Intramolecular cycloaddition of azomethine ylides, from imines of O-acylsalicylic aldehyde and ethyl diazoacetate, to ester carbonyl - Experimental and DFT computational study

Article abstract of DOI:10.1039/c2ob25676b

Intramolecular 1,3-dipolar cycloaddition of alkoxycarbonyl-substituted azomethine ylides to ester carbonyl was realized for the first time in the reaction of imines of O-acylsalicylic aldehyde with ethyl diazoacetate in the presence of Cu(tfacac)₂

Full text of DOI:10.1039/c2ob25676b

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PAPER
Intramolecular cycloaddition of azomethine ylides, from imines of
O-acylsalicylic aldehyde and ethyl diazoacetate, to ester
carbonyl – experimental and DFT computational study†
Anastasia P. Kadina,a Alexander F. Khlebnikov,*a Mikhail S. Novikov,a Pedro J. Pérezb and Dmitry S. Yufitc
Received 5th April 2012, Accepted 1st June 2012
DOI: 10.1039/c2ob25676b
Intramolecular 1,3-dipolar cycloaddition of alkoxycarbonyl-substituted azomethine ylides to ester
carbonyl was realized for the first time in the reaction of imines of O-acylsalicylic aldehyde with ethyl
diazoacetate in the presence of Cu(tfacac)2. The stereoselectivity of the cycloaddition is explained using
DFT calculations.
Introduction
1,3-Dipolar cycloaddition of azomethine ylides is an efficient
synthetic tool for the synthesis of nitrogen containing hetero-
cyclic compounds.1,2 The intramolecular version of this reaction
is very effective in the preparation of complex polycyclic mole-
cules.2a,r,t,u,y,3 Earlier we found that azomethine ylides generated
from carbenes/carbenoids and imines of O-alkenyl- or O-alky-
nylsalicylic aldehyde undergo highly regio- and stereoselective
intramolecular 1,3-dipolar cycloaddition to the multiple carbon–
carbon bond to give chromenopyrrole derivatives.4 Azomethine
ylides generated from dihalocarbenes and imines of O-acyl-
salicylic aldehyde undergo the quite rare cycloaddition to ester
carbonyl giving derivatives of 2,5-epoxy-1,4-benzoxazepine
Scheme 1 Reactions of imines of O-acylsalicylic aldehyde with
dihalocarbenes.
(Scheme 1).5
Though the biological activity of this heterocyclic system has
yet to be investigated, derivatives of 2,5-epoxy-1,4-oxazepine-3-
carboxylic acid were found among the products of decompo-
sition of β-lactamase inhibitor clavulanic acid.6 Derivatives of
aDepartment of Chemistry, Saint Petersburg State University,
Universitetskii pr. 26, 198504 St. Petersburg, Russia.
E-mail: alexander.khlebnikov@pobox.spbu.ru; Fax: +7 812 4286939;
Tel: +7 812 4284021
bLaboratorio de Catálisis Homogénea, Departamento de Química y
Ciencias de los Materiales, Unidad Asociada al CSIC, Centro de
Investigación en Química Sostenible (CIQSO), Universidad de Huelva,
Campus de El Carmen s/n, 21007 Huelva, Spain.
E-mail: perez@dqcm.uhu.es; Fax: +34 959219942;
Scheme 2 Retrosynthetic approach to derivatives of 2,5-epoxy-1,4-
benzoxazepine.
Tel: +34 959 219956
cDepartment of Chemistry, University of Durham, Durham, South Road,
DH1 3L, UK.
E-mail: d.s.yufit@durham.ac.uk; Fax: +44 191-334-2051;
Tel: +44 191-334-2004
†Electronic supplementary information (ESI) available: X-Ray diffrac-
tion data, refinement information and Cartesian coordinates. CCDC
874425 for exo-2a. For ESI and crystallographic data in CIF or other
2,5-epoxy-1,4-benzoxazepine-3-carboxylic acid could be pre-
pared via the intramolecular cycloaddition to the CvO bond of
the azomethine ylide, which was generated by reaction of imines
of O-acylsalicylic aldehyde with metallocarbenoids from
electronic format see DOI: 10.1039/c2ob25676b
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Scheme 3 Reaction of imines of O-acylsalicylic aldehyde with ethyl diazoacetate.
diazocarbonyl compounds (Scheme 2). In this paper we present
the results of the investigation of this reaction using ethyl diazo-
acetate (EDA) as the source of the carbenoid.
Results and discussion
Rh- and Cu-carbenoids, derived from diazo compounds and
Rh(II)- and Cu-salts or complexes, are mostly used for the gen-
eration of azomethine ylides from imines.1,7,8 Rh- and Cu-cata-
lysts were, therefore, tested in a primary screening of catalysts
for the generation of azomethine ylide from imine 1a and ethyl
diazoacetate (Scheme 3). Some of the tested catalysts decom-
posed ethyl diazoacetate (2 mol% Rh2(OAc)4, 10 mol%
Cu-powder) but did not provide ylides 3a, whereas others
(10 mol% Cu(acac)2, CuI, or Fe(acac)3) did not even decompose
the diazo compound. Probably in the latter cases the imine
deactivates the catalyst.
Fig. 1 X-Ray crystal structure of exo-2a.
Table 1 Reaction of imines 1 and ethyl diazoacetate in the presence of
equivalent of Cu(tfacac)2 in CH2Cl2 at 40 °C
Copper(II) trifluoroacetoacetate, Cu(tfacac)2, proved to be the
catalyst of choice. This catalyst decomposes ethyl diazoacetate
with formation of a carbenoid which reacts with imine 1a,
giving ylide 3a, and this in turn adds to the ester carbonyl with
formation of 2,5-epoxy-1,4-benzoxazepine 2a. It was found that
the stereoselectivity of the reaction depends on temperature, thus
in boiling methylene chloride the only product was the endo-
isomer 2a, whereas in boiling benzene both isomers were
formed.
Imine R1
R2
Yield of endo/exo-2, %
1a
1b
1c
1d
1h
1e
1f
4-MeOC6H4
Ph
4-BrC6H4
4-BrC6H4
4-ClC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
41/0
39/0
27/0
40/0
18/0
17/20
29/9
11/9
0/0
4-MeOC6H4
4-MeC6H4
trans-CHvCHPh
4-NCC6H4
4-O2NC6H4
3-O2NC6H4
1g
1i
trans-C(Ph)vCHPh Ph
The former conditions (equivalent of Cu(tfacac)2/CH2Cl2/40 °C)
were employed to carry out the reactions of imines 1a–m with
ethyl diazoacetate. All the newly obtained compounds were fully
characterized using standard spectral and analytical methods.
To distinguish between endo- and exo-2 it is possible to use the
chemical shifts of the methylene protons of the ethoxy group.
