Hydroxymethylation Hydroxyalkylation

Hydroxyalkylthiazoles are also obtained by cyclization or from alkoxyalkyl-thiazoles by hydrolysis (36, 44, 45, 52, 55-57) and by lithium aluminium hydride reduction of the esters of thiazolecarboxylic acids (58-60) or of the thiazoleacetic adds. The Cannizzaro reaction of 4-thiazolealdehyde gives 4-(hydroxymethyl)-thiazole (53). The main reactions of hydroxyalkyl thiazoles are the synthesis of halogenated derivatives by the action of hydrobroraic acid (55, 61-63), thionyl chloride (44, 45, 63-66), phosphoryl chloride (52, 62, 67), phosphorus penta-chloride (58), tribromide (38, 68), esterification (58, 68-71), and elimination that leads to the alkenylthiazoles (49, 72). 

Di(hydroxyall l) Peroxides. The lowest molecular weight member of this group (2, X = Y = OH), di(hydroxymethyl) peroxide (R = R = OH) is a dangerously explosive soHd. With increasing molecular weight, di(hydroxyalkyl) peroxides become Hquids and eventually soHds of... 

Pyrrole, 3-hydroxy-geometry, 4, 158 synthesis, 4, 343 tautomerism, 4, 36, 198 Pyrrole, 3-([Pg.816]

Hydroperoxides, as optically active oxidizing agents 289-291 Hydrosulphonylation 172 /J-Hydroxyacids 619 a-Hydroxyaldehydes, synthesis of 330 a-Hydroxyalkyl acrylates, chiral 329 j -Hydroxycarboxylic esters, chiral 329 3-Hydroxycycloalkenes, synthesis of 313 Hydroxycyclopentenones, synthesis of 310 -Hydroxyesters 619 synthesis of 616 Hydroxyketones 619, 636 Hydroxymethylation 767 a-Hydroxysulphones, synthesis of 176 / -Hydroxysulphones 638, 639 reactions of 637, 944 electrochemical 1036 synthesis of 636 y-Hydroxysulphones 627 synthesis of 783... 

Novolacs are prepared with an excess of phenol over formaldehyde under acidic conditions (Fig. 7.6). A methylene glycol is protonated by an acid from the reaction medium, which then releases water to form a hydroxymethylene cation (step 1 in Fig. 7.6). This ion hydroxyalkylates a phenol via electrophilic aromatic substitution. The rate-determining step of the sequence occurs in step 2 where a pair of electrons from the phenol ring attacks the electrophile forming a car-bocation intermediate. The methylol group of the hydroxymethylated phenol is unstable in the presence of acid and loses water readily to form a benzylic carbo-nium ion (step 3). This ion then reacts with another phenol to form a methylene bridge in another electrophilic aromatic substitution. This major process repeats until the formaldehyde is exhausted. 

A demulsifier composition that is a blend of (1) a propoxylated-ethoxylated block copolymer of a bis-hydroxyalkyl ether and (2) a propoxylated-ethoxylated block copolymer of 2-hydroxymethyl-1,3-propanediol has been described [1750,1751]. 

The blend is partially crosslinked with a vinyl monomer when dissolved in an organic aprotic solvent and has a pH of 5.0 or lower. The first block copolymer is prepared by polycondensing a bis-hydroxyalkyl ether, such as dipropylene glycol, diethylene glycol, and the like, with propylene oxide. Next, the resulting propoxylated diol is reacted with ethylene oxide to produce the block copolymer. The second copolymer is prepared by polycondensing 2-amino-2-hydroxymethyl-1,3-propanediol, commonly known as TRIS, with... 

The observed instability of CpFe(CO)2CH2OH (4) augments a growing body of evidence concerning thermal instability of a-hydroxyalkyl complexes (38,39,40,41,42). A similar hydroxymethyl complex CpRe(C0)N0(CH20H), the only fully characterized a-hy-droxymethyl complex to date (38 39), likewise converts to its methoxymethyl complex in methanol. 

Interestingly, some /V-(hydroxymcthyl) derivatives (RR N-CH2OH) and, more generally, /V-(l-hydroxyalkyl) derivatives (RR N-CH(R")OH), were examined as prodrug candidates. The /V-(hydroxymethyl) derivative of nitro-... 

