Ring Expansion of Donor-Acceptor Cyclopropane via Substituent Controlled Selective N-Transfer of Oxaziridine: Synthetic and Mechanistic Insights

Article abstract of DOI:10.1021/acs.orglett.6b02417

A distinctive N-substituent controlled electrophilic N-transfer of oxaziridines with donor-acceptor cyclopropanes in the presence of MgI₂ is reported. Contrary to earlier reports, the oxaziridine having bulkier N-substituents can also give N-transferred product instead of the O-transferred one. Interestingly, the oxaziridines having α-H containing N-substituents lead to the pyrrolidine derivatives through [3 + 2] cycloaddition. A mechanistic reasoning for this divergent reactivity is depicted by density functional theory calculations and validated through energy decomposition analysis.

Full text of DOI:10.1021/acs.orglett.6b02417

Letter
pubs.acs.org/OrgLett
Ring Expansion of Donor−Acceptor Cyclopropane via Substituent
Controlled Selective N‑Transfer of Oxaziridine: Synthetic and
Mechanistic Insights
Asit Ghosh,† Subhajit Mandal,‡ Pratim Kumar Chattaraj,*,‡ and Prabal Banerjee*,†
†Department of Chemistry, Indian Institute of Technology Ropar, Nangal Road, Rupnagar, Punjab 140001, India
‡Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal 721302, India
S
* Supporting Information
ABSTRACT: A distinctive N-substituent controlled electrophilic N-transfer of
oxaziridines with donor−acceptor cyclopropanes in the presence of MgI2 is
reported. Contrary to earlier reports, the oxaziridine having bulkier N-
substituents can also give N-transferred product instead of the O-transferred
one. Interestingly, the oxaziridines having α-H containing N-substituents lead
to the pyrrolidine derivatives through [3 + 2] cycloaddition. A mechanistic reasoning for this divergent reactivity is depicted by
density functional theory calculations and validated through energy decomposition analysis.
xaziridines, the members of the subcategory composed of
oxygen−nitrogen heterocycles, were first synthesized by
interested in further exploring the role of N-substituent over
oxaziridine reactivity. We paid particular attention to establish-
ing the N-transfer ability of oxaziridines to the carbon
nucleophile, which can give direct access to different valuable
acyclic or cyclic N-containing molecular entities. Our work
imparts a novel N-transfer reactivity of oxaziridine to donor−
acceptor cyclopropane11,12 (DAC) for the synthesis of azetidine
derivatives. MgI2 catalyzes this transformation with good yield
(Scheme 1B). Contrary to earlier investigations, we established
the fact that bulky substituents on nitrogen of oxaziridine, such
as N-sulfonyl and N-tert-butyl, can also be transferred to give N-
transferred adduct. Interestingly, the oxaziridines having α-
hydrogen containing an N-substituent like N-methyl, N-
isopropyl, etc. led to [3 + 2] cycloaddition instead of N-
transfer under same reaction conditions (Scheme 1B). A
mechanistic study for this divergent reactivity is portrayed by
density functional theory calculations and validated through
energy decomposition analysis.
