A Nanovessel-Catalyzed Three-Component Aza-Darzens Reaction

A Nanovessel-Catalyzed Three-Component Aza-Darzens Reaction

Communication

Stephen M. Bierschenk, Robert G. Bergman,* Kenneth N. Raymond,* and F. Dean Toste *

Cite This: https://dx.doi.org/10.1021/jacs.9b13177

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sı Supporting Information

ABSTRACT: It has been previously demonstrated that nanovessels can be highly competent catalysts providing high rate

accelerations and unique selectivity to the organic transformations which they mediate. However, for supramolecular assemblies to

be considered a standard reagent in organic synthesis they must ﬁrst demonstrate the ability to catalyze increasingly complex

transformations. Herein, we report a three-component Aza-Darzens reaction that generates N-phenylaziridines, catalyzed by a

supramolecular host, that provides the stereoisomer opposite to the one generated in bulk solution (trans vs cis). This transformation

constitutes a rare catalytic three-component coupling within a supramolecular assembly, providing a supramolecular solution to a

synthetically challenging transformation.

ontrol of reactions at the macroscopic level can be

achieved through the manipulation of standard param-

enables solubility in polar solvents, such as water. The

hydrophobic interior allows recognition and binding of

lipophilic substrates in water, and the overall anionic charge

eters such as temperature, solvent, and exclusion of deleterious

components such as oxygen or water. Alternatively, container

molecules and supramolecular assemblies (“nanovessels”)

provide the opportunity for microscopic control of reactions

beyond the bounds of the ﬂask. This possibility has inspired

21,22

permits strong binding of cationic species.

In addition,

shift of up

nitrogenous and phosphorus bases experience a pK

to 4−5 units, due to stabilization of their protonated form

within the host. Also solvent exclusion and charge

stabilization by the cavity of 1 enable the encapsulation and

stabilization of hydrolytically unstable iminium ions within the

−8

the preparation of a variety of self-assembled nanovessels,

which provide disparate selectivity from bulk reactions, often in

−16

host, despite water as solvent.

a stoichiometric sense, but increasingly catalytically.

The

The properties imposed by the cavity of 1 on its guests have

led to the discovery of a variety of catalytic transformations

reactivity of such container molecules has been attributed to

the unique environment within their cores, which are often

25−28

17−19

that occur within its binding site.

For example, we have

compared to the active sites of enzymes.

Within this

previously shown that host 1 catalyzes the Aza-Prins reaction

via stabilization of an in situ generated iminium ion, which

cyclizes upon encapsulation. This reaction, and the prevalence

of iminium intermediates in multicomponent reactions and in

internal space, the supramolecular host provides a reaction

environment, distinct from that of bulk solvent, that enables

recognition and energetic stabilization of molecules and

transition states.

The Raymond tetrahedron (1) has been investigated as a

catalyst for a number of organic and organometallic trans-

formations, due to the unique microenvironment generated by

its internal cavity (Scheme 1). This host contains a

hydrophobic binding site while its overall dodecanionic charge

29,30

supramolecular catalysis,

inspired us to investigate whether

the iminium-stabilizing property of 1 could enable multi-

component reactions involving that species within the

nanovessel cavity. While a multicomponent reaction presents

inherent challenges, catalysis of these transformations by

supramolecular assemblies raises the unique question of

whether multiple guests can be accommodated in their

constrained environment; if so, will the reactivity and

selectivity diﬀer from the coupling in bulk solvent? More

speciﬁcally, we wondered whether the Aza-Darzens synthesis

of N-substituted aziridines from imines, which is typically

Scheme 1. General Reactivity for Three-Component Aza-

Darzens Reaction within the Raymond Tetrahedron

31−35

Bronsted or Lewis acid catalyzed,

would be amenable to

supramolecular catalysis. Herein, we report the development of

a diastereoselective three-component Aza-Darzens reaction of

anilines, aldehydes, and α-diazo esters catalyzed by supra-

Received: December 7, 2019

XXXX American Chemical Society

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society

Communication

molecular assembly 1. Three-component couplings of this type

control experiment, the cavity of 1 was blocked with an

equivalent of tetraethylammonium chloride, a strongly binding

guest, which lowered the yield of the reaction to 10% after 24

h. This result demonstrates the necessity of the host cavity for

the reaction to proceed eﬃciently (Scheme 2c).

These initial results encouraged us to explore the generation

of more complex products where diastereomeric selectivity

could be investigated. Acetaldehyde was ﬁrst selected as a

coupling partner, which could undergo the reaction with

aniline and EDA to provide disubstituted N-phenylaziridines

where the formation of both cis- and trans-aziridines would be

possible (Scheme 3a). The presence of 5 mol % 1 with aniline,

36−38

have been seldom promoted by supramolecular hosts

and

are exceedingly rare within a self-assembled container

molecule.

