Asymmetric Neber Reaction in the Synthesis of Chiral 2-(Tetrazol-5-yl)-2 H -Azirines

Article abstract of DOI:10.1055/s-0039-1691533

A successful one-pot methodology for the synthesis of chiral 2-tetrazolyl-2 H -azirines has been established, resorting to organocatalysis. The protocol involves the in situ tosylation of β-ketoxime-1 H -tetrazoles followed by the Neber reaction, in the presence of chiral organocatalysts. Among the organocatalysts studied a novel thiourea catalyst derived from 6β-aminopenicillanic acid afforded excellent enantioselectivities.

Full text of DOI:10.1055/s-0039-1691533

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–F
letter
A
en
C. Alves et al.
Letter
Synlett
Asymmetric Neber Reaction in the Synthesis of Chiral 2-(Tetrazol-
5-yl)-2H-Azirines
Cláudia Alvesa
Carla Grossoa
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Pedro Barrulasb,c
José A. Paixãod
Ana L. Cardosoa
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Anthony J. Burkeb
Américo Lemosa,e
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Teresa M. V. D. Pinho e Melo*a
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a CQC and Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal
tmelo@ci.uc.pt
b Centro de Química de Évora and Department of Chemistry, University of Évora, 7000 Évora,
Portugal
c HERCULES Laboratory, Évora University, Largo Marquês de Marialva 8, 7000-809 Évora,
Portugal
d CFisUC and Department of Physics, University of Coimbra, Coimbra 3004-516, Portugal
e FCT, University of Algarve, Campus Gambelas, 8005-139 Faro, Portugal
Published as part of the ISySyCat2019 Special Issue
Received: 14.10.2019
Accepted after revision: 27.11.2019
Published online: 17.12.2019
chiral 2H-azirine-2-carboxylates using alkaloid-promoted
Neber reactions10 as well as asymmetric Neber reaction us-
ing bifunctional chiral thioureas as catalysts have been de-
scribed.11 These methodologies have been applied to the
synthesis of (–)-(Z)-dysidazirine10d,e,11 and both isomers (E)
and (Z) of antazirine.10f More recently, an organocatalytic
asymmetric Neber approach towards chiral spirooxindole-
2H-azirine and spiropyrazolone-2H-azirine derivatives
promoted by hydroquinidine 1,4-phthalazinediyl diether
[DHQD)2PHAL] has been reported.12
DOI: 10.1055/s-0039-1691533; Art ID: st-2019-b0551-l
Abstract A successful one-pot methodology for the synthesis of chiral
2-tetrazolyl-2H-azirines has been established, resorting to organocatal-
ysis. The protocol involves the in situ tosylation of -ketoxime-1H-tetra-
zoles followed by the Neber reaction, in the presence of chiral organo-
catalysts. Among the organocatalysts studied a novel thiourea catalyst
derived from 6-aminopenicillanic acid afforded excellent enantioselec-
tivities.
Key words 2H-azirines, asymmetric Neber reaction, organocatalysis,
tetrazoles, thiourea, 6-aminopenicillanic acid
N
N
N
CO2Me
CO2Me
Me
CO2H
Br
Due to their unique structural features, 2H-azirines
have been widely used as valuable synthetic intermediates
in the synthesis of a plethora of nitrogen-containing com-
pounds.1–7 In fact, the high ring strain along with the acti-
vated iminic bond and the N-lone pair on the azirine make
these heterocycles highly reactive and enable them to par-
ticipate in organic reactions not only as nucleophiles and
electrophiles, but also as dienophiles and dipolarophiles.
Moreover, under the appropriate reaction conditions, high-
ly reactive intermediates such as vinylnitrenes, nitrile
ylides, and iminocarbenes can be generated from selective
bond cleavage, broadening the reactivity of these small
molecules.
