Enamine

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The general structure of an enamine Enamine-2D-skeletal.png
The general structure of an enamine

An enamine is an unsaturated compound derived by the condensation of an aldehyde or ketone with a secondary amine. [1] [2] Enamines are versatile intermediates. [3] [4]

Contents

Condensation to give an enamine. Enamine.png
Condensation to give an enamine.

The word "enamine" is derived from the affix en-, used as the suffix of alkene, and the root amine. This can be compared with enol, which is a functional group containing both alkene (en-) and alcohol (-ol). Enamines are considered to be nitrogen analogs of enols. [6]

If one or both of the nitrogen substituents is a hydrogen atom it is the tautomeric form of an imine. This usually will rearrange to the imine; however there are several exceptions (such as aniline). The enamine-imine tautomerism may be considered analogous to the keto-enol tautomerism. In both cases, a hydrogen atom switches its location between the heteroatom (oxygen or nitrogen) and the second carbon atom.

Enamines are both good nucleophiles and good bases. Their behavior as carbon-based nucleophiles is explained with reference to the following resonance structures.

EnamineResStructures.png

Formation

Enamines are labile and therefore chemically useful moieties which can be easily produced from commercially available starting reagents. A common route for enamine production is via an acid-catalyzed nucleophilic reaction of ketone [7] or aldehyde [8] species containing an α-hydrogen with secondary amines. Acid catalysis is not always required, if the pKaH of the reacting amine is sufficiently high (for example, pyrrolidine, which has a pKaH of 11.26). If the pKaH of the reacting amine is low, however, then acid catalysis is required through both the addition and the dehydration steps [9] (common dehydrating agents include MgSO4 and Na2SO4). [10] Primary amines are usually not used for enamine synthesis due to the preferential formation of the more thermodynamically stable imine species. [11] Methyl ketone self-condensation is a side-reaction which can be avoided through the addition of TiCl4 [12] into the reaction mixture (to act as a water scavenger). [13] [14] An example of an aldehyde reacting with a secondary amine to form an enamine via a carbinolamine intermediate is shown below:

Enamine synthesis with a carbinolamine intermediate. Enamine Synthesis from a Secondary Amine and an Aldehyde.png
Enamine synthesis with a carbinolamine intermediate.

Reactions

Alkylation

Even though enamines are more nucleophilic than their enol counterparts, they can still react selectively, rendering them useful for alkylation reactions. The enamine nucleophile can attack haloalkanes to form the alkylated iminium salt intermediate which then hydrolyzes to regenerate a ketone (a starting material in enamine synthesis). This reaction was pioneered by Gilbert Stork, and is sometimes referred to by the name of its inventor (the Stork enamine alkylation). Analogously, this reaction can be used as an effective means of acylation. A variety of alkylating and acylating agents including benzylic, allylic halides can be used in this reaction. [15]

Alkylation of an enamine and a dehydration to form a ketone. Enamine Alkylation via SN2 reaction with a Bromo-alkane.png
Alkylation of an enamine and a dehydration to form a ketone.

Acylation

In a reaction much similar to the enamine alkylation, enamines can be acylated to form a final dicarbonyl product. The enamine starting material undergoes a nucleophilic addition to acyl halides forming the iminium salt intermediate which can hydrolyze in the presence of acid. [16]

Enamine nucleophile attacks acetyl chloride to form a dicarbonyl species Enamine Acylation to form a Dicarbonyl Species.png
Enamine nucleophile attacks acetyl chloride to form a dicarbonyl species

Metalloenamines

Strong bases such as LiNR2 can be used to deprotonate imines and form metalloenamines. Metalloenamines can prove synthetically useful due to their nucleophilicity (they are more nucleophilic than enolates). Thus they are better able to react with weaker electrophiles (for example, they can be used to open epoxides. [17] ) Most prominently, these reactions have allowed for asymmetric alkylations of ketones through transformation to chiral intermediate metalloenamines. [18]

Halogenation

β-halo immonium compounds can be synthesized through the halogenation reaction of enamines with halides in diethyl ether solvent. Hydrolysis will result in the formation of α-halo ketones. [19] Chlorination, bromination, and even iodination have been shown to be possible. The general reaction is shown below:

Chlorination/brominatio of enamines takes place in diethyl ether. Enamine Halogenation.png
Chlorination/brominatio of enamines takes place in diethyl ether.

