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The intramolecular Heck reaction (IMHR) in chemistry is the coupling of an
aryl In organic chemistry, an aryl is any functional group or substituent derived from an aromatic ring, usually an aromatic hydrocarbon, such as phenyl and naphthyl. "Aryl" is used for the sake of abbreviation or generalization, and "Ar" is used as ...
or alkenyl
halide In chemistry, a halide (rarely halogenide) is a binary chemical compound, of which one part is a halogen atom and the other part is an element or radical that is less electronegative (or more electropositive) than the halogen, to make a f ...
with an
alkene In organic chemistry, an alkene is a hydrocarbon containing a carbon–carbon double bond. Alkene is often used as synonym of olefin, that is, any hydrocarbon containing one or more double bonds.H. Stephen Stoker (2015): General, Organic, an ...
in the same
molecule A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bio ...
. The reaction may be used to produce carbocyclic or
heterocyclic A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different elements as members of its ring(s). Heterocyclic chemistry is the branch of organic chemistry dealing with the synthesis, properties, and ...
organic compounds In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. The ...
with a variety of ring sizes.
Chiral Chirality is a property of asymmetry important in several branches of science. The word ''chirality'' is derived from the Greek (''kheir''), "hand", a familiar chiral object. An object or a system is ''chiral'' if it is distinguishable from i ...
palladium Palladium is a chemical element with the symbol Pd and atomic number 46. It is a rare and lustrous silvery-white metal discovered in 1803 by the English chemist William Hyde Wollaston. He named it after the asteroid Pallas, which was itself nam ...
complexes can be used to synthesize chiral intramolecular Heck reaction products in non-
racemic In chemistry, a racemic mixture, or racemate (), is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates. ...
form.


Introduction

The Heck reaction is the palladium-catalyzed coupling of an aryl or alkenyl
halide In chemistry, a halide (rarely halogenide) is a binary chemical compound, of which one part is a halogen atom and the other part is an element or radical that is less electronegative (or more electropositive) than the halogen, to make a f ...
with an alkene to form a substituted
alkene In organic chemistry, an alkene is a hydrocarbon containing a carbon–carbon double bond. Alkene is often used as synonym of olefin, that is, any hydrocarbon containing one or more double bonds.H. Stephen Stoker (2015): General, Organic, an ...
. Intramolecular variants of the reaction may be used to generate cyclic products containing ''endo'' or ''exo'' double bonds. Ring sizes produced by the intramolecular Heck reaction range from four to twenty-seven
atoms Every atom is composed of a nucleus and one or more electrons bound to the nucleus. The nucleus is made of one or more protons and a number of neutrons. Only the most common variety of hydrogen has no neutrons. Every solid, liquid, gas ...
. Additionally, in the presence of a chiral palladium catalyst, the intramolecular Heck reaction may be used to establish tertiary or quaternary stereocenters with high enantioselectivity.Overman, L. E. ''Pure Appl. Chem.'' 1994, ''66'', 1423. A number of tandem reactions, in which the intermediate alkylpalladium complex is intercepted either intra- or intermolecularly before β-hydride elimination, have also been developed. ''(1)''


Mechanism and Stereochemistry


The Neutral Pathway

As shown in Eq. 2, the neutral pathway of the Heck reaction begins with the oxidative addition of the aryl or alkenyl halide into a coordinatively unsaturated palladium(0) complex (typically bound to two phosphine ligands) to give complex I. Dissociation of a phosphine ligand followed by association of the alkene yields complex II, and
migratory insertion In organometallic chemistry, a migratory insertion is a type of reaction wherein two ligands on a metal complex combine. It is a subset of reactions that very closely resembles the insertion reactions, and both are differentiated by the mecha ...
of the alkene into the carbon-palladium bond establishes the key carbon-carbon bond. Insertion takes place in a suprafacial fashion, but the
dihedral angle A dihedral angle is the angle between two intersecting planes or half-planes. In chemistry, it is the clockwise angle between half-planes through two sets of three atoms, having two atoms in common. In solid geometry, it is defined as the un ...
between the alkene and palladium-carbon bond during insertion can vary from 0° to ~90°. After insertion, β-hydride elimination affords the product and a palladium(II)-hydrido complex IV, which is reduced by base back to palladium(0). ''(2)''


