A novel strategy for the synthesis of thermally stable and apoptosis-inducing 2,3-dihydroazetes

Article abstract of DOI:10.1039/c6ob00588h

A general and concise approach to thermally and hydrolytically stable alkyl 2,3-dihydroazete-2,3-di-/2,2,3-tricarboxylates from alkyl 2-bromoazirine-2-carboxylates or 4-bromo-5-alkoxyisoxazoles is reported. The synthesis involves the formation of 2-azabut

Full text of DOI:10.1039/c6ob00588h

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Trulioff and G. Nikolay, Org. Biomol. Chem., 2016, DOI: 10.1039/C6OB00588H.
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A novel strategy for the synthesis of thermally stable and
apoptosis-inducing 2,3-dihydroazetes†
Ilia A. Smetanin,a Mikhail S. Novikov,*a Anastasiya V. Agafonova,a Nikolai V. Rostovskii,a Alexander
F. Khlebnikov,a Igor V. Kudryavtsev, b Maxim A. Terpilowski,c Maria K. Serebriakova,b Andrey S.
Trulioff,b Nikolay V. Goncharovc
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A general and concise approach to thermally and hydrolytically stable alkyl 2,3-dihydroazete-2,3-di-/2,2,3-tricarboxylates
from alkyl 2-bromoazirine-2-carboxylates or 4-bromo-5-alkoxyisoxazoles is disclosed. The synthesis involves formation of
2-azabuta-1,3-diene by reaction of rhodium carbenoid with isoxazole or azirine followed by
cyclization/hydrodebromination cascade. The latter reaction is the first example of the selective hydrodehalogenation of a
valence isomer under equilibrium conditions. In vitro cytotoxicity tests on THP-1 cell line revealed that the 2,3-
dihydroazetes greatly differ in their ability to induce apoptosis and/or necrosis. To adequately describe and quantitatively
assess these properties, the difference between the two areas under the curves of concentration dependancy of
apoptosis/necrosis induction within the concentration range was used. Trimethyl 4-phenyl-2,3-dihydroazete-2,2,3-
tricarboxylate was found to display the maximal apoptotic potential coupled with high cytotoxic and minimal necrotic
potential.
To further explore the biological potential of four-membered
aza-heterocyclic compounds, in particular anti-cancer activity,
we proposed synthesizing dehydrogenated analogues of
Introduction
A four-membered aza-heterocyclic pattern is present in a wide
range of natural products and synthetic bioactive compounds.1
monascumic acid, namely 2,3-dihydroazete-2,3-dicarboxylates
. The latter possess higher rigidity and lower N-basicity than
2
The majority of these strained cyclic elements have either a
lactam or azetidine structure. Azetidine-2-carboxylic acid (Aze),
cyclic homologue of proline, is constituent of
β-
azetidine derivatives and
a
different topology of the
substituents due to С(sp2) atom.
a
a
nicotianamine2 and mugineic acid3, which are iron transporters
in plants (Scheme 1). Aze and its substituted analogues are
also used as non-protein amino acid components for the
CO2H
CO2H
R1
H
N
N
CO2H
design of novel peptides and peptidomimetics.4 Acid
1 was
NH
CO2H
R2
Aze
found to act as HCMV serine protease inhibitor.5 Monascumic
acids, azetidine-2,3-dicarboxylic acid derivatives, isolated from
the extracts of Monascus pilosus-fermented rice, exhibited
potent inhibitory effect on the Epstein-Barr virus early antigen
(EBV-EA) activation and moderate inhibitory effects on NOR 1
activation.6 Quite recently it was shown that some iminosugars
containing the 3-fluoroazetidine unit display inhibition of
growth PANC-1 cells comparable with those for gemcitabine.7
nicotianamine (R1 = H; R2 = NH2)
mugineic acid (R1 = R2 = OH)
Ph
CO2R4
R2
R3O2C
CO2H
O
CO2H
NH
Monascumic acid
HO2C
N
N
R1
[this work]
Ph
2
O
1
Scheme 1 Bioactive compounds containing azetidine-2-carboxylic unit.
2,3-Dihydroazetes (or 1-azetines) having no heteroatom
substituent at the multiple bond are much less accessible
compounds than both their hydrogenated analogues,
azetidines, and cyclic unsaturated homologues: azirines and 1-
pyrrolines.1,8
A few photolytic reactions leading to 2,3-
dihydroazetes (2+2)-cycloaddition of nitriles to alkenes,9 and
cyclization of N-acetyl α-dehydrophenylalanines10 are known.
2,3-Dihydroazete derivatives were synthesized by pyrolysis of
1-azabicyclo[4.2.0]oct-3-en-2-one derivatives,11 recyclization
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of 2-azido-1,1-dichlorocyclopropanes12 and (3+1)-cycloaddition olefin proton signal in the 1H NMR spectra which is shifted
of the nitrilio-bis(trifluoromethyl)methanides to isonitriles.13 downfield for the Z isomer.17 Compounds E-
and Z- were
All these methods have very limited application, in particular, separated by column chromatography (49 and 32% yield) and
for the preparation of the derivatives with ester and related refluxed in toluene. Isomer E- after 4 h gave dihydroazete
functions. The only known approach enabling the introduction in 53% yield, which showed high thermal stability up to 150
6
6
6
2′a
°C.
of ester groups into the 2,3-dihydroazete ring is a Rh(II)- Isomer Z-
6
proved to be unreactive and did not cyclize to
2′
a
carbenoid-mediated azirine ring expansion (Scheme 2).14 The even at higher temperatures. Thus, a two-step carbenoid-
reaction proceeds via electrophilic attack of the rhodium mediated azirine ring expansion of 3b provided dihydroazete
carbenoid on the nitrogen of the azirine followed by 1,4-
electrocyclization of the resulting 2-azabuta-1,3-diene.15,16 cyclization on the configuration of the C=C bond of azadiene
Unfortunately, this reaction has serious limitations on the and low stereoselectivity of its formation are the reasons for
2′a in only 23% overall yield. High dependence of the 1,4-
6
structure of
dihydroazetes
a
diazo compound. Thus, thermally stable the poor yield of
can be prepared only from the diazomalonic
2′a.
4
acid esters or its amidoesters. Besides the successful results
are known only for 2,3-diphenyl-2H-azirine (3a). For example,
3-monosubstituted azirine 3b and trisubstituted azirines 3c,d
do not furnish dihydroazetes at all.15,16 Thereby, synthetic
problems mentioned above make them hitherto hardly
accessible compounds with poorly known reactivity and
practically unknown biological properties.
Scheme 3 Synthesis of dihydroazete 2′a from azirine 3e.
We supposed that the problem can be solved by introduction
of efficient directing group to the azirine ring (Scheme 4,
structure 7) for selective ring opening into such stereoisomer,
which is capable of undergoing 1,4-cyclization into
dihydroazete
9. It is also important that a directing group
should be easy to remove. Recently we have discovered that
the reaction of 2-bromo-substituted azirine 7a with 5а under
Rh(II)-catalysis occurs with full E-stereoselectivity, providing
azadiene 8a exclusively. Moreover, this is able to cyclize
reversibly into dihydroazete 9a at elevated temperatures.18
feasible alternative route to dihydroazetes could, therefore,
be started from bromoazirines but have to involve a selective
hydrodebromination of thermally unstable dihydroazetes
A
2
7
9.
