4-Halo-2-azabuta-1,3-dienes as intermediates in the rhodium carbenoid-initiated transformation of 2-halo-2H-azirines into 2,3-dihydroazetes and 2,5-dihydrooxazoles

Article abstract of DOI:10.1016/j.tet.2015.05.022

A wide range of electron-poor 4-bromo-/4-chloro-2-azabuta-1,3-dienes were synthesized by the Rh₂(OAc)₄-catalyzed reaction of diazo esters and diazo ketones with methyl 2-halo-2H-azirine-2-carboxylates. The E stereoselectivity with respect to the configuration of the CC bond of the 2-azadiene moiety is in good agreement with the results of DFT (M06-2X/6-31+G(d,p)) calculations of the reaction pathway. The reaction proceeds via the formation of an azirinium ylide intermediate followed by ring opening with outward rotation of the halogen atom. Depending on the substitution pattern at C¹ electron-poor 4-halo-2-azabutadienes can undergo two types of cyclization at elevated temperatures: reversible 1,4-electrocyclization to give 2,3-dihydroazetes or 1,5-exo-trig cyclization to give 5-methylene-2,5-dihydrooxazoles, both in good yields. The dihydrooxazole derivatives can be also obtained at ambient temperature under DBU catalysis.

Full text of DOI:10.1016/j.tet.2015.05.022

Tetrahedron xxx (2015) 1e13
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
4-Halo-2-azabuta-1,3-dienes as intermediates in the rhodium
carbenoid-initiated transformation of 2-halo-2H-azirines into
2,3-dihydroazetes and 2,5-dihydrooxazoles
,
a
Ilia A. Smetanin a, Mikhail S. Novikova , Nikolai V. Rostovskii ,
*
Alexander F. Khlebnikov a, Galina L. Starova a, Dmitry S. Yufit b
a Institute of Chemistry, Saint-Petersburg State University, Universitetskii pr. 26, 198504 St. Petersburg, Russia
b Department of Chemistry, University of Durham, South Road, Durham DH1 3LE, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A wide range of electron-poor 4-bromo-/4-chloro-2-azabuta-1,3-dienes were synthesized by the
Rh2(OAc)4-catalyzed reaction of diazo esters and diazo ketones with methyl 2-halo-2H-azirine-2-
carboxylates. The E stereoselectivity with respect to the configuration of the C]C bond of the 2-
azadiene moiety is in good agreement with the results of DFT (M06-2X/6-31þG(d,p)) calculations of
the reaction pathway. The reaction proceeds via the formation of an azirinium ylide intermediate fol-
lowed by ring opening with outward rotation of the halogen atom. Depending on the substitution
pattern at C1 electron-poor 4-halo-2-azabutadienes can undergo two types of cyclization at elevated
temperatures: reversible 1,4-electrocyclization to give 2,3-dihydroazetes or 1,5-exo-trig cyclization to
give 5-methylene-2,5-dihydrooxazoles, both in good yields. The dihydrooxazole derivatives can be also
obtained at ambient temperature under DBU catalysis.
Received 20 February 2015
Received in revised form 18 April 2015
Accepted 6 May 2015
Available online xxx
Keywords:
2-Azabutadienes
Azirines
Diazo compounds
2,3-Dihydroazetes
2,5-Dihydrooxazoles
Heterocyclizations
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
C10 (reaction 2, X¼O) and C]N11 (reaction 3) can be easily formed
by Wittig or aza-Wittig reaction. The Mannich reaction of benz-
2-Azabuta-1,3-dienes are valuable building blocks for the con-
struction of various five- and six-membered nitrogen heterocycles.1
Electron-poor 2-azadienes bearing one or more electron-
withdrawing substituents are of particular interest due to their
high activity both in cycloadditions2 and various thermal,3 cata-
lytic4 and nucleophile-initiated heterocyclizations.5 There are two
different synthetic approaches to electron-poor 2-azadienes. The
first involves the eliminative formation of double bonds in the
saturated precursor to give the target azadiene, as, for example, by
destruction of 2-aryl-4-thiazolidinecarboxylates under action of
Ag2CO3/DBU6 or dehydration of arylidene derivatives of serine es-
ters.7 An alternative approach implies the formation of one of the
three bonds of the azadiene moiety: C1¼N, NeC3 or C3¼C4. This
methodology is illustrated by reactions 1e4 (Scheme 1), where the
hydrylidene glycinates12 (reaction 2, X¼H2) can serve as an alter-
native to the first of these methods, while a carbenoid-mediated
azirine ring opening3aec,13 (reaction 4) can serve as an alternative
to the aza-Wittig reaction. It is important that an electron-
withdrawing substituent can be introduced by methods 3 and 4
into any position of the 2-azadiene fragment.
In view of our interest in electron-poor 2-azabutadienes as
starting materials for the construction of 3e7 membered nitrogen
heterocycles with unusual substitution patterns we envisaged
the monohalogeno-substituted derivatives as perspective in-
termediates for heterocyclizations. The first syntheses of electron-
poor 4-bromo- and 4-chloro-2-azabuta-1,3-dienes from methyl 2-
bromo- and 2-chloro-3-phenyl-2H-azirine-2-carboxylates by
a Rh2(OAc)4-catalyzed reaction with alkyl 2-acetyl- and 2-benzoyl-
2-diazoacetates and dimethyl diazomalonate have been reported in
our preliminary publication.14 It was also revealed that some 4-
halo-2-azabuta-1,3-dienes at elevated temperatures exist in equi-
librium with their valence isomers, 2,3-dihydroazetes.
possible location of a
p-acceptor group is highlighted with blue.
Construction of the azadiene moiety by formation of a CeN single
bond can be realized starting from NH-imines8 or N-silylimines9
and electron-deficient acetylenes (reaction 1). Double bonds C]
In the present work the scope of Rh(II)-catalyzed reaction of 2-
bromo- and 2-chloroazirine-2-carboxylates with diazo carbonyl
compounds for the preparation of electron-poor 4-halo-2-azabuta-
* Corresponding author. Tel.: þ7 (812) 428 93 44; fax: þ7 (812) 363 67 22; e-mail
address: m.s.novikov@chem.spbu.ru (M.S. Novikov).
http://dx.doi.org/10.1016/j.tet.2015.05.022
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Smetanin, I. A.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.022

2
I.A. Smetanin et al. / Tetrahedron xxx (2015) 1e13
Scheme 1. Synthetic approaches to electron-poor 2-azabuta-1,3-dienes.
1,3-dienes was studied. The latter proved to be useful starting
materials for the synthesis of azete and oxazole derivatives by
heterocyclization reactions and this is discussed in the second part
of the paper.
Scheme 2. The reaction of azirines 1aeg with diazo compounds 2aem.
results in a dramatic decrease in yields and this necessitates a rapid
pass through a chromatographic column. Thus, 1H NMR analysis of
the reaction mixture derived from azirine 1a and diazo compound
2d revealed that conversion into azadiene 4f is practically quanti-
tative, but falls to 52% after chromatographic purification (Table 1,
entry 8). Azadiene 4c cannot be isolated in pure form by chroma-
tography at all, as it completely decomposes on SiO2 (Table 1, entry
5). The 1H NMR spectrum of the reaction mixture containing aza-
diene 4c indicated an 80% yield, by use of internal standard, and it
was used for further experiments in crude form.
2. Results and discussion
2.1. Synthesis of 4-halo-2-azabuta-1,3-dienes
To evaluate the scope and limitations of the carbenoid-mediated
ring opening of 2-halo-2H-azirines 1aeg into 4-halo-2-
azabutadienes 4 we employed structurally diverse diazo com-
pounds: diazo keto esters 2aee, diazo diester 2f, ethyl 2-cyano-2-
diazoacetate 2g, ethyl 2-diazo-2-(dimethoxyphosphoryl)acetate
2h, diazo diketone 2i, diazo esters 2jel and diazo ketone 2m
(Scheme 2). This set of diazo compounds allowed the generation of
both acceptor/acceptor and donor/acceptor substituted carbenoids,
which have different reactivity towards azirines 1aeg and target
azadienes 4. It was found that slow addition of a solution of diazo
compound 2a in 1,2-dichloroethane (DCE) to a refluxing solution of
azirine 1a and 2 mol % Rh2(OAc)4 in DCE (method A) provided
azadiene 4a (43%) and an 1:1 mixture of diastereomeric dihy-
droazetes 5a (22%) (Table 1, entry 1). The ratio 4a/5a decreases with
the decrease of addition rate of the diazo compound. Special ex-
periments showed that 4a slowly cyclizes into 5a under the re-
action conditions. The yield of azadiene 4a was improved to 62% by
changing the procedure: addition of the catalyst to the refluxing
solution of 1a and 2a in DCE followed by heating of the reaction
mixture for the time required to decompose the diazo compound
(30 s for 2a) (method B).
This procedure was used for the preparation of various aza-
dienes 4, listed in the Table 1. However, if an azadiene is stable at
the reaction temperature, it is expedient to carry out the reaction
according to method A. This requires a considerably smaller excess
of diazo compound and provides higher yields due to the decrease
of losses of the product at the chromatographic purification stage.
For example, the synthesis of azadiene 4r by method B requiring
12-fold excess of diazoacetylacetone 2i gave 4r in 12% yield only,
while method A (6-fold excess of the 2i) provided the product in
54% yield (Table 1, entry 21).
Changing bromine in azirine 1 for chlorine does not influence
the course of the reaction but leads to the increase of the azadiene/
dihydroazete ratio (Table 1).
The yields of isolated azadienes 4d,e (entries 6, 7) are low for
both methods in spite of the absence of cyclic products 5d,e. This is
due to the side reaction of ethyl 2-benzoyl-2-diazoacetate 2c,
which produces substantial amounts of oxetanone 6, the intra-
molecular CH-insertion product of the intermediate rhodium car-
benoid (Scheme 2).15 The proximity of the Rf values of 6 and 4d,e is
the reason for the notable losses of azadienes 4d,e during chro-
matographic purification. The CH-insertion byproduct was practi-
cally not formed, when the methyl ester of benzoyldiazoacetic acid
2d was reacted with azirines 1aec under the same conditions.
Methyl ester 2d, therefore, provides substantially higher yields of
azadienes (Table 1, entries 9e11).
Azadienes bearing a
p
-donating heteroaryl substituent at C3
(Table 1, entries 16e18) were also synthesized following method B.
Furyl-substituted azadienes 4m,n are formed along with small
amounts of compounds 7a,b, which are the products of furan ring
opening under the action of rhodium carbenoid.
Azadiene 4x can be obtained in good yield from azirine 1a and
-diazo-a-phenylacetone 2m by crystallization without chro-
matographic purification (Table 1, entry 27). The use of ethyl
diazoacetate 2n and azirine 1a for the preparation of the C1-mon-
osubstituted azadiene was not successful. Under Rh2(OAc)4-catal-
ysis only the consumption of the diazo compound was observed,
while the azirine remained unaffected.
a
The overall yields of compounds 4, 5 are usually high. However,
partial decomposition of some azadienes (4a,b,d,e,g,p) on silica gel
The structures of azadienes 4 and dihydroazetes 5 were verified
by 1H and 13C NMR spectroscopy, mass-spectrometry and the
Please cite this article in press as: Smetanin, I. A.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.022

