Redox-Neutral Aromatization of Cyclic Amines: Mechanistic Insights and Harnessing of Reactive Intermediates for Amine α- and β-C?H Functionalization

Article abstract of DOI:10.1002/chem.201603839

Cyclic amines such as pyrrolidine and piperidine are known to undergo condensations with aldehydes to furnish pyrrole and pyridine derivatives, respectively. A combined experimental and computational study provides detailed insights into the mechanism of pyrrole formation. A number of reactive intermediates (e.g., azomethine ylides, conjugated azomethine ylides, enamines) were intercepted, outlining strategies for circumventing aromatization as a valuable pathway for amine C?H functionalization.

Full text of DOI:10.1002/chem.201603839

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Accepted Article
Title: Redox-Neutral Aromatization of Cyclic Amines: Mechanistic
Insights and Harnessing of Reactive Intermediates for Amine α-
and β-C-H Functionalization
Authors: Longle Ma, Anirudra Paul, Martin Breugst, and Daniel Seidel
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To be cited as: Chem. Eur. J. 10.1002/chem.201603839
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Redox-Neutral Aromatization of Cyclic Amines: Mechanistic
Insights and Harnessing of Reactive Intermediates for Amine α-
and β-C–H Functionalization
Longle Ma,[a] Anirudra Paul,[a] Martin Breugst,*[b] and Daniel Seidel*[a]
Abstract: Cyclic amines such as pyrrolidine and piperidine are known
to undergo condensations with aldehydes to furnish pyrrole and
pyridine derivatives, respectively. A combined experimental and
computational study provides detailed insights into the mechanism of
pyrrole formation.
A number of reactive intermediates (e.g.,
azomethine ylides, conjugated azomethine ylides, enamines) were
intercepted; outlining strategies for circumventing aromatization as a
valuable pathway for amine C–H functionalization.
Introduction
Condensations of fully or partially saturated cyclic amines with
aldehydes or ketones can lead to substrate aromatization. These
rather unusual transformations are often facilitated by carboxylic
acids and are among the oldest reactions that result in the
functionalization of relatively unreactive C–H bonds in α-, β-, and
γ-position of an amine nitrogen atom (Scheme 1).[1–7] Reactions
in which pyrroles are formed from pyrrolidine or pyrroline, or
indole from indoline, represent redox-neutral transformations. No
external oxidants are required and water is produced as the sole
byproduct.[8]
economy.[9]
Such reactions are ideal in terms of redox-
If substrate aromatization could be prevented
through interception of reactive intermediates with appropriate
reaction partners, attractive new pathways for the
functionalization of amines would result. Here we report a
detailed study that sheds light on the mechanism of pyrrole
formation from pyrrolidine and aldehydes. Several strategies are
presented that divert aromatization and provide access to new
chemical space.
Scheme 1. Examples of redox-neutral amine aromatization.
Based on our previous studies on the redox-neutral α-
functionalization of amines[7u, 10] as well as historic insights and
facilitated by a carboxylic acid.
Addition of pyrrolidine to
3d, 11, 12]
recent studies by others,[2e,
we developed a working
benzaldehyde is thought to initially give rise to N,O-acetal 2, a
species that could exist in equilibrium with iminium ion 3.
Elimination of water or carboxylic acid results in the formation of
azomethine ylide 4 which could then be captured to form N,O-
acetal 5, possibly via the intermediacy of 6 with which 5 could
also exist in equilibrium. Loss of HOR from 5 or 6 gives enamine
7 which is considered to be a key intermediate of the overall
hypothesis regarding the mechanism of formation of 1,3-
dibenzylpyrrole (1) from pyrrolidine and benzaldehyde (Scheme
2). Pyrrole formation could occur in an uncatalyzed fashion or be
[a]
[b]
Dr. Longle Ma, Mr. A. Paul, Prof. Dr. D. Seidel
Department of Chemistry and Chemical Biology
Rutgers, The State University of New Jersey
Piscataway, New Jersey 08854, USA
E-mail: seidel@rutchem.rutgers.edu
Homepage: http://seidel-group.com
process.
Reaction of 7 with benzaldehyde leads to β-
functionalization, possibly involving intermediates 8–10. Several
possibilities exist as to how intermediate 10 could ultimately
isomerize to the final pyrrole product 1. Importantly, all plausible
paths linking 7 and 1 appear to require the intermediacy of a
conjugated azomethine ylide (either 11 or 17).
