Aza-Cope rearrangement
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.[1] Aza-Cope
rearrangements are generally classified by the position of the nitrogen in the molecule (see figure):
The first example of an aza-Cope rearrangement was the ubiquitous cationic 2-aza-Cope rearrangement,
which takes place at temperatures 100-200 °C lower than the Cope rearrangement due to the facile nature
of the rearrangement.[2] The facile nature of this rearrangement is attributed both to the fact that the cationic
2-aza-Cope is inherently thermoneutral, meaning there's no bias for the starting material or product, as well
as to the presence of the charged heteroatom in the molecule, which lowers the activation barrier. Less
common are the 1-aza-Cope rearrangement and the 3-aza-Cope rearrangement, which are the microscopic
reverse of each other. The 1- and 3-aza-Cope rearrangements have high activation barriers and limited
synthetic applicability, accounting for their relative obscurity.[3][4][5]
To maximize its synthetic utility, the cationic 2-aza-Cope rearrangement is normally paired with a
thermodynamic bias toward one side of the rearrangement. The most common and synthetically useful
strategy couples the cationic 2-aza-Cope rearrangement with a Mannich cyclization, and is the subject of
much of this article. This tandem aza-Cope/Mannich reaction is characterized by its mild reaction
conditions, diastereoselectivity, and wide synthetic applicability. It provides easy access to acyl-substituted
pyrrolidines, a structure commonly found in natural products such as alkaloids, and has been used in the
synthesis of a number of them, notably strychnine and crinine.[6] Larry E. Overman and coworkers have
done extensive research on this reaction.[1]
Contents
The cationic 2-aza-Cope rearrangement
Reaction mechanism
Rate acceleration due to positively charged nitrogen
Transition state and stereochemistry
Additional considerations for stereochemistry
Possible thermodynamic sinks for biasing a rearrangement product
The aza-Cope/Mannich reaction
The first aza-Cope/Mannich reaction
, Reaction mechanism
Synthetic applications of the 2-aza-Cope/Mannich reaction
(−)-Strychnine total synthesis
Synthesis of (−)-crinine
Synthesis of bridged tricyclic alkaloids
General ring opening and expansion
Scope of the aza-Cope/Mannich reaction
Amine addition and iminium formation
Epoxide ring opening
Iminium ion formation
Amine alkylation
Oxazolidine use
Installation of the vinyl substituent
Vinylation of ketones
Cyanomethyl group use
The 1- and 3-aza-Cope rearrangements
The 3-aza-Cope rearrangement
The 1-aza-Cope rearrangement
See also
References
The cationic 2-aza-Cope rearrangement
The cationic 2-aza-Cope rearrangement, most properly called the 2-
azonia-[3,3]-sigmatropic rearrangement, has been thoroughly
studied by Larry E. Overman and coworkers. It is the most
extensively studied of the aza-Cope rearrangements due to the mild
conditions required to carry the arrangement out, as well as for its
many synthetic applications, notably in alkaloid synthesis.
Thermodynamically, the general 2-aza-Cope rearrangement does not
have a product bias, as the bonds broken and formed are equivalent in either direction of the reaction,
similar to the Cope rearrangement. The presence of the ionic nitrogen heteroatom accounts for the more
facile rearrangement of the cationic 2-aza-Cope rearrangement in comparison to the Cope rearrangement.
Hence, it is often paired with a thermodynamic sink to bias a rearrangement product.[1]
In 1950, Horowitz and Geissman reported the first example of the 2-aza-Cope rearrangement, a surprising
result in a failed attempt to synthesize an amino alcohol.[2] This discovery identified the basic mechanism of
the rearrangement, as the product was most likely produced through a nitrogen analog of the Cope
rearrangement. Treatment of an allylbenzylamine (A) with formic acid and formaldehyde leads to an amino
alcohol (B). The amino alcohol converts to an imine under addition of acid (C), which undergoes the
cationic 2-aza-Cope rearrangement (D). Water hydrolyses the iminium ion to an amine (E). Treating this
starting material with only formaldehyde showed that alkylation of the amine group occurred after the
cationic 2-aza-Cope rearrangement, a testament to the quick facility of the rearrangement.[2]
, Horowitz and Geissman report the first aza-Cope rearrangement. This also exemplifies one
of the many methods for carrying out iminium ion formation by reductive amination.
