Radical cyclization
Encyclopedia
Radical cyclization reactions are organic chemical transformations
that yield cyclic products via radical intermediates. They usually proceed in three basic steps: selective radical generation, radical cyclization, and conversion of the cyclized radical to product.
products through the action of radical intermediates. Because they are intramolecular
transformations, they are often very rapid and selective. Selective radical generation can be achieved at carbons bound to a variety of functional group
s, and reagents used to effect radical generation are numerous. The radical cyclization step usually involves the attack of a radical on a multiple bond. After this step occurs, the resulting cyclized radicals are quenched through the action of a radical scavenger, a fragmentation process, or an electron-transfer reaction. Five- and six-membered rings are the most common products; formation of smaller and larger rings is rarely observed.
Three conditions must be met for an efficient radical cyclization to take place:
Advantages: because radical intermediates are not charged species, reaction conditions are often mild and functional group tolerance is high. Reactions can be carried out in nearly any solvent
, and products are often synthetically useful compounds that can be carried on using existing functionality or groups introduced during radical trapping
.
Disadvantages: the relative rates of the various stages of radical cyclization reactions (and any side reactions) must be carefully controlled so that cyclization and trapping of the cyclized radical is favored. Side reactions are sometimes a problem, and cyclization is especially slow for small and large rings (although macrocyclizations, which resemble intermolecular radical reactions, are often high yielding).
(1)
Substituents that affect the stability of these transition states can have a profound effect on the site selectivity of the reaction. Carbonyl substitutents at the 2-position, for instance, encourage 6-endo ring closure. Alkyl substituents at positions 2, 3, 4, or 6 enhance selectivity for 5-exo closure.
Cyclization of the homologous 6-heptenyl radical is still selective, but is much slower—as a result, competitive side reactions are an important problem when these intermediates are involved. Additionally, 1,5-shifts can yield stabilized allylic radicals at comparable rates in these systems. In 6-hexenyl radical substrates, polarization of the reactive double bond
with electron-withdrawing functional groups is often necessary to achieve high yields. Stabilizing the initially formed radical with electron-withdrawing groups provides access to more stable 6-endo cyclization products preferentially.
(2)
Cyclization reactions of vinyl, aryl, and acyl radicals are also known. Under conditions of kinetic control, 5-exo cyclization takes place preferentially. However, small concentrations of a radical scavenger establish thermodynamic control and provide access to 6-endo products—not via 6-endo cyclization, but by 5-exo cyclization followed by 3-endo closure and rearrangement. Aryl radicals exhibit similar reactivity.
(3)
Cyclization can involve heteroatom-containing multiple bonds such as nitrile
s, oxime
s, and carbonyl
s. Attack at the carbon atom of the multiple bond is almost always observed. In the latter case attack is reversible; however alkoxy radicals can be trapped using a stannane trapping agent.
shown above. Placing substituents in pseudoequatorial positions in the transition state leads to cis products from simple secondary radicals. Introducing polar substituents can favor trans products due to steric or electronic repulsion between the polar groups. In more complex systems, the development of transition state models requires consideration of factors such as allylic strain and boat-like transition states
(4)
Chiral auxiliaries have been used in enantioselective radical cyclizations with limited success. Small energy differences between early transition states constitute a profound barrier to success in this arena. In the example shown, diastereoselectivity (for both configurations of the left-hand stereocenter) is low, and enantioselectivity is only moderate.
(5)
Substrates with stereocenters between the radical and multiple bond are often highly stereoselective. Radical cyclizations to form polycyclic products often take advantage of this property.
, silicon
, and mercury
hydrides) is common in radical cyclization reactions; the primary limitation of this method is the possibility of reduction of the initially formed radical by H-M. Fragmentation methods avoid this problem by incorporating the chain-transfer reagent into the substrate itself—the active chain-carrying radical is not released until after cyclization has taken place. The products of fragmentation methods retain a double bond as a result, and extra synthetic steps are usually required to incorporate the chain-carrying group.
