Primary alcohols nucleophile

A few type la reductive cycUzations leading to indoles have been reported. A palladium (II) trifluoroacetate catalyst was effective in the reductive cyclization of orfho-nitrostyrenes to 2-substituted indoles <05T6425>. The Batcho-Leimgruber indole synthesis, the reductive cyclization of p-amino-2-nitrostyrenes, was utilized in a synthesis of 5-formylindole <05JHC137>. A partial reduction of a nitroarene provided a route to iV-hydroxyindoles <05AG(E)3736>. Treatment of nitro ketoester 90 with tin chloride in the presence of a primary alcohol nucleophile provided Al-hydroxyindole 93 via hydroxylamine intermediate 91. 

Shown below is the Bronsted plot for the reaction of ATP, and the complex between Mg and ATP ", as a function of thep/C. of primary alcohol nucleophiles (closed and open circles, respectively). The values of )3nuc are 0.07 and 0.06, respectively, reflecting that the nucleo-philicity of the alcohols has little effect on the rate of the reaction. This indicates very little bond formation to the nucleophiles in the transition state. 

Primary alcohols do not react with hydrogen halides by way of carbo cation intermediates The nucleophilic species (Br for example) attacks the alkyloxonium ion and pushes off a water molecule from carbon m a bimolecular step This step is rate determining and the mechanism is Sn2... 

The reactions of alcohols with hydrogen halides to give alkyl halides (Chapter 4) are nucleophilic substitution reactions of alkyloxonium ions m which water is the leaving group Primary alcohols react by an 8 2 like displacement of water from the alkyloxonium ion by halide Sec ondary and tertiary alcohols give alkyloxonium ions which form carbo cations m an S l like process Rearrangements are possible with secondary alcohols and substitution takes place with predominant but not complete inversion of configuration... 

When applied to the synthesis of ethers the reaction is effective only with primary alcohols Elimination to form alkenes predominates with secondary and tertiary alcohols Diethyl ether is prepared on an industrial scale by heating ethanol with sulfuric acid at 140°C At higher temperatures elimination predominates and ethylene is the major product A mechanism for the formation of diethyl ether is outlined m Figure 15 3 The individual steps of this mechanism are analogous to those seen earlier Nucleophilic attack on a protonated alcohol was encountered m the reaction of primary alcohols with hydrogen halides (Section 4 12) and the nucleophilic properties of alcohols were dis cussed m the context of solvolysis reactions (Section 8 7) Both the first and the last steps are proton transfer reactions between oxygens... 

We saw an example of nucleophilic ring opening of epoxides in Section 15 4 where the reaction of Grignard reagents with ethylene oxide was described as a synthetic route to primary alcohols... 

FIGURE 22.5 The diazonium ion generated by treatment of a primary alkylamine with nitrous acid loses nitrogen to give a carbocation. The isolated products are derived from the carbocation and include, in this example, alkenes (by loss of a proton) and an alcohol (nucleophilic capture by water). 

Methods of synthesis for carboxylic acids include (1) oxidation of alkyl-benzenes, (2) oxidative cleavage of alkenes, (3) oxidation of primary alcohols or aldehydes, (4) hydrolysis of nitriles, and (5) reaction of Grignard reagents with CO2 (carboxylation). General reactions of carboxylic acids include (1) loss of the acidic proton, (2) nucleophilic acyl substitution at the carbonyl group, (3) substitution on the a carbon, and (4) reduction. 

We said in Section 17.4 that carboxylic acids are reduced by L1AIH4 to give primary alcohols, but we deferred a discussion of the reaction mechanism at that time. In fact, the reduction is a nucleophilic acyl substitution reaction in which —H replaces -OH to give an aldehyde, which is further reduced to a primary alcohol by nucleophilic addition. The aldehyde intermediate is much more reactive than the starting acid, so it reacts immediately and is not isolated. 

