Isotope effects and mechanism of the asymmetric BOROX br?nsted acid catalyzed aziridination reaction

Article abstract of DOI:10.1021/jo302783d

The mechanism of the chiral VANOL-BOROX Br?nsted acid catalyzed aziridination reaction of imines and ethyldiazoacetate has been studied using a combination of experimental kinetic isotope effects and theoretical calculations. A stepwise mechanism where re

Full text of DOI:10.1021/jo302783d

Article
pubs.acs.org/joc
Isotope Effects and Mechanism of the Asymmetric BOROX Brønsted
Acid Catalyzed Aziridination Reaction
Mathew J. Vetticatt,* Aman A. Desai, and William D. Wulff*
Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, United States
S
* Supporting Information
ABSTRACT: The mechanism of the chiral VANOL-BOROX Brønsted acid catalyzed aziridination reaction of imines and
ethyldiazoacetate has been studied using a combination of experimental kinetic isotope effects and theoretical calculations. A
stepwise mechanism where reversible formation of a diazonium ion intermediate precedes rate-limiting ring closure to form the
cis-aziridine is implicated. A revised model for the origin of enantio- and diastereoselectivity is proposed based on relative
energies of the ring-closing transition structures.
Scheme 1. Diverging Pathways of the Putative Diazonium
Ion Intermediate 3
INTRODUCTION
■
The Brønsted acid catalyzed reaction of imines (1) and diazo
nucleophiles (2) can at first glance appear to be a capricious
reaction. Although reactions of N-diarylmethyl or N-aryl imines
with ethyldiazoacetate typically give cis-aziridines (cis-4) as the
major product,1−3 reactions of N-acyl imines give alkylation
products (5) via C−H bond cleavage.4 Changing the
nucleophile to a secondary diazoacetamide reverses the
diastereoselectivity, and trans-aziridines can be selectively
formed.5,6 Enamine formation (6) typically accompanies all
these reaction modes to a greater or lesser degree. A diazonium
ion 3, resulting from the initial carbon−carbon bond-forming
event, is assumed to be the common intermediate that
partitions these three pathways as shown in Scheme 1. The
intermediacy of 3 has been proposed for aziridine-forming
reactions of imines and diazo compounds that are mediated by
both Lewis and Brønsted acids,7−10 and some indirect evidence
for the intermediacy of 3 has been presented in certain
reactions.11
Over the past decade, we have reported and have continued
to develop a catalytic asymmetric version of the cis-selective
aziridination reaction of N-diarylmethyl imines and ethyl-
diazoacetate.1 A typical example is the reaction of 3,3′,5,5′-
tetramethyldianisylmethyl (MEDAM) imine 1a and ethyl-
diazoacetate 2a catalyzed by the chiral VANOL-BOROX1c
Brønsted acid catalyst (7) that proceeds with excellent yield
and enantioselectivity, producing almost exclusively one
enantiomer of the cis-aziridine 4a with typically a maximum
of 1−3% of the enamine side product 6 (Scheme 2).1a Does
this aziridination reaction proceed via a stepwise mechanism (as
shown in Scheme 1), or is a concerted mechanism, where all
bonds are formed and broken in one transition state, a
reasonable possibility?12 If a diazonium ion intermediate (3) is
formed (stepwise mechanism), does the subsequent ring-
closure step forming the aziridine (4) occur via an SN2-like
pathway (where ring closure and elimination of N2 occur in one
step), or is an SN1 pathway with formation of a discrete
Received: January 2, 2013
© XXXX American Chemical Society
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Scheme 2. Typical Aziridination Reaction Catalyzed by (R)-
VANOL-BOROX Catalyst
Scheme 3. Design of Experiment for the Determination of
Intermolecular KIEs
respect to the limiting reagent). The product 4a isolated from
this reaction (labeled “Sample A” in Scheme 3) has undergone
partial conversion (20 2%) in 2a and quantitative conversion
in 1a. The second reaction was performed under identical
conditions, except that the stoichiometry of 1a and 2a was
reversed. The product 4a isolated from this reaction (labeled
“Sample B” in Scheme 3) has undergone partial conversion (20
2%) in 1a and quantitative conversion in 2a.16
carbocation intermediate possible? The primary focus of this
work is to address these fundamental questions about the
mechanism of the title reaction. We recently published a
computational study in which we examined the origin of the cis-
selectivity observed in this reaction.10 In doing so, we assumed
a stepwise mechanism with the formation of the diazonium ion
intermediate as the rate-limiting step. This assumption was a
reasonable one because the entropically favored intramolecular
ring-closure step that follows diazonium ion formation is
expected to be facile. Although this mechanism has been
suggested as the most reasonable possibility,7b,11 it has not been
addressed experimentally in any related aziridination reaction.
