Cyclohexylamine preparation

Crystalline solid m.p. 35-36 "C, b.p. 154--156 C, prepared by oxidizing A,A -dicycIo-hexylthiourea with HgO in carbon disulphide solution, also obtained from cyclohexylamine and phosgene at elevated temperatures. Used as a mild dehydrating agent, especially in the synthesis of p>eptides from amino-acids. Potent skin irritant. 

Batch syntheses comparable to those used for MDA produce 3,3 -dimethy1methy1enedi(cyclohexylamine) marketed under the trade name Laromia C-260. The starting aromatic diamiae, 3,3 -dimethy1methy1enediani1ine [838-88-0] is prepared from o-toluidine [95-53-4] condensation with formaldehyde. Similarly 3,3 -dimethyldicyclohexylaniiae [24066-10-2] may be produced (38) from o-toHdine [119-93-7] derived from o-nitrotoluene [88-72-2]. The resultant isomer mixtures are dependent on reduction conditions as ia MDA hydrogeaatioa. 

Before a 1/1 /70 FDA ban (rescission proposed in early 1990), cyclamate noncaloric sweeteners were the major derivatives driving cycloliexylamine production. The cyclohexylsulfamic acid sodium salt (39) [139-05-9J and mote thermally stable calcium cyclohexylsulfamic acid (40) [139-06-1] salts were prepared from high purity cyclohexylamine by, among other routes, a reaction cycle with sulfamic acid. 

Sulfamation is the formation (245) of a nitrogen sulfur(VI) bond by the reaction of an amine and sulfur trioxide, or one of the many adduct forms of SO. Heating an amine with sulfamic acid is an alternative method. A practical example of sulfamation is the artificial sweetener sodium cyclohexylsulfamate [139-05-9] produced from the reaction of cyclohexylamine and sulfur trioxide (246,247) (see Sweeteners). Sulfamic acid is prepared from urea and oleum (248). Whereas sulfamation is not gready used commercially, sulfamic acid has various appHcations (see SuLFAMiC ACID AND SULFAMATES) (249—253). 

In the discussion of the relative acidity of carboxylic acids in Chapter 1, the thermodynamic acidity, expressed as the acid dissociation constant, was taken as the measure of acidity. It is straightforward to determine dissociation constants of such adds in aqueous solution by measurement of the titration curve with a pH-sensitive electrode (pH meter). Determination of the acidity of carbon acids is more difficult. Because most are very weak acids, very strong bases are required to cause deprotonation. Water and alcohols are far more acidic than most hydrocarbons and are unsuitable solvents for generation of hydrocarbon anions. Any strong base will deprotonate the solvent rather than the hydrocarbon. For synthetic purposes, aprotic solvents such as ether, tetrahydrofuran (THF), and dimethoxyethane (DME) are used, but for equilibrium measurements solvents that promote dissociation of ion pairs and ion clusters are preferred. Weakly acidic solvents such as DMSO and cyclohexylamine are used in the preparation of strongly basic carbanions. The high polarity and cation-solvating ability of DMSO facilitate dissociation... 

An amine-terminated poly ether (ATPE) is prepared as follows. Charge poly(tetramethylene oxide) diol (PolyTHF 1000, BASF, 75.96 g, 0.0759 m) to a 500-mL three-neck round-bottom flask fitted with a thermocouple, a mechanical stirrer, and a vacuum port. Add tert-butylacetoacetate (24.04 g, 0.1582 m) and apply vacuum. Heat at 175° C for 4 h, Fourier transform infrared (FTIR) analysis should indicate complete loss of the polyol OH absorption at 3300 cm. The room temperature viscosity of the product should be about 520 mPa-s. React this acetoacetylated product (85.5 g, 0.0649 m) with cyclohexylamine (14.5 g, 0.1465 m) at 110° C under vacuum for several hours. Cool the resultant cyclohexylaminocrotonate poly ether product to room temperature (1790 mPa-s at room temperature). 

Amiard, G. Heymes, R. (1956) N, N -Dicyclohexylcarbodiimide. Preparation from Urea and Cyclohexylamine. Bulletin de la Sociiti Chimique de France, 1360-1361. 