Dr. M. Breugst
Department fꢀr Chemie
Universitꢁt zu Kꢂln
Previous studies on the redox-neutral C–H functionalization of
pyrrolidine have pointed at the intermediacy of some of the
species thought to be relevant to the formation of 1. The
Greinstraße 4, 50939 Kꢂln, Germany
E-mail: mbreugst@uni-koeln.de
Homepage: http://physorg.uni-koeln.de
Supporting information for this article is given via a link at the end of
the document.
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Scheme 2. Potential reaction pathways for pyrrole formation from pyrrolidine.
Experimental results and discussion
Our first goal was to establish unambiguously that azomethine
ylides can indeed form from pyrrolidine and benzaldehyde under
conditions known to effect the formation of pyrrole 1 (i.e., under
thermal conditions in the absence of additives).[4a] We reasoned
that the best indirect evidence for the existence of these high-
energy intermediates would be to trap azomethine ylides via
intermolecular (3+2) cycloadditions. Due to its high reactivity and
well-known propensity to undergo various (3+2) cycloadditions
with azomethine ylides, N-methyl maleimide was selected as the
dipolarophile of choice.[17] Evidence for the formation of not only
azomethine ylide 4 but also the proposed conjugated azomethine
ylide 11 was obtained as shown in Scheme 4. Interestingly, by
allowing pyrrolidine, benzaldehyde and N-methyl maleimide to
react under relatively mild conditions (reflux in toluene), (3+2)
product 27 was obtained as a 1.5:1 mixture of diastereomers in
18% yield. In addition, products 28a–d were obtained in 16%
overall yield. The relative configuration of the major diastereomer
28a was determined unambiguously by X-ray crystallography.
Perhaps not surprisingly, conjugate addition product 29 was
obtained as the major product in 64% yield. When the reaction
was conducted in the presence of benzoic acid (1.2 equivalents)
but otherwise identical conditions, the same products were
obtained albeit in substantially different ratios. The yield of 28a
increased to 19% at the expense of 27 which was isolated in 6%
yield only. The other diastereomers of 28 were also formed in
increased amounts (33 % overall yield of 28a–d). An increase of
the amount of benzaldehyde relative to pyrrolidine resulted in the
exclusive formation of 28a–d in an overall yield of 45%, with the
main diastereomer 28a being formed in 29% yield. To rule out
the possibility that 28 could be formed from 27 via an alternate
pathway that does not involve conjugated azomethine ylide 11
(e.g., via temporary ring-opening and formation of an intermediate
enamine, etc.), 27 was exposed to the reaction conditions in the
presence of benzaldehyde. No formation of 28 was observed
with 27 being recovered in 90%.
Scheme 3. Support for azomethine ylide/enamine formation from pyrrolidine.
involvement of 5 and/or 6 can be inferred from the above
11d, 11h]
mentioned studies on amine α-functionalization,[10,
although for intramolecular reactions, additional functional groups
10g, 10i]
on the aldehyde often play specific roles.[10e,
For
intermolecular reactions, specific aldehydes/ketone reaction
partners are often required. There is less direct evidence for the
formation of azomethine ylides (e.g., 4) from pyrrolidine and
simple aldehydes. As outlined in Scheme 3, Hajra and coworkers
reported the formation of (3+2) cycloaddition product 22 via a
potassium acetate catalyzed reaction of pyrrolidine and two
equivalents of benzaldehyde.[11e] Our group has reported a
related intramolecular (3+2) cycloaddition in which an azomethine
ylide intermediate is formed upon benzoic acid catalyzed
condensation of pyrrolidine with 23 to ultimately afford product
24.[13] The potential of pyrrolidine-derivatives to form enamines
such as 7 was indicated in the formation of 26, in which 25
underwent α,β-difunctionalization upon reaction with para-
chlorobenzaldehyde.[14–16] However, more direct evidence for
enamines is lacking. To our knowledge, these species have
never been isolated from a condensation of pyrrolidine with
aldehydes.
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Scheme 4. Evidence for simple and conjugated azomethine ylides.
