Enolizable Carbonyls and N,O‐Acetals: A Rational Approach for Room‐Temperature Lewis Superacid‐Catalyzed Direct α‐Amidoalkylation of Ketones and Aldehydes

Abstract

An efficient catalytic room-temperature direct α-amidoalkylation of carbonyl donors, that is, ketones and aldehydes with unbiased N,O-acetals, is described. Sn(NTf2 )4 is an optimal catalyst to promote this challenging transformation at low loading and the reaction shows promising scope. A comprehensive and rational evaluation of this reaction has led to the establishment of an empirical scale of nucleophilic reactivity for a broad set of ketones that should be helpful in the synthetic design and development of carbonyl α-functionalization methods.

1-Aminoalkylphosphonium Derivatives: Smart Synthetic Equivalents of N-Acyliminium-Type Cations, and Maybe Something More: A Review

“…α-Amidoalkylation reactions play an increasingly important role in organic synthesis as convenient and effective methods for the formation of C-C and C-heteroatom bonds, particularly of the intramolecular type, allowing the synthesis of carbo- or heterocyclic systems. In most cases, N -acylimine 2 or N -acyliminium cations 3 are the correct α-amidoalkylating agents and they are generated from precursors with the relevant structure 1 ( Scheme 1 ) [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ].…”

1-(N-Acylamino)alkyltriarylphosphonium Salts with Weakened Cα-P+ Bond Strength—Synthetic Applications

“…The presence of a positively charged nucleofugal phosphonium moiety in the close surroundings of the N -acyl group determines its unique chemical properties such as high reactivity in α-amidoalkylations [1,2,3,4,5,6,7,8,9,10]. This type of reactions has enjoyed unflagging interest for years as a synthetic method with great potential, especially valuable for C-C and C-heteroatom bond formation [1,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37]. …”

“…Of course, the reactivity of N -acyliminium cation 2 or N -acylimine 3 toward a nucleophile is also significant [1,2,3]. To produce the proper α-amidoalkylating agents, for instance N -acyliminium cation 2 or N -acylimine 3 from the most popular precursors such as α-amido sulfones (Z = SO 2 Ar), N -(1-benzotriazolil)alkylamides (Z = Bt), and N -(1-alkoxyalkyl)amides (Z = OR), it is necessary to use catalysts, mainly Lewis acids (route a , Scheme 1 (I)) [18,19,20,21,22,23,24,25,29,30,31,32,33,34,35,36,37]. In contrast, 1-( N -acylamino)alkyltriphenylphosphonium salts 1 (Z = Ph 3 P + X − ) do not require the use of acidic catalysts because of the permanent positive charge on the phosphonium group.…”

Novel Hybrid Prins/Aza‐Prins Oxocarbenium/N‐Acyliminium Cascade: Expedient Access to Complex Indolizidines

“…Our reactiond esign combines a Mukaiyama-Manniche ventt os et the keyo xocarbenium intermediate II, [6,7] along with first use of at ertiary enamide functionality [5,8,9] as the central dipolara lkene. [10] Upon generating an N-acyliminium ion III, [11,12] which is efficiently trapped by an enoxysilane in the terminatings tep of the catalytic cycle( Scheme 1, d), [13,14] the tertiaryenamide acts as the expected 1,2-dipole. [9] This Mukaiyama-Mannich-Prins cascade transformation operates through an uncommon multi-step catalytic cycle which reveals sequentially two N-acyliminium I and III and one silyloxycarbenium II intermediates, providing us with an unusual hybrid Prins/aza-Prins [15][16][17][18] approach(Scheme1,c and d).…”

“…In the context of ever-growing environmental concerns that stimulate the need for improved reaction sequences and synthetic strategies, we thusi magined to shorten and improve flexibility of our initial methodology by combining in ao nepot event the Mannich-Prins cyclisation cascade with the catalytic isomerization [28] of the readily available N-allyl N,O-acetals (Scheme 3). [12,24] Besides saving time, waste and cost, this would also establish an innovative chemical bi-catalytic development. [29] The efficient catalytic isomerization of N-allyl imides including the pillar phthalimide and succinimide representatives is well documented in the literature, [28] and it wasa lso exploited for the initial construction route of our aminal substrates (see Scheme 3).…”