Atom-transfer methods rely on the movement of an atom from the acyclic starting material to the cyclic radical to generate the product. These methods use catalytic amounts of weak reagents, preventing problems associated with the presence of strong reducing agents (such as tin hydride). Hydrogen- and halogen-transfer processes are known; the latter tend to be more synthetically useful.
(6)
Oxidative and reductive cyclization methods also exist. These procedures require fairly electrophilic and nucleophilic radicals, respectively, to proceed effectively. Cyclic radicals are either oxidized or reduced and quenched with either external or internal nucleophiles or electrophiles, respectively.
(7)
Polycycles and macrocycles can also be formed using radical cyclization reactions. In the former case, rings can be pre-formed and a single ring closed with radical cyclization, or multiple rings can be formed in a tandem process (as below). Macrocyclizations, which lack the FMO requirement of cyclizations of smaller substrates, have the unique property of exhibiting endo selectivity.
(8)
s, do not require strongly acidic conditions, and can be kinetically controlled. Cationic cyclizations are usually thermodynamically controlled. Radical cyclizations are much faster than analogous anionic cyclizations, and avoid β-elimination side reactions. Anionic Michael
-type cyclization is an alternative to radical cyclization of activated olefins. Metal-catalyzed cyclization reactions usually require mildly basic conditions, and substrates must be chosen to avoid β-hydride elimination. The primary limitation of radical cyclizations with respect to these other methods is the potential for radical side reactions.
A mixture of bromo acetal 1 (549 mg, 1.78 mmol), AIBN (30.3 mg, 0.185 mmol), and Bu3SnH (0.65 mL, 2.42 mmol) in dry benzene
(12 mL) was heated under reflux for 1 hour and then evaporated under reduced pressure. Silica gel column chromatography of the crude product with hexane
–EtOAc
(92:8) as eluant gave tetrahydropyran 2 (395 mg, 97 %) as an oily mixture of two diastereomers. (c 0.43, CHCl3); IR (CHCl3
):1732 cm–1;1H NMR
(CDCl3)δ 4.77–4.89 (m, 0.6H), 4.66–4.69 (m, 0.4H), 3.40–4.44 (m, 4H), 3.68 (s, 3H), 2.61 (dd, J = 15.2, 4.2 Hz, 1H), 2.51 (dd, J = 15.2, 3.8 Hz, 1H), 0.73–1.06 (m, 3H); mass spectrum
: m/z 215 (M+–Me); Anal. Calcd for C12H22O4: C, 62.6; H, 9.65. Found: C, 62.6; H, 9.7.
Organic reaction
Organic reactions are chemical reactions involving organic compounds. The basic organic chemistry reaction types are addition reactions, elimination reactions, substitution reactions, pericyclic reactions, rearrangement reactions, photochemical reactions and redox reactions. In organic synthesis,...
that yield cyclic products via radical intermediates. They usually proceed in three basic steps: selective radical generation, radical cyclization, and conversion of the cyclized radical to product.
Introduction
Radical cyclization reactions produce mono- or polycyclicPolycyclic compound
In organic chemistry, a polycyclic compound is a cyclic compound with more than one hydrocarbon loop or ring structures . In general, the term includes all polycyclic aromatic compounds, including the polycyclic aromatic hydrocarbons, the heterocyclic aromatic compounds containing sulfur,...
products through the action of radical intermediates. Because they are intramolecular
Intramolecular
Intramolecular in chemistry describes a process or characteristic limited within the structure of a single molecule, a property or phenomenon limited to the extent of a single molecule.- Examples :...
transformations, they are often very rapid and selective. Selective radical generation can be achieved at carbons bound to a variety of functional group
Functional group
In organic chemistry, functional groups are specific groups of atoms within molecules that are responsible for the characteristic chemical reactions of those molecules. The same functional group will undergo the same or similar chemical reaction regardless of the size of the molecule it is a part of...
s, and reagents used to effect radical generation are numerous. The radical cyclization step usually involves the attack of a radical on a multiple bond. After this step occurs, the resulting cyclized radicals are quenched through the action of a radical scavenger, a fragmentation process, or an electron-transfer reaction. Five- and six-membered rings are the most common products; formation of smaller and larger rings is rarely observed.
