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New dipeptide–dihydroquinolinone derivatives were successfully synthesised by benzotriazole mediated nucleophilic acyl substitution reaction and their structures were elucidated by spectroscopic and analytic techniques. The carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity of the new compounds was determined against four human (h) isoforms, hCA I, hCA II, hCA IX and hCA XII. While all compounds showed moderate to good in vitro CA inhibitory properties against hCA IX and hCA XII with inhibition constants in the micromolar level (37.7–86.8 and 2.0–8.6 µM, respectively), they did not show inhibitory activity against hCA I and hCA II up to 100 µM concentration. The antioxidant capacity of the peptide–dihydroquinolinone conjugates was determined using 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging method. Most of the synthesised compounds showed low antioxidant activities compared to the control antioxidant compounds BHA and α-tocopherol.

1. Formation of 1-O-acyl-β-d-glucuronide conjugates is a significant pathway in the metabolism of drugs containing a carboxylic acid group. The formation of acyl glucuronides results in an increase in both the aqueous solubility and molecular mass of the conjugate in comparison to the parent drug and thus facilitates excretion in both urine and bile. 2. Acyl glucuronides are effectively esters, which undergo first order decomposition by both hydrolysis and the intra-migration of the acyl group around the glucuronide ring to yield 2-, 3- and 4-O-glucuronic acid esters which, unlike the metabolically formed 1-O-acyl-β-d-glucuronides, are not substrates for β-glucuronidase. The first order degradation half-life is therefore a composite value of these two reactions and a useful indicator of chemical reactivity and potential toxicity. 3. Intra-molecular migration is expected to be the predominant pathway due to entropic considerations. 4. Such conjugates, together with their isomeric ester derivatives, react with nucleophilic sites on proteins and small endogenous molecules, such as glutathione, which potentially contributes to the observed toxicity and adverse drug reactions associated with some drugs. 5. Examination of the stability of the 1-O-acyl-β-d-glucuronides of aryl acetic acid, α-carbon substituted aryl acetic acid, aliphatic and aromatic acids, as determined by their first order degradation half-lives, indicates the significance of electronic and steric features that contribute to conjugate stability under physiological conditions. 6. Examination of the of the electronic properties of the carbonyl carbon atom in acyl glucuronides, as measured by the pKa of the parent acid, together with the steric substituents about the acyl carbonyl provides insight into the reactivity of these conjugates. 7. The investigations reported herein on a large number of 1-O-acyl-β-d-glucuronides has allowed rationalisation of their physicochemical properties in relation to the structure of the parent drug and has the potential to contribute to the design of carboxylic acid containing drug molecules with increased stability of a major metabolite with potential reduction in toxicity and adverse drug reactions.