It is of interest to compare the results of Scheme 4 to reactions of
pyrrolidine and benzaldehyde that were performed in the absence
of N-methyl maleimide (Scheme 5). Simple heating of a 1:2
mixture of pyrrolidine and benzaldehyde in toluene under reflux
provided 22% of pyrrole 1 and 13% of (3+2) cycloaddition product
22 in addition to polar unidentified byproducts. The reaction
attack an aldehyde, it seemed that performing reactions with
excess pyrrolidine could reduce the propensity for such
subsequent aldol-type reactions.
A
reduction of the
nucleophilicity of the enamine by using a more electron-deficient
aldehyde reaction partner appeared to be another promising
strategy to stabilize these typically rather reactive intermediates.
remained incomplete as judged by the presence of benzaldehyde. Based on these considerations and our previous success with
In the presence of benzoic acid, an otherwise identical reaction
provided pyrrole 1 in 28% yield. Unreacted benzaldehyde
remained and polar unidentified byproducts were observed.
However, no 22 was obtained. This suggests that any potential
formation of 22 is inconsequential for the synthesis of pyrrole. To
provide evidence that 22 can readily undergo retro-(3+2)
cycloaddition, this material was exposed to the reaction
conditions in the presence of benzoic acid. As a result, 1 was
obtained in virtually identical yield as before (27%). Again, polar
unidentified byproducts were formed.
2,6-dichlorobenzaldehyde in bringing about redox-isomerizations
with pyrrolidine, this aldehyde was selected for attempts to
prepare pyrrolidine enamines (Scheme 6). A reaction of 2,6-
dichlorobenzaldehyde and pyrrolidine (1:5 ratio), after being
heated under reflux in toluene for two hours, provided a mixture
of products: the enamine dimer 30 (3% yield), a compound
corresponding to the addition product of 7 to 9 (31, 17% yield),
aminal 32 (27% yield) and recovered aldehyde (18%, not shown).
When an identical reaction was performed until the aldehyde was
consumed fully,[18] the yields of 30 and 31 increased to 35% and
26%, respectively. Interestingly, addition of 20 mol% of benzoic
acid led to complete consumption of the aldehyde within two
hours and allowed for the isolation of enamine dimer 30 in 65%
yield.[19] In this instance, product 31 was not observed. A marked
solvent effect was noted. Simply switching the solvent from
toluene to methanol afforded 31 as the only isolable product in
45% yield. In a control experiment, aminal 32 was found to
convert to 30 under the reaction conditions. It should be noted
that the dimerization of endocyclic enamines is a well-known
phenomenon[20] and plays a role in the biosynthesis of certain
natural products.[21] Attempts to generate enamine dimers from
reactions of pyrrolidine with parent benzaldehyde led to inferior
results. This finding is consistent with the computationally
predicted lower stability of the benzaldehyde-derived enamine
dimers (vide infra).
Scheme 5. Pyrrole formation and (3+2) cycloaddition.
Although the intermediacy of enamines is implicated from the
results of the experiments described above (formation of 28), no
direct evidence for these transient species was obtained. We
rationalized that enamines may become isolable if subsequent
reactions of these species could be prevented or at least
minimized. Considering that once an enamine forms it will readily
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Scheme 8. Pyrrole formation from enamine dimer.
An attractive use for enamine dimers would be their selective β-
functionalization, in analogy to the known β-functionalization of
more stable, monomeric N-aryl enamines.[16i–k] We speculated
that equilibration between enamine dimer and its monomer might
be most effective in protic polar solvents. Following some
experimentation, this was indeed found to be the case. As
outlined in Scheme 9, a reaction of 30 with β-nitrostyrene in
methanol gave rise to the desired product 36 in 77% yield.
Scheme 9. Enamine dimer monomerization/β-functionalization.
Scheme 6. Evidence for enamine intermediates.
To test the generality of enamine dimer formation, a number of
other amines were exposed to the reaction conditions that
allowed for the formation of 30 (Scheme 10). Gratifyingly,
piperidine, morpholine and thiomorpholine all underwent the
desired reaction to provide the corresponding enamine dimers 37
in good to excellent yields. This finding is quite remarkable,
considering that typically much harsher conditions are required to
bring about the α-functionalization of these amines. Morpholine-
derived enamine dimer 37b was characterized by X-ray
crystallography. In analogy to pyrrolidine-derived enamine dimer
30, enamine dimers 37 also underwent facile β-functionalization
with β-nitrostyrene (Scheme 11).
In order to probe the reactivity of enamine dimer 30, this
compound was exposed to β-naphthol under a number of
conditions (Scheme 7). In the absence of any additive or in the
presence of benzoic acid, β-naphthol adds to 30 in a highly
efficient manner to provide product 34 as a single diastereomer.