Scheme 2 One-atom azirine ring expansion to 2,3-dihydroazetes.
In the present work we report an effective two-step method
for the preparation of thermally stable and differently
substituted at C2- and C4-positions alkyl 2,3-dihydroazete-2,3-
di-/2,2,3-tricarboxylates
2 that can operate both with alkyl 2-
bromo-azirine-2-carboxylates and 4-bromo-5-alkoxyisoxazoles
as starting material. Bioassay results obtained with THP-1 cell
line on apoptosis and/or necrosis inducing activity of
representative 2,3-dihydroazete derivatives are also
presented.
Scheme 4 Synthetic scheme for dihydroazete 2a
.
To verify the workability of this approach and to find suitable
hydrodehalogenation conditions azadiene 8a was synthesized
from azirine 7a and dimethyl diazomalonate 5a according to
the known procedure.18 Tributylstannane was tried as a
potential selective reagent for the hydrodebromination. The
highest yields of 2a were achieved by slow addition of a
diluted Bu3SnH solution to the solution of an equilibrium
Results and discussion
The synthesis of a series of dihydroazetes
the 2,3-dihydroazete-2,2,3-tricarboxylates 2a, 2
Initially we tried to synthesize compound
azirine 3e and dimethyl diazomalonate 5а via cyclization of
azadiene (Scheme 3). Heating azirine 3e with 1.5 equiv of 5a
in the presence of Rh2(OAc)4 (1 mol %) gave a 1.5:1 mixture of
E and Z isomers of azadiene in 81% total yield. Assignment of
2
was begun with
(Scheme 3).
2′a directly from
′
a
mixture of 8a and 9a at 110 °С. These conditions enable a
selective reduction of the dihydroazete isomer 9a. It is
important that the addition of azobisisobutyronitrile (AIBN, 4
mol %) noticeably suppresses the formation of side products.
These conditions allowed the preparation of 2a in 78% yield
calculated on azirine 7a using on the first stage only a simple
6
6
the C=C bond configuration in stereoisomers
6 is based on an
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filtration of the reaction mixture through a silica gel pad. To of
the best of our knowledge, it is the first example of the diastereoselectivity of the formation of 2f
selective hydrodehalogenation of a valence isomer under increases with the increase of the steric volume of R2
equilibrium conditions. substituent: COMe < CF3 < P(O)(OMe)2.
Next we explored the scope of the two-step “4-bromoazadiene A limitation of the method that did appear is the inaccessibility
formation/hydrodebromination” sequence with a set of of bromoazirines with electron-withdrawing substituents in
enolizable
4-bromo-2-azadienes
8i,j 18
predictably
.
The
−
j
7
azirines 7a
−
e
and α-diazocarbonyl compounds 5a
−
d
(Table 1).
benzene ring, such as halogen atoms. In search for an
alternative approach to dihydroazetes with electron-poor aryl
substituents at C4 we selected 4-bromo-5-methoxyisoxazoles
10 as potential synthetic equivalents of the corresponding 2-
bromoazirines (Table 2). The formation/generation of 2-
azabuta-1,3-dienes by reactions of non-halogenated isoxazoles
with Rh(II)-carbenoids derived from diazo compounds17,19 or 1-
sulfonyl-1,2,3-triazoles20 are known. The use of 4-halogeno-
substituted 5-alkoxyisoxazoles in such reactions is limited by a
Table 1 Synthesis of dihydroazetes 2a−j from azirines 7a−ea
MeO2C CO2R3
CO2Me
Br
R1
R2
H
N
N
R1
7a
CO2R3
5a
e
2a
j
R2
Rh2(OAc)4
DCE, 84
Bu3SnH,
AIBN
toluene
110
C
C
d
N2
MeO2C CO2R3
Br
R2
R1
CO2Me
reaction
of
4-iodo-5-methoxy-3-phenylisoxazole.18
were synthesized in three steps from
4-
R2
CO2R3
110
C
Br
N
N
Bromoisoxazoles 10a
−
h
R1
equilibrium mixture
8a
j
9a
j
β-ketoesters and hydroxylamine in good yields of the products
at each stage (ESI). The reaction of 10a with 5а in the presence
of Rh2(OAc)4 followed by the hydrodebromination of the
1
2
CO2Me
CO2Me
3
MeO2C
MeO2C
CO2Me
CO2Me
MeO2C
Ph
CO2Me
N
CO2Me
equilibrium mixture 8a⇄9a with Bu3SnH/AIBN gave practically
the same yield of dihydroazete 2a as the “azirine method”
N
N
S
(Scheme 5, entry 1).
2a (78%, from 7a + 5a)
MeO
2b (85%, from 7b + 5a)
2c (80%, from 7c + 5a)
4
5
6
Table 2 Synthesis of dihydroazetes 2a,b,k−p from isoxazoles 10a−ha
CO2Me
CO2Me
MeO2C
CO2Me
CO2Me
MeO2C
CO2Et
MeO2C
CF3
N
N
N
Ph
O
2d (42%, from 8d)b
2f (56%, from 7a + 5b)
dr = 12:1c
2e (66%, from 7e + 5a)
7
8
CO2Me
CO2Et
CF3
MeO2C
MeO2C
P(O)(OMe)2
N
N
MeO
MeO
2h (66%, from 7b + 5c)
2g (72%, from 7b + 5b)
dr = 7:1c
9
10
CO2Et
CO2Et
MeO2C
MeO2C
COMe
COMe
N
N
Ph
2i (37%, from 8i)b
dr = 1.25:1
MeO
2j (45%, from 8j)b
dr = 1.1:1
a
Reaction conditions. Stage 1: addition of Rh2(OAc)4 (2 mol %) to solution of 7 (0.5
mmol) and 5 (0.6−1.1 mmol) in DCE (1.5 mL); Stage 2: Bu3SnH (1 mmol), AIBN (0.02
mmol), toluene (2 mL). b The yields of 8d,i,j are 74, 67 and 62%, respectively (see ESI). c
(2RS,3RS)/(2RS,3SR)-ratio.
All synthesized dihydroazetes
2 are stable up to about 150 °C
and do not undergo hydrolytic ring-opening during
chromatography on silica gel. Electron-donating aryl and
hetaryl substituents (entries
1−5) tolerate the reaction
a For reaction conditions see footnote to Table 1.
conditions, providing good yields of dihydroazetes 2a−e.
Functional groups such as CF3 and P(O)(OMe)2 can be
To test the practicality of this method a gram-scale reaction of
1.56 g of 10b and 1.3 g of 5a was carried out. Dihydroazete 2b
in this case was isolated in 84% yield, highlighting the synthetic
utility of the method (entry 2). An ortho-substituent in the aryl
introduced into the dihydroazete by use of diazo compounds
5b,c (entries 6−8). Ethyl diazoacetoacetate 5d is also a suitable
substrate for the reaction, although it provides lower yields of
dihydroazetes 2i,j (entries 9, 10) probably due to side reactions
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group also tolerates the reaction conditions (entry 4). p- would be additional research with normal cell lines (e.g.