Catalytic Tsuji-Trost allylation has become a ubiquitous method for allylation of active methylene compounds.[1] While monoallylation products are typically formed, bisallylation of malonates and related ketone enolates leads to 1,6-dienes.[2] Given the utility of these 1,6-heptadienes in metal-catalyzed cycloisomerization reactions,[3] it would be beneficial if one could perform controlled bisallylation of less stabilized carbon nucleophiles. Unfortunatly, the one-pot bisallylation of other carbon nucleophiles is not well documented and usually requires harsh reaction conditions.[4] Moreover, the addition of two different allyl electrophiles to form unsymmetric 1,6-dienes in a one-pot operation is exceedingly rare.[5] Herein, we describe the development of an unsymmetric bisallylation of carbon nucleophiles and introduce catalytic deacylative allylation as a new strategy for tandem in situ generation and coupling of nucleophiles with allyl electrophiles (eq. 1).1 (1) We initiated our pursuit of a 3-component catalytic bisallylation reaction with the investigation of the deacylative allylation of nitroalkanes. Palladium-catalyzed allylation of nitroalkanes is a well-known, albeit non-trivial, process.[6,7] For example, monoallylation of nitromethane and primary nitroalkanes is complicated by competing bisallylation, so excess nitroalkane is often required to achieve monoallylation.[6] To begin, it was expected that we could take advantage of the ease of Tsuji-Trost allylation of highly stabilized nitroacetone nucleophiles to form allylated nitroketones (eq. 2).[8] Ballini and others have shown that simple nitroalkanes can be generated by deacylation of related nitroacetone derivatives.[9,10] Indeed performing Tsuji-Trost reactions in the presence of methanol and base proceeded with deacylation to selectively afford the monoallylated nitroalkanes (eq. 2). Similar treatment of the cyclic nitroketones likewise provided clean monoallylated products containing a pendant ester (eq. 3). Thus, clean one-pot monoallylation of nitroalkanes is possible using a deacylative Tsuji-Trost reaction.[8,11] (2) (3) Like most other deacylative (retro-Claisen) reactions,[12] our monoallylation reactions simply use the acyl group as an activating group that can be readily removed. However, we hypothesized that an allyl alcohol could deacylate the intermediate α-nitroketone to generate a nitronate anion and simultaneously generate an allyl acetate electrophile (eq. 1). Such a process would allow selective 3-component bisallylation using nitroacetones, an allyl acetate or carbonate, and an allylic alcohol (Scheme 1). Because allyl alcohols are relatively nonreactive toward palladium catalysts, the nitroacetone is expected to undergo rapid, selective Tsuji-Trost allylation with the allylic acetate. The resulting product nitroketone can undergo further allylation only via a deacylative allylation protocol. Ultimately, it was anticipated that these kinetically distinct steps could be combined to afford a 3-component unsymmetric bisallylation reaction. Scheme 1 Proposed bisallylation via deacylative allylation. The proposed coupling hinged on the hypothesis that an allyl alcohol could decacylate an α-nitroketone to generate an allyl acetate and a nitronate anion in situ. To begin, a model allylated nitroacetone was synthesized via Tsuji-Trost allylation and treated under a variety of reaction conditons. We were pleased to find that various primary allyl alcohol derivatives participated in Pd(PPh3)4-catalyzed deacylative allylation when 1 equivalent of Cs2CO3 base was added (Table 1). The allylation worked well for 2-hexenol as well as for cinnamyl alcohol, providing the linear allylation products 2b and 2c respectively. However, the coupling of cinnamyl alcohol did require a higher palladium catalyst loading of 10 mol % to achieve high yield. The higher catalyst concentration promotes the desired C-allylation of the intermediate nitronate at the expense of problematic vinylogous Hass-Bender oxidation of cinnamyl acetate to cinnamaldehyde.[7b,13] When crotyl alcohol was the coupling partner, a decrease in linear to branched selectively (3.8:1) was observed (entry 5, Table 1). A similar drop in regioselectivity was noted in the decarboxylative allylation of nitroacetates with crotyl alcohol derivatives.7b While the primary alcohol derivatives provided products in good to excellent yields, the deacylative allylation appears to have a steric limitation as a secondary allylic alcohol provided the desired product in poor yield (entry 6, Table 1). Table 1 Deacylative allylation scope Having demonstrated the requisite deacylative allylation, we turned our attention to the 3-component bisallylation of an α-nitroketone. Indeed treatment of α-methyl nitroacetone with an allyl carbonate (or acetate) and allyl alcohol selectively produced the desired nitroalkyl 1,6-diene 2c in high yield (eq. 4). Importantly, attempts to make the same product directly from nitroethane gave rise to a complex mixture of allylated products. Thus, deacylative allylation provides a unique avenue to unsymmetrically substituted 1,6-dienes. (4) Since the allyl carbonate provided a higher yield than the allyl acetate (eq 5), subsequent exploration of the reaction scope focused on coupling of allyl carbonate derivatives (Table 2).[14] A comparison of 2c (derived from allyl alcohol) and 2c′ (derived from cinnamyl alcohol) suggests that the allyl carbonate and alcohol partners can be reversed with little or no change in yield. With regard to the nitroketone substrate, α-phenyl and alkyl ketones were viable coupling partners (e.g. 2g and 2h, Table 2). Notably, an α-substituent with a base sensitive methyl ester moiety survived the reaction conditions leading to the functionalized products 2i–k. Importantly, the fact that the methyl ester remains intact shows that acyl substitution of nitroacetones by allyl alcohols is more facile than acyl substitution of esters. Lastly, a cyclic α-nitroketone provides the ring-opened nitroalkane with a pendant carboxylic acid (eq. 5). The carboxylic acid could be obtained in good yield, however it was necessary to convert it to the methyl ester to effect complete purification. Table 2 3-component unsymmetric bisallylation (5) While the bisallylation reactions described above utilize secondary nitroketones, trisallylation of a primary nitroketone is possible using 2 equivalents of an allyl carbonate and 1.3 equivalents of allyl alcohol (eq. 6). Thus, deacylative allylation allows the selective synthesis of 2m from 4 reactant molecules via the formation of 3 new C–C bonds in 81% yield. (6) In addition to the deacylative allylations of nitroketones, preliminary studies suggest that deacylative allylation will also allow intermolecular allylations of activated ketones (Table 3). We and others have previously developed decarboxylative allylations of ketones which proceed via formation of ketone enolates via C–C cleavage.1c–f While these reactions have significant utility, their use is somewhat hampered by the need to incorporate the electrophile and nucleophile in the same molecular entity prior to decarboxylative coupling. The allylations in Table 3 suggest that deacylative allylation may allow similar reactions to take place in an intermolecular fashion. Finally, ketone substrates that participate in deacylative allylation also allow selective 3-component coupling to form unsymmetric heptadienes (eq. 7). Table 3 Deacylative allylation of nitrophenyl acac. (7) In closing, we have developed deacylative allylation as a synthetic strategy for directly utilizing inexpensive, readily available allyl alcohols in electrophilic allylation reactions. Not only does deacylative allylation allow selective monoallylation of nitronates, but it also can be used in tandem with Tsuji-Trost allylation of stabilized nitronates to allow controlled synthesis of unsymmetric 1,6-dienes via 3-component coupling. Precise control of the kinetics of the couplings obviates many possible side reactions (e.g. homoallylation, allylation of alkoxide intermediates), leading to a highly selective bisallylation. Similar strategies are expected to allow the selective multi-component allylations of a wide variety of acyl pronucleophiles using allyl alcohols.