I.A. Smetanin et al. / Tetrahedron xxx (2015) 1e13
3
Table 1
Rh2(OAc)4-catalyzed reactions of azirines 1aeg with diazo compounds 2aem
Entry
Azirine
Hal
R1
Diazo compound
R2
R3
Methoda
Yield of 4, %
Yield of 5, %
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1a
1a
1b
1a
1a
1b
1c
1a
1a
1b
1c
1d
1e
1f
Br
Br
Cl
Cl
Br
Br
Cl
Br
Br
Cl
Br
Br
Br
Cl
Br
Br
Cl
Br
Br
Br
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2a
2a
2a
2a
2b
2c
2c
2d
2d
2d
2d
2e
2f
2f
2f
2f
2f
2f
2g
2h
COMe
COMe
COMe
COMe
COCH2Cl
COPh
COPh
COPh
COPh
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OEt
A
B
A
B
B
A
A
A
B
B
B
B
B
B
B
B
B
B
B
B
43 (4a)
62 (4a)
56 (4b)
77 (4b)
80 (4c)c
35 (4d)d
30 (4e)d
52 (4f)
83 (4f)
82 (4g)
86 (4h)
55 (4i)
22 (5a)b
Traces (5a)
10 (5b)b
Traces (5b)
0 (5c)
0 (5d)
0 (5e)
0 (5f)
0 (5f)
0 (5g)
0 (5h)
0 (5i)
14 (5j)
7 (5k)
45 (5l)
10 (5m)
0 (5n)
28 (5o)
Traces (5p)
17 (RS,RS-5q)
9 (RS,SR-5q)
0 (5r)
9
Ph
Ph
10
11
12
13
14
15
16
17
18
19
20
COPh
COPh
4-MeOC6H4
Ph
Ph
4-NCC6H4CO
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CN
81 (4j)
90 (4k)
50 (4l)
Ph
4-MeOC6H4
2-Furyl
2-Furyl
2-Thienyl
Ph
73 (4m)e
87 (4n)f
45 (4o)
82 (4p)g
40 (4q)
1a
1a
Ph
PO(OMe)2
OMe
21
22
23
24
25
26
27
1a
1a
1c
1g
1a
1a
1a
Br
Br
Br
Br
Br
Br
Br
Ph
Ph
2i
2j
2j
2j
2k
2l
2m
COMe
CF3
CF3
CF3
Ph
Me
A
B
B
B
B
B
B
54 (4r)
90 (4s)
92 (4t)
OEt
OEt
OEt
OMe
OMe
Me
0 (5s)
0 (5t)
0 (5u)
0 (5v)
0 (5w)
0 (5x)
4-MeOC6H4
CO2Et
Ph
Ph
Ph
56 (E/Z 4u)h
92 (E-4v)
87 (E-4w)
76 (4x)
4-O2NC6H4
Ph
a
Method A: slow addition of a 1.77 M solution of diazo compound 2 in DCE to a solution of azirine 1 and Rh2(OAs)4 (2 mol %) in DCE at reflux under argon. Method B: the
addition in one portion of Rh2(OAs)4 (2 mol %) to a solution of azirine 1 and diazo compound 2 in DCE at reflux under argon.
b
Diastereomeric ratio is presented in Table 2.
c
The yield was measured by 1H NMR spectroscopy with CHBr2CHBr2 as internal standard.
d
3-Benzoyl-4-methyloxetan-2-one (6) was formed as a byproduct (method A).
Compound 7a was isolated as a byproduct in 12% yield.
Compound 7b was isolated as a byproduct in 11% yield.
An equilibrium mixture 4p/5p (8:1) was obtained on storage in CDCl3 for 7 d at rt.
e
f
g
h
A 1:1.3 mixture of E/Z-isomers across C]C bond.
structures of 4e, 5k, RS,RS-5q, 5t were confirmed by X-ray analysis
data (Fig. 1). All reactions except the transformation of azirine 1g
proceed completely stereoselectively to give 4-halo-2-
azabutadienes with E configuration of the C]C bond. The re-
action of the 3-ethoxycarbonyl-substituted azirine 1g with diazo
compound 2j (Table 1, entry 24) furnished mixture of fumaric and
maleic acid derivatives 4u in a 1:1.3 ratio and in an overall yield of
56%, calculated based on the corresponding azide, used for the
preparation of azirine 1g (azirine 1g was used without purification
because of the instability on silica gel).
stereoselectivity on going from H to Cl or Br can be explained by
destabilizing repulsions of nitrogen and halogen lone pairs in TS2
and TS4, which make them more late and much less stable than TS1
and TS3 (Fig. 2, pictures of TS1 and TS2). With this replacement the
reactivity of formed azadienes E,E-and Z,E-4y is also dramatically
changed: 1,4-cyclization into dihydroazetes 5y (Fig. 2, pink lines)
became competitive with 1,6-cyclization into 2H-1,4-oxazine 9
(Fig. 2, blue lines), the sole cyclic products of non-halogenated
analogs. In the above mentioned experiments dihydroazetes 5 are
the only isolated products of cyclization of azadienes 4. It is notable
that in any reaction of azirines 1aec with acyl-substituted diazo
compounds 2aee,i (Table 1) no 2-halo-2H-1,4-oxazine of the type 9
was detected that can be explained by thermal instability of the
latter.
It is notable that compounds 4d14 and 4e in the crystal have the
Z configuration of the C]N bond (Fig. 1), while in solution all
synthesized azadienes 4 are mixtures of rapidly interconverting
E,Z-isomers.14
The stereochemical outcome of the reaction of azirines 1aef
with rhodium carbenoids 3aem is in good agreement with the
reaction mechanism involving the formation of a metal-free aziri-
nium ylide 8 (Scheme 2). Quantum-chemical calculations (DFT
M06-2X/6-31þG(d,p)) carried out for the transformations of model
ylides E- and Z-8y (Fig. 2) into azadienes E,E-, E,Z-, Z,E- and Z,Z-4y
(the first descriptor displays the configuration of the C]N bond,
the second onedof the S¼S bond) predict azirinium ring opening
with the CO2Me group moving exclusively inwards. Free energy
barriers for the ring opening of ylides Z-8y and E-8y into E,Z- and
Z,Z-4y azadienes (outward rotation of CO2Me, red lines) are higher
by 6.6e7.2 kcal/mol than those for transformations into E,E- and
Z,E-4y azadienes (inward rotation of CO2Me, black lines). It is no-
table that non-chlorinated analogs of ylide 8y (H instead of Cl)
undergo unselective ring opening and this was confirmed by ex-
perimental and computational experiments.13a The increase in
2.2. Synthesis of 3-halo-2,3-dihydroazetes and azadiene-
dihydroazete valence isomerism
Dihydroazetes 5a,b,jem,oeq (Table 1), isolated (or detected) in
the reactions of azirines 1aed,f with diazo compounds 2aec,fej,
are the products of reversible 1,4-electrocyclization of azadienes
4a,b,jem,oeq proceeding at elevated temperatures. The 1-cyano-
substituted derivative 4p slowly isomerizes into 5p even at room
temperature (Scheme 3). Actually, heating a solution of azadiene
4jet or the solution of its dihydroazete isomer 5jet in benzene-d6
at 100 ꢀC in a vial with a screw-on cap provides an equilibrium
mixture 4 and 5 (Table 2, entries 4e14). The cyclization rate in-
creases with the increasing electron-withdrawing ability of C1-
substituents: 4p>4j>4s. For example, the change of the CO2Me
group at atom C1 in azadiene 4j for CF3 (azadiene 4s) increases the
Please cite this article in press as: Smetanin, I. A.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.022

4
I.A. Smetanin et al. / Tetrahedron xxx (2015) 1e13
Fig. 1. X-ray crystal structures of compounds 4e, 5k, RS,RS-5q, 5t.
Fig. 2. Free energy profiles (M06-2X/6-31þG(d,p), kcal/mol, 357 K) for the transformations of ylides 8y to azadienes 4y, dihydroazetes 5y, and 2H-1,4-oxazine 9 in 1,2-
dichloroethane (PCM).
Please cite this article in press as: Smetanin, I. A.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.022

I.A. Smetanin et al. / Tetrahedron xxx (2015) 1e13
5
Scheme 3. 1,4-Electrocyclization of azadienes 4a,b,f,jeq,s,t,z into dihydroazetes 4f,jeq,s,t,z.
Table 2
The effect of substituents on the azadiene/dihydroazete valence isomerism (C6D6, 100 ꢀC)a
Entry
Azadiene
Hal
R1
R2
R3
Equilibrium ratio 4:5
dr of 5
1
2
3
4
5
6
7
8
4a
4b
4f
Br
Cl
Br
Br
Cl
I
Br
Br
Cl
Br
Br
Br
Br
Br
Br
Ph
Ph
Ph
Ph
Ph
Ph
COMe
COMe
COPh
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CN
OEt
OEt
db
1:1
1:1
4:1
db
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OEt
3:1c
1:1
4j
4k
4z
4l
4m
4n
4o
4p
4q
4s
4t
2.6:1
1:1.3
1:2.5
3.9:1
20:1
1:1.2
8:1d
1.8:1
2.4:1
1:1
4-MeOC6H4
2-Furyl
2-Furyl
2-Thienyl
Ph
9
10
11
12
13
14
15
One isomer
2:1
One isomer
One isomer
Ph
Ph
PO(OMe)2
CF3
CF3
OMe
OEt
OEt
4-MeOC6H4
CO2Et
4u
CF3
OEt
de
a
Equilibrium ratio 4:5 and diastereomeric ratio for 5 are determined by 1H NMR spectroscopy with CHBr2CHBr2 as internal standard.
Equilibrium ratio was not determined because of the decomposition of the 2-azadiene (benzene, at 100 ꢀC).
Heating in benzene at 80 ꢀC in the presence of K2CO3.
b
c
d
e
Measured at 20 ꢀC.
Compound 4u does not cyclize at 100 ꢀC.
time taken to reach equilibrium from 25 to 100 min. Azadienes E-
The introduction of the electron-donor p-methoxy substituent
in C3-phenyl of azadiene 4l,t stabilizes the cyclic form 5l,t (Table 2,
entries 4, 7 and 13, 14). This result can be explained by the stabi-
lizing effect of the direct polar conjugation of the p-methoxy group
and the C]N bond of the dihydroazete system. Azadiene 4u with
a CO2Et group at C3 does not cyclize into dihydroazete 5u.
Dihydroazetes 5jem,o,qet,y are rather stable at room tem-
perature and therefore can be prepared from the corresponding
azadienes (Scheme 3). Thus, dihydroazete 5j was synthesized in
83% yield by five-fold heating of the solution of azadiene 4j and
chromatographic separation of the product after equilibrium was
achieved. Iodinated dihydroazete 5z was prepared in an analo-
gous way in 77% yield by four-fold heating using crystallization
instead of chromatography. A problem arises during the prepa-
ration of the dihydroazete 5p from 1-cyano-substituted 2-
azadiene 4p. The latter hydrolyzes under prolonged separation
from dihydroazete 5p on silica gel, producing substantial
amounts of methyl (E)-2-bromo-3-(2-ethoxy-2-oxoacetamido)-
3-phenylacrylate 11.
4v,w having a C1-aryl substituent instead of an ester group are
stable under these conditions. At higher temperatures (o-xylene,
144ꢀS, 17 h) only azadiene Z-4v,w, the product of isomerization of
azadiene E-4v,w across C]C bond, was isolated. Thus, the presence
of two strong electron-withdrawing substituents at atom C1 is
a requisite for the 1,4-cyclization of azadiene to occur.
To reveal the influence of a halogen substituent on the 1,4-
cyclization of azadienes 4, in addition to bromides and chlorides
4aex, 4-iodoazadiene 4z was synthesized. Attempts to prepare this
compound by the above described azirineecarbenoid coupling
procedure proved to be poor and this is due to problems with
synthesis and stability of the corresponding iodoazirine. We
turned, therefore, to a recently reported protocol for the prepara-
tion of some electron-poor 2-azadienes by carbenoid-mediated
isoxazole ring opening.16 Starting iodoisoxazole 10 was synthe-
sized according to published procedure17 and reacted with di-
methyl diazomalonate 2f in the presence of Rh2(OAc)4 (Scheme 3).
After chromatographic separation of the reaction mixture azadiene
4z and dihydroazete 5z were isolated in 44 and 15% yield re-
spectively. Thermolysis experiments on azadienes 4j,k,z showed
that the replacement of bromine with chlorine leads to the stabi-
lization of the open-chain form 4 (Table 2, entries 4, 5 and 8, 9),
while the replacement with iodine shifts the equilibrium towards
dihydroazete 5 (Table 2, entries 4, 6).
1,4-Cyclization of 1-benzoyl-substituted azadiene 4f in benzene
at 100 ꢀC was accompanied by formation of side-products. As-
suming that the latter are the result of side reactions initiated by
traces of HBr, we conducted the reaction in refluxing benzene in the
presence of K2CO3. Azadiene 4f under these conditions smoothly
cyclizes into 5f, giving an equilibrium 3:1 mixture of 4f and 5f
Please cite this article in press as: Smetanin, I. A.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.022

6
I.A. Smetanin et al. / Tetrahedron xxx (2015) 1e13
(Table 2, entry 3). Heating
a
benzene solution of 1-acetyl-
diastereomers of 2,5-dihydrooxazole 12d (1:1, 93% overall yield)
was formed (Table 3, entry 4). This 1,5-exo-trig cyclization was
found to be accelerated by catalytic amounts of 1,8-diazabicyclo
[5.4.0]undec-7-ene (DBU) or piperidine. Thus, the formation of
12d proceeds practically quantitatively at room temperature in the
presence of DBU (Table 3, entry 5). Analogously dihydrooxazoles
12aec with an acceptor substituent at C4 were synthesized in good
yields (Table 3, entries 1e3).
Dihydrooxazoles 12aed are most probably the products of a 1,5-
cyclization of azadienes 4a,c,r,x, occurring under nucleophilic ca-
talysis: a reversible addition of nucleophile to the carbonyl group
results in the formation of zwitterion 13, which undergoes cycli-
zation followed by elimination (Scheme 4). Addition reactions of
DBU18 as well as examples of its use in nucleophilic catalysis19 are
well known. The reaction of azadiene 4x with piperidine along with
dihydrooxazole 12d (40%) gave adduct 14 (45%) (Scheme 4, Table 3,
entry 6). This provides evidence in favor of nucleophilic catalysis
and not base catalysis of the reaction, and this was substantiated
when compound 12d did not transform into 14 under the reaction
conditions.
substituted azadienes 4a,b at 100 ꢀC for 20 min leads to a complex
mixture of products including dihydroazetes 5a,b (1:1 mixture of
diastereomers in both cases), which were isolated by column
chromatography in 20 and 19% yield,14 respectively (Table 2, entries
1, 2). In these cases addition of K2CO3 does not improve the product
yields. It is obvious that an acyl group in position 1 of azadiene 4
takes part in certain processes competing with 1,4-cyclization. One
of these reaction proved to be a 1,5-exo-trig cyclization of 1-acyl-4-
halo-2-azabuta-1,3-dienes into 2,5-dihydrooxazoles.
2.3. Thermal and base-catalyzed cyclizations of 1-acyl-4-halo-
2-azabuta-1,3-dienes into 2,5-dihydrooxazoles
Previously we have shown that non-halogenated 1-acyl-2-
azabuta-1,3-dienes easily undergo 1,6-electrocyclization into 2H-
1,4-oxazines at 60e80 ꢀC.13a The most thermally stable of the
studied compounds, ethyl 2-[(Z)-3-methoxy-3-oxo-1-phenylprop-
1-en-1-yl)imino]-3-oxobutanoate (Scheme 4, compound 4a, X¼H,
R4¼Et), slowly cyclizes into an oxazine in boiling toluene, in con-
trast to the bromo-analog 4a, which cyclizes into the corresponding
dihydroazete 5a at 100 ꢀC. In order to cyclize relatively unreactive
azadiene 4x into the corresponding dihydroazete or 2H-1,4-oxazine
we refluxed it in toluene for 6 h. Unexpectedly a mixture of
The cyclization was found to be rather general and also occurs
with non-halogenated and C3-alkyl-substituted 2-azadienes. Thus,
dihydrooxazole 12e was prepared from azadiene 1513a in 78% yield
(Scheme 4, Table 3, entry 7).
Compounds 12aee were fully characterized by spectroscopic
methods, the structures of diastereomers (RS,RS)-12b and (RS,RS)-
12d were verified by X-ray analysis (Fig. 3).
3. Conclusion
In conclusion, we have developed an efficient and convenient
method for the synthesis of electron-poor 4-bromo-/4-chloro-2-
azabuta-1,3-dienes by the Rh2(OAc)4-catalyzed reaction of diazo
esters and diazo ketones with methyl 2-halo-2H-azirine-2-
carboxylates. The E stereoselectivity in respect to the configura-
tion of the C]C bond of the 2-azadiene moiety is kinetically con-
trolled according to the DFT-calculations of the reaction pathway,
which involves the formation of an azirinium ylide followed by ring
opening with an outward rotation of the halogen atom. 4-Halo-2-
azabutadienes with electron-withdrawing substituents at the
1,1,4-positions undergo, at elevated temperatures, reversible 1,4-
cyclization into 3-halo-2,3-dihydroazetes, which can be isolated
in good yields. The enhancement of the electron-withdrawing
ability of substituents at C1 and electron-donating ability of aryl
substituents at C3 as well as the increase of halogen atom size at C4
of 2-azadienes shift the equilibrium towards the dihydroazete va-
lence isomer side. 1,5-exo-trig-Cyclization of 4-halo-2-
azabutadienes having aliphatic acyl group at the S1 atom into 5-
methylene-2,5-dihydrooxazoles occurs under DBU-catalysis at
ambient temperature. This process can proceed under heating
without a catalyst whenever the S1 atom has only one
p-acceptor
Scheme 4. Cyclization of azadienes 4a,c,r,x, 15 into dihydrooxazoles 12aee and
substituent.
plausible reaction mechanism.
Table 3
Thermal and catalytic cyclizations of azadienes 4a,c,r,x, 15 into oxazolines 12aee
Entry
Azadiene 4
X
R1
R2
R3
R4
R5
Conditions
Yield of 12, %
dr (RS,SR)/(RS,RS)a
1
2
3
4
5
6
7
4a
4c
4r
4x
4x
4x
15
Br
Br
Br
Br
Br
Br
H
CO2Et
CO2Et
COMe
Ph
Ph
Ph
Me
CH2Cl
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Et
H
Cl
H
H
H
H
H
DBU, DCM, rt, 10 min
DBU, DCM, rt, 10 min
DBU, DCM, rt, 10 min
Toluene, 110 ꢀC, 6 h
DBU, DCM, rt, 10 min
Piperidine, DCM, rt, 30 min
DBU, DCM, rt, 10 min
88 (a)
72 (b)
85 (c)
93 (d)
95 (d)
40 (d)b
78 (e)
2:1
5.5:1
2:1
1:1
1.4:1
3:1
Me
Me
CO2Et
a
Diastereomeric ratio for 12 is determined by 1H NMR spectroscopy.
Compound 14 was also isolated in 45% yield.
b
Please cite this article in press as: Smetanin, I. A.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.022