In the endo-isomer 2 the chemical shift of the methylene protons
of the ethoxy group is 4.2–4.4 ppm and in the exo-isomer it is
3.6–3.9 ppm. The methylene protons in isomer exo-2 are in the
shielding area of the magnetic field generated by the 2-aryl ring
which is cis-situated relatively to the oxazolidine ring (see
structures endo- and exo-2 (R1 = R2 = Ph) optimized at DFT
B3LYP/6-31G(d) level in the ESI†). A similar shielding of the
methylene protons of the ethoxy group was found in oxazolidine
derivatives with a cis-situated ethoxycarbonyl and aryl groups.9
The relative configuration of compound exo-2a was elucidated
by X-ray analysis (Fig. 1).
1j
1k
1l
4-MeOC6H4
4-MeOC6H4
Ph
4-MeOC6H4 0/0
Ph
Ph
0/0
0/0
1m
4-O2NC6H4
4-MeOC6H4 0/0
isomers 2b–h (Table 1). The absence of the exo-isomers was
proved by an analysis of the 1H NMR spectra of the correspond-
ing reaction mixtures. Imines 1e–g, containing electron with-
drawing substituents in the benzoyl group, unexpectedly yielded
both isomers under the same reaction conditions (Table 1). The
cycloadducts endo-2 can only have originated from the intramo-
lecular cycloaddition of U-ylides 3. The cycloadducts exo-2 are
derived only from the cycloaddition of S-ylides 3 (Scheme 4).10
Several hypotheses can be proposed to explain the experimental
stereoselectivity. The first hypothesis is that the stereoselectivity
of the reaction is determined by the formation from (E)-imine
and carbenoid of only the S- or only U-isomer of ylides 3, or
both, depending on the substituents in compounds 1.
Reaction of imines 1b–h with ethyl diazoacetate in the pre-
sence of Cu(tfacac)2 in CH2Cl2 also gave rise to the endo-
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To check the possibility of formation of both isomeric
ylides under conditions where the only the endo-2 isomer of
intramolecular cycloaddition was detected, we performed the
catalytic reaction of EDA with imine 1d in the presence of
excess fumaronitrile as the external dipolarophile. In this case
along with intramolecular cycloadduct endo-2d (29%) the
sole intermolecular cycloadduct, compound 4, was detected
by 1H NMR, and isolated by chromatography in 9% yield
(Scheme 5).
The stereochemistry of cycloadduct 4 was established by
2D-1H-NOESY (see the ESI†). Cycloaddition of the U- and
S-ylides should lead to pyrrolidines of different configurations.
As one can see from Scheme 5, compound 4 is the product of
cycloaddition of the S-ylide to the CvC bond of fumaronitrile.
Consequently, the product of intramolecular cycloaddition, com-
pound endo-2d, and of intermolecular cycloaddition, compound
4, are derived from ylides of different types. According to DFT
B3LYP/6-31G(d) computations the barriers of intermolecular
cycloaddition of the U-ylide are much higher than the corres-
ponding barriers of the S-ylide and this is in accordance with the
experimental result. We can conclude from this that both iso-
meric ylides are formed in the reactions and that we can reject
the first hypothesis.
boiling CH2Cl2 for 8 h led to decomposition of 33% of the com-
pound to a complex unidentified mixture and conversion of less
than 5% to isomer exo-2a. Isomer exo-2a was shown to be stable
under these conditions. It was also found that isomer endo-2f,
containing an electron withdrawing substituent in the benzoyl
group, did not convert into isomer exo-2f or other products under
the reaction conditions. These results then disprove the second
hypothesis.
A third hypothesis assumes the formation of both the S- and
U-ylides 3 in the reaction of imine 1 with ethyl diazoacetate, but
considers that the barrier of transformation of the S-ylide to an
exo-2, for substrates which do not contain electron withdrawing
substituents in the benzoyl group, is higher than the barrier of
transformation of the S- to the U-ylide 3 and higher than the
barrier for transformation of the U-ylide 3 into the cycloadduct
endo-2.
The computations at the DFT B3LYP/6-31G(d) level of the
model compounds were used to check this third hypothesis. The
sequence of transformations of the ylides 3, generated from the
imines 1 and the carbenoid (from diazoacetic acid for simpli-
city), leading to cycloadducts exo- and endo-2 is shown in
Fig. 2.
Interaction of the lowest energy conformation of (E)-imines 1
with the carbenoid leads to the formation of unfolded confor-
mers of ylides S-3′, S-3′′ and U-3′, U-3′′. These ylides can
adopt the higher energy conformations of S-3 and U-3 via
rotation about single bonds, and these are the immediate precur-
sors of exo- and endo-2, respectively. The free energy profile of
transformations of the model ylides 3l* and 3n* calculated at
DFT B3LYP/6-31G(d) level is shown in Fig. 3.
The second reason for the stereoselectivity found could be
interconversion of isomers of compound 2 under the reaction
conditions. Isomer endo-2a in the presence of Cu(tfacac)2 in
The formation of the ylides S-3 and U-3 from ylides S-3′ and
U-3′ occurs by rotation about single C–O and C–C bonds. Trans-
formation of ylide S-3′ to ylide U-3′ (and back) can occur in two
ways: (i) S-3′ ⇄ S-3′′ ⇄ U-3′; (ii) S-3′ ⇄ U-3′′ ⇄ U-3′.
According to calculations (Fig. 3) the second pathway has a
higher barrier than the first one.
For ylides containing an unsubstituted benzoyl group the free
energy of the transition state for the formation of endo-cyclo-
adduct (TSS-3/exo-2) and the energy of the transition state for the
transformation of ylide S-3′′ into ylide U-3′ (TSS-3′′/U-3′) is
Scheme 4 Structure of ylides leading to stereoisomers of compound 2.
Scheme 5 Reaction of imine 1d with EDA in the presence of fumaronitrile.
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Fig. 2 The sequence of transformations of ylides 3* leading to cycloadducts 2* (See formulas in Fig. 3). The molecules presented correspond to the
stationary points (minima) on the potential energy surface. Hydrogen atoms on aromatic rings are omitted for clarity.
Fig. 3 Energy profiles for transformations of ylides 3*. Relative free energies [kcal mol−1, 298K] computed at the B3LYP/6-31G(d) level.
higher than the energy of the transition state for the formation of
exo-cycloadduct (TSU-3/endo-2). In this case therefore, according
to the calculations, the endo-cycloadduct has to be the main
product. The situation became quite different for compounds
containing electron-withdrawing substituents in the benzoyl
group. Introduction of a cyano group leads to a small increase in
the free energy of the transition state for the interconversion of
the ylides and a relatively big decrease in energy of the transition
state for the transformation of the ylides into cycloadducts
(Fig. 3). This permits an easier transformation of ylide S-3 into
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Table 2 Energy barriers of transformation of ylides S-3 into
cycloadducts exo-2 and ylides U-3 into cycloadducts endo-2 (See
formulas in Fig. 2 and 3). ΔG# [kcal mol−1, 297 K] computed at the
B3LYP/6-31G(d) level
ylide S-3 →
cycloadduct exo-2
ylide U-3 →
cycloadduct endo-2
X
Y
H
CN
H
OH
H
H
H
Cl
H
OH
17.3
15.3
17.1
18.1
17.5
14.3
12.2
13.3
15.3
14.5
Scheme 6 Reaction of imine 1j with EDA in the presence of
fumaronitrile.
the exo-2 cycloadduct, than for the transformation into ylide
U-3, the precursor of the endo-2 cycloadduct.