Hyaluronic Acid (HA) is a non-sulphated glycosaminoglycan that, despite its high molecular weight, is soluble in water and is not resistant to enzymatic degradation, the latter of which hinders its wider application as a biomedical material. Auto-crosslinked polymer (ACP) gels of HA are fully biocompatible hydrogels that exhibit improved viscoelastic properties and prolonged in vivo residence times compared to the native polymer. Crosslinking is achieved through a base-catalysed reaction consisting of the activation of HA carboxyl groups by 2-chloro-1-methylpyridinium iodide (CMPI) and subsequent nucleophilic acyl substitution by the hydroxyl groups of HA in organic solvent. In this study, a number of ACP hydrogels have been obtained via reactions using varying ratios of CMPI to HA. The crosslinking reaction was monitored by rheological measurements in organic solvents during CMPI addition to the reaction mixture. The ACP intermediates, powders and hydrogels were characterized, helping to elucidate the crosslinking process. A two-step mechanism was proposed to explain the observed trends in viscosity and particle size. Syntheses were carried out by varying the reaction temperature, respectively at 0 °C, 25 °C and 45 °C in N-Methyl-2-Pyrrolidone (NMP), as well as the solvent respectively in NMP, DMSO and DMF at 25 °C. Interestingly, varying these parameters did not substantially affect the degree of crosslinking but likely did influence the intra/inter-molecular crosslinking ratio and, therefore, the viscoelastic properties. A wide range of crosslinking densities was confirmed through ESEM analysis. Finally, a comparative hyaluronidase degradation assay revealed that the ACPs exhibited a higher resistance toward enzymatic cleavage at low elastic modulus compared to other more chemically resistant, crosslinked HAs. These observations demonstrated the importance of crosslinking density of matrix structures on substrate availability.

The synthesis of hydantoins and dihydrouracils from ureidoacetamides has been carried out at high temperature in glycol solvents. A series of substrates were prepared and examined to determine the effect of substrate structure, N -acyl substitution (X), and solvent on the course of the reaction. A dramatic effect was observed when using ureidoacetamides (e.g., X= N -methyl- N -phenyl), which led to higher yields, faster reaction times, and lower racemization of chiral substrates. The rate of racemization of a chiral hydantoin in the presence of dibenzylamine and N -methyl aniline has also been determined. The thermal cyclization methodology has been applied to the preparation of a complex hydantoin.

A thorough analysis of the chemistry of vinylogous acyl triflates provides insight into important chemical processes and opens new directions in synthetic technology. Tandem nucleophilic addition/C-C bond cleaving fragmentation reactions of cyclic vinylogous acyl triflates 1 yield a variety of acyclic acetylenic compounds. Full details are disclosed herein. A wide array of nucleophiles, such as organolithium and Grignard reagents, lithium enolates and their analogues, hydride reagents, and lithium amides, are applied. The respective reactions produce ketones 2, 1,3-diketones and their analogues 3, alcohols 4, and amides 5. The present reactions are proposed to proceed through a 1,2-addition of the nucleophile to the carbonyl group of starting triflates 1 to form tetrahedral alkoxide intermediates C, followed by Grob-type fragmentation, which effects C-C bond cleavage to yield acyclic acetylenic compounds 2-5 and 7. The potent nucleofugacity of the triflate moiety is channeled through the sigma-bond framework of 1, providing direct access to the fragmentation pathway without denying other typical reactions of cyclic vinylogous esters. The synthetic versatility of vinylogous acyl triflates, including functionalization reactions of the cyclic enone core (1 --6 or 8), is also illustrated.

The enediyne moiety is a versatile functional group found in natural anticancer and anti-infective agents, undergoing the Bergman cyclization reaction to afford a diradical which cleaves double-stranded DNA. We have incorporated the enediyne group into 10- (4-10) and 12-membered ring (11) cyclic amino acids and dipeptides, respectively, and explored their relative reactivity toward cyclization, varying N-substitution in the case of the 10-membered ring substrate, which gave the expected cyclization products in good yields when using either thermal conditions in the presence or absence of microwave irradiation. The N-tosyl substituted derivative (4) was shown to nick double-stranded supercoiled DNA. N-Arylsulfonyl substitution on the ring promoted the cyclization, when compared to N-mesyl or acyl substitution, possibly because of a pi-pi stacking effect as an endo-relationship of the aryl group with the enediyne was demonstrated in both the solid state and in solution. The 12-membered ring enediyne dipeptide (11) was inert to the Bergman cyclization under a variety of conditions. When this substrate was irradiated with ultraviolet light, regio- and stereospecific reduction was observed in which one of the alkynes was reduced to a Z-olefin (47).

Alpha-chymotrypsin-catalyzed peptide synthesis was carried out between an N-protected D-amino acid ester and an L-amino acid amide (acyl donor, 10 mM; acyl acceptor, 50 mM; enzyme, 2 mg ml(-1); pH 8). By using a highly reactive carbamoylmethyl (Cam) ester as acyl donor, the D-amino acid was incorporated into the N-terminus of the resulting dipeptide amide. N-Protected dipeptide amides bearing D-amino acids such as D-Phe, D-Leu and D-Ala at their N-terminus were synthesized in high yields (up to 80%) in 1-3 h.