A different outcome is observed in the presence of triethylamine.
Interestingly partial monomerization of enamine dimer occurs
under these conditions, providing product 33[10f] in 37% yield in
addition to 34 (48%). Given these observations, it appears
possible (if not likely) that enamine dimers such as 30 can be
intermediates in reactions that result in redox-neutral amine α-
functionalization.
Scheme 10. Synthesis of other enamine dimers.
Scheme 7. Reactions of the enamine dimer with β-naphthol.
It appeared likely that enamine dimers such as 30, upon
monomerization to the corresponding monomeric enamines,
could still undergo formation of pyrroles. To test this notion, 30
was exposed to 2,6-dichlorobenzaldehyde in the presence of
benzoic acid (Scheme 8). In accord with our hypothesis, pyrrole
35 was formed in 40% yield.
Scheme 11. Reactions of enamine dimers with β-nitrostyrene.
In case of azepane, the corresponding enamine dimer proved to
be less stable. To circumvent the need for isolation, the crude
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material was allowed to react with β-nitrostyrene, leading to the
synthesis of 39 in 33% yield over two steps (Scheme 12).
Uncatalyzed Reaction. To identify the origin of the catalytic
effect of carboxylic acids, we initially calculated the energy profile
for the uncatalyzed redox-neutral aromatization of pyrrolidine and
benzaldehyde.[4a] The lowest-energy pathway for the uncatalyzed
reaction between pyrrolidine and benzaldehyde is summarized in
Scheme 13. This reaction starts with the thermoneutral formation
of the hemiaminal 2a which is converted to the azomethine ylide
4 and subsequently to the enamine intermediate 7. This process
most likely occurs through the formation of the iminium
hydroxides 3a and 6a. In both cases, the breaking of the C–O
bond of the hemiaminals proceeds barrierless and the formed ion
pairs are very unstable. According to our calculations, the
dissociated ions (i.e., free iminium cations and hydroxide anions)
are much higher in energy (ΔG ≈ 88 kcal mol–1) which indicates
that the deprotonation of the iminium ions (through TS01–TS03)
occurs directly from the tight ion pair. Next, the enamine
intermediate 7 attacks benzaldehyde through TS04 and the
resulting alkoxide moiety is immediately protonated by water (→
40). According to our calculations, the free zwitterionic
intermediate is unstable under the reaction conditions and reverts
to the enamine and PhCHO. This implies that both processes,
nucleophilic attack and protonation, are coupled to each other.
After a formal 1,3-OH shift (probably through 9a), the second
azomethine ylide 11 is formed. A series of elimination, addition,
and elimination of water eventually leads to the pyrrole product 1.
Scheme 12. β-Functionalization of azepane.
Computational results and discussion
As computational investigations not only permit the direct
comparison of free-energy profiles of different mechanistic
pathways but also allow the characterization of intermediates too
unstable to be detected experimentally, we analyzed the
mechanisms of the reactions between pyrrolidine and different
benzaldehydes with density functional theory. These studies
should on the one hand answer why carboxylic acids like acetic
or benzoic acids significantly accelerate the reactions. On the
other hand, the computational investigations should complement
the experimental investigations described above and, as a
consequence, should lead to a better understanding of the
underlying reaction mechanism.
Scheme 13. Calculated free energy profile for the lowest-energy pathway for the uncatalyzed reaction between benzaldehyde and pyrrolidine [in kcal mol–1; M06-2X-
D3/def2-QZVP/IEFPCM(toluene)//M06-L-D3/6-31+G(d,p)/IEFPCM].
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Scheme 14. Calculated free energy profile and selected transition state structures for the lowest-energy pathway for the acetic-acid-catalyzed reaction between
benzaldehyde and pyrrolidine [in kcal mol–1 and Å; M06-2X-D3/def2-QZVP/IEFPCM(toluene)//M06-L-D3/6-31+G(d,p)/IEFPCM].