The present investigation was initiated to establish the N-
transfer process using oxaziridines to DACs (Table 1). We first
examined the reaction without employing any catalyst at reflux
condition in DCE but observed that both the reactants
remained unreacted after a long reaction time (Table 1, entry
1). In the methodologies developed in our group to date
concerning the utility of DACs,13 MgI2 played the role of active
catalyst. With that hope, we took MgI2 as a catalyst for the said
transformation. Gratifyingly, we got the desired aminated
product with 46% yield using 10 mol % of MgI2 (Table 1, entry
2). To improve the product yield, we further optimized the
other reaction parameters like the amount of catalyst and
solvent (Table 1, entries 3−5, and for solvent variation see the
Supporting Information, Table 1). We observed that 20 mol %
O
Emmons in 1957.1 The presence of two electronegative atoms
at adjacent positions in a three-membered strained ring makes
its reactivity quite fascinating. In addition, oxaziridines are easy
to prepare and have unusual physical properties.2 As a result,
the chemistry of oxaziridines has been largely exploited over the
past few decades. Various distinctive reactivities of oxaziridines,
like transition-metal-promoted rearrangements,1,3 cycloaddi-
tions,4 oxyaminations,5 etc., are well established where
oxaziridine acts as an O-transfer agent. However, their roles
as N-transfer agents are yet to be established. In this context,
the initial work by Collet and co-workers indicated the ability of
the N-alkoxycarbonyl-oxaziridines to deliver the N-alkoxycar-
bonyl fragment to various nucleophiles.6 Nevertheless, the
competitive oxidation and aldol reaction hampered the
amination process, resulting in low yield of the aminated
product (Scheme 1A). It is necessary to mention here that the
substituents on the nitrogen atom of oxaziridines play a
significant role in atom transfer reactions.7−10 Perceiving the
diversity of oxaziridine reactivity developed to date, we are
Scheme 1. Reactivity of Oxaziridine toward N-Transfer
Received: August 12, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02417
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Letter
a
Table 1. Optimization of Reaction Conditions for
Electrophilic N-Transfer
Scheme 2. Scope of N-Transfer
a
b
c
entry
Lewis acid
LA (mol %) temp (°C) solvent
yield (%)
d
1
80
30
30
30
30
30
30
30
30
30
30
30
30
30
DCE
nr
2
MgI2
10
20
40
100
20
20
20
20
20
20
20
20
20
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
46
75
75
3
MgI2
4
MgI2
e
5
MgI2
cm
d
6
Mg(OTf)2
MgBr2
Sc(OTf)3
InCl3
nr
7
8
d
8
nr
d
9
nr
d
10
11
12
13
14
Yb(OTf)3
CuCl2
TiCl4
nr
d
nr
a
e
Unless otherwise specified, all reactions were carried out in DCM at
30 °C with 1 equiv of 1 and 1.5 equiv of 2 in the presence of MgI2 (20
cm
d
FeCl2
nr
b
d
mol %) and molecular sieves (4 Å). Reaction was carried out at 40 °C
ZnI2
nr
in DCM while the other conditions remained the same.
a
Reactions were carried out with 1 equiv of 1a and 1.5 equiv of 2a in
b
the presence of molecular sieves (4 Å). DCM = dichloromethane.
DCE = dichloroethane. Isolated yield. nr = no reaction. cm =
complex mixture.
DACs and in situ generated imine instead of giving N-
transferred adduct (Scheme 3; for details see the Supporting
c
d
e
a
Scheme 3. Scope of [3 + 2] Cycloaddition
of MgI2 gave the best yield in DCM (Table 1, entry 3). Excess
oxaziridine (1.5 equiv) was used in every case as oxaziridine
itself rearranges to produce the corresponding aldehyde and
imine in the presence of Lewis acid. Among the other
magnesium containing Lewis acids, MgBr2 gave the aminated
product in trace amount (Table 1, entry 7). When we used
TiCl4, both the substrates readily decomposed to give a
complex mixture (Table 1, entry 12). Other commercially
available Lewis acids, like Sc(OTf)3, InCl3, Yb(OTf)3, CuCl2,
FeCl2, and ZnI2, failed to catalyze the transformation (Table 1,
entries 8−11 and 13−14).
Employing the optimized reaction conditions, (Table 1, entry
3) the scope of this transformation was assessed with various
DACs and oxaziridines (Scheme 2). To our delight, DACs
bearing electron donating substituents gave the best yield of the
aminated compound (Scheme 2, 3a−3d and 3f). As we moved
to a relatively less activated one, like p-tolyl-substituted DAC, it
required high temperature and longer time to give the product
(Scheme 2, 3e). However, phenyl-substituted DAC remained
unreacted at the same reaction conditions (like 3e) after 8 h. A
range of ester-substituted DACs worked smoothly affording the
desired aminated products in good yield (Scheme 2, 3h−3k).
The DAC bearing heteroatom containing donor substituents,
like N-phthalimide-substituted DAC, also gave the N-trans-
ferred adduct (Scheme 2, 3g). To examine the feasibility and
control over the said transformation due to changes in N-
substituents of oxaziridines, we carried out the amination
reaction with different N-sulfonyl and N-alkyl oxaziridines. As
expected we obtained the aminated adduct with N-
benzenesulfonyl-, N-(4-chlorophenyl)sulfonyl-, and N-tert-
butyl-substituted oxaziridines in good yield (Scheme 2, 3l−
3n). In all the cases selectively N-transferred adduct was
formed, O-transferred adduct was not observed.
a
Reactions were carried out with 1 equiv of 1 and 2 in the presence of
b
MgI2 (20 mol %) and molecular sieves (4 Å). dm = diastereomeric
mixture.
