Stereospecific Alkene Aziridination Using a Bifunctional Amino-Reagent: An Aza-Prilezhaev Reaction

Article abstract of DOI:10.1021/jacs.8b10485

In situ deprotection (TFA) of O-Ts activated N-Boc hydroxylamines triggers intramolecular aziridination of N-tethered alkenes to provide complex N-heterocyclic ring systems. Synthetic and computational studies corroborate a diastereospecific aza-Prilezhaev-type mechanism. The feasibility of related intermolecular alkene aziridinations is also demonstrated.

Full text of DOI:10.1021/jacs.8b10485

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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Stereospecific Alkene Aziridination Using a Bifunctional Amino-
Reagent: An Aza-Prilezhaev Reaction
Joshua J. Farndon, Tom A. Young, and John F. Bower*
School of Chemistry, University of Bristol, Bristol BS8 1TS, United Kingdom
S
* Supporting Information
electron withdrawing groups on nitrogen. The absence of
ABSTRACT: In situ deprotection (TFA) of O-Ts
activated N-Boc hydroxylamines triggers intramolecular
aziridination of N-tethered alkenes to provide complex N-
heterocyclic ring systems. Synthetic and computational
studies corroborate a diastereospecific aza-Prilezhaev-type
mechanism. The feasibility of related intermolecular
alkene aziridinations is also demonstrated.
reagents that can promote simple metal-free Prilezhaev-like
aziridinations is surprising. Existing metal-free aziridinations of
nonpolarized alkenes either require strong external oxidants
and/or are not stereospecific and/or offer limited flexibility
with respect to the nitrogen substituent.6 Consequently, the
provision of a simple and stereospecific alkene aziridination
protocol that provides N-alkylated products is a challenging
and worthwhile objective.
Recently, we reported that in situ deprotection of O-Ts
activated N-Boc hydroxylamines 3 generates a potent electro-
philic aminating agent (4) that can be harnessed for C−N
bond forming dearomatizations or C−H aminations of
pendant arenes (Scheme 1B).8a,9 Key features of these
processes include (a) their operational simplicity and (b)
direct access to the substrates via Mitsunobu alkylation of
commercially available bifunctional amino-reagent 2.10 The
free base of intermediate 4 (4′) has an obvious structural
analogy to m-CPBA, and this led us to question whether
Prilezhaev-like alkene aziridinations might be feasible. In these
processes, N-alkylation of reagent 2 would precede alkene
aziridination, with the two-step sequence using 2 as a synthetic
linchpin equivalent to an “N-+-” synthon. Outlined below is
the successful realization of this idea, which provides unique
examples of aza-Prilezhaev reactions. Our results offer a
counterpoint to established metal-catalyzed alkene aziridina-
tions and provide a framework for the development of a
general metal-free protocol.
poxidations of nonpolarized alkenes are commonly
E
achieved by their exposure to peracids, usually m-CPBA
(Scheme 1A).1 This process, reported in 1909 by Prilezhaev
Scheme 1. Introduction
Our studies commenced by examining the intramolecular
aziridination of system 5a (R1 = Ph), which contains a trans-
configured styrene (Table 1A); this was easily accessed by
Mitsunobu alkylation of 2 (93% yield; see the SI). Remarkably,
exposure of a TFE solution of 5a to TFA (200 mol %) resulted
in efficient aziridination to provide 6a in 76% yield and as a
single diastereomer. More common alcohols (e.g., EtOH) were
not effective solvents, whereas appreciable quantities of 6a
were observed using CH2Cl2 (40%) or PhMe (32%) (see the
SI). When the corresponding system containing a cis-styrene
(5b, R3 = Ph) was subjected to the TFE/TFA conditions,
aziridine 6b, the diastereomer of 6a, was generated as the sole
product in 78% yield. Thus, the process is diastereospecific
with respect to olefin geometry. Further studies sought to
evaluate scope with respect to the alkene. Electron deficient
variants do not participate, as evidenced by attempted
aziridination of acrylate system 5c, which did not provide
(Prileschajew), has become a cornerstone reaction of organic
chemistry because it is operationally simple and diastereospe-
cific.2 This latter facet is attributed to a mechanism wherein
simultaneous formation of both new C−O bonds occurs via
butterfly like transition state 1.3 By contrast, analogous
stereospecific alkene aziridinations are virtually unknown;
instead, this transformation is typically achieved under
mechanistically distinct metal-catalyzed conditions, often
involving nitrenoids.4−7 Although there are exceptions,5e
such methods can only usually generate aziridines with
Received: September 28, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.8b10485
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Journal of the American Chemical Society
Communication
formation of 6f and 6g. For substrates containing very electron
rich styrenes, reaction efficiency is compromised by the
instability of the aziridine product under the reaction
conditions (vide infra); this accounts for the diminished
yield in the conversion of 5k to 6k. Classically, bicyclic
aziridines related to those described in Table 1 have been
accessed by Pb(OAc)2-mediated cyclization of primary amines
onto alkenes;11 the present method offers much wider scope
and has the obvious benefit of circumventing the requirement
for stoichiometric quantities of a toxic Pb-based reagent.