Introduction of an electron-donating substituent into the
benzoyl fragment leads as expected to an enlarged barrier to
cycloaddition, and it has a small effect on the barrier for the
interconversion of the ylides (Table 2).
Thus the found stereoselectivity of the reaction of the sub-
strates without electron withdrawing substituents on the benzoyl
group is due to the free energy of the transition state for the for-
mation of cycloadduct exo-2 being higher than the energy of the
transition state for the isomerization of the S-ylide 3 to the
U-ylide 3. The latter undergoes transformation into the endo-2
cycloadduct through a relatively low-energy transition state.
Introduction of an electron withdrawing substituent in the p-pos-
ition of the benzoyl group of the starting imine makes the cyclo-
addition of S-ylide 3, leading to cycloadduct exo-2, more
favorable than the S-ylide ⇄ U-ylide interconversion.
The reaction of EDAwith imine 1h containing both CvO and
CvC dipolarophilic fragments yielded only the cycloadduct
endo-2h. The lack of cycloadducts to the CvC bond is probably
explained by a high rigidity of the 4-atomic linker with three sp2
centers, preventing effective overlap of orbitals of the 1,3-dipole
and the CvC bond. Imine 1h demonstrated a similar behavior in
the reaction with difluorocarbene.5a
Unexpectedly, the reaction of EDA with imines 1i–1m, which
do not contain halogen in the N-aryl group, gave no cyclo-
addition to the CvO bond. This is maybe due to (i) the ylide
not being formed in this case, (ii) the intramolecular cyclo-
addition having a higher activation barrier so the ylide undergoes
nonselective decomposition or reacts faster with the external
dipolarophiles, dimethyl maleate and dimethyl fumarate, which
are both practically always formed as byproducts during catalytic
decomposition of ethyl diazoacetate.7 In fact, according to calcu-
lations at the DFT B3LYP/6-31G(d) level, the introduction of a
chlorine atom into the N-phenyl ring diminishes the barrier for
the intramolecular cycloaddition, making this process more com-
petitive and leading to the formation of the endo-2 cycloadduct
(Table 2).
As mentioned above, imines 1i–m, in the catalytic reaction
with EDA, did not give the products of intramolecular cyclo-
addition of their corresponding ylides. To check whether the
ylides 2i–m were still formed under the conditions used, the
reaction of imine 1j was performed in the presence of excess
fumaronitrile as external dipolarophile, and cycloadduct 5 was
isolated as the sole product (Scheme 6).
Scheme 7 Catalysts used in the reaction of 1a with EDA.
from the S-ylide. This result confirms the formation of ylide 3j,
which however does not undergo intramolecular cycloaddition to
the CvO bond. As one can see from Table 2 the electron donat-
ing substituents both on the benzoyl and on the N-phenyl groups
lead to an enlarging of barriers to intramolecular cycloaddition
to the CvO bond making this reaction noncompetitive with
reactions leading to byproducts. In accordance with this assump-
tion the reaction of imine 1f, containing electron withdrawing
substituents, led exclusively to products of intramolecular cyclo-
addition to the CvO bond, even in the presence of excess
fumaronitrile as external dipolarophile.
Choice of catalyst is often the critical point in the reactions of
alkyl diazoacetates with imines.7 Rhodium derivatives which
were most widely used as catalysts in the reaction of alkyl di-
azoacetates with olefinic substrates can be used in reactions with
some simple imines. It usually failed, however, in the reactions
with imines containing functional groups.6 For example,
Rh2(AcO)4 does not work as catalyst in the reaction of salicylic
aldehyde derived imines with EDA.4e
The results obtained show that it is also important that the
catalyst should not promote the formation of carbene dimers,
which can react as external dipolarophiles. It prompted us to
look at catalysts based on Cu complexes with neutral (NHC) or
anionic (Tpx) ligands which are known to decompose EDA in
the presence of olefinic substrates without producing the carbene
dimers.11 Here we investigated their capability of forming of
azomethine ylides from EDA and imines. Reactions of imine 1a
with EDA in CH2Cl2 at r.t. were performed in the presence of
catalysts 6–12 (Scheme 7), but only catalyst 7 gave any corres-
ponding cycloadduct of ylide 3 (compound endo-2a, 23%).
Conclusions
The configuration of cycloadduct 5 was the same as the
configuration of cycloadduct 4, therefore also being derived
The products of the intramolecular 1,3-dipolar cycloaddition of
alkoxycarbonyl-substituted azomethine ylides to ester carbonyl
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2-(4-Bromophenyliminomethyl)phenyl 4-methylbenzoate (1d).
(1.4 g, 75%) was obtained from 2-formylphenyl 4-methylbenzo-
ate (1.13 g, 4.7 mmol) and 4-bromoaniline (0.81 g, 4.7 mmol).
Mp = 133.5–134.5 °C (EtOH). 1H NMR (CDCl3): δ = 2.47 (3H,
s, CH3), 6.95–8.22 (12H, m, HAr), 8.56 (1H, s, CHvN). 13C
NMR (CDCl3): δ = 21.8 (CH3), 119.5, 122.5, 123.1, 126.1,
126.3, 128.2, 128.6, 129.5, 130.3, 132.1, 132.5, 144.9, 150.9,
were obtained for the first time in the reaction of imines of
O-acylsalicylic aldehyde with ethyl diazoacetate in the presence
of Cu(tfacac)2. It was found that the stereoselectivity of the
cycloaddition depends on the substituents on the benzoyl group
of the substrate. Imines with electron withdrawing substituents in
the p- or m-position of the benzoyl group gave a mixture of
endo- and exo-isomers of ethyl 2,5-epoxy-1,4-benzoxazepine-
3-carboxylates, whereas substrates without such substituents
gave the endo-isomers exclusively. According to DFT compu-
tations the change of stereoselectivity of cycloaddition is caused
by a decrease of the barrier to cycloaddition and a small increase
of the barrier to the U- and S-ylide interconversion when an
electron withdrawing substituent is introduced on the benzoyl
group of the reactant.
151.1 (CAr), 155.4 (CHvN), 165.1 (CO2R). IR (CHCl3) νmax
:
1750 (CO2R), 1625 (CHvN) cm−1
.
Anal. calcd for
C21H16BrNO2, %: C, 64.0; H, 4.1; N, 3.55. Found, %: C, 63.9;
H, 4.2; N, 3.7.
2-(4-Bromophenyliminomethyl)phenyl 4-nitrobenzoate (1f).
