3- -1 chloropropane, synthesis

Replacement of one of the phenyl groups by an alkyl group of similar bulk, on the other hand, alters the biologic activity in this series. Alkylation of phenylacetonitrile with isopropyl bromide affords the substituted nitrile, 136. Treatment of the anion prepared from 136 with strong base with 2-dimethylamino-l-chloropropane gives isoaminile (137). It is of note that alkylation of this halide, isomeric with that used in the early methadone synthesis, is apparently unaccompanied by isomer formation. Isoaminile is an agent with antitussive activity. 

Addition of the Grignard reagent, prepared from 3-aryl-2-/.sopropyl-1 -chloropropane (340) to nitrone (339) is a very important step toward the synthesis of compound (342a) which is used in preparing the antihypertensive agent SPP-100B and its epimer (342b) (Scheme 2.143) (197). 

A very significant mortality in Western countries is associated with cardiac arrhythmias Consequently an intensive search is underway for agents to combat this condition - particularly for compounds with an unusual mode of action A class Ic (local anesthetic-like) agent of interest in ihis context is Indecainide (50) One of several routes to this compound covered by patents begins with sodium amide mediated alkylation of 9 cyanofluorene (48) with 3 isopropylamino-1 chloropropane to give amine 49 The synthesis concludes by partial hydrolysis of the nitnle func tion to a carboxamide linkage with sulfunc acid to produce indecainide (50) [15]... 

The first way of synthesis is by the alkylation of 10,ll-dihydro-5//-dibenz[b,f]azepme using l-bromo-3-chloropropane in the presence of sodium amide into a chloro derivative (7.1.12) and the subsequent reaction of this with methylamine, giving desipramine (7.1.13) [18-20]. 

Reactions of this type have been widely used for the synthesis of 1,5-benzoxazepines by the reactions of o-aminophenols and their derivatives with a variety of functionalized three-carbon chains. Thus reaction with 3-bromo-l-chloropropane gives (360) and reaction with 3-chloropropionyl chloride gives the analogous 4-oxo derivative. Similarly a,/3-unsatur-ated Icetones give (361), /3-ketoesters give (362), l,3-oxazolid-5-ones give (363), and the reaction of the sodium salt of N-methanesulfonyl-o-aminophenol with epichlorohydrin gives... 

Use of l,2-dibromo-3-chloropropane as a pesticide, soil fumigant and a nematocide resulted in the direct release of this compound to the environment. Its production and use as an intermediate in organic synthesis also may have resulted in its release to the environment through various waste streams. It has been detected at low levels in ambient and urban air, groundwater, drinking-water and soil samples (United States National Library of Medicine, 1997). 

SYNTHESIS To a solution of 3.3 g of KOH pellets in 150 mL hot MeOH, there was added 10 g 2,5-dimethoxythiophenol (see recipe for 2C-T-2 for its preparation) followed by 10 g 1-bromo-3-chloropropane. The reaction was exothermic, and immediately deposited white solids of KC1. The reaction mixture was warmed for a few min on the steam bath, and then quenched in HzO. The basic reaction mixture... 

Di Nunno, L. Franchini, C. Scilimati, A. Sinicropi, M. S. Tortorella, P. Chemical and hemoenzymatic routes to l-(benzothiazol-2-yl-sulfanyl)-3-chloropropan-2-ol, a precursor of drugs with potential /-blocker activity. Tetrahedron Asymmetry 2000, 11, 1571-1583. Cavelier, F. First synthesis of the enantiomerically pure a-hydroxy analogue of S-tert-butyl cysteine. Tetrahedron Asymmetry 1997, 8, 41-43. 

This reaction was easily extended to produce substituted cyclic ethers in a one-pot synthesis (Scheme 3). Thus, by carrying out the carbonylation of phenyllithium in the presence of l-bromo-3-chloropropane at — 78 °C, the lithium enolate intermediate 3 was obtained which cyclizes to 4 by warming up the reaction mixture. 

In the synthesis of 2-[3-(methylsulfanyl)propyl]-lf/-indole 572, the key step was the alkylation of indolyllithium 570 with excess of l-bromo-3-chloropropane (Scheme 116) <200381191 >. Treatment of the indole 571 with sodium methanethiolate gave the target sulfide 572 in high yield. This compound was used in the synthesis of 5-methyl-2,3,4,5-tetrahydrothiopyrano[3,2- ]indole (see Section 3.02.4.8). 

