Synthesis of derivatives

One of the most versatile methods for the synthesis of derivatives with the acetylene or cumulene system consists In deprotonatlon of the starting acetylene or cumulene and subsequent reaction of the anionic or organometal1ic intermediate with an electrophilic reagent. 

The recent discovery that propadiene can be converted into a lithio compound, which is stable enough at low temperature to allow functionalization, has made it an important starting compound for the synthesis of derivatives. A fortunate circumstance is that allene can be obtained in > 30% yield in an extremely simple... 

The direct conversion of aniline into aminophenols may be achieved by hydrogen peroxide hydroxylation in SbE —HE at —20 to —40° C. The reaction yields all possible aminophenols via the action of H20" 2 on the anilinium ions the major product is 3-aminophenol (64% yield) (70,71). This isomer may also be made by the hydrolysis of 3-aminoaniline [108-45-2] in dilute acid at 190°C (72). Another method of limited importance, but useful in the synthesis of derivatives, is the dehydrogenation of aminocyclohexenones (73). 

One of tfie most important applications of 4-chloiophenol is in the synthesis of derivatives of quinizarin [81-64-17, anthraquinone dyes (see Dyes,... 

At = Ph) or ethyl 3-(4-acetylphenyl)prop-2-ynoate 150 (Ar = 4-MeCOCeH4) in ethanol (81PHA471) (Scheme 40). The synthesis of derivatives 156c,d from ethyl 3-phenylprop-2-ynoate 150 (R = Ph)and l-hydrazino-4-phenylphthalazine 155 (R = Bz) or 1 -hydrazino-4-benzyl Aithalazine 155 (R = Bz) woriced equally well in methanol at room temperature for 72 h or in refluxing methanol for 1 h (91PHA105). 

The first synthesis of derivatives (77) of pentatetraene-carboxylic acid has been reported using a Wittig reaction of 1-H-allene-l,3-dicarboxylate monoester chlorides (76) in the presence of triethylamine.60 In one case an intermediate was obtained and was converted to (77) by further treatment with base. The reaction of carbon suboxide with phosphonium ylides has also... 

Many versatile approaches to the construction of fused heterocyclic systems (6 5 6) with ring junction heteroatoms have been reported. More general reactions which can be used for synthesis of derivatives of several tricyclic systems, and transformations which have potential for use in the preparation of a series of substituted compounds, are discussed in this section. Formation of the five-membered ring is presented first because it is a conceptually simple approach. It should be noted, however, that the addition of a fused six-membered ring to a bicyclic component offers much more versatility in the construction of a (6 5 6) system. Each subsection below starts with intramolecular cyclization of an isolated intermediate product. Reactions which follow are one-pot intermolecular cyclizations. 

Another approach to the construction of the central ring is an intramolecular cyclization of a substrate composed of two six-membered heterocycles and bridged by a one-atom unit. This method has been applied to the synthesis of derivatives of 3, 6, 12, and 13 C1995BML163, 1996JHC1147, 2001JHC1173, 2002T5733>. 

A Mitsunobu process simultaneously coupled the enyne acid fragment 4 to /J-lactam 10 and inverted the CIO stereochemistry to the required (S)-configured ester 11 in 93% yield. A deprotection provided alcohol 12, the key /J-lactam-based macrolactonization substrate, which, under conditions similar to those reported by Palomo for intermolecular alcoholysis of /J-lactams (Ojima et al, 1992, 1993 Palomo et al, 1995), provided the desired core macrocycle 13 of PatA 13 (Hesse, 1991 Manhas et al, 1988 Wasserman, 1987). Subsequent Lindlar hydrogenation gave the required E, Z-dienoate. A Stille reaction and final deprotection cleanly provided (-)-PatA that was identical in all respects to the natural product (Romo etal, 1998 Rzasaef al, 1998). This first total synthesis confirmed the relative and absolute configuration of the natural product and paved the way for synthesis of derivatives for probing the mode of action of this natural product. 

Synthesis of Derivatives of Pateamine A and Structure Activity Relationship Studies... 

A stereodivergent synthesis of derivatives of 1,2-diols with an Se 2-retention pathway can be performed via a-alkoxyorganolead compounds. 