(3.7 g, 87%) was obtained from 2-formylphenyl 4-nitrobenzoate
(2.8 g, 10 mmol) and 4-bromoaniline (1.72 g, 10 mmol). Mp =
115–117 °C (EtOH). 1H NMR (CDCl3): δ = 6.86–8.42 (12H, m,
HAr), 8.48 (1H, s, CHvN). 13C NMR (CDCl3): δ = 119.7,
122.3, 123.1, 123.8, 126.9, 127.8, 130.5, 131.4, 132.2, 132.5,
134.6, 149.9, 150.6, 150.9 (CAr), 155.6 (CHvN), 163.3
Experimental section
General methods
(CO2R). IR (CHCl3) νmax: 1740 (CO2R), 1620 (CHvN) cm−1
.
Melting points were determined on a hot stage microscope
(Boetius) and are uncorrected. IR spectra were recorded on a
Anal. calcd for C20H13BrN2O4, %: C, 56.5; H, 3.1; N, 6.6.
Found, %: C, 56.5; H, 3.1; N, 6.4.
1
Specord M80 spectrometer. H (300 MHz) and 13C (75 MHz)
NMR spectra were determined in CDCl3 or DMSO-d6 with a
Bruker DPX 300 spectrometer. Chemical shifts (δ) are reported
in ppm downfield from tetramethylsilane. Elemental analysis
was performed on a Hewlett-Packard 185B CHN-analyser. The
single crystal X-ray data were collected at 120(1)K on a Bruker
SMART CCD 6000 diffractometer equipped with a Cryostream
(Oxford Cryosystems) cryostat using graphite monochromated
MoKα radiation (λ = 0.71073 Å). The structure was solved by
direct method and refined by full-matrix least squares on F2 for
all data using OLEX2 software. All non-hydrogen atoms
were refined with anisotropic displacement parameters, H-atoms
were located on the difference map and refined isotropically.
Flash chromatography was performed using Merck silica
(0.040–0.063 mm). TLC analysis was performed on glass
backed plates (Merck) coated with 0.2 mm silica layer with
UV-indicator 60F254.
2-(4-Bromophenyliminomethyl)phenyl 3-nitrobenzoate (1g)
(a) 2-Formylphenyl 3-nitrobenzoate. (14.1 g, 87%) was
obtained from salicylic aldehyde (7.3 g, 0.06 mol), K2CO3
(12.4 g, 0.09 mol) and 3-nitrobenzoyl chloride (14.5 g,
1
0.078 mol). Mp = 119–121 °C (EtOH). H NMR (CDCl3): δ =
7.31–9.04 (8H, m, HAr), 10.10 (1H, s, CHO). 13C NMR
(CDCl3): δ = 123.4, 125.3, 127.0, 128.0, 128.2, 139.0, 130.7,
132.4, 135.5, 135.9, 148.4, 150.7 (CAr), 163.0 (CO2R), 188.6
(CHvO). IR (KBr) νmax: 1760 (CO2R), 1700 (CHvO) cm−1
.
Anal. calcd for C14H9NO5, %: C, 62.0; H, 3.3; N, 5.2. Found,
%: C, 61.95; H, 3.1; N, 5.05.
(b) 2-(4-Bromophenyliminomethyl)phenyl 3-nitrobenzoate (1g).
(7.01 g, 82%) was obtained from 2-formylphenyl 3-nitrobenzo-
ate (5.4 g, 20 mmol) and 4-bromoaniline (3.44 g, 20 mmol).
1
Mp = 129–131 °C (EtOH). H NMR (CDCl3): δ = 6.88–8.55
(12H, m, HAr), 9.07 (1H, s, CHvN). 13C NMR (CDCl3): δ =
119.7, 122.3, 123.1, 125.2, 126.9, 127.9, 128.1, 130.0, 130.4,
131.0, 132.2, 132.5, 135.8, 148.4, 150.0, 150.7 (CAr), 155.6
(CHvN), 163.1 (CO2R). IR (CHCl3): νmax: 1760 (CO2R), 1635
(CHvN) cm−1. Anal. calcd for C20H13BrN2O4, %: 56.5; H, 3.1;
N, 6.6. Found, %: C, 56.3; H, 3.1; N, 6.6.
Imines 1
O-Acylsalicylaldehydes were synthesized by acylation of salicyl-
aldehyde with the corresponding acid chlorides in dry DMF in
the presence of anhydrous K2CO3. Imines were prepared by con-
densation of aldehydes with amines in ethanol.12 Imines 1a, b,
e, i–l were described earlier.5
2-(4-Bromophenyliminomethyl)phenyl cinnamate (1h). (1.58 g,
78%) was obtained from 2-formylphenyl cinnamate (1.26 g,
5 mmol) and 4-bromoaniline (0.86 g, 5 mmol). Mp =
1
111–112 °C (EtOH). H NMR (CDCl3): δ = 6.71 (1H, d, J = 16
2-(4-Chlorophenyliminomethyl)phenyl 4-methoxybenzoate (1c).
(1.14 g, 78%) was obtained from 2-formylphenyl 4-methoxy-
benzoate (1.0 g, 4 mmol) and 4-chloroaniline (510 mg,
Hz, CHvCHPh), 7.05–7.64 (12H, m, HAr), 7.95 (1H, d, J = 16
Hz, CHvCHPh), 8.20–8.23 (1H, m, HAr), 8.58 (1H, s, CHvN).
13C NMR (CDCl3): δ = 116.4, 119.5, 122.6, 123.0, 126.3,
128.1, 128.4, 128.5, 129.0, 131.0, 132.2, 132.5, 133.9, 147.5,
150.9, 151.1 (CAr, CHvCHPh, CHvCHPh), 155.5 (CHvN),
165.2 (CO2R). IR (CHCl3) νmax: 1740 (CO2R), 1640 (CHvN),
1590 (CvC) cm−1. Anal. calcd for C22H16BrNO2, %: C, 65.0;
H, 4.0; N, 3.45. Found, %: C, 65.0; H, 3.7; N, 3.5.
1
4 mmol). Mp = 101–102 °C (EtOH). H NMR (CDCl3): δ =
3.90 (3H, s, OCH3), 6.99–8.22 (12H, m, HAr), 8.57 (1H, s,
CHvN). 13C NMR (CDCl3): δ = 55.5 (OCH3), 114.0, 121.1,
122.1, 123.2, 126.3, 128.3, 128.5, 129.2, 131.6, 132.4, 150.5,
151.1, 155.3 (CAr), 164.2 (CHvN), 164.7 (CO2R). IR (CHCl3)
νmax: 1730 (CO2R), 1603 (CHvN) cm−1. Anal. calcd for
C21H16ClNO3, %: C, 68.95; H, 4.4; N, 3.8. Found, %: C, 69.15;
H, 4.5; N, 3.9.
2-(4-Methoxyphenyliminomethyl)phenyl 4-methoxybenzoate (1j).
(1.53 g, 85%) was obtained from 2-formylphenyl 4-
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methoxybenzoate (1.28 g, 5 mmol) and 4-methoxyaniline
(738 mg, 6 mmol). Mp = 74–76 °C (EtOH). H NMR (CDCl3):
exo-2a: Mp = 150–151.5 °C (ether–hexane). 1H NMR
(CDCl3): δ = 0.88 (3H, t, J = 7.2 Hz, CH2CH3), 3.84 (3H, s,
OCH3), 3.60–3.88 (2H, m, CH2CH3), 4.55 (1H, s, C3H), 6.56
(1H, s, C5H), 6.45–6.48 (2H, m, CArH), 6.81–6.97 (4H, m,
CArH), 7.17–7.32 (4H, m, CArH), 7.70–7.73 (2H, m, CArH).