Due to the mild heating conditions of the reaction carried out, unlike the more stringent ones for a purely
hydrocarbon Cope rearrangement, this heteroatomic Cope rearrangement introduced the hypothesis that
having a positive charge on a nitrogen in the cope rearrangement significantly reduces the activation barrier
for the rearrangement.[2]
Reaction mechanism
Rate acceleration due to positively charged nitrogen
The aza-Cope rearrangements are predicted by the
Woodward-Hoffman rules to proceed suprafacially.
However, while never explicitly studied, Overman and
coworkers have hypothesized that, as with the base-
catalyzed oxy-Cope rearrangement, the charged atom
distorts the sigmatropic rearrangement from a purely
concerted reaction mechanism (as expected in the Cope
rearrangement), to one with partial diradical/dipolar character, due to delocalization of the positive charge
onto the allylic fragment, which weakens the allylic bond. This results in a lowered activation barrier for
bond breaking. Thus the cationic-aza-Cope rearrangement proceeds more quickly than more concerted
processes such as the Cope rearrangement.[6][7]
Transition state and stereochemistry
The cationic 2-aza-Cope rearrangement is characterized by its high stereospecificity, which arises from its
high preference for a chair transition state. In their exploration of this rearrangement's stereospecificity,
Overman and coworkers used logic similar to the classic Doering and Roth experiments,[8] which showed
that the Cope rearrangement prefers a chair conformation.[9] By using the cationic 2-aza-Cope/Mannich
reaction on pyrrolizidine precursors, they showed that pyrrolizidines with cis substituents from E-alkenes
and trans substituents from Z-alkenes are heavily favored, results that are indicative of a chair transition
state. If a boat transition state was operative, the opposite results would have been obtained (detailed in
image below).[9] As is the trend with many reactions, conversion of the Z-enolate affords lower selectivity
due to 1,3 diaxial steric interactions between the enolate and the ring, as well as the fact that substituents
prefer quasi-equatorial positioning. This helps explain the higher temperatures required for Z-enolate
conversion.[6][9] The boat transition state is even less favored by the cationic-2-aza-Cope rearrangement
than it is for the Cope rearrangement: in analogous situations to where the Cope rearrangement takes on a
boat transition state, the aza-Cope rearrangement continues in the chair geometry.[1][6][10] These results are
in accord with computational chemistry results, which further assert that the transition state is under kinetic
control.[11]
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.[1] Aza-Cope
rearrangements are generally classified by the position of the nitrogen in the molecule (see figure):
The first example of an aza-Cope rearrangement was the ubiquitous cationic 2-aza-Cope rearrangement,
which takes place at temperatures 100-200 °C lower than the Cope rearrangement due to the facile nature
of the rearrangement.[2] The facile nature of this rearrangement is attributed both to the fact that the cationic
2-aza-Cope is inherently thermoneutral, meaning there's no bias for the starting material or product, as well
as to the presence of the charged heteroatom in the molecule, which lowers the activation barrier. Less
common are the 1-aza-Cope rearrangement and the 3-aza-Cope rearrangement, which are the microscopic
reverse of each other. The 1- and 3-aza-Cope rearrangements have high activation barriers and limited
synthetic applicability, accounting for their relative obscurity.[3][4][5]
To maximize its synthetic utility, the cationic 2-aza-Cope rearrangement is normally paired with a
thermodynamic bias toward one side of the rearrangement. The most common and synthetically useful
strategy couples the cationic 2-aza-Cope rearrangement with a Mannich cyclization, and is the subject of
much of this article. This tandem aza-Cope/Mannich reaction is characterized by its mild reaction
conditions, diastereoselectivity, and wide synthetic applicability. It provides easy access to acyl-substituted
pyrrolidines, a structure commonly found in natural products such as alkaloids, and has been used in the
synthesis of a number of them, notably strychnine and crinine.[6] Larry E. Overman and coworkers have
done extensive research on this reaction.[1]
Contents
The cationic 2-aza-Cope rearrangement
Reaction mechanism
Rate acceleration due to positively charged nitrogen
Transition state and stereochemistry
Additional considerations for stereochemistry
Possible thermodynamic sinks for biasing a rearrangement product
The aza-Cope/Mannich reaction
The first aza-Cope/Mannich reaction
, Reaction mechanism
Synthetic applications of the 2-aza-Cope/Mannich reaction
(−)-Strychnine total synthesis
Synthesis of (−)-crinine
Synthesis of bridged tricyclic alkaloids
General ring opening and expansion
Scope of the aza-Cope/Mannich reaction
Amine addition and iminium formation
Epoxide ring opening
Iminium ion formation
Amine alkylation
Oxazolidine use
Installation of the vinyl substituent
Vinylation of ketones
Cyanomethyl group use
The 1- and 3-aza-Cope rearrangements
The 3-aza-Cope rearrangement
The 1-aza-Cope rearrangement
See also
References
The cationic 2-aza-Cope rearrangement
The cationic 2-aza-Cope rearrangement, most properly called the 2-
azonia-[3,3]-sigmatropic rearrangement, has been thoroughly
studied by Larry E. Overman and coworkers. It is the most
extensively studied of the aza-Cope rearrangements due to the mild
conditions required to carry the arrangement out, as well as for its
many synthetic applications, notably in alkaloid synthesis.