Chloro- and p-bromophenyl-substituted dihydroazetes were endothelial cells, fibroblasts, etc.) to find out if the AND is of
also synthesized but in somewhat lower yields (entries 5, 6). the same level or principally different from that of malignant
The reaction of the p-cyanophenyl-substituted isoxazole 10g cells. The next stage of research is supposed to be in vivo
proceeds via a Rh(II)-carbenoid-induced transformation of the experiments within the frame of preclinical studies.
cyano-group to oxazole moiety, affording dihydroazete 2o in
44% yield (entry 7).
The structures of compounds 2a−p
were verified by 1H, 13C
NMR spectra, and HRMS. Structures of compounds 2a,h were
confirmed by X-ray analysis, compound 2f – by 2D 1H-19F
HOESY experiment (ESI).
Our studies on the anti-cancer activity of the synthesized 2,3-
dihydroazetes were focused on their pro-apoptotic potential,
because it is well-recognized that the failure of many anti-
cancer chemotherapeutics arises from their inability to induce
apoptosis at a cellular level.21
A cell suspension culture of THP-1 (human monocytic leukemia
cells) was selected as the object for the biological studies. DNA
binding dyes, YO-PRO-1 and propidium iodide, were used for
the assessment of the cell viability.22 Testing the panel of 2,3-
dihydroazetes within the range of 10-5 to 2×10-4 M, we have
found that they significantly differ in their ability not only to
induce the cell death, but also in the way they do so, by
inducing predominantly apoptosis or necrosis. To adequately
describe and quantitatively assess their apoptotic and/or
necrotic potential, on one hand, and their general cytotoxic
potential, on the other hand, we took the difference between
the two areas under the curves, apoptotic and necrotic, within
the concentration range (apoptotic/necrotic difference, AND).
The sense of the values obtained should not be mixed with or
reduced to that of “apoptotic index” widely used for years to
describe the cell death observed by various techniques.23
According to the obtained results, dihydroazete 2a exhibited
the maximal AND on the THP-1 cell line (Figures 1, 2a);
compounds 2m,n,k (Figures 2b,c,d) showed a lower AND due
to higher necrotic potential at nearly the same cytotoxicity as
2a; dihydroazetes 2b,e (Figures 2e,f) and 9a (Figure 2g)
showed a lower AND that significantly differ from 2a due to
higher necrotic potential and/or lower cytotoxicity;
dihydroazete 2h (Figure 2h) had both a very low AND value
and a very low cytotoxicity, and dihydroazetes 9c,g (Figures
2i,j) exhibited a negative AND due to predominantly necrotic
cell death at a moderate to high level of cytotoxicity.
Figure
2a,b,e,h,k,m,n and 9a,c,g exhibited on the THP-1 cell line ((A) p<0.05; (B) p<0.01;
(C) p<0.001).
1 The apoptotic/necrotic difference (AND) of the dihydroazetes
a
b
d
c
Many cancers can develop pro-survival adaptations and anti-
apoptotic signaling pathways, and many efforts of the
synthetic chemists have been made to overcome the challenge
of drug resistance. To this end, it is worth mentioning a recent
attempt to develop prodrugs that induce targeted necrosis as
a novel strategy to circumvent apoptosis-resistance.24 We
don’t share this approach because hold the opinion that
necrosis should be the natural outcome of primary and fully
developed apoptosis, in order to maximally avoid side effects
with healthy tissues at the stage of preclinical and clinical
studies. So this row of 2,3-dihydroazetes seems to be of great
interest for molecular oncologists to conducting
cytophysiological research with different cancer cell lines and
identifying death-effector molecules. Of special importance
f
e
h
g
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received. 2H-Azirines 3e,25 7a,26 7b–d18 were prepared by the
reported procedures.
General procedure for preparation of dihydroazetes 2a−p
Rh2(OAc)4 (2 mol % on azirine/isoxazole) was added to a
refluxing solution of azirine 7a−e (0.5 mmol) or isoxazole
10a−h (0.5 mmol) and diazo compound 5a−d (in amounts
indicated below) in anhydrous DCE (1.5 mL) under argon. The
stirred mixture was heated under reflux until nitrogen
j
i
evolution stopped (10 min for 5a, 10 s for 5b, 50 min for 5c
,
Figure 2 Concentration dependency (C = mol×L-1) of apoptosis and necrosis
induction. Percentage of dead cells as determined by DNA binding dyes YO-PRO-
1 and propidium iodide via flow cytometry after treatment of THP-1 cells for 24 h
and 30 s for 5d). The solvent was evaporated under reduced
pressure, and the residue was filtered through a pad of silica
gel using hexane/EtOAc mixture as eluent (pure azadiene 8d,i,j
were isolated by column chromatography, benzene/EtOAc
mixture as eluent, 100:1 to 10:1). The filtrate was
concentrated under reduced pressure and the residue (or pure
azadiene 8d,i,j) was dissolved in anhydrous toluene (2 mL) and
refluxed for 45 min under stirring (10 min for 8i,j).
Azobisisobutyronitrile (AIBN) (0.02 mmol) was added to the
with different concentrations of 2,3-dihydroazetes 2a,b,e,h,k,m,n and 9a,c,g
.
Conclusions
In conclusion, we have shown that thermally and hydrolytically
stable 2,3-dihydroazete-2,3-di-/2,2,3-tricarboxylates can be
effectively synthesized from both 2-bromoazirines and 4-
bromoisoxazoles using two-step “4-bromo-2-azadiene
formation/hydrodebromination” procedure. The reduction of
3-bromo-2,3-dihydroazetes from an equilibrium mixture with
4-bromo-2-azadienes is the first example of the selective
hydrodehalogenation of a valence isomer under equilibrium
conditions. In vitro cytotoxicity tests on THP-1 cell line
resulting refluxing equilibrium mixture 8a−p/9a−p and then a
solution of Bu3SnH (1 mmol, 2 equiv) in anhydrous toluene (3
mL) was added dropwise over 40 min. The reaction mixture
was treated with saturated NaF solution (15 mL) and the
aqueous layer was extracted with dichloromethane (2×5 mL).
The combined organic layers were dried over Na2SO4 and
concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel to give
revealed that the 2,3-dihydroazete-2,3-dicarboxylates
differ in their ability to induce apoptosis and/or necrosis. To
adequately describe and quantitatively assess
2 greatly
dihydroazete 2a−p
.
Trimethyl 4-phenyl-2,3-dihydroazete-2,2,3-tricarboxylate
apoptosis/necrosis potential, the difference between the two
areas under the curves of concentration dependency of
apoptosis/necrosis induction within the concentration range is
expedient to use. Trimethyl 4-phenyl-2,3-dihydroazete-2,2,3-
tricarboxylate 2a has got the maximal apoptotic potential
coupled with high cytotoxic and minimal necrotic potential,
being a good candidate for further studies of its anti-cancer
activities.