Eormation and subsequent cyclization of a hydroxyalkyl carbamate bearing an activating O-substituent can also be achieved in a one-pot procedure. When 2-(hydroxymethyl)aniline 394 was treated with -nitrophenyl chloroformate, the formation of the /)-nitrophenylcarbamate intermediate 395 was followed by in situ ring closure to give the 3,1-benzoxazin-2-one derivative efavirenz 250 in high yield and with high purity, free from the intermediate 395 (Scheme 74) <1998JOC8536>. 

These redox chain reactions, which cycle iron(II) and iron(III), have advantages over methods that use stoichiometric quantities of oxidants because the hydroxymethyl radical is also a good reductant and, at high oxidant concentrations, it may be oxidized more rapidly than it adds to (72). The disadvantage of this type of reaction is that the initial radical is generated by a relatively non-selective hydrogen atom abstraction reaction. To be efficient, the H-donor must be used in large excess it is often a cosolvent. Nonetheless, this is a very practical method to prepare hydroxyalkylated and acylated heteroaromatic and related derivatives. 

In order to assess the synthetic potential of enzymatic oxidations for organosilicon chemistry, the (hydroxyalkyl)silanes 95, 97 and 99 have been studied for their oxidation (dehydrogenation) with horse liver alcohol dehydrogenase (HLADH E.C. l.l.l.l)79. For this purpose, these compounds were incubated with HLADH in a TRIS-HC1 buffer/THF system in the presence of NAD+. As monitored spectrophotometrically (increase of absorbance of the NADH formed), the (2-hydroxyethyl)silane 97 and the (3-hydroxypropyl)silane 99 were better substrates for HLADH than ethanol, whereas the related (hydroxymethyl)silane 95 was not a substrate under the experimental conditions used. Interestingly, the corresponding carbon analogue 101 was found to be accepted by HLADH. On the other hand, the (2-hydroxyethyl)silane 97 was found to be a better... 

Another study on the enzymatic oxidation of the (hydroxyalkyl)silanes 95, 97 and 99 [and related (hydroxyalkyl)silanes] with HLADH also demonstrated that these compounds (including 95) are oxidized by this enzyme under the experimental conditions used80. Although the (hydroxymethyl)silane 95 was claimed to be not a substrate for HLADH in Reference 79, the order of activity of HLADH on the Si/C pairs 95/101 and 97/103 reported in References 79 and 80 is the same. 

Although a-hydroxyalkyl radicals such as the hydroxymethyl radical are oxidized without an adduct being noticed [reaction (14) k= 1.6 x 108 dm3 mol1 s 1], such a complex becomes apparent in the case of P-hydroxyalkyl radicals [reactions (15) and (16) k15 = 3 x 107 dm3 mol1 s k16 = 330 s Freiberg and Meyer-stein 1980], whereby the epoxide is formed (Soylemez and von Sonntag 1980). 

Note This process affords (extranuclear) hydroxyalkyl-l,8-naphthyridines. Dimethyl l,8-naphthyridine-2,7-dicarboxylate gave 2,7-bis(hydroxymethyl)-1,8-naphthyridine (12) [NaB(OMe)3H, THF, CH2C12, 25°C 55% or NaBH4, EtOH, 25°C 19%].473... 

It is interesting to contrast this substitution reaction with a complementary method for achieving the hydroxyalkylation of pyridines and quinolines developed by Minisci et al. <85T617>. They found that addition of hydroxylamine-(9-sulfonic acid to an acidic solution of 4-cyanopyridine in methanol containing catalytic iron(Il) sulfate, gave 2-(hydroxymethyl)-4-cyanopyridine 70 on work-up (Scheme 25). No products derived from ipso-substitution of the cyano-fiinction were observed. 

Oxidation of substituents such as hydroxyalkyl or aldehyde can also give carboxylic acid groups, and once the carboxyl group has been introduced it can easily be converted into the usual acid derivatives, or reduced to an alcohol or aldehyde [3] it is usually preferable to reduce the carboxyl group all the way to hydroxymethyl, then reoxidize this to the aldehyde (see Section 8.3.2). 

---