The >50:1 cis:trans ratio was explained on the basis of the lower
energy of the transition state for the carbon−carbon bond
formation along the cis-pathway. This work also aims to provide
an experimental basis for the mechanistic assumptions that
formed the basis of the transition-state model proposed in ref
10.
The 13C composition of Samples A and B was compared
using NMR analysis. The peak for the methyl carbon of the
ester moiety was used as a standard for integration in the NMR
analysis with the assumption that the isotope effect at this
position is negligible. From the changes in 13C isotopic
composition and the reaction conversions, the intermolecular
13C KIEs were calculated in a standard way.17 The resulting 13
C
KIEs for the two key bond-forming carbon atoms C1 (the
iminium carbon of 1a) and C2 (the nucleophilic carbon of 2a),
obtained from a set of two independent experiments (four total
reactions) with six measurements per experiment, are shown in
Figure 1.18
Kinetic isotope effects (KIEs) provide valuable information
about the rate-limiting transition-state geometry of a reaction.
Singleton and co-workers have pioneered the determination of
13C KIEs employing NMR methodology at natural abun-
dance.13 The experimental isotope effects thus determined can
be quantitatively associated to a reaction mechanism by
modeling the relevant transition-state geometries using
computational methods. This approach has been successfully
used to probe the mechanism of several fundamental organic
reactions.14 We report here, using this combined experimental
and theoretical approach, detailed insight into the mechanism
of the chiral Brønsted acid catalyst (7) as it functions in the
aziridination reaction of MEDAM imine (1a) and ethyl-
diazoacetate (2a).
13
12
13
Figure 1. Experimental C KIEs (k C/k C) for the aziridination
reaction of 1a and 2a catalyzed by 7 from two independent
experiments with six measurements per experiment. The numbers in
parentheses represent the standard deviation on the last digit from the
six measurements of each of the experiments.
In a catalytic reaction, the KIEs report on bonding changes
occurring up to the first irreversible step between free substrate
and product. The magnitude of the KIEs is indicative of the
extent of bond forming/breaking occurring at the transition-
state geometry of this irreversible step. The near unity KIE on
the iminium carbon (C1) suggests that it does not participate in
this isotope sensitive step. This establishes two key aspects of
the mechanism: (a) a concerted one-step mechanism is unlikely
because such a mechanism would have resulted in a larger KIE
on C1, and (b) assuming a stepwise mechanism, the initial
carbon−carbon bond-forming step to form the diazonium ion
intermediate is reversible because irreversible carbon−carbon
bond formation would also have resulted in a significant KIE on
C1. The large KIE on C2 suggests the involvement of this
carbon atom in the KIE-determining transition state. Hence the
qualitative interpretation of the experimental KIEs is that the
aziridination reaction of 1a and 2a proceeds via a stepwise
RESULTS AND DISCUSSION
■
Experimental 13C Isotope Effects. The reaction of 1a and
2a catalyzed by (R)-VANOL-BOROX catalyst 7 was chosen for
the determination of intermolecular KIEs by analysis of
product.15 For a bimolecular reaction, this is typically
accomplished by comparative NMR analysis of the 13C isotopic
composition of two product samples, one isolated from a low
conversion (∼20%) reaction versus one isolated from a reaction
taken to 100% conversion, for each of the reactants. This
approach requires isolation of four product samples to obtain
one complete set of isotope effects for a bimolecular reaction.
A simple modification of this methodology, illustrated in
Scheme 3, accomplishes the same goal but with half the effort.
Each experiment consists of two reactions. The first reaction
was performed using 1a as the limiting reagent, a 5-fold excess
of 2a, and 20 mol % (R)-VANOL-BOROX catalyst 7 (with
B
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mechanism. The carbon−carbon bond-forming step to form
the diazonium ion intermediate precedes the first irreversible
step in the catalytic cycle.19 A detailed examination of different
possible stepwise mechanisms is required for the quantitative
interpretation of the experimental KIEs.