In general, our calculations predict very unfavorable transition
states and iminium-hydroxide intermediates for the uncatalyzed
reaction. However, the accurate description of these species in
toluene solution is problematic because of the probability of
specific solvent-solute interactions which are not considered in
continuum models. Although the activation barriers are probably
slightly overestimated, the rate-limiting step for the uncatalyzed
reaction should be a deprotonation of an iminium hydroxide (e.g.,
TS01–03, TS05). The calculated high barriers are also reflected
in the harsh experimental conditions and the moderate yield
obtained in the synthesis of pyrrole 1 (Scheme 1). Obviously, the
high exergonicity of the overall reaction (ΔG = –22.7 kcal mol–1) is
the thermodynamic driving force and partially compensates the
high activation barrier under these conditions.
Similar to the uncatalyzed reaction, the first step of the acid-
catalyzed pathway is the formation of an acetylated N,O-acetal
(2b) in a slightly endergonic step. However, we were unable to
calculate any transition states for the formation of 2b, as the
addition of acetate to the corresponding iminium ion occurs
barrierless. A reaction involving a concerted proton transfer and
substitution between the hemiaminal 2a (Scheme 13) and acetic
acid did not result in any transition states either, probably due to
the unfavorable alignment of the acetate as a hydrogen-bond
acceptor and the attacking nucleophile. In contrast to the reaction
in the absence of AcOH, no iminium acetates are formed in this
process. These species are either unstable and collapse to the
corresponding N,O-acetals or are significantly higher in energy.
Instead, a concerted elimination of acetic acid through TS07
(Scheme 14) takes place forming the azomethine ylide 4 from the
N,O-acetal 2b. Similar transition states have been described for
comparable transformations in the past.[3d,10j] Within TS07, the C–
O bond is already completely broken (3.39 Å) while the proton
transfer is still in progress. Addition of AcOH in the other
orientation through TS08 leads to the regioisomeric, slightly more
stable hemiaminal 5b. After 1,2-elimination of acetic acid,
enamine 7 is formed and subsequently attacks benzaldehyde to
give the hydrogen-bonded complex 41. Acetylation leads to 8b
and an isomerization to 10b occurs. This process can either take
place in a concerted fashion through TS11 (ΔG‡ = 32.3 kcal mol–
Carboxylic-acid-catalyzed reaction.
After establishing the
reaction mechanism for the uncatalyzed reaction, we investigated
the role of acetic acid as a model carboxylic acid in these
transformations. In previous investigations, the catalytic efficiency
of AcOH was traced back to either proton-shuttle
mechanisms[10g,i] or the formation of acetylated N,O-acetals,[3d,10j]
and both effects could also play an important role in these
transformations. Scheme 14 summarizes the lowest-energy
pathway for the acetic-acid-catalyzed reaction.
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1) or stepwise via 9b. According to our calculations, both breaking
and forming the C–OAc bonds occur without significant barriers
which renders the concerted pathway via TS11 less likely.
After another elimination of AcOH through TS12, the same
azomethine ylide (11) is obtained that has been discussed above
for the uncatalyzed reaction. Next, acetic acid is added (→ 12b)
and no transition states could be located for this process. It is
likely that this process occurs in a stepwise manner, as the
corresponding iminium acetate (not shown in Scheme 14) was
located only 3 kcal mol–1 above 11. Another cascade of
elimination and re-addition of acetic acid via TS13 and TS14
(Scheme 14) yields the N,O-acetal 15b. A final 1,2-elimination of
AcOH (TS15) then leads to pyrrole 1.
Several transition states (TS07, TS13, and TS14) fall within a
very small range of less than 0.5 kcal mol–1 and could all be the
rate-limiting step of this transformation. In general, the calculated
activation free energy of ca 26–27 kcal mol–1 is also in reasonable
agreement with the experimental conditions (elevated
temperatures, prolonged reaction times) for this transformation.
2,6-Dichlorobenzaldehyde. In the course of the experimental
investigations, we realized that the replacement of benzaldehyde
with 2,6-dichlorobenzaldehyde allowed the isolation of different
side products that provided valuable insights into important
intermediates. Therefore, we decided to additionally investigate
the reaction involving 2,6-dichlorobenzaldehyde before focusing
Intermediate 15b can also be formed in a different pathway
starting from the N,O-acetal 10b (Scheme 15). Regioisomeric
elimination of acetic acid in 10b (via TS16) yields the azomethine
ylide 17, which is less stable than its exocyclic isomer 11. This
ylide can again add acetic acid (via the second resonance
formula) and form 15b and no transition states could be located
for either protonation or C–O bond formation.
on reactions that trap these intermediates.
A
complete
mechanistic analysis is presented in the supporting information
and Scheme 17 summarizes the lowest-energy pathway.
