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The stereochemistry of the reaction of methyl- and phenyllithium at the keto group of γ-piperidones - E.A. Mistryukov, G.I. Smirnova and N.I. Aronova – Russ Chem Bull 19(6), 1301-1305 (1970) - DOI: 10.1007/BF00852679

The stereochemistry of the reaction of methyl- and phenyllithium at the keto group of γ-piperidones - E.A. Mistryukov, G.I. Smirnova and N.I. Aronova – Russ Chem Bull 19(6), 1301-1305 (1970) - DOI: 10.1007/BF00852679

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The stereochemistry of the reaction of methyl- and phenyllithium at the keto group of γ-piperidones - E.A. Mistryukov, G.I. Smirnova and N.I. Aronova – Russ Chem Bull 19(6), 1301-1305 (1970) - DOI: 10.1007/BF00852679
http://www.springerlink.com/content/t14334h753k5364x/
1970, Volume 19, Number 6, 1301-1305, DOI: 10.1007/BF00852679
Authors: EA Mistryukov, GI Smirnova and NI Aronova
Journal: Russian Chemical Bulletin, Russ. Chem. Bull., Russ Chem Bull
ISSN: 1066-5285 (print) 1573-9171 (online) 10665285 15739171

ABSTRACT:
(1) The stereochemistry of the reaction of methyl- and phenyllithium at the keto-group of some γ-piperidones has been studied. gamma-piperidones
(2) A quantitative estimate has been made using gas-liquid chromatography of the proportions of reaction products of certain substituted 4-ketopiperidines with methyl- and phenyllithium under different conditions of synthesis.

Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 6, pp. 1381–1387, June, 1970.
Izvestiya Akademii Nauk SSSR, Otdelenie Khimicheskikh Nauk
Proceedings of the Academy of Sciences SSSR, Department of Chemical Sciences
Izvestiya Akademii Nauk SSSR Otdelenie Khimicheskikh Nauk
Izvestiya Akademii Nauk SSSR Seriya Khimicheskaya
Izvestiya Akademii Nauk SSSR Seriya Khimicheskaya
Izvestiya Akademii Nauk S.S.S.R., Seriya Khimicheskaya
Bull. Acad. Sci. U.S.S.R., Chem. Series
Bulletin of the Academy of Science USSR, Chemistry Series