Scheme 4. SN2-like Mechanism Giving cis-4a
Theoretical Analysis of Reaction Mechanism. We have
already established, using experiment and theory, the mode of
catalysis of this unique chiral BOROX catalyst.1b,c,10 The
current work builds on the findings in ref 10 and presents a
comprehensive analysis of the geometries, energies, and KIEs of
all mechanistically relevant transition structures. All transition
structures for the (S)-VANOL-BOROX catalyzed reaction20 of
1a and 2a were located in ONIOM(M062x/6-31+G**:AM1)
calculations21 as implemented in Gaussian 09.22 The division of
layers for the ONIOM calculations is shown in Figure 2. All
Figure 2. Division of layers for the ONIOM calculations. The portions
in red are modeled using the DFT method. The blue portions are
calculated using the semiempirical method.
to O3 of the boroxinate core of the catalyst via a short, strong
hydrogen bond (H-bonding interaction at 2.17 Å). There is
also π-stacking between the phenyl substituent of the imine 1a
and the boroxinate core. A H-bonding interaction between the
α-CH of 2a and O1 (1.94 Å) facilitates the si-facial attack of
2a.23 Electrostatic interactions of the polarized N2 moiety with
the boroxinate O2 (2.67 Å) and the iminium nitrogen (2.95 Å)
further stabilize this transition structure.24
reported distances are in angstroms. Energies of all transition
structures/intermediates reported in this work are Gibbs free
energies from the ONIOM calculations and are relative to the
(catalyst−1a complex + 2a) combination (which is assumed to
be 0.0 kcal/mol).
Possible Mechanisms Based on Experimental KIEs.
The experimental KIEs (Figure 1) provide persuasive evidence
for the reversible formation of a diazonium ion intermediate.
Also, the first irreversible step in the catalytic cycle likely
follows this diazonium ion formation. In order to correctly
interpret our experimental KIEs, we explored three reasonable
stepwise mechanisms assuming the initial carbon−carbon
bond-forming step to be reversible.
(A) SN2-like Mechanism. This is the widely accepted
mechanism for this reaction.7−11 However, there is little
evidence in the literature regarding the existence of the
diazonium ion intermediate or the identity of the rate-limiting
step in this mechanism.7b,11 On the basis of our experimental
KIEs, we propose that reversible formation of the catalyst-
bound diazonium ion intermediate (gauche 3a′/anti 3a′)
could be followed by an irreversible SN2-like ring-closure step
(rate-limiting step) to form the aziridine with concomitant
elimination of N2 (Scheme 4). At the transition state for this
step, C2 would have bond order to both the intramolecular
nucleophile and the leaving group that are in an antiperiplanar
orientation (anti 3a′). This could account for the large
observed KIE on C2. In this section, we discuss the results from
a comprehensive evaluation of the reaction coordinate for the
SN2-like mechanism of 1a.
The initial carbon−carbon bond-forming step (TS1) results
in a catalyst-bound gauche diazonium ion intermediate (gauche
3a′) that maintains all the stabilizing interactions present in
TS1 (Figure 3B). Before SN2-like nucleophilic attack can occur
+
to close the ring, the activated leaving group (−N2 ) should be
antiperiplanar to the trajectory of the intramolecular
nucleophile. A conformational change occurs involving rotation
of the imine portion of the diazonium ion intermediate while
maintaining the H-bonding interaction between the α-CH and
O1 (2.05 Å), resulting in anti 3a′ (Figure 3C). The dihedral
angle defined by the four atoms highlighted as spheres in B and
C in Figure 3 changes from 24° to −174° on going from
gauche 3a′to anti 3a′. The key difference between Figure 3B
and Figure 3C is that the imine-NH···O3 H-bond (2.38 Å) in
gauche 3a′ is replaced by an intramolecular catalyst-
independent H-bonding interaction in anti 3a′ between the
imine -NH and the carbonyl oxygen of the ester moiety (2.32
Å) of the diazonium ion intermediate.
TS2 is the lowest energy transition structure for the SN2-like
ring closure to form 4a with elimination of N2 and has a
geometry very similar to that of anti 3a′ (Figure 4). The H-
bonding interaction between the α-CH and O1 remains intact
(1.97 Å). The intramolecular H-bond between the imine
nitrogen and the carbonyl oxygen of the ester moiety is
maintained (2.43 Å) as the C−N bond forms. The diazonium
C2 atom has significant bond order to both the nucleophile and
the leaving group, analogous to a classical SN2 transition state.
Formation of Side Products. Commonly observed side
products in these reactions are enamines.1a,7a,8 These products
TS1 is the lowest energy transition structure for the
nucleophilic addition of 2a to the iminium ion of 1a (Figure
3A). This transition structure is sustained by multiple
noncovalent interactions that lower the barrier to catalysis
(Figure 3, expanded view). The protonated imine 1a is bound
C
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Figure 3. Reversible steps preceding ring closure to form cis-4a in the SN2-like mechanism.
presumably arise from elimination of the N2 leaving group from
the diazonium ion intermediate 3a by migration of either the
hydrogen atom or the phenyl substituent from C1 to C2
(instead of ring closure to form cis-4a as described in Figure 4).