Given our previous results employing iminium intermediates

in reactions catalyzed by 1, we ﬁrst sought to identify a

nucleophile that would be compatible with the host and the

reaction conditions, and which could be employed in a

multicomponent reaction. These eﬀorts identiﬁed ethyl-

diazoacetate (EDA) as a nucleophile that met these require-

ments and showed a propensity to bind to host 1. Next, we

examined the amine component required for formation of the

electrophilic iminium component with formaldehyde, in the

presence of 1 and EDA. While basic amines (BnNH and

Scheme 3. (a) Eﬀect of n-Aldehyde Substituent on

Reactivity and (b) Blocked Host Control (Reported as

NMR Yields)

IPrNH ) and amides (AcNH ) did not aﬀord any desired

azirdine, we found that aniline and aqueous formaldehyde (37

wt %) coupled with EDA to form N-phenylaziridine 2a in an

aza-Darzens reaction, promoted by catalytic amounts of host 1

(Scheme 2a). Building on this initial result, we sought to ﬁnd

Scheme 2. (a) Initial Screening for Multicomponent Aza-

Darzens Reaction, (b) Scope of Monosubstituted Aziridines

(

Reported As Isolated Yields) and (c) Blocked Host

Control (Reported as NMR Yield)

acetaldehyde, and EDA gave the N-phenyl trans-aziridine (3)

as the major diastereomer (20:1, H NMR) in 68% yield. This

selectivity for the trans diastereomer was maintained for

propanal (4) and butanal (5); however, yields and selectivity

for the trans product diminished when pentanal (6) was

employed. The lack of reactivity with pentanal was attributed

to the increased size of this substrate preventing coencapsu-

lation within 1 and subsequent reactivity. The high selectivity

(

20:1) for the trans-aziridine in this Aza-Darzens reaction

catalyzed by 1 was surprising, as literature examples for this

reaction typically provide the cis-aziridine as the major isomer

when α-diazo esters are employed as nucleophiles.

In contrast, when the reaction was performed with Et N -

blocked 1, only minor background conversion (ca. 7%) to the

aziridine product was observed (Scheme 3b). Further

investigation of the product revealed that the cis-aziridine

was formed in the uncatalyzed process as opposed to the trans-

aziridine generated when the host cavity was not blocked. This

reversal in selectivity between the host-catalyzed and back-

ground reactions demonstrates that the conﬁned interior of the

host not only accelerates the reaction but also overrides the

inherent diastereoselectivity of the uncatalyzed process.

Several substitutions on the aniline ring were tolerated at the

meta and para positions, all of which were selective for the

disubstituted N-phenyl trans-aziridine (Scheme 4). Both

electron-rich and -deﬁcient rings were reactive, and there was

optimal reaction conditions and explore the scope of this

reaction. While poor solubility of the reaction components

precluded reactivity in water, and pure methanol gave poor

reactivity due to the lack of a hydrophobic driving force for the

encapsulation of reagents within the host, using a 50% (v/v)

methanol/pH 8 water mixture, N-phenylaziridine (2a) was

isolated in good yield and at low catalyst loading (82%,

Scheme 2b). Substitution on the aniline ring was tolerated for

both electron-withdrawing and -donating groups at both the

para (2b,c) and meta positions (2d,e), providing the

corresponding N-phenylaziridines in moderate yield. As a

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society

Communication

Scheme 4. Eﬀect of Aryl Substitution on Disubstituted

Aziridine Synthesis (Reported as NMR Yields)

catalyzed by 1, gave the trisubstituted N-phenylaziridine in

70% yield, with excellent selectivity for the trans-(Me, CO Et)-

diastereomer as determined by 1D NOE correlation (Scheme

, 8b). Further substitution of the α-diazo ester was tolerated

Scheme 6. Trisubstituted Aziridine Synthesis (Reported as

NMR Yields)

to some degree; however, yields diminished when the longer α-

propyl substituted α-diazo ester was employed (8e), again

demonstrating the impact of the nucleophile’s size on this

transformation.