I.A. Smetanin et al. / Tetrahedron xxx (2015) 1e13
7
Fig. 3. X-ray crystal structures of compounds (RS,RS)-12b, (RS,RS)-12d.
4. Experimental section
4.1. General methods
whether the frequency indeed pertains to the desired reaction
coordinate.
4.3. Synthesis of azirines 1cef
Melting points were determined on a hot stage microscope and
are uncorrected. 1H (300 or 400 MHz) and 13C (75 or 100 MHz) NMR
spectra were determined in CDCl3. Chemical shifts (d) are reported
in parts per million downfield from tetramethylsilane. Electrospray
ionization mass spectra were measured on a Bruker micrOTOF mass
spectrometer. IR spectra were recorded on a SPECORD M80 spec-
trometer for solutions in CHCl3. Single crystal X-ray data were
collected on an Saphire 3 (for 4e, 5k at temperature of 120 K) and
Agilent Technologies Xcalibur Eos (for (RS,RS)-5q, 5t, (RS,RS)-12c
and (RS,RS)-12c) at temperature of 100 K) diffractometers using
Azirines 1cef were synthesized according to the published
procedure.22
4.3.1. General procedure. To a stirred solution of 2-(1-methoxy-1,3-
dioxo-3-aryl/heteroarylpropan-2-ylidene)triphenylphosphorane31
(12 mmol) in anhydrous dichlorometane (100 mL) a solution of
trimethylsilyl azide (18 mmol) and corresponding N-hal-
osuccinimide (18 mmol) in anhydrous dichlorometane (250 mL)
was added dropwise. The reaction mixture was stirred at room
temperature for 24 h, and then the solvent was removed under
vacuum. The residues obtained from heteroaryl-substituted phos-
phoranes were additionally filtered through the pad of silica gel
(hexaneeEtOAc, 2:1), the solvents were evaporated, the residue
was dissolved in anhydrous benzene and heated under refluxed for
1 h. Azirines 1cef were purified by chromatography on silica gel
(hexaneeEtOAc, from 20:1 to 5:1) followed by crystallyzation from
Et2O.
graphite monochromated MoKa radiation. An empirical absorption
correction was applied in CrysAlisPro program complex using
spherical harmonics implemented in Scale 3 Abspackslaling algo-
rithm. The structure has been solved by direct methods using the
SHELX-9720 program incorporated in the OLEX221 program pack-
age. Positions of H atoms were refined isotropically in the struc-
tures 4e, 5k and modelled using the ‘riding’ model in other
structures. Crystallographic data for the structures have been de-
posited with the Cambridge Crystallographic Data Centre as sup-
plementary publication no. CCDC-1048829 (for 4e), CCDC-1048830
(for 5k), CCDC-1047062 (for (RS,RS)-5q), CCDC-1047064 (for 5t),
CCDC-1047061 (for (RS,RS)-12c), CCDC-1047054 (for (RS,RS)-12d).
Silica gel Merck 60 was used for column chromatography. Thin-
layer chromatography (TLC) was conducted on alumina sheets
precoated with SiO2 ALUGRAM SIL G/UV254. The known com-
pounds 1a,b,g,22 2aed,k,l,23 2e,13a 2f,24 2g,25 2h,26 2i,27 2j,28 2m29
were prepared by the reported procedures.
4.3.2. Methyl 2-bromo-3-(4-methoxyphenyl)-2H-azirine-2-
carboxylate (1c). Yield 46%. Pale yellow solid; mp 59e63ꢀS (Et2O/
hexane); Rf (50% EtOAc in hexane) 0.23; dH (400 MHz, CDCl3) 3.82
(3O, s), 3.94 (3O, s), 7.09e7.15 (2O, m), 7.88e7.94 (2O, m); dC
(100 MHz, CDCl3) 44.3, 54.0, 55.7, 111.6, 115.3, 133.2, 162.9, 165.1,
167.5; HRMS (ESI-TOF): MHþ, found 283.9925; S11O1719BrNO3 re-
quires 283.9917.
4.3.3. Methyl 2-bromo-3-(furan-2-yl)-2H-azirine-2-carboxylate
(1d). Yield 31%. Brown solid; mp 61e65ꢀS (Et2O/hexane); Rf (25%
EtOAc in hexane) 0.29; dH (400 MHz, CDCl3) 3.83 (3O, s), 6.79 (1O,
dd, J 3.6, 1.6 Hz), 7.46 (1O, d, J 3.6 Hz), 7.96 (1O, d, J 1.6 Hz); dC
(100 MHz, CDCl3) 43.2, 54.2, 113.6, 124.1, 136.8, 150.8, 154.2, 166.6;
HRMS (ESI-TOF): MNaþ, found 265.9415; S8O769BrNNaO3 requires
265.9423.
4.2. Calculation details
All calculations were performed with the density functional
method by using the Gaussian 09 suite of quantum chemical pro-
grams.30 Geometry optimizations of intermediates, transition
states, reactants, and products in 1,2-dichloroethane were per-
formed at the DFT M06-2X/6-31þG(d,p) level using PCM model.
Stationary points on the respective potential-energy surfaces were
characterized at the same level of theory by evaluating the corre-
sponding Hessian indices. Careful verification of the unique imag-
inary frequencies for transition states was carried out to check
4.3.4. Methyl 2-chloro-3-(furan-2-yl)-2H-azirine-2-carboxylate
(1e). Yield 35%. Brown solid; mp 52e56ꢀS (Et2O/hexane); Rf (25%
EtOAc in hexane) 0.28; dH (400 MHz, CDCl3) 3.82 (3O, s), 6.77 (1O,
dd, J 3.6, 1.6 Hz), 7.44 (1O, d, J 3.6 Hz), 7.94 (1O, d, J 1.6 Hz); dC
Please cite this article in press as: Smetanin, I. A.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.022