The Cationic Pathway

Most asymmetric Heck reactions employing chiral phosphines proceed by the
cationic An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...
pathway, which does not require the dissociation of a phosphine ligand. Oxidative addition of an
aryl In organic chemistry, an aryl is any functional group or substituent derived from an aromatic ring, usually an aromatic hydrocarbon, such as phenyl and naphthyl. "Aryl" is used for the sake of abbreviation or generalization, and "Ar" is used as ...
perfluorosulfonate generates a
cationic An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...
palladium aryl complex V. The mechanism then proceeds as in the neutral case, with the difference that an extra site of coordinative unsaturation exists on palladium throughout the process. Thus, coordination of the alkene does not require
ligand In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's ele ...
dissociation.
Stoichiometric Stoichiometry refers to the relationship between the quantities of reactants and products before, during, and following chemical reactions. Stoichiometry is founded on the law of conservation of mass where the total mass of the reactants equ ...
amounts of base are still required to reduce the palladium(II)-hydrido complex VIII back to palladium(0). Silver salts may be used to initiate the cationic pathway in reactions of aryl halides. ''(3)''


The Anionic Pathway

Reactions involving palladium(II) acetate and phosphine ligands proceed by a third mechanism, the
anionic An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...
pathway.Amatore, C.; Jutand, A. ''Acc. Chem. Res.'' 2000, ''33'', 314. Base mediates the oxidation of a phosphine ligand by palladium(II) to a
phosphine oxide Phosphine oxides are phosphorus compounds with the formula OPX3. When X = alkyl or aryl, these are organophosphine oxides. Triphenylphosphine oxide is an example. An inorganic phosphine oxide is phosphoryl chloride (POCl3). Structure and bonding ...
. Oxidative addition then generates the
anionic An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...
palladium complex IX. Loss of halide leads to neutral complex X, which undergoes steps analogous to the neutral pathway to regenerate anionic complex IX. A similar anionic pathway is also likely operative in reactions of bulky palladium tri(''tert''-butyl)phosphine complexes. ''(4)''


Establishing Tertiary or Quaternary Stereocenters

Asymmetric Heck reactions establish quaternary or tertiary stereocenters. If migratory insertion generates a quaternary center adjacent to the palladium-carbon bond (as in reactions of trisubstituted or 1,1-disubstituted alkenes), β-hydride elimination toward that center is not possible and it is retained in the product. Similarly,
β-hydride elimination β-Hydride elimination is a reaction in which an alkyl group bonded to a metal centre is converted into the corresponding metal-bonded hydride and an alkene. The alkyl must have hydrogens on the β-carbon. For instance butyl groups can undergo th ...
is not possible if a
hydrogen Hydrogen is the chemical element with the symbol H and atomic number 1. Hydrogen is the lightest element. At standard conditions hydrogen is a gas of diatomic molecules having the formula . It is colorless, odorless, tasteless, non-toxic ...
''syn'' to the palladium-carbon bond is not available. Thus, tertiary stereocenters can be established in conformationally restricted systems. ''(5)''