13C NMR (CDCl3): δ = 13.6 (CH2CH3), 55.4 (OCH3), 61.6
(CH2CH3), 72.0 (C3), 87.3 (C5), 107.6 (C2), 111.3, 113.3, 115.5,
116.3, 120.6, 122.0, 125.0, 126.2, 127.5, 130.3, 132.2, 140.8,
150.0, 160.6 CAr), 168.1 (CO2Et). IR (CHCl3) νmax: 1750
(CO2Et) cm−1. Anal. calcd for C25H22BrNO5, %: C, 60.5;
H, 4.5; N, 2.8. Found, %: C, 60.4; H, 4.6; N, 2.5. Crystal data
for exo-2a: C25H22BrNO5, M = 496.35, triclinic, a = 8.1931(2),
b = 11.5561(3), c = 13.5965(4) Å, α = 65.4650(10), β =
89.4570(10), γ = 70.3560(10)°, U = 1090.13(5) Å3, T = 120(2),
1
δ = 3.79 (3H, s, OCH3), 3.90 (3H, s, OCH3), 6.85–8.24 (12H,
m, HAr), 8.62 (1H, s, CHvN). 13C NMR (CDCl3): δ =
55.4 (OCH3), 55.5 (OCH3), 114.0, 114.3, 121.4, 122.2, 123.1,
126.2, 128.4, 128.8, 131.8, 132.4, 150.0, 150.9, 152.9,
158.4 (CAr), 164.1 (CHvN), 164.8 (CO2R). IR (CHCl3)
νmax: 1740 (CO2R), 1620 (CHvN) cm−1. Anal. calcd for
C22H19NO4, %: C, 73.1; H, 5.3; N, 3.9. Found, %: C, 73.1; H,
5.3; N, 3.9.
2-(4-Methoxyphenyliminomethyl)phenyl 4-nitrobenzoate (1m).
(1.32 g, 95%) was obtained from 2-formylphenyl 4-nitrobenzo-
ate (1.0 g, 3.7 mmol) and 4-methoxyaniline (585 mg,
3.7 mmol). Mp = 97.5–98.5 °C (EtOH). 1H NMR (CDCl3):
δ = 3.77 (3H, s, OCH3), 6.81–8.42 (12H, m, HAr), 8.52 (1H, s,
CHvN). 13C NMR (CDCl3): δ = 55.4 (OCH3), 114.3, 122.0,
123.0, 123.7, 126.8, 128.3, 130.3, 131.4, 131.8, 134.8, 144.5,
149.7, 150.9, 153.0 (CAr), 158.5 (CHvN), 163.4 (CO2R).
IR (CHCl3) νmax: 1740 (CO2R), 1620 (CHvN) cm−1. Anal.
calcd for C21H16N2O5, %: C, 67.0; H, 4.3; N, 7.4. Found, %:
C, 67.1; H, 4.2; N, 7.5.
ˉ
space group P1 (no. 2), Z = 2, μ(Mo-Kα) = 1.923, 12 682 reflec-
tions measured, 6586 unique (Rint = 0.0155) which were used in
all calculations. Final wR2(F2) = 0.070 for all data (377 refined
parameters), conventional R1(F) = 0.0283 for 5629 reflections
with I ≥ 2σ, GOF = 1.097. Crystallographic data for the structure
have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication CCDC 874425.
Ethyl (2RS,3SR,5RS)-4-(4-bromophenyl)-2-phenyl-2,3,4,5-tetra-
hydro-2,5-epoxy-1,4-benzoxazepine-3-carboxylate (endo-2b).
(90 mg, 39%) was obtained using procedure A from imine 1b
(190 mg, 0.5 mmol) and EDA (798 mg, 7 mmol). Mp =
General procedures for the reactions of imines 1 with EDA
A: A solution of EDA in dry CH2Cl2 was added using a syringe
pump to a solution of imine 1 and equivalent of Cu(tfacac)2 in
dry CH2Cl2 at 40 °C under Ar (ca. 8 h). The reaction was moni-
tored by TLC (hexane–EtOAc, 5 : 1). After completion of the
reaction the solvent was removed on rotary evaporator and the
residue was separated by column chromatography on silica gel
(hexane–EtOAc).
B: A solution of EDA in dry benzene was added using a
syringe pump to a solution of imine 1 and Cu(tfacac)2 (10 mol%)
in dry benzene at 80 °C under Ar. The reaction was monitored
by TLC (hexane–EtOAc, 5 : 1). After completion of the reaction
the solvent was removed on rotary evaporator and the residue
was separated by column chromatography on silica gel (hexane–
EtOAc).
1
120–122 °C (ether–hexane). H NMR (CDCl3): δ = 1.06 (3H,
t, J = 7.1 Hz, CH2CH3), 4.02–4.18 (2H, m, CH2CH3), 4.65 (1H,
s, C3H), 6.47 (1H, s, C5H), 6.52–6.55 (2H, m, CArH), 6.88–6.99
(2H, m, CArH), 7.22–7.49 (7H, m, CArH), 7.80–7.83 (2H, m,
CArH). 13C NMR (CDCl3): δ = 13.9 (CH2CH3), 61.5 (CH2CH3),
74.3 (C3), 88.6 (C5), 106.2 (C2), 111.4, 114.0, 115.6, 121.1,
123.5, 123.7, 125.7, 128.3, 129.6, 129.9, 132.3, 136.1, 143.2,
150.9 (CAr), 167.3 (CO2Et). IR (CHCl3) νmax: 1750 (CO2Et)
cm−1. Anal. calcd for C24H20BrNO4, %: C, 61.8; H, 4.3; N, 3.0.
Found, %: C, 61.8; H, 4.5; N, 2.7.
Ethyl (2RS,3SR,5RS)-4-(4-chlorophenyl)-2-(4-methoxyphenyl)-
2,3,4,5-tetrahydro-2,5-epoxy-1,4-benzoxazepine-3-carboxylate
(endo-2c). (61 mg, 27%) was obtained using procedure A from
imine 1c (183 mg, 0.5 mmol) and EDA (844 mg, 10 mmol).