Three conditions must be met for an efficient radical cyclization to take place:
- A method must be available to generate a radical selectively on the substrate.
- Radical cyclization must be faster than trapping of the initially formed radical.
- All steps must be faster than undesired side reactions such as radical recombination or reaction with solvent.
Advantages: because radical intermediates are not charged species, reaction conditions are often mild and functional group tolerance is high. Reactions can be carried out in nearly any solvent
Solvent
A solvent is a liquid, solid, or gas that dissolves another solid, liquid, or gaseous solute, resulting in a solution that is soluble in a certain volume of solvent at a specified temperature...
, and products are often synthetically useful compounds that can be carried on using existing functionality or groups introduced during radical trapping
Chemical trap
In chemistry, a chemical trap is a chemical compound that is used to detect a certain molecule when* The concentration of this molecule is very small and below detection limit...
.
Disadvantages: the relative rates of the various stages of radical cyclization reactions (and any side reactions) must be carefully controlled so that cyclization and trapping of the cyclized radical is favored. Side reactions are sometimes a problem, and cyclization is especially slow for small and large rings (although macrocyclizations, which resemble intermolecular radical reactions, are often high yielding).
Prevailing Mechanism
Because many reagents exist for radical generation and trapping, establishing a single prevailing mechanism is not possible. However, once a radical is generated, it can react with multiple bonds in an intramolecular fashion to yield cyclized radical intermediates. The two ends of the multiple bond constitute two possible sites of reaction. If the radical in the resulting intermediate ends up outside of the ring, the attack is termed "exo"; if it ends up inside the newly formed ring, the attack is called "endo." In many cases, exo cyclization is favored over endo cyclization (macrocyclizations constitute the major exception to this rule). 5-hexenyl radicals are the most synthetically useful intermediates for radical cyclizations, because cyclization is extremely rapid and endo selective. Although the exo radical is less thermodynamically stable than the endo radical, the more rapid exo cyclization is rationalized by better orbital overlap in the chair-like exo transition state (see below).(1)
Substituents that affect the stability of these transition states can have a profound effect on the site selectivity of the reaction. Carbonyl substitutents at the 2-position, for instance, encourage 6-endo ring closure. Alkyl substituents at positions 2, 3, 4, or 6 enhance selectivity for 5-exo closure.
Cyclization of the homologous 6-heptenyl radical is still selective, but is much slower—as a result, competitive side reactions are an important problem when these intermediates are involved. Additionally, 1,5-shifts can yield stabilized allylic radicals at comparable rates in these systems. In 6-hexenyl radical substrates, polarization of the reactive double bond
Double bond
A double bond in chemistry is a chemical bond between two chemical elements involving four bonding electrons instead of the usual two. The most common double bond, that between two carbon atoms, can be found in alkenes. Many types of double bonds between two different elements exist, for example in...
with electron-withdrawing functional groups is often necessary to achieve high yields. Stabilizing the initially formed radical with electron-withdrawing groups provides access to more stable 6-endo cyclization products preferentially.
(2)
Cyclization reactions of vinyl, aryl, and acyl radicals are also known. Under conditions of kinetic control, 5-exo cyclization takes place preferentially. However, small concentrations of a radical scavenger establish thermodynamic control and provide access to 6-endo products—not via 6-endo cyclization, but by 5-exo cyclization followed by 3-endo closure and rearrangement. Aryl radicals exhibit similar reactivity.
