6 equiv), followed by the addition of an alkylating agent.4 InChIKey = KWGRBVOPPLSCSI-WCBMZHEXBE The use of lithium chloride leads to a substantial acceleration 1R,2R-(−) in the rate of alkylation and is essential for complete reaction. [321-97-1] C10H15ON (MW 165.24) In addition, O-alkylation of the secondary hydroxyl group of the InChI = 1/C10H15NO/c1-8(11-2)10(12)9-6-4-3-5-7-9/h3-8,10- pseudoephedrine auxiliary is suppressed in the presence of lithium 12H,1-2H3/t8-,10+/m1/s1 chloride. Although the specific role of lithium chloride in the reac- InChIKey = KWGRBVOPPLSCSI-SCZZXKLOBW tion is not known, there is ample precedent in the literature, notably in the work of Seebach and co-workers, documenting the benefi- (reagent used as a practical chiral auxiliary for asymmetric cial influence of lithium chloride in enolate alkylation reactions. synthesis) These studies suggest that lithium chloride modifies the aggrega- 5–8 Alternate Name: α-[1-(methylamino)ethyl] benzenemethanol; - tion state, and thereby the reactivity of an enolate in solution. ephedrine; isoephedrine. ◦ Table 2 Diastereoselective alkylation of pseudoephedrine amides Physical Data: mp 118–120 C. with alkyl halides Solubility: sparingly soluble in water, soluble in ether, alcohol, and many other organic solvents. CH3 O Form Supplied in: white crystalline solid; widely available. 1. LDA, LiCl, THF R Purity: recrystallization from water. N 2. R'X Handling, Storage, and Precaution: stable; combustible; incom- OH CH3 patible with strong oxidizing agents; eye, skin, and respiratory CH3 O −1 irritant; toxicity (oral) rat LD50: 660 mg kg . R N OH CH3 R' Asymmetric Alkylation. d-Pseudoephedrine ([1S,2S]-(+)) is R R'X Isolated de (%) Isolated yield (%) a commodity chemical employed in over-the-counter medications CH3 n-BuI ≥99 80 with annual worldwide production in excess of 300 metric tons. CH3 BOMBr 98 80 The enantiomer, l-pseudoephedrine, is also readily available in t-Bu BnBr ≥99 84 bulk and is inexpensive. Pseudoephedrine has been shown to be 2-Thiophene CH3I 95 88 highly effective as a chiral auxiliary in asymmetric alkylation reactions.1,2 Treatment of either enantiomer of pseudoephedrine A useful mnemonic for deriving the preferred diastereomer with carboxylic acid chlorides and anhydrides leads to efficient formed in the alkylation reaction of pseudoephedrine amide eno- and selective N-acylation to form the corresponding tertiary amide lates with alkyl halides is as follows: the alkyl halide enters from derivatives (Table 1).2 Typically, the only by-product in the acy- the same face as the methyl group of the pseudoephedrine auxil- lation reactions is a small amount (<5%) of the N,O-diacylated iary when the (putative) (Z)-enolate is drawn in a planar, extended conformation (eq 1).1 Table 1 Preparation of pseudoephedrine amides O 1. LDA, LiCl CH3 O CH3 CH3 O THF R R H X R N 2. R′X N N base OH CH3 OH CH3 OH CH3 (S, S)-pseudoephedrine R X Isolated yield (%) CH3 RCH2CO2 95 CH3 O 1, 4-syn (1) CH3 CH3O 89 R i-Pr Cl 92 N ′ 3-Pyridyl t-BuCO2 72 OH CH3 R Avoid Skin Contact with All Reagents 2 PSEUDOEPHEDRINE Table 3 Diastereoselcetive alkylation of pseudoephedrine amides β-branced electrophiles O O O CH 1. LDA, LiCl, THF R R ψ 3 ψ + ψ X 2. RI, 23 °C X X CH3 CH3 A B Xψ = pseudoephedrine auxiliary RI Product Ratio of A:B Isolated yield (%) O IPhXψ+ Ph 142:1 93 CH3 CH3 CH3 CH3 CH3 (matched) O IPhXψ– Ph 1:70 96 CH3 CH3 CH3 CH3 CH3 (mismatched) O IPhXψ+ Ph 66:1 93 CH3 CH3 CH3 CH3 CH3 (mismatched) O IPhXψ– Ph 1:199 94 CH3 CH3 CH3 CH3 CH3 (matched) The superior nucleophilicity and excellent thermal stability of Table 4 Diastereoselective alkylation of pseudoephedrine amides pseudoephedrine amide enolates make possible alkylation reac- with matched epoxides tions with substrates that are ordinarily unreactive with the cor- responding ester and imide-derived enolates, such as β-branched CH3 O primary alkyl iodides.2 Also, alkylation reactions of pseudoephe- R 1. LDA, LiCl N 2. O drine amide enolates with chiral β-branched primary alkyl iodides H proceed with high diastereoselectivity for both the matched and OH CH3 mismatched cases (Table 3).9 R′ Epoxides can also be used as substrates in pseudoephedrine amide enolate alkylation reactions, but react with opposite di- CH3 O R′ astereofacial selectivity (suggesting a change in mechanism, pro- N posed to involve