Алкилирование енаминов, бета-дикетонов и енаминокетонов

выделяемого из соснового скипидара:

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Результирующее соединение IV используется далее в синтезе оптически

активных комплексных соединений, используемых в асимметрическом катализе.

Кетонитрил I представляет собой вязкую темную жидкость, растворимую в

органических растворителях и нерастворимую в воде. Реакция (а) проходит

гладко и с высоким выходом (~80%) дает продукт конденсации – (3-амино-6,6-

диметилбицикло[3.1.0]гекс-2-ен-2-ил)метилкетон II.

Отдельного рассмотрения заслуживает процесс бензилирования соединения

II. Эта реакция при комнатной температуре протекает крайне неоднозначно, с

выходом целевого продукта менее 10% и образованием трудноразделимой смеси

изомерных продуктов и продуктов полиалкилирования. Схема превращений и

идентифицированные продукты представлены на следующем рисунке:

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Показанные на схеме процессы обладают повторяемостью – по данным

тонкослойной хроматографии в продуктах нескольких проведенных реакций набор

компонентов один и тот же. Выходы выделенных веществ тоже примерно

одинаковы. Спектры ядерного магнитного резонанса N-алкилированого продукта

имеются в Приложениях. Его выход составляет 10%, но (!) – зимой. В тех же

реакциях, осуществленных летом, продукт N-алкилирования зафиксирован не

был.

Предположение о связи направления алкилирования с температурой

реакционной смеси (а в методике указана комнатная температура)

подтвердилось – проведение реакции при 35єС дало в качестве преобладающего

продукта (с выходом ~60%) целевой С-замещенный енаминокетон, алкилирование

прошло так, как описано в “летней” методике. Попытки дальнейшего повышения

температуры пока не предпринимались.

Полученный (3-амино-2-бензил-6,6-диметилбицикло[3.1.0]гекс-2-

ил)метилкетон III был введен в реакцию с избытком боргидрида натрия для

восстановлния карбонильной группы в спиртовую.

Точный состав и строение комплекса IV неизвестны – парамагнитный ион

меди II препятствует получению спектров ЯМР, по данным ИК-спектра что-либо

определенное сказать затруднительно. Сводка полученных характеристик

соединений дана ниже:

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Результаты проделанной работы можно суммировать следующим образом:

- синтезированы и охарактеризованы спектрально и хроматографически

некоторые производные природного терпена 3-карена.

- обнаружена значительная зависимость хода реакции бензилирования (3-амино-

6,6-диметилбицикло[3.1.0]гекс-2-ен-2-ил)метилкетона от температуры

реакционной смеси. Установлено, что оптимальный выход С-бензилированного

производного достигается при t?35?C.

- установлен тот факт, что “комнатная” температура – весьма ненадежная

характеристика методики синтеза.

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Литература.

1. S. Dyke // Chemistry of enamines. // Cambridge University Press,

Cambridge, 1973.

2. A. Cook (ed) // Enamines: synthesis, structure and reactions. // Marcell

Decker, New York, 1969.

3. I. Chaaban, J. Greenhill, M. Ramli // Reactions between enaminones and

enones. Part 2. C versus N-alkylation with cyclohex-2-enone. Structure

confirmation by reduction of a dienaminone derivative of a dehydrated

dimedone dimer. // J. Chem. Soc. Perkin Trans., 1981, 1, 3120-3124.

4. J. Whitesell, M. Whitesell // Alkylation of ketones and aldehydes via

their nitrogen derivatives. // Synthesis, 1983, 7, 517-536.

5. A. Zanina, S. Shergina, I. Sokolov, M. Shvartsberg // Alkylation of

sterically hindered 1,3-diketones under phase-transfer conditions. //

Russ. Chem. Bl., 1996, 45, 2389-2392 // Izv. Akad. Nauk Ser. Khim. 1996,

10, 2518-2521.

6. S. Lu, A. Lewin // Enamine-imine tautomerism in ?,?-unsaturated ?-amino

acids. // Tetrahedron, 1998, 54, 15097-15014.