In order to gain insight into the mechanism of the three-

component coupling, a series of in situ NMR experiments were

conducted. First, we examined the binding of the separate

components with the supramolecular host 1. Thus, a mixture

of aniline, aldehyde, and 1 showed only an equilibrium

between the aniline/aldehyde and the corresponding hemi-

aminal, without observable signals for imine either in solution

or within the cavity of the host. While it might be anticipated

that encapsulation of a cationic protonated imine/aniline

might be favorable in the dodecanionic host, the low basicity of

the aniline and the unfavorable equilibrium for imine

formation in water are apparently not overcome by this

association. In contrast, a mixture of 1 and α-diazo ester

resulted in noticeable broadening of the signals associated with

the α-diazo ester, consistent with a rapid and reversible, on the

NMR time scale, binding of this guest. Second, kinetic analysis

was performed to examine the kinetic proﬁle of the

components (see Supporting Information). The reaction

showed ﬁrst-order kinetics in aldehyde and saturation kinetics

in α-diazo ester. Saturation kinetics in α-diazo ester is

consistent with a preequilibrium host−guest complex, while

the ﬁrst-order kinetics in aldehyde suggests that preequilibrium

for iminium ion encapsulation is not relevant to the

functioning catalytic processes. On the basis of these

experiments, we propose that the Aza-Darzens reaction

catalyzed by 1 proceeds via initial encapsulation of the α-

diazo ester within the cavity of 1 (Scheme 7). This initial

binding equilibrium is followed by rate-determining encapsu-

lation of an equivalent of an in situ generated iminium ion,

driven by the anionic charge of 1, to provide intermediate III.

Inside the assembly the α-diazo ester undergoes nucleophilic

addition to the iminium ion, followed by intramolecular

nucleophilic displacement of an equivalent of nitrogen, to yield

the protonated aziridine V. It is then proposed that the

aziridine leaves the host and is deprotonated in the bulk pH 8

solution, regenerating the catalyst.

no major eﬀect on selectivity. As previously observed when

pentanal was used as a coupling partner, size exclusion also

appears to play a role in the aniline component. For example,

the formation of 3-methylaniline-derived trans-aziridine

occurred in 53% yield in 24:1 trans selectivity (4b), while

minimal reactivity was observed in the host-catalyzed reaction

of 3,5-dimethylaniline (4f).

The experiments with 3,5-dimethylaniline (Scheme 4, 4f)

and pentanal (Scheme 3b, 6) are consistent with the

hypothesis that the iminium must be small enough to ﬁt

within the host for the reaction to proceed eﬃciently.

Therefore, the size limitation of the third component, the α-

diazo ester, was examined using a larger tert-butyl ester as the

nucleophilic component of the Aza-Darzens reaction (Scheme

a). This larger α-diazo ester gave only an 11% yield of the

Scheme 5. (a) Eﬀect of Bulky Ester on Aza-Darzens

Reaction and (b) Blocked Host Control (Reported as NMR

Yields)

disubstituted N-phenylaziridine (7); moreover, in the presence

of a stoichiometric amount of tetraethylammonium as an

inhibitor, 7% yield of the aziridine was obtained (Scheme 5b).

Taken together, these observations suggest that for the

reaction to proceed eﬃciently, and with high selectivity for

the trans-aziridine, all three components of this transformation

must ﬁt within the cavity of the supramolecular host.

To further explore the synthetic applications of this

transformation, the formation of trisubstituted aziridines

from substituted α-diazo esters was investigated. The reaction

of α-ethyl substituted α-diazo ester, acetaldehyde, and aniline,

In conclusion, a rare example of a three-component reaction

within a supramolecular host is reported. This Aza-Darzens

reaction within 1 displays divergent reactivity from the

uncatalyzed background reaction, giving the trans isomer of

the disubstituted N-phenylaziridine. The reaction proceeds

with low yield when the host cavity is blocked, and larger

substrates proceed with minimal conversion, providing

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society

Communication

Scheme 7. Proposed Mechanism for Aza-Darzen Reaction

within the Raymond Tetrahedron

DE-AC02-05CH1123). We thank the LBNL Catalysis Facility

supported by DOE Basic Energy Sciences (BES) program for

access to ESI MS. We thank College of Chemistry’s NMR

facility for resources provided and the staﬀ for their assistance.

Instruments in CoC-NMR are supported in part by NIH

S10OD024998.

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ASSOCIATED CONTENT

sı Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/jacs.9b13177.

Assembly. Angew. Chem., Int. Ed. 2014, 53, 13510−13513.

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AUTHOR INFORMATION

Corresponding Authors

■

12) Ward, M. D.; Hunter, C. A.; Williams, N. H. Coordination

Robert G. Bergman − University of California,

California, ; Email: rbergman@berkeley.edu

Kenneth N. Raymond − University of California,

California, ; orcid.org/0000-0001-6968-9801 ;

Email: raymond@socrates.berkeley.edu

F. Dean Toste − University of California, California, ;

orcid.org/0000-0001-8018-2198 ; Email: fdtoste@

berkeley.edu

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