organic chemistry, medicinal chemistry, molecular biology, biochemistry, drug synthesis, drug manufacture, opioids, opiates, methamphetamine, MDMA, fentanyl, methadone, buprenorphine, diacetylmorphine oxycodone, oxycontin, morphine, opium poppy, narcotic analgesic analgetic, alkaloids, Papaver somniferum, dextropropoxyphene, hydrocodone, vicodin, percocet, lortab, darvocet, darvon, thebaine, oripavine, tramadol, hydromorphone, oxymorphone, diacetylmorphine, heroin, partial mixed agonist antagonist, μ-opioid receptor, naloxone, naltrexone, narcan, kratom, salvinorin A B, Salvia divinorum, semi-synthetic, papaverine, noscapine, endogenous opioid peptides, endorphins, enkephalins, dynorphins, endomorphins, levorphanol, dextromoramide, DXM dextromethorphan, chronic pain, NMDA antagonists, Tricyclic antidepressants, analgetic, analgesia, anesthetic, anesthesia, paracetamol, Tylenol 3 III, cough suppressant, antitussive, psychedelic, cannabinoid, cannabis, marijuana, delta 9 tetrahydrocannabinol THC, GABAergic, neurotransmitters, opioid-receptor-like receptor 1 ORL1, ketazocine, cyclazocine, etorphine, hallucinogen, cocaine, methamphetamine, dextroamphetamine, levoamphetamine, clandestine opioid opiate synthesis syntheses, dextromethamphetamine, desoxyn, adderall, concerta, ritalin, methylphenidate, sulphate, hydrochloride, stereochemical resolution, enantiomeric enantiomers, isomers, stereochemistry, dl-amphetamine, dl-methamphetamine, racemic, racemate, fentanyl analogs analogues, carfentanil, betahydroxyfentanyl, ohmefentanyl, sufentanil, brifentanil, lofentanyl, lofentanil, thiofentanil, thiofentanyl, alphamethylfentanyl, AMF, alpha-methylfentanyl, 3-methylfentanyl, 3MF, TMF, mefentanyl, subutex, suboxone, codeine, diprenorphine, addiction, controlled substance, psychomotor stimulants, mu u kappa delta opioid receptor agonist antagonist, sigma receptor, painkillers, ephedrine, pseudoephedrine, synephrine, recreational use, addiction treatment, withdrawal, tolerance, dependence, constipation, diarrhea, respiratory depression, sedatives, nausea, emesis, antiemetic, azaprocin, benzodiazepines, barbiturates, alprazolam, clonazepam, diazepam, flunitrazepam, midazolam, loperamide, difenoxin, diphenoxylate, paregoric, laudanum, piritramide, Benzitramide, Bezitramide, pharmacology, pharmacy, medicine, pharmaceutical formulation, bioorganic, inorganic chem, pharmacokinetics, pharmacodynamics, dipipanone, phenadoxone, Paul A.J. Janssen, Janssen Pharmaceutica Pharmaceuticals, GSK, Pfizer, Merck,
The stereochemistry of the reaction of methyl- and phenyllithium at the keto group of γ-piperidones - E.A. Mistryukov, G.I. Smirnova and N.I. Aronova – Russ Chem Bull 19(6), 1301-1305 (1970) - DOI: 10.1007/BF00852679
http://www.springerlink.com/content/t14334h753k5364x/
1970, Volume 19, Number 6, 1301-1305, DOI: 10.1007/BF00852679
Authors: EA Mistryukov, GI Smirnova and NI Aronova
Journal: Russian Chemical Bulletin, Russ. Chem. Bull., Russ Chem Bull
ISSN: 1066-5285 (print) 1573-9171 (online) 10665285 15739171

ABSTRACT:
(1) The stereochemistry of the reaction of methyl- and phenyllithium at the keto-group of some γ-piperidones has been studied. gamma-piperidones
(2) A quantitative estimate has been made using gas-liquid chromatography of the proportions of reaction products of certain substituted 4-ketopiperidines with methyl- and phenyllithium under different conditions of synthesis.

Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 6, pp. 1381–1387, June, 1970.
Izvestiya Akademii Nauk SSSR, Otdelenie Khimicheskikh Nauk
Proceedings of the Academy of Sciences SSSR, Department of Chemical Sciences
Izvestiya Akademii Nauk SSSR Otdelenie Khimicheskikh Nauk
Izvestiya Akademii Nauk SSSR Seriya Khimicheskaya
Izvestiya Akademii Nauk SSSR Seriya Khimicheskaya
Izvestiya Akademii Nauk S.S.S.R., Seriya Khimicheskaya
Bull. Acad. Sci. U.S.S.R., Chem. Series
Bulletin of the Academy of Science USSR, Chemistry Series