delivery of the epoxide electrophile by coordina- OH CH3 ROH tion to a side-chain associated lithium ion), and are more limited in scope (Tables 4 and 5).10 1,3-syn A pictorial representation of the opposing diastereoselectivities R ′ Isolated de (%) Isolated yield (%) of alkyl halides and epoxides is shown in Figure 1.10 A similar R CH 93 88 electrophile dependence upon diastereoselectivity was first noted 3 CH3 CH 96 84 in the alkylation of prolinol amide enolates.11 3 CH2OTBS Bn ≥95 86 Although alkylation reactions of pseudoephedrine amide eno- C6H6 Bn CH OBn ≥95 87 lates are successful with a broad range of electrophiles, a few 2 problematic substrates have been identified. Among these are secondary alkyl halides, such as cyclohexyl bromide, and alkyl halides that are both β-branched and β-alkoxy substituted.2 However, there is evidence that the thermal stability of pseu- Compounds), amino (described in detail in the section Synthe- doephedrine amide enolates may be such that extended reaction sis of α-Amino Acids), and 2-pyridyl groups,2 undergo highly times at ambient temperature, or even heating, may be tolerated; diastereoselective alkylation reactions. However, to date, no gen- both approaches have led to successful alkylation reactions with eral solution has emerged for the diastereoselective alkylation of problematic electrophiles (eqs 2, 3, and 4).12,2,13 pseudoephedrine amides with an α-oxygenated substituent. Eno- Pseudoephedrine amides with a wide variety of α-substituents, lization of pseudoephedrine α-hydroxyacetamide with 3.2 equiv including aryl,1 branched alkyl,14 chloro,1,2 fluoro (described in of LDA furnishes a presumed trianion, with partial decomposition detail in the section Asymmetric Synthesis of Organofluorine of the starting material. Alkylation of the resulting enolate (1.65 A list of General Abbreviations appears on the front Endpapers PSEUDOEPHEDRINE 3 equiv) with benzyl bromide (limiting reagent) then produces the derivatives of α-hydroxyacetamide has been examined in a search corresponding C-benzylated product with 82% de (eq 5).2 for an alternative alkylation substrate [TBS, TBDPS, THP, Bn, BOM, Piv, and methyl(1-methoxyethyl)], none has provided satis- factory results nor offered any improvement over pseudoephedrine Table 5 Diastereoselective alkylation of pseudephedrine amides 2 with mismatched epoxides α-hydroxyacetamide itself. CH3 O CH3 O 1. LDA, LiCl, THF CH R 1. LDA, LiCl 3 N 2. OTBS N 2. O R′ OH CH3 I OH CH3 CH3 H 61% after 46 h at 45 °C CH3 O R′ CH O N 3 OTBS (3) OH CH3 ROH N 1,3-anti OH CH3 CH3 CH3 R R′ Isolated de (%) Isolated yield (%) 99% de CH3 CH3 73 86 CH3 O CH3 CH2OTBS 12 78 1. LDA, LiCl, THF Bn C H 46 72 6 6 N Bn 36 80 2. 2-Iodopropane CH2OBn 23 °C → reflux OH CH3 OCH3 52% O(CH2)3OCH3 Epoxides CH3 O N OH CH H OLi 3 Pr-i H OCH3 (4) H3C OLi > N 95% de O(CH2)3OCH3 CH H3C 3 H CH O 3 1. LDA, LiCl, THF OH N 2. BnBr 84% OH CH3 Alkyl Halides CH3 O OH (5) Figure 1 N OH CH3 Bn 82% de CH3 O 1. LDA, LiCl, THF CH3 α,β-Unsaturated pseudoephedrine amides undergo γ-deproton- N 2. OPMB ation when subjected to standard conditions for pseudoephedrine OH CH3 I CH3 amide enolate formation. The resulting enolate can be α-alkylated 68% after 3 d with high diastereoselectivity to provide β,γ-unsaturated alky- at 23 °C lated products (eq 6).15 CH3 OCH3 CH3 O 1. LDA, LiCl, THF OPMB (2) N N CH3 2. EtI OH CH 93% OH CH3 CH3 CH3 3 ~13:1 CH3 O The diastereoselectivity of the reaction is lower than that ob- N CH3 (6) tained in benzylations of pseudoephedrine amide enolates lacking OH CH3 the α-hydroxyl group. Although an extensive series of O-protected CH3 Avoid Skin Contact with All Reagents 4 PSEUDOEPHEDRINE Transformations of Alkylated Pseudoephedrine Amides. Addition of alkyllithium reagents to pseudoephedrine amides Alkylation products of pseudoephedrine amides are readily trans- leads to the formation of enantiomerically enriched ketones1,2,21 formed in a single operation into highly enantiomerically en- (eqs 9 and 10).19,20 The protocol developed to transform alkylated riched carboxylic acids, aldehydes, ketones, lactones or primary pseudoephedrine amides into ketones was optimized to avoid pre- alcohols.1,2 Alkylated pseudoephedrine amides can be hydrolyzed mature breakdown of the tetrahedral intermediate generated fol- under acidic or basic conditions to form carboxylic acids.