Br
(+)-(Z)-antazirine (3)
azirinomycin (1)
(–)-(E)-dysidazirine (2)
Figure 1 Naturally occurring chiral 2H-azirines
The chemistry of these interesting molecules has been
one of our topics of research. We have previously developed
a highly efficient method for the preparation of 2-halo-2H-
azirines starting from -oxophosphorus ylides, based on a
nonclassical Wittig reaction.13 These compounds have prov-
en to be versatile building blocks for several transforma-
tions giving rise to an array of cyclic and acyclic nitrogen-
containing compounds.14
The isolation of chiral naturally occurring 2H-azirines,
such as azirinomycin (1), dysidazirine (2), and antazirine
(3), with promising biological properties, has raised the in-
terest in the development of efficient asymmetric synthetic
methodologies towards chiral 2H-azirine-2-carboxylates
and their analogues (Figure 1).8,9 In fact, the synthesis of
On the other hand, we reported the synthesis of (1H-
tetrazol-5-yl)-allenes,15 tetrazolyl-tryptamines, and 2-halo-
2-(tetrazol-5-yl)-2H-azirines and the use of these com-
pounds for the construction of tetrazolyl-heterocycles,
namely 3-tetrazolyl--carbolines with anticancer activi-
ty.15–18
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–F
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
C. Alves et al.
Letter
Synlett
Building blocks bearing a tetrazolyl substituent are a
particularly interesting synthetic tool to explore carboxylic
acid/tetrazole bioisosterism as a way to find new molecules
with enhanced biological activity. In this context, we have
selected 2-(tetrazol-5-yl)-2H-azirines as our target mole-
cules due not only to their interesting chemical features but
also considering that these heterocycles are bioisosters of
relevant 2H-azirine-2-carboxylates.19,20 The established
synthetic methodology involves the preparation of -ketox-
imes-1H-tetrazoles which undergo in situ tosylation and
the subsequent Neber reaction to give 2-(tetrazol-5-yl)-2H-
azirines, bearing phenyl, furan-2-yl, thiophen-2-yl, or pyr-
rol-2-yl substituents at C-3. Furthermore, it was demon-
strated that the alkaloid-mediated Neber reaction allows
the asymmetric synthesis of 2-(tetrazol-5-yl)-2H-azirines.
Using a stoichiometric amount of quinidine (6), a smooth
conversion of tosylate ketoxime 4 into the desired enriched
2H-azirine was observed affording predominantly the R en-
antiomer (54% ee) whereas in the presence of quinine (8)
the S enantiomer was selectively formed (44% ee). Thus, the
pseudoenantiomers of the alkaloids gave opposite antipo-
des of the 2H-azirine (Scheme 1).
started our investigations using quinidine (6) as organocat-
alyst. Optimization studies were carried out, and different
parameters such as solvent, temperature, reaction time,
and co-base were evaluated in order to improve the selec-
tivity of this transformation (Table 1).
Table 1 Optimization of the Model Reaction
N
quinidine 6, TsCl (1.1 equiv)
(R)
N
co-base, solvent
Ph
N
N
N
NOH
N
N
PNB
N
N
Ph
(R)-7
PNB
N
quinine 8, TsCl (1.1 equiv)
(S)
5
N
K2CO3 (10 equiv), toluene, rt Ph
N
N
N
PNB
(S)-7
Entry Solvent
Base
Temp. Time Catalyst Yield ee
(h)
(mol%)
(%)
(%)a
1
2
CH3CN
CH2Cl2
K2CO3
K2CO3
rt
rt
rt
rt
24
6 (100)
6 (20)
6 (20)
6 (20)
6 (20)
6 (20)
6 (20)
6 (100)
6 (10)
8 (60)
8 (20)
8 (20)
8 (20)
–
–
24
24
24
24
48
48
72
48
48
24
48
72
45 (R)
n.d.
42
<40
67
19
87
24
7
3
diethyl ether K2CO3
N
N
O
O
NOH
N
N
H2NOH•HCl
EtOH/Py
1. NaN3, ZnBr2
2. PG-X, NEt3
4
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
K2CO3
60 (R)
55 (R)
66 (R)
55 (R)
68 (R)
63 (R)
51 (S)
41 (S)
44 (S)
7 (S)
N
N
CN
N
N
R
R
R
5
Na2CO3 rt
PG
PG
6
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
rt
TsCl, NEt3
7
0 °C
rt
R = Ph
NH
O
S
N
8
N
R
9
rt
66
52
48
61
15
N
N
N
10
11
12
13
rt
PG
rt
59–86%
rt
OMe
N
N
rt
a Determined by HPLC analysis on a chiral stationary column.