Information). The structure of 3b and 4b was confirmed
unambiguously using single crystal X-ray analysis (Scheme 2
and Scheme 3 respectively; also see the Supporting
Information).14
A plausible mechanism is proposed to describe the
electrophilic N-transfer (Figure 1a) and verified through
density functional theory based calculations at the wB97XD/
def2-SVP level.15 In the presence of MgI2, DAC (A1)
undergoes nucleophilic ring opening to give the reactive open
chain intermediate A3 (see Figure S1). A3 can act as a
nucleophile to attack the N-atom of the activated oxaziridine
OB2 (oxaziridine (B1) activated by MgI2) leading to the
formation of intermediate OC2. The intermediate OC2 under-
goes structural rearrangements (via TS-OC2−3, C3, TS-OC3−4
)
O
and finally follows SN2 ring closure to give the N-transferred
adduct. Two successive SN2 pathways are followed during the
whole process; the first one is SN2 ring opening of DAC, and
the second one is SN2 ring closure. This was experimentally
Excitingly, the other N-alkyl-substituted oxaziridines with α-
hydrogen like N-methyl, N-isopropyl, etc. produced pyrrolidine
derivatives (4a−4f) by [3 + 2] cycloaddition reactions between
B
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Figure 1. (a) Plausible mechanism of electrophilic N-transfer. (b) Reaction profile for the competing N-transfer and O-transfer pathways.
proved when the said transformation was performed with
enantiomerically pure (S)-DAC where (S)-enantiomer of the
azetidine derivative was obtained in excess (see the Supporting
Information).
scan suggests the initial removal of iodine and regeneration of
MgI2, followed by formation of the 4-membered rings and
removal of the side products which supports the third
possibility. In OC2 the natural charge on the C1 atom is
As a catalyst, MgI2 can coordinate with oxaziridine (B1)
through either N-atom (NB2) or O-atom (OB2) (see Figure S2),
but not with the electropositive C1 atom (N1, −0.41; O1,
−0.41; C1, 0.29 |e|). During the reaction, A3 and B2 will
generate dispersion complexes, viz., OC1 (complex of A3 and
OB2) and NC1 (complex of A3 and NB2) (see Figure 1b).
−0.29 |e|, which changes to −0.02 |e| in TS (TS-OC2−3
)
corresponding to the iodine removal and gradually becomes
positive (0.08 |e|) in the corresponding intermediate, OC3. This
step has a small activation barrier (Δ⧧G2−3 = 3.84 kcal/mol),
and the reaction energy is slightly exergonic (ΔrG2−3 = −0.38
kcal/mol). Like the O-coordinated system, in the N-
coordinated system also the C1 atom gradually becomes
positively charged (−0.37 in NC2 to 0.02 in TS-NC2−3 to 0.06 |e|
in NC3). Interestingly, this step has a high activation barrier
(Δ⧧G2−3 = 31.76 kcal/mol) and the reaction energy is highly
endergonic (ΔrG2−3 = 29.63 kcal/mol). The huge difference
between the two activation barriers for the iodine removal step
eventually makes this step as the determining step to selectively
produce N-transfer product rather than O-transfer product.
Energy decomposition analysis (EDA) shows that in TS-C2−3
and C3 the interaction between MgI2 and the remaining unit is
mostly guided by electrostatic interaction (ΔEelstat), whereas for
C2 structures ΔEorb is the major contributor toward the total
interaction energy (ΔEint) (see Table 10 in the Supporting
Information). The change in dissociation energy (ΔDe) is small
N
Between two dispersion complexes, C1 is slightly more stable
O
O
than C1, which indicates the more reactive nature of C1. It
may be noted that the OC1 and NC1 will eventually result in the
N-transfer and O-transfer products, respectively. The C3 atom
is nucleophilic (−0.39 |e|) in both OC1 and NC1. For OC1, in the
following step a nucleophilic attack of C3 occurs to the N-atom
of oxaziridine, which results in the breaking of the N−O bond
and the formation of a new C−N bond. The C−N bond
distance changes from 3.184 Å (in OC1) to 2.553 Å in the
transition state (TS) (TS-OC1−2, Δ⧧G1−2 = 9.66 kcal/mol) and
becomes 1.447 Å in the corresponding intermediate (OC2). On
the other hand, for NC1 the C3 attacks the O-atom and forms a
new C−O bond and breaks the N−O bond in NC2 through
TS-NC1−2 (Δ⧧G1−2 = 10.56 kcal/mol).