According to our calculations, the reactions of both aldehydes
proceed through the same reaction mechanism and the free-
energy profile for benzaldehyde (Scheme 14) and 2,6-
dichlorobenzaldehyde (Scheme 17) are qualitatively similar. In
general, the additional chlorine substituents stabilize most
species involved in the transition state and the largest effects
were calculated for the zwitterionic azomethine ylides (e.g., 43,
50, 52). However, this stabilization effect is not paralleled in the
transition states to the same extent. As a consequence, the
transition-state energies for the crucial steps increase for chlorine
substituents [e.g., +26.4 vs. +27.5 kcal mol–1 (for TS07 and TS24),
or 26.6 vs. 30.2 kcal mol–1 (for TS13 and TS29)]. Therefore, the
activation free energy for the rate-limiting step (TS24) in the
dichlorobenzaldehyde series was found to be 3.6 kcal mol–1
higher in energy than in the corresponding benzaldehyde series
(Scheme 14). These higher transition state energies calculated
for the reaction involving 2,6-dichlorobenzaldehyde also provide a
rationalization for why it is easier to trap reactive intermediates
compared to the unsubstituted benzaldehyde.
Scheme 15. Alternate pathway for the acetic-acid-catalyzed conversion of 10b
to 15b [in kcal mol–1].
Another series of addition/elimination sequences is also
conceivable for the formation of pyrrole 1 and was also included
into our computational study (Scheme 16). Starting from the
azomethine ylide 11, an isomerization to the less stable
azomethine ylide 19 occurs through addition and elimination of
acetic acid (TS17 and TS18). Transformation to the N,O-acetal
20b (via TS19) and 1,2-elimination (TS20) affords the dienamine
intermediate 21 which can isomerize to the final product 1. Based
on our computational results, this alternate pathway has to be
considered less likely, as TS18 is approximately 4 kcal mol–1
higher in energy than the transition states of Scheme 14.
Alternate Products. The computational studies have so far
shown why carboxylic acids are required for an efficient
transformation and that the redox-neutral aromatization is less
favorable
for
dichlorobenzaldehyde.
The
experimental
investigations additionally provided strong evidence for the
presence of azomethine ylides (e.g., 4 or 11) in the reaction
mixture, and these species could be trapped in different (3+2)
cycloaddition reactions with either benzaldehyde (→ 22, Scheme
3) or N-methylmaleimide (→ 27 and 28, Scheme 4). In addition,
intermediately formed enamines (e.g., 7) could be detected and
higher enamine aggregates could be isolated. Accordingly, we
have included these pathways in our DFT analysis and compare
them with the energy profiles of Schemes 13 and 14.
Scheme 16. Alternate pathway for the acetic-acid-catalyzed conversion of 11 to
1 [in kcal mol–1].
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Scheme 17. Calculated free energy profile for the lowest-energy pathway for the acetic-acid-catalyzed reaction between 2,6-dichlorobenzaldehyde and pyrrolidine
[in kcal mol–1; M06-2X-D3/def2-QZVP/IEFPCM(toluene)//M06-L-D3/6-31+G(d,p)/IEFPCM].
Based on our findings, all (3+2) trapping reactions proceed in an
exergonic fashion (Figure 1, for more details see the Supporting
Information). Combinations of azomethine ylides with N-methyl
maleimide occur rapidly with small activation free energies
(TS33 and TS34) that are significantly lower than the rate-
limiting step of Scheme 14. A small energy difference (ΔG = 1.3
kcal mol−1) between 4 and TS33 has been calculated on the
M06-L potential energy surface, while a negative barrier was
obtained from M06-2X-D3 single-point calculations, which
product 31 is almost comparable to the pyrrole 35. This
particularly large thermodynamic driving force together with the
higher transition state energies for the chlorine-substitution also
explain why these enamine products were predominantly
isolated in reactions involving dichlorobenzaldehyde.
indicates
a
barrierless reaction. In contrast, the (3+2)
cycloaddition between 4 and benzaldehyde requires a higher
activation energy (TS32). These computational results match the
experimental observations that the (3+2) cycloadducts are
formed preferentially in the presence of N-methyl maleimide and
indicate that one of the later transition states (TS13 or TS14,
Scheme 14) is the rate-limiting step for the carboxylic-acid-
catalyzed pathway. Furthermore, the calculated high barriers for
the (3+2) reaction with benzaldehyde also explain why
cycloadduct 22 is not formed under acid catalysis.