8
I.A. Smetanin et al. / Tetrahedron xxx (2015) 1e13
(100 MHz, CDCl3) 53.4, 54.0, 113.5, 123.9, 136.6, 150.7, 153.4, 167.2;
HRMS (ESI-TOF): MNaþ, found 221.9947; S8O635ClNNaO3 requires
221.9928.
(from 300:1 to 30:1) as eluent for chromatography. Azadiene 4b
(154 mg, 77%) was obtained according to procedure B from the
same amounts of 1b and 2a. Compound 4b. Orange oil; Rf (33%
EtOAc in hexane) 0.43; dH (400 MHz, CDCl3) 1.29 (3O, t, J 7.2 Hz),
2.55 (3O, s), 3.81 (3H, s), 4.28 (2O, q, J 7.3 Hz), 7.42e7.44 (3O, m),
7.54e7.56 (2O, m); dC (100 MHz, CDCl3) 13.9, 25.6, 52.8, 62.4, 104.6,
128.3, 128.6, 129.9, 134.2, 154.5, 155.0, 160.7, 163.0, 195.6; HRMS
(ESI-TOF): MNaþ, found 360.0600; S16O1365ClNNaO5 requires
360.0609. Compound 5b (mixture of two diastereomers 1:1). Col-
orless oil; Rf (33% EtOAc in hexane) 0.29; dH (400 MHz, CDCl3) 1.34
(3O, t, J 7.2 Hz), 1.36 (3O, t, J 7.2 Hz), 2.44 (6O, s), 3.82 (3O, s), 3.86
(3O, s), 4.26e4.37 (2H, m), 4.40 (2H, q, J 7.2 Hz), 7.48e7.54 (4O, m),
7.58e7.64 (2O, m), 7.84 (2O, d, J 7.5 Hz), 7.89 (2O, d, J 7.5 Hz); dC
(100 MHz, CDCl3) 13.9, 14.1, 26.7, 28.1, 54.10, 54.12, 63.0, 63.3, 65.4,
66.0, 82.4, 84.4,127.0,127.2,127.6,127.8,128.93,128.94,133.3,133.4,
164.1, 164.8, 164.84, 165.2, 183.8, 183.9, 198.2, 198.4; HRMS (ESI-
TOF): MNaþ, found 360.0610; S16O1365ClNNaO5 requires 360.0609.
Compound 5b was also obtained with 19% yield from azadiene 4b
after refluxing 0.13 M solution of 4b for 3 h in anhydrous toluene.
4.3.5. Methyl 2-bromo-3-(thiophen-2-yl)-2H-azirine-2-carboxylate
(1f). Yield 33%. Brown solid; mp 73e76ꢀS (Et2O/hexane); Rf (25%
EtOAc in hexane) 0.31; dH (400 MHz, CDCl3) 3.83 (3O, s), 7.37 (1O,
dd, J 5.0, 3.8 Hz), 7.87 (1O, dd, J 3.8, 1.1 Hz), 8.05 (1O, dd, J 5.0,
1.1 Hz); dC (100 MHz, CDCl3) 44.5, 54.2, 121.2, 129.1, 136.9, 137.8,
157.9, 166.9; HRMS (ESI-TOF): MNaþ, found 281.9206;
S8O769BrNNaO2S requires 281.9195.
4.4. Synthesis of azadienes 4aet and dihydroazete
5a,d,f,g,i,qet,z
4.4.1. General procedure (method A). To a stirred solution of azirine
1a,b (0.59 mmol) and Rh2(OAs)4 (2 mol % on azirine) in anhydrous
DCE (1.5 mL) at reflux under argon a 1.77 M solution of diazo
compound 2a,c,d in anhydrous DCE was added dropwise with
a syringe at a rate of 3.0 mL/h until the azirine was consumed
completely (control by TLC). Diazo compound 2i was added drop-
wise without solvent over 2 min at 60 ꢀC. The solvent was removed
under vacuum, and the residue was purified by column chroma-
tography on silica gel.
4.4.5. Ethyl 2-[(E)-2-bromo-3-methoxy-3-oxo-1-phenylprop-1-
enylimino]-4-chloro-3-oxobutanoate (4c). Azadiene 4c (80%, de-
termined by 1H NMR, 1,1,2,2-tetrabromoethane as internal stan-
dard) was prepared as dark orange oil according to procedure B
from azirine 1a (150 mg, 0.59 mmol) and diazo compound 2b
(259 mg, 1.36 mmol) using filtration of the reaction mixture
through a pad of Celite. Rf (33% EtOAc in hexane) 0.4; dH (300 MHz,
CDCl3) 1.32 (3H, t, J 7.4 Hz), 3.81 (3O, s), 4.31 (2H, q, J 7.4 Hz), 4.78
(2H, s) 7.41e7.46 (3O, m), 7.51e7.54 (2O, m).
4.4.2. General procedure (method B). To a solution of azirine 1
(0.59 mmol) and diazo compound 2 (quantities are indicated be-
low) in anhydrous DCE (1.5 mL) at reflux under argon Rh2(OAs)4
(2 mol %) was added. The stirred mixture was heated under reflux
until nitrogen evolution stopped (10 s for diazo compound 2g,jem,
30 s for 2a,b,d,e, 15 min for diazomalonate 2f and 50 min for 2h).
The resulting mixture was evaporated under reduced pressure, and
the residue purified by column chromatography on silica gel.
4.4.6. Methyl (2E)-2-bromo-3-(1-ethoxy-1,3-dioxo-3-phenylpropan-
2-ylideneamino)-3-phenylacrylate (4d). Azadiene 4d14 (92 mg, 35%)
and (3RS,4SR)-3-benzoyl-4-methyloxetan-2-one 6 (27 mg) were
obtained according to procedure A from azirine 1a (150 mg,
0.59 mmol) and diazo compound 2c (772 mg, 3.54 mmol) using
benzene as eluent for chromatography. Compound 6. Colorless
solid, mp 62e64ꢀS (Et2O/hexane) (lit.15a 64e65ꢀS (Et2O/hexane);
dH (300 MHz, CDCl3) 1.73 (3O, d, J 6.2 Hz), 4.97 (1H, d, J 4.0 Hz), 5.39
(1O, dq, J 6.2, 4.0 Hz), 7.53e7.58 (2O, m), 7.65e7.70 (1O, m),
8.09e8.12 (2O, m).
4.4.3. Ethyl 2-[(E)-2-bromo-3-methoxy-3-oxo-1-phenylprop-1-
enylimino]-3-oxobutanoate (4a) and 2-ethyl 3-methyl 2-acetyl-3-
bromo-4-phenyl-2,3-dihydroazete-2,3-dicarboxylate (5a). Azadiene
4a (97 mg, 43%) and dihydroazete 5a (50 mg, 22%) were prepared
according to procedure A from azirine 1a (150 mg, 0.59 mmol) and
diazo compound 2a (276 mg, 1.77 mmol) using benzene/EtOAc
(from 300:1 to 30:1) as eluent for chromatography. Azadiene 4a
(140 mg, 62%) was obtained according to procedure B from the same
amounts of 1a and 2a. Compound 4a. Orange oil; Rf (33% EtOAc in
hexane) 0.5; nmax(CHCl3) 1710, 1742 cmꢁ1 (S¼O); dH (300 MHz,
CDCl3) 1.31 (3O, t, J 7.3 Hz), 2.54 (3O, s), 3.81 (3H, s), 4.30 (2O, q, J
7.3 Hz), 7.43e7.45 (3O, m), 7.52e7.55 (2O, m); dC (75 MHz, CDCl3)
14.0, 25.7, 53.1, 62.5, 94.5, 128.3, 128.6, 129.9, 135.9, 154.3, 156.5,
160.8, 163.3, 195.6; HRMS (ESI-TOF): MKþ, found 419.9820;
4.4.7. Methyl (2E)-2-chloro-3-(1-ethoxy-1,3-dioxo-3-phenylpropan-
2-ylideneamino)-3-phenylacrylate (4e). Azadiene 4e (71 mg, 30%)
and oxetanone 6 (20 mg) were obtained according to procedure A
from azirine 1b (124 mg, 0.59 mmol) and diazo compound 2c
(772 mg, 3.54 mmol) using benzene as eluent for chromatography.
Compound 4e. Orange solid, mp 82e84ꢀS (Et2O/hexane); dH
(300 MHz, CDCl3) 1.29 (3O, t, J 7.3 Hz), 3.85 (3H, s), 4.34 (2O, q, J
7.3 Hz), 7.38e7.40 (3O, m), 7.47e7.52 (4O, m), 7.63e7.68 (1O, m),
7.90e8.30 (2O, m); dC (75 MHz, CDCl3) 13.9, 52.9, 62.8, 102.7, 128.1,
128.6, 128.9, 129.8, 130.3, 133.7, 134.5, 134.9, 155.0, 155.4, 159.4,
S
16O1769BrKNO5 requires 419.9843. Compound 5a (mixture of two
diastereomers 1:1). Colorless oil; Rf (33% EtOAc in hexane) 0.34; dH
(300 MHz, CDCl3) 1.33 (3O, t, J 7.2 Hz),1.39 (3O, t, J 7.2 Hz), 2.44 (3O,
s), 2.49 (3O, s), 3.84 (3O, s), 3.87 (3O, s), 4.28e4.34 (2H, m), 4.43 (2H,
t, J 7.2 Hz), 7.51e7.61 (6O, m) 7.89e7.91 (2O, m), 7.97e8.00 (2O, m);
dC (75 MHz, CDCl3) 13.9, 14.2, 26.9, 28.0, 53.0, 54.0, 54.1, 54.9, 63.1,
63.2, 82.1, 84.2, 127.3, 127.6, 127.8, 127.9, 128.7, 128.8, 133.25, 133.3,
164.6,165.2,165.35,165.4,184.3,184.7,198.1,198.8; HRMS (ESI-TOF):
MNaþ, found 404.0093; S16O1769BrNNaO5 requires 404.0104. Com-
pound 5a was also obtained in 20% yield from azadiene 4a after
refluxing a 0.13 M solution of 4a for 3 h in anhydrous toluene.
163.4, 189.3; HRMS (ESI-TOF): MNaþ, found 422.0766;
35
S
O SlNNaO5 requires 422.0766. Crystal data (CCDC-1048829):
21 18
C
21H18ClNO5, M¼399.81, triclinic, a¼8.96435(11), b¼9.64848(12),
ꢀ
c¼11.48667(14)ꢀ
A,
a
¼95.8547(10),
b
¼97.2866(10),
3
ꢀ
g
¼102.1789(10) , V¼954.77(2) A , space group P-1 (no. 2), Z¼2,
m(Mo
K
a)¼0.233, 30,140 reflections measured, 5566 unique
(Rint¼0.0356) were used in all calculations. The final wR2 was
0.0864 (all data) and R1 was 0.0323 (4894 reflection with I>2 (I)).
s
4.4.4. Ethyl 2-[(E)-2-chloro-3-methoxy-3-oxo-1-phenylprop-1-
enylimino]-3-oxobutanoate (4b) and 2-ethyl 3-methyl 2-acetyl-3-
chloro-4-phenyl-2,3-dihydroazete-2,3-dicarboxylate (5b). Azadiene
4b (112 mg, 56%) and dihydroazete 5b (20 mg, 10%) were prepared
according to procedure A from azirine 1b (124 mg, 0.59 mmol) and
diazo compound 2a (276 mg, 1.77 mmol) using benzene/EtOAc
4.4.8. Methyl (2E)-2-bromo-3-(1-methoxy-1,3-dioxo-3-
phenylpropan-2-ylideneamino)-3-phenylacrylate (4f). Azadiene 4f
(211 mg, 83%) was prepared according to procedure B from azirine
1a (150 mg, 0.59 mmol) and diazo compound 2d (722 mg,
3.54 mmol) using benzene/EtOAc (from 200:1 to 30:1) as eluent for
chromatography. Yellow solid, mp 89e91ꢀS (Et2O/hexane); Rf (50%
Please cite this article in press as: Smetanin, I. A.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.022

I.A. Smetanin et al. / Tetrahedron xxx (2015) 1e13
9
EtOAc in hexane) 0.51; dH (400 MHz, CDCl3) 3.84 (3O, s), 3.88 (3H,
s), 7.34e7.42 (3O, m), 7.47e7.51 (4O, m), 7.62e7.69 (1O, m),
7.90e8.30 (2O, m); dC (75 MHz, CDCl3) 52.9, 53.1, 92.3, 128.1, 128.6,
128.7, 129.7, 130.2, 133.6, 134.5, 136.4, 154.0, 157.1, 159.6, 163.5,
189.1; HRMS (ESI-TOF): MNaþ, found 452.0117; S20O1769BrNNaO5
requires 452.0104.
and dihydroazete 5j14 (34 mg, 15%) were obtained according to
procedure B from azirine 1a (150 mg, 0.59 mmol) and diazo com-
pound 2f (142 mg, 0.9 mmol) using benzene/EtOAc mixture (from
100:1 to 10:1) as eluent for chromatography.
4.4.14. Synthesis of 5j from 4j. A solution of azadiene (200 mg,
0.52 mmol) in anhydrous toluene (5 mL) was refluxed for 30 min.
The solvent was removed under vacuum and the residue (mixture
of 4j and 5j) was separated by column chromatography on silica gel
using hexane/EtOAc mixture (4:1 to 1:1). The azadiene fraction was
evaporated under reduced pressure, the residue was dissolved in
anhydrous toluene (4 mL) and the performed operations (heating
and chromatographic separation using the same column) were
repeated four more times. The collected dihydroazete fractions
were evaporated to give 5j (166 mg, 83%).
4.4.9. Dimethyl 2-benzoyl-3-bromo-4-phenyl-2,3-dihydroazete-2,3-
dicarboxylate (5f). A mixture of compound 4f (305 mg,
0.71 mmol) and anhydrous K2CO3 powder (300 mg) in anhydrous
benzene (4 mL) was refluxed for 1 h under stirring. After cooling
and filtration the solvent was removed under vacuum, and the
residue purified by column chromatography on silica gel (hexane/
Et2O, from 20:1 to 5:1) to give 4f (150 mg), major isomer of 5f
(51 mg, 17%) and minor isomer of 5f (25 mg, 8%). Major isomer of 5f.
Pale yellow oil; Rf (50% EtOAc in hexane) 0.45; dH (400 MHz, CDCl3)
3.85 (3O, s), 3.86 (3H, s), 7.47e7.70 (6O, m), 7.91 (2O, d, J 7.2 Hz),
8.29 (2O, d, J 7.2 Hz); dC (100 MHz, CDCl3) 53.6, 54.2, 56.6, 85.0,
127.3, 127.9, 128.8 (2S), 129.8, 133.2, 133.7, 134.3, 165.2, 166.2, 183.8,
189.6; HRMS (ESI-TOF): MHþ, found 430.0301; S20O1779BrNO5 re-
quires 430.0285. Minor isomer of 5f. Pale yellow oil; Rf (50% EtOAc
in hexane) 0.44; dH (400 MHz, CDCl3) 3.73 (3O, s), 3.98 (3H, s),
7.49e7.77 (6O, m), 8.01e8.04 (2O, m), 8.18e8.20 (2O, m); dC
(100 MHz, CDCl3) 52.3, 53.7, 54.1, 81.8, 127.7, 128.1, 128.6, 128.7,
129.4,133.2,133.9,134.6,166.2,166.8,184.6,189.7; HRMS (ESI-TOF):
MHþ, found 430.0302; S20O1779BrNO5 requires 430.0285.
4.4.15. Dimethyl 2-[(E)-2-chloro-3-methoxy-3-oxo-1-phenylprop-1-
enylimino]malonate (4k) and trimethyl 3-chloro-4-phenyl-2,3-
dihydroazete-2,2,3-tricarboxylate (5k). Azadiene 4k (181 mg, 90%)
and dihydroazete 5k (14 mg, 7%) were obtained according to pro-
cedure B from azirine 1b (124 mg, 0.59 mmol) and diazo compound
2f (142 mg, 0.9 mmol) using benzene/EtOAc (from 100:1 to 10:1) as
eluent for chromatography. Compound 4k. Orange oil; Rf (50%
EtOAc in hexane) 0.43; dH (300 MHz, CDCl3) 3.79 (3O, s), 3.88 (6H,
s), 7.39e7.42 (3O, m), 7.53e7.61 (2O, m); dC (75 MHz, CDCl3) 52.8,
53.3 (2C), 103.0, 128.2, 128.7, 129.8, 134.3, 149.5, 154.8, 163.0 (two
signals of C]O carbons are not observable); HRMS (ESI-TOF):
MNaþ, found 362.0409; S15O1345ClNNaO6 requires 362.0402.
4.4.10. Methyl (2E)-2-chloro-3-(1-methoxy-1,3-dioxo-3-
phenylpropan-2-ylideneamino)-3-phenylacrylate (4g). Azadiene 4g
(187 mg, 82%) was prepared according to the procedure B from
azirine 1b (124 mg, 0.59 mmol) and diazo compound 2d (722 mg,
3.54 mmol) using benzene/EtOAc (from 200:1 to 30:1) as eluent for
chromatography. Yellow solid, mp 88e90ꢀS; Rf (33% EtOAc in
hexane) 0.36; dH (300 MHz, CDCl3) 3.84 (6O, s), 7.37e7.65 (8O, m),
7.90e8.28 (2O, m); dC (75 MHz, CDCl3) 52.7, 53.0, 102.6, 128.0,
128.6, 128.7, 129.7, 130.2, 133.5, 134.5, 134.7, 154.7, 155.2, 159.6,
163.3, 189.2; HRMS (ESI-TOF): MNaþ, found 408.0615;
Compound 5k. Colorless solid, mp 117e118ꢀS (CH2Cl2/hexane);
Rf (50% EtOAc in hexane) 0.33; dH (300 MHz, CDCl3) 3.84 (3O, s), 3.87
(3H, s), 3.91 (3H, s), 7.47e7.52 (2O, m), 7.57e7.63 (1O, m), 7.86 (2O,
d, J 7.4); dC (75 MHz, CDCl3) 53.56, 53.58, 54.2, 65.8, 79.4,127.2,127.5,
128.9, 133.5, 164.5, 164.6, 165.0, 184.2; HRMS (ESI-TOF): MNaþ,
found 362.0400; S15O1345ClNNaO6 requires 362.0402. Crystal data
(CCDC-1048830): C15H14ClNO6, M¼339.72, triclinic, a¼8.3328(7),
ꢀ
b¼9.7783(7)ꢀ, c¼10.3923(6) A,
a
¼88.067(5),
b
¼66.395(7),
3
ꢀ
g
¼85.313(6) , V¼773.33(10) A , space group P-1 (no. 2), Z¼2,
m
(Mo
S
20O1365ClNNaO5 requires 408.0609.
Ka
)¼0.278, 7754 reflections measured, 4121 unique (Rint¼0.0272),
which were used in all calculations. The final wR2 was 0.0950 (all
data) and R1 was 0.0364 (3506 reflections with I>2 (I)).
4.4.11. Methyl (2E)-2-bromo-3-(1-methoxy-1,3-dioxo-3-
phenylpropan-2-ylideneamino)-3-(4-methoxyphenyl)acrylate
(4h). Azadiene 4h (234 mg, 86%) was prepared according to pro-
cedure B from azirine 1c (168 mg, 0.59 mmol) and diazo compound
2d (722 mg, 3.54 mmol) using benzene/EtOAc (from 200:1 to 30:1)
as eluent for chromatography. Orange oil; Rf (33% EtOAc in hexane)
0.28; dH (300 MHz, CDCl3) 3.82 (3O, s), 3.83 (3O, s), 3.86 (3H, s),
6.89 (2H, d, J 8.6 Hz), 7.38e7.52 (4O, m), 7.62e7.68 (1O, m),
7.80e8.39 (2O, m); dC (75 MHz, CDCl3) 52.9, 53.1, 55.2, 91.5, 113.4,
128.2, 128.6, 130.2, 130.4, 133.6, 134.5, 153.8, 157.0, 159.7, 160.6,
163.6, 189.3; HRMS (ESI-TOF): MHþ, found 460.0392; S21O1799BrNO6
requires 460.0390.
s
4.4.16. Dimethyl 2-[(E)-2-bromo-3-methoxy-1-(4-methoxyphenyl)-
3-oxoprop-1-enylimino]malonate (4l) and trimethyl 3-bromo-4-(4-
methoxyphenyl)-2,3-dihydroazete-2,2,3-tricarboxylate
(5l). Azadiene 4l (122 mg, 50%) and dihydroazete 5l (110 mg, 45%)
were obtained according to procedure B from azirine 1c (168 mg,
0.59 mmol) and diazo compound 2f (142 mg, 0.9 mmol) using
benzene/EtOAc (from 100:1 to 10:1) as eluent for chromatography.
Compound 4l. Orange oil; Rf (50% EtOAc in hexane) 0.41; dH
(400 MHz, CDCl3) 3.69 (3O, s), 3.74 (3O, s), 3.80 (6H, s), 6.84 (2O, d, J
8.8 Hz), 7.42 (2O, d, J 8.8 Hz); dC (100 MHz, CDCl3) 52.9, 53.2, 55.2
(2S), 92.1, 113.5, 128.2, 130.3, 148.6, 156.7, 160.3 (2S), 160.6, 163.3;
HRMS (ESI-TOF): MHþ, found 414.0188; S16O1779BrNO7 requires
414.0183. Compound 5l. Colorless solid, mp 141e143ꢀS (CH2Cl2/
hexane); Rf (50% EtOAc in hexane) 0.28; dH (300 MHz, CDCl3) 3.85
(6O, s), 3.88 (3H, s), 3.93 (3H, s), 6.98 (2O, d, J 8.7 Hz), 7.91 (2O, d, J
8.7 Hz); dC (75 MHz, CDCl3) 53.3, 53.6, 53.9, 54.0, 55.5, 79.2, 114.2,
120.4, 129.7, 163.7, 165.1, 165.4, 165.5, 184.0; HRMS (ESI-TOF): MHþ,
found 414.0189; S16O1779BrNO7 requires 414.0183.
4.4.12. Methyl (2E)-2-bromo-3-[1-(4-cyanophenyl)-3-methoxy-1,3-
dioxopropan-2-ylideneamino]-3-phenylacrylate (4i). Azadiene 4i
(148 mg, 55%) was prepared according to procedure B from azirine
1a (150 mg, 0.59 mmol) and diazo compound 2e (270 mg,
1.18 mmol) using benzene as eluent for chromatography. Orange oil;
Rf (33% EtOAc in hexane) 0.34; dH (300 MHz, CDCl3) 3.84 (3O, s), 3.88
(3H, s), 7.40e7.51 (5O, m), 7.79e7.83 (2O, m), 8.15e8.46 (2O, m); dC
(75 MHz, CDCl3) 53.1, 53.3, 92.1,117.4,117.7,128.3,128.7,130.0,130.9,
132.3, 136.1, 136.8, 153.1, 157.2, 159.2, 163.7, 187.9; HRMS (ESI-TOF):
MNaþ, found 477.0050; S21O1759BrN2NaO5 requires 477.0057.
4.4.17. Dimethyl 2-[(E)-2-bromo-1-(furan-2-yl)-3-methoxy-3-
oxoprop-1-enylimino]malonate (4m), trimethyl 3-bromo-4-(furan-
2-yl)-2,3-dihydroazete-2,2,3-tricarboxylate (5m) and trimethyl (6E)-
7-bromo-6-(1,3-dimethoxy-1,3-dioxopropan-2-ylideneamino)-5-
4.4.13. Dimethyl 2-[(E)-2-bromo-3-methoxy-3-oxo-1-phenylprop-1-
enylimino]malonate (4j) and trimethyl 3-bromo-4-phenyl-2,3-
dihydroazete-2,2,3-tricarboxylate (5j). Azadiene 4j14 (184 mg, 81%)
oxohepta-1,3,6-triene-1,1,7-tricarboxylate
(7a). Azadiene
4m
(161 mg, 73%), dihydroazete 5m (22 mg, 10%) and ester 7a (36 mg,
Please cite this article in press as: Smetanin, I. A.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.022