Acid halides are among the most reactive of carboxylic acid derivatives and can be converted into many other kinds of compounds by nucleophilic acyl substitution mechanisms. The halogen can be replaced by -OH to yield an acid, by —OCOR to yield an anhydride, by -OR to yield an ester, or by -NH2 to yield an amide. In addition, the reduction of an acid halide yields a primary alcohol, and reaction with a Grignard reagent yields a tertiary alcohol. Although the reactions we ll be discussing in this section are illustrated only for acid chlorides, similar processes take place with other acid halides. 

Conversion of Acid Chlorides into Alcohols Reduction Acid chlorides are reduced by LiAJH4 to yield primary alcohols. The reaction is of little practical value, however, because the parent carboxylic acids are generally more readily available and can themselves be reduced by L1AIH4 to yield alcohols. Reduction occurs via a typical nucleophilic acyl substitution mechanism in which a hydride ion (H -) adds to the carbonyl group, yielding a tetrahedral intermediate that expels Cl-. The net effect is a substitution of -Cl by -H to yield an aldehyde, which is then immediately reduced by UAIH4 in a second step to yield the primary alcohol. 

Sulfonic esters are most frequently prepared by treatment of the corresponding halides with alcohols in the presence of a base. The method is much used for the conversion of alcohols to tosylates, brosylates, and similar sulfonic esters. Both R and R may be alkyl or aryl. The base is often pyridine, which functions as a nucleophilic catalyst, as in the similar alcoholysis of carboxylic acyl halides (10-21). Primary alcohols react the most rapidly, and it is often possible to sulfonate selectively a primary OH group in a molecule that also contains secondary or tertiary OH groups. The reaction with sulfonamides has been much less frequently used and is limited to N,N-disubstituted sulfonamides that is, R" may not be hydrogen. However, within these limits it is a useful reaction. The nucleophile in this case is actually R 0 . However, R" may be hydrogen (as well as alkyl) if the nucleophile is a phenol, so that the product is RS020Ar. Acidic catalysts are used in this case. Sulfonic acids have been converted directly to sulfonates by treatment with triethyl or trimethyl orthoformate HC(OR)3, without catalyst or solvent and with a trialkyl phosphite P(OR)3. ... 

The coupling of a secondary alcohol 1 with a primary alcohol 2 is achieved by the temporary removal of from each substrate which generates the ketone 3 and aldehyde 4 intermediates. A crossed aldol condensation occurs under the reaction conditions by the enolate derived from ketone 3 undergoing nucleophilic addition... 

A-Protected amines were assembled on solid-phase via sulfonamide-based handle 58 (Scheme 27) [67]. Tertiary sulfonamides were generated upon reaction with allylic, benzylic and primary alcohols under Mitsu-nobu conditions. Secondary amines were released from the support using mild nucleophilic conditions such as treatment with thiophenol and potassium carbonate. 

Figure 14-3. Transesterification reaction of the dinucleotide model where the nucleophile-containing ribose sugar is modelled by a tetrahydrofurane structure, whereas the cleaving sugar is further simplified and modelled as a simple primary alcohol (ethanol)...

In the reduction of acids there is a tendency for the lithium salt, RCO20Li to separate from the ethereal solution, and thus bring reduction to a halt this can be avoided by first converting the acid to a simple, e.g. Me or Et, ester. In the reduction of the latter, the initial nucleophilic attack by AIH4 results in an addition/elimination reaction—OR is a good leaving group in (40)—followed by normal attack, as above, on the resultant carbonyl compound (41) to yield the primary alcohol (42) ... 

Activation of a primary alcohol 174 by in situ mesylation and nucleophilic attack of a pyridine nitrogen atom was used in the last steps of a synthesis of cyclohexa[tf]quinolizidines 176. These compounds were obtained by direct NaBH4 reduction of intermediate pyridinium salts 175, and were proposed as tricyclic models containing the ABC-part of 8-azasteroids (Scheme 30) <1999T9269>. 

Cyclization of the nucleophilic imine was observed any time the primary alcohol was converted to either a leaving group or a carbonyl-containing functional group. 

