Redox-neutral α-oxygenation of amines: Reaction development and elucidation of the mechanism

Article abstract of DOI:10.1021/ja501988b

Cyclic secondary amines and 2-hydroxybenzaldehydes or related ketones react to furnish benzo[e][1,3]oxazine structures in generally good yields. This overall redox-neutral amine α-C-H functionalization features a combined reductive N-alkylation/oxidative α-functionalization and is catalyzed by acetic acid. In contrast to previous reports, no external oxidants or metal catalysts are required. Reactions performed under modified conditions lead to an apparent reductive amination and the formation of o-hydroxybenzylamines in a process that involves the oxidation of a second equivalent of amine. A detailed computational study employing density functional theory compares different mechanistic pathways and is used to explain the observed experimental findings. Furthermore, these results also reveal the origin of the catalytic efficiency of acetic acid in these transformations.

Full text of DOI:10.1021/ja501988b

Article
pubs.acs.org/JACS
Redox-Neutral α‑Oxygenation of Amines: Reaction Development and
Elucidation of the Mechanism
Matthew T. Richers,† Martin Breugst,‡,§ Alena Yu. Platonova,†,∥ Anja Ullrich,‡,⊥ Arne Dieckmann,‡
K. N. Houk,*,‡ and Daniel Seidel*,†
†Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854,
United States
‡Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States
§Department fur Chemie, Universitat zu Koln, Greinstraße 4, 50939 Koln, Germany
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∥Department of Organic Synthesis Technology, Ural Federal University, Yekaterinburg 620002, Russia
⊥Institut fur Bioorganische Chemie, Heinrich-Heine Universitat Dusseldorf, Stetternicher Forst, 52426 Julich, Germany
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S
* Supporting Information
ABSTRACT: Cyclic secondary amines and 2-hydroxybenzal-
dehydes or related ketones react to furnish benzo[e][1,3]-
oxazine structures in generally good yields. This overall redox-
neutral amine α-C−H functionalization features a combined
reductive N-alkylation/oxidative α-functionalization and is
catalyzed by acetic acid. In contrast to previous reports, no external oxidants or metal catalysts are required. Reactions
performed under modified conditions lead to an apparent reductive amination and the formation of o-hydroxybenzylamines in a
process that involves the oxidation of a second equivalent of amine. A detailed computational study employing density functional
theory compares different mechanistic pathways and is used to explain the observed experimental findings. Furthermore, these
results also reveal the origin of the catalytic efficiency of acetic acid in these transformations.
crucial; replacement with a hydrogen substituent led to the
recovery of 3 and pyrrolidine (from the decarboxylation of
proline). The use of pipecolic acid (piperidine-2-carboxylic
acid) in place of proline resulted in the formation of only trace
amounts of the corresponding product. Recently, during the
preparation of this paper, Maycock and co-workers9r reported
an oxidative, copper(II) acetate-catalyzed synthesis of benzox-
azines such as 2c from o-aminomethylnaphthols (e.g., 4) and
-phenols (eq 3). This report was closely followed by an
independent publication by Jana and co-workers9t in which the
essentially identical transformation was described with super-
stoichiometric amounts of Ag2O as the oxidant. All previous
methods for benzo[e][1,3]oxazine synthesis involve either a
prefunctionalized amine moiety (an amino acid or imine), an
external oxidant, and/or a metal catalyst.11 In 2008, one of our
groups12 reported the synthesis of aminals such as 6 from o-
aminobenzaldehydes (e.g., 5) and unactivated secondary
amines such as pyrrolidine (eq 4). These reactions feature a
combined reductive N-alkylation/oxidative α-amination and
function most efficiently in alcoholic solvents in the absence of
any additives.13 The overall redox-neutral nature of this
reaction distinguishes it from oxidative approaches to the C−
H functionalization of amines, which continue to dominate
most of the research efforts conducted in this area.14 The Seidel
group has worked extensively on developing redox-neutral
INTRODUCTION
■
As drug discovery programs have come to rely on high-
throughput screenings of diverse chemical libraries, the ability
to rapidly construct complex, heterocyclic small molecules from
simple starting materials is of great importance.1 The N,O-
acetal moiety can be found in a diverse set of natural products2
and useful synthetic intermediates.3 Benzoxazines in particular
have been studied as nonsteroidal progesterone receptor
agonists,4 as antibacterial agents5 and as non-nucleoside reverse
transcriptase inhibitors for the treatment of human immuno-
deficiency virus (HIV)6 as well as for a wide array of other
applications.7 For example, benzo[e][1,3]oxazines such as PD
102 807 (2a) have been identified as potent, selective inhibitors
of the m4 muscarinic receptor, which have made such
compounds important leads in Parkinson’s disease research.8
A number of methods for the synthesis of benzo[e][1,3]-
oxazines have been reported (Scheme 1).3i,l,o,q,v,9 One early
approach to polycyclic benzoxazines such as N,O-acetal 2a
involves the addition of a 3,4-dihydroisoquinoline (DHIQ) to a
phenolic Mannich base (e.g., 1), proceeding via an o-quinone
methide intermediate and generally resulting in low to
moderate yields (eq 1).8,9g,o−q,10 An intriguing and unantici-
pated entry to the N,O-acetal motif was reported by Cohen et
al. in 1979 (eq 2).9h Proline was found to react with 2-
hydroxyacetophenones (e.g., 3) via a decarboxylative process to
yield products such as 2b. Unfortunately, this method exhibited
a rather narrow substrate scope. The presence of a methyl
group in the ortho-position of the ketone was reported to be
Received: February 25, 2014
Published: April 1, 2014
© 2014 American Chemical Society
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Scheme 1. Selected Previous Approaches to N,O-Acetals and
Aminals
Scheme 2. Initial Studies on N,O-Acetal Formation
methods for the α-functionalization of amines,15 many of which
involve iminium isomerization through azomethine ylide
intermediates.16,17 Our two groups recently published a joint
computational and experimental study of the amination
reaction (eq 4) that revealed some interesting mechanistic
features.12c Simple iminium ions do not appear to play a role in
this reaction, and the rate-determining step most likely involves
a 1,6-proton transfer event. On the basis of the ability of o-
aminobenzaldehydes to undergo these condensations with
amines, we decided to explore the analogous reaction with
salicylaldehydes in an effort to gain access to the N,O-acetal
functionality in a facile, redox-neutral fashion. Here we report
the successful development of this α-oxygenation, the scope of
the reaction, and a detailed computational study of the
mechanism.