10
I.A. Smetanin et al. / Tetrahedron xxx (2015) 1e13
12%) were obtained according to procedure B from azirine 1d
(144 mg, 0.59 mmol) and diazo compound 2f (111 mg, 0.7 mmol)
using benzene/EtOAc (from 100:1 to 10:1) as eluent for chroma-
tography. Compound 4m. Yellow solid, mp 50e53ꢀS (from oil); Rf
(50% EtOAc in hexane) 0.41; dH (400 MHz, CDCl3) 3.76 (3O, s),
3.49e4.20 (6H, br s), 6.55 (1O, dd, J 3.6, 1.6 Hz), 7.42 (1O, d, J 3.6 Hz),
7.53 (1O, d, J 1.6 Hz); dC (100 MHz, CDCl3) 53.0, 53.3 br (2C), 90.5,
112.0, 117.5, 144.7, 145.0, 145.5, 152.1, 158.9, 161.3, 163.1; HRMS (ESI-
TOF): MHþ, found 373.9864; S13O1739BrNO7 requires 373.9870.
Compound 5m. Colorless solid, mp 104.5e106ꢀS (Et2O/hexane); Rf
(50% EtOAc in hexane) 0.28; dH (400 MHz, CDCl3) 3.84 (3O, s), 3.86
(3H, s), 3.94 (3H, s), 6.62 (1O, dd, J 3.6, 1.6 Hz), 7.23 (1O, d, J 3.6 Hz),
7.70 (1O, d, J 1.6 Hz); dC (100 MHz, CDCl3) 53.0, 53.3, 53.7, 54.0, 80.7,
112.5, 119.0, 143.5, 147.5, 164.7, 164.9, 165.1, 175.5; HRMS (ESI-TOF):
MHþ, found 373.9864; S13O1739BrNO7 requires 373.9870. Compound
7a. Orange oil; Rf (50% EtOAc in hexane) 0.3; dH (400 MHz, CDCl3)
3.81 (3O, s), 3.86 (3O, s), 3.90 (3H, s), 3.95 (6H, s), 6.74 (1O, dd, J
11.6, 1.2 Hz), 7.09 (1O, t, J 11.6 Hz), 8.39 (1O, dd, J 11.6, 1.2 Hz); dC
(100 MHz, CDCl3) 52.7, 52.8, 53.6, 53.7 (2C), 93.2, 130.4, 133.6, 137.6,
138.1, 151.7, 152.6, 159.9 br (2C), 162.1, 164.1, 164.6, 185.0; HRMS
(ESI-TOF): MHþ, found 504.0148; S18O7199BrNO11 requires 504.0136.
using benzene as eluent for chromatography. Orange oil; Rf (33%
hexane in Et2O) 0.47; dH (400 MHz, CDCl3) 1.43 (3O, t, J 7.2 Hz), 3.84
(3H, s), 4.47 (2O, q, J 7.2 Hz), 7.46e7.49 (3O, m), 7.53e7.56 (2O, m);
dC (100 MHz, CDCl3) 13.9, 53.4, 64.3, 97.8, 109.1, 128.5, 128.8, 130.5,
135.1, 156.3, 157.7, 162.8 (2C); HRMS (ESI-TOF): MHþ, found
365.0140; S15O1749BrN2O4 requires 365.0131.
4.4.21. 2-Ethyl 3-methyl 3-bromo-2-cyano-4-phenyl-2,3-
dihydroazete-2,3-dicarboxylate (5p). A solution of compound 4p
(200 mg, 0.55 mmol) in CDCl3 (1.5 mL) was stored for 7 days at
room temperature. The solvent was removed under vacuum and
the residue purified by column chromatography (hexane/Et2O,
from 10:1 to 1:1) to give compound 4p (42 mg), (E)-2-bromo-3-(2-
ethoxy-2-oxoacetamido)-3-phenylacrylate 11 (23 mg, 15% on
reacted 4p) and a 2:1 mixture of 5p and 11 (50 mg). Compound 5p
(not separated from 11). Rf (33% hexane in Et2O) 0.41; dH (300 MHz,
CDCl3) 1.44 (3O, t, J 7.2 Hz), 3.99 (3O, s), 4.49 (2H, q, J 7.2 Hz),
7.51e7.59 (2O, m), 7.63e7.69 (1O, m), 7.94e7.98 (2O, m); dC
(75 MHz, CDCl3) 14.1, 54.6, 54.7, 64.4, 67.6, 112.8, 127.2, 127.8, 128.9,
134.1, 161.8, 164.1, 185.8; HRMS (ESI-TOF): MHþ, found 365.0140;
S
15O1749BrN2O4 requires 365.0131. Compound 11. Colorless solid, mp
98e99ꢀS (Et2O/hexane); Rf (33% hexane in Et2O) 0.4; dH (400 MHz,
CDCl3) 1.38 (3O, t, J 7.1 Hz), 3.95 (3O, s), 4.38 (2H, q, J 7.1 Hz),
7.29e7.32 (2O, m), 7.44e7.46 (3O, m), 12.59 (1O, s); dC (100 MHz,
CDCl3) 13.8, 53.6, 63.7, 98.2, 127.8, 128.3, 129.3, 134.9, 150.5, 153.1,
159.9, 166.1; HRMS (ESI-TOF): MNaþ, found 377.9941;
4.4.18. Dimethyl 2-[(E)-2-chloro-1-(furan-2-yl)-3-methoxy-3-
oxoprop-1-enylimino]malonate (4n) and trimethyl (6E)-7-chloro-6-
(1,3-dimethoxy-1,3-dioxopropan-2-ylideneamino)-5-oxohepta-1,3,6-
triene-1,1,7-tricarboxylate (7b). Azadiene 4n (170 mg, 87%) and
ester 7b (30 mg, 11%) were obtained according to procedure B from
azirine 1e (118 mg, 0.59 mmol) and diazo compound 2f (111 mg,
0.7 mmol) using benzene/EtOAc mixture (from 100:1 to 10:1) as
eluent for chromatography. Compound 4n. Yellow solid, mp
53e55ꢀS (from oil); Rf (50% EtOAc in hexane) 0.37; dH (400 MHz,
CDCl3) 3.77 (3O, s), 3.97 (6H, br s), 6.56 (1O, dd J 3.6 Hz, J 1.6 Hz),
7.35 (1O, d, J 3.6 Hz), 7.52 (1O, d, J 1.6 Hz); dC (100 MHz, CDCl3) 52.8,
53.3 (2C), 101.2, 112.3, 117.7, 143.8, 144.0, 144.8, 152.6, 158.7, 161.3,
162.8; HRMS (ESI-TOF): MNaþ, found 352.0201; S13O1325ClNNaO7
requires 352.0195. Compound 7b. Orange oil; Rf (50% EtOAc in
hexane) 0.27; dH (400 MHz, CDCl3) 3.82 (3O, s), 3.86 (3O, s), 3.90
(3H, s), 3.94 (6H, s), 6.75 (1O, dd, J 11.6, 0.8 Hz), 7.08 (1O, t, J 11.6 Hz),
8.36 (1O, dd, J 11.6, 0.8 Hz); dC (100 MHz, CDCl3) 52.7, 52.8, 52.9,
53.4, 53.6, 105.7, 130.8, 133.6, 137.7, 137.8, 150.5, 152.0, 160.5 br,
162.1, 164.0, 164.6, 166.7, 184.4; HRMS (ESI-TOF): MNaþ, found
428.0507; S18O1385ClNNaO11 requires 428.0491.
S
14O1749BrNNaO5 requires 377.9948.
4.4.22. Methyl (2E)-2-bromo-3-[1-(dimethoxyphosphoryl)-2-
methoxy-2-oxoethylideneamino]-3-phenylacrylate (4q) and di-
methyl 3-bromo-2-(dimethoxyphosphoryl)-4-phenyl-2,3-
dihydroazete-2,3-dicarboxylate (5q). Azadiene 4q (103 mg, 40%),
dihydroazete (RS,RS)-5q (44 mg, 17%) and dihydroazete (RS,SR)-5q
(23 mg, 9%) were obtained according to procedure B from azirine 1a
(150 mg, 0.59 mmol) and diazo compound 2h (258 mg, 1.24 mmol)
using hexane/EtOAc (from 5:1 to 1:2) as eluent for chromatography.
Compound 4q. Orange oil; Rf (EtOAc) 0.34; dH (400 MHz, CDCl3)
3.78 (3O, s), 3.89 (3H, s), 3.91 (6O, d, J 11.1 Hz), 7.40e7.42 (3O, m),
7.55e7.58 (2O, m); dC (100 MHz, CDCl3) 52.9, 53.3, 54.6 (d, J 6.5 Hz),
90.5,128.2, 128.7, 129.8, 136.2 (d, J 1.7 Hz),154.9 (d, J 211.3 Hz), 158.4
(d, J 25.7 Hz), 158.6 (d, J 41.3 Hz), 163.2; HRMS (ESI-TOF): MHþ,
found 434.0002; S15O1789BrNO7P requires 433.9999. Compound
(RS,RS)-5q. Colorless solid, mp 64e75ꢀS (Et2O/hexane, dec); Rf
(EtOAc) 0.27; dH (400 MHz, CDCl3) 3.90 (3H, s), 3.91 (3H, d, J
11.0 Hz), 3.94 (3H, d, J 11.0 Hz), 3.96 (3H, s), 7.47e7.53 (2O, m)
7.56e7.62 (1O, m), 8.03e8.06 (2O, m); dC (100 MHz, CDCl3) 53.0 (d,
J 2.8 Hz), 53.3, 54.0, 54.9 (d, J 6.6 Hz), 55.3 (d, J 6.6 Hz), 78.6 (d, J
148.6 Hz), 127.8, 128.3, 128.5, 133.1, 165.3 (d, J 2.1 Hz), 165.6 (d, J
1.2 Hz), 185.1 (d, J 11.7 Hz); HRMS (ESI-TOF): MHþ, found 433.9995;
4.4.19. Dimethyl 2-[(E)-2-bromo-3-methoxy-3-oxo-1-(thiophen-2-
yl)prop-1-enylimino]malonate (4o) and trimethyl 3-bromo-4-(thio-
phen-2-yl)-2,3-dihydroazete-2,2,3-tricarboxylate (5o). Azadiene 4o
(103 mg, 45%) and dihydroazete 5o (64 mg, 28%) were obtained
according to procedure B from azirine 1f (153 mg, 0.59 mmol) and
diazo compound 2f (142 mg, 0.9 mmol) using benzene/EtOAc (from
100:1 to 10:1) as eluent for chromatography. Compound 4o. Orange
oil; Rf (50% EtOAc in hexane) 0.4; dH (400 MHz, CDCl3) 3.78 (3O, s),
3.89 (6H, br s), 7.08e7.13 (1O, m), 7.52e7.61 (2O, m); dC (100 MHz,
CDCl3) 53.1, 53.4 br (2C), 92.0, 126.8, 130.1, 131.8, 135.0, 149.7, 151.4,
156.8, 161.3, 163.2; HRMS (ESI-TOF): MNaþ, found 411.9465;
S
S
15O1789BrNO7P requires 433.9999. Crystal data (CCDC-1047062):
15O17BrNO7P, M¼334.18, triclinic, a¼7.8769(7), b¼11.3147(4),
ꢀ
c¼11.5857(5) A,
a
¼82.468(3),
b
¼77.405(3),
g
¼76.860(3)ꢀ,
3
ꢀ
V¼977.73(6) A , space group P-1 (no. 2), Z¼2,
m
(Mo K
a
)¼2.261,
16,785 reflections measured, 4410 unique (Rint¼0.0342), which
S
13O1729BrNNaO6S requires 411.9461. Compound 5o. Colorless solid,
were used in all calculations. The final wR2 was 0.0688 (all data)
mp 118e121ꢀS (Et2O/hexane, dec); Rf (50% EtOAc in hexane) 0.3; dH
(400 MHz, CDCl3) 3.85 (3O, s), 3.87 (3H, s), 3.95 (3H, s), 7.19 (1O, dd,
J 4.8, 4.0 Hz), 7.70 (1O, d, J 4.8 Hz), 7.76 (1O, d, J 4.0 Hz); dC (100 MHz,
CDCl3) 53.3, 53.7, 53.8, 54.0, 80.1, 128.2, 130.8, 133.1, 133.4, 164.8,
165.2, 165.3, 180.0; HRMS (ESI-TOF): MNaþ, found 411.9465;
and R1 was 0.0602 (3963 reflections with I>2s(I)). Compound
(RS,SR)-5q. Colorless oil; Rf (EtOAc) 0.26; dH (400 MHz, CDCl3) 3.80
(3H, s), 3.88 (3H, s), 3.95 (3H, d, J 11.0 Hz), 3.97 (3H, d, J 11.0 Hz),
7.47e7.52 (2O, m) 7.57e7.62 (1O, m), 7.91e7.94 (2O, m); dC
(100 MHz, CDCl3) 53.4, 54.5, 54.89 (2C, d, J 6.9 Hz), 54.90 (d, J
2.8 Hz), 77.6 (d, J 160.3 Hz), 127.2, 128.0, 128.8, 133.3, 165.0 (d, J
2.2 Hz), 166.0 (d, J 2.1 Hz), 183.3 (d, J 10.2 Hz); HRMS (ESI-TOF):
MHþ, found 433.9993; S15O1789BrPNO7 requires 433.9999.
S
13O1729BrNNaO6S requires 411.9461.
4.4.20. Methyl (2E)-2-bromo-3-(1-cyano-2-ethoxy-2-
oxoethylideneamino)-3-phenylacrylate (4p). Azadiene 4p (168 mg,
78%) was prepared according to procedure B from azirine 1a
(150 mg, 0.59 mmol) and diazo compound 2g (97 mg, 0.7 mmol)
4.4.23. Methyl (E)-2-bromo-3-(2,4-dioxopentan-3-ylideneamino)-3-
phenylacrylate (4r). Azadiene 4r (112 mg, 54%) was prepared
Please cite this article in press as: Smetanin, I. A.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.022