(2a). Dihydroazete 2a (119 mg, 78%) was prepared according
to the general procedure from azirine 7a (127 mg, 0.5 mmol)
and diazo compound 5a (119 mg, 0.75 mmol) using
hexane/EtOAc mixture (from 5:1 to 1:1) as eluent for
chromatography.
Colorless
solid, mp
99
−
101
°С
(Et2O hexane). H (400 MHz; CDCl3; Me4Si) 3.76 (3 Н, s), 3.866
−
δ
(3 Н, s), 3.874 (3 Н, s), 5.02 (1 H, s), 7.47 (2 Н, t, J 7.6 Hz ), 7.57
(1 Н, t, J 7.6 Hz) 7.82 (2 Н, d, J 7.6 Hz). δC (100 MHz, CDCl3,
Me4Si) 52.7, 53.2, 53.60, 53.64, 72.0, 126.5, 128.7, 130.3,
133.0, 166.4, 166.5, 166.8, 186.3. HRMS (ESI-TOF): [M + Na]+
calcd for С15Н15NNaO6+ 328.0792, found 328.0793. Crystal data
(CCDC-1449965): С15Н15NO6, M = 305.28, monoclinic, space
group P 1 21/n 1, a = 9.47048(18), b = 8.60587(17), c =
Experimental
General methods
Melting points were determined on a melting point apparatus
1
18.2016(4) Å, β = 98.1319(17)°
, V = 1468.55(5) Å3, Z = 4, T =
SMP30 and are uncorrected. H (400 MHz) and 13C (100 MHz)
100 K, d = 1.381 mg mm−3, F(000) = 640, μ = 1.5418 mm−1.
8087 reflections measured, 2800 unique (Rint = 0.0169) were
NMR spectra were recorded on a Bruker AVANCE 400
spectrometer in CDCl3. Electrospray ionization (ESI) mass
spectra were measured on a Bruker MaXis mass spectrometer.
Single crystal X-ray data were collected by means of Agilent
Technologies «Supernova» and «Xcalibur» diffractometers.
Crystallographic data for the structures 2a,h have been
deposited with the Cambridge Crystallographic Data Centre.
Thin-layer chromatography (TLC) was conducted on aluminum
sheets precoated with SiO2 ALUGRAM SIL G/UV254. Toluene
was distilled over sodium wire. 1,2-Dichloroethane was
washed with concentrated H2SO4, water, then distilled from
P2O5 and stored over anhydrous K2CO3. Commercially obtained
N-bromosuccinimide and tributylstannane were used as
used in all calculations. The final R1 was 0.0322 (2555>2
and wR2 was 0.0827 (all data). Compound 2a was also
obtained in 82% yield from isoxazole 10a
Trimethyl 4-(4-methoxyphenyl)-2,3-dihydroazete-2,2,3-
σ(I))
.
tricarboxylate (2b). Dihydroazete 2b (142 mg, 85%) was
prepared according to the general procedure from azirine 7b
(142 mg, 0.5 mmol) and diazo compound 5a (119 mg, 0.75
mmol) using hexane/EtOAc mixture (from 5:1 to 1:1) as eluent
for chromatography. Colorless solid, m.p. 93
−
(Et2O/hexane). H (400 MHz; CDCl3; Me4Si) 3.74 (3 Н, s), 3.85 (3
95
°С
δ
Н, s), 3.86 (6 Н, s), 4.98 (1 H, s), 6.95 (2 Н, d, J 8.8 Hz), 7.76 (2
Н, d, J 8.8 Hz). δC (100 MHz, CDCl3, Me4Si) 52.7, 53.1, 53.5,
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55.4, 71.7, 114.1, 123.1, 128.5, 163.4, 166.5, 166.8, 167.1, (Et2O
185.1. HRMS (ESI-TOF): [M + H]+ calcd for С16Н18NO7+ 336.1078, H, s), 3.90 (3 Н, s), 5.15 (1 H, s), 7.52
found 336.1079. (3 Н, m), 7.96 8.02 (1 Н, m), 8.21 (1 Н, br. s). δC (100 MHz,
−
hexane).
δH (400 MHz; CDCl3; Me4Si) 3.79 (3 H, s), 3.89 (3
−
7.63 (2 Н, m), 7.85 7.95
−
−
Gram-scale synthesis of dihydroazete 2b from isoxazole 10b. CDCl3, Me4Si) 52.8, 53.2, 53.6, 53.8, 72.2, 121.6, 126.9, 127.8,
To a refluxing solution of isoxazole 10b (1.56 g, 5.5 mmol) and 127.9, 128.4, 128.5, 128.7, 129.1, 132.5, 135.5, 166.4, 166.6,
+
dimethyl diazomalonate 5a (1.3 g, 8.25 mmol) in anhydrous 166.9, 186.3. HRMS (ESI-TOF): [M + Ag]+ calcd for С19Н17AgNO6
DCE (12 mL) Rh2(OAc)4 (49 mg, 2 mol %) was added under 462.0101, found 462.0123.
argon. The stirred mixture was refluxed until nitrogen 2-Ethyl
3-methyl
4-phenyl-2-(trifluoromethyl)-2,3-
evolution stopped (10 min). The solvent was evaporated under dihydroazete-2,3-dicarboxylate (2f). Dihydroazete 2f (92 mg,
reduced pressure and the residue was filtered through a pad 56%) was prepared as non-separated 12:1 mixture of two
of silica gel using hexane/EtOAc 2:1 mixture as eluent. The diastereomers according to the general procedure from azirine
filtrate was concentrated under reduced pressure, and the 7a (127 mg, 0.5 mmol) and diazo compound 5b (109 mg, 0.6
residue was dissolved in anhydrous toluene (20 mL) and mmol) using hexane/EtOAc mixture (from 8:1 to 2:1) as eluent
refluxed for 45 min under stirring. AIBN (0.035 g, 0.22 mmol) for chromatography. Compound 2f (12:1 mixture). Colorless
+
was added to the resulting refluxing mixture and then a oil; HRMS (ESI-TOF): [M + H]+, found 330.0956; С15Н15F3NO4
solution of Bu3SnH (3.2 g, 11 mmol) in anhydrous toluene (30 requires 330.0948.
mL) was added dropwise over 40 min. The reaction mixture Compound (2RS,3RS)-2f (major isomer). δH (400 MHz; CDCl3;
was treated with saturated NaF solution (150 mL) and the Me4Si) 1.34 (3 Н, t, J 7.2 Hz), 3.78 (3 Н, s), 4.36 (2 H, q, J 7.2
aqueous layer was extracted with dichloromethane (2
The combined organic layers were dried over Na2SO4 and 7.82
concentrated under reduced pressure. The residue was filtered 1.5 Hz), 52.8, 62.9, 69.7 (q, J 30.7 Hz), 122.5 (q, J 282.3 Hz),
through a pad of silica gel using hexane EtOAc 2:1 mixture as 126.7, 128.8, 129.9, 133.4, 163.9, 165.5, 187.0. δF (376 MHz,
×
25 mL). Hz), 4.68 (1 H, s), 7.48−7.52 (2 Н, m), 7.58−7.64 (1 Н, m)
−
7.87 (2 Н, m). C (100 MHz, CDCl3, Me4Si) 13.9, 51.5 (q, J
δ
−
eluent. The filtrate was concentrated under reduced pressure, CDCl3; CFCl3): -75.10.
the residue was washed twice with a cold Et2O/hexane (1:2) Compound (2RS,3SR)-2f (minor isomer). δH (400 MHz; CDCl3;
mixture to afford pure 2b (1.56 g, 84%).