N,O-acetal was observed alongside 8f (37%) and DHIQ (33%).
In addition, n-butyl ether 9 was isolated in 19% yield.
There are a number of different mechanistic scenarios that
could account for the formation of reduced product 8f (Scheme
3). First, 8f could be formed from the desired product 2f.
Scheme 3. Potential Reaction Pathways and Experimental
Support
EXPERIMENTAL RESULTS AND DISCUSSION
■
Evaluation of Various Reaction Conditions. To facilitate
reaction development, we began our investigation using
microwave conditions that had proven successful in the
analogous aminal formation (Scheme 2).12d Surprisingly, a
reaction of pyrrolidine with salicylaldehyde (7) in n-butanol
solvent (optimized conditions for aminal formation) did not
lead to desired N,O-acetal product 2d. Instead, 2-hydrox-
ybenzylamine 8d, the apparent product of a reductive
amination, was isolated in 92% yield (eq 5). Similar
observations were made in the corresponding reactions of
morpholine (eq 6) and 1,2,3,4-tetrahydroisoquinoline (THIQ)
(eq 7). In the case of THIQ, 3,4-dihydroisoquinoline (DHIQ)
was isolated as a second product in 65% yield. This indicates
that THIQ functions as the reductant in the formation of 8f. In
order to avoid the formation of undesired product 8f, milder
conditions were employed and the amount of THIQ was
reduced. Heating a 1:1.1 mixture of 7 and THIQ under reflux
in ethanol did, indeed, lead to isolation of N,O-acetal 2f, albeit
in only 10% yield alongside a substantial amount of 8f and
DHIQ (eq 8). When an otherwise identical reaction was
performed under reflux in n-butanol (eq 9), a trace amount of
Fragmentation of 2f, either via a retro [4 + 2] reaction or a
stepwise pathway via zwitterion 10f, would result in the
formation of o-quinone methide 11f and DHIQ. Reaction of
the highly reactive 11f with THIQ would be expected to readily
form 8f.18 Alternatively, the formation of 8f and DHIQ could
be explained by reduction of 10f (or the regioisomeric
zwitterion from the condensation of 7 and THIQ) via
intermolecular hydride transfer from THIQ with concurrent
oxidation of the latter to DHIQ (not shown). The formation of
9 (eq 9) is consistent with the intermediacy of 11f but not with
the hydride transfer pathway. To obtain further insights into
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Table 1. Optimization of N,O-Acetal-Forming Reaction between Salicylaldehyde and THIQ
entry
7, mmol
THIQ, mmol
additive (equiv)
solvent (M)
T, °C
t, h
yield of 2f, %
yield of 12, %
a
1
2
1
−
PhMe (0.25)
PhMe (0.25)
PhMe (0.25)
PhMe (0.25)
PhMe (0.25)
DMF (0.25)
EtOH (0.25)
MeCN (0.25)
PhMe (0.25)
PhMe (0.25)
PhMe (0.25)
PhMe (0.1)
PhMe (0.1)
PhMe (0.1)
PhMe (0.1)
PhMe (0.1)
rt
48
35
38
54
62
38
23
22
62
75
94
95
97
64
98
59
98
36
2
2
1
PhCO2H (0.2)
rt
18
24
24
48
3
1.1
1.1
1
1
PhCO2H (0.2)
rt
25
b
4
1
2-EHA (0.2)
rt
21
a
5
1.1
1.1
1.1
1.1
1.1
1.3
1.3
1.3
1.3
1.3
1.3
1.3
2-EHA (0.2)
2-EHA (0.2)
2-EHA (0.2)
2-EHA (0.2)
2-EHA (1.3)
2-EHA (1.3)
2-EHA (1.3)
2-EHA (1.3)
2-EHA (1.3)
AcOH (1.3)
AcOH (0.2)
rt
48
trace
trace
31
a
6
1
rt
48
a
7
1
rt
48
a
8
1
rt
48
32
a
9
1
rt
48
trace
trace
trace
−
−
−
10
11
12
1
rt
48
1.5
3
1
60
60
60
60
60
60
1
c
a
13
1
6
14
15
16
1
3
3
3
1
−
−
1
AcOH (1.0)
a
b
c
Reaction incomplete. 2-EHA = 2-ethylhexanoic acid. No molecular sieves.