7. J. Henriksen, S. Hammerum // Heats of formation of imine and enamine

radical cations and the corresponding neutral molecules // Int. J. Mass

Spect, 1998 179/180, 301-308.

8. S. Caccamese, G Principato // Resolution of the enantiomers of

tetrahydrozoline by chiral HPLC. The racemization of the enantiomers via

an imine-enamine tautomerism. // Tetrahedron: Asymmetry, 1998, 9, 2939-

2945.

9. M. Shimizu, A. Morita, T. Kaga // Double nucleophilic addition to ?,?-

unsaturated aldimines induced by titanium tetrahalides. // Tetrahedron

Lett., 1999, 40, 8401-8405.

10. S. Knьppel, R. Frцlich, G. Erker // Formation of functionalized

[3]ferrocenophane derivatives by an enamine condensation reaction.// J.

Organomet. Chem., 2000, 595, 308-312.

11. A. Tkachev, A. Rukavishnikov // Enaminones of the 2-acetylcyclopent-1-

en-1-ylamine type derived from the terpenic compounds limonene, 3-carene

and ?-cadinol. // Mendeleev Commun., 1992, 1, 161-162.

12. S. Popov, A. Tkachev // New chiral agents for resolution of racemic cis-

permethric and cis-Z-cyhalothric acids. // Tetrahedron: Asymmetry, 1995,

6, 4, 1013-1018.

13. J. Greenhill, A. Moten // N-Alkylation of enaminones. // Tetrahedron,

1983, 39, 3405-3408.

14. A. Tkachev, S. Popov // Alkylation of enaminoketone with a modified

carane skeleton. Formation of stable ?-diketone monoimines. // Russ. J.

Org. Chem., 1997, 33, 5, 601-606.

15. T. Tiner-Harding, P. Mariano // Intramolecular photoarylations of N-

(haloaryl)ethyl-?-enaminones. // J. Org. Chem., 1982, 47, 482-485.

16. P. Bugler, I. Cottrell, C. Cowden, A. Davies, U. Dolling // An

investigation into the alkylation of 1,2,4-triazole // Tetrahedron

Lett., 2000, 41, 1297-1301.

Приложение 1.

Данные и аннотации некоторых статей (Belstein Abstracts).

Alkylation of Enaminoketone with a Modified Carane Skeleton. Formation of

Stable (-Diketone Monoimines

A. V. Tkachev; S. A. Popov

Source details: Russ.J.Org.Chem. 1997, 33 : 5 601-606.

Document type: Journal

CODEN: RJOCEQ

Language: EN

CNR: 6090629

Original Source: Zh.Org.Khim. 1997, 33 : 5 660-665.

CODEN: ZORKAE

Language: RU

Abstract

Alkylation of a bicyclic enaminoketone, 1-((1R,5R)-3-amino-6,6-

dimethylbicyclo[3.1.0]hex-2-en-2-yl))ethanone, with highly reactive alkyl

halides (methyl iodide, benzyl halides, and allyl halides) in a two-phase

system benzene-40% aqueous NaOH in the presence of benzyltriethylammonium

chloride (BTEA) as phase-transfer catalyst results in formation of stable (-

diketone monoimines, derivatives of the series of 1-((1R,5R)-2-alkyl-3-

imino-6,6-dimethylbicyclo[3.1.0]hex-2-yl)ethanone, in 53-81% yields.

Alkylation of sterically hindered 1,3-diketones under phase-transfer

conditions

A. S. Zanina; S. I. Shergina; I. E. Sokolov; M. S. Shvartsberg

Source details: Russ.Chem.Bl. 1996, 45 : 10 2389-2392.

Document type: Journal

CODEN: RCBUEY

Language: EN

CNR: 6056087

Original Source: Izv.Akad.Nauk Ser.Khim. 1996, 10 2518-2521.