Scope and Limitations

The intramolecular Heck reaction may be used to form rings of a variety of sizes and topologies. β-Hydride elimination need not be the final step of the reaction, and tandem methods have been developed that involve the interception of palladium alkyl intermediates formed after migratory insertion by an additional reactant. This section discusses the most common ring sizes formed by the intramolecular Heck reaction and some of its tandem and asymmetric variants. 5-''Exo'' cyclization, which establishes a five-membered ring with an exocyclic alkene, is the most facile
cyclization A cyclic compound (or ring compound) is a term for a compound in the field of chemistry in which one or more series of atoms in the compound is connected to form a ring. Rings may vary in size from three to many atoms, and include examples where ...
mode in intramolecular Heck reactions. In this and many other modes of intramolecular Heck cyclization, annulations typically produce a ''cis'' ring juncture. ''(6)''
6-''Exo'' cyclization is also common. The high stability of Heck reaction catalysts permits the synthesis of highly strained compounds at elevated temperatures. In the example below, the arene and alkene must both be in energetically unfavorable axial positions in order to react. ''(7)''
''Endo'' cyclization is observed most often when small or large rings are involved. For instance, 5-''endo'' cyclization is generally preferred over 4-''exo'' cyclization. The yield of ''endo'' product increases with increasing ring size in the synthesis of cycloheptenes, - octenes, and - nonenes. ''(8)''
Tandem reactions initiated by IMHR have been extensively explored. Palladium alkyl intermediates generated after migratory insertion may undergo a second round of insertion in the presence of a second alkene (either intra- or intermolecular). When dienes are involved in the intramolecular Heck reaction, insertion affords π-allylpalldium intermediates, which may be intercepted by nucleophiles. This idea was applied to a synthesis of (–)-
morphine Morphine is a strong opiate that is found naturally in opium, a dark brown resin in poppies ('' Papaver somniferum''). It is mainly used as a pain medication, and is also commonly used recreationally, or to make other illicit opioids. Ther ...
. ''(9)''
Asymmetric IMHR may establish tertiary or quaternary stereocenters. BINAP is the most commonly chiral ligand used in this context. An interesting application of IMHR is group-selective
desymmetrization Desymmetrization in stereochemistry is the modification of a molecule that results in the loss of one or more symmetry elements. A common application of this class of reactions involves the introduction of chirality.Willis, Michael C. "Enantiosel ...
(enantiotopic group selection), in which the chiral palladium aryl intermediate undergoes insertion predominantly with one of the enantiotopic double bonds. ''(10)''


Synthetic Applications

The high
functional group In organic chemistry, a functional group is a substituent or moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions regardless of the res ...
tolerance of the intramolecular Heck reaction allows it to be used at a very late stage in synthetic routes. In a synthesis of (±)-FR900482, IMHR establishes a
tricyclic Tricyclics are chemical compounds that contain three interconnected rings of atoms. Many compounds have a tricyclic structure, but in pharmacology, the term has traditionally been reserved to describe heterocyclic drugs. Among these are anti ...
ring system in high yield without disturbing any of the sensitive functionality nearby. ''(11)''
Intramolecular Heck reactions have been employed for the construction of complex natural products. An example is the late-stage, macrocyclic ring closure in the total synthesis of the
cytotoxic Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are an immune cell or some types of venom, e.g. from the puff adder (''Bitis arietans'') or brown recluse spider (''Loxosceles reclusa''). Cell physiology Treating ...
natural product (–)- Mandelalide A. In another example a fully intramolecular tandem Heck reaction is used in a synthesis of (–)-scopadulcic acid. A 6-exo cyclization sets the quaternary center and provides a neopentyl σ-palladium intermediate, which undergoes a 5-exo reaction to provide the ring system. ''(12)''


Comparison with Other Methods

The closest competing method to IMHR is radical cyclization. Radical cyclizations are often reductive, which can cause undesired side reactions to occur if sensitive substrates are employed. The IMHR, on the other hand, can be run under reductive conditions if desired. Unlike the IMHR, radical cyclization does not require the coupling of two sp2-hybridized carbons. In some cases, the results of radical cyclization and IMHR are complementary.