OH
N
(S)
N
Ph
Ph
(1.0 equiv)
quinine
N
It was found that the solvent plays an important role in
the reaction, with the desired product (R)-7 being obtained
when the reactions were performed in dichloromethane,
diethyl ether, or toluene (Table 1, entries 2–4, respectively)
whereas no reaction occurred when using acetonitrile (Ta-
ble 1, entry 1). Among the former, the reaction carried out
in toluene, in the presence of only 20 mol% of quinidine, al-
lowed the synthesis of the target compound in the highest
yield (67%) along with 60% ee (Table 1, entry 4). In addition,
the use of K2CO3 led to the product in higher yield than car-
rying out the reaction in the presence of Na2CO3 (Table 1,
entries 4 and 5, 67% vs. 19% yield). Based on these prelimi-
nary results, toluene and K2CO3 were selected for further
studies. To our delight, by increasing the reaction time to 48
h it was possible to isolate 2H-azirine (R)-7 in excellent
yield (87%) albeit with moderate enantiomeric excess (66%
ee, Table 1, entry 6).
N
NOTs
N
N
N
N
PNB
N
Ph
74%, 44% ee
PNB
4
quinidine
(1.0 equiv)
N
(R)
N
N
OMe
N
N
N
PNB
63%, 54% ee
OH
N
Scheme 1 The Neber approach to 2-(tetrazol-5-yl)-2H-azirines16
Herein, we report a one-pot synthetic approach towards
chiral 2-(tetrazol-5-yl)-2H-azirine derivatives by carrying
out the in situ tosylation of -ketoxime tetrazoles followed
by the Neber reaction in the presence of chiral organocata-
lysts. We selected the conversion of -ketoxime 5 into the
corresponding 2H-azirine 7 as our model reaction and
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–F

C
C. Alves et al.
Letter
Synlett
Unfortunately, decreasing the reaction temperature to 0
°C resulted in poorer efficiency and lower enantioselectivi-
ty (24% yield and 55% ee, Table 1, entry 7). In addition, the
increase of the reaction time to 72 h led to a drastic drop in
the yield (7%, Table 1, entry 8). This outcome is presumably
due to the lack of stability of these heterocycles when sub-
jected to long reaction times. Lastly, the amount of quini-
dine was decreased to 10 mol% affording the 2H-azirine (R)-
7 in moderate yield (66%) and 63% ee (Table 1, entry 9).
Thus, the best results were obtained carrying out the syn-
thesis of 2-(tetrazol-5-yl)-2H-azirine (R)-7 in toluene in the
presence of 10 equivalents of K2CO3 and 20 mol% of quini-
dine at room temperature for 48 h (Table 1, entry 6).21
Aiming at the formation of the 2H-azirine (S)-7, quinine,
the pseudoenantiomer of quinidine, was also evaluated as
organocatalyst (Table 1). Carrying out the reaction in tolu-
ene in the presence of 60 mol% of quinidine at room tem-
perature for 48 h, the target heterocycle (S)-7 was obtained
in moderate yield (52%) and 51% ee (Table 1, entry 10). Us-
ing 20 mol% of quinine, 2H-azirine was obtained in slightly
lower yield and lower enantiomeric excess after carrying
out the reaction of ketoxime 5 for 24 h (48% yield and 41%
ee, Table 1, entry 11). However, increasing the reaction time
to 48 h raised the conversion to 61% yield and improved
slightly the enantiomeric excess to 44% (Table 1, entry 12).
Carrying out the reaction for 72 h led to a dramatic de-
crease in the efficiency of the reaction (15% yield and 7% ee,
Table 1, entry 13), as previously observed when quinidine
was used as organocatalyst.
Next, under the previously optimized reaction condi-
tions using quinidine, we explored a series of epi-cinchoni-
dine derivatives bearing different amino acids and hetero-
cycle moieties at the C-9 carbon as catalysts (Figure 2).22 In
some cases, the synthesis of 2-(tetrazol-5-yl)-2H-azirine
was performed in dichloromethane due to the poor solubil-
ity of these catalysts in toluene. As expected, reactions car-
ried out with these organocatalysts afforded the R enantio-
mer as the major product. In general, organocatalysts bear-
ing triazolyl moieties afforded the lowest yields (4–20%
yield) and ee (14–27%) whereas organocatalysts bearing
amino acid moieties led to better results (for details, see
Supporting Information). Among the latter, compound 9a
bearing a N-benzoyl substituent was the most promising
organocatalyst affording (R)-7 in 55% yield and 56% ee
(Scheme 2).