Preparation of 3 - Chloro-6 -cyclohexylaminoJluoran (85a). A mixture of 3, 6 -dichlorofluoran (0.1 mol), cyclohexylamine hydrochloride (0.15 mol), zinc chloride (0.3 mol), and zinc oxide (0.2 mol) was fused at 190-200 °C for 4 h. After being cooled, the solidified mixture was powdered, heated with 4% hydrochloric acid (1000 ml) to dissolve zinc chloride, and filtered. Then, the filter cake was refluxed with a mixture of toluene (400ml) and 5% aqueous sodium hydroxide (100 ml) for 1 h. The toluene layer was separated, washed with hot water, and concentrated. The residue was refluxed with methanol (200ml) for 1 h. After being cooled, the precipitate was filtered off, washed with methanol, and dried to give 3 -chloro-6 -cyclohexylaminofluoran in 60% yield as an off-white powder, mp 178-181 °C. 

Recently, Borner and coworkers described an efficient Rh-deguphos catalyst for the reductive amination of a-keto acids with benzyl amine. E.e.-values up to 98% were obtained for the reaction of phenyl pyruvic acid and PhCH2COCOOH (entry 4.9), albeit with often incomplete conversion and low TOFs. Similar results were also obtained for several other a-keto acids, and also with ligands such as norphos and chiraphos. An interesting variant for the preparation of a-amino acid derivatives is the one-pot preparation of aromatic a-(N-cyclohexyla-mino) amides from the corresponding aryl iodide, cyclohexylamine under a H2/ CO atmosphere catalyzed by Pd-duphos or Pd-Trost ligands [50]. Yields and ee-values were in the order of 30-50% and 90 >99%, respectively, and a catalyst loading of around 4% was necessary. 

The 2-phenylcyclobutylamines Structures 14 and 15 have also been prepared (161). In contrast to the cyclopropylamine, however, 15 showed no clinical activity following oral administration of a dose up to 25 mg of the racemic hydrochloride (199). The trimethoxy congener 14 has not been tested. The appropriately ring-substituted tran.s-2-phenylcyclopentyl or cyclohexylamines have not been reported. Based on the apparent lack of activity for 15, as well as the lack of activity for alpha-ethyl phenethylamine derivatives, however, these might be predicted to be inactive. 

Isopropylidenedi(cyclohexylamine) manufacture, 2 505 physical properties of, 2 500t Isopropylideneglycerol, preparation of, 76 554... 

Cyclohexylurea has been prepared by the reaction of cyclo-hexyl isocyanate with gaseous ammonia or ammonium hydroxide, by thermal decomposition of cyclohexyl allophanamide, by treating cyclohexylamine hydrochloride with an aqueous solution of potassium cyanate," by heating nitrosomethylurea with cyclohexylamine, and by heating an ethanolic solution of cyclohexylamine and 3,5-dimethyl-l-carbamylpyrazole. 2,6-DimethyIphenyIthiourea has been synthesized by allowing 2,6-dimethylaniline hydrochloride to react with ammonium thiocyanate. ... 

Further routes of cyclizations have been studied in parallel in the case of cis- and rra/J5-2-hydroxymethyl-l-cyclohexylamine (106) (880PP73). The preparation of thiourea or urea adducts 107 and 108 with phenyl isothiocyanate or phenyl isocyanate proceeds smoothly. The reaction of 107 with methyl iodide and subsequent alkali treatment, by elimination of methyl mercaptan, resulted in the iminooxazine 109 in high yields. The ring closures of both cis and trans thiourea adducts to 1,3-oxazines proceed with retention. Cyclodesulfuration of the adduct 107 by mercury(II) oxide or N,N -dicyclohexylcarbodiimide resulted in the iminooxazine 109, but the yield was low and the purification of the product was cumbersome. The ring closure of 108 with thionyl chloride led to the iminooxazine 109 in only moderate yield. 

In the reactions of cis- and rrans-2-aminomethyl-l-cyclohexanol or -1-cycloheptanol or cis- and trans-2-hydroxymethyl-l-cyclohexylamine or -1-cycloheptylamine with ethyl 4-chlorobenzimidate, the stereo- and regio-isomeric derivatives and homologs 164 and 165 were prepared (79T799). The amidine intermediate 166 of the benzimidate ring closure was also... 