Oxidative coupling

Enamines can be efficiently cross-coupled with enol silanes through treatment with ceric ammonium nitrate. These reactions were reported by the Narasaka group in 1975, providing a route to stable enamines as well as one instance of a 1,4-diketone (derived from a morpholine amine reagent). [20] Later, these results were exploited by the MacMillan group with the development of an organocatalyst which used the Narasaka substrates to produce 1,4 dicarbonyls enantioselectively, with good yields. [21] Oxidative dimerization of aldehydes in the presence of amines proceeds through the formation of an enamine followed by a final pyrrole formation. [22] This method for symmetric pyrrole synthesis was developed in 2010 by the Jia group, as a valuable new pathway for the synthesis of pyrrole-containing natural products. [23]

Annulation

Enamines chemistry has been implemented for the purposes of producing a one-pot enantioselective version of the Robinson annulation. The Robinson annulation, published by Robert Robinson in 1935, is a base-catalyzed reaction that combines a ketone and a methyl vinyl ketone (commonly abbreviated to MVK) to form a cyclohexenone fused ring system. This reaction may be catalyzed by proline to proceed through chiral enamine intermediates which allow for good stereoselectivity. [24] This is important, in particular in the field of natural product synthesis, for example, for the synthesis of the Wieland-Miescher ketone – a vital building block for more complex biologically active molecules. [25] [26]

Reactivity

Enamines act as nucleophiles that require less acid/base activation for reactivity than their enolate counterparts. They have also been shown to offer a greater selectivity with less side reactions. There is a gradient of reactivity among different enamine types, with a greater reactivity offered by ketone enamines than their aldehyde counterparts. [27] Cyclic ketone enamines follow a reactivity trend where the five membered ring is the most reactive due to its maximally planar conformation at the nitrogen, following the trend 5>8>6>7 (the seven membered ring being the least reactive). This trend has been attributed to the amount of p-character on the nitrogen lone pair orbital - the higher p character corresponding to a greater nucleophilicity because the p-orbital would allow for donation into the alkene π- orbital. Analogously, if the N lone pair participates in stereoelectronic interactions on the amine moiety, the lone pair will pop out of the plane (will pyramidalize) and compromise donation into the adjacent π C-C bond. [28] [29]

Modulating enamine nucleophilicity via stereoelectronicand inductive Effects Modulating Enamine Nucleophilicity via Stereoelectronicand Inductive Effects.png
Modulating enamine nucleophilicity via stereoelectronicand inductive Effects

There are many ways to modulate enamine reactivity in addition to altering the steric/electronics at the nitrogen center including changing temperature, solvent, amounts of other reagents, and type of electrophile. Tuning these parameters allows for the preferential formation of E/Z enamines and also affects the formation of the more/less substituted enamine from the ketone starting material. [30]

See also

Related Research Articles

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<span class="mw-page-title-main">Organolithium reagent</span> Chemical compounds containing C–Li bonds

In organometallic chemistry, organolithium reagents are chemical compounds that contain carbon–lithium (C–Li) bonds. These reagents are important in organic synthesis, and are frequently used to transfer the organic group or the lithium atom to the substrates in synthetic steps, through nucleophilic addition or simple deprotonation. Organolithium reagents are used in industry as an initiator for anionic polymerization, which leads to the production of various elastomers. They have also been applied in asymmetric synthesis in the pharmaceutical industry. Due to the large difference in electronegativity between the carbon atom and the lithium atom, the C−Li bond is highly ionic. Owing to the polar nature of the C−Li bond, organolithium reagents are good nucleophiles and strong bases. For laboratory organic synthesis, many organolithium reagents are commercially available in solution form. These reagents are highly reactive, and are sometimes pyrophoric.

<span class="mw-page-title-main">Imine</span> Organic compound or functional group containing a C=N bond

In organic chemistry, an imine is a functional group or organic compound containing a carbon–nitrogen double bond. The nitrogen atom can be attached to a hydrogen or an organic group (R). The carbon atom has two additional single bonds. Imines are common in synthetic and naturally occurring compounds and they participate in many reactions.

<span class="mw-page-title-main">Michael addition reaction</span> Reaction in organic chemistry

In organic chemistry, the Michael reaction or Michael 1,4 addition is a reaction between a Michael donor and a Michael acceptor to produce a Michael adduct by creating a carbon-carbon bond at the acceptor's β-carbon. It belongs to the larger class of conjugate additions and is widely used for the mild formation of carbon-carbon bonds.

<span class="mw-page-title-main">Enolate</span> Organic anion formed by deprotonating a carbonyl (>C=O) compound

In organic chemistry, enolates are organic anions derived from the deprotonation of carbonyl compounds. Rarely isolated, they are widely used as reagents in the synthesis of organic compounds.

