Synthesis of Weinreb and their Derivatives (A Review)

Introduction

N-methoxy-N-methylamides or Weinreb amides become a worthy synthetic precursor in organic synthesis¹.The first synthesis of Weinreb moiety was reported in 1981²which performed via treatment of N,O-dimethyl hydroxylamine with AlMe₃ as a coupling reagent. Thereafter, several methods for Weinreb amide synthesis have been reported, like direct transformation of carboxyl group into the corresponding aldehyde or ketone. Exceptionally, the efficiency of Weinreb structure to subject a unique substitution reaction with excess of organometallic reagents in the laboratory and industrial synthesis processes ³.Weinreb structure reacts closely with organolithium⁴, Grignard reagents⁵, LiAlH₄⁶and Wittig reagents to produce aldehydes orketones⁷. Currently, much effort has been devoted to develop their soft and universal synthesis. Such, Weinreb amides can be synthesized from carboxylic acids⁸, acid chlorides⁹, amides¹⁰, esters¹¹, lactones¹², and anhydrides¹³.Due to the fast evolution of Weinreb amides synthesis and their applications in the last twenty years, it was interesting to review commonalty issue papers in the duration from 2001 to 2009 and detail several neoteric developments of these strategy processes.

In 2001, Giacomelli and co-workers¹⁴, described a flexible process for the synthesis of hydroxamates, Weinreb amides4 and hydroxamic acids (Scheme 1). The procedure is used coupling agents like triazine derivatives, carboxylic acids and N-protected amino acids  as reactants for preparation of N-methoxy-N-methyl amides (Weinreb amides). However, the organic compound like hydroxamic acids can be formed from the transformation of hydroxamates and Weinreb amides as O-benzyl and O-silyl hydroxamates. In addition, handling of reactant for example carboxylic acid 1 with 2-chloro-4,6-dimethoxy-triazine (CDMT) 2 and N-methylmorpholine (NMM) in THF. Subsequently, treatment with N,O-dimethylhydroxylamine 3, yields the desired N-methoxy-N-methylamide products 4(Weinreb amide and O-benzyl- or tert-butyldiphenylsilyl hydroxylamine for hydroxamates).

Scheme 1: Synthesis of  Weinreb amides4 and hydroxamic acids  Click here to View Scheme

While, Fehrentz and co-workers ¹⁵ detailed a facile synthesis of lipopeptides via using Weinreb (N-methoxy,N-methyl) amide as an aldehyde function precursor on the side chains of Asp or Glu residues(Scheme 2). The reducing of amide 5 by LiAlH₄ produce the reactive aldehyde function 6. Subsequently, the latter can undergo reaction with yilde 7to form unsaturated or saturated side8 chains or with various nucleophiles to yield non-coded amino acid residues incorporated into the sequence. Lastly, racemization by enol formation cannot take place when aldehyde function is formed in position of γ or δ. This condition is not like form of α-amino aldehydes.

Scheme 2 Click here to View Scheme

In parallel, Jeong group¹⁶ reported a novel approach to the synthesis of β-trifluoromethyl enaminones with good yields (Scheme 3). Here, the protocol focused on the treatment of N-methoxy-N-methylbenzamide10 (1.0 eq.) with trifluoropropynyl9 (4.0 eq.)at -78°C with cooling of water and warming to 0°C, followed by quenching with H₂O in the presence of a variety of amines 11. Furthermore, using of hydrazine or benzamidine as an amine source in this reaction, afforded the expected pyrazole or pyrimidine products.

Scheme 3 Click here to View Scheme

Furthermore, Lete and co-workers¹⁷revealed the efficient role of N-(O-iodobenzyl)-pyrrole-2-carboxyamides as internal electrophiles induced proximity effect (CIPE)in Parham-type cyclization reactions, allowing the efficient construction of the indolizinone nucleus(Scheme 4).So, Li-iodine exchange 14i could be selected firstly due to the coordination between organolithium and amide group and secondly the stabilization of the aryllithium moiety. Under reaction condition, Weinreb amides 13have also been successful applied as internal electrophiles in cyclization reactions of organo-lithiums educed from alkyliodides and accessing cyclic ketones 14. Furthermore, this cyclization process, delivered the effective build of the fused pyrrolo[1,2-b]isoquinolines, thieno-[2,3-f]indolizinones, and pyrrolo[1,2-b]acridinones in high yields. This protocol has also been widespread to heteroaryllithums, allowing a flexible direction to heterocyclic frameworks with prospective pharmacological features that could compete with previously reported strategies.