N
R
(S)
N
9
NH2
NH2
H
N
H
H
N
N
9b R =
9e R =
9c R =
9a R =
9d R =
O
N
O
O
O
H
N
N
N
N
9f R =
N
N
N
OMe
Figure 2 Organocatalysts derived from epi-cinchonidine
N
(S)
NHCOPh
N
9a (20 mol%)
TsCl (1.1 equiv)
K2CO3 (10 equiv), rt, 48 h
dichloromethane:
toluene:
41% yield, 43% ee
55% yield, 56% ee
N
NOH
N
N
(R)
N
N
Ph
N
Ph
N
PNB
N
N
5
PNB
(R)-7
using 10a: 15% yield, 52% ee
using 10b: 19% yield, 13% ee
TsCl (1.1 equiv), toluene
K2CO3 (10 equiv), 24–48 h, rt
H2N
O
S
N
CO2R
10a R = H
10b R = Bzh
(20 mol%)
Scheme 2 Asymmetric Neber reaction using an epi-cinchonidine de-
rivative and 6-APA as catalysts (Bzh = benzhydryl group)
improve the efficiency, on the contrary, (R)-7 was obtained
in less than 5% yield. We thought that this outcome could
result from the low solubility of 6-APA in toluene, so we de-
cided to synthesize its benzhydryl ester analogue and eval-
uate its catalytic activity. Thus, the 6-APA benzhydryl ester
10b was prepared following a previously developed two-
step procedure starting from 6-APA.25 The reaction of 10a
with diphenyldiazomethane in dichloromethane for 2 days
at room temperature, followed by treatment with HCl, af-
forded the corresponding hydrochloride of 6-APA benzhy-
dryl ester in quantitative yield. This, upon treatment with
base, originates 10b which was then used as catalyst in our
The asymmetric Neber reaction of -ketoxime tosylate,
generated in situ from -ketoxime 5 and TsCl, promoted by
6-aminopenicilanic acid (10a, 6-APA) was also investigat-
ed. 6-APA is a very cheap, easily available, enantiopure chi-
ral compound and it is the active nucleus common to all
penicillins.23 As far as we know, 6-APA has only been used
as organocatalyst for a direct cross-aldol reaction.24 After 24
h of reaction, 2H-azirine (R)-7 was isolated in only 15%
yield and 52% ee, with this catalyst inducing selectivity for
the R isomer. Increasing the reaction time to 48 h did not
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–F

D
C. Alves et al.
Letter
Synlett
transformation. Unfortunately, the reaction outcome was
not very different from the one observed in the 6-APA-pro-
moted reaction, furnishing 2H-azirine (R)-7 in slightly
higher yield (19%) but with very poor enantioselectivity
(13% ee, Scheme 2). These disappointing results observed
with 6-APA and its ester may be attributed to the presence
of the unprotected amino group, since the presence of TsCl
in the reaction medium may lead to the catalyst amino
group tosylation.
Table 2 Asymmetric Neber Reaction Using 6-APA-Derived Thiourea 12
as Catalyst
CF3
CO2CHPh2
O
S
N
S
F3C
N
N
H
H
N
NOH
N
N
12 (20 mol%)
N
(R)
N
N
Ph
Ph
TsCl (1.1 equiv)
K2CO3 (10 equiv)
toluene
N
PNB
N
N
PNB
5
Based on the aforementioned considerations we decid-
ed to attempt the synthesis of a new 6-APA derivative, a bi-
functional thiourea (Scheme 3). In the past decade bifunc-
tional thioureas have been successfully used as organocata-
lysts in several asymmetric reactions, namely the Neber
reaction.11 Inspired by these reports, we envisaged that a
6-APA-derived thiourea could be an effective catalyst for
our transformations. Thus, 6-APA benzhydryl ester (10b)
reacted smoothly with 3,5-bis(trifluoro)phenyl isothiocya-
nate (11) in THF at room temperature for 3 h, affording the
corresponding 6-APA-derived thiourea 12 in 48% yield
(Scheme 3).