Me4Si) 1.38 (3 H, t, J 7.2 Hz), 3.81 (3 Н, s), 5.04 (1 H, s),
Trimethyl 4-(2-thienyl)-2,3-dihydroazete-2,2,3-tricarboxylate 7.87
−
7.92 (2 Н, m), (other signals are overlapped). δC (100
(2c). Dihydroazete 2c (124 mg, 80%) was prepared according MHz, CDCl3, Me4Si) 52.7, 63.3, 127.3, 128.6, 130.1, 133.3, 165.0,
to the general procedure from azirine 7c (130 mg, 0.5 mmol) 188.7 (signals of five carbons are overlapped). δF (376 MHz,
and diazo compound 5a (119 mg, 0.75 mmol) using CDCl3; CFCl3): -71.45.
hexane/EtOAc mixture (from 5:1 to 1:1) as eluent for 2-Ethyl 3-methyl 4-(4-methoxyphenyl)-2-(trifluoromethyl)-
chromatography.
(Et2O hexane). H (400 MHz; CDCl3; Me4Si) 3.78 (3 Н, s), 3.86 (3 mg, 72%) was prepared as non-separated 7:1 mixture of two
Н, s), 3.88 (3 H, s), 5.02 (1 H, s), 7.15 (1 Н, dd, J 4.9, 3.8 Hz), diastereomers according to the general procedure from azirine
7.60 (1 Н, dd, J 3.8, 1.0 Hz ), 7.64 (1 Н, dd, J 4.9,1.0 Hz). C (100 7b (142 mg, 0.5 mmol) and diazo compound 5b (109 mg, 0.6
Colorless
solid,
m.p.
88−
89
°С
2,3-dihydroazete-2,3-dicarboxylate (2g). Dihydroazete 2g (129
−
δ
δ
MHz, CDCl3, Me4Si) 52.8, 53.2, 53.6, 54.4, 73.1, 128.0, 132.4, mmol) using hexane/EtOAc mixture (from 8:1 to 2:1) as eluent
132.5, 133.9, 165.9, 166.5, 166.9, 180.3. HRMS (ESI-TOF): [M + for chromatography.
H]+ calcd for С13Н14NO6S+ 312.0536, found 312.0542.
Compound 2g (7:1 mixture). Colorless oil. HRMS (ESI-TOF): [M
+ H]+ calcd for С16Н17F3NO5+ 360.1053, found 360.1055.
Trimethyl 4-(furan-2-yl)-2,3-dihydroazete-2,2,3-tricarboxylate Compound (2RS,3RS)-2g (major isomer). δH (400 MHz; CDCl3;
(2d). Azadiene 8d was synthesized from azirine 7d and diazo Me4Si) 1.30 (3 Н, t, J 7.1 Hz), 3.74 (3 Н, s), 3.84 (3 Н, s), 4.31 (2
compound 5a according to the known procedure in 74% H, q, J 7.1 Hz), 4.63 (1 H, s), 6.91
yield.18 Dihydroazete 2d (62 mg, 42%) was prepared according Н, m,).
C (100 MHz, CDCl3, Me4Si) 13.7, 51.3 (q, J 1.5 Hz), 52.6,
to the general procedure from azadiene 8d (187 mg, 0.5 mmol) 55.4, 62.7, 69.4 (q, J 30.5 Hz), 114.2, 122.5, 122.6 (q, J 282.3
using hexane EtOAc mixture (from 5:1 to 1:1) as eluent for Hz), 128.7, 163.74, 164.1, 165.6, 185.8.
chromatography. Compound 2d. Colorless solid, mp 86 87 Compound (2RS,3SR)-2g (minor isomer). δH (400 MHz; CDCl3;
(Et2O hexane). H (400 MHz; CDCl3; Me4Si) 3.77 (3 Н, s), 3.86 (3 Me4Si) 1.34 (3 H, t, J 7.2 Hz), 3.77 (3 Н, s), 5.00 (1 H, s),
Н, s), 3.87 (3 H, s), 4.94 (1 H, s), 6.57 (1 Н, dd, J 3.5, 1.7 Hz), 7.81 7.85 (2 Н, m), (other signals are overlapped). δC (100
−7.00 (2 Н, m,), 7.74−7.80 (2
δ
−
−
°С
−
δ
−
7.14 (1 Н, d, J 3.5 Hz), 7.64 (1 Н, d, J 1.7 Hz). δC (100 MHz, MHz, CDCl3, Me4Si) 52.5, 63.1, 72.0 (q, J 30.5 Hz), 114.0, 122.5
CDCl3, Me4Si) 52.7, 53.2, 53.5, 53.6, 73.9, 112.4, 117.1, 145.7, (q, J 282.2 Hz), 122.7, 129.3, 163.67, 164.9, 165.1, 187.4 (signals
146.9, 165.8, 166.4, 166.7, 175.9. HRMS (ESI-TOF): [M + H]+ of three carbons are overlapped).
calcd for С13Н14NO7+ 296.0765, found 296.0778.
Trimethyl 4-(naphthalen-2-yl)-2,3-dihydroazete-2,2,3- methoxyphenyl)-2,3-dihydroazete-2,3-dicarboxylate
Dimethyl
(2RS,3SR)-2-(dimethoxyphosphoryl)-4-(4-
(2h).
tricarboxylate (2e). Dihydroazete 2e (117 mg, 66%) was Dihydroazete 2h (127 mg, 66%) was prepared according to the
prepared according to the general procedure from azirine 7e general procedure from azirine 7b (142 mg, 0.5 mmol) and
(152 mg, 0.5 mmol) and diazo compound 5a (119 mg, 0.75 diazo compound 5c (218 mg, 1.05 mmol) using hexane/EtOAc
mmol) using hexane/EtOAc mixture (from 3:1 to 1:1) as eluent mixture (from 3:1 to 100% EtOAc) as eluent for
for chromatography. Colorless solid, mp 123
−
125
°
С
chromatography. Colorless solid, mp 126
−
128
°С
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ARTICLE
(Et2O
3.80
Hz), 7.68 (2 Н, d, J 8.4 Hz). δC (100 MHz, CDCl3, Me4Si) 52.7, 128.7, 163.4, 163.5, 166.7, 166.8, 167.0, 167.3, 185.3, 185.4,
−
hexane). δH (400 MHz; CDCl3; Me4Si) 3.72 (3 Н, s), Me4Si) 13.9, 14.0, 25.7, 28.2, 52.0, 52.5, 52.7, 54.0, 55.45,
−
3.98 (12 Н, m), 4.85 (1 H, d, J 7.0 Hz), 6.92 (2 Н, d, J 8.4 55.48 62.4, 62.8, 76.1, 77.4, 114.2, 114.3, 123.2, 123.4, 128.2,
53.0, 53.8 (d, J 3.3 Hz), 54.5 (d, J 6.6 Hz), 54.6 (d, J 6.6 Hz), 199.6, 203.1. HRMS (ESI-TOF): [M
55.3, 69.3 (d, J 150.4 Hz), 114.1, 123.1, 128.0, 163.3, 166.5 (d, J С17Н19NNaO6+ 356.1105, found 356.1103.
