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armageddon:
I have a question about chirality/optical rotation. in some other thread I stated the following:

"oxime reductions result usually in more potent product, as the syn/anti ratio of the intermediate oxime is 9:1 or something like that. In most cases, this means a more potent phenylisopropylamine - not with 3,4-methylenedioxy compounds, but in most other cases"

 - first question: can anybee confirm this? Or did I write bogus?

 - next question: Assume that said oxime is hydrolyzed back to P2P (e.g. ketone purification via oxime): what is the rotation of the P2P? Or is it again racemic?

 - last question: if said P2P is reductively aminated w/NH4COOH àla Leuckart: is the end product (after hydrolysis) THEN racemic? I would guess so?

THX A

moo:
Racemic P2P? Did you miss the stereochem classes? ;)  :P  You are mistaking the stereochemistry of the oxime group with the stereochemistry of the asymmetric carbon of amphetamine molecule - they are two different things (you wrote bogus). The chiral center of the alpha carbon isn't present in P2P or its oxime. It is formed during the reduction of the imine/oxime/schiff base of P2P and unless the method used is stereoselective, which Leuckart isn't, the product is going to be racemic. Discussion about oximes in a Leuckart thread is quite off-topic, btw.

lugh:
The article requested in Post 518070 (moo: "Please", Novel Discourse) and abstracted in Post 512060 (missing) (moo: "Nickel catalyzed Leuckart reaction.", Methods Discourse)

J. Gen. Chem. U.S.S.R. 25, 1377-81(1955)(Engl. translation)




8)

moo:
Thank you very much lugh! :)  That article really made my day. It also made me notice there were a few references on the subject that I had missed completely! They might not be so good as the one above, but I'll include them for the sake of completeness. ;)  The first one actually uses the very same catalyst Zealot uses in his procedure. Urushibara nickel might work too by the way. Dedicated to Uncle Fester praising the Leuckart reaction while calling Soviet scientists lying commies. :P



Reaction of formamide with carbonyl compounds in the presence of nickel catalyst.
Kost, A. N.; Terent'ev, A. P.; Shvekhgeimer, G. A.
Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, , 150-60 (1951).
CAN 45:60003  ISSN 0002-3353

