Grob fragmentations

Cyril A. Grob (1917-2003) was a professor at the University of Basel, Switzerland from 1951-1987, and his studies into heterolytic cleavage reactions began early in his academic career. He first reported the reaction that would ultimately bear his name in 1955. This report details fragmentation of a variety of substrates including the cleavage of trans-, A-dibromocyclohexane in the presence of zinc to yield 1,5-hexadiene. 

There are three potential options for the mechanism of Grob fragmentation reactions, one concerted and two stepwise. The stepwise reactions, which result from initial loss of either the nucleofuge or electrofuge, are less useful in synthesis since they often promote side reactions. However, one highly efficient stepwise transformation was reported by Kato. Treatment of diol 6 with pyridinium chloride results in formation of benzyl carbocation 8. Cleavage of this alcohol yields monocycle 9 and, ultimately, the ketone product 10.  

The key stereochemical requirement for a concerted fragmentation is an anti orientation between the leaving group and the b-c bond in 1. This enables constructive orbital overlap in the transition state between the forming and breaking bonds. The orientation of the a-b bond has no effect on the outcome of the reaction.  

Grob clearly demonstrated these mechanistic details in a variety of systems including reactions of the A -methyldecalin derivatives shown below. In tosylates 11 and 12, the C-OTs and Cc-Cd bonds are oriented antU thus these molecules efficiently fragment to monocycles 14 and 15, respectively.  

Further demonstration of the stereoselectivity of the reaction is that cis decalin 11 leads to a cis alkene in 14, while rani-decalin 12 generates a trans alkene in 15. Compound 13 is unable to undergo fragmentation since the C-OTs and Cc-Cd bonds are oriented gauche. Instead, this molecule reacts either by substitution or elimination (to yield 16).  

In Grieco s synthesis of compactin, the required stereochemical information in the A ring was embedded in the oxabicyclic subunit of compound 225 [192]. Ring opening was induced by base promoted Grob fragmentation which generated formaldehyde and decalin 226, Eq. 138. 

C-C bond cleavage primarily via a concerted process involving a five atom system. General scheme  

Miyamoto, K. Ochiai, M. Chem. Pharm. Bull. 2004, 52, 1143. 

Decarboxylating elimination has been observed with / -bromo carboxylic acids  

Insofar as such decarboxylations with -elimination occur by an E2 mechanism they are very highly stereospecific. Thus frmy-2,3-dibromo-3-phenylpropionic acid is decarboxylated in acetone homogeneously to cw -bromostyrene. If this reaction is carried out in water, El elimination preponderates and trans-bromostyrene is the main product (78%) along with 22% of the os-isomer. Bulky substituents on the two carbon atoms participating in the -elimination occasionally hinder such decarboxylating eliminations. 

All decarboxylations occurring with -elimination can be considered as Grob fragmentations.46 

Fleming and Harley-Mason48 showed that enol arenesulfonates fragment with decarboxylation to afford acetylenic carboxylic acids even under physiological conditions  

The decarboxylation of diazotized anthranilic acid carried out by Stiles and Miller49 is also a fragmentation reaction it affords dehydrobenzene (benzyne), which reacts at once as a dienophile with, e.g., furan, giving 1-naphthol by way of an epoxide. 

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Most diaziridines are not sensitive towards alkali. As an exception, diaziridines derived from 2-hydroxyketones are quickly decomposed by heating with aqueous alkali. Acetaldehyde, acetic acid and ammonia are formed from (162). This reaction is not a simple N—N cleavage effected intramolecularly by a deprotonated hydroxy group, since highly purified hydroxydiaziridine (162) is quite stable towards alkali. Addition of small amounts of hydroxybutanone results in fast decomposition. An assumed reaction path — Grob fragmentation of a hydroxyketone-diaziridine adduct (163) — is in accord with these observations (B-67MI50800). 

The classification fragmentation applies to reactions in which a carbon-carbon bond is broken. One structural feature that permits fragmentation to occur readily is the presence of a carbon that can accommodate carbocationic character (3 to a developing electron deficiency. This type of reaction, known as the Grob fragmentation, occurs particularly readily when the y-atom is a heteroatom, such as nitrogen or oxygen, that has an unshared electron pair that can stabilize the new cationic center.96... 

It should be noted that the Grob fragmentation reaction and the reductive cyclization (homoallylation) discussed in this section involve the same oxanickellacyclopentane 66 as a common intermediate (Scheme 17). The reversibility of these C - C bond cleavage reaction and C - C bond formation reaction is also supported by the isolation and characterization (by X-ray analysis) of an oxanickellacyclopentane-like 66 (without a tether), which is prepared from a stoichiometric amount of Ni(cod)2, a diene, an aldehyde, and a monodentate phosphine ligand [41]. 

Fig. 12. a) Mechanisms for the Grob fragmentation, (i) is a two-step mechanism, (2) is a concerted single-step mechanism, b) Level diagram for the second step of path (i) fragmentation vs. reclosure. 

If we now consider a 1,3-diol (3), accepting a similar mechanism to the abovementioned for 1,2-diols, in acid conditions the fragmentation of the molecule will take place according to a process known as "Grob fragmentation" [2] to give water as the "nucleofuge", an alkene (4) and a carbonyl compound (5) as the... 

The Wharton-Grob fragmentation and the cationic cyclisation of polyolefins. Synthesis o/Cecropia juvenile hormone and d, -progesterone. 

The less hindered peripheric secondary hydroxyl group of the key intermediate 28 was chemoselectively tosylated (29), submitted to an internal Wharton-Grob fragmentation (30). After attack on the carbonyl group (3i) with methyllithium and activation of the secondary alcohol as the corresponding tosylate, the resulting... 

Marshall boronate fragmentation is a variation of the Grob fragmentation (page 273) category. 

Vamos M, Ozboya K, Kobayashi Y (2007) Synthesis of bicyclic pyroglutamic acid featuring the Ugi reaction and a unique stereoisomerization at the angular position by Grob fragmentation followed by a transannular ketene [2-1-2] cycloaddition reaction. Synlett 1595-1599. Kreye O, Westermann B, Wessjohann LA (2007) A stable, convertible isonitrile as a formic acid carbanion [-COOH] equivalent and its application in multicomponent reactions. S3mlett 20 3188-3192... 

The [i,y fragmentation is known as Grob fragmentation. Its synthetic application is usually in the construction of medium-sized rings by fragmentation of fused ring systems. 

The cyclodextrin-supported cleavage of 1,3-oxathianes with IBX (cf Scheme 76, Section 8.11.6.4.6) <2006SC3771>, as well as the copper-catalyzed aminolysis of 1,3-dithianes <2006OL2547> has been published. l,3-Dioxane-2-ones readily undergo a Grob fragmentation (Equation 100) <2006CC4303>. This reaction is catalyzed by Ni- (24-99% yield) or by Pd-complexes (42-93% yield). 

Gngnard reagents, reaction with acyl chlorides, 66, 116 Grob Fragmentation, 66, 173... 

Generation of xanthyl cation from 2-(9-xanthyl)ethanol [87] is an extended Grob fragmentation. The intervening chain of separating the terminal donor groups may also incorporate heteroatoms, as shown in the deconvolution of a decalindione monoxime tosylate [88]. 

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