Since acetic acid and acetic anhydride mixtures are excellent solvents for amides derived from primary carbinamines and cyclohexylamines, A-nitroso derivatives can be prepared in this solvent medium with sodium nitrite. The method appears to be somewhat more rapid than that carried in an aqueous medium, but fails when amides derived from secondary carbinamines are to be nitrosated. As the reaction medium is one which will also acetylate primary amines, appropriate amines may be dissolved in the reaction medium and, in turn, acetylated and nitrosated without the isolation of the intermediate amide. 

Phosphoenolpyruvic acid tris(cyclohexylamine) salt [35556-70-8] M 465.6, m 155-180°(dec). Recrystd from aqueous Me2CO and dried in a vacuum. At 4° it is stable for >2 years and has IR at 1721cm (C=O). [Wold and Ballou JBC 227 301 1957 Clark and Kirby Biochemical Preparations 11 103 7966 for the monocyclohexylamine salt]. 

Using essentially the same method the following amines have been prepared in 50-60 per cent yields M-butylamine, b. p. 75-80°, from butyraldoxime sec.-butylamine, b. p. 59-65° from ethylmethyl ketoxime cyclohexylamine, b. p. 133-1350, from cyclohexanoneoxime. Greater care must be observed in drying the butylamines. 

SYNTHESIS In 50 mL of benzene there was dissolved 31.6 g 2,5-dimethoxy-4-methylbenzaldehyde (see recipe for 2C-D for its preparation), 20.2 mL 1-nitropropane, and 6 mL cyclohexylamine. This solution was held at reflux in a Dean Stark apparatus for 24 h, effectively removing the water of reaction. Upon cooling, there was deposited 19.6 g of 1 -(2,5-dimethoxy-4-methylphenyl)-2-nitro-1 -butene as brilliant orange crystals. The mp, after recrystallization from MeOH, was 114-115 °C and a second recrystallization increased the mp another 2 °C. Anal. 

Notwithstanding, conformational factors apparently play a part in the enamine-imine equilibrium of the SchifF base prepared from cyclohexanone and cyclohexylamine, as shown by their infrared spectra 28 the base appears to be a mixture of both tautomeric forms, N-cyclo-hexylidenecyclohexylamine and N-1 -cyclohexenyIcyclohexylamine. Replacement of the cyclohexyl group by a phenyl group appears to stabilize the imino form.24... 

As the last example of an SN reaction at the carboxyl carbon of a carbonic acid derivative, consider the synthesis of dicyclohexylurea in Figure 6.39. In this synthesis, two equivalents of cyclohexylamine replace the two methoxy groups of dimethyl carbonate. Dicyclohexylurea can be converted into the carbodiimide dicyclohexylcarbodiimide (DCC) by treatment with tosyl chloride and triethylamine. The urea is dehydrated. The mechanism of this reaction is identical to the mechanism that is presented in Figure 8.9 for the similar preparation of a different carbodiimide. 

An example of the simplicity and potential of the photo-oxygenation reaction is described for the preparation of (Z)-l-hydroperoxy-A-[(Z)-3-methoxycarbonyl)-2-propenylidene]cyclohexylamine A-oxide (P) starting from 2-methoxyfuran and cyclohexanone oxime, which both can be purchased and used without further purification. 

Only one aldehyde derivative has been prepared. Treatment of l-(2-hydroxyethyl)-l//-pyrazolo[3,4-b]pyrazine-5-carboxylaldoxine (272a) with sodium nitrite and HC1 gave the aldehyde (273) (92%) which is readily converted into the imine (272b) on treatment with cyclohexylamine (Equation (33)) <90JAP02172988>. 

Potassium 2-methoxytellurobenzoate was prepared from bis[2-methoxybenzoyl] tellurium and potassium ethoxide in dichloromethane under an atmosphere of argon at — 30°. The ammonium salts were formed similarly by addition of cyclohexylamine, piperidine, or morpholine to diacyl telluriums2. 

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