Abstract
The reaction of HCO2NH2 with carbonyl compds. is accelerated by the presence of hydrogenation catalysts (Ni, Co, Pt, Pd, etc.), and the limit of active temp. is lowered by 20-80 Deg.  Particularly effective are such substances in reactions of naphthenic compds.  The use of catalysts improves the yield of primary amines.  The results indicate that the mechanism of the reaction is such the H2O-removing substances have little bearing on it and the true mechanism may proceed by addn. of HOCNH2 to R2CO in the sense of addn. of the HOC and NH2 (or NR2) fragments across the CO link of the carbonyl; the resulting R2C(NH2 or NR2)OCHO then decomp. into CO2 and the amine R2CHNH2 (or NR2).  The above mentioned catalysts give 2-5% better yields of RNH2 at 110-30 Deg in comparison with the 180 Deg required without a catalyst.  The Ni catalyst was prepd. by treating Ni carbonate with excess HCO2H 10-12 hrs. at room temp., filtering the Ni formate, and thermally decompg. the requisite amt. just before use after moistening with a little HCO2H; the decompn. was done by an ordinary burner.  Typical reactions with HCO2NH2 (I) (from the reaction of 82% HCO2H with (NH4)2CO3, followed by concn.) follow.  Heating 60 g. I, 1 g. Ni catalyst, and 24.5 g. MeEtCO 60 hrs. at 90 Deg and 6 hrs. at 160 Deg, then hydrolysis by boiling 2 hrs. with 100 ml. concd. HCl, gave 51.5% 2-aminobutane, b758 61-3 Deg; picrate, m. 137-8 Deg.  Similarly 60 g. I and 30 g. MePrCO with 1 g. Ni gave 43.5% 2-aminopentane, b750 88-91 Deg; HCl salt, m. 168 Deg (from EtOH).  To 60 g. I and 1 g. Ni in a Claisen flask heated to 130 Deg was slowly (0.5 hr.) added 25 g. EtPrCO and the mixt. heated 7 hrs. at 125-30 Deg with recycling of the distd. ketone, yielding 32.8% 3-aminohexane, b751 118-22 Deg; HCl salt, m. 225 Deg.  Similarly MeAmCO gave 55.1% 2-aminoheptane, b756 140-3 Deg; HCl salt, m. 133 Deg; heating at 120-5 Deg 4 hrs. gave a 49% yield.  Similarly Pr2CO after 8 hrs. at 140 Deg gave 63.8% 4-aminoheptane, b753 138-41 Deg; HCl salt, m. 240-1 Deg (from EtOH); at 130-5 Deg the yield is 64.4%, when the proportion of the ketone is higher.  I (75 g.) and 48 g. MeCOC6H13 gave in 2 hrs. at 155-60 Deg 59.4% 2-amino.ovrddot.octane, b752 164-7 Deg; HCl salt, m. 83.5 Deg (from EtOH).  Heating 120 g. I, 2 g. Ni, and 34.2 g. iso-Pr8CO to 100-10 Deg, when reaction starts, and gradually heating to 150 Deg over 8 hrs. gave, after 6 hrs.' hydrolysis by hot HCl, 61.5% 3-amino-2,4-dimethylpentane, b756 124-6 Deg.  Repetition with 90 g. I and 27 g. iso-Pr2CO, 6 hrs. at 120-30 Deg with 4 hrs.' hydrolysis, gave 45.9% above amine and 5.9 g. 3-formamido-2,4-dimethylpentane, b754 240 Deg, b9 128-30 Deg, n20D 1.4569.  Heating 60 g. I with 30 g. AcCMe3 and 1 g. Ni 10 hrs. at 105-10 Deg and hydrolysis 2 hrs. with concd. HCl gave 73.4% 3-amino-2,2-dimethylbutane, b756 101-3 Deg; HCl salt, sublimes at 245 Deg; a lesser excess of I and shorter hydrolysis period (1 hr.) gave 65% of the above amine and 18.7% 3-formamido-2,2-dimethylbutane, b756 232-5 Deg, b6 107.5 Deg, n20D 1.4506; if the heating period is 10 hrs. at 160-70 Deg and the hydrolysis 5 hrs., 50 g. I and 23 g. ketone give only a trace of the above amine, the main product (44% yield) being the formyl deriv., b11-12 120-5 Deg, n20D 1.4532, d204 0.9243, and a substance, b. above 250 Deg, whose structure is unknown.  Addn. of 29.4 g. cyclohexanone to 90 g. I and 1 g. Ni preheated to 130 Deg and heating 30-5 min. at 130-5 Deg, followed by boiling 10-15 min. with concd. HCl, gave 55.2% cyclohexylamine, b750 132-4 Deg [HCl salt, m. 206 Deg (from EtOH)], and 26% dicyclohexylamine, b14 122-5 Deg [HCl salt, m. 338 Deg (from EtOH)].  I (60 g.) and 29.4 g. ketone gave, after 1 hr. at 120 Deg and 10-min. hydrolysis, 53% RNH2 and 3% R2NH; heating 15 min. to 150 Deg gives complete reaction and a 25% yield of RNH2.  Reaction with 2-methylcyclohexanone at 160-75 Deg (10-15 min.) with 0.5-hr. hydrolysis gave 51% 2-methylcyclohexylamine, b758 150-50.5 Deg [picrate, m. 77.5 Deg; HCl salt, m. 268 Deg (from EtOH)]; some 15.6% bis(2-methylcyclohexyl)amine, R2NH, b12 135-7 Deg (HCl salt, m. 281 Deg), also forms along with some formyl deriv. of the primary amine.  Similarly 3-methylcyclohexanone gave 44% 3-methylcyclohexylamine, b750 150-1 Deg (HCl salt, m. 174 Deg), and 19.6% bis(3-methylcyclohexyl)amine, b7 127.5-8.5 Deg, b12 132-5 Deg, b750 168-70 Deg, n20D 1.4783, d204 0.8967; 90 g. I and 52 g. ketone gave after 70 min. at 100-5 Deg and 2 hrs.' hydrolysis 26% primary and 44% secondary amine.  Reaction of 90 g. I, 1.5 g. Ni, and 60 g. AcPh 1.5 hrs. at 130-40 Deg, followed by diln. with H2O, extn. with Et2O, and hydrolysis of the ext. by hot concd. HCl (2 hrs.), gave 67.5% PhCHMeNH2, b756 185-8 Deg; HCl salt, m. 158 Deg.  PhCOEt gave in 3 hrs. at 150 Deg, followed by 6 hrs.' hydrolysis, 64.1% PhCHEtNH2, b758 203-5 Deg (HCl salt, m. 187 Deg); an excess of the ketone after 1 hr. at 150-60 Deg with 10 hrs.' hydrolysis gives 68%.  Reaction of EtNHCHO (from 50 g. EtNH2), 46 g. cyclohexanone, and 1 g. Ni gave in 1.5 hrs. at 130-40 Deg, 23.3% ethylcyclohexylamine, b764 163-6 Deg (HCl salt, m. 182 Deg; phenylureide, m. 124-5 Deg); in addn. some 53.3% N-ethyldicyclohexylamine, b5 114.5-15.0 Deg, b748 246-50 Deg, n20D 1.4838, was formed.  Reaction without catalyst (7 hrs. at 160-80 Deg) gave 33% tertiary amine and no secondary amine.  PhNHCHO (from 90 g. PhNH2) with 2 g. Ni and 29.4 g. cyclohexanone after 1 hr. at 110-20 Deg, with 2 hrs.' hydrolysis by concd. HCl, gave 51% N-cyclohexylaniline, b9 139-41 Deg, b10 140 Deg, n20D 1.5659 [HCl salt, m. 227 Deg; picrate, m. 164 Deg (from MeOH)]; heating 1 hr. at 100-10 Deg gave 54% yield; without catalyst, 46% is obtained in 7 hrs. at 180-90 Deg.  Usually, lower reaction temps. and shorter reaction times require shorter hydrolysis periods (brief heating suffices), while reaction time of over 1 hr. usually requires more drastic hydrolysis because of the considerable amts. of formyl deriv. formed.