the course of the reaction, benzoxazine 2f was subjected to high
temperatures in the presence of an excess of pyrrolidine
(Scheme 3). In the event, o-hydroxybenzyl pyrrolidine 8d and
DHIQ were isolated in good yields, providing additional
support for the fragmentation pathway.
using acetic acid in stoichiometric amounts led to the best
result and allowed for the isolation of 2f in 98% yield following
a reaction time of 3 h (entry 16).
Substrate Scope. Optimized conditions were employed to
evaluate the scope of the α-oxygenation with a number of
different salicylaldehydes and related o-hydroxy ketones
(Scheme 4). Salicylaldehydes with simple alkyl groups
appended to the ring provided the corresponding products in
good yields but required a higher temperature of 80 °C to
achieve reasonable reaction rates (2g and 2h). Both electron-
withdrawing and electron-donating groups were tolerated,
although more electron-deficient salicylaldehydes such as 3,5-
dibromo- (2l) and 5-nitrosalicylaldehyde (2m) provided
products with slightly decreased yields. o-Hydroxyketones
required higher temperatures and afforded N,O-acetal products
in relatively low yields but as single diastereomers (2q and 2r).
While ketones with some steric demand in the 6-position did
yield the desired products, neither 2-hydroxyacetophenone nor
2-hydroxybenzophenone underwent the formation of N,O-
acetals with THIQ under a variety of conditions, an observation
that is in line with Cohen’s findings on the related
decarboxylative process.9h
The scope of the reaction with regard to other amines was
evaluated next (Scheme 5). Not surprisingly, cyclic secondary
amines with benzylic protons in α-position to the ring nitrogen
proved to be the most reactive substrates. Tetrahydroisoquino-
lines with methoxy groups appended to the aryl ring, upon
reaction with 7, resulted in the formation of products in
excellent yields (2s and 2t). A THIQ derivative with a phenyl
group at the 1-position required more forcing conditions in
order to form the corresponding N,O-acetal 2u. Nevertheless,
this highly substituted product was obtained in 72% yield. N,O-
Acetal products could also be obtained with pyrrolidine,
piperidine, and azepane. However, acyclic amines such as
methylbenzyl amine failed to undergo the title reaction.
Due to the formation of undesired side products at higher
temperatures and with nucleophilic solvents, we decided to
evaluate the reaction under milder conditions (Table 1).
Toluene, a solvent that had previously been shown to be
optimal for other redox-isomerization reactions,15h−j,l−o was
selected as the reaction medium. To further facilitate product
formation, molecular sieves were added to sequester the water
released during the condensation. Remarkably, the desired
reaction was found to proceed at room temperature in the
absence of any acid additives to provide N,O-acetal 2f in 35%
isolated yield (entry 1). In addition, the apparent [3 + 2]
product 12 was formed in 36% yield, consistent with the
intermediacy of an azomethine ylide.12c,19 The relative
stereochemistry of 12 was not confirmed unambiguously, but
literature precedent suggests that the phenolic groups should be
trans-configured.19 The 1:1 diastereomeric ratio is the result of
conformational instability of the N,O-acetal (see Supporting
Information). Addition of catalytic amounts of benzoic acid
dramatically accelerated the rate of the reaction while increasing
the yield of both 2f and 12 (entry 2). Reduction of the amount
of salicylaldehyde (7) led to a more favorable product ratio
with partial suppression of the [3 + 2] product 12 (entry 3). 2-
Ethylhexanoic acid (2-EHA) performed slightly better than
benzoic acid (entry 4), and acetic acid was later found to be still
better (entry 14). Several protic and aprotic solvents were
evaluated as potential alternatives to toluene, but all either
resulted in lower yields (entries 6 and 7) or promoted the [3 +
2] reaction (entry 8). The formation of product 12 was
completely suppressed with a reduction in solvent concen-
tration (entry 12). Elevating the temperature to 60 °C and
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a
a
Scheme 4. Variation of Salicylaldehyde Moiety
Scheme 5. Variation of Secondary Amine
a
All reactions were performed on a 1 mmol scale. bFor this reaction, 1
mmol of amine, 2 equiv of ketone, and xylenes (0.1 M) were used.
a
All reactions were performed on a 1 mmol scale. bFor these reactions,
1 mmol of amine, 2 equiv of aldehyde or ketone, and xylenes (0.1 M)
were used.
Interestingly, attempted reactions with pyrrolidine and parent
salicylaldehyde (7) did not yield N,O-acetal 2d under a variety
of conditions. Despite different experimental and computa-
tional attempts, this result could so far not be rationalized.
Pyrrolidine underwent reaction with 3,5-di-t-butylsalicylalde-
hyde to form the corresponding N,O-acetal 2x in 55% yield.