A notable feature of the new aziridination protocol is its
ability to construct highly substituted aziridines (Table 1B).
Cyclizations involving trisubstituted alkenes proceeded
smoothly to provide targets 6o−t and 6v−x with minimal
variation in efficiency. The reaction conditions are sufficiently
mild that O-TBS protected phenols remain intact (e.g., 5v to
6v) and acid promoted isomerization of skipped dienes (5r to
6r) was not observed. Tetrasubstituted alkenes are also
effective reaction partners as evidenced by the formation of
6u, which occurred in 90% yield. The ability to form highly
congested C−N bonds suggests that the method will be of high
value in target directed settings, especially alkaloid synthesis.
Although the intramolecular aziridination process is most
effective for 5-ring cyclizations, we have also found that 6-ring
processes occur with synthetically useful levels of efficiency
(Table 2). Cyclization of styrene-based system 7a was
Table 1. Aziridinations of Di-, Tri- and Tetrasubstituted
Alkenes
Table 2. Aziridinations to Give Azabicyclo[4.1.0]heptanes
relatively demanding, and 8a was isolated in 44% yield.
Conversely, aziridination to generate benzofused system 8b
was more efficient, occurring in 60% yield. As with 5-ring
cyclizations, nonstyrenyl alkenes also participate; for example,
aziridinations involving acyclic trisubstituted olefins provided
8c, 8d and 8f in modest to good yields. Intramolecular
aziridination of a cyclic alkene (7e) provided highly complex
tricyclic system 8e in 51% yield.
As noted earlier, aziridine 6k was unstable to the reaction
conditions with competitive formation of 1,2-aminoetherifica-
tion product 9k (15:1 d.r.) observed in 20% yield (Scheme
2A). When 6k was resubjected to the aziridination conditions
9k was formed as the sole identifiable product. These
observations are consistent with the electron rich naphthyl
unit of 6k facilitating acid promoted ionization of the aziridine
a
b
c
Isolated as the TsOH salt. 72 h. The free alcohol of 5l/m (R = H)
did not undergo efficient aziridination.
detectable quantities of target 6c. However, other classes of
electron rich alkene are suitable, such that 1,2-dialkylated
system 5d provided 6d in 55% yield. Extension to a range of
styrenes and 1,2- or 1,1-disubstituted alkenes provided
products 6e−n in an efficient manner; the structure of 6i
was confirmed by single crystal X-ray diffraction. Protected
alcohols are tolerated, providing the protecting group is
relatively stable to acid (cf. 6l vs 6m). Systems containing
additional substitution at either C1 or C3 undergo highly
diastereoselective cyclization, as highlighted by the efficient
B
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optimized aziridination conditions, inclusion of trimethox-
ybenzene as an exogenous nucleophile enabled the direct
conversion of alkene 5a to 1,2-aminoarylation product 12 in
50% yield and 20:1 d.r.14 1,2-Aminoazidation product 13 was
accessed by exposing aziridine 6a to TMSN3 under acidic
conditions; in this case, direct conversion of 5a (the alkene
precursor to 6a) to 13 was less efficient.15 Formal alkene
hydroaminations can be achieved by hydrogenative C−N
reduction of benzylic aziridines; for example, 6t was converted
to 14 in 98% yield. Ring expansions to piperidines are facile as
evidenced by the efficient conversion of 6n to 15a−c.16 The
relative stereochemistries of 9y, 11 and 12 were determined by
single crystal X-ray diffraction of crystalline derivatives.
Stereochemical assignments of 9k and 9z are made by analogy,
and the assignment of 13 is based on comparison to reported
NMR data.
Scheme 2. Aziridination-Triggered Aminofunctionalizations
The diastereospecificity of the processes described here (cf.
6a and 6b) suggests that, following Boc-deprotection (TFA),
alkene aziridination proceeds in a concerted manner, where
both new C−N bonds form simultaneously. Mechanistically,
this could be rationalized either by the formation and capture
of a nitrenium ion or by an aza-Prilezhaev-type mechanism. To
our knowledge, efficient alkene aziridinations using nitrenium
ions without stabilizing groups are unknown.17 Indeed,
computational studies on the conversion of 5a′ (the Boc-
deprotected version of 5a) to 6a indicate that formation of a
solvent-stabilized nitrenium ion has a large energy barrier
(TS2, ΔG‡ = 49.6 kcal mol−1) (Figure 1). On the other hand,
a
An X-ray structure of a derivative was obtained (see the SI).