Synthesis of amines by the method of Leuckart.
Kost, A. N..
Nauchnye Doklady Vysshei Shkoly, Khimiya i Khimicheskaya Tekhnologiya, (No. 1), 125-9. (1958).
CAN 53:16978  ISSN 0470-469X

Abstract
The use of Ni and Co catalysts in the Leuckart reaction is studied.  The procedure for the synthesis of a few amines is given.  To 60 g. dry formamide (I) heated to 130 Deg is added 1 g. skeletal Co and then during 1 hr. 35 g. AmCOMe in 35 ml. 85% HCO2H (originally read HCHO but that must be a typo)(II), the mixt. refluxed under a small condenser 4 hrs. (120-40 Deg) (water and a little ketone evap. which neutralized with NaOH are returned to the flask), giving on cooling, hydrolyzing, extg. and distg. 60%, 2-aminoheptane, b752 140-2 Deg, and di(2-heptyl)amine b6 110-1 Deg, n20D 1.4421, d2020 0.8073.  Dry I (75 g.) and 48 g. Me hexyl ketone in 30 ml. 85% II soln. treated as above (130-60 Deg, 3.5 hrs.) in the presence of skeletal Ni yielded 65% 2-amino.ovrddot.octane, b758 165-7 Deg, and 8% di(2-octyl)amine, b7 140-1 Deg, n20D 1.4432, d2020 0.8058.  Dry I (1 part NH4O2CH and 6-7 parts I) (50 g.), 30 g. cyclopentanone (III), and 20 g. 85% II soln. heated to 120 Deg in the presence of 2 g. skeletal Co 4 hrs., cooled, dild. with water, and extd. 6 hrs. with Et2O yielded after fractional distn. 45% dicyclopentylamine, b16 118-20 Deg, 10% formylcyclopentylamine, b10 127-30 Deg, and 8 g. residue, b10 above 180 Deg.  To I, obtained from 139 g. aniline and 86 g. 80% II soln., is added at 120 Deg 1 g. Co and 25 g. cyclopentanone, the mixt. refluxed 4 hrs., decanted from the catalyst with excess 15% HCl, leached, extd. with Et2O, and distd. giving 80% cyclopentylaniline.  I (27 g.), 10 ml. dry II, and 0.5 g. skeletal Ni is heated 0.5 hr. at 130 Deg, 12 g. 3-methylcyclohexen-2-one added dropwise, then 5 ml. II, the mixt. refluxed 2 hrs. more, cooled, 250 ml. 15% HCl added, the soln. boiled 5 hrs., decompd. by NaOH under a layer of C6H6, the aq. layer extd. 6 hrs. with Et2O, and the ext. dried giving 3-methylcyclohexylamine, b750 149-52 Deg.  Urea (60 g.), 58.4 g. cyclohexanone (IV), 35 ml. 85% II, and 1 g. skeletal Ni is refluxed 4 hrs. vigorously, 65 ml. 85% II added dropwise, the mixt. cooled, decanted, evapd. in a porcelain dish with 400 ml. concd. HCl nearly to dryness, the residue leached under reflux with 170-200 ml. 40% KOH, the sepd. layer extd. with Et2O, dried over molten KOH, and distd. yielding 22-30 g. cyclohexylamine and 23-29 g. dicyclohexylamine. To I, obtained by neutralizing 93 g. freshly-distd. aniline with 85% II soln. and subsequent evapn. of the H2O, is added 2 g. Ni and 29.4 g. IV and the mixt. refluxed 1 hr. giving by the usual treatment 43-51% cyclohexylaniline and 36.5% N,N-dicyclohexylaniline.  To 30 g. I and 0.3 g. Ni is added at 130 Deg 18 g. butyrophenone in 10 ml. anhyd. II during 1 hr. while the temp. of the mixt. rises gradually to 150 Deg, the mixt. then heated gradually to 170 Deg 4 hrs., replacing from time to time the evapd. butyrophenone (after neutralizing with NaOH), when reaction ceases 100 ml. 20% HCl added, the soln. refluxed 8 hrs., and treated as usual giving 75% a-phenylbutylamine.  Dry 60 g. I is heated to 100 Deg with 1.5 g. Ni and during 0.5 hr. 40 g. BzH in 46 g. anhyd. II added, after the vigorous boiling of the soln. ceases heated 1 hr. more at 130 Deg, on cooling 200 ml. 10% HCl added, the soln. refluxed 3 hrs., neutralized with 40% KOH, extd. with Et2O, dried, and evapd. yielding 32.2 g. benzylamine, the aq. layer still contg. 3.6 g. (overall yield 88.5%).