Thermodynamically, the general 2-aza-Cope rearrangement does not
have a product bias, as the bonds broken and formed are equivalent in either direction of the reaction,
similar to the Cope rearrangement. The presence of the ionic nitrogen heteroatom accounts for the more
facile rearrangement of the cationic 2-aza-Cope rearrangement in comparison to the Cope rearrangement.
Hence, it is often paired with a thermodynamic sink to bias a rearrangement product.[1]
In 1950, Horowitz and Geissman reported the first example of the 2-aza-Cope rearrangement, a surprising
result in a failed attempt to synthesize an amino alcohol.[2] This discovery identified the basic mechanism of
the rearrangement, as the product was most likely produced through a nitrogen analog of the Cope
rearrangement. Treatment of an allylbenzylamine (A) with formic acid and formaldehyde leads to an amino
alcohol (B). The amino alcohol converts to an imine under addition of acid (C), which undergoes the
cationic 2-aza-Cope rearrangement (D). Water hydrolyses the iminium ion to an amine (E). Treating this
starting material with only formaldehyde showed that alkylation of the amine group occurred after the
cationic 2-aza-Cope rearrangement, a testament to the quick facility of the rearrangement.[2]
, Horowitz and Geissman report the first aza-Cope rearrangement. This also exemplifies one
of the many methods for carrying out iminium ion formation by reductive amination.
Due to the mild heating conditions of the reaction carried out, unlike the more stringent ones for a purely
hydrocarbon Cope rearrangement, this heteroatomic Cope rearrangement introduced the hypothesis that
having a positive charge on a nitrogen in the cope rearrangement significantly reduces the activation barrier
for the rearrangement.[2]
Reaction mechanism
Rate acceleration due to positively charged nitrogen
The aza-Cope rearrangements are predicted by the
Woodward-Hoffman rules to proceed suprafacially.
However, while never explicitly studied, Overman and
coworkers have hypothesized that, as with the base-
catalyzed oxy-Cope rearrangement, the charged atom
distorts the sigmatropic rearrangement from a purely
concerted reaction mechanism (as expected in the Cope
rearrangement), to one with partial diradical/dipolar character, due to delocalization of the positive charge
onto the allylic fragment, which weakens the allylic bond. This results in a lowered activation barrier for
bond breaking. Thus the cationic-aza-Cope rearrangement proceeds more quickly than more concerted
processes such as the Cope rearrangement.[6][7]
Transition state and stereochemistry
The cationic 2-aza-Cope rearrangement is characterized by its high stereospecificity, which arises from its
high preference for a chair transition state. In their exploration of this rearrangement's stereospecificity,
Overman and coworkers used logic similar to the classic Doering and Roth experiments,[8] which showed
that the Cope rearrangement prefers a chair conformation.[9] By using the cationic 2-aza-Cope/Mannich
reaction on pyrrolizidine precursors, they showed that pyrrolizidines with cis substituents from E-alkenes
and trans substituents from Z-alkenes are heavily favored, results that are indicative of a chair transition
state. If a boat transition state was operative, the opposite results would have been obtained (detailed in
image below).[9] As is the trend with many reactions, conversion of the Z-enolate affords lower selectivity
due to 1,3 diaxial steric interactions between the enolate and the ring, as well as the fact that substituents
prefer quasi-equatorial positioning. This helps explain the higher temperatures required for Z-enolate
conversion.[6][9] The boat transition state is even less favored by the cationic-2-aza-Cope rearrangement
than it is for the Cope rearrangement: in analogous situations to where the Cope rearrangement takes on a
boat transition state, the aza-Cope rearrangement continues in the chair geometry.[1][6][10] These results are
in accord with computational chemistry results, which further assert that the transition state is under kinetic
control.[11]