to provide a benzylic carbocation, which is captured by TFE in
a diastereocontrolled SN1 reaction.12 For substrates 5y and 5z,
which bear highly stabilizing para-methoxyphenyl or 2-thienyl
substituents, aziridine products 6y and 6z were not observed
and competing alkene 1,2-aminoetherification products formed
exclusively. Attempts to suppress ring opening of the initially
formed aziridine by varying the reaction solvent or acid were
unsuccessful; in part, this reflects the observation that TFE/
TFA is easily the most effective combination found so far for
the aziridination process. However, by switching to less
nucleophilic HFIP as solvent, we were able to use BnOH as
an external nucleophile and this provided 1,2-aminoether-
ification product 11 in 42% yield (14:1 d.r.) directly from
alkene 10.13 On this basis, we examined whether the
aziridination-ionization sequence could be adapted to other
classes of alkene 1,2-difunctionalization (Scheme 2B). Under
Figure 1. Reaction profiles for the generation of a nitrenium ion
(gray) and aziridination of 5a′ via an aza-Prilezhaev mechanism
(black). Solvated Gibbs free energies are quoted at PBE0/6-311+
+G(2d,p)//PBE0-D3BJ/6-31+G(d), SMD(TFE). Free energy con-
tributions have been calculated at 298 K. See the SI for details.
the transition state for an aza-Prilezhaev pathway (TS1) is
accessible (ΔG‡ = 22.0 kcal mol−1) and strongly resembles the
spiro “butterfly” transition state involved in m-CPBA-mediated
alkene epoxidations (see the SI for details).3,18,19 Thus, in line
with our initial reaction design, we favor an aza-Prilezhaev
pathway for the processes described here.
Although our focus so far has been on the development of
intramolecular aziridinations, we have also validated the
C
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Journal of the American Chemical Society
Communication
method in intermolecular settings (Scheme 3). Exposure of cis-
β-methylstyrene to reagent 16 (120 mol %) in the presence of
AUTHOR INFORMATION
Corresponding Author
*john.bower@bris.ac.uk
ORCID
■
Scheme 3. Preliminary Intermolecular Aziridination Results
John F. Bower: 0000-0002-7551-8221
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Bristol Chemical Synthesis CDT, funded by
EPSRC (EP/G036764/1) for a studentship (J.F.), the Royal
Society for a URF (J.F.B.) and the European Research Council
for financial support via the EU’s Horizon 2020 Programme
(ERC grant 639594 CatHet). We thank Dr. Xiaofeng Ma
(Bristol) for substrate synthesis and Dr. Natalie Fey (Bristol)
for advice on computations. We thank the School of Chemistry
X-ray Crystallographic Service for product analysis. The Centre
for Computational Chemistry is thanked for computational
resources.
TFA delivered cis-configured aziridine 17a as the sole
diastereomer in 42% yield. Similarly, aziridination of trans-β-
methylstyrene provided trans-configured aziridine 17b in 32%
yield. The diastereospecificity of these reactions mirrors
observations made earlier, which suggests that an analogous
reaction pathway is operative. Notably, the OTs analogue of 16
was not effective for the formation of 17a and 17b.20
Accordingly, modification of the electrophilic nitrogen source
can improve reaction efficiency and this provides an avenue for
the development of a more general intermolecular protocol;
studies toward this objective are ongoing. Notably, N-Me
aziridines have previously been prepared by metal-catalyzed
nitrenoid transfer from reagents that bear a close similarity to
the Boc-deprotected form of 16;5e the results in Scheme 3
highlight the feasibility of a complementary metal-free
alternative.
In summary, we show that activated hydroxylamines engage
alkenes in a process that resembles an aza-variant of the m-
CPBA promoted Prilezhaev reaction, a process reported over
one hundred years ago. The substrates are easily accessed by
Mitsunobu alkylation of commercially available “linchpin”
reagent 2.21 Intramolecular versions of the aziridination
process provide direct access to structurally intriguing N-
heterocyclic ring systems. These can be modified further in a
distinct step, or harnessed in tandem one-pot processes, as the
basis of an approach to alkene 1,2-amino-functionalization.
Preliminary studies demonstrate the feasibility of related
intermolecular aziridinations. Our studies provide unique
examples of transition metal-free stereospecific alkene
aziridinations that provide N-alkylated products. Efforts to
broaden the utility of the process are underway and will be
reported in due course.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b10485.
■
S
Experimental details, characterization data, crystallo-
graphic data and computational details including
method evaluation and consideration of alternative
reaction pathways (PDF)
Data for C11H12ClN (CIF)
Data for C20H21F3N2O6S, C4H10O (CIF)
Data for C26H27N3O7S (CIF)
Data for C26H28N2O7S (CIF)
Data for C15H20ClNO2 (CIF)
́
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(19) Further computational studies are presented in the SI. These
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homolysis to generate an N-centered radical. The stereospecific
nature of the aziridination process is also not consistent with a radical
mechanism.
(20) At the present stage of development, more highly substituted
styrenes and nonconjugated alkenes do not participate in
intermolecular aziridination.
(21) DSC analyses of compounds 2, 16 and OTs-16 are given in the
SI. Compounds related to 2 have been used on scale: Mendiola, J.;
́
Rincon, J. A.; Mateos, C.; Soriano, J. F.; de Frutos, O.; Niemeier, J. K.;
Davis, E. M. Org. Process Res. Dev. 2009, 13, 263.
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