Besides azomethine ylides, the experimental investigations also
revealed that the formation of enamine di- and trimers (e.g., 30
and 31) can become the major reaction pathway under carefully
optimized conditions. As these species can be formed in many
different reactions, we only investigate the thermodynamic
stabilities of these products. As shown in Scheme 18, both
alternatives 30 and 31 (as well as 54 and 55) are formed in
exergonic reactions. However, the chlorine substituents have a
large impact on the thermodynamic stability and significantly
lower the energies of the formed enamines. This is also reflected
in the experimental observations as these enamine species
were isolated predominantly from reactions involving 2,6-
dichlorobenzadehyde. In terms of thermodynamic stabilities,
Figure 1. Calculated activation and reaction free energies and transition states
for the trapping of the azomethine ylides 4 and 11 [in kcal mol–1 and Å, M06-
2X-D3/def2-QZVP/IEFPCM(toluene)//M06-L-D3/6-31+G(d,p)/IEFPCM].
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computational investigations revealed that carboxylic acids
facilitate the redox-neutral aromatization through the formation
of acetylated N,O-acetals and a series of addition/elimination
steps of acetic acid. Several protocols were developed that
allow interception of reactive intermediates as a valuable path to
rapidly access new chemical space.
Acknowledgements
Financial support from the NIH–NIGMS (R01GM101389), the
Fonds der chemischen Industrie (Liebig scholarship to M.B.),
and the University of Cologne within the excellence initiative is
gratefully acknowledged. We thank Dr. Tom Emge (Rutgers
University) for crystallographic analysis and the Regional
Computing Center of the University of Cologne (RRZK) for
providing computing time on the DFG-funded High Performance
Computing (HPC) system CHEOPS as well as for their support.
Scheme 18. Calculated thermodynamics for the formation enamine
intermediates [in kcal mol–1; M06-2X-D3/def2-QZVP/IEFPCM(toluene)//M06-L-
D3/6-31+G(d,p)/IEFPCM].
Computational Details
For the computational investigations, the conformational space
for each structure was explored using the OPLS-2005 force
Keywords: C–H functionalization • redox-neutral • azomethine
ylides • heterocycles
field[22] and
a
modified Monte Carlo search algorithm
implemented in MacroModel 10.6.[23] An energy cut-off of 20 kcal
mol–1 was employed for the conformational analysis, and
structures with heavy-atom root-mean-square deviations
(RMSD) less than 2 Å after the initial force field optimizations
were considered to be the same conformer. The remaining
structures were subsequently optimized with the dispersion-
corrected M06-L functional[24] with Grimme’s dispersion-
correction D3[25] and the double- basis set 6-31+G(d,p).
Solvation by toluene was taken into account by using the
integral equation formalism polarizable continuum model
(IEFPCM)[26] for all calculations. Vibrational analysis verified that
each structure was a minimum or transition state. Following the
intrinsic reaction coordinates (IRC) confirmed that all transition
states connected the corresponding reactants and products on
the potential energy surface. Thermal corrections were obtained
from unscaled harmonic vibrational frequencies at the same
level of theory for a standard state of 1 mol L–1 and 298.15 K.
Entropic contributions to the reported free energies were derived
from partition functions evaluated with the quasiharmonic
approximation by Truhlar and coworkers.[27] Electronic energies
were subsequently obtained from single point calculations of the
M06-L-D3 geometries employing the meta-hybrid M06-2X
functional,[28] Grimme’s dispersion-correction D3 (zero-
damping),[25] the large quadruple- basis set def2-QZVP,[29] and
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The
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Entry for the Table of Contents
FULL PAPER
Longle Ma, Anirudra Paul, Martin
Breugst,* Daniel Seidel*
Page No. – Page No.
Redox-Neutral Aromatization of
Cyclic Amines: Mechanistic Insights
and Harnessing of Reactive
Intermediates for Amine α- and β-C–H
Functionalization
A combined experimental and computational study provides detailed insights into
the mechanism of pyrrole formation from pyrrolidine and aromatic aldehydes. A
number of reactive intermediates (e.g., azomethine ylides, conjugated azomethine
ylides, enamines) were intercepted; outlining strategies for circumventing
aromatization as a valuable pathway for amine C–H functionalization.
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