I.A. Smetanin et al. / Tetrahedron xxx (2015) 1e13
11
according to procedure A from azirine 1a (150 mg, 0.59 mmol) and
diazo compound 2i (446 mg, 3.54 mmol) using benzene as eluent
for chromatography. Red oil; Rf (17% EtOAc in hexane) 0.31; dH
(400 MHz, CDCl3) 2.45 (6O, s), 3.79 (3H, s), 7.42e7.46 (3O, m),
7.55e7.61 (2O, m); dC (100 MHz, CDCl3) 27.5 br (2C), 52.9, 90.7,
128.3, 128.7, 129.8, 136.7, 158.0, 158.7, 163.5, 197.0 (2C); HRMS (ESI-
TOF): MHþ, found 352.0179; S15O1759BrNO4 requires 352.0179.
EtOAc mixture (10:1 to 5:1) for chromatography to give azadiene
4u (133 mg, 56% on azides) as a 1:1.3 mixture of isomers across C]
C bond. Orange oil; Rf (33% EtOAc in hexane) 0.46; dH (400 MHz,
CDCl3) 1.26e1.40 (6O, m), 3.79 and 3.87 (3H, 2s), 4.22e4.40 (4O,
m); dC (100 MHz, CDCl3) 13.7 (2C), 13.8 (2C), 53.45, 53.46, 63.1, 63.2,
63.57, 63.64, 98.5, 100.2, 117.7 (2C, q, J 278.8 Hz), 143.5, 144.4, 148.7
(q, J 37.1 Hz), 148.8 (q, J 37.1 Hz) 155.8 (2C), 160.1, 160.8, 162.0, 162.4;
HRMS (ESI-TOF): MNaþ, found 425.9776; S12O1739BrF3NNaO6 re-
quires 425.9771.
4.4.24. Methyl (2E)-2-bromo-3-(3-ethoxy-1,1,1-trifluoro-3-
oxopropan-2-ylideneamino)-3-phenylacrylate (4s) and 2-ethyl 3-
methyl (2RS,3RS)-3-bromo-4-phenyl-2-(trifluoromethyl)-2,3-
dihydroazete-2,3-dicarboxylate (5s). Azadiene 4s (217 mg, 90%)
was prepared according to procedure B from azirine 1a (150 mg,
0.59 mmol) and diazo compound 2j (129 mg, 0.71 mmol) using
hexane/EtOAc (from 30:1 to 10:1) as eluent for chromatography.
When the reaction mixture was additionally refluxed for 60 min
azadiene 4s (159 mg 66%) and dihydroazete 5s (48 mg, 20%) were
obtained. Compound 4s. Orange oil; Rf (17% EtOAc in hexane) 0.4;
dH (400 MHz, CDCl3) 1.38 (3O, t, J 7.2 Hz), 3.80 (3H, s), 4.39 (2O, q, J
7.2 Hz), 7.44e7.47 (3O, m), 7.59e7.64 (2O, m); dC (100 MHz, CDCl3)
13.8, 53.0, 63.4, 91.5, 117.8 (q, J 278.7 Hz), 128.3, 128.8, 130.1, 135.7,
145.1 (q, J 36.7 Hz),155.6,155.9,163.2; HRMS (ESI-TOF): MHþ, found
408.0049; S15O1749BrF3NO4 requires 408.0053. Compound 5s. Col-
orless oil; Rf (17% EtOAc in hexane) 0.3; dH (400 MHz, CDCl3) 1.41
(3O, t, J 7.2 Hz), 3.91 (3O, s), 4.40e4.53 (2H, m), 7.51e7.56 (2O, m)
7.62e7.66 (1O, m), 8.04e8.07 (2O, m); dC (100 MHz, CDCl3) 14.1,
51.0, 54.2, 63.5, 77.2 (q, J 30.2 Hz), 121.6 (q, J 283.9 Hz), 127.6, 128.1,
128.7, 133.7, 162.7, 164.7, 185.8; HRMS (ESI-TOF): MHþ, found
408.0055; S15O1749BrF3NO4 requires 408.0053.
4. 4. 27. Methyl (2E)-2-bromo-3-(2-methoxy-2-oxo-1-
phenylethylideneamino)-3-phenylacrylate (E-4v). Azadiene E-4v
(218 mg, 92%) was prepared according to procedure B from azirine
1a (150 mg, 0.59 mmol) and diazo compound 2k (114 mg,
0.65 mmol) using benzene as eluent for chromatography. Yellow
solid, mp 83e85ꢀS (CH2Cl2/hexane); Rf (33% EtOAc in hexane) 0.4;
dH (400 MHz, CDCl3) 3.76 (3O, s), 3.91 (3H, s), 7.38e7.47 (5O, m),
7.51e7.59 (3O, m), 7.80e7.82 (2O, m); dC (100 MHz, CDCl3) 52.5,
52.9, 93.3, 128.0, 128.5, 128.58, 128.59, 129.4, 132.0, 133.1, 137.5,
156.8, 158.8, 163.0, 163.8; HRMS (ESI-TOF): MNaþ, found 424.0157;
S
19O1769BrNNaO4 requires 424.0155.
4. 4. 28. Methyl (2Z)-2-bromo-3-(2-methoxy-2-oxo-1-
phenylethylideneamino)-3-phenylacrylate (Z-4v). A solution of
compound E-4v (200 mg, 0.45 mmol) in anhydrous o-xylene (3 mL)
was refluxed for 17 h under stirring. The solvent was removed under
vacuum and the residue purified by column chromatography
(hexane/Et2O, from 20:1 to 5:1) to give compound E-4v (70 mg) and
compound Z-4v (68 mg, 52% on isomerized E-4v). Compound Z-4v.
Yellow solid, mp 111e112ꢀS (CH2Cl2/hexane); Rf (33% EtOAc in
hexane) 0.39; dH (400 MHz, CDCl3) 3.62 (3O, s), 3.87 (3H, s),
7.33e7.41 (5O, m), 7.45e7.49 (2O, m), 7.53e7.57 (1O, m), 7.84e7.87
(2O, m); dC (100 MHz, CDCl3) 52.6 (2C), 94.6, 128.0, 128.1, 128.6,
128.7,129.3,132.2,133.0,136.3,157.9,158.2,162.7,164.4; HRMS (ESI-
TOF): MNaþ, found 424.0157; S19O1769BrNNaO4 requires 424.0155.
4.4.25. Methyl (2E)-2-bromo-3-(3-ethoxy-1,1,1-trifluoro-3-
oxopropan-2-ylideneamino)-3-(4-methoxyphenyl)acrylate (4t) and
2-ethyl 3-methyl (2RS,3RS)-3-bromo-4-(4-methoxyphenyl)-2-(tri-
fluoromethyl)-2,3-dihydroazete-2,3-dicarboxylate (5t). Azadiene 4t
(238 mg, 92%) was prepared according to procedure B from azirine
1c (168 mg, 0.59 mmol) and diazo compound 2j (129 mg,
0.71 mmol) using hexane/EtOAc (from 300:1 to 10:1) as eluent for
chromatography. When the reaction mixture was additionally
refluxed for 60 min azadiene 4t (98 mg, 38%) and dihydroazete 5t
(119 mg, 46%) were obtained. Compound 4t. Orange oil; Rf (25%
EtOAc in hexane) 0.43; dH (400 MHz, CDCl3) 1.37 (3O, t, J 7.2 Hz), 3.78
(3H, s), 3.86 (3H, s), 4.37 (2O, q, J 7.2 Hz), 6.96 (2O, d, J 8.8 Hz), 7.57
(2O, d, J 8.8 Hz); dC (100 MHz, CDCl3) 13.9, 52.9, 55.3, 63.3, 90.8,
113.6, 117.9 (q, J 278.6 Hz), 127.9, 130.5, 144.8 (q, J 36.7 Hz), 155.6,
155.8, 160.9, 163.4; HRMS (ESI-TOF): MHþ, found 438.0155;
4.4.29. Methyl (2E)-2-bromo-3-[2-methoxy-1-(4-nitrophenyl)-2-
oxoethylideneamino]-3-phenylacrylate
(E-4w). Azadiene E-4w
(230 mg, 87%) was prepared according to procedure B from azirine
1a (150 mg, 0.59 mmol) and diazo compound 2l (181 mg,
0.82 mmol) using benzene/EtOAc (100:1) as eluent for chromatog-
raphy. Yellow solid, mp 102e104ꢀS (Et2O/hexane); Rf (33% EtOAc in
hexane) 0.37; dH (400 MHz, CDCl3) 3.77 (3O, s), 3.93 (3H, s),
7.38e7.47 (3O, m), 7.53e7.62 (2O, m), 7.96e8.05 (2H, m), 8.29 (2O,
d, J 8.7 Hz); dC (100 MHz, CDCl3) 52.95, 52.97, 92.8,123.6,128.2,128.5,
129.7,129.8,137.0,138.9,149.5,154.7,158.3,161.5,163.6; HRMS (ESI-
TOF): MKþ, found 484.9742; S19O1759BrKN2O6 requires 484.9745.
S
16O1769BrF3NO5 requires 408.0158. Compound 5t. Colorless solid,
mp 69e72ꢀS (Et2O/hexane); Rf (25% EtOAc in hexane) 0.3; dH
(400 MHz, CDCl3) 1.39 (3O, t, J 7.2 Hz), 3.886 (3O, s), 3.889 (3O, s),
4.38e4.51 (2H, m), 7.01 (2O, d, J 8.8 Hz), 7.99 (2O, d, J 8.8 Hz); dC
(100 MHz, CDCl3) 14.0, 51.0, 54.0, 55.5, 63.3, 77.0 (q, J 30.2 Hz), 114.1,
120.1, 121.7 (q, J 283.9 Hz), 130.2, 163.0, 164.0, 164.8, 184.7; HRMS
(ESI-TOF): MHþ, found 438.0158; S16O1769BrF3NO5 requires 408.0158.
4.4.30. Methyl (2Z)-2-bromo-3-[2-methoxy-1-(4-nitrophenyl)-2-
oxoethylideneamino]-3-phenylacrylate (Z-4w). A solution of com-
pound E-4w (200 mg) in anhydrous o-xylene (3 mL) was refluxed
for 17 h under stirring. The solvent was removed under vacuum and
the residue purified by column chromatography (hexane/EtOAc,
from 20:1 to 10:1) to give compound E-4w (69 mg) and compound
Z-4w (103 mg, 79% on isomerized E-4w). Compound Z-4w. Orange
solid, mp 77e78ꢀS (Et2O/hexane); Rf (33% EtOAc in hexane) 0.33;
dH (400 MHz, CDCl3) 3.62 (3O, s), 3.91 (3H, s), 7.33e7.47 (5O, m),
7.94e8.17 (2O, m), 8.24e8.38 (2H, m); dC (100 MHz, CDCl3) 52.7,
53.1, 94.5, 123.6, 128.0, 128.1, 129.6, 129.7, 135.5, 138.6, 149.6, 156.2,
156.9, 161.4, 164.0; HRMS (ESI-TOF): MKþ, found 484.9742;
Crystal data (CCDC-1047064): C16H15BrF3NO5, M¼438.20, triclinic,
ꢀ
a¼6.8415(7), b¼9.0864(10), c¼15.721(2) A,
a
¼85.067(10),
3
ꢀ
ꢀ
b
¼89.723(10),
g
¼69.573(10) , V¼921.14(18) A , space group P-1 (no.
)¼2.309, 7497 reflections measured, 3997 unique
2), Z¼2,
m(Mo Ka
(Rint¼0.0311), which were used in all calculations. The final wR2 was
0.1383 (all data) and R1 was 0.0335 (3049 reflections with I>2 (I)).
s
4.4.26. 4-Ethyl 1-methyl 2-bromo-3-(3-ethoxy-1,1,1-trifluoro-3-
oxopropan-2-ylideneamino)but-2-enedioate (4u). A solution of 1-
ethyl 4-methyl 2-azido-3-bromobut-2-enedioate22 (mixture of E/Z
isomers) (164 mg, 0.59 mmol) in anhydrous heptane (80 mL) was
refluxed for 1 h under stirring. The solvent was removed under
vacuum and the crude azirine 1g was reacted with diazo compound
2j (129 mg, 0.71 mmol) according to the procedure B using hexane/
S
19O7159BrKN2O6 requires 484.9745.
4.4.31. Methyl (2E)-2-bromo-3-(2-oxo-1-phenylpropylideneamino)-
3-phenylacrylate (4x). Azadiene 4x (173 mg, 76%) was prepared
according to procedure B from azirine 1a (150 mg, 0.59 mmol) and
diazo compound 2m (216 mg, 1.35 mmol) using filtration of the
Please cite this article in press as: Smetanin, I. A.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.022

