Guanidines, bicyclic

Thereafter, molecules have been synthesised with a bicyclic ring, such as a quinoleine or an indole, inserted. Many of these compounds like zoniporide and BMS-284640 are selective NHE1 inhibitors, but some inhibit also other isoforms. Most recently, an additional group of compounds with 4-substituted (benzo[b]thiophene-2-carbonyl) guanidines has been synthesised and these are potent NHE1 inhibitors. A structurally distinct compound, S-3226, was found to be the first selective NHE3 inhibitor. 

A l,5,7-triazabicyclo[4.4.0]dec-5-ene containing a bicyclic guanidine system was obtained from a 4,4 -iminobis(butan-2-ylamine) and NJV -thiocarbonyldiimidazole [ 125]... 

The intermolecular cyclization that involves the peri positions of unsubstituted systems (6 6) has been applied to the construction of fused (6 6 6) systems. An example of this approach is the reaction of bicyclic guanidine 123 with 1,3-dibromopropane furnishing the /wi-fused product 124 which can be isolated as tetrafluoroborate salt (Equation 12) C1996CB21, 1997TL1911>. 

When the reaction of diethyl oxomalonate 381 was carried out with the free 5-methyl isothiosemicarbazide, triazine 281 was obtained in addition to its isomeric triazine 382. Reaction of 382 with phosphorus oxychloride gave 383, whose reaction with guanidine or benzamidine gave 384, which cyclized to 385. This represents (85JOC2293) the first example of a preparation of this bicyclic system from a 1,2,4-triazine. 

Corey, E. J. Grogan, M. J. Enantioselective Synthesis of a-Amino Nitriles from N-Benzhydryl Imines and HCN with a Chiral Bicyclic Guanidine as Catalyst Org Lett. 1999,1,157-160. 

Six-membered cyclic guanidine 197 was transformed into the corresponding bicyclic guanidine hemiaminal after deprotection of the Cbz and contemporary cyclization on the masked aldehyde function (Equation 4). This product, 198, was then employed in a Biginelli reaction to form a precursor of alkaloid batzelladine F <1999JOC1512>. 

Krai has recently reported a related system in which porphyrins bearing bicyclic guanidine substituents (such as the tetra-substituted species 70 shown is Scheme 35) form highly ordered chiral assemblies in aqueous solution [92]. 

FIGURE 4. Molecular structure of nitric salt of chiral bicyclic guanidine (13)78. Reproduced by per-mission of the Royal Society of Chemistry... 

The effect of steric hindrance on the rates and kinetic isotope effects for reactions of l-nitro-l-(4-nitrophenyl)alkanes and their deuterated analogues with two bicyclic guanidines of comparable basicity (l,5,7-triazabicyclo[4.4.0]dec-5-ene, TBD, and its 7-methyl derivative, MTBD) in THF has been studied. The results disagree with the notion that deuterium kinetic isotope effects are enhanced by steric hindrance, since for the reactions of MTBD with various carbon acids the KIEs decrease with steric hindrance in the carbon acid but the converse is true for reactions of TBD. 

In 2006, Tan and co-workers reported the first asymmetric guanidine catalyzed Diels-Alder addition of anthrone to maleimides (Scheme 75) [130], The authors observed very high yields and enantioselectivities using a derivative of Corey s C2-symmetric bicyclic gnanidine catalyst. The addition of anthrones to maleimide also worked well for snbstitnted anthrones. Interestingly, the anthors observed the oxidized prodnct when the anthrone was substituted at the meto-positions (Scheme 76). 

Several years later, Corey disclosed the C2 symmetric bicyclic guanidine 19 as an effective bifunctional catalyst for the Strecker reaction (Scheme 5.40) [74]. According to the catalytic cycle, HCN should hydrogen bond to the catalyst to form guanidinium-cyanide complex A. A subsequent increase in acidity of the catalyst N—H proton allows donation of a hydrogen bond to the aldimine to form TS assembly B. Enantiofacial attack of CN to the bound aldimine gives the Strecker product. 

Recently, Tan reported related bicyclic guanidine 20 as a chiral Br0nsted base to promote the highly enantioselective Diels-Alder reaction of various anthrones and maleimides (Scheme 5.41) [75]. Interestingly, use of dithranol led to the exclusive formation of the enantio-enriched Michael adducts. 

The bicyclic system has also been prepared by annulation of a pyrimidine ring onto an existing thiazine (Scheme 97) the cyclization fails with acetamidine or d -methylthiourea <1996JHC235>. Alternatively, a pyrimidine ring is formed by reaction of guanidine with the lactim ether formed by 0-methylation of a 2-methoxycarbonyl-l,4-thiazin-2-one (Scheme 98)<1997JME2502>. 

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