(R)-7
Entry
Time (h)
Temp
Yield (%)
ee (%)a
1
2
3
4
48
24
48
72
rt
34
–
5
–
0 °C
0 °C
0 °C
51
12
92
84
a Determined by HPLC analysis on a chiral stationary column.
as resulting from the double hydrogen-bonding interaction
between the thiourea NH groups and the S=O moieties of
the in situ generated ketoxime tosylate, as previously ob-
served in asymmetric Neber reactions promoted by other
chiral thioureas.11
CF3
R–N=•=S
O
H2N
O
CO2CHPh2
S
11
S
N
N
THF, rt, 3 h
F3C
N
H
N
H
S
CO2CHPh2
This study was extended to the asymmetric synthesis of
tetrazolyl-2H-azirine derivatives bearing heterocyclic sub-
stituents at C-3 (e.g., furan-2-yl and thiophen-2-yl, Table 3).
Thus, the enantioselective Neber reaction of -ketoxime to-
sylates, generated in situ from -ketoximes 13 and TsCl, was
carried out in toluene for 48 h using thiourea 12, quinidine,
and quinine as catalysts. In the synthesis of 2-(tetrazol-5-
yl)-3-(thiophen-2yl)-2H-azirine (14a), higher selectivity for
the R isomer was achieved under thiourea 12 catalysis with
an enantiomeric excess of up to 74% (Table 3, entry 1)
whereas the quinidine-mediated reaction afforded 14a in
the highest yield (86%) albeit with slightly lower enantiose-
lectivity (55% ee, Table 3, entry 3). On the other hand, the
quinine-catalyzed reaction led to the preferential formation
of the S isomer of azirine 14a in good yield (52%) although
with low enantiomeric excess (29%, Table 3, entry 5).
In general, reactions with ketoxime 13b bearing a fura-
nyl substituent afforded lower conversions and selectivity
than those with ketoximes 5 and 13a (Table 3, entries 2, 4,
and 6). In fact, 2-(tetrazol-5-yl)-3-(furan-2-yl)-2H-azirine
(14b) was isolated under thiourea 12 catalysis in moderate
yield (57%) with 8% ee (Table 3, entry 2). Nevertheless, bet-
ter results were achieved using quinidine as catalyst, pro-
viding 3-(furan-2-yl)-2-(tetrazol-5-yl)-2H-azirine (14b) in
good yield (71%), albeit with 24% ee (Table 3, entry 4). Fur-
thermore, the quinine-mediated Neber reaction led to the
preferential formation of the S-isomer of 14b in 41% yield
and 8% ee (Table 3, entry 6). These rather disappointing re-
sults could be derived from the lower stability of these fura-
nyl-substituted 2H-azirine derivatives.
10b
12 48%
Scheme 3 Synthesis of 6-APA-derived thiourea 12
After successfully synthesizing the 6-APA-derived
thiourea, we set out to investigate its application as organo-
catalyst in the conversion of -ketoxime 5 into the corre-
sponding 2H-azirine (R)-7 (Table 2). Initially, the reaction
was performed under the previously optimized reaction
conditions for quinidine in toluene at room temperature for
48 h using K2CO3 as co-base, in the presence of 20 mol% of
thiourea 12 (Table 2, entry 1). Unfortunately, the reaction
outcome was not as expected, leading to the isolation of the
product in 34% yield along with 5% ee. No reaction occurred
when -ketoxime 5 was left to react at 0 °C for 24 h (Table 2,
entry 2). However, to our delight, after 48 h at 0 °C our tar-
get azirine was isolated in 51% yield with 92% ee (Table 2,
entry 3). Increasing the reaction time to 72 h did not im-
prove the efficiency of the reaction, and 2H-azirine was iso-
lated in lower yield with slightly lower ee (12% yield, 84%
ee, Table 2, entry 4).