The dynamic kinetic resolution of secondary alcohols using a lipase and a ruthenium catalyst as developed by Backvall required some improvements to make it suitable for its use in an industrial process. The use of p-chlorophenyl acetate as acyl donor is not desirable in view of the toxicity of the side product. We herein report that simple alkyl esters can be used as acyl donors if the alcohol or ketone residue formed during the enzymatic acylation is continuously removed during the reaction. The addition of a ketone speeds up the racemisation process and allowed us to reduce the amounts of enzyme and ruthenium catalyst. The scope of this method was explored and a suitable range of acyl donors found. Various benzylic and aliphatic alcohols were reacted using isopropyl butyrate or methyl phenylacetate as acyl donor and in most cases the ester was isolated in >95% yield and 99% ee. Furthermore, it was demonstrated that the alcohol by-products of the enzymatic resolution could be used as the hydrogen source in the asymmetric reductive transesterification of ketones.

Reactions of N-arylsulfonyl(acyl)arenesulfenamide sodium salts with phenyl isothiocyanate afforded N-arylsulfanyl-N-arylsulfonyl(acyl)-N′-phenylthioura sodium salts which were found to increase thermal stability of finely dispersed poly(vinyl chloride).

Among the various kinds of acyl donors, the 1-alkoxyvinyl esters have characteristic features, such as a high reactivity under nearly neutral conditions and the generation of neutral and volatile esters as single coproducts. Although their use in organic syntheses began in the middle of the 1950s, no significant progress has been seen. This is probably because the existing method of preparing alkoxyvinyl esters used toxic mercuric salts and was not totally applicable for those esters having functionalized acyl moieties. We have discovered that the use of a catalytic amount of the less toxic [RuCl2(p-cymene)]2 effectively accelerates the addition of carboxylic acids to ethoxyacetylene to give ethoxyvinyl esters bearing a variety of functionalized acyl groups in high yields. This discovery has opened a new avenue for developing new reactions and new synthetic methodologies based on the design and use of these acyl donors with suitable functional groups. Such examples include (i) the installation of hydrophilic acyl moieties on biologically active compounds, (ii) asymmetric Pummerer-type reactions, (iii) aromatic Pummerer-type reactions, (iv) the lipase-catalyzed desymmetrization of symmetrical 1,3-diols, and (v) lipase-catalyzed domino reactions. Future possibilities for these acyl donors are also discussed.

Cyanuric chloride was loaded onto a modified Wang resin, which was successfully used to convert carboxylic acids to their corresponding acyl chlorides. The formation of acyl chlorides were confirmed by condensation with various amines or alcohols to form the corresponding amides or esters.

In this paper, we report a novel and efficient route for the synthesis of 5-nitrobenzoxazole derivatives starting from 2-fluoro-5-nitroaniline and various benzoyl chloride derivatives under solvent-free conditions at 130 °C in the presence potassium carbonate. Benzoyl chlorides easily underwent nucleophilic acyl substitution followed by intramolecular cyclization via concomitant removal of fluorine to obtain the title compounds in high yields.

Two series of natural and natural-like mono- and bicyclic acylphloroglucinols derived from secondary metabolites in the genus Hypericum (Hypericaceae) were synthesised and tested in vitro for anti-proliferative and tube-formation inhibitory activity in human microvascular endothelial cells (HMEC-1). In addition, their anti-oxidative activity was determined via an ORAC-assay. The first series of compounds ( 4a – e ) consisted of geranylated monocyclic acylphloroglucinols with varying aliphatic acyl substitution patterns, which were subsequently cyclised to the corresponding 2-methyl-2-prenylchromane derivatives ( 5a and 5d ). The second series involved compounds containing a 2,2-dimethylchromane skeleton with differing aromatic acyl substitution ( 6a – d and 7a – e ). Compound 7a , (5,7-dihydroxy-2,2-dimethylchroman-6-yl)-(3,4-dihydroxyphenyl)methanone), showed the highest in vitro anti-proliferative activity with an IC 50 of 0.88 ± 0.08 μM and a remarkable anti-oxidative activity of 2.8 ± 0.1 TE from the ORAC test. Interestingly, the high anti-proliferative activity of these acylphloroglucinols was not associated with tube-formation inhibition. Compounds ( E )-1-(3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4,6-trihydroxyphenyl)-2-methylbutan-1-one ( 4d ) and (5,7-dihydroxy-2,2-dimethylchroman-6-yl)(3,4-dimethoxyphenyl)methanone ( 6a ) exhibited moderate to weak anti-proliferative effects (IC 50 11.0 ± 1 μM and 48.0 ± 4.3 μM, respectively) and inhibited the capillary-like tube formation of HMEC-1 in vitro , whereas 7a was inactive. The most active compound in the ORAC assay was 7c , which exhibited an anti-oxidative effect of 6.6 ± 1.0 TE. However, this compound showed only weak activity during the proliferation assay (IC 50 53.8 ± 0.3) and did not inhibit tube-formation.

The mixture of the compounds (III) and (IV) is converted but only the compound (III) reacts to the tetrahydroisoquinoline (VI).