Scheme 4 Click here to View Scheme

Independently, Lee and co-worker¹⁸  illustrated the synthesis of  various enantiomericallypure 2-acylaziridinederivatives(Scheme 5). Generally, this method started firstly through reaction between N,O-dimethylhydroxylamine hydrochloride 16 and readily available N-[(R)-(+)-α-methylbenzyl]-2(S)-aziridinecarboxylic acid menthol ester 15 using AlMe₃as a coupling reagent in DCM affords the Weinreb’s amide 17 in excellent yields. Furthermore, the latter was then  reacted with different organometallic reagents 18 to provide the expected ketone products 19 with higher yields. Applying this protocol, (1R,2S)-N-Boc-norephedrine, N-Boc-safingol, N-Boc-D-erythro-sphinganine, and N-Boc-spisulosine have been prepared in high yields.

Scheme  5 Click here to View Scheme

In 2004, Fehrentz and co-workers¹⁹described the synthesis of α-amino aldehydes linked to the support by their amine function(Scheme 6). This method was completed by reduction with LiAlH₄ of the corresponding Weinreb amide linked to the resin. The aldehydes procured were then implicated in Wittig or reductive amination processes. Moreover, the two-step methods, including the conversion of N-protected α-amino acids 21to the corresponding Weinreb amides 22then reduction by LiAlH₄, is an effective process for the synthesis of N-protected α-amino aldehyde23.

Scheme 6 Click here to View Scheme

Furthermore, kunishima and co-workers²⁰illustrated the synthesis of Weinreb amides through the reaction of carboxylic acids with N,O-dimethylhydroxylamine hydrochloride in the presence of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) in different solvents such as alcohols and acetonitrile, that can dissolve DMT-MM(Scheme 7). In this context, the preparation of Weinreb amides was doneby converting carboxylic acids 24to the desired Weinreb amide products26in higher yields by easily combined with DMT-MM and N,O-dimethylhydroxylamine hydrochloride substrates25.

Scheme 7  Click here to View Scheme

Later, Jeong and co-workers²¹declared amodern and efficient method for the synthesis of β-trifluoromethylated enone derivatives via reaction of Weinreb amides with trifluoropropynyl lithium, then treated with H₂O in the mediation of amine derivatives (Scheme 8). Essentially, this method afforded stereo-selectively β-trifiuoromethylated enaminones with very good yields. The latter was reacted with satirically less hindered amine derivatives to produce amine products with high stereo specifically. In addition, the reaction mixture  of N-methoxy-N-methylbenzamide 28(1 eq.) and trifluoropropynyl lithium 27(2 eq.) at -78 ᵒC then 0 ᵒC, followed by addition of H₂O in the mediation of amine derivatives29, β-trifiuoromethylated enaminone products30  were resulted with perfect stereo-specifically.

Scheme 8 Click here to View Scheme

Moreover, Franck and co-workers²²examined the cycloaddition of Weinreb amide bearing nitrile oxide/nitrones  functional groups with a scope of dipolarophiles (Scheme 9).However,  there are two synthetic route options for the synthesis of Weinreb amide nitrile oxide 39and nitrones41. Firstly, Weinreb amide nitrile oxide 39was prepared by reaction of trans-cinnamic acid 31in two procedures. Cinnamic acids33 is displayed to ozonolysis to give the expected compound separated as the mixture of aldehyde 33 and its hemiacetal, in methanol as a co-solvent for this process. This mixture of the expected products, anyway, was simplyisolated from benzaldehyde through flash chromatography. Handling of aldehyde34 with hydroxylamine hydrochloride 35gave with quantitative yield of the crude Weinreb amide-oxime 36. The latter38can be transformed to nitrile oxide39through the classical chlorination method in the presence ofNCS37thenelimination of HCl usesEt₃N(Synthetic Option 1). Subsequently, the Weinreb amide-nitrone 41was prepared by reaction between Weinreb aldehyde 34andN-benzyl hydroxylamine hydrochloride40.The crude nitrone 41was directly used in the cycloaddition process without additional purification(Synthetic Option 2).