+
Na]+ calcd for
2.3 Hz), 166.7 (d, J 2.8 Hz), 184.0 (d, J 12.1 Hz). HRMS (ESI- Trimethyl
4-(4-methylphenyl)-2,3-dihydroazete-2,2,3-
TOF): [M + Ag]+ calcd for С16Н20AgNO8P+ 491.9972, found tricarboxylate (2k). Dihydroazete 2k (120 mg, 75%) was
491.9972. Crystal data (CCDC-1449943): С16Н20NO8P, M = prepared according to the general procedure from isoxazole
385.30, triclinic, space group P-1, a = 8.8135(7), b = 9.3935(9), 10c (134 mg, 0.5 mmol) and diazo compound 5a (119 mg, 0.75
c = 11.2015(10) Å, α = 78.735(8), β = 81.657(7), γ = 85.426(7)
V = 898.60(14) Å3, Z = 2, T = 100 K, d = 1.424 mg mm−3, F(000) = for chromatography. Colorless solid, mp 94
404, μ = 0.7107 mm−1, 8555 reflections measured, 4127 unique (Et2O
hexane). H (400 MHz; CDCl3; Me4Si) 2.42 (3 Н, s), 3.75 (3
(Rint = 0.0267) were used in all calculations. The final R1 was Н, s), 3.86 (3 Н, s), 3.87 (3 Н, s), 5.00 (1 H, s), 7.27 (2 Н, d, J 8.4
0.0377 (3510>2 (I)) and wR2 was 0.0982 (all data). Hz), 7.71 (2 Н, d, J 8.4 Hz). δC (100 MHz, CDCl3, Me4Si) 21.7,
°,
mmol) using hexane/EtOAc mixture (from 5:1 to 1:1) as eluent
−
95
°С
−
δ
σ
2-Ethyl 3-methyl 2-acetyl-4-phenyl-2,3-dihydroazete-2,3- 52.7, 53.1, 53.56, 53.58, 71.9, 126.5, 127.7, 129.4, 143.9,
dicarboxylate (2i). Azadiene 8i was prepared from azirine 7a 166.4, 166.7, 166.9, 186.0. HRMS (ESI-TOF): [M + Ag]+ calcd for
and diazo compound 5d according to the known procedure in С16Н17AgNO6+ 426.0101, found 426.0120.
67% yield.18 Dihydroazete 2i (56 mg, 37%) was prepared Trimethyl
4-(2,4-dimethylphenyl)-2,3-dihydroazete-2,2,3-
according to the general procedure from azadiene 8i (191 mg, tricarboxylate (2l). Dihydroazete 2l (78 mg, 47%) was prepared
0.5 mmol) using hexane/EtOAc mixture (from 5:1 to 1:1) as according to the general procedure from isoxazole 10d (141
eluent for chromatography. Compound 2i (non-separated mg, 0.5 mmol) and diazo compound 5a (119 mg, 0.75 mmol)
mixture of two diastereomers 1:0.8). Colorless oil. δH (400 using hexane/EtOAc/CHCl3 mixture (from 10:4:1 to 4:4:1) as
MHz; CDCl3; Me4Si) 1.33 (5.4 H, t, J 7.2 Hz), 2.47 (3 Н, s), 2.51 eluent for chromatography. Colorless solid, mp 68
(2.4 Н, s), 3.75 (5.4 Н, s), 4.28 4.37 (3.6 H, m), 4.97 (0.8 H, s), (Et2O hexane). H (400 MHz; CDCl3; Me4Si) 2.37 (3 H, s), 2.64 (3
4.99 (1 H, s), 7.44 7.86 (9 Н, m). δC (100 MHz, CDCl3, Me4Si) H, s), 3.73 (3 Н, s), 3.87 (6 Н, s), 5.07 (1 H, s), 7.02 7.13 (2 Н,
−70 °С
−
−
δ
−
−
13.9, 14.0, 25.7, 28.2, 52.1, 52.5, 52.7, 54.1, 62.5, 62.9, 76.4, m), 7.34 (1 Н, d, J 7.6 Hz). δC (100 MHz, CDCl3, Me4Si) 21.5,
77.7, 126.1, 126.6, 128.7, 128.9, 130.4, 130.6, 132.9, 133.0, 21.7, 52.7, 53.1, 53.6, 55.1, 71.8, 126.2, 126.5, 129.1, 132.5,
166.4, 166.6, 166.7, 167.1, 186.4, 186.5, 199.2, 202.7. HRMS 139.7, 142.9, 166.8 (2 C), 167.0, 187.2. HRMS (ESI-TOF): [M +
+
(ESI-TOF): [M + Na]+ calcd for С16Н17NNaO5 326.0999, found Ag]+ calcd for С17Н19AgNO6+ 440.0258, found 440.0250.
326.0993.
Trimethyl
2-[(E)-2-bromo-3-methoxy-1-(4-methoxyphenyl)-3- tricarboxylate (2m). Dihydroazete 2m (85 mg, 50%) was
solution of prepared according to the general procedure from isoxazole
4-(4-chlorophenyl)-2,3-dihydroazete-2,2,3-
Ethyl
oxoprop-1-enylimino]-3-oxobutanoate (8j).
A
azirine 7b (250 mg, 0.88 mmol) and diazo compound 5d (440 10e (144 mg, 0.5 mmol) and diazo compound 5a (174 mg, 1.1
mg, 2.82 mmol) in anhydrous 1,2-dichloroethane (3 mL) was mmol) using hexane/EtOAc/CHCl3 mixture (from 10:4:1 to
heated to reflux under an argon atmosphere and then 4:4:1) as eluent for chromatography. Colorless solid, mp 74
−75
Rh2(OAс)4 (8 mg, 2 mol%) was added in one portion. The С (Et2O hexane). δH (400 MHz; CDCl3; Me4Si) 3.76 (3 Н, s),
°
−
mixture was stirred under reflux until nitrogen evolution 3.86 (3 Н, s), 3.88 (3 Н, s), 4.99 (1 H, s), 7.45 (2 Н, d, J 8.5 Hz),
stopped (ca. 30 s). The resulting mixture was concentrated 7.77 (2 Н, d, J 8.5 Hz). δC (100 MHz, CDCl3, Me4Si) 52.8, 53.2,
under reduced pressure and the residue was purified by 53.60, 53.64, 72.3, 127.9, 128.7, 129.1, 139.4, 166.1, 166.3,
column chromatography on silica gel using benzene
mixture (from 100:1 to 30:1) to give pure 8j (225 mg, 62%). С15Н14AgClNO6+ 445.9555, found 445.9574.