(3)
Cyclization can involve heteroatom-containing multiple bonds such as nitrile
Nitrile
A nitrile is any organic compound that has a -C≡N functional group. The prefix cyano- is used interchangeably with the term nitrile in industrial literature. Nitriles are found in many useful compounds, one example being super glue .Inorganic compounds containing the -C≡N group are not called...
s, oxime
Oxime
An oxime is a chemical compound belonging to the imines, with the general formula R1R2C=NOH, where R1 is an organic side chain and R2 may be hydrogen, forming an aldoxime, or another organic group, forming a ketoxime. O-substituted oximes form a closely related family of compounds...
s, and carbonyl
Carbonyl
In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups....
s. Attack at the carbon atom of the multiple bond is almost always observed. In the latter case attack is reversible; however alkoxy radicals can be trapped using a stannane trapping agent.
Stereoselectivity
The diastereoselectivity of radical cyclizations is often high. In most all-carbon cases, selectivity can be rationalized according to Beckwith's guidelines, which invoke the reactant-like, exo transition stateTransition state
The transition state of a chemical reaction is a particular configuration along the reaction coordinate. It is defined as the state corresponding to the highest energy along this reaction coordinate. At this point, assuming a perfectly irreversible reaction, colliding reactant molecules will always...
shown above. Placing substituents in pseudoequatorial positions in the transition state leads to cis products from simple secondary radicals. Introducing polar substituents can favor trans products due to steric or electronic repulsion between the polar groups. In more complex systems, the development of transition state models requires consideration of factors such as allylic strain and boat-like transition states
(4)
Chiral auxiliaries have been used in enantioselective radical cyclizations with limited success. Small energy differences between early transition states constitute a profound barrier to success in this arena. In the example shown, diastereoselectivity (for both configurations of the left-hand stereocenter) is low, and enantioselectivity is only moderate.
(5)
Substrates with stereocenters between the radical and multiple bond are often highly stereoselective. Radical cyclizations to form polycyclic products often take advantage of this property.
Radical Generation Methods
The use of metal hydrides (tinTin
Tin is a chemical element with the symbol Sn and atomic number 50. It is a main group metal in group 14 of the periodic table. Tin shows chemical similarity to both neighboring group 14 elements, germanium and lead and has two possible oxidation states, +2 and the slightly more stable +4...
, silicon
Silicon
Silicon is a chemical element with the symbol Si and atomic number 14. A tetravalent metalloid, it is less reactive than its chemical analog carbon, the nonmetal directly above it in the periodic table, but more reactive than germanium, the metalloid directly below it in the table...
, and mercury
Mercury (element)
Mercury is a chemical element with the symbol Hg and atomic number 80. It is also known as quicksilver or hydrargyrum...
hydrides) is common in radical cyclization reactions; the primary limitation of this method is the possibility of reduction of the initially formed radical by H-M. Fragmentation methods avoid this problem by incorporating the chain-transfer reagent into the substrate itself—the active chain-carrying radical is not released until after cyclization has taken place. The products of fragmentation methods retain a double bond as a result, and extra synthetic steps are usually required to incorporate the chain-carrying group.
Atom-transfer methods rely on the movement of an atom from the acyclic starting material to the cyclic radical to generate the product. These methods use catalytic amounts of weak reagents, preventing problems associated with the presence of strong reducing agents (such as tin hydride). Hydrogen- and halogen-transfer processes are known; the latter tend to be more synthetically useful.
(6)
Oxidative and reductive cyclization methods also exist. These procedures require fairly electrophilic and nucleophilic radicals, respectively, to proceed effectively. Cyclic radicals are either oxidized or reduced and quenched with either external or internal nucleophiles or electrophiles, respectively.
Ring Sizes
In general, radical cyclization to produce small rings is difficult. However, it is possible provided the cyclized radical can be trapped prior to re-opening. This process can be facilitated by fragmentation (see the three-membered case below) or by stabilization of the cyclized radical (see the four-membered case). Five- and six-membered rings are the most common sizes produced by radical cyclization.(7)
Polycycles and macrocycles can also be formed using radical cyclization reactions. In the former case, rings can be pre-formed and a single ring closed with radical cyclization, or multiple rings can be formed in a tandem process (as below). Macrocyclizations, which lack the FMO requirement of cyclizations of smaller substrates, have the unique property of exhibiting endo selectivity.