But now, a strategy, used for the synthesis of derivative (622) (lit. synthesis (622) see in Ref. 555), which is the most efficient analog of the commercial drug rolipram with a broad spectrum of action (in particular, anti-inflammatory, antidepressant, neuroprotective, and immunodepressing effects), is presented in Scheme 3.286. (The principle action of rolipram is based on selective inhibition of adenosine monophosphate (AMP)-specific phosphodiesterase.) Derivative (622) is almost 10 times more efficient than rolipram, but the biological activity of (622) was determined only for the racemate (555). 

Due to the importance of this heterocycle in medicinal chemistry, solid-phase synthesis of derivatives based on this condensation reaction have been investigated. The first report in this area uses a sodium benzenesulfinate resin 247 and gives access in five steps and good overall yields to a library of imidazo[l,2- ]pyridines 248 functionalized at C-2 with an enone moiety <2002OL3935>. Later on, the preparation of libraries of compounds related to 250 or 251 from Rink amide resin 249 have been published (Scheme 68) <2003TL6265>. 

An efficient synthesis of 2-amino derivatives 256 is depicted in Scheme 70 2-halopyridines are first Ar-alkylated with various halides under microwave activation and next reacted with cyanamide under basic conditions <1999T2317>. A rapid parallel synthesis of derivatives bearing a benzoyl substituent at C-3 based on this reaction has been described <2002SL1544>. 

Katritzky et al. <2000JOC9201> reported an efficient synthesis of derivatives 259 based on the reaction of 2-amino-l-[a-benzotriazol-l-ylmethyl]pyridinium chlorides 257 with aldehydes in the presence of l,8-diazabicyclo[5.4.0]undec-7-ene (DBLJ) as a base. This method is, however, limited to the use of aromatic aldehydes (Scheme 71). 

For the synthesis of derivatives of this ring system also, several other reports appeared. These results are shown in Scheme 41. 

Another method of synthesis of derivatives of 3-methyl-D-glucose lies in the scission of the anhydro-ring of 2,3-anhydro-D-allose derivatives with sodium methoxide, when the entry of the methoxyl group is accompanied by a Walden inversion on C3.82... 

E Fischer, E Otto. Synthesis of derivatives of some dipeptides. Ber Deutsch Chem... 

Strong bases such as alkali metal hydrides deprotonate B5H9 at —78 °C in ether solution to the octahydropentaborate(l—) which not only is a strong base but also an important reagent for the synthesis of derivatives [52]. The anion itself is not... 

Experimentally, derivatives 33b-d were synthesized and fully characterized [13]. These planar non-classical organoboranes exhibit a unique chemistry [13]. We first described 33b-d as valence-isomeric boriranylideneboranes 33 b d until their electronic structure was understood during the theoretical analysis of the electronic structure of 12a [44] (Scheme 3.2-17). The synthesis of derivatives of 34B, which is isoelectronic with 12B, remains a challenge. 

There also exist a number (very few due to the relative difficulty of synthesis) of derivatives containing four or five carbon bridges.15 Unfortunately, the electrochemistry of these compounds has not been studied. 

Among the valence-bond isomerisations leading to heterocyclic systems, the synthesis of derivatives of azepine (22) and oxepin (28) have been specially successful (Scheme 6.13) [32]. 

An extensive use of (TMS)3SiH can be found in the key steps of alkaloid syntheses. The synthesis of derivative 55, as the key intermediate for the preparation of alkaloid (ih)-pancracine [67], has been obtained from the reaction of 54 under normal conditions, in an 84 % yield as a single stereoisomer (Reaction 7.56). 

Needless to say, it would be interesting to apply the same type of chemistry described in Figure 2 for the methylcarbamate esters to the synthesis of derivatives of the formamidine insecticides. However, additional work with the formamidines, particularly those related to chlordimeform, has been discouraged because of the mutagenic and carcinogenic potential of the aryla-mine metabolic products. 

The chemical synthesis of derivatives and emalogs has long coimnanded much interest, as such compounds are required for the study of structure—activity relationships in the action of trehalases (23,28), may serve as substitutes for 51 in the synthesis of cord-factor analogs to be used as probes in the field of mycobacterial biochemistry (29, 30), and could possibly prove to possess interesting properties as enzyme inhibitors or antibiotic agents. 

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