Orange oil. H (400 MHz; CDCl3; Me4Si) 1.29 (3 Н, t, J 7.1 Hz), Trimethyl 4-(4-bromophenyl)-2,3-dihydroazete-2,2,3-
2.54 (3 Н, s), 3.79 (3 H, s), 3.84 (3 H, s), 4.28 (2 Н, q, J 7.1 Hz), tricarboxylate (2n). Dihydroazete 2n (100 mg, 52%) was
6.91 6.97 (2 Н, m), 7.49 (2 Н, d, J 8.8 Hz). C (100 MHz, CDCl3, prepared according to the general procedure from isoxazole
Me4Si) 13.9, 25.6, 52.9, 55.2, 62.4, 93.8, 113.6, 127.9, 130.2, 10f (167 mg, 0.5 mmol) and diazo compound 5a (174 mg, 1.1
154.2, 156.3, 160.68, 160.74, 163.3, 195.6. HRMS (ESI-TOF): [M mmol) using hexane EtOAc CHCl3 mixture (from 10:4:1 to
+ Na]+ calcd for С17Н18BrNaNO6+ 434.0210, found 434.0218.
4:4:1) as eluent for chromatography. Colorless solid, mp 66 67
2-Ethyl 3-methyl 2-acetyl-4-(4-methoxyphenyl)-2,3- С (Et2O hexane). δH (400 MHz; CDCl3; Me4Si) 3.76 (3 Н, s),
−EtOAc 166.7, 185.4. HRMS (ESI-TOF): [M +
Ag]+ calcd for
δ
−
δ
−
−
−
°
−
dihydroazete-2,3-dicarboxylate (2j). Dihydroazete 2j (75 mg, 3.86 (3 Н, s), 3.88 (3 Н, s), 4.99 (1 H, s), 7.62 (2 Н, d, J 8.5 Hz),
45%) was prepared according to the general procedure from 7.70 (2 Н, d, J 8.5 Hz). δC (100 MHz, CDCl3, Me4Si) 52.8, 53.3,
azadiene 8j (206 mg, 0.5 mmol) using hexane/EtOAc mixture 53.6, 53.7, 72.3, 128.0, 128.0, 129.1, 132.1, 166.1, 166.3,
(from 5:1 to 1:1) as eluent for chromatography. Compound 2j 166.6, 185.6. HRMS (ESI-TOF): [M
(non-separated mixture of two diastereomers 1.1:1). Colorless С15Н14AgBrNO6+ 489.9050, found 489.9068.
oil. H (400 MHz; CDCl3; Me4Si) 1.33 (6 Н, t, J 7.1 Hz), 2.46 (3 Н, Trimethyl 4-{4-[5-methoxy-4-(methoxycarbonyl)oxazol-2-
s), 2.50 (3 Н, s), 3.742 (3 Н, s), 3.745 (3 Н, s), 3.88 (6 Н, s), yl]phenyl}-2,3-dihydroazete-2,2,3-tricarboxylate (2o).
4.21 4.39 (4 H, m), 4.95 (1 H, s), 4.96 (1 H, s), 6.90 7.05 (4 Н, Dihydroazete 2o (102 mg, 44%) was prepared according to the
m), 7.70
+
Ag]+ calcd for
δ
−
−
−
7.73 (2 Н, m), 7.76
−
7.80 (2 Н, m).
δC (100 MHz, CDCl3, general procedure from isoxazole 10g (140 mg, 0.5 mmol) and
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Journal Name
diazo compound 5a (363 mg, 2.3 mmol) using hexane/EtOAc 72.0, 126.5, 128.7, 130.3, 133.0, 165.9, 166.5, 166.8, 186.4.
+
mixture (from 3:1 to 100% EtOAc) as eluent for HRMS (ESI-TOF): [M + Na]+ calcd for С16Н17NNaO6 342.0948,
chromatography. Colorless solid, mp 87
(Et2O hexane, dec.). H (400 MHz; CDCl3; Me4Si) 3.76 (3 H, s),
3.86 (3 H, s), 3.87 (3 Н, s), 3.92 (3 Н, s), 4.29 (3 Н, s), 5.02 (1 H,
s), 7.90 (2 Н, d, J 8.4 Hz), 8.07 (2 Н, d, J 8.4 Hz). C (100 MHz,
−
96
°
С, 140
−
143
°
С
found 342.0954.
−
δ
Acknowledgements
δ
CDCl3, Me4Si) 51.9, 52.8, 53.2, 53.7 (2 C), 59.9, 72.4, 108.1,
We gratefully acknowledge the financial support of the Russian
Foundation for Basic Research (grant no. 14-03-00187, 16-03-
00596, 16-33-60130, 16-33-00651) and Saint Petersburg State
University (grant no. 12.38.239.2014, 12.38.217.2015). This
research used resources of ‘Magnetic Resonance Research
Centre’, ‘Chemical Analysis and Materials Research Centre’,
‘Centre for X-ray Diffraction Studies’ and ‘Chemistry
Educational Centre’ of Research Park of Saint Petersburg State
University.
125.9, 127.0, 130.1, 131.6, 149.6, 161.6, 162.0, 166.1, 166.3,
166.6, 185.7. HRMS (ESI-TOF): [M
С21Н20AgN2O10+ 567.0163, found 567.0188.
+
Ag]+ calcd for
Trimethyl
4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2,3-
dihydroazete-2,2,3-tricarboxylate (2p). Dihydroazete 2p (131
mg, 72%) was prepared according to the general procedure
from isoxazole 10h (156 mg, 0.5 mmol) and diazo compound
5a (119 mg, 0.75 mmol) using hexane/EtOAc mixture (from 5:1
to 1:1) as eluent for chromatography. Colorless solid, mp
88
s), 3.85 (3 H, s), 3.86 (3 Н, s), 4.25
6.92 (1 Н, d, J 8.4 Hz ), 7.28 7.35 (2 Н, m).
−
90
°
С (Et2O
−
hexane).
δ
H (400 MHz; CDCl3; Me4Si) 3.75 (3 H,
4.32 (4 Н, m), 4.95 (1 H, s),
C (100 MHz, CDCl3,
−
−
δ
Notes and references
Me4Si) 52.7, 53.1, 53.51, 53.54, 64.0, 64.6, 71.6, 115.7, 117.6,
1
(a) N. De Kimpe, In Comprehensive Heterocyclic Chemistry II,
ed. A. Padwa, Elsevier, Oxford, 1996, vol. 1, Chapter 1, p. 21;
(b) D. E. Davies, , R. C. Storr, In Comprehensive Heterocyclic
Chemistry, ed. W. Lwowski, Pergamon, Oxford, 1984, vol. 7,
120.6, 123.8, 143.7, 148.0, 166.5, 166.7, 167.0, 185.1. HRMS
+
(ESI-TOF): [M + Ag]+ calcd for С17Н17AgNO8 470.0000, found
470.0004.
part 5, p. 237
M. Takahashi, Y. Terada, I. Nakai, H. Nakanishi, E. Yoshimura,
S. Mori, N. K. Nishizawa, The Plant Cell, 2003, 15, 1263 1280.
T. Takemoto, K. Nomoto, S. Fushiya, R. Ouchi, G. Kusano, H.
Hikino, S. Takagi, Y. Matsuura, M. Kakudo, Proc. Japan Acad.,
−284.