Furthermore, the Neber reactions promoted by thiourea
12 led to the preferential formation of the R isomer of 2H-
azirine (R)-7, indicating that the new thiourea induces the
same selectivity as quinidine. It is noteworthy that this syn-
thetic methodology involves two consecutive reactions, the
in situ tosylation followed by the Neber reaction, and there-
fore, the efficiency and selectivity obtained with this cata-
lyst is quite remarkable. This selectivity can be rationalized
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–F

E
C. Alves et al.
Letter
Synlett
Table 3 Asymmetric Neber Reaction of -Ketoximes 13 with Several
Organocatalysts
angle between the least-squares planes of the two rings be-
ing 9.76(9)°. The tetrazole ring is almost perpendicular to
each of the aromatic rings (dihedral angles of 85.11(8)° and
75.35(9)° for rings C10.C15 and C19.C24, respectively). The
observed molecular conformation in the crystal maximizes
the – interaction between the electron clouds of the phe-
nyl rings and minimizes steric repulsion effects. As the mol-
ecules lacks any strong H-bonding donor, the only signifi-
cant intermolecular interactions spotted in the crystal
structure involve C–H groups acting as donors (D) and N or
O atoms as acceptors (A), namely C(15)–H(15).N(5)i, i = 1–x,
1–y, 1–z (D···A = 3.435(4) Å) and C(22)–H(22).O(17)ii, ii =
2–x, –1/2+y, 3/2–z (D···A = 3.466(3) Å). In addition, the two
short intramolecular contacts C(9)–H(9A).N(1) (D···A =
3.102(3) Å) and C(15)–H(15).N(8) (2.861(3) Å) deserve to
be remarked.
In conclusion, a one-pot synthetic methodology towards
chiral 2-(tetrazol-5-yl)-2H-azirines starting from -ketox-
ime-1H-tetrazoles has been developed by exploring or-
ganocatalysis.26 The target 2H-azirines were obtained in
moderate to high yields (up to 87% yield) and moderate to
excellent enantioselectivities (up to 92% ee). Within the cat-
alysts tested, the novel 6-APA-derived thiourea presented a
remarkable catalytic activity, yielding 3-phenyl-2-(tetrazol-
5-yl)-2H-azirine 7 in 92% ee.
organocatalyst
(20 mol%)
N
NOH
N
N
N
∗
N
N
R
TsCl (1.1 equiv)
K2CO3 (10 equiv)
toluene, 48 h
R
N
PNB
N
N
PNB
13a R = thiophen-2-yl
13b R = furan-2-yl
14a R = thiophen-2-yl
14b R = furan-2-yl
Entry
Catalyst
Temp
Product 14 Yield (%) ee (%)a
1
2
3
4
5
6
12
12
6
0 °C
0 °C
rt
14a
14b
14a
14b
14a
14b
44
57
86
71
52
41
74 (R)b
8 (R)b
55 (R)
24 (R)
29 (S)
8 (S)
6
rt
8
rt
8
rt
a Determined by HPLC analysis on a chiral stationary column.
b Using 18 mol% of 12.
Structure of 2H-azirine 7 was confirmed by single-crys-
tal X-ray diffraction. Details of the data collection and crys-
tallographic structure refinement are given in the supple-
mentary data. The compound crystallizes in the centrosym-
metric monoclinic space group P21/c with unit cell
parameters a = 15.228(4), b = 7.231(2), c = 13.866(4) Å,  =
97.008(11)°. An ORTEP plot of the molecule with the atom
numbering scheme is depicted in Figure 3.
Funding Information
The Coimbra Chemistry Centre (CQC) is supported by the Portuguese
Agency for Scientific Research, ‘Fundação para a Ciência e a Tecnolo-
gia’ (FCT), through Project UID/QUI/00313/2019. Carla Grosso ac-
knowledges FCT for the PhD research grant SFRH/BD/130198/2017
and Cláudia C. Alves for the PhD research grant PD/BD/143159/2019.
The Evora Chemistry Centre (CQE) received funding through the stra-
tegic FCT project Pest-OE/QUI/UI0619/2019.
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Acknowledgment
We acknowledge the UC-NMR facility for the NMR spectroscopic data
(www.nmrccc.uc.pt). Thanks are also due to Alexandre Pires Felguei-
ras for his contribution during the BSc project, carried out at Depart-
ment of Chemistry, University of Coimbra.