Ethyl
(2RS,3SR,5RS)-4-(4-bromophenyl)-2-(4-methoxy-
1
phenyl)-2,3,4,5-tetrahydro-2,5-epoxy-1,4-benzoxazepine-3-
carboxylate (endo-2a) (32 mg, 13%), and ethyl (2RS,3RS,
5RS)-4-(4-bromophenyl)-2-(4-methoxyphenyl)-2,3,4,5-tetra-
hydro-2,5-epoxy-1,4-benzoxazepine-3-carboxylate (exo-2a)
(35 mg, 14%) were obtained using procedure B from imine 1a
(205 mg, 0.5 mmol) and EDA (684 mg, 6 mmol). Compound
endo-2a (102 mg, 41%) was obtained using procedure A from
imine 1a (205 mg, 0.5 mmol) and EDA (684 mg, 6 mmol).
endo-2a: Mp = 130.5–131.5 °C (ether–hexane). 1H NMR
(CDCl3): δ = 1.06 (3H, t, J = 7.1 Hz, CH2CH3), 3.85 (3H, s,
OCH3), 4.03–4.16 (2H, m, CH2CH3), 4.64 (1H, s, C3H), 6.43
(1H, s, C5H), 6.51–6.54 (2H, m, CArH), 6.86–6.99 (4H, m,
CArH), 7.21–7.36 (4H, m, CArH), 7.72–7.75 (2H, m, CArH).
13C NMR (CDCl3): δ = 13.9 (CH2CH3), 55.3 (OCH3), 61.5
(CH2CH3), 74.2 (C3), 88.4 (C5), 106.4 (C2), 111.2, 113.7, 113.8,
115.6, 121.0, 123.5, 123.6, 127.1, 128.3, 129.9, 132.3, 143.1,
151.0, 160.5 (CAr), 167.3 (CO2Et). IR (CHCl3) νmax: 1750
(CO2Et) cm−1. Anal. calcd for C25H22BrNO5, %: C, 60.5; H,
4.5; N, 2.8. Found, %: C, 60.5; H, 4.6; N, 2.6.
Mp = 133–134 °C (ether–hexane). H NMR (CDCl3): δ = 1.06
(3H, t, J = 7.1 Hz, CH2CH3), 3.85 (3H, s, OCH3), 4.02–4.18
(2H, m, CH2CH3), 4.65 (1H, s, C3H), 6.44 (1H, s, C5H),
6.57–6.60 (2H, m, CArH), 6.87–6.99 (4H, m, CArH), 7.21–7.24
(4H, m, CArH), 7.73–7.77 (2H, m, CArH). 13C NMR (CDCl3):
δ = 13.9 (CH2CH3), 55.3 (OCH3), 61.5 (CH2CH3), 74.4 (C3),
88.6 (C5), 106.4 (C2), 113.5, 113.7, 115.6, 121.0, 123.5, 123.6,
124.2, 127.1, 128.4, 129.4, 129.9, 142.8, 151.0, 160.5 (CAr),
167.4 (CO2Et). IR (CHCl3) νmax: 1750 (CO2Et) cm−1. Anal.
calcd for C25H22ClNO5, %: C, 66.45; H, 4.9; N, 3.1. Found, %:
C, 66.5; H, 5.0; N, 2.8.
Ethyl (2RS,3SR,5RS)-4-(4-bromophenyl)-2-(4-methylphenyl)-
2,3,4,5-tetrahydro-2,5-epoxy-1,4-benzoxazepine-3-carboxylate
(endo-2d). (94 mg, 40%) was obtained using procedure A from
imine 1d (197 mg, 0.5 mmol) and EDA (684 mg, 6 mmol).
1
Mp = 120–124 °C (ether–hexane). H NMR (CDCl3): δ = 1.06
(3H, t, J = 7.1 Hz, CH2CH3), 2.41 (3H, s, CH3), 4.01–4.18 (2H,
m, CH2CH3), 4.64 (1H, s, C3H), 6.45 (1H, s, C5H), 6.51–6.54
5588 | Org. Biomol. Chem., 2012, 10, 5582–5591
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(2H, m, CArH), 6.87–6.98 (2H, m, CArH), 7.22–7.36 (6H, m,
CArH), 7.68–7.70 (2H, m, CArH). 13C NMR (CDCl3): δ = 13.9
(CH2CH3), 21.3 (CH3), 61.5 (CH2CH3), 74.2 (C3), 88.4 (C5),
106.3 (C2), 111.2, 113.9, 115.6, 121.0, 123.5, 123.6, 125.5,
129.0, 129.9, 132.3, 133.2, 139.5, 143.1, 150.9 (CAr), 167.3
(CO2Et). IR (KBr) νmax: 1750 (CO2Et) cm−1. Anal. calcd for
C25H22BrNO4, %: C, 62.5; H, 4.6; N, 2.9. Found, %: C, 62.5;
H, 4.6; N, 2.75.
m, CH2CH3), 4.61 (1H, s, C3H), 6.61 (1H, s, C5H), 6.46–6.49
(2H, m, CArH), 6.87–6.93 (2H, m, CArH), 7.21–7.24 (2H, m,
CArH), 7.31–7.34 (2H, m, CArH), 7.99–8.02 (2H, m, CArH),
8.30–8.33 (2H, m, CArH). 13C NMR (CDCl3): δ = 13.6
(CH2CH3), 61.9 (CH2CH3), 71.9 (C3), 87.7 (C5), 106.7 (C2),
111.8, 115.6, 116.4, 121.2, 121.7, 123.2, 125.1, 127.6, 130.6,
132.3, 140.5, 148.7, 149.4 (CAr), 167.7 (CO2Et). IR (KBr) νmax
:
1745 (CO2Et) cm−1. Anal. calcd for C24H19BrN2O4, %: C, 56.4;
H, 3.75; N, 5.5. Found, %: C, 56.5; H, 3.9; N, 5.6.
Ethyl (2RS,3SR,5RS)-4-(4-bromophenyl)-2-(4-cyanophenyl)-
2,3,4,5-tetrahydro-2,5-epoxy-1,4-benzoxazepine-3-carboxylate
(endo-2e) (42 mg, 17%) and (2RS,3RS,5RS)-4-(4-bromophenyl)-
2-(4-cyanophenyl)-2,3,4,5-tetrahydro-2,5-epoxy-1,4-benzoxazepine-
3-carboxylate (exo-2e) (48 mg, 20%). Obtained using procedure
A from imine 1e (203 mg, 0.5 mmol) and EDA (684 mg,
6 mmol).
Ethyl
(2RS,3SR,5RS)-4-(4-bromophenyl)-2-(3-nitrophenyl)-
2,3,4,5-tetrahydro-2,5-epoxy-1,4-benzoxazepine-3-carboxylate
(endo-2g) (27 mg, 11%) and (2RS,3RS,5RS)-4-(4-bromophenyl)-
2-(3-nitrophenyl)-2,3,4,5-tetrahydro-2,5-epoxy-1,4-benzoxazepine-
3-carboxylate (exo-2g) (23 mg, 9%). Obtained using procedure
A from imine 1g (213 mg, 0.5 mmol) and EDA (912 mg,
8 mmol).
