Addition of 2 Amines

The solid-state reaction of cyanide with using the high speed vibration mill  

As shown by mass spectrometry and NMR spectroscopy, these amine derivatives of Cgfl, after work up, are dehydrogenated adducts [81]. After nucleophilic addition, the H atoms brought in by the diamines were oxidatively eliminated. The final adduct formation of the secondary diamines proceeds exclusively at [6,6] bonds. Besides the monoadduct, most of the regioisomeric bisadducts of piperazine or N,N -dimefhylethylenediamine and Cjq could be separated by column chromatography. The structure of the monoadduct and some of these bis-adducts were proven by X-ray crystal-structure analysis [90]. 

Addition of amines to Cgg starts, mechanistically, with an electron transfer. Therefore these additions can also be carried out imder photochemical conditions, either aerobic or anaerobic. The yields of the addition of N,N -dimethylethylene-diamine or piperazine could be improved and the reaction time was shortened by irradiation with visible light [92, 93]. Aerobic conditions, irradiation and a large excess of a secondary diamine leads almost quantitatively to a well-defined tetraaminoadduct (Chapter 10). 

As already mentioned, tertiary amines can not form similar addition products. With stabilized amines such as leuco crystal violet, leucomalachite green and similar dyes neutral and stable charge-transfer complexes were formed [94]. 

If - dependent on the nature of the tertiary amine - the initially formed CT complex or respective zwitterion is not stable, other reaction pathways such as cycloaddition or insertion of Cjq into an alkyl-CH bond can be observed [87, 95-99]. More details of these reactions can be found in Chapter 6. 

Recall from Section 9.8 that the major product formed In acid-catalyzed dehydration of an alcohol Is the more substituted alkene. 

Show two methods to synthesize each alkene a one-step method using a Wittig reagent, and a two-step method that forms a carbon-carbon bond with an organometaiiic reagent in one of the 

Both 1° and 2° amines react with aldehydes and ketones. We begin by examining the reaction of aldehydes and ketones with 1° amines. 

Treatment of an aldehyde or ketone with a 1° amine affords an imine (also called a Schiff base). Nucleophihc attack of the 1° amine on the carbonyl group forms an unstable carbinolamine, which loses water to form an imine. The overall reaction results in replacement of C=O by C=NR. 

Because the N atom of an imine is surrounded by three groups (two atoms and a lone pair), it is sp hybridized, making the C-N-R bond angle 120° (not 180°). Imine formation is fastest when the reaction medium is weakly acidic. 

We now move on to the reaction of aldehydes and ketones with nitrogen and oxygen heteroatoms. Amines, for example, are organic nitrogen compounds that contain a nonbonded eiectron pair on the N atom. Amines are classified as 1°, 2°, or 3° by the number of alkyl groups bonded to the nitrogen atom. 

The mechanism of imine formation (Mechanism 21.5) can be divided into two distinct parts nucleophilic addition of the 1° amine, followed by elimination of HgO. Each step involves a reversible equilibrium, so that the reaction is driven to completion by removing HgO. 

Maleic acid and its derivatives smoothly add ammonia and amines to yield aspartic acid derivatives. Fumaric acid, for example, yields aspartic acid 16 in a 60-65% yield when it is heated with an excess of ammonia in the presence of ammonium chloride. 

Substituted derivatives are prepared similarly, the yields being generally modest. Diamines similarly yield the bis-aspartyl derivative such 

Hydrazine derivatives also react to give the bis addition products. 

An interesting aspartic acid derivative, namely, ureidosuccinic acid 18, 

Isoquinoline 21, on heating with maleic acid, reacts to give a betaine 

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If a bromomethyl- or vinyl-substituted cyclopropane carbon atom bears a hydroxy group, the homoallyiic rearrangement leads preferentially to cyclobutanone derivatives (J. Sa-laun, 1974). Addition of amines to cydopropanone (N. J. Turro, 1966) yields S-lactams after successive treatment with tert-butyl hypochlorite and silver(I) salts (H.H. Wasserman, 1975). For intramolecular cyclopropane formation see section 1.16. 

Amines undergo aminopalladation to alkynes. The intramolecular addition of amines to alkynes yields cyclic imines. The 3-alkynylamine 273 was cyclized to the 1-pyrroline 274, and the 5-alkynylamine 275 was converted into the 2,3,4,5-tetrahydropyridine 276[137]. Cyclization of o-(l-hexynyl)aniline (277)... 

Nucleophilic addition of amines to aide hydes and ketones (Sections 17 10... 

Polymerization. The polymerization of aziridines takes place ia the presence of catalytic amounts of acid at elevated temperatures. The molecular weight can be controlled by the monomer—catalyst ratio, the addition of amines as stoppers, or the use of bifimctional initiators. In order to prevent a vigorous reaction, the heat Hberated during the highly exothermic polymerization must be removed by various measures, ie, suitable dilution, controlled metering of the aziridine component, or external cooling after the reaction has started. 

The l,3-dihydro-2,l-benzisoxazole-3-carboxyIic acid was prepared by either base treatment of N-hydroxyisatin or the rearrangement of N-hydroxyisatin monooxime with dilute acid (67AHC(8)277). The addition of amines to 3-unsubstituted-2,l-benzisoxazolium salts gave 3-amino-l,3-dihydro-2,l-benzisoxazoles (72CPB2209). 

Peifluorinated nitriles are highly electrophihc compounds because of the adjacent electron-accepting substituent Therefore, the addition of amines, alcohols, and mer-captans forming amidines, imidates, and thiobnidates is well-documented [63]. 