Figure 3 ORTEP diagram of 2H-azirine 7 with anisotropic displacement
ellipsoids drawn at the 50% probability level.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1691533.
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n
Bond lengths and angles in this molecule are within the
expected average ranges reported in the CCSD database, the
exceptions being bond lengths C2–C4 (1.455(3) Å) and
C19–C3 (1.440(3) Å) which are shorter than average values.
The azirine N1=C3 double bond length is 1.256(3) Å where-
as the N1–C2 single bond length is 1.549(3) Å. The C2–
N1=C3 angle is 61.41(16)°). The phenyl and nitrobenzyl
rings are in a syn,syn conformation and almost parallel, the
References and Notes
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Azetines, In Topics in Heterocylicic Chemistry; Maes, B. U. W.;
Cossy, J.; Slovenko, P., Ed.; Springer: Berlin, 2015, 1.
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F
C. Alves et al.
Letter
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of 2H-azirines 7, 14a, and 14b
To a solution of the appropriate -ketoxime 5 or 13a,b (0.15
mmol), K2CO3 (1.50 mmol, 10 equiv), and tosyl chloride (0.17
mmol, 1.1 equiv) in toluene (4 mL) under a nitrogen atmo-
sphere was added the organocatalyst (18 or 20 mol%) in toluene
(1 mL). The mixture was stirred for 48 h at the appropriate tem-
perature. The solvent was evaporated under reduced pressure,
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and washed with water (3 × 10 mL). The organic layer was dried
over anhydrous Na2SO4 and filtered, and the solvent was evapo-
rated under vacuum. The crude product was purified by flash
chromatography (ethyl acetate/hexane, 1:1). The characteriza-
tion data for 7, 14a, and 14b agreed with those previously
reported.19
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[3,5-bis(trifluoromethyl)phenyl] thioureido}-aminopenicil-
lanate (12)
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To a solution of benzhydryl 6-aminopenicillanate 10b (1.94
mmol, 0.74 g) under inert atmosphere in dry THF (3.5 mL) was
added dropwise 3,5-bis(trifluoromethyl)phenyl isothiocyanate
(11, 1.94 mmol, 0.35 mL). After stirring for 3 h at room tempera-
ture, the solvent was evaporated, and the crude product was
purified by flash chromatography (eluting with ethyl ace-
tate/hexane, 1:2) and recrystallized with diethyl ether/hexane;
yield 48%; white solid; mp 77.0–78.0 °C. IR (KBr):  = 682, 697,
1128, 1251, 1175, 1276, 1491, 1735, 2968, 2933, 3032, 3066,
3271, 3291 cm–1 1H NMR (400 MHz, CDCl3):  = 7.93 (s, 1 H),
.
7.84 (s, 2 H), 7.50 (s, 1 H), 7.35–7.31 (m, 11 H), 6.96 (s, 1 H), 5.19
(d, J = 2 Hz, 1 H), 4.25 (dd, J = 3.2 Hz and J = 1.2 Hz, 1 H), 3.92 (s,
1 H), 1.64 (s, 3 H), 1.00 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
 = 182.8, 170.6, 167.3, 139.1, 138.9, 133.9, 132.4 (q, J = 34.0 Hz,
2 C), 128.8, 128.9, 128.6, 128.5, 128.2, 127.9, 127.7, 126.9, 126.8,
126.6, 124.1, 122.9 (m, 1 C), 121.4, 78.7, 73.3, 66.5, 65.5, 65.1,
60.6, 26.3, 26.1 ppm. 19F NMR (376 MHz CDCl3):  = 62.8 (s, 6 F).
HRMS (ESI): m/z calcd for C30H26F6N3O3S2 [MH+]: 654.1314;
found: 654.1301.
(16) Cardoso, A. L.; Sousa, C.; Henriques, M. S. C.; Paixão, J. A.; Pinho
e Melo, T. M. V. D. Molecules 2015, 20, 22351.
(17) Jorda, R.; Lopes, S. M. M.; Řezníčková, E.; Kryštof, V.; Pinho e
Melo, T. M. V. D. ChemMedChem 2017, 12, 701.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–F