A chlorophosphite-modified, Staudinger-like acylation of azides involving a highly chemoselective, direct nucleophilic acyl substitution of carboxylic acids is described. The reaction provides the corresponding amides with analytical purity in 32-97% yield after a simple aqueous workup without the need for a pre-activation step. The use of chlorophosphites as dual carboxylic acid-azide activating agents enables the formation of acyl C-N bonds in the presence of a wide range of nucleophilic and electrophilic functional groups, including amines, alcohols, amides, aldehydes, and ketones. The coupling of carboxylic acids and azides for the formation of alkyl amides, sulfonyl amides, lactams, and dipeptides is described.

The three-step one-pot reaction proceeds via acyl chlorination followed by a Schmidt reaction of the acyl chloride and concluding electrophilic intramolecular addition of the isocyanate ion to the aromatic ring.

Secondary and tertiary sulfonamides (R-SO(2)NR(1)R(2)) are defined by the single or double N-alkyl or N-aryl/heteroaryl substitution of the primary sulfonamide respectively. They can be obtained easily by the classical S(N)2 or nucleophile acyl substitution displacements using the appropriate synthones. Many classes of compounds used in therapy present the substituted sulfonamide groups and there is also a continuous interest in different fields such as the herbicides herein schematically reported.The intent of this article is to give a comprehensive overview of the most important patents in the last decade related to pathologies of great interest. All selected patents claim new compounds bearing the secondary or/and tertiary sulfonamide moiety, and state to have biological activities. The article is neither intended for detailed discussions of the sulfonamides mode of action on the specific therapeutic targets, nor for their contribution to the physicochemical properties of the molecules they are introduced into, as the scientific literature in such topics is exhaustive and in many cases, debates are still ongoing. The main fields covered are related to pathologies affecting the CNS, cardiac disorders, anti-virals, inflammation diseases, glaucoma, bone remodeling, anti-cancer, and finally a section is also dedicated to herbicides.The insertion of the secondary/tertiary sulfonamide group into the organic scaffolds is chemically straightforward and not associated to particular toxicity in the cells or in the organisms. Therefore, it is possible to create large libraries of compounds, which can be tested for different diseases. As demonstrated by the patents reported in the present review, the research in medicinal chemistry, and other fields, takes big advantages as new leads are created, and might be further developed.

The carboxylic esters are mostly prepared by the reaction of carboxylic acids or their derivatives with alcohols and a large number of methods have been known. However, a few methods have been reported on the derivation of carboxylic esters from the alkoxycarbonylation of organometallics via σ bond formation between α-carbon and carbonyl carbon. Among them, the reaction of alkynyllithiums with methyl chloroformate or 2,2,2-trichloroethyl chloroformate affords the corresponding α,β-alkynoic esters at low temperature, but it requires an excess of chloroformate reagents to avoid competing side reactions. Although the treatment of ethyl chloroformate with organomanganates or organocopper reagents associated with magnesium salt under Pd catalysis produces the corresponding ethyl esters, these organometallics are prepared by an additional step and the scope is limited to primary and alkenyl group, respectively. The direct alkoxycarbonylation of Grignard reagents with dialkyl carbonates or alkyl chloroformates affords the corresponding esters, but the former requires 2 equiv of dialkyl carbonates and the latter is limited to the preparation of α-diazo esters at −78 C. Instead, the alkoxycarbonylation of Grignard reagents proceeds well with 1 equiv of 2-pyridyl carbonates, but the yield of 2,2,2-trichloroethyl ester depends on reaction temperature. Recently, alkyl cyanoformates have been utilized for the alkoxycarbonylation of organometallics. Thus, the alkoxycarbonylation of alkynyllithiums or allenyllithiums with 2 equiv of methyl or ethyl cyanoformate provides methyl akynoates or ethyl allenates, respectively. The reaction of heteroaromatic magnesium halides with an excess of alkyl cyanoformates also affords carboxylic esters in moderate to high yields. Furthermore, the treatment of methyl cyanoformate with magnesium metalated nitriles, derived from αbromonitriles and isopropylmagnesium chloride, at −78 C affords methyl α-cyanoates in moderate to high yields. Thus, the success of carboxylic esters synthesis by the alkoxycarbonylation of organometallics depends largely on the nature/amount of alkoxycarbonylating reagents and metals employed. However, there are no reports of alkoxycarbonylating reagents that can produce 2 equiv of carboxylic esters with organometallics. Inspired by our previous reports on ketones synthesis using pyrimidyl diesters, we investigated the synthesis of carboxylic esters from 2-methyl-4,6pyrimidyl dicarbonates and Grignard reagents. In choosing 2-methyl-4,6-pyrimidyl group as active moiety, we considered i) chelation effect between nitrogen atom and magnesium atom ii) thermal stability and storage of 2-methyl-4,6-pyrimidyl dicarbonates rather than other pyrimidyl dicarbonates. 2-Methyl-4,6-pyrimidyl dicarbonates 3 were newly prepared by the addition of 2 equiv of alkyl chloroformates 2 to a suspended solution of 4,6-dihydroxy-2-methylpyrimidine 1 and 2 equiv of triethylamine in THF at room temperature (Scheme 1). The nucleophilic acyl substitution of 2 with 1 was completed in 2-10 h at room temperature because 1 was slightly soluble in THF. After completion of the reaction, the resulting triethylamine hydrochloride precipitate was filtered off. After usual workup, the residue was subjected to silica gel (Davisil, pH = 7) or recystallized to afford 3 in 67-89% yields. During the synthesis of 2-methyl-4,6-pyrimidyl diisobutyl dicarbonate 3a, a small amount (~10%) of N,Ndiethyl isobutyl carbamate was produced by the nucleophilic acyl substitution of isobutyl chloroformate with triethylamine, which was distilled out under vacuum. However, 2