Formation of product 2c from pyrrolidine and 2-hydroxy-1-
benzoylnaphthalene proceeded in 71% yield but required more
forcing conditions (reflux in xylenes). Maycock and co-
workers9r did not observe benzoxazine 2c as a product with
the same starting materials in an experiment conducted at 130
°C in xylenes. This failure to obtain product 2c is likely due to
the fact that neither acidic additives nor molecular sieves were
employed. While products 2c, 2y, 2z, and 2b were all isolated as
single diastereomers, product 2aa, which is different in that it
lacks a substituent in the 6-position of the aryl ring, was formed
as a 2.5:1 mixture of diastereomers.
Interestingly, when 1-methyl THIQ was subjected to the
reaction conditions, the desired N,O-acetal 2ac was not
obtained. Instead, the spirobenzopyran 13 was obtained in
essentially quantitative yield (Scheme 6). In this case, N,O-
acetal 2ac or the corresponding zwitterion (not shown) could
undergo transformation into or exist in equilibrium with
enamine 14. The latter can engage a second molecule of
salicylaldehyde to give 13. Reactions of structurally related
enamines with salicylaldehydes have been previously re-
ported.20
Scheme 6. Reaction of Salicylaldehyde with
1-Methyltetrahydroisoquinoline
Scheme 7. Effect of Water on Condensation Reaction
resulted in an incomplete reaction and furnished the expected
N,O-acetal 2f in only 52% yield. Remarkably, an otherwise
identical reaction performed in the presence of a Dean−Stark
apparatus (for water removal) was completed after only 1 h and
provided 2f in nearly quantitative yield (98%, Scheme 7). These
experiments nicely illustrate not only the ease with which this
To demonstrate that the redox-neutral synthesis of N,O-
acetals is amenable to scale-up, the reaction of salicylaldehyde
(7) and THIQ was performed on a 1-g scale in benzene as the
solvent (Scheme 7). In the absence of molecular sieves, heating
of the reaction mixture under reflux for a period of 24 h
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Scheme 8. Possible Mechanistic Pathways for Formation of N,O-Acetal 2f and Benzylamine 8f
reaction can be performed under optimized conditions but also
the importance of removing water from the reaction mixture.
Conceivable Mechanistic Pathways. A network of
interrelated pathways presented itself when we considered
possible mechanisms that would account for the formation of
all observed products from the reaction of salicylaldehyde (7)
and THIQ (Scheme 8). Based on the isolation of apparent [3 +
2] product 12, it appears highly likely that the overall
transformation involves the intermediacy of azomethine ylide
19f. The reaction most likely initiates by addition of THIQ to
salicylaldehyde (7) to form N,O-acetal 15f, a step that may be
facilitated by the presence of acetic acid. Subsequent
elimination of water could occur either with the assistance of
acetic acid, yielding iminium 16f, or in a concerted intra-
molecular fashion to give zwitterion/quinoidal species 17f. Due
to the presence of acetic acid, 16f and 17f may exist in
equilibrium. Azomethine ylide 19f could be formed from 17f
via a 1,6-proton transfer; an analogous step was established in
the formation of the corresponding aminals.12c Another
pathway to 19f would involve deprotonation of 16f.
Alternatively, 18f, which could exist in equilibrium with 16f,
could suffer concerted loss of acetic acid to generate
azomethine ylide 19f, consistent with a proposal by Yu and
co-workers21 for a related process. Azomethine ylide 19f would
then progress to zwitterion 10f either by a stepwise
protonation/deprotonation pathway via 20f or by direct proton
transfer. Ring closure finally leads to N,O-acetal product 2f.
N,O-Acetal 2f can undergo further transformation to “reduced”
product 8f via the addition of THIQ to o-quinone methide 11f,
formed in a formal retro-[4 + 2] reaction that also generates
DHIQ. It should be noted that the retro-[4 + 2] step may occur
in a stepwise manner via zwitterion 10f. Facile ring-opening of
benzoxazines and the potential existence of an equilibrium
between 2f and 10f is supported by an observation about the
appearance of benzoxazine 2f. While 2f is a white solid in pure
form, solutions of 2f turn bright yellow in the presence of an
acid (e.g., acetic acid or silica gel), suggesting the formation of a
new species.
withdrawing groups stabilize the phenoxide, allowing the
N,O-acetal to rapidly equilibrate with zwitterionic form 10l.
This process is suppressed or slowed down at lower
temperatures, as illustrated by a series of H NMR spectra of
product 2l that were recorded at temperatures between 20 and
−60 °C (Figure 1).
1
1
Figure 1. Temperature-dependent H NMR spectra of 2l in CDCl3
(400 MHz).
With regard to the above-mentioned oxidative N,O-acetal
syntheses reported by Maycock and co-workers9r (eq 3) and
Jana and co-workers,9t different mechanisms were proposed by
the two groups. Jana and co-workers proposed an initial
oxidation of 4 at the benzylic position and deprotonation of the
resulting iminium ion, followed by a pathway that is based on
our previously established mechanism for the corresponding
aminal formation, namely, 1,6-proton abstraction to generate an
azomethine ylide and subsequent proton transfer and ring
closure (not shown). Interestingly, Maycock’s mechanistic
proposal is radically different (Scheme 9). It involves oxidation
of amine 4 at the seemingly less activated endocyclic position
rather than the benzylic position to give intermediate 10c.