organic chemistry, medicinal chemistry, molecular biology, biochemistry, drug synthesis, drug manufacture, opioids, opiates, methamphetamine, MDMA, fentanyl, methadone, buprenorphine, diacetylmorphine oxycodone, oxycontin, morphine, opium poppy, narcotic analgesic analgetic, alkaloids, Papaver somniferum, dextropropoxyphene, hydrocodone, vicodin, percocet, lortab, darvocet, darvon, thebaine, oripavine, tramadol, hydromorphone, oxymorphone, diacetylmorphine, heroin, partial mixed agonist antagonist, μ-opioid receptor, naloxone, naltrexone, narcan, kratom, salvinorin A B, Salvia divinorum, semi-synthetic, papaverine, noscapine, endogenous opioid peptides, endorphins, enkephalins, dynorphins, endomorphins, levorphanol, dextromoramide, DXM dextromethorphan, chronic pain, NMDA antagonists, Tricyclic antidepressants, analgetic, analgesia, anesthetic, anesthesia, paracetamol, Tylenol 3 III, cough suppressant, antitussive, psychedelic, cannabinoid, cannabis, marijuana, delta 9 tetrahydrocannabinol THC, GABAergic, neurotransmitters, opioid-receptor-like receptor 1 ORL1, ketazocine, cyclazocine, etorphine, hallucinogen, cocaine, methamphetamine, dextroamphetamine, levoamphetamine, clandestine opioid opiate synthesis syntheses, dextromethamphetamine, desoxyn, adderall, concerta, ritalin, methylphenidate, sulphate, hydrochloride, stereochemical resolution, enantiomeric enantiomers, isomers, stereochemistry, dl-amphetamine, dl-methamphetamine, racemic, racemate, fentanyl analogs analogues, carfentanil, betahydroxyfentanyl, ohmefentanyl, sufentanil, brifentanil, lofentanyl, lofentanil, thiofentanil, thiofentanyl, alphamethylfentanyl, AMF, alpha-methylfentanyl, 3-methylfentanyl, 3MF, TMF, mefentanyl, subutex, suboxone, codeine, diprenorphine, addiction, controlled substance, psychomotor stimulants, mu u kappa delta opioid receptor agonist antagonist, sigma receptor, painkillers, ephedrine, pseudoephedrine, synephrine, recreational use, addiction treatment, withdrawal, tolerance, dependence, constipation, diarrhea, respiratory depression, sedatives, nausea, emesis, antiemetic, azaprocin, benzodiazepines, barbiturates, alprazolam, clonazepam, diazepam, flunitrazepam, midazolam, loperamide, difenoxin, diphenoxylate, paregoric, laudanum, piritramide, Benzitramide, Bezitramide, pharmacology, pharmacy, medicine, pharmaceutical formulation, bioorganic, inorganic chem, pharmacokinetics, pharmacodynamics, dipipanone, phenadoxone, Paul A.J. Janssen, Janssen Pharmaceutica Pharmaceuticals, GSK, Pfizer, Merck,

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THE STEREOCHEMISTRY OF THE REACTION OFMETHYL- AND PHENYLLITHIUM AT THE KETOGROUP OF ~/-PIPERIDONESE. A. IVIistryukov, G. I. Smirnova,and N. I. Aronova
UDC 541.63 + 547.559.44 + 547.824
Problems in the stereochemistry of the metaloorganic synthesis using ~-piperidones have been con-sidered repeatedly already (see [I] and references in this paper). However the evaluation of various fac-tors which determine the stereochemistry of this reaction has been hindered to a considerable extent bythe absence of sufficiently reliable quantitative data on the relationship between the epimeric tertiary al-cohols formed in this way, and the variety of conditions of carrying out the synthesis. A quantitative eva-luation using gas - liquid chromatography (GLC) has been carried out in the current work on the proportionsof the reaction products of some substituted 4-ketopiperidones with methyl- and phenyllithium. The resultsobtained are given in Tables 1 and 2.*If the two ketones 1,3-dimethylpiperidone and 2-methylcyclohexanone, which are close in structure[see Table 1 (I) and (If)], are compared, then attention is drawn to the far greater sensitivity of piperidone(II) to the synthetic conditions compared with ketone (1). Furthermore a dependence of the proportion ofepimeric alcohols on the type of lithium salt present in the metaloorganic reagent was observed for someof the piperidones investigated. Maximal stereodirectivity in the reaction was observed in Lhe case of lithi-um iodide [see Table 1 (IIa, IIb, and IIc)]. On the other hand for the conformationally rigid system trans-decahydroquinol-4-one (III) r for ketones with hindered nitrogen functions (IV and VI) the result of the reactiondepended to a far lesser degree onboth the method of conducting the reaction and on the type of lithium salt.These data can serve as a confirmation of the participation of the nitrogen function of ~/-piperidones on thereaction of the carbonyl of these ketones with metaloorganic reagents. It is logical to suppose that com-plex formation takes place in the first stage of the reaction at the nitrogen function of the ~/-piperidone withthe electrophilic reagent, viz., the organolithium compound [ ] and the lithium salt present in this solution ofreagent. Complex formation at the nitrogen function will obviously be maximal in the case of the strongerLewis acids, lithium chloride and bromide. In the case of piperidine compounds unhindered at the nitrogenatom it is possible to suppose that, by analogy with the quaternization reaction with alkyl halides [9], a com-plex of type A in Scheme 1 with axial orientation of bulky groupings will be present in significant relativeproportion [I0].This, in turn, can lead to a significant increase in the relative proportion of axial conformer B forthe conformationally labile compounds (II) and especially (V). This conclusion, which has been inferred,was confirmed by comparison of the results for ketones (II) and (IV). In fact for ketone (IV), which is hind-ered at nitrogen, complex formation at nitrogen must be strongly hindered also since this unstable complex* The stereochemistry of N-methyl substituted 4-methylpiperid-4-ols has been deduced by analogy with theconstitution of the corresponding 4-phenylpiperid-4-ols, where the axial epimer always predominates [I, 2],from GLC data (in all cases axial epimers had lower retention volumes in comparison with equatorials onchromatography on PEG- Chromosorb/KOH), by TLC data (on basic A[203 the Rf of an axial alcohol isgreater than the corresponding value for the equatorial alcohol [3]), and by potentiometrie titration data(in all cases investigated axial alcohols were 0.2-0.3 pK a units more basic [4]). The configuration of N-tert-butanol, apart from by chromatographic data, is demonstrated by its correlation with the correspond-ing N-methyl analog as regards the method of methylation - dequaternization.N. D. Zelinskii Institute of Organic Chemistry, Academy of Sciences of the USSR. Translated fro-~Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 6, pp. 1381-1387, June, 1970. Original articlesubmitted September 28, 1968.
9 Consultants Bureau, a divisior~ of Plenum Publishing Corporatiorz, 227 West 17th Street, New York,N. Y. 10011. All rights reserved. This article cannot be reproduced for any purpose whatsoever withoutpermission of the publisher. A copy of this article is available fro,z the publisher for $I5.00.
1301
 