12
I.A. Smetanin et al. / Tetrahedron xxx (2015) 1e13
reaction mixture through a pad of Celite and recrystallization from
Et2O/hexane. Yellow solid, mp 76e77ꢀS (Et2O/hexane); Rf (33%
EtOAc in hexane) 0.44; dH (300 MHz, CDCl3) 2.53 (3O, s), 3.80 (3H,
s), 7.32e7.49 (10O, m); dC (75 MHz, CDCl3) 27.3, 52.9, 93.1, 128.0,
128.1, 128.26, 128.28, 129.4, 130.8, 132.8, 137.9, 158.5, 163.2, 163.6,
199.1; HRMS (ESI-TOF): MNaþ, found 408.0197; S19O1769BrNNaO3
requires 408.0206.
129.4, 137.0, 156.1, 157.8, 159.8, 166.1; HRMS (ESI-TOF): MNHþ4 ,
found 399.0553; S16O7290BrN2O5 requires 399.0550.
4.5.3. Ethyl
2-(1-bromo-2-methoxy-2-oxoethyl)-5-((Z)-chloro-
methylene)-2-phenyl-2,5-dihydrooxazole-4-carboxylate
(12b). Diastereomer (RS,RS)-12b (118 mg, 48% on azirine 1a) was
obtained as a colorless solid according to the general procedure
from crude azadiene 4c. The second fraction (55 mg) obtained after
chromatography according to 1H NMR spectrum contained isomer
(RS,SR)-12b. Compound (RS,RS)-12b. Colorless solid, mp
101.5e102.5ꢀS (CH2Cl2/hexane); Rf (20% EtOAc in hexane) 0.3; dH
(300 MHz, CDCl3) 1.43 (3O, t, J 7.1 Hz), 3.60 (3O, s), 4.39e4.51 (2O,
m), 5.01 (1H, s), 6.59 (1H, s), 7.36e7.46 (3O, m), 7.62e7.71 (2O, m);
dC (75 MHz, CDCl3) 14.0, 50.3, 53.0, 63.1, 100.1, 110.2, 126.4, 128.6,
129.6, 135.2, 152.6, 154.8, 159.1, 165.7; HRMS (ESI-TOF): MNaþ,
found 437.9715; S16O7159Br35ClNNaO5 requires 437.9714. Crystal
4.4.32. Dimethyl 2-[(E)-2-iodo-3-methoxy-3-oxo-1-phenylprop-1-
enylimino]malonate (4z) and trimethyl 3-iodo-4-phenyl-2,3-
dihydroazete-2,2,3-tricarboxylate (5z). To a boiling solution of 3-
phenyl-5-methoxy-4-iodoisoxazole 10 (120 mg, 0.4 mmol) and
diazo compound 2f (145 mg, 0.92 mmol) in anhydrous DCE was
added Rh2(OAs)4 (4 mg, 2 mol % on isoxazole). The mixture was
stirred under reflux until nitrogen evolution stopped (ca. 10 min).
The solvent was removed under vacuum and the residue purified
by column chromatography (benzene/EtOAc, from 100:1 to 10:1) to
give compound 4z (77 mg, 44%) and compound 5z (26 mg, 15%).
Compound 4z. Orange oil; Rf (50% EtOAc in hexane) 0.46; dH
(400 MHz, CDCl3) 3.77 (3O, s), 3.90 (6H, s), 7.35e7.46 (3O, m),
7.49e7.57 (2O, m); dC (100 MHz, CDCl3) 53.2, 53.3 (2C), 67.3, 128.3,
128.6, 129.8, 138.7, 148.2, 160.0 (2C), 160.6, 164.1; HRMS (ESI-TOF):
MHþ, found 431.9947; S15O15INO6 requires 431.9939. Compound
5z. Colorless solid, mp 159e161ꢀS (CH2Cl2/hexane); Rf (50% EtOAc
in hexane) 0.39; dH (400 MHz, CDCl3) 3.84 (6O, s), 3.99 (3H, s),
7.47e7.55 (2O, m), 7.56e7.62 (1O, m), 8.04e8.12 (2O, m); dC
(100 MHz, CDCl3) 29.3, 53.2, 53.76, 53.78, 80.1, 128.0, 128.1, 128.5,
133.3, 165.3, 165.4, 167.4, 187.0; HRMS (ESI-TOF): MHþ, found
431.9947; S15O15INO6 requires 431.9939.
data (CCDC-1047061):
C
16H15ClNO5, M¼416.65, tetragonal,
ꢀ
a¼21.8606(3), b¼21.8606(3), c¼7.1356(3) A,
a
¼90.00,
b
¼90.00,
3
ꢀ
ꢀ
g
¼90.00 , V¼3410.01(14) A , space group P 42, Z¼4,
m
(Mo K
a
)¼
2.593, 13,061 reflections measured, 5664 unique (Rint¼0.0390),
which were used in all calculations. The final wR2 was 0.1368 (all
data) and R1 was 0.1284 (4786 reflections with I>2s(I)). Compound
(RS,SR)-12b (not isolated). dH (300 MHz, CDCl3) 1.42 (3O, t, J 7.1 Hz),
3.66 (3O, s), 4.40e4.48 (2O, m), 4.93 (1H, s), 6.57 (1H, s), 7.55e7.58
(3O, m), 7.64e7.67 (2O, m).
4.5.4. Methyl 2-(4-acetyl-5-methylene-2-phenyl-2,5-dihydrooxazol-
2-yl)-2-bromoacetate (12c). Diastereomers (RS,SR)-12c (80 mg,
57%) and (RS,SR)-12c (40 mg, 28%) were prepared according to the
general procedure from azadiene 4r (141 mg, 0.4 mmol) as colorless
oils. Compound (RS,RS)-12c. Rf (25% Et2O in hexane) 0.36; dH
(400 MHz, CDCl3) 2.65 (3O, s), 3.59 (3O, s), 4.95 (1H, s), 5.07 (1H, d, J
2.3 Hz), 5.25 (1H, d, J 2.3 Hz), 7.36e7.44 (3O, m), 7.61e7.64 (2O, m);
dC (100 MHz, CDCl3) 27.6, 51.0, 53.0, 90.6, 107.8, 126.4, 128.5, 129.4,
136.2, 155.9, 159.8, 166.2, 194.5; HRMS (ESI-TOF): MNaþ, found
374.0005; S15O1749BrNNaO4 requires 373.9998. (RS,SR)-12c. Rf (25%
Et2O in hexane) 0.34; dH (400 MHz, CDCl3) 2.68 (3O, s), 3.64 (3O, s),
4.88 (1H, s), 4.99 (1H, d, J 2.4 Hz), 5.24 (1H, d, J 2.4 Hz), 7.40e7.45
(3O, m), 7.60e7.63 (2O, m); dC (100 MHz, CDCl3) 27.6, 51.8, 53.0,
90.4, 108.3, 126.5, 128.5, 129.5, 136.9, 155.0, 160.5, 166.1, 194.6;
HRMS (ESI-TOF): MNaþ, found 374.0007; S15O1749BrNNaO4 requires
373.9998.
4.4.33. Synthesis of 5z from 4z. A solution of azadiene 4z (65 mg,
0.15 mmol) in anhydrous toluene (4 mL) was refluxed for 1 h. The
solvent was removed under vacuum and the crystalline 5z was
washed with Et2O/hexane (1:1) mixture. Filtrate was evaporated
under reduced pressure, the residue was dissolved in anhydrous
toluene (3 mL) and the performed operations (heating and wash-
ing) were repeated three more times to give dihydroazete 5z
(50 mg, 77%).
4.5. Synthesis of dihydrooxazoles 12aee
4.5.1. General procedure for preparation of dihydrooxazoles
12aee. To a stirred solution of azadiene 4a,c,r,x (0.4 mmol) in an-
hydrous DCM (2 mL) was added DBU (24 mg, 0.16 mmol) at room
temperature. The mixture was stirred for 15 min, the solvent was
removed under vacuum and dihydrooxazole 12aee was purified by
column chromatography (Et2O/hexane, from 1:20 to 1:10).
4.5.5. Methyl 2-bromo-2-(5-methylene-2,4-diphenyl-2,5-
dihydrooxazol-2-yl)acetate
12d. Diastereomers
(RS,RS)-12d
(85 mg, 55%) and (RS,SR)-12d (62 mg, 40%) were obtained according
to the general procedure from azadiene 4x (154 mg, 0.4 mmol).
Compound (RS,RS)-12d. Colorless solid, mp 73.5e75ꢀS (Et2O/hex-
ane); Rf (25% Et2O in hexane) 0.31; dH (300 MHz, CDCl3) 3.60 (3O, s),
4.70 (1H, d, J 2.6 Hz), 5.01 (1H, s), 5.08 (1H, d, J 2.6 Hz), 7.34e7.59
(6O, m), 7.69e7.81 (4O, m); dC (75 MHz, CDCl3) 52.3, 52.9, 87.6,
108.0, 126.6, 128.4, 128.56, 128.63, 129.1, 130.7, 131.1, 137.1, 158.9,
166.1, 166.7; HRMS (ESI-TOF): MNaþ, found 408.0205;
4.5.2. Ethyl 2-(1-bromo-2-methoxy-2-oxoethyl)-5-methylene-2-
phenyl-2,5-dihydrooxazole-4-carboxylate
(12a). Diastereomers
(RS,RS)-12a (90 mg, 59%) and (RS,SR)-12a (45 mg, 29%) were pre-
pared according to the general procedure from azadiene 4a
(153 mg, 0.4 mmol) as colorless oils. Compound (RS,RS)-12a. dH
(400 MHz, CDCl3) 1.43 (3O, t, J 7.2 Hz), 3.56 (3O, s), 4.39e4.51 (2O,
m), 5.02 (1H, s), 5.12 (1H, d, J 2.6 Hz), 5.23 (1H, d, J 2.6 Hz), 7.35e7.44
(3O, m), 7.62e7.66 (2O, m); dC (100 MHz, CDCl3) 14.0, 51.1, 53.0,
62.8, 89.9, 108.5, 126.4, 128.6, 129.4, 135.8, 156.9, 157.1, 159.7, 166.1;
HRMS (ESI-TOF): MNH4þ, found 399.0553; S16O7290BrN2O5 requires
399.0550. Compound (RS,SR)-12a. dH (400 MHz, CDCl3) 1.42 (3O, t, J
7.2 Hz), 3.68 (3O, s), 4.40e4.48 (2O, m), 4.90 (1H, s), 5.05 (1H, d, J
2.6 Hz), 5.19 (1H, d, J 2.6 Hz), 7.39e7.45 (3O, m), 7.62e7.65 (2O, m);
dC (100 MHz, CDCl3) 14.0, 50.6, 53.1, 62.7, 89.6, 109.4, 126.5, 128.5,
S
19O1769BrNNaO3 requires 408.0206. Crystal data (CCDC-1047054):
C
19H16BrNO3, M¼386.24, triclinic, a¼7.8418(2), b¼10.3843(3),
ꢀ
c¼11.0708(3) A,
a
¼111.553(3),
b
¼94.818(2),
g
¼91.093(2)ꢀ,
3
ꢀ
V¼834.30(4) A , space group P-1 (no. 2), Z¼2,
m
(Mo K
a
)¼2.480,
13,595 reflections measured, 3826 unique (Rint¼0.0190), which
were used in all calculations. The final wR2 was 0.0482 (all data)
and R1 was 0.0195 (3627 reflections with I>2s(I)). Compound
(RS,SR)-12d. Colorless oil; Rf (25% Et2O in hexane) 0.28; dH
(300 MHz, CDCl3) 3.64 (3O, s), 4.70 (1H, d, J 2.6 Hz), 4.93 (1H, s),
5.01 (1H, d, J 2.6 Hz), 7.37e7.58 (6O, m), 7.68e7.82 (4O, m); dC
Please cite this article in press as: Smetanin, I. A.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.022