Scheme 9 Click here to View Scheme

While Dake and co-workers²³ described an appropriate strategy for the transformation of bulky carboxylic acids 42to N-methoxy-N-methylamides45. Therefore, this transformation can be efficiently completed with of methanesulfonyl chloride43(1.1 eq.),  triethylamine (3 eq.), and N-methoxy-N-methylamine44(1.1 eq.) (Scheme 10).The percentage yields for this process range  were up to88%. Remarkable, removal of, N-methoxy-N-methylmethanesulfonamide  as the major byproduct in such reactions, was done by set it under vacuum for overnight.Furthermore, this process was necessaryfor dissolving their individual synthetic problem, and could demonstrate valuable for other practitioners of organic chemistry.

Figure 10  Click here to View Scheme

In 2005, Lee and co-workers²⁴provided a novel preparation of N-methoxy-N-methylamides through the reaction ofS-2-Pyridyl Thiocarbamate with Grignard reagents (Scheme 11). The authors suggested to prepare N-methoxy-N-methylamides 50in the convenience of one step operation, and also can be recently made through the reaction of S-2-pyridyl Thiocarbamate 48with Grignard reagents 49under mild conditions. Subsequently, preparation of S-2-Pyridyl Thiocarbamate 48throughreaction ofN,O-dimethylhydroxylamine hydrochloride 47withS,S-di(2-pyridyl) dithiocarbonate 46 in the presence of triethylaminein DCM at 0 ^oC, However, the successful synthesis of N-methoxy-N-methylamides 50using S-2-PyridylThiocarbamate reliesbroadly on the selective of 2-thiopyridyl group in the substitution reaction.

Scheme 11  Click here to View Scheme

Later, Davis and co-workers²⁵reported innovative strategy for the preparation of N-Sulfinylβ-Amino carbonyl compounds (Scheme 12). Here, an inclusive methodology protocol has been submitted by the addition of the potassium enolate of N-methoxy-N-methylacetamide 52to sulfinimines 51or by handling N-sulfinyl β-amino esters 53with lithium N,O-dimethylhydroxyamine54,produce the related N-sulfinyl β-amino Weinreb amide products with high diastereo selectivity. This new method reveal as a common resolution to the problem of β-amino carbonyl compounds 57synthesis, via reaction with different organometallic compounds56which are significantly moieties and ingredients of natural products. Additionally, this methodology performed a universal solution to the matter of β-amino carbonyl syntheses, which are remarkable chiral frameworks and components of natural products.

Scheme 12 Click here to View Scheme

Murphy and co-workers²⁶demonstrated the direct transformation of Weinreb Amides(N-methoxy-N-methylamides) to the related ketones through unusual Wittig reaction (Scheme 13). Moreover, this reaction proceeds through treatment of N-methoxy-N-methylamides58 with alkylidenetriphenylphosphoranes 59,followed by one-pothydrolysis of the intermediate to produce the corresponding ketone products 60.Furthermore, this conversion takes place in a way which prevent the quite reactivity of organometallic reagents. Finally, the reaction conditions were considerably reasonable than the transformation route in the presence of organometallic reagents. In addition Its chemo selectivity is mostly observed in the pure conversions of cyano- or halo-substituted substrates.

Scheme 13 Click here to View Scheme

Moreover, Conrad and co-workers²⁷, revealed An effective one-pot method for α-amino ketone 63synthesis through the arylation of Weinreb amides whereas retaining chirality of the main amide(Scheme 14). Actually, this reaction improved quietness when i-PrMgCl (2.5 eq.) was straightway added into the solution of Weinreb amide61 and 3,5-bis (trifluoromethylbromobenzene 62at 10 °C. The method, distinctly proves that the Knochel magnesiztions are kinetically going slower than deprotonating comparing to organolithium transmetallations.

Scheme 14 Click here to View Scheme

In 2006, Pelkey and co-workers²⁸have reported a functional synthetic path to 3,4-disubstituted pyrrole-2-carboxaldehydes  and 3-pyrrolin-2-ones  starting from Pyrrole Weinreb Amides (Scheme 15). Here, aregion-controlled preparation of 3,4-disubstituted pyrrole-2-carboxaldehydes was achieved over two main steps using acyclic substrates. (i) Barton-Zard pyrrole method through reaction betweenN-methoxy-N-methyl-2-isocyanoacetamide 66and β-nitroacetates64orα-nitroalkenes65, providing pyrrole Weinreb amides67; (ii) reduction reaction step of pyrrole-2-carboxaldehydes68; and (iii) the regioselective oxidation step of 3-pyrrolin-2-ones69. Remarkably, this method licensed to the preparation of non-syn metrical pyrrole-2-carboxaldehydes68 and 3-pyrrolin-2-ones 69with estimate to substituent’sexisting in the α-positions, and this could demonstrate helpful for the synthesis of oligopyrrole compounds.