TABLE 1. The Reaction of 7-Piperidones with an Ether Solution of MethyllithiumStartiflg ketoneoII CHs/\/
'" U
oII
CH3/\/
I I
'N/N
I
EllsOII
qq
nI) ~/\/ (trans)N
I
CI-IzO
II
CH,/\/
I I
\/N
I
C(CH,)sO:
IJ
\/\N CHs
I
GHsOCHs 1[ CHiN/N/(VI) ~J\CH,N
I
CH3O'
It
CH,IX/(VII)/~; (trans)Gila
N[GH3
Proportion ofConditions
alcohols,
%
a *
b~b*a*c~b*a*btb*a*
a~
a*a~c *at
a*
c~
a e1482 i871 2962 3880,5 t9,76 2~77 2384**
[6'
33 t7?9 H
~6
~4~4 1613 i7~2 i885 570
~0
(xHI)Starting ketone(xlv)OII CH,(vm) (trans)\/\
N CH~CII30
J[
CHa/\/
(Ix, CIts\[ [
/\/CHa N
I
CH.0
[I
CH,(x) (cis)CH,
\~(
I
C(CHD3o[I
CH./\/
CIt~ NC(CH.hOI[
CH.
(Y
(XII) X/\ (cis)
N
CH3
I
C(CHD.0
CHs
II
CHs
N/N/N
I
O
CH.
[i
CHa\/\/
N
I
G(CHD3Zonditions
a I
a *
80e I" 62cl 95cl 96c~ 20'
:~
98"
~t ~4Proportion ofalcoholse20325,4$**80**25 **ii$ **Note: Synthesis conditions: a) M solution of CHsLi and LiBr inether; b)l M solution of CHsLi and LiI; c) 1 M solution of CHsLiand LiBr in the presence of LiC1 (taken out in reactions with hydrochlorides).*Direct addition.?Reverse addition (see Experimental section).$Isomer not isolated in a pure form.**Structure of the alcohol was confirmed by the method in [7].will be conformationally homogeneous because of the significant volume of the tert-butyl grouping. Further,the comPlex (with one or the other conformation at the nitrogen center) reacted by the usual scheme [11] atthe keto-group giving a mixture of equatorial and axial alcohols (after decomposition with water). Thus theorienting effect of a positive (partial) charge on nitrogen is evidently small. This conclusion follows froma comparison of the experiments with ketones (I), (II), (iII), and (IV). A far more important influence onthe stereochemistry of the reaction with methyllithium (see Table 1) or phenyllithium (see Table 2) is shownby steric factors. In all the examples investigated, with the exception of trans-ketone (XI) and ketone (VI)equatorial attack of reagent predominated. In addition phenyllithium was somewhat more stereospecific.Meta-axial methyl [compounds (IX), (X), and (XII) see Tables 1 and 2] almost completely blocked axial at-tack by methyl- and phenyllithium. From these data it is also possible to draw the opposite conclusion butthe high stereodirecting property of the keto-groups in (X) and (XII) [11] indicates the result of the pre-dominant partipation of conformers with axial methyl at C 2 [XA, see Scheme 1]. Also of interest is theinfluence of an axial methyl substituent at the side of a carbonyl group as in (VI) on the proportions of al-cohols formed. From the data given in Table 1 [see ketones (VI) and (XIII), (XIV)] itis evident that such1302
 