(8)
Comparison with Other Methods
In comparison to cationic cyclizations, radical cyclizations avoid issues associated with Wagner-Meerwein rearrangementWagner-Meerwein rearrangement
A Wagner–Meerwein rearrangement is a class of carbocation 1,2-rearrangement reactions in which a hydrogen, alkyl or aryl group migrates from one carbon to a neighboring carbon.Several reviews have been published....
s, do not require strongly acidic conditions, and can be kinetically controlled. Cationic cyclizations are usually thermodynamically controlled. Radical cyclizations are much faster than analogous anionic cyclizations, and avoid β-elimination side reactions. Anionic Michael
Michael reaction
The Michael reaction or Michael addition is the nucleophilic addition of a carbanion or another nucleophile to an alpha, beta unsaturated carbonyl compound. It belongs to the larger class of conjugate additions. This is one of the most useful methods for the mild formation of C-C bonds...
-type cyclization is an alternative to radical cyclization of activated olefins. Metal-catalyzed cyclization reactions usually require mildly basic conditions, and substrates must be chosen to avoid β-hydride elimination. The primary limitation of radical cyclizations with respect to these other methods is the potential for radical side reactions.
Typical Conditions
Radical reactions must be carried out under inert atmosphere. Because the relative rates of a number of processes are important to the reaction, concentrations must be carefully adjusted to optimize reaction conditions. However, reactions can be carried out in almost any solvent (limited only by the solubility of starting materials).Example Procedure
(9)A mixture of bromo acetal 1 (549 mg, 1.78 mmol), AIBN (30.3 mg, 0.185 mmol), and Bu3SnH (0.65 mL, 2.42 mmol) in dry benzene
Benzene
Benzene is an organic chemical compound. It is composed of 6 carbon atoms in a ring, with 1 hydrogen atom attached to each carbon atom, with the molecular formula C6H6....
(12 mL) was heated under reflux for 1 hour and then evaporated under reduced pressure. Silica gel column chromatography of the crude product with hexane
Hexane
Hexane is a hydrocarbon with the chemical formula C6H14; that is, an alkane with six carbon atoms.The term may refer to any of four other structural isomers with that formula, or to a mixture of them. In the IUPAC nomenclature, however, hexane is the unbranched isomer ; the other four structures...
–EtOAc
Ethyl acetate
Ethyl acetate is the organic compound with the formula CH3COOCH2CH3. This colorless liquid has a characteristic sweet smell and is used in glues, nail polish removers, and cigarettes...
(92:8) as eluant gave tetrahydropyran 2 (395 mg, 97 %) as an oily mixture of two diastereomers. (c 0.43, CHCl3); IR (CHCl3
Chloroform
Chloroform is an organic compound with formula CHCl3. It is one of the four chloromethanes. The colorless, sweet-smelling, dense liquid is a trihalomethane, and is considered somewhat hazardous...
):1732 cm–1;1H NMR
NMR spectroscopy
Nuclear magnetic resonance spectroscopy, most commonly known as NMR spectroscopy, is a research technique that exploits the magnetic properties of certain atomic nuclei to determine physical and chemical properties of atoms or the molecules in which they are contained...
(CDCl3)δ 4.77–4.89 (m, 0.6H), 4.66–4.69 (m, 0.4H), 3.40–4.44 (m, 4H), 3.68 (s, 3H), 2.61 (dd, J = 15.2, 4.2 Hz, 1H), 2.51 (dd, J = 15.2, 3.8 Hz, 1H), 0.73–1.06 (m, 3H); mass spectrum
Mass spectrometry
Mass spectrometry is an analytical technique that measures the mass-to-charge ratio of charged particles.It is used for determining masses of particles, for determining the elemental composition of a sample or molecule, and for elucidating the chemical structures of molecules, such as peptides and...
: m/z 215 (M+–Me); Anal. Calcd for C12H22O4: C, 62.6; H, 9.65. Found: C, 62.6; H, 9.7.