2-O-alpha-D-Glucopyranosyl-6-O-octanoyl-L-ascorbic acid was enzymatically synthesized from 2-O-alpha-D-glucopyranosyl-L-ascorbic acid (AA-2G) and vinyl octanoate with a protease from Bacillus subtilis in pyridine. Furthermore, with various linear saturated fatty acid vinylesters as acyl donors, AA-2G was also converted to their corresponding 6-O-acyl AA-2G in the same manner. The reactivities of transacylation decreased with increasing length of the acyl groups. Thus, short chain acyl groups were transferred to AA-2G by this protease more efficiently than were long chain acyl groups. This enzymatic method is recommended for the synthesis of 6-Acyl-AA-2G with short or medium length chain acyl groups.

Photosensitive polyimides have been used to form thermally and mechanically stable fine patterns utilized for such as buffer-coat layers and inter-layer dielectrics in electronic devices. Conventional photosensitive polyimides usually contain poly(amic acid)s as polyimide precursors or functionalized polyimides as their polymer component. Here, we report a novel design for preparation of photosensitive polyimides, reaction development patterning(RDP). RDP utilizes nucleophilic acyl substitution reaction of nucleophiles in developer with imide groups in polyimides as the key reaction of pattern formation, and therefore, no introduction of specific functional groups into polyimide framework is needed. In addition, RDP can afford photosensitivity to engineering plastics having carboxylic-acid-derivative linkages other than polyimide. We have developed both positive- and negative-tone RDPs. Positive-tone RDP utilizes main-chain scission of engineering plastics by amines in developer for pattern formation. Negative-tone RDP realizes higher sensitivity with smaller amount of photosensitive agent than positive-tone RDP. Application of industrially-used alkaline developer to negative-tone RDP is also achieved. Further reduction of the amount of photosensitive agent with increasing sensitivity is examined by introduction of chemical amplification mechanism to RDP.

Intramolecular nucleophilic acyl substitution reactions involving a broad range of halo substituted carboxylic acid derivatives have been accomplished in excellent yield employing samarium(II) iodide as the reductive coupling agent. Although particular substrates cyclized most effectively in THF in the presence of tripiperidinophosphine oxide, carboxylic acid esters, the focus of this report, cyclize equally well without such an additive in the presence of a catalytic quantity of iron(III) complexes. Thus a comprehensive series of halo substituted esters were cyclized in excellent yield to the corresponding 4-, 5-, and 6-members carbocycles. The reaction is extremely mild and selective as demonstrated by experiments wherein alkyl chlorides, acetals, and olefins remain completely intact under the reaction conditions. In addition to introducing a convenient procedure for preparing stereodefined spirocyclic systems, a new ring expansion sequence has been developed that appears extremely general for the preparation of various ring systems

Intramolecular nucleophilic acyl substitution (INAS) reactions of subs- tituted 3-iodopropyl carboxylates have been achieved using samarium(II) iodide (SmI 2 ) in the presence of an iron(III) catalyst. Diverse ester starting materials containing stereogenic centers placed in varying po- sitions on the substrates have been converted to acyclic 4-hydroxy ke- tone derivatives in good yields using this method. No racemization of stereogenic centers α to the carbonyl was observed in any of the reac- tions examined. Consequently, the method serves as a convenient, high- yield synthesis of functionalized, enantiomerically enriched acyclic ketones possessing stereogenic centers far removed from one mother

Treatment of carbonates of alka-3,5-dien-1-ols with (η2-propene)Ti(OPri)2 resulted in intramolecular nucleophilic acyl substitution (INAS) reaction to afford allyltitanium compounds containing lactone or ester moieties, which add regiospecifically to aldehydes.

Samarium(II) iodide has been employed to promote a tandem intramolecular nucleophilic acyl substitution/intramolecular ketyl−olefin coupling cyclization sequence, generating bicyclic, tricyclic, and spirocyclic ring systems in excellent yield and with high diastereoselectivity. This versatile reaction sequence allows entry to several different naturally occurring tricyclic systems containing the angular and linear triquinane framework.

Treatment of 3,4-alkadienyl carbonates 2a−i with a low-valent titanium reagent diisopropoxy(η2-propene)titanium (1), readily generated by the reaction of Ti(O-i-Pr)4 with 2 i-PrMgCl, resulted in an...

In addition to the previously recorded reactions of diethyl lithio(difluoromethyl)phosphonate (8) with primary triflates and aldehydes, we report here that 8 reacts with functionalized, but unactivated, methyl esters to give efficient acyl substitution. Thus, 8 reacts cleanly (−78 °C, THF) with the following methyl esters (product, yield): methyl (S)-isopropylideneglycerate (14, 99%), methyl (S)-3-O-(tert-butyldimethylsilyl)-2 -O-tetrahydropyranylglycerate (16, 85%), and the Garner ester derived from d-serine (15, 77%). Expeditious treatment of the resultant α,α-difluoro-β-keto phosphonates with hydride or Grignard reagents followed by alcohol deoxygenation provides a general method for the synthesis of (α,α-difluoroalkyl)phosphonate analogues of secondary phosphates. For tertiary alcohols, Dolan−MacMillan deoxygenation conditions are employed. The requisite methyl oxalate esters are obtained by an improved procedure wherein the lithium alkoxide of the hindered tertiary alcohol is irreversibly generated ...