Nucleophilic addition of amines to aldehydes and ketones (Sections 17.10, 17.11) Primary amines undergo nucleophilic addition to the carbonyl group of aldehydes and ketones to form carbinol-amines. These carbinolamines dehydrate under the conditions of their formation to give A/-substituted imines. Secondary amines yield enamines. 

Although the emphasis in this chapter has been on tbe synthesis and mechanism of formation of simple enamines, brief mention will be made of the addition of amines to activated acetylenes to indicate the interest and activity in this area of substituted enamines. Since such additions tend to be stereospecific, inclusion in this section seems apropos. The addition of amines to acetylenes has been much studied 130), but the assigning of the stereochemistry about the newly formed double bond could not be done unequivocally until the techniques of NMR spectroscopy were well developed. In the research efforts described below, NMR spectroscopy was used to determine isomer content and to follow the progress of some of the reactions. 

In reaetions with nueleophilie reagents diaeetylene behaves as aeetylene aeti-vated with aeeeptor group that is eommon to eonjugated polyynes. Therefore, the nueleophilie addition of amines, aleohols, and thiols oeeurs to its terminal position and leads to the formation of the eorresponding l-heteroalk-l-en-3-ynes readily involved in diverse eyelization reaetions. 

As mentioned in the introduction, l-heterobut-l-en-3-ynes, RXCH=CHC=CH (X = RN, O, S R = organic radical), are the nearest and most important diacetylene derivatives readily formed by nucleophilic addition of amines, alcohols, and thiols to diacetylene. In many heterocyclization reactions (especially those leading to fundamental heterocycles) l-heterobut-l-en-3-ynes behave as diacetylene synthetic equivalents, but unlike diacetylene, they are nonhazardous. Therefore, the syntheses of heterocycles therefrom are often more attractive in preparative aspect. 

Acylurea derivatives are readily prepared in one step by addition of amines to acyl isocyanates in high yields (Eqs. 1 and 2)14>. 

Nucleophilic Addition of Amines Imine and Enamine Formation... 

Carbinolamine (Section 19.8) A molecule that contains the R2C(OH)NH2 functional group. Carbinolamines are produced as intermediates during the nucleophilic addition of amines to carbonyl compounds. 

Although the nucleophilic addition of secondary amines to thiirene dioxides can be interpreted as following the same mechanistic pathway, the reaction was found to be second order in amine119 (which is typical for the addition of amines to olefins in appropriate solvents13 2 133), and the addition is syn. As a result, mechanisms with a cyclic-concerted addition across the carbon-carbon bond, or a stepwise addition involving two molecules of amine per one molecule of thiirene dioxide, have been proposed. 

McDowell and Stirling194 studied electronic effects upon the reactivity of aryl vinyl sulfones towards amines. Rate constants for t-butylamine addition in ethanol at 25 °C were well correlated by the Hammett equation, with p = 1.59. Comparison of this with p values for H-D exchange mentioned above191 suggested considerable carbanionic character in the transition state, perhaps in a concerted mechanism. Rates of addition of amines to alkenyl, allenyl and alkynyl p-tolyl sulfones have also been measured195. 

Abbott and coworkers229 found that nucleophilic addition of amines to a, p-unsaturated sulfoxide gave asymmetrically induced adducts. For example, treatment of (R)-(—)-cis-propenyl p-tolyl sulfoxide 184 with piperidine in methanol gave a quantitative mixture of the diastereomeric adduct 185. Reduction of this mixture gave (Rs)-(Sc)-2-piperidinopropyl p-tolyl sulfide 186 in 74% optical yield, suggesting that the amines attack from the opposite side of the bulky aryl group at the transition state, as shown above (Figure 6). 

The effect of the solvent on the product distribution is observed in the conjugate addition of amines to 1-bromo-l-(phenylsulfonyl)alkenes (54) (equation 54)46. When the reaction is conducted in benzene at room temperature for 4 days, the adduct 55 is formed in good yield. On the other hand, the reaction in DMSO at 80-90 °C for 2.5 h affords 2-(phenylsulfonyl)aziridines (56) and no adduct (55) is isolated. 

Addition of amines to a,/J-unsaturated sulfones has been used in synthesis of key intermediates of biotin. In this reaction, benzylamine serves first as a base in the reaction with 60 to afford thiophene 1,1-dioxide (61) and also as a nucleophile to introduce two amino groups (equation 57)49. 

The stereochemistry of the addition of amines to acetylenic sulfones has been investigated by Truce and coworkers74. Reaction of phenyl 1-propynyl sulfone with ethylamine gives a mixture of ( )- and (Z)-isomeric adducts (equation 90)75. 

Scheme 5 Access to / -amino-substituted a,/ -unsaturated Fischer carbene complexes 30 by Michael-type addition of amines to alkynylcarbene complexes 23 (R=Et) [30,33]...

Reduction of iV-(3-bromopropyl) imines gives a bromo-amine in situ, which cyclizes to the aziridine. Five-membered ring amines (pyrrolidines) can be prepared from alkenyl amines via treatment with N-chlorosuccinimide (NCS) and then BusSnH. " Internal addition of amine to allylic acetates, catalyzed by Pd(PPh3)4, leads to cyclic products via a Sn2 reaction. Acyclic amines can be prepared by a closely related reaction using palladium catalysts. Three-membered cyclic amines (aziridines)... 

The Addition of Amines to Carbon Disulfide and Carbon Dioxide... 

Addition of amides to alkenes addition of amines to ketenes... 

Alkylation of enamines Addition of amines to triple-bond compounds Addition of amines to aldehydes or ketones Reaction between Grignard reagents and formamides Reaction of phosphonates with aldehydes or ketones... 

Intramolecular addition of amines to carbonyl groups (cyclic imines)... 

Addition of amines to isocyanates or isothiocyanates Addition of amines to CO2 or CS2... 

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