Experimental Conditions and Procedure


Typical Conditions

A variety of experimental concerns exist for IMHR reactions. Although most of the common Pd(0) catalysts are commercially available (Pd(PPh3)4, Pd2(dba)3, and derivatives), they may also be prepared by simple, high-yielding procedures. Palladium(II) acetate is cheap and may be reduced ''in situ'' to palladium(0) with
phosphine Phosphine ( IUPAC name: phosphane) is a colorless, flammable, highly toxic compound with the chemical formula , classed as a pnictogen hydride. Pure phosphine is odorless, but technical grade samples have a highly unpleasant odor like rotti ...
. Three equivalents of phosphine per equivalent of palladium acetate are commonly used; these conditions generate Pd(PR3)2 as the active catalyst. Bidentate phosphine ligands are common in asymmetric reactions to enhance stereoselectivity. A wide variety of bases may be used, and the base is often employed in excess.
Potassium carbonate Potassium carbonate is the inorganic compound with the formula K2 CO3. It is a white salt, which is soluble in water. It is deliquescent, often appearing as a damp or wet solid. Potassium carbonate is mainly used in the production of soap and gl ...
is the most common base employed, and
inorganic In chemistry, an inorganic compound is typically a chemical compound that lacks carbon–hydrogen bonds, that is, a compound that is not an organic compound. The study of inorganic compounds is a subfield of chemistry known as ''inorganic chemis ...
bases are generally used more often than organic bases. A number of additives have also been identified for the Heck reaction—silver salts may be used to drive the reaction down the cationic pathway, and halide salts may be used to convert aryl triflates via the neutral pathway.
Alcohol Alcohol most commonly refers to: * Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom * Alcohol (drug), an intoxicant found in alcoholic drinks Alcohol may also refer to: Chemicals * Ethanol, one of sev ...
s have been shown to enhance
catalyst Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
stability in some cases,Ohrai, K.; Kondo, K.; Sodeoka, M.; Shibasaki, M. ''J. Am. Chem. Soc.'' 1994, ''116'', 11737. and
acetate An acetate is a salt formed by the combination of acetic acid with a base (e.g. alkaline, earthy, metallic, nonmetallic or radical base). "Acetate" also describes the conjugate base or ion (specifically, the negatively charged ion called ...
salts are beneficial in reactions following the anionic pathway.


Example Procedure

''(13)''
A solution of the amide (0.365 g, 0.809 mmol), Pd(PPh3)4 (0.187 g, 0.162 mmol), and
triethylamine Triethylamine is the chemical compound with the formula N(CH2CH3)3, commonly abbreviated Et3N. It is also abbreviated TEA, yet this abbreviation must be used carefully to avoid confusion with triethanolamine or tetraethylammonium, for which TEA ...
(1.12 mL, 8.08 mmol) in MeCN (8 mL) in a sealed tube was heated slowly to 120°. After stirring for 4 hours, the reaction mixture was cooled to room temperature, and the solvent was evaporated. The residue was chromatographed (loaded with CH2Cl2) to give the title product 316 (0.270 g, 90%) as a colorless oil; Rf 0.42 (EtOAc/
petroleum ether Petroleum ether is the petroleum fraction consisting of aliphatic hydrocarbons and boiling in the range 35–60 Â°C, and commonly used as a laboratory solvent. Despite the name, petroleum ether is not classified as an ether; the term is used ...
10:1); �sub>22D +14.9 (c, 1.0, CHCl3); IR 3027, 2930, 1712, 1673, 1608, 1492, 1343, 1248 cm−1; 1H NMR (400 MHz) δ 7.33–7.21 (m, 6 H), 7.07 (dd, J = 7.3, 16.4 Hz, 1 H), 7.00 (t, J = 7.5 Hz, 1 H), 6.77 (d, J = 7.7 Hz, 1 H), 6.30 (dd, J = 8.7, 11.4 Hz, 1 H), 5.32 (d, J = 15.7 Hz, 1 H), 5.04 (s, 1 H), 4.95 (s, 1 H), 4.93 (d, J = 11.1 Hz, 1 H), 4.17 (s, 1 H), 3.98 (d, J = 15.7 Hz, 1 H), 3.62 (d, J = 8.7 Hz, 1 H), 3.17 (s, 3 H), 2.56 (dd, J = 3.5, 15.5 Hz, 1 H), 2.06 (dd, J = 2.8, 15.5 Hz, 1 H); 13C NMR (100 MHz) δ 177.4, 172.9, 147.8, 142.2, 136.5, 132.2, 131.6, 128.8, 128.4, 128.2, 127.7, 127.1, 123.7, 122.9, 107.9, 105.9, 61.0, 54.7, 49.9, 44.4, 38.2, 26.4; HRMS Calcd. for C24H22N2O2: 370.1681. Found: 370.1692.


References

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