Samarium(II) iodide has been employed to promote a sequential intramolecular nucleophilic acyl substitution/intramolecular ketyl olefin coupling cyclization sequence to provide bicyclic, tricyclic, and spiro-fused oxygen heterocycles in excellent yield and with high diastereoselectivity.

A rapid and mild method for the conversion of carboxylic acids to amides via the intermediacy of acid chlorides is presented.

An efficient and practical method for the preparation of optically active 5-t-butyldimethylsiloxy-2-cyclohexenone (3), a convenient chiral 2,5-cyclohexadienone synthon, from readily available ethyl 4-chloro-3-hydroxy-butyrate (7) has been developed where Ti(II)-mediated intramolecular nucleophilic acyl substitution and FeCl3-mediated ring expansion are the key reactions. The synthesis of racemic 6-t-butyldimethylsiloxy-2-cycloheptenone (10), a potential 2,6-cycloheptadienone synthon, is also described.

Treatment of Ti (O-i-Pr) 4 with 2 equiv of i-PrMgX (X =Cl or Br) provides (η2-propene) Ti (O-i-Pr) 2 in essentially quantitative yield. This new low-valent titanium complex nicely acts as a versatile titanium (II) equivalent to effect the following unique transformations. Thus, alkynes afforded titaniumalkyne complexes which, in turn, react with aldehydes, ketones, or imines to furnish the corresponding addition products. Allylic or propargylic compounds such as halides and alcohol derivatives gave allylic- or allenylic titanium species, which could be utilized in chemo- and diastereoselective reactions with carbonyl compounds. While acetylenic esters resulted in an intramolecular nucleophilic acyl substitution (INAS) reaction to provide unsaturated ketones, olefinic ones furnished cyclopropanols. 1, 6- or 1, 7-Dienes, enynes, and diynes underwent cyclometallation to give dialkoxytitanacycles, which show some distinctive reactivities among the metallacycles of early transition metal complexes. A few applications to natural product synthesis by taking advantage of these methods are also illustrated.

Samarium(II) iodide (SmI2) has been employed in a one-pot, three-step, nucleophilic acyl substitution/ketyl−olefin coupling/β-elimination reaction sequence. This novel protocol combines two recently developed SmI2-mediated processes to permit the net delivery of an alkenyl moiety to a ketone carbonyl generated as an intermediate along the sequential reaction pathway. A remarkable measure of stereocontrol over three to five contiguous stereocenters is established in the process as a result of the excellent facial selectivity conveyed in the ketyl−olefin coupling reaction. Unique to the SmI2-mediated process, the relative asymmetric induction engendered in these addition reactions is complementary to more traditional nucleophilic addition reactions in that the alkenyl group is delivered to the carbonyl center by an attached tether. Moreover, the protocol avoids the basic reaction conditions characteristic of alkenylmagnesium halides and alkenyllithium reagents.

Samarium(II) iodide has been employed to promote a tandem intermolecular carbonyl addition/intramolecular nucleophilic acyl substitution sequence, generating seven- through nine-membered monocyclic, bicyclic, and tricyclic ring systems with good yields and high diastereoselectivities. This tandem reaction consists of an intermolecular reaction followed by an intramolecular ring expansion that results in a formal [m + n] cycloaddition, starting from extremely simple, readily available substrates. The regioselectivity and stereoselectivity of the process arise from a tuning of the reducing power of samarium(II) iodide with nickel(II) iodide in the first step and irradiation with visible light in the second. By using this method, a variety of structural motifs have been assembled rapidly in good yields.

A samarium(II) iodide-promoted sequence consisting of an intermolecular ketyl-olefin coupling followed by an intramolecular nucleophilic acyl substitution is described. This process leads to functionalized six- to eight-membered monocyclic and bicyclic ring systems in moderate to good yields.

An efficient and highly stereoselective method for synthesizing optically active γ-trityloxymethyl-α-alkylidene-γ-butyrolactones having a stereodefined mono or disubstituted exocyclic double bond, starting from commercially available non-racemic glycidyl tritylether has been developed in which a titanium(II)-mediated intramolecular nucleophilic acyl substitution reaction is a key reaction.

Samarium(II) iodide (SmI2) has been successfully utilized as a reducing agent for the intramolecular coupling of ketones with nitriles. The use of visible light to promote the reductive coupling represents an improvement over previously reported protocols. The procedure also avoids overreduction of the resulting α-hydroxy ketones. Monocyclic, fused bicyclic, and bridged bicyclic α-hydroxy ketones composed of a number of substitution patterns have been synthesized in moderate to excellent yield via this method. A sequential reaction consisting of a nucleophilic acyl substitution followed by a ketyl−nitrile coupling has also been accomplished.