This results in an iminium ion intermediate that subsequently is
deprotonated to the more stable enamine product as shown in
the reaction scheme in Figure 5. Transition structures were
located for the migration of a hydride (TS2-H-migration) and
the phenyl group (TS2-phenylmigration) from C1 to C2. In
each of these transition structures, the migrating group is
antiperiplanar to the −N2 leaving group. The product ratio
ultimately depends on the relative energies of the three
transition structures shown in Figure 5, all of which emanate
from the common diazonium ion intermediate 3a.
products in the reaction with MEDAM imines.1a The triflic acid
catalyzed aziridination reaction of an analogous imine (with a
benzhydryl protecting group) and the same diazo nucleophile
gives significant amounts of enamine side products.2 We believe
that it is the superior stabilization of TS2 relative to enamine
transition structures, by the (S)-VANOL-BOROX counterion
as compared to the triflate anion, that is responsible for the
contrastingly high selectivity observed for the aziridine product
in our reaction (proton is the catalyst in both reactions).
(B) SN1 Mechanism. A reasonable alternative is an SN1
mechanism with dissociation of N2 from the diazonium ion
intermediate as the first irreversible step (Scheme 5). This will
lead to the formation of a contact ion pair between the anionic
boroxinate catalyst and the resulting carbocation intermediate.
Such a step would be followed by rapid capture of this
carbocation by the intramolecular nitrogen nucleophile to give
the aziridination product.
The transition structures TS2-phenylmigration and TS2-H-
migration are higher in energy than TS2 by 3.7 and 7.7 kca/
mol, respectively, consistent with ≤1−3% prevalence of these
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Figure 4. Lowest energy ring-closing transition structure (TS2) giving cis-4a via the SN2-like mechanism.
Figure 5. Reaction scheme and transition structures for the formation of enamine side products 6a/6b from the common diazonium ion
intermediate 3a. All distances are in angstroms. TS2 is also depicted for comparison.
Within the framework of such a mechanism, the dissociation
of N2 from the diazonium ion intermediate would be the first
irreversible step, and the KIEs would reflect the transition-state
geometry for this step. How the resulting carbocation forms the
aziridination product will be of interest only if the SN1
transition-state geometry is energetically feasible and repro-
duces the experimental KIEs. We therefore located a transition
structure, TS2-SN1, for the irreversible formation of the
catalyst-bound carbocation from gauche 3a′ (Figure 6). This
was a challenging task because as the N2 moiety dissociates
from gauche 3a′, there is a propensity for the groups on C1 to
migrate to the carbocationic center (C2), resulting in an
iminium ion intermediate that eventually forms the enamine
side product (as described in Figure 5). TS2-SN1 has a
geometry that is characterized by the same interactions that
stabilize gauche 3a′, the only difference being the elongated
+
C2−leaving group (−N2 ) bond (2.2 Å). This leads to
significant carbocation character on C2, characteristic of SN1
transition states.
(C) Miscellaneous Mechanisms. There are two additional
possibilities that could be construed to be possibly consistent
with the experimental KIEs. One of these involves nucleophilic
participation of the boroxinate anion to displace N2 from the
diazonium ion intermediate, resulting in a covalently bound
catalyst−substrate complex.25 The aziridine 4a can then be
formed by a “double displacement” mechanism with regener-
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Scheme 5. SN1 Mechanism Giving cis-4a
Scheme 6. Double Displacement and Concerted
Asynchronous Mechanisms Leading to cis-4a
mechanism. The key result of note here is that the rate-limiting
step (highest free energy barrier) in this mechanism is the
intramolecular SN2-like ring closure to form cis-4a (TS2). All
preceding transition structures (TS1 and TSrot) result in high
energy intermediates (gauche 3a′ and anti 3a′, respectively)
that face a higher barrier to go forward than reverse along the
reaction coordinate. The KIEs should therefore reflect the
geometry of TS2, the first irreversible step between free starting
material and product along the reaction coordinate.