Argon. An Organic Syntheses procedure for the dialkylation of 1,3-dithiane with 1 -bromo-3-chloropropane, as a first step in the synthesis of cyclobutanone, specified that argon, if available, be used as the inert gas in preference lo nitrogen because of its greater density. ... 

The synthesis of 2-chloromethyl-5,6-diphenyl-2,3-dihydropyrazine from 1,2-diamino-3-chloropropane and benzil has been described (349) in Section II.2 and 2,5-bis(trichloropropenyl)pyrazine from 2,5-dimethylpyrazine and chloral (708) in Section lV.2C(5)(a). 

The preparation of the bisthioketal of cyclohexane-1,3-dione (25) illustrates the use of 2-lithio-1,3-dithiane for synthesis of cyclic diketones. The lithio derivative (2) is transformed as above into the bisdithiane (24), which is then heated successively with n-butyllithium, l-iodo-3-chloropropane, and finally /i-butyllithium.8... 

Consult ref. [157]. Transformation (b) is an example of a domino reaction (cf. problem 130). Aldehyde Y is obtained in 2 steps from (iy-cyclohexyl)butane-l-imine and l-bromo-3-chloropropane. Formulate this synthesis. 

The use of HMPA was mandatory for the success of the synthesis. Alternatively. (3-phosphanylpropyl)-cyclopentadlenyl anions 12 and 13 were prepared In 51% and 65% yield In a sequence of nucleophilic substitution reactions starting from l-bromo-3-chloropropane (11) by treatment with lithium phos-phides ° and then with NaCp in THF. followed by hydrolysis and deprotonation with butyllithium."... 

The synthesis of N-alkyl and N-aryl derivatives started from N - substituted o-phenylenediamines which reacted with urea to the benzimidazolones and were then alkylated with 1-bromo-3-chloropropane as described in Scheme 2. 

Synthesis of a vinyl cyclic acetal monomer is similar to the synthesis of a NVGA but includes a dehydrohalogenation step as shown in Figure 4. Stoichiometric amounts of the appropriate aryl aldehyde and 3-chloropropane-l,2-diol were reacted and worked up as previously described. The chloromethyl cyclic acetal intermediate was dissolved in toluene and added slowly to three equivalents of potassium rm-butoxide in toluene in a round bottom flask cooled in an ice bath. When the addition was complete, the mixture was allowed to warm to room temperature and stirred vigorously overnight. The dark reaction mixture was vacuum filtered through a paper filter covered with a small amount of silica gel. The filtrate was dried and concentrated as before. 

Scheme 13.6 Casillas and Townsend s synthesis of 0-methylsterigmatocystin (96). Reagents and conditions a) SbClg, 2-chloropropane b) K2CO3 c) Me0H/H20 d) SEMCl, DIPEA e) n-BuLi f) LiAlH4 g) TPAP, NMO h) n-BuLi i) BrCH2C02Et j) tartaric acid (aq) k) TIPSOTf, EtsN 1) LiAlH4 m) m-CPBA n) TPAP, NMO o) Et3N-(HP)3 p) PhSeH, Amberlyst 15 q) m-CPBA...

Matiychuk and co-workers were able to synthesize several trisubstituted pyrroles containing aryl substituents at position 4 via Hantzsch pyrrole synthesis. 3-Aryl-2-chloropropanals 11, 13, 15, and 17 reacted with ethyl acetoacetate 8 in the presence of ammonia to form the desired pyrroles 12, 14, 16, and 18 in modest yields. Modest yields were also obtained for benzyl acetoacetate derivatives in the same report using a similar protocol. 

Scheme 2 Crombie s synthesis of -)-(S,S)-homaline (1). Reagents and conditions (a) 2,2 -clithiodipyridine, PPhs, MeCN, reflux, 12 h (b) 1-bromo-3-chloropropane, KOH, DMSO, rt, overnight (c) liquid NH3, rt, 3 days (d) 1,4-dibromobutane, KOH, DMSO, rt, overnight (e) aq formaldehyde, NaBHsCN, MeCN, AcOH, rt, 1 h.

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