While 10c may undergo direct ring closure to product 2c, the
observed diastereoselectivity was rationalized via a different
pathway. According to Maycock and co-workers, intermediate
10c undergoes fragmentation to o-quinone methides trans-11c
and cis-11c and 1-pyrroline. The isomer cis-11c is proposed to
Another observation consistent with the existence of
zwitterions in equilibrium with benzoxazines is that benzox-
azine products with an electron-deficient phenolic ring (i.e., 2i,
1
2l, and 2m) exhibit broadened peaks in their H NMR spectra
(see Supporting Information). Presumably, the electron-
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TZVPP/IEFPCM//TPSS-D2/6-31+G(d,p)/IEFPCM]. We
will first discuss the mechanisms for the uncatalyzed and
acetic-acid-catalyzed reaction using the model system salicy-
laldehyde (7) and THIQ before we analyze the influence of
substituents at the carbonyl and variation of the amine as well
as potential side reactions.
Scheme 9. Proposed Mechanism of Maycock and Co-
workers9r for Oxidative N,O-Acetal Formation
Uncatalyzed Reaction in Toluene. Although the
uncatalyzed reaction between the aldehyde and the amine
results in low yields of the corresponding benzoxazines (Table
1), this background reaction is important for the acid-catalyzed
reaction as well. Therefore, we first carefully analyzed the
mechanism for the prototypic reaction between salicylaldehyde
(7) and tetrahydroisoquinoline (THIQ) in toluene solution in
the absence of any catalyst (cf. Scheme 8). The calculated free
energy profile is depicted in Figure 2 (black lines), and selected
calculated structures are discussed in Figures 3−5.
In the first step of this transformation, the aldehyde 7 and
THIQ form the hemiaminal 15f in a slightly endergonic
reaction (ΔG = +1.9 kcal·mol−1). Next, water is eliminated
from the hemiaminal, yielding the zwitterionic intermediate
17f. This reaction could occur either in a concerted mechanism
(ΔG⧧ = +22.5 kcal·mol−1, via cis-TS1, Figure 3) or in a
stepwise reaction through an iminium ion. In line with previous
investigations of the synthesis of tetrahydroquinazolines,12c the
putative iminium ion obtained from the elimination of a
hydroxy group was located 38 kcal·mol−1 above cis-TS1 and is
not shown in Figure 2. As a consequence, the concerted
elimination is also preferred over the stepwise elimination of
hydroxide and subsequent deprotonation in these trans-
formations. In principle, both eliminations to the cis and the
trans zwitterions 17f are possible (Figure 3). Our calculations
engage in an endo-[4 + 2] cycloaddition with 1-pyrroline to
selectively form 2c in the observed relative configuration. An
alternative and more likely explanation that accounts for the
essentially exclusive formation of 2c over its other diastereomer
is based on equilibration between the two possible diaster-
eomers via zwitterion 10c. In fact, the equilibration of
diastereomers of closely related benzoxazines was studied in
detail by Fulop, Kleinpeter, and co-workers,9q who concluded
̈
̈
that the diastereomer corresponding to 2c represents the
thermodynamically more stable product.
COMPUTATIONAL RESULTS AND DISCUSSION
■
In order to investigate the underlying mechanism and to
identify the most important pathways for the formation of
benzoxazines under these conditions, we have employed
density functional theory calculations [M06-2X-D3/def2-
Figure 2. Free energy profile [in kcal·mol−1, M06-2X-D3/def2-TZVPP/IEFPCM//TPSS-D2/6-31+G(d,p)/IEFPCM] for uncatalyzed (black) and
acetic-acid-catalyzed (red) transformation of 7 and THIQ to benzoxazine 2f in toluene.
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Figure 4. Calculated structures [M06-2X-D3/def2-TZVPP/
IEFPCM//TPSS-D2/6-31+G(d,p)/IEFPCM], relative free energies
(in kcal·mol−1), selected bond lengths (in Å), and selected NBO
charges for transition state TS2.
Figure 3. Calculated structures [M06-2X-D3/def2-TZVPP/
IEFPCM//TPSS-D2/6-31+G(d,p)/IEFPCM], relative free energies
(in kcal·mol−1), selected bond lengths (in Å), and dihedrals for
different conformers of transition state TS1 and zwitterion 17f.
pathway. The oxazinane 2f is subsequently obtained by a
barrierless cyclization of the zwitterionic intermediate 10f in an
overall exergonic reaction (ΔG = −2.4 kcal·mol−1).