The reaction coordinate for the SN1 pathway is identical to
the SN2-like mechanism up until formation of gauche 3a′. TS2-
SN1, the transition structure for the dissociation of N2 from
gauche 3a′, is the rate-limiting step in the SN1 pathway. TS2-
SN1 is 10.2 kcal/mol higher in energy than the rate-limiting step
in the SN2-like pathway. On the basis of energetics alone, the
SN2-like mechanism appears to be more likely than the SN1
mechanism. Further support for the SN2-like mechanism is
obtained from the theoretical prediction of KIEs of the relevant
transition structures. The predicted KIEs for C1 and C2,
assuming each of the transition structures TS1, TSrot, TS2, and
TS2-SN1 to be KIE determining, are shown in Figure 7 along
with the experimental KIEs. The predicted KIEs for TS2 are in
excellent agreement with the experimental KIEs for both C1
and C2. Additionally, the predicted KIEs for TS1, TSrot, and
TS2-SN1 are clearly inconsistent with the experimental values.
ation of the catalyst as shown in Scheme 6A. Alternatively, the
experimental KIEs could also result from a very late
asynchronous concerted transition structure where all bond
making and bond breaking occur in one chemical step (Scheme
6B). Despite our best efforts and rigorous exploration of the
reaction surface, saddle points could not be located for either of
these possibilities.
Energetic Considerations and Predicted KIEs for
Calculated Mechanisms. The stationary points along the
reaction coordinate for the SN1 and SN2-like mechanisms are
shown in Figure 7 along with their free energy estimates relative
to the catalyst−1a complex and 2a. The KIEs for all transition
structures in Figure 7 were predicted from their scaled
theoretical vibrational frequencies based on conventional
transition-state theory using the program ISOEFF 98.26
Tunneling corrections were applied to the predicted KIEs
using a one-dimensional infinite parabolic barrier model.27 The
reaction coordinate shown in black represents the SN2-like
Figure 6. Transition structure (TS2-SN1) for the irreversible dissociation of N2 from the diazonium ion.
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Figure 7. Gibbs free energies (25 °C) for all stationary points along the reaction coordinate and the predicted KIEs for the SN2-like and SN1
mechanisms.
Figure 8. Key stationary points on the reaction coordinate for the formation of trans-4a.
The energy considerations and the quantitative match of
experimental and predicted KIEs for TS2, taken together,
provide strong support for a stepwise mechanism with
reversible formation of a diazonium ion intermediate followed
by rate-limiting SN2-like ring closure to form cis-4a.
Re-evaluation of the Origin of cis-Diastereoselection
and Enantioselectivity. In our earlier study, we rationalized
the cis-selectivity observed in the (R)-VANOL-BOROX
catalyzed aziridination reaction of 1a and 2a based on the
relative energy of the carbon−carbon bond-forming (e.g., TS1)
transition structures along the diastereomeric pathways leading
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Figure 9. Overlay of the reaction coordinate Gibbs free energies (25 °C) for the cis- and trans-aziridination pathways along with key transition
structures in the enantiomeric cis-pathway.
to cis- and trans-aziridines (cis favored over trans by 3.1 kcal/
mol based on B3LYP/6-31+G* single point energies performed
on ONIOM(B3LYP/6-31G*:AM1) optimized transition struc-
tures).10 In addition to assuming a stepwise mechanism, we had
also made the reasonable assumption that the entropically
disfavored nucleophilic addition of 2a to 1a was the rate-
limiting step of the reaction.12 Although our assumption about
the stepwise mechanism was correct, the experimental KIEs
reported in this work clearly establish that it is the
intramolecular SN2-like ring closure, not the addition step,
that is rate-limiting. Our explanation of the origin of the
observed cis-diastereoselection thus warrants a re-evaluation.
Having experimentally established the rate-limiting step in the
cis-pathway and having validated it by calculations, we decided
to carry out a calculational analysis of the reaction coordinate
for the formation of trans-4a.28 A comparison of the relative
energies of the rate-limiting steps along each pathway would
then constitute our revised model for the origin of cis-
diastereoselection observed in this reaction.
It has been established that trans-4a (minor diastereomer)
formed in this reaction has the opposite facial selectivity to the
imine as compared to cis-4a.6 We therefore modeled the attack
of 2a on the re-face of 1a (as opposed to the si-facial attack in
TS1). Structure TS3 (Figure 8A) is the lowest energy carbon−
carbon bond-forming transition structure leading to the
diazonium ion intermediate along the trans-pathway. Compar-
ison of the expanded view of TS3 in Figure 8 to that of TS1 in
Figure 3 reveals a very similar geometry of the catalyst and 2a.
The only difference between TS3 and TS1 is the face of
catalyst-bound 1a that is exposed to attack by 2a. As a result,
the diazonium ion formed from TS3 (trans anti 3a′) has an
antiperiplanar orientation of the N(imine)−C1−C2−N(diazo)
bond (highlighted as spheres in Figure 8B) and is already “set
up” for SN2-like ring closure without an intervening bond
rotation event, as in the cis-pathway (see Figure 7, TSrot).