CODEN: IASKEA

Language: RU

Abstract

Sterically hindered 1,3-diketones react selectively with propargyl and

allyl bromides under conditions of phase transfer catalysis to give C-

alkylated products, whereas reactions with butyl and benzyl chlorides yield

mixtures of C- and O-isomers.An increase in the size of the substituents

present in the initial 1,3-diketone hampers introduction of the second

propargyl group.The propargyl-substituted 1,3-diketones undergo cyclization

under the alkylation conditions to give substituted furans.

Sequence of alkylation of cyclohexane-1,3-dione. Alternative synthesis of

(+/-)-angustione

A. A. Zenyuk; L. G. Lis; L. I. Ukhova

Source details: Chem.Nat.Compd.(Engl.Transl.) 1991, 27 : 4

400-403.

Document type: Journal

CODEN: CHNCA8

Language: EN

CNR: 5645800

Original Source: Khim.Prir.Soedin. 1991, 4 460-463.

CODEN: KPSUAR

Language: RU

Abstract

A method is proposed for introducing one, two, or three alkyl substituents

into positions 4 and 6 of the cyclohexane-1,3-dione molecule by successive

alkylation under the action of strong bases. (+/-)-Angustione (a natural

-diketone) has been synthesized.

A Tandem Amino-Cope Rearrangement/Enamine Alkylation Reaction

Steven M. Allin; Martin A. C. Button; Stephen J. Shuttleworth

Source details: Syn.Lett. 1997, 6 725-727.

Document type: Journal

CODEN: SYNLES

Language: EN

CNR: 6086563

Abstract

Thermally induced (3,3)-sigmatropic rearrangement of 3-amino-1,5-diene

substrates occurs to give the corresponding enamine products in high yield

and with excellent trans:cis enamine selectivity.The enamine produced

during the amino-Cope rearrangement has been directly derivatized,

representing the first report of a tandem amino-Cope rearrangement/enamine

alkylation reaction.The potential of this novel synthetic strategy is

outlined.

N-alkylation of enaminones

John V. Greenhill; Ashraf M. Moten

Source details: Tetrahedron 1983, 39 : 20 3405-3408.

Document type: Journal

CODEN: TETRAB

Language: EN

CNR: 5609239

Abstract

The base catalyzed N-alkylation of a series of primary and secondary

enaminones has been examined in detail.The enaminone anion was found to be

a weak nucleophile.Best results were obtained in tetrahydrofuran or dioxane

with sodium hydride and an alkyl iodide.

Alkylation of Ketones and Aldehydes via their Nitrogen Derivatives

James K. Whitesell; Marilyn A. Whitesell

Source details: Synthesis 1983, 7 517-536.

Document type: Journal

CODEN: SYNTBF

Language: EN

CNR: 5572282

Abstract

In this review, methods for the alkylation of the aldehydes and ketones

via formation of nitrogen derivatives such as enamines, metallated imines

(imine anions), metallated N,N-dialkylhydrazones (N,N-dialkylhydrazone

anions), dimetallated oximes (oxime dianions), and metallated O-

methyloximes (O-methyloxime anions) are described.Scope, limitations, and

advantages or disadvantages of the methods over comparative reactions of

enolates are also mentioned.

Intramolecular Photoarylations of N-(Haloaryl)ethyl ?-Enaminones

Tammy Tiner-Harding; Patrick S. Mariano

Source details: J.Org.Chem. 1982, 47 : 3 482-485.

Document type: Journal

CODEN: JOCEAH

Language: EN

CNR: 5570323

Abstract

The photochemistry of several N-(haloaryl)ethyl ?-enaminones was

investigated in order to develop methods for preparation of tricyclic

enaminone systems.The efficiencies of intramolecular photoarylations of the

haloaryl systems were found to be dependent upon the wavelength of

irradiation.Accordingly, irradiations of the haloaryl ?-enaminones 9a,c,d,f

with Pyrex-filtered light leads to formation of the reduced N-cyclized and

C-cyclized products 9b or 9e, 8a or 8b, and 10a or 10b, respectively. The

major products in these processes are the reduced materials.In contrast,

irradiations of the bromoaryl enaminones 9c or 9f with Vycor-filtered light

results in high yielding conversions to the C-cyclized tricyclic enaminones

10a and 10b in synthetically useful yields ranging from 50% to 85%.A

discussion of reasons for these wavelength dependencies is given in terms

of excited-state discrimination in these bichromophoric systems.Possible

reaction mechanisms are considered.The origin of another major product, 11,

generated by irradiation of 9f with Vycor-filtered light, is also

discussed.