predict cis-TS1 to be significantly favored over trans-TS1
(ΔΔG⧧ = 3.2 kcal·mol−1), while the product cis-17f is
essentially isoenergetic to its isomer trans-17f. The slight
thermodynamic preference for the trans conformer can be
rationalized by the greater planarity of the exocyclic π-system
(as reflected by the dihedral angle θ in Figure 3). Analysis of
the charge distribution [e.g, natural bond orbital (NBO) or
ChelpG] in 17f as well as of smaller model systems revealed
that the zwitterionic and neutral resonance structures should be
equally important (see Supporting Information for more
details). The next step of the mechanism requires abstraction
of one of the α-hydrogens of the heterocycle, which, in an
intramolecular reaction, is possible only from the cis
conformation of 17f. However, previous calculations on the
corresponding aminobenzaldehyde-derived intermediates have
shown that cis- and trans-17f can be directly interconverted
with small barriers.12c
A subsequent proton transfer via TS2 leads to the
azomethine ylide 19f in another endergonic transformation
(Figure 4). The endergonicity of this step is also reflected in the
short O−H bond length of the late transition state TS2. This
reaction could proceed via either a 1,6-hydride shift or a 1,6-
proton transfer, and our charge calculations (NBO or ChelpG)
indicate that the latter is more likely due to a significant positive
charge on the transferred hydrogen atom.
As an alternative pathway, azomethine ylide 19f may be
trapped via the reaction with excess salicylaldehyde 7, affording
the [3 + 2] adduct 12 (Scheme 8, Figure 6). As the relative
stereochemistry of the experimentally isolated adduct has not
been determined, we have investigated all four possible
stereoisomers and their corresponding transition states. Our
calculations indicate that RSS-12 is the most stable stereo-
isomer of the four [ΔΔG(RRR-12) = +2.2, ΔΔG(RSR-12) =
+2.9, and ΔΔG(RRS-12) = +3.6 kcal·mol−1; see Supporting
Information for more details] and only RSS-12 is formed in an
exergonic reaction (ΔG = −1.5 kcal·mol−1, Figure 6). The
lowest-energy transition states were calculated to be RRR-TS4
(ΔG⧧ = 32.6 kcal·mol−1) and RSS-TS4 (ΔG⧧ = 33.0 kcal·
mol−1). As the formation of RRR-12 is endergonic, the
computational data predict the formation of RSS-12 to be the
preferred [3 + 2] pathway (Figure 6). Both pathways leading to
the benzoxazine 2f and the alternate product RSS-12 are similar
in both activation and reaction free energies. While formation
of the [3 + 2] adduct has a slightly smaller activation free
energy (kinetic preference), the benzoxazine is preferred
thermodynamically. This also explains why the [3 + 2]
cycloaddition is facilitated when the aldehyde is present in
large concentrations and used in excess over the amine (e.g.,
entries 1 and 2 in Table 1).
Acetic-Acid-Catalyzed Reaction in Toluene. As the rate-
limiting step for the uncatalyzed reaction was calculated to be
rather high and significant accelerations could be observed in
the experiments with acetic acid as a catalyst, we subsequently
investigated how acetic acid can catalyze the synthesis of
benzoxazinanes (Figures 2−4).
Previous calculations on similar redox isomerizations by Yu
and co-workers,21 employing MP2/6-31+G(d)//B3LYP/6-
31+G(d)/CPCM, have already highlighted the crucial role of
The azomethine ylide 19f then undergoes another, rate-
limiting proton transfer yielding the zwitterion 10f. This
transformation can either occur in an intramolecular reaction
(TS3, Figure 5) or in a salicylaldehyde-mediated reaction
(TS3-Sali, Figure 5). The entropic penalty (−TΔS) for the
intermolecular reaction through TS3-Sali involving a second
molecule of salicylaldehyde 7 is compensated by the very
favorable activation enthalpy rendering TS3-Sali the preferred
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Figure 5. Calculated structures [M06-2X-D3/def2-TZVPP/IEFPCM//TPSS-D2/6-31+G(d,p)/IEFPCM], relative free energies (in kcal·mol−1),
and selected bond lengths (in Å) for transition state TS3.
Scheme 10. Potential Acceleration of Acetic Acid (cf. Ref 21)
Figure 6. Calculated activation and reaction free energies of different
pathways involving the azomethine ylide 19f [M06-2X-D3/def2-
destabilized by acetic acid. As the barrier for the uncatalyzed
TZVPP/IEFPCM//TPSS-D2/6-31+G(d,p)/IEFPCM] and transition
reaction is already very small (with respect to 19f), the
additional entropy penalty (−TΔS) cannot be compensated by
the more favorable enthalpy. As a consequence, the intra-
molecular proton transfer is preferred over the intermolecular
process for this step. In contrast, a large stabilization has been
calculated for the rate-limiting proton transfer TS3 in TS3-
HOAc (Figure 5), indicating a substantial stabilization of the
transition state. In summary, this large difference in free energy
for TS3 (ΔΔG⧧ = 8.6 kcal·mol−1) is also the origin of the
favorable acetic acid catalysis. This role of acetic acid in N,O-
acetal formation has a parallel in the corresponding synthesis of
aminals. In the latter case, the solvent, ethanol, has been shown
to serve as the proton shuttle.12c
Comparison of Selected Carbonyl-Amine Combina-
tions. To better understand the observed reactivities, we next
analyzed selected carbonyl-amine combinations including
electron-rich and -poor carbonyls and two different amines.