endo-2e: Mp = 144–148 °C (EtOAc–hexane). 1H NMR
(CDCl3): δ = 1.05 (3H, t, J = 7.1 Hz, CH2CH3), 4.02–4.17 (2H,
m, CH2CH3), 4.56 (1H, s, C3H), 6.50 (1H, s, C5H), 6.54–6.57
(2H, m, CArH), 6.88–7.00 (2H, m, CArH), 7.27–7.39 (4H, m,
CArH), 7.75–7.95 (4H, m, CArH). 13C NMR (CDCl3): δ = 13.8
(CH2CH3), 61.8 (CH2CH3), 74.4 (C3), 88.9 (C5), 105.3 (C2),
112.0, 113.5, 114.2, 115.6, 118.3 (CN), 121.6, 123.2, 123.9,
126.6, 130.2, 132.2, 132.4, 141.0, 143.1, 150.9 (CAr), 166.9
(CO2Et). IR (KBr) νmax: 1715 (CO2Et), 2230 (CN) cm−1. Anal.
calcd for C25H19BrN2O4, %: C, 61.1; H, 3.9; N, 5.7. Found, %:
C, 61.0; H, 3.8; N, 5.8.
endo-2g: Mp = 138–141 °C (EtOAc–hexane). 1H NMR
(CDCl3): δ = 1.10 (3H, t, J = 7.1 Hz, CH2CH3), 4.04–4.23 (2H,
m, CH2CH3), 4.60 (1H, s, C3H), 6.52 (1H, s, C5H), 6.54–6.57
(2H, m, CArH), 6.92–7.04 (2H, m, CArH), 7.28–7.39 (4H, m,
CArH), 7.64–7.68 (1H, m, CArH), 8.12–8.15 (1H, m, CArH),
8.31–8.35 (1H, m, CArH), 8.71–8.73 (1H, m, CArH). 13C NMR
(CDCl3): δ = 13.9 (CH2CH3), 61.9 (CH2CH3), 74.3 (C3), 88.9
(C5), 105.1 (C2), 112.0, 114.2, 115.6, 121.5, 121.7, 123.2,
123.9, 124.5, 129.5, 130.2, 131.7, 132.4, 138.4, 143.1, 148.2,
150.3 (CAr), 166.8 (CO2Et). IR (KBr) νmax: 1755 (CO2Et) cm−1
Anal. calcd for C24H19BrN2O4, %: C, 56.4; H, 3.75; N, 5.5.
Found, %: C, 56.6; H, 3.7; N, 5.6.
.
exo-2e: Mp = 163–166 °C (dec.) (ether–hexane). 1H NMR
(CDCl3): δ = 0.85 (3H, t, J = 7.1 Hz, CH2CH3), 3.58–3.87 (2H,
m, CH2CH3), 4.58 (1H, s, C3H), 6.59 (1H, s, C5H), 6.45–6.48
(2H, m, CArH), 6.86–6.91 (2H, m, CArH), 7.20–7.33 (4H, m,
CArH), 7.74–7.95 (4H, m, CArH). 13C NMR (CDCl3): δ = 13.5
(CH2CH3), 61.9 (CH2CH3), 71.8 (C3), 87.6 (C2), 106.6 (C5),
111.8, 113.7, 115.6, 116.3, 118.1 (CN), 121.2, 121.7, 125.1,
127.1, 130.6, 131.8, 132.3, 138.8, 140.3, 149.4 (CAr), 167.7
exo-2g: Mp = 137–140 °C (EtOAc–hexane). 1H NMR
(CDCl3): δ = 0.84 (3H, t, J = 7.2 Hz, CH2CH3), 3.59–3.87 (2H,
m, CH2CH3), 4.61 (1H, s, C3H), 6.62 (1H, s, C5H), 6.46–6.49
(2H, m, CArH), 6.87–6.95 (2H, m, CArH), 7.22–7.34 (4H, m,
CArH), 7.63–7.68 (1H, m, CArH), 8.12–8.14 (1H, m, CArH),
8.32–8.34 (1H, m, CArH), 8.70–8.72 (1H, m, CArH). 13C NMR
(CDCl3): δ = 13.5 (CH2CH3), 61.9 (CH2CH3), 71.8 (C3), 87.7
(C5), 106.5 (C2), 111.8, 115.7, 116.4, 121.2, 121.8, 124.6,
125.1, 129.2, 130.6, 132.2, 132.3, 136.2, 140.4, 148.0, 149.4
(CAr), 167.8 (CO2Et). IR (KBr) νmax: 1745 (CO2Et) cm−1. Anal.
calcd for C24H19BrN2O4, %: C, 56.4; H, 3.75; N, 5.5. Found, %:
C, 56.5; H, 3.8; N, 5.2.
(CO2Et). IR (CHCl3) νmax: 1760 (CO2Et), 2240 (CN) cm−1
.
Anal. calcd for C25H19BrN2O4, %: C, 61.1; H, 3.9; N, 5.7.
Found, %: C, 61.0; H, 3.9; N, 5.5.
Ethyl
(2RS,3SR,5RS)-4-(4-bromophenyl)-2-(4-nitrophenyl)-
2,3,4,5-tetrahydro-2,5-epoxy-1,4-benzoxazepine-3-carboxylate
(endo-2f) (75 mg, 29%) and (2RS,3RS,5RS)-4-(4-bromophenyl)-
2-(4-nitrophenyl)-2,3,4,5-tetrahydro-2,5-epoxy-1,4-benzoxazepine-
3-carboxylate (exo-2f) (23 mg, 9%). Obtained using procedure
A from imine 1f (213 mg, 0.5 mmol) and EDA (1140 mg,
10 mmol).
Ethyl
(2RS,3SR,5RS)-4-(4-bromophenyl)-2-[(E)-2-phenyl-
vinyl)]-2,3,4,5-tetrahydro-2,5-epoxy-1,4-benzoxazepine-3-carboxy-
late (endo-2h). (44 mg, 18%) Obtained using procedure A from
imine 1h (246 mg, 0.5 mmol) and EDA (456 mg, 4 mmol).
Mp = 129.5–130.5 °C (dec.) (EtOAc–hexane). 1H NMR
(CDCl3): δ = 1.11 (3H, t, J = 7.1 Hz, CH2CH3), 4.10–4.20 (2H,
m, CH2CH3), 4.59 (1H, s, C3H), 6.37 (1H, s, C5H), 6.51–6.54
(2H, m, CArH), 6.59 (1H, d, J = 16.1 Hz, CHvCHPh),
6.84–6.98 (2H, m, CArH), 7.18–7.51 (10H, m, CArH,
CHvCHPh). 13C NMR (CDCl3): δ = 13.9 (CH2CH3), 61.6
(CH2CH3), 74.9 (C3), 88.5 (C5), 105.4 (C2), 111.2, 113.8, 115.5,
121.0 (CAr), 122.4 (CHvCHPh), 123.5, 127.2, 128.7, 128.8,
129.9, 132.3 (CAr), 133.6 (CHvCHPh), 135.2, 143.1, 150.8
(CAr), 167.2 (CO2Et). IR (KBr) νmax: 1720 (CO2Et) cm−1. Anal.
calcd for C26H22BrNO4, %: C, 63.4; H, 4.5; N, 2.8. Found, %:
C, 63.2; H,4.3; N, 3.1.
endo-2f: Mp = 157–160 °C (dec.) (CH2Cl2–hexane). 1H NMR
(CDCl3): δ = 1.06 (3H, t, J = 7.1 Hz, CH2CH3), 4.02–4.19 (2H,
m, CH2CH3), 4.58 (1H, s, C3H), 6.52 (1H, s, C5H), 6.55–6.58
(2H, m, CArH), 6.90–7.04 (2H, m, CArH), 7.28–7.39 (4H, m,
CArH), 7.99–8.01 (2H, m, CArH), 8.31–8.34 (2H, m, CArH).