Regioselective control of N-aryl enaminone alkylation

Denise Dugat; Daniel Gardette; Jean-Claude Gramain; Bertrand Perrin

Source details: Bull.Soc.Chim.Fr. 1994, 131 : 1 66-70.

Document type: Journal

CODEN: BSCFAS

Language: EN

CNR: 5851695

Abstract

The regioselectivity of the C-alkylation of unsubstituted N-aryl

enaminones prepared from cyclohexane-1,3-dione may be controlled by the

nature of the base used.Our results indicate that monoalkylation is

completely regioselective; lithium diisopropylamide leads to ?’-alkylated

compounds while lithium bis(trimethylsilyl)amide affords ?-alkylated

products.In contrast, alkylation of ?’- or ?-substituted compounds always

occurs in the ?’-position regardless of the base.

Regiospecificity and Regioselectivity of the Alkylation, Acylation,

Sulfenylation and Sulfonylation of Pyrrolidine Enaminones

Thomas Burgemeister; Gerd Dannhardt; Ernst Eibler; Brigitte Paulus; Klaus

Ziereis

Source details: Arch.Pharm.(Weinheim Ger.) 1988, 321 : 345-

348.

Document type: Journal

CODEN: ARPMAS

Language: GE

CNR: 5807249

Abstract

Different methods to modify a pyrrolidine enaminone regiospecifically or

regioselectively at the N- and C-atom, respectively, are described.All

compounds have been isolated and characterized, in case of the alkylation

reactions the ratio of regioisomers is determined by HPLC.NOE experiments

are performed in order to prove the configuration of some adducts.

Reactivity of N-substituted enaminones with unsaturated carbonyl compounds

Esther Caballero; Blanca Madrigal; Manuel Medarde; Pilar Puebla; Zoila

Honores; et al.

Source details: Ach.Mod.Chem. 1998, 135 : 4 457-474.

Document type: Journal

CODEN: ACMCEI

Language: EN

CNR: 6101721

Abstract

The reactivity of enaminones of 2-aminoethanol and 2-aminoethanothiol

towards polyelectrophilic reagents has been studied.A brief overview of our

previous results with this enaminones, which allowed us to describe new

synthesis of fused heterocycles, is included. In the present work, only the

formation of C-C bond is a common feature of the reaction, to produce

derivatives or simple heterocycles.Although no fused heterocycles were

obtained, the reaction products have complex functionalization which will

allow further cyclization to such a class of polyfused systems.

Reactions between Enaminones and Enones. Part 2. C versus N-Alkylation with

Cyclohex-2-enone. Structure Confirmation by Reduction of a Dienaminone

Derivative of Dehydrated Dimedone Dimer

Ibrahim Chaaban; John V. Greenhill; Mohamed Ramli

Source details: J.Chem.Soc.Perkin Trans.1 1981, 3120-3124.

Document type: Journal

CODEN: JCPRB4

Language: EN

CNR: 5625982

Abstract

Primary and secondary enaminones derived from cyclohexane-1,3-dione,

dimedone, and acetylacetone react with cyclohexenone to give exclusively C-

alkylated derivatives.In every case the products form carbinolamines which

exist as 1-hydroxy-2-azacyclo[3.3.1]nonenes.This was confirmed in some

examples by formation of an extra ring between nitrogen and oxygen.A series

of dienaminones were prepared from 2-(5,5-dimethyl-3-oxocyclohex-1-enyl)-

5,5-dimethylcyclohexane-1,3-dione and one of these was reduced to give an

azanonene identical with that from C-alkylation.

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