Synthesis of substituted benzhydrylamines by Leuckart reaction.
Kalamar, J.; Ryban, B.
Chemicke Zvesti, 20(1), 79-84 (1966).  Journal written in Slovak.
CAN 64:93044  ISSN 0366-6352
 
Abstract
A modified method for the synthesis of benzhydrylamines by the Leuckart reaction from benzophenones, HCO2H, urea, and a small amt. Ni as catalyst gave the following I.HCl (R, R1, m.p.,% yield, and m.p. N-acetyl deriv. given): H, H, 290 Deg, 95, 149 Deg; 2-Cl, H, 235 Deg, 95, --; 3-Cl, H, 230 Deg, 90.3, 124 Deg: 4-Cl, H, 279 Deg, 96, 130-1 Deg; 4-Cl, 4-Cl, 278-9 Deg, 90, --; 2-Br, H, 257-8 Deg, 67.2, 191 Deg; 3-Br, H, 244 Deg, 85, 114 Deg; 4-Br, H, 246 Deg, 85, 152 Deg; 4-Br, 4-Br, 243 Deg, 84, --; 2-OMe, H, 216-17 Deg, 75, --; 4-OMe, H, 229 Deg, 75, 165 Deg; 4-OMe, 4-OMe, 199-200 Deg, 52.6, --; 3-Me, H, 230 Deg, 74.8, 108 Deg; 4-Me, H, 260 Deg, 90, 136 Deg; 4-Me, 4-Me, 243 Deg, 92, 164 Deg; 4-NH2.HCl, H, 290 Deg (decompn.), 60, --. a-Naph- thylphenylmethylamine-HCl m. 292 Deg; N-acetate m. 228 Deg.

armageddon:
Hi! VEEERY interesting! But maybe these combined CTH/leuckart is just for theoretical argument - in real live, I wouldn't bother with the 2-5% higher yield if the workup would become much more work-intensive (hydrolysis while non-noble metals are present? No THX...  ;) )

And instead of taking care of a proper leuckart-conform heating AND babysitting a CTH, I would therefore rather choose one of these methods than trying to combine them...

Yields are nearly the same; product purity is better with pure CTH, leuckart rxn is scalable almost indefinately...

(ok when multiple kilo scaleups are on the plan, the few percent higher yield may become of interest..  :) )

But as the leuckart is characterized by being a non-catalyzed reaction using formate ion as the reducing agent for imines, whereas CTH uses different hydrogen donors in conjunction with a H+-transferring catalyst and sometimes involves different intermediates, I would rather say this is DEFINATELY a CTH...

(at least we know that these reductions can both be carried out in same flask simultaneously - competing, but not interfering maybe?)


Greetz A

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