Scheme 15  Click here to View Scheme

In parallel  John A. Murphy and co-workers²⁹detailed the efficient transformation of Weinreb amides of formic acid to aldehyde products 72under Wittig reaction conditions (Scheme 16). Under the optimal reaction conditions, treatment of phosphorus on the Weinreb amide of formic acid 70with organometallics like organolithium or Grignard reagents69. The qualification of this method is imputed to the stability of tetrahedral intermediate, that does not undergo fragmentation to the expected aldehyde product 72until work-up.

Scheme 16 Click here to View Scheme

Furthermore, Buchwald and co-workers³⁰developed the efficient protocol for the synthesis of Weinreb amides through Pd-catalyzed aminocarbonylation of aryl bromide substrates at atmospheric pressure(Scheme 17). The reaction is the transformation of aryl bromides 73to the corresponding Weinreb amide products76under 1 atm. of CO75 and catalytic conditions. A wide range of functional groups, including electron-deficient, -neutral, and -rich aryl bromides 72were tested and shown their effectiveness transformation to the desired products76.

Scheme 17  Click here to View Scheme

Meanwhile, Collum and co-workers³¹described acylation mechanism of Weinreb amide with Lithium phenylacetylide (Scheme 18). The protocol here described the reaction of dimeric lithium acetylide via a mono solvated monomer-based transition structure. The sturdy tetrahedral intermediate stylesconsecutive a C1 2:2 mixed tetramer in the presence of excess lithium acetylide 78and a 1:3 (alkoxide-rich) mixed tetramer. The stabilization of the mixed tetramers iscompatible with a declared auto inhibition. In addition, the tetrahedral intermediate reacts with lithium phenylacetylide (PhCCLi) 78in the presence of Weinreb amide 77as a reagent to form ketone compound derivative79.

Scheme 18  Click here to View Scheme

Independently, John Nielsen and co-workers³²detailed the preparation of (E)-N-methoxy-N-methyl-β-enaminoketoesters and also novel synthetic pioneers for the region-selective synthesis of heterocyclics(Scheme 19). First, Weinreb amides 81treat with the Li- or Na- acetylide of ethyl propynoate 80in a hitherto acyl substitution−conjugate addition series to produce (E)-N-methoxy-N-methyl-β-enaminoketoesters82, second, this protocol affords a variety access to violently functionalized heterocyclics, inclusive pyrazoles 84through region-selective cyclo-condensations with hydrazine compounds83applying microwave-assisted reaction.

Scheme 19  Click here to View Scheme

In 2007, Davis and co-workers³³reported the asymmetric preparation of syn–α-substituted β-amino acidsthrough a reaction of  pro-chiral lithium enolates of Weinreb amides and sulfinimines (N-sulfinyl imines)(Scheme 20). The protocol here first focused on the reaction of sulfinimine-derived α-substituted β-amino Weinreb amide with organometallic compounds. While the direct synthesis of major α-substituted β-amino Weinreb amide products 87 proceeded through the addition of a prochiral Weinreb amide enolate 86to a sulfinimine 85. Moreover, the sulfinimine-derived chiral building blocks are considered as significant pioneers of syn–α-substituted β-amino acid derivatives, through hydrolysis, reduction, and reaction with Grignard reagents, individually.

Scheme 20 Click here to View Scheme

Though, Kim and co-workers³⁴suggested a novel and effective procedure for the transformation of different carboxylic acids to their analogical Weinreb amides employing  triphosgene as an acid activator (Scheme 21). This reaction encompasses the treatment of carboxylic acid 89with triphosgene 90to give an acid chloride or anhydride, followed by handling with N,O-dimethylhydroxylamine 91to produce the expected Weinreb amide92. The current method afforded high yields, short reaction time, and workable accessibility.