In organic chemistry, the Mannich reaction is a three-component organic reaction that involves the amino alkylation of an acidic proton next to a carbonyl functional group by formaldehyde and a primary or secondary amine or ammonia. The final product is a β-amino-carbonyl compound also known as a Mannich base. Reactions between aldimines and α-methylene carbonyls are also considered Mannich reactions because these imines form between amines and aldehydes. The reaction is named after Carl Mannich.

<span class="mw-page-title-main">Chiral auxiliary</span> Stereogenic group placed on a molecule to encourage stereoselectivity in reactions

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<span class="mw-page-title-main">Nucleophilic conjugate addition</span> Organic reaction

Nucleophilic conjugate addition is a type of organic reaction. Ordinary nucleophilic additions or 1,2-nucleophilic additions deal mostly with additions to carbonyl compounds. Simple alkene compounds do not show 1,2 reactivity due to lack of polarity, unless the alkene is activated with special substituents. With α,β-unsaturated carbonyl compounds such as cyclohexenone it can be deduced from resonance structures that the β position is an electrophilic site which can react with a nucleophile. The negative charge in these structures is stored as an alkoxide anion. Such a nucleophilic addition is called a nucleophilic conjugate addition or 1,4-nucleophilic addition. The most important active alkenes are the aforementioned conjugated carbonyls and acrylonitriles.

<span class="mw-page-title-main">Weinreb ketone synthesis</span> Chemical reaction

The Weinreb–Nahm ketone synthesis is a chemical reaction used in organic chemistry to make carbon–carbon bonds. It was discovered in 1981 by Steven M. Weinreb and Steven Nahm as a method to synthesize ketones. The original reaction involved two subsequent nucleophilic acyl substitutions: the conversion of an acid chloride with N,O-Dimethylhydroxylamine, to form a Weinreb–Nahm amide, and subsequent treatment of this species with an organometallic reagent such as a Grignard reagent or organolithium reagent. Nahm and Weinreb also reported the synthesis of aldehydes by reduction of the amide with an excess of lithium aluminum hydride.

Silyl enol ethers in organic chemistry are a class of organic compounds that share a common functional group composed of an enolate bonded through its oxygen end to an organosilicon group. They are important intermediates in organic synthesis.

<span class="mw-page-title-main">Stork enamine alkylation</span> Reaction sequence in organic chemistry

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In organic chemistry, aldol reactions are acid- or base-catalyzed reactions of aldehydes or ketones.

Electrophilic amination is a chemical process involving the formation of a carbon–nitrogen bond through the reaction of a nucleophilic carbanion with an electrophilic source of nitrogen.

The Baylis–Hillman reaction is a carbon-carbon bond forming reaction between the α-position of an activated alkene and a carbon electrophile such as an aldehyde. Employing a nucleophilic catalyst, such as a tertiary amine and phosphine, this reaction provides a densely functionalized product. It is named for Anthony B. Baylis and Melville E. D. Hillman, two of the chemists who developed this reaction while working at Celanese. This reaction is also known as the Morita–Baylis–Hillman reaction or MBH reaction, as K. Morita had published earlier work on it.

The Tsuji–Trost reaction is a palladium-catalysed substitution reaction involving a substrate that contains a leaving group in an allylic position. The palladium catalyst first coordinates with the allyl group and then undergoes oxidative addition, forming the π-allyl complex. This allyl complex can then be attacked by a nucleophile, resulting in the substituted product.

<span class="mw-page-title-main">Enders SAMP/RAMP hydrazone-alkylation reaction</span>

The Enders SAMP/RAMP hydrazone alkylation reaction is an asymmetric carbon-carbon bond formation reaction facilitated by pyrrolidine chiral auxiliaries. It was pioneered by E. J. Corey and D. Enders in 1976, and was further developed by D. Enders and his group. This method is usually a three-step sequence. The first step is to form the hydrazone between (S)-1-amino-2-methoxymethylpyrrolidine (SAMP) or (R)-1-amino-2-methoxymethylpyrrolidine (RAMP) and a ketone or aldehyde. Afterwards, the hydrazone is deprotonated by lithium diisopropylamide (LDA) to form an azaenolate, which reacts with alkyl halides or other suitable electrophiles to give alkylated hydrazone species with the simultaneous generation of a new chiral center. Finally, the alkylated ketone or aldehyde can be regenerated by ozonolysis or hydrolysis.