13C NMR (CDCl3): δ = 13.9 (CH2CH3), 61.8 (CH2CH3),
74.5 (C3), 89.0 (C5), 105.3 (C2), 112.1, 114.3, 115.6, 121.7,
123.2, 123.6, 123.9, 127.0, 130.2, 132.5, 142.8, 143.2, 150.3
(CAr), 166.9 (CO2Et). IR (KBr) νmax: 1745 (CO2Et) cm−1. Anal.
calcd for C24H19BrN2O4, %: C, 56.4; H, 3.75; N, 5.5. Found, %:
C, 56.4; H, 3.7; N, 5.5.
1
exo-2f: Mp = 149–158 °C (dec.) (CH2Cl2–hexane). H NMR
(CDCl3): δ = 0.86 (3H, t, J = 7.1 Hz, CH2CH3), 3.59–3.88 (2H,
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 5582–5591 | 5589

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General procedure for the reactions of imines 1 with EDA in the
presence of fumaronitrile
imaginary frequencies for transition states was carried out to
check whether the frequency indeed pertains to the desired reac-
tion coordinate. Intrinsic reaction coordinates (IRC) were calcu-
lated to authenticate all transition states.15
A solution of EDA in dry CH2Cl2 was added using a syringe
pump to a solution of fumaronitrile, imine 1 and 10 mol% of
Cu(tfacac)2 in dry CH2Cl2 at 40 °C under Ar (ca. 8 h). The reac-
tion was monitored by TLC (hexane–EtOAc, 5 : 1). After com-
pletion of the reaction the solvent was removed on rotary
evaporator and the residue was separated by column chromato-
graphy on silica gel (hexane–EtOAc).
Acknowledgements
We gratefully acknowledge the financial support of the Russian
Foundation for Basic Research (project 11-03-00186), Federal
Grant-in-Aid Program “Human Capital for Science and
Education in Innovative Russia” (Governmental Contract no.
16.740.11.0442), and Saint Petersburg State University for a
research grant (№ 12.38.78.2012).
Ethyl
(2RS,3RS,4RS,5RS)-1-(4-bromophenyl)-3,4-dicyano-
5-(2-(4-methylbenzoyloxy)phenyl)pyrrolidine-2-carboxylate (4).
Compound 4 (25 mg, 9%) and endo-2d (69 mg, 29%) were
obtained from imine 1d (197 mg, 0.5 mmol), fumaronitrile
(312 mg, 4 mmol), and EDA (912 mg, 8 mmol). Compound 4:
Mp = 194–196 °C (CH2Cl2–hexane). 1H NMR (CDCl3): δ =
1.08 (3H, t, J = 7.1 Hz, CH2CH3), 2.46 (3H, s, CH3), 3.60–3.63
Notes and references
1 L. M. Harwood and R. J. Vickers, in Synthetic Applications of 1,3-
Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Pro-
ducts, ed. A. Padwa, W. H. Pearson, John Wiley and Sons, New York,
2002.
1
(1H, dd, J = 4.2 Hz, J = 2.9 Hz, C4H), 3.71–3.73 (1H, dd, J =
2.9 Hz, J = 2 Hz, C3H), 4.02–4.20 (2H, m, CH2CH3), 5.10 (1H,
d, J = 2 Hz, C2H), 5.38 (1H, d, J = 4.2 Hz, C5H), 6.45–6.48
(2H, m, CArH), 7.21–7.44 (8H, m, CArH), 8.16–8.19 (2H, m,
CArH). 13C NMR (CDCl3): δ = 13.7 (CH2CH3), 21.8 (CH3),
35.4 (C4), 39.8 (C3), 61.5 (C2), 62.8 (CH2CH3), 65.9 (C5),
113.1, 116.9 (2*CN), 117.8, 123.5, 125.5, 126.9, 127.2, 129.5,
130.3, 130.6, 132.2, 142.4, 145.3, 148.6 (CAr), 165.4 (CO2R),
2 For recent examples, see:
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167.2 (CO2Et). IR (KBr) νmax: 1730 (CO2R), 2250 (CN) cm−1
.
Anal. calcd for C29H24BrN3O4, %: C, 62.4; H, 4.3; N, 7.5.
Found, %: C, 62.4; H, 4.3; N, 7.4.
Ethyl (2RS,3RS,4RS,5RS)-3,4-dicyano-5-(2-(4-methoxybenzoyl-
oxy)phenyl)-1-(4-methoxyphenyl)pyrrolidine-2-carboxylate (5).
Compound (5) (30 mg, 11%) was obtained from imine 1j
(180 mg, 0.5 mmol), fumaronitrile (156 mg, 2 mmol), and EDA
(912 mg, 8 mmol). 5: Mp = 173–174 °C (CH2Cl2–hexane).
1H NMR (CDCl3): δ = 1.03 (3H, t, 7.1 Hz, CH2CH3), 3.55–3.57
(1H, dd, J = 5.4 Hz, J = 3.8 Hz, C4H), 3.67–3.69 (1H, dd, J =
3.8 Hz, J = 2 Hz, C3H), 3.69 (3H, s, OCH3), 3.90 (3H, s,
OCH3), 3.96–4.14 (2H, m, CH2CH3), 5.05 (1H, d, J = 2 Hz,
C2H), 5.40 (1H, d, J = 5.4 Hz, C5H), 6.60–6.63 (2H, m, CArH),
6.73–6.76 (2H, m, CArH), 7.01–7.04 (2H, m, CArH), 7.19–7.49
(4H, m, CArH), 8.25–8.28 (2H, m, CArH). 13C NMR (CDCl3):
δ = 13.7 (CH2CH3), 35.2 (C4), 40.2 (C3), 55.3 (OCH3), 55.5
(OCH3), 61.0 (C2), 62.3 (CH2CH3), 66.8 (C5), 114.0 (CN),
114.5 (CN), 117.2, 117.4, 118.5, 120.7, 123.3, 127.0, 129.9,
132.8, 136.7, 148.8, 154.1, 164.3, 165.0 (CO2R), 169.1
(CO2Et). IR (KBr) νmax: 1720 (CO2Et), 2250 (CN) cm−1. Anal.
calcd for C30H27N3O6, %: C, 68.6; H, 5.2; N, 8.0. Found, %: C,
68.6; H, 5.2; N, 8.1.
Computational details
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All calculations were performed with the B3LYP density func-
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cal programs. Geometry optimizations of intermediates,
transition states, reactants, and products in the gas phase were
performed at the B3LYP/6-31G(d) level using Gaussian 03.14
Stationary points on the respective potential-energy surfaces
were characterized at the same level of theory by evaluating the
corresponding Hessian indices. Careful verification of the unique
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