Cyanomethyl formate

Formyloxy acetonitrile (cyanomethyl formate)/i50760-95-5y M 85.1, b 62-64 /12mm, 172-173 /atm, 0.903, n 1.4330. Purify it by fractional distillation and redistilling the middle fraction. 

In contrast, reaction of 82 with NaCN in DMF-H2O at reflux results in the formation of 7-cyano-6-nitroindole (201, 15%) and 83 (4%) as isolable products together with tar matter, and, to our surprise, 2- and/or 3-cyano-6-nitroindoles are not detected at all. When the reaction is carried out in DMSO at 150°C, only demethoxylation occurred to give 83 (62%). On the other hand, utilizing KOt-Bu and p-chlorophenoxyacetonitrile (25), the vicarious substitution reaction (87ACR282) of 82 proceeds smoothly to give a 7-cyanomethylated indole (202, 67%) (2001H1151). 

Replacement of the carbaldehyde function by other carbonyl groups is successful and leads to the formation of bcnzazcpincs bearing additional substituents at the 1- and 5-positions.100 For example, 1,2-dibenzoylbenzene (69) and TV.A -bisIcyanomethyOisopropylamine yield the pentasubstituted 3/7-3-benzazcpinc 70. However, condensations with other bis(cyanomethyl)-alkylamines and with bis(cyanomethyl)arylamines produce only acyclic condensation products. 

Fig. 12 Formation of A-(cyanomethyl)amides in the MCR between primary isocyano amides, aldehydes/ketones, and amines...

Another approach toward protection against overoxidation of primary amines is based on a three-step sequence involving selective mono-cyanomethylation of a primary amine such as 133 (equation 90) to cyanomethyl secondary amine 134, regioselective nitrone 135 formation using MCPBA and hydroxylaminolysis " of the resultant nitrones releasing hydroxylamine 136 (equation 90). 

Finally, lV-(cyanomethyl)iminodiacetic acid was obtained from the ester of iminodiacetic acid and chloroacetonitrile as illustrated in Scheme l.10 The purified ester is hydrolyzed selectively at the methylester groups with zinc perchlorate in a 70% alcoholic solution and formation of the 1 1 complex (3) occurs. The substituted iminodiacetic acid is extracted with ether after zinc separation as ZnS by treatment with H2S, and crystallized in a chloroform ethanol solution. 

A method used to prepare four of six possible thienopyridines (1992S528, 1997S949, 1998S1095) holds considerable promise. In particular, the synthesis of thieno[2,3-6]pyridine derivatives 31 and 32 involves the reaction of 2-chloro-3-(cyanomethyl)pyridine (33) and ethyl 2-chloro-3-pyridylacetate (34) with hetero-cumulenes, such as carbon disulfide and phenyl isothiocyanate. The reaction proceeds through the formation of the corresponding dianions 35 and 36 followed by cyclization through intramolecular nucleophilic substitution of the chlorine atom. 

Achiwa s procedure is well suited to promote formation of an azomethine ylid from Af-methoxymethy I-/V-( tri methyl si I y I methyljalkyl amines (see Section VII.D.2). It is also efficient and gives similar results when one uses /V-cyanomethyl-A -(trimethylsilylmethyl) alkylamines as the precursor.415... 

O-protonated 3-azathiopyrylium forms 38 (Scheme 8). On the basis of H NMR spectra it was assumed that 2-cyanomethyl-l,3-benzothiazin-4-one exists in one of its three protonated forms (84H1677). In several papers (53AP437 57MI1 60MI1), the formation of crystalline hydrochlorides of 1,3-benzo-TA was mentioned these compounds proved to be unstable,... 

Several new routes involve formation of one carbon-carbon bond in pre-formed substrates. Palladium-catalyzed cyclization of /3-hydroxyenamine derivatives has been employed in a route to substituted pyrroles and 4,5,6,7-tetrahy-droindoles with multiple substituents by formation of the C-3-C-4 bond as the key feature, as illustrated by construction of the molecule 534 (Equation 146) <2006T8533>. Zinc perchlorate-catalyzed addition of alcohols to the nitrile functionality of a-cyanomethyl-/3-ketoesters, followed by annulation gave access to a series of substituted ethyl 5-alkoxypyrrole-3-carboxylates <2007T461>. Similar chemistry has also been used for synthesis of a related set of pyrrole-3-phosphonates <2007T4156>. A study on preparation of 3,5,7-functionalized indoles by Heck cyclization of suitable A-allyl substituted 2-haloanilines has also appeared <2006S3467>. In addition, indole-3-acetic acid derivatives have been prepared by base induced annulation of 2-aminocinnamic acid esters (available for instance from 2-iodoani-lines) <2006OL4473>. 

An elaboration of this work involves the 3CR between primary a-isocyanoa-mides 67, carbonyl components 6 and primary amines 146, which could be directed towards either 2//-2-imidazolines 153 or M-(cyanomethyl)amides 156 by Ag -catalysis vs. Brpnsted acid mediated reaction, respectively (Scheme 14) [60]. The selective formation of M-(cyanomethyl)amides 156 (also earlier mentioned in the SRR approach. Scheme 7) can be rationalized by the same criteria as the formation of trisubstituted oxazoles 152 (Scheme 13), since the use of a Brpnsted acid, prevents the formation of 2-imidazolines 153 by the decreased pH. By applying a Brpnsted acid, the reaction initially proceeds via the same mechanism as for the oxazole MCR. However, when intermediate 155 is formed, it does not tautomerize to form the 5-aminooxazole 157. Instead, proton abstraction at the exocyclic imine nitrogen and subsequent ring opening gave the corresponding M-(cyanomethyl)amides 156. 

Scheme 14 Directing the MCR towards 2//-2-imidazolines 153 and A -(cyanomethyl)anudes 156 and the suggested mechanism for the formation of W-(cyanomethyl)amides 156...

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