<i>N</i>-<i>tert</i>-Butylbenzenesulfinimidoyl chloride Chemical compound

N-tert-Butylbenzenesulfinimidoyl chloride is a useful oxidant for organic synthesis reactions. It is a good electrophile, and the sulfimide S=N bond can be attacked by nucleophiles, such as alkoxides, enolates, and amide ions. The nitrogen atom in the resulting intermediate is basic, and can abstract an α-hydrogen to create a new double bond.

<span class="mw-page-title-main">Hydrogen-bond catalysis</span>

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Rearrangements, especially those that can participate in cascade reactions, such as the aza-Cope rearrangements, are of high practical as well as conceptual importance in organic chemistry, due to their ability to quickly build structural complexity out of simple starting materials. The aza-Cope rearrangements are examples of heteroatom versions of the Cope rearrangement, which is a [3,3]-sigmatropic rearrangement that shifts single and double bonds between two allylic components. In accordance with the Woodward-Hoffman rules, thermal aza-Cope rearrangements proceed suprafacially. Aza-Cope rearrangements are generally classified by the position of the nitrogen in the molecule :

The ketimine Mannich reaction is an asymmetric synthetic technique using differences in starting material to push a Mannich reaction to create an enantiomeric product with steric and electronic effects, through the creation of a ketimine group. Typically, this is done with a reaction with proline or another nitrogen-containing heterocycle, which control chirality with that of the catalyst. This has been theorized to be caused by the restriction of undesired (E)-isomer by preventing the ketone from accessing non-reactive tautomers. Generally, a Mannich reaction is the combination of an amine, a ketone with a β-acidic proton and aldehyde to create a condensed product in a β-addition to the ketone. This occurs through an attack on the ketone with a suitable catalytic-amine unto its electron-starved carbon, from which an imine is created. This then undergoes electrophilic addition with a compound containing an acidic proton. It is theoretically possible for either of the carbonyl-containing molecules to create diastereomers, but with the addition of catalysts which restrict addition as of the enamine creation, it is possible to extract a single product with limited purification steps and in some cases as reported by List et al.; practical one-pot syntheses are possible. The process of selecting a carbonyl-group gives the reaction a direct versus indirect distinction, wherein the latter case represents pre-formed products restricting the reaction's pathway and the other does not. Ketimines selects a reaction group, and circumvent a requirement for indirect pathways.