Figure 8C shows the transition structure for the formation of
trans-4a. It is important to note that unlike the cis-pathway, all
transition structures and intermediates in the trans-pathway are
stabilized by the same noncovalent interactions, namely, (a) the
imine NH−O3 hydrogen bond, (b) the α-CH−O1/O2
hydrogen bond, and (c) the electrostatic interaction between
the polarized N2 leaving group and O1. As a result, the addition
and ring-closing transition structures in the trans-pathway (TS3
and TS4) are much closer in energy than their counterparts in
the cis-pathway.
A comparison of the free energy profiles for the reaction
coordinates of the diastereomeric aziridination pathways is
shown in Figure 9. The transition structure for the SN2-like ring
closure is the highest barrier (rate-limiting step) along both
diastereomeric pathways, though the difference between TS3
and TS4 (0.6 kcal/mol) is not as significant as the difference
between TS1 and TS2 (4.0 kcal/mol). Comparison of the
relative energies of TS2 and TS4 gives a theoretical cis:trans
ratio of ∼10:1. This is in reasonable agreement with the
experimental >50:1 cis:trans ratio observed for this reaction.
Therefore, on the basis of the experimental KIEs and
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F-254 indicator. Visualization was by short wave (254 nm) and long
wave (365 nm) ultraviolet light, or by staining with phosphomolybdic
acid reagent (20 wt % in ethanol).
calculations presented in this work, we wish to revise our
hypothesis on the origin of cis-diastereoselection observed in
the title reaction. We propose that the observed diastereose-
lectivity is a result of the lower energy of TS2 as compared to
that of TS4, the rate-limiting steps in each of the diastereomeric
pathways. Finally, calculations accurately predict the enantio-
selectivity of the reaction. TS1-ent, the carbon−carbon bond-
forming transition structure for the minor enantiomer of cis-4a,
was found to be 3.9 kcal/mol higher in energy than TS1, and
TS2-ent, the ring-closing transition structure for the minor
enantiomer of cis-4a, was also found to be 3.9 kcal/mol higher
in energy than TS2. This is consistent with the experimentally
observed 99% ee.29 Therefore, Figure 9 provides a new basis for
the observed enantio- and diastereoselectivity of the reaction:
the relative energies of the respective ring-closing transition
structures.
Procedure for the Aziridination Reactions. Preparation of the
Catalyst Stock Solution. A 100 mL glass Schlenk flask fitted with a
magnetic stir bar was connected via vacuum tubing to a double-
manifold vacuum line equipped with an argon ballast. The Schlenk
flask was made in a glass blowing shop by fusing together a high-
vacuum Teflon valve and a 100 mL recovery flask. The side arm of the
high-vacuum valve was modified with a piece of 3/8th in. glass tubing
to fit with the vacuum tubing attached to the double manifold. The
double manifold had two-way high-vacuum valves, which could be
alternated between high vacuum (0.1 mmHg) and an argon supply
(ultra high purity, 99.999%). The Schlenk flask was then flame dried
under high vacuum and cooled under a low flow of argon. To the flask
were added sequentially (R)-VANOL (463 mg, 1.06 mmol),
triphenylborate (1.23 g, 4.23 mmol), dry toluene (20 mL), and
water (19 μL, 1.06 mmol) under a low flow of argon. The threaded
Teflon valve on the Schlenk flask was then closed, and the mixture
heated at 80 °C for 1 h. The valve was opened to gradually apply high
vacuum (0.1 mmHg), and the solvent was removed. The vacuum was
maintained for a period of 30 min at 80 °C. The flask was then
removed from the oil bath and allowed to cool to room temperature
under a low flow of argon. The residue was then completely dissolved
in 50 mL of dry toluene to afford the stock solution of the catalyst.
Aziridination Reaction, Illustrated for Reaction 1 (First Run,
Scheme 7). A 50 mL round-bottom single-neck (24/40 joint) flask
CONCLUSION
■
Experimental KIEs unambiguously reveal the mechanism of the
(R)-VANOL-BOROX catalyzed aziridination reaction of
MEDAM imine 1a and ethyl diazoacetate. The near unity
13C KIE for the iminium carbon atom of 1a and the large 13C
KIE of ∼5% on the α-carbon of ethyl diazoacetate suggest that
the first irreversible step in the catalytic cycle is the ring closure
to form the cis-aziridine. This is the first experimental study that
provides direct evidence for a stepwise mechanism involving
the formation of a diazonium ion intermediate. The predicted
KIEs for SN2-like intramolecular ring closure to form the cis-
aziridine from the diazonium ion intermediate are in
quantitative agreement with the experimental KIEs. Detailed
theoretical analysis of the reaction energy profile reveals
reversible formation of the diazonium ion intermediate
followed by rate-limiting ring closure, consistent with
interpretation of the observed KIEs.