Optically active 6-amino-2-cycloheptenone 5 has been prepared from ethyl 2(E),6-heptadienoate where the Michael addition of a chiral amine, Ti(II)-mediated intramolecular nucleophilic acyl substitution reaction and FeCl3-mediated ring expansion are the key steps. The compound 5 undergoes highly diastereoselective conjugate addition of a Grignard reagent in the presence of a catalytic amount of Li2Cu(CN)Cl2 to provide the corresponding cis-adducts which, in turn, are converted in to 6-alkyl substituted 2-cycloheptenones by treatment with p-TSA.

Samarium(II) iodide promotes an efficient one-pot annulation reaction between ω-iodo esters and 2-(ω-chloroalkyl)cycloalkanones. An initial intermolecular carbonyl addition reaction between the iodo ester and the ketone generates a lactone intermediate. The lactone undergoes a subsequent nucleophilic acyl substitution reaction with an organosamarium derived from the chloride. Nickel(II) iodide is an efficient catalyst for the first step of the process, and light is utilized to promote the second step. Seven-, eight-, and nine-membered rings can be accessed by this sequential dianionic process. This annulative approach to carbocycles is complementary to previously reported procedures.

Optically active 5-(tert-butyldimethylsiloxy)-2-cyclohexenone (1) and its 6-substituted derivatives 2a,b were synthesized from the readily available optically active ethyl 3-(tert-butyldimethylsiloxy)-5-hexenoate (4), where the Ti(II)-mediated intramolecular nucleophilic acyl substitution reaction and the FeCl3-mediated ring expansion reaction of a 1-hydroxybicyclo[3.1.0]hexane are the key reactions. The enone 1 reacted with higher-order cyanocuprates with excellent diastereoselectivity to afford the trans-addition products, trans-13, in excellent yields. The reaction of 1 with lower-order cyanocuprates proceeded with moderate to excellent syn-selectivity to afford cis-13. Treatment of trans- and cis-13 with DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) or catalyst p-TSA (p-toluenesulfonic acid) resulted in a β-elimination reaction to furnish the corresponding optically active 5-substituted-2-cyclohexenones 14. The 1,4-addition reaction of 2a and 2b with organocyanocuprates followed by treatment of the resulti...

Optically active bicyclic oxazolidinylpiperidines 1a, 1b, 1c and 1d, known chiral building blocks for preparing 1-deoxyazasugars, were synthesized in high overall yield from D-serine by a method wherein the titanium(II)-mediated intramolecular nucleophilic acyl substitution and FeCl3-mediated ring enlargement of bicyclic cyclopropanols are the key reactions.

A variety of nucleophiles have been investigated for their reactions with formyl and acetyl esters in the gas phase in our flowing afterglow. The reactions that are permitted in the gas phase are more varied than those seen in the condensed phase. The rates of reactions of methyl and ethyl esters as well as various lactones have been undertaken with various nucleophiles: H2N–, HO–, CH3O–, NCCH2–, F–, CH3C(O)CH2–, CH3S– and O2NCH2– . For example, the reaction rate of NCCH2– + HCO2CH2CH3 has been found to be (1.3 ± 0.2) × 10–10 cm3 molecule–1 s–1 and the only product is HC(O–)CHCN which results from nucleophilic acyl substitution (BAC2) followed by a proton transfer within the ion–molecule complex. Other reaction mechanisms that have been observed include β-elimination (E2), bimolecular nucleophilic substitution at the alkyl group (BAL2), and the Riveros reaction (elimination of CO). A mechanism for the F– + HCO2CH3 reaction has been determined at the B3LYP/6-31+G(d) level. Most notably, channels were determined computationally (BAL2 and Riveros), and these channels are also observed experimentally. Furthermore, the BAC2 pathway which proceeds via nucleophilic attack on the carbonyl group also leads to the Riveros products, F–(CH3OH) and CO.

The synthesis of lipid A-type pyrancarboxylic acid derivatives, which have a carboxylic acid group in the anomeric position of the reducing part of the disaccharide instead of the phosphate group in lipid A, is described. One of the compounds thus synthesized, which has an acyl substitution pattern similar to that of Escherichia coli lipid A, showed lipopolysaccharide (LPS)-agonistic activity. The other, which contains four lipid chains in the molecule, exhibited strong LPS-antagonistic activity toward human monoblastic U937 cells.

Asymmetric aldol additions using chlorotitanium enolates of N-acyloxazolidinone, oxazolidinethione, and thiazolidinethione propionates proceed with high diastereoselectivity for the Evans or non-Evans syn product depending on the nature and amount of the base used. With 1 equiv of titanium tetrachloride and 2 equiv of (−)-sparteine as the base or 1 equiv of (−)-sparteine and 1 equiv of N-methyl-2-pyrrolidinone, selectivities of 97:3 to >99:1 were obtained for the Evans syn aldol products using N-propionyl oxazolidinones, oxazolidinethiones, and thiazolidinethiones. The non-Evans syn aldol adducts are available with the oxazolidinethione and thiazolidinethiones by altering the Lewis acid/amine base ratios. The change in facial selectivity in the aldol additions is proposed to be a result of switching of mechanistic pathways between chelated and nonchelated transition states. The auxiliaries can be reductively removed or cleaved by nucleophilic acyl substitution. Iterative aldol sequences with high diastere...