References

  1. ↑ Clayden, Jonathan (2001). Organic chemistry . Oxford, Oxfordshire: Oxford University Press. ISBN   978-0-19-850346-0.
  2. ↑ Smith, Michael B.; March, Jerry (2007), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (6th ed.), New York: Wiley-Interscience, ISBN   978-0-471-72091-1
  3. ↑ Enamines: Synthesis: Structure, and Reactions, Second Edition, Gilbert Cook (Editor). 1988, Marcel Dekker, NY. ISBN   0-8247-7764-6
  4. ↑ R. B. Woodward, I. J. Pachter, and M. L. Scheinbaum (1974). "2,2- (Trimethylenedithio)cyclohexanone". Organic Syntheses . 54: 39.{{cite journal}}: CS1 maint: multiple names: authors list (link); Collective Volume, vol. 5, p. 1014
  5. ↑ R. D. Burpitt and J. G. Thweatt (1968). "Cyclodecanone". Organic Syntheses . 48: 56.; Collective Volume, vol. 5, p. 277
  6. ↑ Imines and Enamines | PharmaXChange.info
  7. ↑ Stork, Gilbert.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.; Terrell, R. (1963). "The Enamine Alkylation and Acylation of Carbonyl Compounds". Journal of the American Chemical Society. 85 (2): 207–222. doi:10.1021/ja00885a021. ISSN   0002-7863.
  8. ↑ Mannich, C.; Davidsen, H. (1936). "Über einfache Enamine mit tertiär gebundenem Stickstoff" [On simple enamines with triple-bonded nitrogen]. Berichte der Deutschen Chemischen Gesellschaft (A and B Series) (in German). 69 (9): 2106–2112. doi:10.1002/cber.19360690921. ISSN   0365-9488.
  9. ↑ Capon, Brian; Wu, Zhen Ping (April 1990). "Comparison of the tautomerization and hydrolysis of some secondary and tertiary enamines". The Journal of Organic Chemistry. 55 (8): 2317–2324. doi:10.1021/jo00295a017.
  10. ↑ Lockner, James. "Stoichiometric Enamine Chemistry" (PDF). Baran Group, The Scripps Research Institute. Retrieved 26 November 2014.
  11. ↑ Farmer, Steven (2013-10-16). "Enamine Reactions". UC Davis Chem Wiki.
  12. ↑ Carlson, R; Nilsson, A (1984). "Improved Titanium Tetrachloride Procedure for Enamine Synthesis". Acta Chemica Scandinavica. 38B: 49–53. doi: 10.3891/acta.chem.scand.38b-0049 .
  13. ↑ Lockner, James. "Stoichiometric Enamine Chemistry" (PDF). Baran Group, The Scripps Research Institute. Retrieved 26 November 2014.
  14. ↑ White, William Andrew; Weingarten, Harold (January 1967). "A versatile new enamine synthesis". The Journal of Organic Chemistry. 32 (1): 213–214. doi:10.1021/jo01277a052.
  15. ↑ Wade, L.G. (1999). Organic Chemistry . Saddle River, NJ: Prentice Hall. pp.  1019. ISBN   9780139227417.
  16. ↑ Farmer, Steven (2013-10-16). "Enamine Reactions". UC Davis Chem Wiki.
  17. ↑ Evans, D. "Enolates and Metalloenamines II" (PDF). Retrieved 10 December 2014.[ permanent dead link ]
  18. ↑ Meyers, A. I.; Williams, Donald R. (August 1978). "Asymmetric alkylation of acyclic ketones via chiral metallo enamines. Effect of kinetic vs. thermodynamic metalations". The Journal of Organic Chemistry. 43 (16): 3245–3247. doi:10.1021/jo00410a034.
  19. ↑ Seufert, Walter; Eiffenberger, Franz (1979). "Zur Halogenierung von Enaminen — Darstellung von β-Halogen-iminium-halogeniden". Chemische Berichte. 112 (5): 1670–1676. doi:10.1002/cber.19791120517.
  20. ↑ Ito, Y; Konoike, T; Saegusa, T (1975). "Synthesis of 1,4-diketones by the reaction of silyl enol ether with silver oxide. Regiospecific formation of silver(I) enolate intermediates". Journal of the American Chemical Society. 97 (3): 649–651. doi:10.1021/ja00836a034.
  21. ↑ Jang, HY; Hong, JB; MacMillan, DWC (2007). "Enantioselective organocatalytic singly occupied molecular orbital activation: the enantioselective alpha-enolation of aldehydes" (PDF). J. Am. Chem. Soc. 129 (22): 7004–7005. doi:10.1021/ja0719428. PMID   17497866.
  22. ↑ Li, Q; Fan, A; Lu, Z; Cui, Y; Lin, W; Jia, Y (2010). "One-pot AgOAc-mediated synthesis of polysubstituted pyrroles from primary amines and aldehydes: application to the total synthesis of purpurone". Organic Letters. 12 (18): 4066–4069. doi:10.1021/ol101644g. PMID   20734981.
  23. ↑ Guo, Fenghai; Clift, Michael D.; Thomson, Regan J. (September 2012). "Oxidative Coupling of Enolates, Enol Silanes, and Enamines: Methods and Natural Product Synthesis". European Journal of Organic Chemistry. 2012 (26): 4881–4896. doi:10.1002/ejoc.201200665. PMC   3586739 . PMID   23471479.
  24. ↑ List, Benjamin (2002). "Proline-catalyzed asymmetric reactions". Tetrahedron. 58 (28): 5573–5590. doi:10.1016/s0040-4020(02)00516-1.
  25. ↑ Bui, Tommy; Barbas (2000). "A proline-catalyzed asymmetric Robinson Annulation". Tetrahedron Letters. 41 (36): 6951–6954. doi:10.1016/s0040-4039(00)01180-1.
  26. ↑ Wiener, Jake. "Enantioselective Organic Catalysis:Non-MacMillan Approaches" (PDF). Archived from the original (PDF) on 26 October 2017. Retrieved 29 November 2014.
  27. ↑ Hickmott, Peter (May 1982). "Enamines: Recent advances in synthetic, spectroscopic, mechanistic, and stereochemical aspects—II". Tetrahedron. 38 (23): 3363–3446. doi:10.1016/0040-4020(82)85027-8.
  28. ↑ Mayr, H. (2003). "Structure-Nucleophilicity Relationships for Enamines". Chem. Eur. J. 9 (10): 2209–18. doi:10.1002/chem.200204666. PMID   12772295.
  29. ↑ Hickmott, Peter (May 1982). "Enamines: Recent advances in synthetic, spectroscopic, mechanistic, and stereochemical aspects—II". Tetrahedron. 38 (23): 3363–3446. doi:10.1016/0040-4020(82)85027-8.
  30. ↑ Lockner, James. "Stoichiometric Enamine Chemistry" (PDF). Baran Group, The Scripps Research Institute. Retrieved 26 November 2014.
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