Scheme 7. Catalyst Preparation and Design of KIE
Experiments
The identification of the rate-limiting step led to a re-
evaluation of the origin of enantio- and diastereoselectivity
observed in this reaction. Calculations suggest that the rate-
limiting step, in both the diastereomeric pathway leading to
trans-aziridine and the enantiomeric pathway leading to the
minor enantiomer of cis-4a, is the intramolecular ring closure.
The >50:1 cis:trans ratio and 99% ee observed in this reaction
are now explained on the basis of the relative energies of the
competing SN2-like ring-closing transition structures. We are
currently exploring the generality of this reaction mechanism
for other Lewis/Brønsted acid catalyzed aziridination reactions,
which are proposed to proceed via similar addition−
cyclization−elimination pathways. The results from these
studies will be reported in due course.
fitted with a magnetic stir bar was flame dried under high vacuum and
cooled under a low flow of argon. To the flask was then added imine
1a (2.05 g, 5.29 mmol, 1 equiv). The flask was then fitted with a
rubber septum and an argon balloon. To this flask was added 10 mL of
the catalyst stock solution (20 mol % catalyst with respect to 2, 0.21
mmol) via a plastic syringe fitted with a metallic needle. To the stirred
solution of this catalyst−imine complex was then added ethyl-
diazoacetate 2 (1.06 mmol, 0.2 equiv). Commercial ethyldiazoacetate
usually contains dichloromethane. The exact amount of ethyl-
diazoacetate was added to the reaction mixture after considering the
ratios of ethyldiazoacetate and dichloromethane from 1H NMR
analysis of the commercial ethyldiazoacetate. The reaction mixture was
then stirred at room temperature for 15 h.
EXPERIMENTAL SECTION
■
General. All experiments were performed under an argon
atmosphere. Flasks were flame dried and cooled under argon before
use. Toluene was dried from sodium under nitrogen. The VANOL
ligand is commercially available. If desired, it could be purified using
column chromatography on regular silica gel using an eluant mixture
of 2:1 dichloromethane:hexanes. Triphenylborate and ethyldiazoace-
tate were used as purchased. The preparation of imine 1a can be found
in a previous report from our group.30
Workup, Purification, and Analysis. The reaction mixture was
diluted with hexanes and subjected to rotary evaporation until the
1
The silica gel for column chromatography was standard grade, 60 Å
porosity, 230 × 400 mesh particle size, 500−600 m2/g surface area,
and 0.4 g/mL bulk density. The 1H and 13C NMR spectra were
recorded in CDCl3, wherein CHCl3 was used as the internal standard
for both 1H NMR (δ = 7.24) and 13C NMR (δ = 77). Analytical thin-
layer chromatography (TLC) was performed on silica gel plates with
solvent was removed. The H NMR analysis of the crude product
revealed a conversion of 20%, determined by the relative integration of
the aziridine ring methine protons versus the iminium methine proton.
Purification of aziridine 4a was done via column chromatography with
regular silica gel and an eluant mixture of 1:20:20 EtOAc:hexanes:di-
chloromethane and then 1:10:10 EtOAc:hexanes:dichloromethane. If
I
dx.doi.org/10.1021/jo302783d | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1H NMR analysis of the product after chromatography showed the
presence of a phenolic impurity, the product was dissolved in EtOAc
and washed twice with 10% aq NaOH, water, and brine and
subsequently dried over Na2SO4. This procedure afforded the pure
product 4a as an off-white solid in 95% isolated yield (475 mg, 1.00
mmol). The optical purity of 4a was determined to be 99% ee by chiral
HPLC analysis. Complete characterization details for 4a can be found
(14) (a) Beno, B. R.; Houk, K. N.; Singleton, D. A. J. Am. Chem. Soc.
1996, 118, 9984−9985. (b) Singleton, D. A.; Merrigan, S. R.; Liu, J.;
Houk, K. N. J. Am. Chem. Soc. 1997, 119, 3385−3386. (c) DelMonte,
A. J.; Haller, J.; Houk, K. N.; Sharpless, K. B.; Singleton, D. A.;
Strassner, T.; Thomas, A. A. J. Am. Chem. Soc. 1997, 119, 9907−9908.
(d) Keating, A. E.; Merrigan, S. R.; Singleton, D. A.; Houk, K. N. J.
Am. Chem. Soc. 1999, 121, 3933−3938. (e) Frantz, D. E.; Singleton, D.
