Imine formation Wittig reaction

The most widespread use of IMPs is in the aza-Wittig reaction. This is the reaction of an IMP with a carbonyl group to generate an imine, or derivative thereof, with concomitant formation of the corresponding phosphine oxide (Scheme 2). The reaction is successful with a wide range of carbonyl containing compounds such as aldehydes, ketones, acyl chlorides, amides, and in some cases esters.2 Exposure to carbon dioxide, carbon disulfide, isocyanates, isothiocyanates, and... 

An example of the use of the tandem Staudinger/aza-Wittig reaction to form a seven-membered ring comes from the total synthesis of the alkaloid (-)-stemospironine (76).34 In this example, azidoaldehyde 74 was treated with triphenylphosphine to form a seven-membered cyclic imine which was then followed by an in situ sodium borohydride reduction to afford 75. Treatment of the resulting amine with iodine initiated the formation of the pyrrolidino butyrolactone system of the final target. 

The formation of phosphazenes was discovered by Staudinger and Meyer in 1919 [64,65]. These authors found that when an azide was treated with aphosphine, an iminophosphorane (phosphazene) was formed. Reaction of this reactive species with carbonyl compounds resulted in the formation of the corresponding imines. The aza-Wittig reaction has been used for the synthesis of different types of azadienes [66-69] and valuable compounds [70], including natural products such as (+)-hamacanthin B [71] and mycosporine [72]. 

A computational and experimental study of the mechanism of the aza-Wittig reaction between phosphazenes and aldehydes showed it to consists of two consecutive asynchronous thermally allowed (because they do not correspond to the n-systems) [2 + 2] cycloaddition (i)-cycloreversion (ii) processes (the second of which controls the stereochemical outcome of the whole reaction) via the relatively stable intermediate Ii (Scheme 4). The results indicate that P-trimethyl-X -phosphazenes are more reactive than their P-triphenyl analogues, and that the formation of the corresponding ( )-imines is preferential or exclusive. 

The formation of flve-membered cyclic imines through a Staudinger/intramolecular aza-Wittig reaction can also be performed by solid-phase synthesis and has been applied for the first synthesis of lanopylin Bi (108). The total synthesis, which takes only four steps, starts with a phase-transfer alkylation of diethyl 2-oxopropylphosphonate 105 with a 2-iodoethyl azide, affording the azido phosphonate 106, which undergoes a phase-transfer Homer-Emmons Wittig reaction with heptadecanal to provide the azido enone 107. An intramolecular aza-Wittig reaction of the enone 107 with polymer-supported triphenylphosphine in toluene completed the first total synthesis of lanopylin Bi (108) in 76% yield (Scheme 15.22). 

The formation of a small amount of naphthalene as a by-product of the reaction of benzyne with iV -methylpyrrole was noted by Wittig and Behnisch. Some related examples have recently been described. The tetrachloronaphthalen-l,4-imine (108) with benz5me gave N-methylcarbazole, which it is tempting to see as arising from the reaction of an intermediate zwitterion (compare 166) with another molecule of benzyne or, more likely, a benzyne precursor. The complementary product, 1,2,3,4-tetrachloronaphthalene, was not identified in this case. 

The formation of anthracene in reactions of 185 and 186 with benzyne, which was unexplained by Wittig et aZ., possibly is due to an alternative reaction of the intermediate zwitterion (202) with another molecule of benzjme or with a benzyne precursor. Benzyne reacted with the isoindole (206) to give the tetramethyltriptycene (208) and, in a separate run using excess of the benzyne precursor, W-benzylcarbazole. The latter product would appear to be made up of the iV-benzyl group from an intermediate anthracen-9,10-imine (207) and two molecules of benzyne. Mass spectral evidence also implicated the adduct 207, and the formation of 208 was attributed to benzyne-induced deamination of 207 to 1,4,9,10-tetramethylanthracene, which was trapped by further addition of benzyne across the 9- and 10-positions. 

Reaction of an imine with a strong base represents the most straightforward avenue for the formation of imine anions. The first bases used were lithium dialkylamides and Grignard reagents (equation 37) employed in the seminal studies of Wittig and Stork. The rate of deprotonation with both reagents is relatively low (for example in comparison to the reaction of ketones with dialkylamide bases) and the... 

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