TABLE 2. Reaction of Y-Piperidones with an Ether Solution of Phenyl-
Proportion
of~ Proportion ofalcohols [i Ketone Condi- alcoholstion~
a e a e
I a* 89 [7] ti'~ VI b*
80II a * 75 [121 25 [t21 VII b "~ 81
[1411II a* 84
[2] t6 [21 X a* 98 [il
IV a* 85 [11 t5"* XI a'~ 60V a * ~7 [t3] 5.3 [tO1 b" 5tb ~: 48
5Z XK
b
%~
Note: Synthesis conditions: a) 1 M solution ,of phenyllithium and LiBr in ether; b) inthe---presence of LiC1 (taken out with ketone hydroehlorides).9 Direct addition (see Table 1),
T
Alcohol not isolated in a pure form.$ ReverSe addition (see
Table I).
',* g~ructu*e
of
th~ alcohol was eong~med by the methovt in
[~3.
lithiumCondi-Ketone
tions2O
19 [~41
2~"
40
49
O O
LSx
(A)
cHs
(B)
(X : CHa, C~Hs
or halide)
,
HaC~ ~O
(CHahC..__,~/-- ~ ~ ( CHa)aC..~g~...._~CHa
(XB) CHa
txg)
Scheme !
an axial methyl substituent, in the same way as an axial methyl at C 2 (or CG) significantly hinders equa-torial attack by the reagent at the keto group as a result of which both sides of the 7-piperidone earbonylin (VI) appear to be completely equally screened, i.e., the screening action of an axial methy[ at Ca surpas-ses in its effect even the action of two equatorial groups [ketones (X]II) and (xIv)J. This screening actionof two equatorial methyls at C a and Cs which prevents axial attack by methyllithium may be estimated bycomparing ketones (II), (XIII), and (XIV).The trans ketone (XI) was of particular interest. Replacement of the tert-butyl group on nitrogen in(XI) by methyl led to a reversal of the stereodireethtg property o[ the reaction at carhonyl. Evidently in
the
case in question these resuits may be regarded as confirming the hypothesis expressed previously [5]on the significant relative importance of a distorted conformation (distorted chair or boat) for this N-left-butyl ketone. This distortion of boat conformation is determined by the significant interaction between thetert-butyl and the neighboring methyl substituent. The faerie isomerization of the irons-ketone (XI) intothe cis-isomer (X) [5] indicates the presence of such an interaction.EXPERIMENTAL
Gas- liquid chromatography (GLC) of mixtures of alcohols was carried out in packed or capillarycolumns as has been described previously [15], at a temperature of 130-150 ~ for r~ethyI and at IV0-180 ~for phenyl alcohols. Correlation of structures of N-methyl and N-tert~butyl derivatives was effected by
dequateri2ation with a solution of lithium in liquid ammonia [5].4-Methyl- and 4-Phenylpiperid-4-ols. (General Method).a) Direct addition. To an ether solution of methyl- or phenyllithium (1 M solution 2.5-5 molecularequivalents, prepared from methyl halide or bromobenzene respectively) was added an ether solution ofthe T-plperidone with stirring under nitrogen and cooling (0~ After ~30 rain stirring and cooling the1303

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