O
(−4.42 kcal/mol) for the C2 → TS-OC2−3 step, while for the
The subsequent step has three possible pathways. The first
one is a highly concerted mechanism where removal of iodine
and side products (benzaldehyde and benzylidenimine) and the
formation of 4-membered ring take place simultaneously. The
second possibility includes the initial removal of side products
followed by a 4-membered ring formation through iodine
removal. Our attempts to locate the TS for prior removal of
side product remain unsuccessful as the energy of the fragments
increases monotonically in the relaxed surface scan. The third
possibility may allow shifting of the iodine atom from C1 to
reunite with MgI, leaving a positive charge on the C1 atom and
thereby facilitating the nucleophilic attack of N1 atom (in OC2)
NC2 → TS-NC2−3 process ΔDe is large (−24.81 kcal/mol). It
indicates that a large amount of energy is required to generate
N
N
N
the TS-C2−3 from C2, and therefore C2 → TS-NC2−3 is a
high energetic pathway compared to the C2 → TS-OC2−3
.
O
In the next step another nucleophilic attack can occur from
the N1 (or O1) atom to the C1 atom to produce the N-transfer
(or O-transfer) product. In OC3, C−N bond breaking occurs to
remove benzaldehyde (through TS-OC3−4, Δ⧧G3−4 = 14.78
kcal/mol), and thereafter a concomitant nucleophilic attack
occurs from N1 (−0.78 |e|) to C1, which produces the 4-
membered N-transfer product (OC4). The transition mode
indicates the removal of benzaldehyde only and discards the
N
or the O1 atom (in C2) to the C1 atom. The relaxed surface
C
DOI: 10.1021/acs.orglett.6b02417
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possibility of any concerted pathway where nucleophilic attack
and removal of the side product can occur simultaneously. For
NC3 the benzylideneimine removal occurs through TS-NC3−4
and O-transfer product (NC4) gets formed.
To check the potentiality of the azetidine dicarboxylate
molecule for further synthetic application, we performed the
decarboxylation reaction. Following a two-step process in the
presence of KOH, ethanol, and HCl, 3a can be easily converted
to 5a (cis-isomer as major) in 68% isolated yield (Scheme 4).16
The monodecarboxylated 5a contains the structural scaffold of
bioactive molecules like azetidine carboxylic acid and mugenic
acid.
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dual reactivity of oxaziridine toward DAC. The scope of
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first example with DAC that gives easy access to the biologically
important azetidine molecule. The overall reaction profile
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rate- as well as the product-selectivity-determining step and is
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ASSOCIATED CONTENT
■
S
* Supporting Information
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(14) (a) CCDC 1408435 contains supplementary crystallographic
data for the compound 3b. (b) CCDC 1451620 contains
supplementary crystallographic data for the compound 4b.
(15) Please see the Supporting Information for the computational
details.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02417.
1H, 13C NMR, and IR spectra, mass data of all new
compounds, single-crystal X-ray data, and DFT and EDA
calculations (PDF)
Crystallographic data for 3b (CIF)
Crystallographic data for 4b (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: pkc@chem.iitkgp.ernet.in
*E-mail: prabal@iitrpr.ac.in
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors wish to acknowledge financial assistance from
Department of Science and Technology, New Delhi (Project
No. EMR/2015/002332). A.G. and S.M. thank IIT Ropar and
UGC, New Delhi, respectively, for their research fellowships.
P.K.C. thanks DST, New Delhi, for the J. C. Bose National
Fellowship. The authors also acknowledge Dr. C. M. Nagaraja,
Department of Chemistry, IIT Ropar, for solving the single
crystal structure presented in this work.
(16) Fritz, S. P.; Moya, J. F.; Unthank, M. G.; McGarrigle, E. M.;
Aggarwal, V. K. Synthesis 2012, 44, 1584.
D
DOI: 10.1021/acs.orglett.6b02417
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