Independent of the combinations of carbonyl and amine, the
overall reaction free energies are all found within a relatively
small range (−5.4 < ΔG < +2.4 kcal·mol−1, Table 2), indicating
that the substituents on the carbonyl and the choice of amine
are less important for the thermodynamics of the overall
reaction. The fact that some intermediates (e.g., for 19ad or
19d) are higher in energy than the corresponding acetic-acid-
catalyzed transition states indicate that acetic acid can
state RSS-TS4 with selected bond lengths (in Å).
acetic acid in these transformations and are possibly important
for the transformations under investigation.
In a first step, we analyzed whether the acetylated
hemiaminal 18f could eliminate acetic acid with formation of
the azomethine ylide 19f as proposed by Yu and co-workers
(Scheme 10).21 However, according to our calculations, the
formation of hemiaminal 18f is significantly endergonic (ΔG =
+11.2 kcal·mol−1) and the transition state for the elimination of
acetic acid TS5 (ΔG⧧ = +35.3 kcal·mol−1) was found to be
comparable in energy to the uncatalyzed reaction [ΔG⧧(TS3-
Sali)= +33.2 kcal·mol−1]. Based on these results, this mode of
activation by acetic acid does not explain the rate acceleration
and has to be rejected for these transformations.
Next, we investigated whether acetic acid can act as a proton
shuttle within the transition states TS1−3 and thereby lower
the activation energy of each step. The activation free energies
for the acetic-acid-catalyzed reactions are summarized in Figure
2 and the optimized structures are depicted in Figures 3−5.
The dehydration of the hemiaminal 15f is slightly facilitated
by acetic acid acting as proton shuttle (cis-TS1-HOAc versus
cis-TS1, Figure 3), while the proton transfer yielding the
azomethine ylide (TS2 and TS2-HOAc, Figure 4) is actually
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a
Table 2. Calculated Free Energies for Different Carbonyl-Amine Combinations in Toluene
a
b
Energies are given in kcal·mol−1, M06-2X-D3/def2-TZVPP/IEFPCM//TPSS-D2/6-31+G(d,p)/IEFPCM. All attempts to locate a transition state
for these reactions failed, and potential energy surface scans indicate a barrierless reaction.
coordinate to the intermediates, which leads to a further
stabilization. While the combination of hydroxyacetophenone
and THIQ resulted in an endergonic reaction (→ 2ad) and no
detectable product formation, the dimethyl analogue yields the
corresponding benzoxazine 2r in an exergonic reaction in line
with an isolated yield of 53% (Scheme 4). Employing truncated
model systems, we could show that this difference can be
attributed to a relief of 1,3-strain present in the reactant 3 but
not in the corresponding oxazine (see Supporting Information
for more details).
by excess THIQ (Figure 7). The high activation free energy for
the hydride transfer (ΔG⧧ = 38.4 kcal·mol−1) renders this
A pronounced substituent effect is observed, however, for the
zwitterionic intermediates 10, as already indicated by the broad
NMR peaks (Figure 1) for the dibromo compound 2l. The
electron-withdrawing bromo substituents in 10l result in a
stabilization of 7.8 kcal·mol−1 compared to 10f, while the
electron-donating methoxy group leads to a destabilization in
10o (ΔΔG = +3.9 kcal·mol−1). The additional benzene ring of
tetrahydroisoquinoline compared to pyrrolidine only translates
to a small difference in free energy (cf. 10f and 10d in Table 2)
indicating that the interaction with the negatively charged
alcoholate is more important for the stability than an
interaction with the iminium substructure.
Figure 7. Calculated transition state TS6 with selected bond lengths
(in Å) and activation and reaction free energies (in kcal·mol−1) for an
intermolecular reduction of the intermediate zwitterion 10f by THIQ
[M06-2X-D3/def2-TZVPP/IEFPCM//TPSS-D2/6-31+G(d,p)/
IEFPCM].
For very bulky substrates (e.g., leading to 2r or 2x), the
additional steric interactions in the transition states cis-TS1-
HOAc and TS3-Sali completely compensate any stabilization
and render them higher in energy than cis-TS1 and TS3,
respectively.
pathway unlikely under the reaction conditions employed
(Table 1). However, a large excess of the amine would favor
this reaction and could slightly reduce the activation free
energy.
Investigation of Side Reactions. Among the possible
pathways for side reactions, we first analyzed the feasibility of
an intermolecular reduction of the intermediate zwitterion 10f
Another possibility, which is also in line with the
experimental isolation of dihydroquinoline (DHIQ), is a
retro-Diels−Alder reaction followed by a nucleophilic attack
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Table 3. Calculated Free Energies for Intermediates of Reductive Isomerization for Different Carbonyl-Amine Combinations in
a
Toluene
a
Energies are given in kcal·mol−1, M06-2X-D3/def2-TZVPP/IEFPCM//TPSS-D2/6-31+G(d,p)/IEFPCM.
of the amine on the formed quinone methide. The energies of
all intermediates for these transformations are summarized in
Table 3. In all cases under investigation, the alternate product 8
is thermodynamically more stable than the corresponding cyclic
N,O-acetal 2 (0.8 < ΔΔG < 4.3 kcal·mol−1) and the
intermediates of the putative retro-[4 + 2] reaction, 11 and
the corresponding imine, are 20−25 kcal·mol−1 higher in
energy. Table 3 further shows that the reduced amines
dihydroquinoline and pyrroline are comparable in stability
(ΔΔG = 1.0 kcal·mol−1). However, we were not able to locate
any transition states for any of these transformations.