A. J. Am. Chem. Soc. 2000, 122, 3288−3295. (f) Zhu, H.; Clemente, F.
R.; Houk, K. N.; Meyer, M. P. J. Am. Chem. Soc. 2009, 131, 1632−
1633.
(15) (a) Frantz, D. E.; Singleton, D. A.; Snyder, J. P. J. Am. Chem. Soc.
1997, 119, 3383−3384. (b) Singleton, D. A.; Schulmeier, B. E. J. Am.
Chem. Soc. 1999, 121, 9313−9317.
(16) For the first report of this modified procedure to measure KIEs
by analysis of product, see: Vetticatt, M. J.; Singleton, D. A. Org. Lett.
2012, 14, 2370−2373 The yields, diastereoselectivity, and enantiose-
lectivity of aziridine 4a obtained under these modified conditions are
essentially identical to those obtained using the optimized reaction
stoichiometry of 1:1.1 (1a:2a).
in a previous report from our group.30 Spectral data for 4a: H NMR
1
(CDCl3, 500 MHz) δ 0.99 (t, 3H, J = 7.1 Hz), 2.21 (s, 6H), 2.27 (s,
6H), 2.59 (d, 1H, J = 6.9 Hz), 3.14 (d, 1H, J = 6.9 Hz), 3.63 (s, 3H),
3.69 (s, 3H), 3.69 (s, 1H), 3.93−3.96 (m, 2H), 7.13 (s, 2H), 7.18−
7.27 (m, 5H), 7.39 (d, 2H, J = 6.9 Hz); 13C NMR (CDCl3, 125 MHz)
δ 10.0, 12.2, 12.2, 42.5, 44.3, 55.3, 55.4, 56.4, 73.0, 123.3, 123.6, 123.7,
123.9, 123.9, 126.5, 126.6, 131.5, 134.0, 134.2, 152.2, 152.3, 163.8.
ASSOCIATED CONTENT
* Supporting Information
■
S
Computational and spectroscopic details and discussions,
relevant pdb files, and coordinates of all calculated structures.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(17) See Supporting Information for method used for calculation of
KIEs from the numerical integrations.
(18) See Supporting Information for KIEs of other carbon atoms and
representative NMR spectra.
AUTHOR INFORMATION
Corresponding Author
*M.J.V.: mjvcatt@gmail.com. W.D.W.: wulff@chemistry.msu.
(19) Johnston and co-workers (ref 11) have published indirect
evidence that the first step involving addition of the diazo compound
to the imine is nonreversible under Brønsted acid catalysis with triflic
acid. However, this reaction involves an activated imine derived from
methyl glyoxylate; thus, there may very well be a mechanism change
for this reaction.
■
edu.
Notes
(20) The KIE experiments were performed using (R)-VANOL, while
all calculations were performed using (S)-VANOL.
The authors declare no competing financial interest.
(21) (a) Svensson, M.; Humbel, S.; Morokuma, K. J. Chem. Phys.
1996, 105, 3654−3661. (b) Vreven, T.; Morokuma, K. J. Comput.
ACKNOWLEDGMENTS
This work was supported by the National Institute of General
Medical Sciences (GM 094478).
■
́
Chem. 2000, 21, 1419−1432. (c) Dapprich, S.; Komaromi, I.; Byun, K.
S.; Morokuma, K.; Frisch, M. J. J. Mol. Struct. 1999, 461, 1−21.
(22) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci,
B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H.
P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.;
Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin,
K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.;
Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega,
N.; Millam, N. J.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.;
Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.;
Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.;
Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.;
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frequencies of the relevant transition structures to that of the lowest
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equilibrium isotope effects for all reversible steps preceding the
transition structure in question.
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(12) We are suggesting that formation of the two bonds between 1
and 2 and loss of N2 to yield the product aziridinium ion might occur
in one step by a concerted mechanism. The preceding protonation of
imine and subsequent deprotonation of the aziridinium ion yielding
aziridine are distinct mechanistic events.
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The Journal of Organic Chemistry
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(28) There is no good experimental method to determine the rate-
limiting step in the trans-pathway because it is formed as a <1:50
minor product in this reaction. Because the energetics of the reaction
coordinate for the cis-pathway were consistent with the interpretation
of the experimental KIEs, we believe that we can compare the relative
energetics of the cis- and trans-pathways using the same calculations.
(29) The coordinates and pdb files of the calculated structures TS1-
ent and TS2-ent are available in the Supporting Information.
(30) Zhang, Y.; Lu, Z.; Desai, A.; Wulff, W. D. Org. Lett. 2008, 10,
5429−5432.
K
dx.doi.org/10.1021/jo302783d | J. Org. Chem. XXXX, XXX, XXX−XXX