Scheme 21 Click here to View Scheme

While, Jeong and his group³⁵reported dynamic one-pot preparation of unusual α, β-dichloro-β-trifluoromethylated enones (Scheme 22). The stages of protocol start with the  reaction of Weinreb benzamides 94 and trifluoropropynyllithium 93in THF at -78 to 0 °C, followed by handling with trifluoromethanesulfonyl chloride 95to produce α, β-dichloro-β-trifluoromethylated enones 96 in moderate yields. While the reaction of α, β-dichloro-β-trifluoromethylated enones96with substitute amidines 98or hydrazinereagents102in reflux mixture of 1,4-dioxane/CH₃CN produced trifluoromethylated chloropyrimidines  99 and chloropyrazoles  103 in acceptable yields. Furthermore, the coupling reactions of trifluoromethylated chloropyrimidines 99 with substituted phenylstannane and allylstannane 100in CH₃CN using Pd(PPh₃)₄catalyst under microwave-assisted conditions, provided the desired phenyl and allyl substituted pyrimidine products101in very good yields. While the same conditions were applied with chloropyrazoles103, but did not lead to the product 104.

Scheme 22  Click here to View Scheme

In 2008, Prandi and co-workers³⁶described the preparation of newfangled species of heterocyclic Weinreb amides through aminocarbonylation reaction of heterocyclic-derived triflates in the presence of Pd catalyst (Scheme 23).This reaction proceeded through the straight forward conversion of lactone-, thiolactone and lactam-derived triflates 105into the corresponding morpholineor N-methoxy-N-methyl Weinreb amides 107. The protocol  here suggested to proceed through using CO 75 under mild conditions. However, the amides steadily reacted with nucleophiles 108to yieldthe desired heterocycle products109. This new protocol discloses the outlet to important dynamically heterocyclic scopes that are favorable as building blocks in total syntheses, and the suggested methodology could be convenient profit for the dienone synthesis, as helpful moieties for Nazarov cyclization.

Scheme 23  Click here to View Scheme

Next, Somfai and co-workers³⁷ reported an efficient and diastereoselective synthesis of aryl glycines 112from Weinreb amides employing α-arylation process(Scheme 24). In such reaction, a novel α-arylation reaction proceeds smoothly through the reaction between amideas electrophile110andaryl Grignard reagents as nucleophile111in the presence of LDA as a base in THF at low temperature. The mechanism of this reaction starts with deprotonating and the generation of enolate, followed by elimination ^tBuO. While the nucleophilic addition of the Grignard reagent to form amide.

Scheme 24  Click here to View Scheme

Recently, Li and co-workers³⁸, described the synthesis of diverse chiral N-phosphonyl β-amino Weinreb amides 115viareaction of chiral N-phosphonyl imines 113with the lithium enolate of N-methoxy-N-methylacetamide114employing  mild conditions(Scheme 25). Generally, the deprotonation base and presence of protection groups on chiral N-phosphonyl imines were the pivotal success of such reactions. Commonly, N-phosphonyl imines uses as electrophiles 113 for some nucleophilic addition reactions, like aza-Darzens, aza-Henry reaction, and allylmagnesium bromide based addition, various wide of Weinreb amides were prepared in excellent yields (up to98%) with high diastereoselectivities. Furthermore, the ultimate structures were uniquely specified by the transformation the products into original samples and equal their optical rotation assessments.

Scheme 25  Click here to View Scheme

Meanwhile, Huet al³⁹reported a wonderful reagent, P[NCH₃(OCH₃)]₃, for the direct synthesis of  Weinreb amides 120from carboxylic acids 119(Scheme 26).So firstly, treatment N,O-dimethylhydroxylaminehydrochloride 116 withPCl₃116in Et₂O uses triethylamine as a base to give P[NCH₃(OCH₃)]₃118in 67% yield. Secondly, P[NCH₃(OCH₃)]₃118can be utilized for the conversion of various kinds ofcarboxylic acids includedaliphatic, aromatic, stericallyhindered, and dioic acids in toluene into the expected Weinrebamide products in excellent yields employing soft conditions.

Scheme 26  Click here to View Scheme

Conclusion

Newly, assorted investigations have itemized the utilization of Weinreb amide developments as an awesome intermediate in natural blend reaction. In this sheet, we displayed this side of the written works,  including an abnormal preparation of Weinreb amides and their employments by explaining convention instances of these procedures. Besides, this paper contains a definitive finish of the specialists and conveniently outfits reaction data for the exceedingly significant reaction and numerous indications to the regional literature.

Acknowlegement

We acknowledge the University of Zakho, Faculty of Science, Department of Chemistry for providing all the facilities.

References

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