Therefore, we investigated the potential energy landscape
around the hemiaminals 2 by performing two-dimensional
relaxed potential energy surface scans at the TPSS-D2/6-
31G(d)/IEFPCM level of theory (Figure 8). Regardless of the
proposed mechanism (e.g., stepwise versus concerted cyclo-
addition), these scans result in a barrierless combination of the
quinone methide 11f and the imine DHIQ, yielding the
experimentally observed N,O-acetal 2f. From these results, we
have to conclude that both a putative retro-[4 + 2] reaction and
the subsequent nucleophilic attack would proceed without
significant barriers. These results are in agreement with
previous kinetic studies by the groups of Freccero, Kresge,
Richard, Rokita, Mayr, and others.22
As a consequence, none of the pathways considered can
account for the unusual reactivity of pyrrolidine and
salicylaldehyde, and a different reason has to be responsible
for the experimental observations.
COMPUTATIONAL DETAILS
■
The conformational space of all intermediates for the benzoxazine
synthesis was explored by use of the OPLS-200523 force field and a
modified Monte Carlo search routine implemented in Macromodel
9.9.24 An energy cutoff of 20 kcal·mol−1 was used for the
conformational analysis, and structures with heavy-atom root-mean-
square deviation (RMSD) less than 1−2 Å after the initial force field
optimization were assumed to be the same conformer. The remaining
structures were subsequently optimized by employing the meta-GGA
functional TPSS25 with Grimme’s dispersion-correction D2,26 and the
double-ζ basis set 6-31+G(d,p). Solvation by toluene was taken into
account by using the integral equation formalism polarizable
continuum model (IEFPCM) for all calculations (optimizations,
frequencies, and single points).27 It has recently been shown that the
use of a polarizable continuum model does not have a large impact on
the calculated frequencies but is necessary for the location of transition
states in some cases.28 Vibrational analysis verified that each structure
was a minimum or a transition state. Following the intrinsic reaction
coordinates (IRC) confirmed that all transition states connected the
corresponding reactants and products on the potential energy surface.
Two-dimensional potential energy surface scans were performed at the
TPSS-D2/6-31G(d)/IEFPCM level of theory. Thermal corrections
were calculated 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 calculated
from partition functions evaluated with quasiharmonic approximation
of Truhlar and co-workers.28 This method uses the same
approximations as the usual harmonic oscillator except that all
vibrational frequencies lower than 100 cm−1 are set equal to 100 cm−1
to correct for the breakdown of the harmonic oscillator approximation
for low frequencies. Electronic energies were subsequently obtained
Figure 8. Calculated potential energy surface scan for the putative
retro-hetero-Diels−Alder reaction involving 2f [in kcal·mol−1, TPSS-
D2/6-31G(d)/IEFPCM].
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from single-point calculations of the TPSS-D2 geometries employing
the meta-hybrid M06-2X functional,29 the large triple-ζ def2-TZVPP
basis set,30 IEFPCM for toluene, and Grimme’s dispersion-correction
D3 (zero-damping),31 a level expected to give accurate energies.32 An
ultrafine grid corresponding to 99 radial shells and 590 angular points
was used throughout this study for numerical integration of the
density.33 All density functional theory (DFT) calculations were
performed with Gaussian 09,34 and the additional D3 corrections for
single-point calculations were carried out with Grimme’s DFT-D3
program.31
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CONCLUSIONS
■
We have developed a mild and highly efficient synthesis of
benzoxazines from the direct condensation of salicylaldehydes
and secondary amines. This redox-neutral process can be used
to rapidly create a wide range of polycyclic N,O-acetals. In
addition, a reductive amination of salicylaldehydes in which
excess amine serves as reductant was discovered. The
mechanism of the α-oxygenation was elucidated by DFT
calculations that correlate well with experimental results.
Further studies on this and related reactions are ongoing.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization data, Cartesian
coordinates, energies of all reported structures, and details of
computational methods. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
houk@chem.ucla.edu
■
seidel@rutchem.rutgers.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work used the Extreme Science and Engineering
Discovery Environment (XSEDE), which is supported by
National Science Foundation Grant OCI-1053575, resources
from the UCLA Institute for Digital Research and Education
(IDRE), and the Cologne High Efficiency Operating Platform
for Sciences (CHEOPS). We are grateful to the Alexander von
Humboldt foundation (Feodor Lynen fellowship to M.B. and
A.D.), the Fonds der Chemischen Industrie (Liebig scholarship
to M.B.), the German Academic Exchange Service (scholarship
to A.U.), and the National Science Foundation for support of
this research through Grant CHE-1059084 to K.N.H. Financial
support from the NIH−NIGMS through Grant
R01GM101389-01 to D.S. is gratefully acknowledged. A.Y.P.
gratefully acknowledges financial support from the Russian
Federation President Grant (order N2057).
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