Dimethyl (E)- and (Z)-2-(3-ethoxy-3-oxo-1-phenylprop-1-
enylimino)malonates (E-6 and Z-6). Rh2(OAc)4 (5 mg, 1 mol %
on azirine) was added to a refluxing solution of azirine 3e (189
mg, 1 mmol) and diazo compound 5a (237 mg, 1.5 mmol) in
anhydrous DCE under stirring. The mixture was stirred under
reflux until nitrogen evolution stopped (ca. 10 min). The
solvent was removed under reduced pressure and the residue
2
3
−
1978, 54, Ser B, 469
(a) I. V. Komarov, A. O. Grigorenko, A. V. Turov, V. P. Khilya,
Russ. Chem. Rev., 2004, 73, 785 810; (b) R. T. Shuman, R. B.
−473.
4
−
Rothenberger, C. S. Campbell, G. F. Smith, D. S. Gifford-
Moore, J. W. Paschal, P. D. Gesellchen, J. Med. Chem., 1995,
38, 4446−4453; (c) D. Kern, M. Schutkowski, T. Drakenberg,
J. Am. Chem. Soc., 1997, 119, 8403 8408.
was purified by column chromatography (Et2O
−
hexane, from
(41 mg,
6/Z-6 (1:4.4, 77 mg,
1:25 to 1:7) to give compounds E- (140 mg, 44%), Z-
6
6
−
13%) and non-separated mixture of E-
5
6
7
8
G. Gerona-Navarro, M. J. Pérez de Vega, M. T. García-López,
G. Andrei, R. Snoeck, J. Balzarini, E. De Clercq, R. González-
Muñiz, Bioorg. Med. Chem. Lett., 2004, 14, 2253–2256.
T. Akihisa, H. Tokuda, K. Yasukawa, M. Ukiya, A.Kiyota, N.
Sakamoto, T. Suzuki, N. Tanabe, H. Nishino, J. Agric. Food
Chem., 2005, 53, 562−565.
Z. Liu, S. F. Jenkinson, T. Vermaas, I. Adachi, M. R. Wormald,
Y. Hata, Y. Kurashima, A. Kaji, C.-Y. Yu, A. Kato, G. W. J. Fleet,
24%).
Compound E-
Н, t, J 7.1 Hz), 3.91 (6 Н, br. s), 4.06 (2 H, q, J 7.1 Hz), 5.34 (1 H,
s), 7.35 7.44 (3 Н, m), 7.46 7.52 (2 Н, m). C (100 MHz, CDCl3,
6. Yellow oil. δH (400 MHz; CDCl3; Me4Si) 1.13 (3
−
−
δ
Me4Si) 13.8, 52.8 (br. s), 53.5 (br. s), 60.1, 102.5, 127.8, 128.5,
129.7, 132.8, 149.0, 160.8 (2C), 161.3, 164.9. HRMS (ESI-TOF):
[M + Na]+, found 342.0950; С16Н17NNaO6+ requires 342.0948.
J. Org. Chem., 2015, 80, 4244−4258.
Compound Z-
Н, t, J 7.1 Hz), 3.89 (6 Н, br. s), 4.17 (2 H, q, J 7.1 Hz), 5.60 (1 H,
s), 7.37 7.45 (3 Н, m), 7.49 7.56 (2 Н, m). C (100 MHz, CDCl3,
6. Yellow oil. δH (400 MHz; CDCl3; Me4Si) 1.28 (3
A. F. Khlebnikov, M. S. Novikov, In Topics in Heterocyclic
Chemistry: Synthesis of 4- To 7-Membered Heterocycles by
Ring Expansion, ed. M. D’hooghe, H.-J. Ha, Springer,
−
−
δ
Switzerland, 2016, vol. 41, p. 143
N.-C. C. Yang, B. Kim, W. Chiang, T. Hamada, J. Chem. Soc.
Chem. Comm., 1976, 729 730.
−232.
Me4Si) 14.1, 53.2 (2 C), 60.2, 97.3, 126.4, 128.7, 130.5, 134.3,
9
150.4, 158.5, 165.2 (signals of two carbons are overlapped).
+
−
HRMS (ESI-TOF): [M + Na]+ calcd for С16Н17NNaO6 342.0948,
10 H. Hoshina, K. Kubo, A. Morita, T. Sakurai, Tetrahedron,
2000, 56, 2941–2851.
11 T. H. Koch, R. H. Higgins, H. F. Schuster, Tetrahedron Lett.,
found 342.0950.
3-Ethyl
2,2-dimethyl
4-phenyl-2,3-dihydroazete-2,2,3-
(100 mg, 0.31
1977, 18, 431−434.
tricarboxylate (2a'). A solution of azadiene E-
6
12 A. B. Levy, A. Hassner, J. Am. Chem. Soc., 1971, 93, 2051-
2053.
mmol) in anhydrous toluene (3 mL) was refluxed for 4 h under
stirring. The solvent was removed under vacuum and the
residue was purified by column chromatography
13 K. Burger, J. Fehn, Angew. Chem. Int. Ed., 1972, 11, 47.
14 (a) A. F. Khlebnikov, M. S. Novikov, A. A. Amer, Tetrahedron
Lett., 2004, 45, 6003−6006. (b) A. F. Khlebnikov, M. S.
Novikov, A. A. Amer, R. R. Kostikov, J. Magull, D. Vidovic,
Russ. J. Org. Chem. 2006, 42, 515−526; (c) M. S. Novikov, A.
F. Khlebnikov, N. V. Rostovskii, S. Tcyrulnikov, A. A.
(hexane
53%) as a colorless oil.
J 7.1 Hz), 3.86 (3 Н, s), 3.87 (3 Н, s), 4.21 (2 H, q, J 7.1 Hz), 5.01
(1 H, s), 7.43 7.50 (2 Н, m), 7.52 7.59 (1 Н, m) 7.80 7.86 (1 Н,
−
EtOAc, from 5:1 to 1:1) to give compound 2a' (53 mg,
δH (400 MHz; CDCl3; Me4Si) 1.26 (3 Н, t,
−
−
−
Suhanova, K. V. Zavyalov, D. S. Yufit, J. Org. Chem., 2015, 80
18−29.
,
m). δC (100 MHz, CDCl3, Me4Si) 13.9, 53.0, 53.6, 53.8, 61.9,
8 | J. Name., 2012, 00, 1-3
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