While the notion that the alkoxides derived from aliphatic alcohols are poor nucleophiles toward 7r-allylmetal complexes has prevailed over the years, much progress made in the recent past has rendered the transition metal-catalyzed allylic alkylation a powerful method for the O-allylation of aliphatic alcohols. In particular, owing to the facility of five- and six-membered ring formation, this process has found extensive utility in the synthesis of tetrahydrofurans (THFs) (Equation (29))150-156 and tetrahydropyrans (THPs).157-159 Of note was the simultaneous formation of two THP rings with high diastereoselectivity via a Pd-catalyzed double allylic etherification using 35 in a bidirectional synthetic approach to halichondrin B (Equation (30)).157 The related ligand 36 was used in the enantioselective cyclization of a Baylis-Hillman adduct with a primary alcohol (Equation (31)).159... 

Due to the poor nucleophilicity of aliphatic alkoxides, the intermolecular O-allylation of aliphatic alcohols has been performed, for the most part, using a large excess of structurally simple primary alcohols (Equation (37))165 and/or unsubstituted allylic substrates.166,167 When allylic systems activated with an electron-withdrawing substituent were employed, only a slight excess of the alcohol was necessary to achieve complete stereospecificity, as exemplified by Equation (38).168,169... 

The nucleophilic attack on an acceptor-substituted allene can also take place at the acceptor itself, especially in the case of carbonyl groups of aldehydes, ketones or esters. Allenic esters are reduced to the corresponding primary alcohols by means of diisobutylaluminum hydride [18] and the synthesis of a vinylallene (allenene) by Peterson olefination of an allenyl ketone has also been reported [172]. The nucleophilic attack of allenylboranes 189 on butadienals 188 was investigated intensively by Wang and co-workers (Scheme 7.31) [184, 203, 248, 249]. The stereochemistry of the obtained secondary alcohol 190 depends on the substitution pattern. Fortunately, the synthesis of the desired Z-configured hepta-l,2,4-trien-6-ynes 191 is possible both by syn-elimination with the help of potassium hydride and by anti-elimination induced by sulfuric acid. Analogous allylboranes instead of the allenes 189 can be reacted also with the aldehydes 188 [250]. 

The study above (Hanna et al., 1992) also addressed the problem of nucleophilic addition of alcohols to DMPO, using Fe111 as the oxidant in an aqueous-alcoholic solution (from 95% to 25% water). Only primary alcohols engaged in this reaction, whereas 2-propanol or 2-methyl-2-propanol did not react even when the alcohol concentration was increased to 70%. This may depend on either decreased reactivity of secondary and tertiary alcohols, perhaps for steric reasons, or lower stability of the corresponding spin adducts. 

From the above it is clear that DMPO can undergo the addition-oxidation mechanism with water as the nucleophile, provided a suitable oxidant is present. With a primary alcohol competing, the O-connected alkoxy spin adduct is formed in addition to HO-DMPO". On the other hand, with a hydroxyl radical source a competing alcohol will undergo hydrogen abstraction by HO" and form an a-hydroxyalkyl radical which forms a C-connected spin adduct. This criterion clearly can distinguish between the two mechanisms at least in model systems (for recent examples, see Reszka and Chignell, 1995 Janzen et al., 1995 Thomas et al., 1996). 

The application of phase-transfer catalysis to the Williamson synthesis of ethers has been exploited widely and is far superior to any classical method for the synthesis of aliphatic ethers. Probably the first example of the use of a quaternary ammonium salt to promote a nucleophilic substitution reaction is the formation of a benzyl ether using a stoichiometric amount of tetraethylammonium hydroxide [1]. Starks mentions the potential value of the quaternary ammonium catalyst for Williamson synthesis of ethers [2] and its versatility in the synthesis of methyl ethers and other alkyl ethers was soon established [3-5]. The procedure has considerable advantages over the classical Williamson synthesis both in reaction time and yields and is certainly more convenient than the use of diazomethane for the preparation of methyl ethers. Under liquidrliquid two-phase conditions, tertiary and secondary alcohols react less readily than do primary alcohols, and secondary alkyl halides tend to be ineffective. However, reactions which one might expect to be sterically inhibited are successful under phase-transfer catalytic conditions [e.g. 6]. Microwave irradiation and solidrliquid phase-transfer catalytic conditions reduce reaction times considerably [7]. 

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