I.A. Smetanin et al. / Tetrahedron xxx (2015) 1e13
13
2. (a) Boger, D. L. In Comprehensive Organic Synthesis; Trost, B. M., Paquete, L. A.,
Eds.;5; Pergamon: Oxford, UK, 1990; 5, pp 451e512; (b) Kametani, T.; Hibino, S.
Adv. Heterocycl. Chem. 1987, 42, 245e333.
3. (a) Novikov, M. S.; Khlebnikov, A. F.; Rostovskii, N. V.; Tcyrulnikov, S.; Suhanova,
A. A.; Zavyalov, K. V.; Yufit, D. S. J. Org. Chem. 2015, 80, 18e29; (b) Khlebnikov,
A. F.; Novikov, M. S.; Amer, A. A. Tetrahedron Lett. 2004, 45, 6003e6006; (c)
Khlebnikov, A. F.; Novikov, M. S.; Amer, A. A.; Kostikov, R. R.; Magull, J. Russ. J.
Org. Chem. 2006, 42, 533e544; (d) Palacios, F.; Gil, M. J.; Martinez de Marigota,
E.; Rodrigues, M. Tetrahedron Lett. 1999, 40, 2411e2414; (e) Molina, P.; Pastor,
A.; Vilaplana, M. J. Tetrahedron Lett. 1993, 34, 3773e3776.
(75 MHz, CDCl3) 52.3, 53.0, 87.5, 108.7, 126.7, 128.3, 128.61, 128.63,
129.1, 130.7, 131.1, 137.9, 158.1, 166.5, 166.6; HRMS (ESI-TOF): MNaþ,
found 408.0204; S19O1769BrNNaO3 requires 408.0206. Compounds
(RS,RS)- and (RS,SR)-12d (dr 1:1) were also obtained in 93% yield by
refluxing 0.06 M toluene solution of 4x for 6 h followed by chro-
matographic purification.
4.5.6. Methyl 2-bromo-2-(5-methyl-2,4-diphenyl-5-(piperidin-1-yl)-
2,5-dihydrooxazol-2-yl)acetate (14). To a stirred solution of aza-
diene 4x (154 mg, 0.4 mmol) in anhydrous DCM (3 mL) was added
piperidine (68 mg, 0.8 mmol) at room temperature. After 30 min
the solvent was removed under vacuum and the residue purified by
column chromatography (Et2O/hexane, from 1:30 to 1:10) to give
compound 14 (85 mg, 45%), compound (RS,RS)-12d (46 mg, 30%)
and (RS,SR)-12d (15 mg, 10%). Compound 14 (1.5:1 mixture of di-
astereomers). Colorless solid, mp 118e130; 146e153ꢀS (hexane); Rf
(25% Et2O in hexane) 0.34; dH (300 MHz, CDCl3) 1.25 (3H, s),
1.49e1.69 (6H, m), 2.55e2.70 (2H, m), 2.95e3.17 (2O, m), 3.68 (3H,
s), 4.66, 4.76 (1H, 2s), 7.30e7.37 (3O, m), 7.40e7.56 (3H, m),
7.65e7.77 (2H, m), 8.39e8.50 (2O, m); dC (75 MHz, CDCl3) 23.9,
24.0, 24.6, 24.7, 26.4, 47.7, 47.8, 52.3, 52.5, 52.6, 53.4, 103.0, 103.4,
107.0, 127.1, 127.3, 127.5, 128.0, 128.2, 128.3, 128.8, 128.9, 130.3,
130.4, 131.5, 139.5, 167.36, 167.4, 169.6, 170.0 (signals of six carbons
are overlapped); HRMS (ESI-TOF): MNaþ, found 493.1097;
4. Legroux, D.; Brom, J.; Fleury, J.-P. Helv. Chim. Acta 1990, 73, 1210e1214.
5. Legroux, D.; Schoeni, J.-P.; Pont, C.; Fleury, J.-P. Helv. Chim. Acta 1987, 70,
187e195.
6. Oehler, E.; Schmidt, U. Chem. Ber. 1979, 112, 107e115.
7. (a) Wulff, G.; Lindner, H. J.; Boehnke, H.; Steigel, A.; Klinken, H. T. Liebigs Ann.
Chem. 1989, 6, 527e531; (b) Wulff, G.; Boehnke, H.; Klinken, H. T. Liebigs Ann.
Chem. 1988, 6, 501e505; (c) Wulff, G.; Boehnke, H. Angew. Chem. 1984, 96, 362.
8. Boehme, H.; Ingendoh, A. Chem. Ber. 1979, 112, 1297e1303.
9. Barluenga, J.; Tomas, M.; Ballesteros, A.; Gotor, V. J. Chem. Soc., Chem. Commun.
1987, 1195e1196.
10. (a) O’Donnell, M. J.; Arasappan, A.; Hornback, W. J.; Huffman, J. C. Tetrahedron
Lett. 1990, 31, 157e160; (b) Bazureau, J. P.; Person, D.; Le Corre, M. Tetrahedron
Lett. 1989, 30, 3065e3068.
11. (a) Barluenga, J.; Ferrero, M.; Palacios, F. Tetrahedron Lett. 1988, 29, 4863e4864;
(b) Barluenga, J.; Ferrero, M.; Palacios, F. J. Chem. Soc., Perkin Trans. 1 1990,
2193e2197; (c) Barluenga, J.; Ferrero, M.; Palacios, F. Tetrahedron Lett. 1990, 31,
3497e3500.
12. Tarzia, G.; Balsamini, C.; Spadoni, G.; Duranti, E. Synthesis 1988, 514e517.
13. (a) Rostovskii, N. V.; Novikov, M. S.; Khlebnikov, A. F.; Khlebnikov, V. A.; Kor-
neev, S. M. Tetrahedron 2013, 69, 4292e4301; (b) Khlebnikov, A. F.; Novikov, M.
S. Tetrahedron 2013, 69, 3363e3401.
14. Novikov, M. S.; Smetanin, I. A.; Khlebnikov, A. F.; Rostovskii, N. V.; Yufit, D. S.
S
24O7297BrN2NaO3 requires 493.1097.
Tetrahedron Lett. 2012, 53, 5777e5780.
15. (a) Lall, M. S.; Ramtohul, Y. K.; James, M. N. G.; Vederas, J. C. J. Org. Chem. 2002,
67, 1536e1547; (b) Balaji, B. S.; Chanda, B. M. Tetrahedron Lett. 1998, 39,
6381e6382.
16. Khlebnikov, A. F.; Novikov, M. S.; Gorbunova, Y. G.; Galenko, E. E.; Mikhailov, K.
I.; Pakalnis, V. V.; Avdontceva, M. S. Beilstein J. Org. Chem. 2014, 10, 1896e1905.
17. Micetich, R. G.; Chin, C. G. Can. J. Chem. 1970, 48, 1371e1376.
18. Ma, L.; Dolphin, D. Tetrahedron 1996, 52, 849e860.
19. (a) Zhang, W.; Shi, M. Org. Biomol. Chem. 2006, 4, 1671e1674; (b) Chakrabarty,
M.; Ghosh, N.; Khasnobis, S. Synth. Commun. 2002, 32, 265e272.
20. Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 64, 112e122.
21. Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.; Puschmann, H. J.
Appl. Crystallogr. 2009, 42, 339e341.
4.5.7. Ethyl 2-(2-ethoxy-2-oxoethyl)-2-methyl-5-methylene-2,5-
dihydrooxazole-4-carboxylate (12e). Compound 12e (80 mg, 78%)
was prepared according to the general procedure from azadiene 15
(102 mg, 0.4 mmol) as a colorless oil. dH (400 MHz, CDCl3) 1.24 (3O,
t, J 7.2 Hz), 1.42 (3O, t, J 7.2 Hz), 1.66 (3O, s), 2.88 and 2.92 (2O, AB-q,
J 15.3), 4.13 (2H, q, J 7.2 Hz), 4.43 (2H, q, J 7.2 Hz), 4.78 (1H, d, J
2.3 Hz), 5.09 (1H, d, J 2.3 Hz); dC (100 MHz, CDCl3) 14.0 (2C), 25.5,
43.3, 60.7, 62.5, 88.1, 108.0, 155.7, 156.0, 160.1, 168.1; HRMS (ESI-
TOF): MNaþ, found 278.0994; S12O17NNaO5 requires 278.0999.
22. Pinho e Melo, T. M. V. D.; Lopes, C. S. J.; Cardoso, A. L.; Rocha Gonsalves, A. M.
d’A. Tetrahedron 2001, 57, 6203e6208.
23. Davies, J. R.; Kane, P. D.; Moody, C. J. Tetrahedron 2004, 60, 3967e3977.
24. Julian, R. R.; May, J. A.; Stoltz, B. M.; Beauchamp, J. L. J. Am. Chem. Soc. 2003, 125,
4478e4486.
Acknowledgements
25. Goddard-Borger, E. D.; Stick, R. V. Org. Lett. 2007, 9, 3797e3800.
26. Hiersemann, M.; Jaschinski, T. Org. Lett. 2012, 14, 4114e4117.
27. Presset, M.; Mailhol, D.; Coquerel, Y.; Rodriguez, J. Synthesis 2011, 16,
2549e2552.
28. Shi, G.; Xu, Y. J. Org. Chem. 1990, 55, 3383e3386.
29. Jiang, Y.; Khong, V. Z. Y.; Lourdusamy, E.; Park, C.-M. Chem. Commun. 2012,
We gratefully acknowledge the financial support of the Russian
Foundation for Basic Research (grant no. 14-03-00187, 14-03-31117)
and Saint Petersburg State University (Grant no. 12.38.239.2014,
12.38.217.2015). This research used resources of the resource center
‘Computer Center’, ‘Research resource center for Magnetic Reso-
nance’, ‘Center for Chemical Analysis and Material Research’, and
‘Research resource Centre for X-ray Diffraction Studies’ of Saint
Petersburg State University.
3133e3135.
30. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Na-
katsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng,
G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery,
J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.;
Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.;
Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, N. J.; Klene, M.;
Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.;
Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dan-
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2015.05.022. These data include MOL files
and InChiKeys of the most important compounds described in this
article.
}
nenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O; Foresman, J. B.; Ortiz, J. V.;
Cioslowski, J.; Fox, D. J. Gaussian 09, Revision C.01; Gaussian: Wallingford CT,
2010.
References and notes
31. Hollick, J. J.; Rigoreau, L. J.; Cano-Soumillac, C.; Cockcroft, X.; Curtin, N. J.; Fri-
gerio, M.; Golding, B. T.; Guiard, S.; Hardcastle, I. R.; Hickson, I.; Hummersone,
M. G.; Menear, K. A.; Martin, N. M.; Matthews, I.; Newell, D. R.; Ord, R.; Ri-
chardson, C. J.; Smith, G. C.; Griffin, R. J. J. Med. Chem. 2007, 50, 1958e1972.
1. (a) Monbaliu, J.-C. M.; Masschelein, K. G. R.; Stevens, C. V. Chem. Soc. Rev. 2011,
40, 4708e4739; (b) Jayakumar, S.; Ishar, M. P. S.; Mahajan, M. P. Tetrahedron
2002, 58, 379e471; (c) Barluenga, J.; Tomas, M. Adv. Heterocycl. Chem. 1993, 57,
1e80.
Please cite this article in press as: Smetanin, I. A.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.022