Ethyl 3-(2-pyridyl)-2H-azirine-2-carboxylate: Synthesis and reaction with dienes

Article abstract of DOI:10.1055/s-2004-837296

Ethyl 3-(2-pyridyl)-2H-azirine-2-carboxylate, the first example of an 3-heteroamatic 2H-azirine has been prepared. The reaction of ethyl 3-(2-pyridyl)-2H-azirine-2-carboxylate with conjugated 1,3-dienes, under mild conditions and in the absence of Lewis acid catalyst, afforded cycloadducts in good yield and high stereoselectivity.

Full text of DOI:10.1055/s-2004-837296

PAPER
555
Ethyl 3-(2-Pyridyl)-2H-azirine-2-carboxylate: Synthesis and Reaction with
Dienes
E
thyl 3-(2-Pyridyl)-2
H
.
-azirine-2-c
aJ
rboxylateosé Alves,*a A. Gil Fortes,*a Américo Lemos,b Cristina Martinsa
a
Departamento de Química, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal
Fax +351(253)678983; E-mail: mja@quimica.uminho.pt; gilf@quimica.uminho.pt
b
Departamento de Química e Bioquímica, Universidade do Algarve, Campus de Gambelas, 8000-117 Faro, Portugal
Received 7 September 2004; revised 14 October 2004
ylpyridine (1) was condensed with diethyl carbonate (2) in
the presence of NaH affording the b-keto ester 3. The usu-
al treatment of the b-keto ester to form the oxime, fol-
lowed by tosylation failed, due to formation of the
Abstract: Ethyl 3-(2-pyridyl)-2H-azirine-2-carboxylate, the first
example of an 3-heteroamatic 2H-azirine has been prepared. The re-
action of ethyl 3-(2-pyridyl)-2H-azirine-2-carboxylate with conju-
gated 1,3-dienes, under mild conditions and in the absence of Lewis
acid catalyst, afforded cycloadducts in good yield and high stereo- isoxazolone6 (Scheme 1).
selectivity.
Key words: 3-heteroaromatic-2H-azirines, hetero Diels–Alder re-
action, Neber reaction
O
O
+
OEt
N
EtO
OEt
N
O
O
2
3
1
2H-Azirines with an alkoxycarbonyl, aminocarbonyl or
phosphonate substituent on the C=N bond are particularly
good dienophiles in Diels–Alder reactions with a great va-
riety of dienes, as a consequence of the conjugated effect
of ring strain and extra activation by the electron-with-
drawing group. Cycloadducts are obtained in good or ex-
cellent yields, with high regio- and stereoselectivity, at
room temperature or on gentle heating and in the absence
of catalyst.1,2
NH2OH⋅HCl
NaOH
TsCl, Py
OEt
O
N
N
N
N
O
O
HO
5
4
Scheme 1
A few examples of Diels–Alder reactions of alkyl- and
aryl-2H-azirines with very reactive dienes such cyclopen-
tadienones and diphenylisobenzofuran are described in
the literature,3 but these ‘non-activated’ azirines failed to
react with simpler dienes such cyclopentadiene. On the
contrary, alkyl-2H-azirines bearing a benzoyl group at the
C=N bond do react.4
In order to overcome this problem it was decided to use o-
mesitylenesulfonylhydroxylamine (6), prepared accord-
ing to literature.7 Reaction of 6 with the b-keto ester 3 af-
forded in one step the corresponding protected imine 7.
Treatment of imine 7 under Neber conditions gave the de-
sired azirine 8 in 94% yield (Scheme 2). This new azirine
seems to be stable even when heated.
Recently it has been demonstrated2d,5 that alkyl- and aryl-
2H-azirines can participate, under Lewis acid catalysis (or
high temperature, in the case of one diene), as dienophiles
in Diels–Alder reactions with electron-rich dienes. Al-
though a remarkable extension of the chemistry of 2H-
azirines was achieved, apparently reactions with less elec-
tron rich dienes such 2,3-dimethylbutadiene were not at-
tempted or failed. With cyclopentadiene, the reaction was
unsuccessful at elevated temperature and at –78 °C an un-
expected rearranged product was obtained.2d Moreover, to
the best of our knowledge, there are no publications re-
porting Diels–Alder reactions of 3-alkyl- and/or 3-aryl-
2H-azirines-2-carboxylates.
O
OEt
S
O NH2
N
+
O
O
O
3
6
N
CO2Et
Et3N
OEt
N
N
O
N
O
O
S
8
7
O
Here we would like to report the first synthesis of a 2H-
azirine bearing a heteroaromatic group on the C=N bond
and its behavior in reactions with various dienes. 2-Acet-
Scheme 2
Diels–Alder reactions were carried out by stirring the azir-
ine with the respective diene at room temperature or at
60–75 °C depending on the diene. Adducts were isolated
after dry- flash chromatography (13–16) or by crystalliza-
SYNTHESIS 2005, No. 4, pp 0555–0558
x
x
.
x
x
.2
0
0
5
Advanced online publication: 23.12.2004
DOI: 10.1055/s-2004-837296; Art ID: P10804SS
© Georg Thieme Verlag Stuttgart · New York

556
M. J. Alves et al.
PAPER
tion of the crude product (17) (Scheme 3). Readily avail- Stereochemistry of adducts 13–17 was established com-
able and volatile dienes were used in large excess, and the bining the NMR data with our previous related work8 and
others (9, 11, 12) were used in equimolar amounts or in is consistent with exclusive addition of the diene to the
small excess. The reaction of 8 with cyclopentadiene (10) less hindered face of the azirine. The transition state of the
was complete in 3 hours affording adduct 15 as a yellow azirine 8 to cyclopentadiene is endo. This is indicated in
oil in 82% yield. The reaction with Danishefsky’s diene 9, particular by the 1H NMR spectrum, where a shielding ef-
was performed in toluene at 65 °C for 12 hours giving the fect of the hydrogen H-3 on the aziridine ring is observ-
adduct 13 after flash chromatography in 41% yield, to- able.8b In the case of adduct 17, the aziridine proton (H-1)
gether with another product identified as the adduct 14 ob- appears at d = 4.11, which is consistent with an exo ap-
tained in 26% yield. The Diels–Alder reaction of 8 and proach between reactants. The structure 17 shows H-1 and
diphenylisobenzofuran was conducted in refluxing THF the oxygen bridge on the same face, which causes a
for 20 hours and afforded adduct 17 in 54% yield after deshielding effect of the proton through space. This be-
crystallization from Et2O–petroleum ether. Reaction with havior has been noticed before.9
methoxybutadiene (11) was carried out in toluene at 75 °C
In summary, a new heteroaromatic 2H-azirine has been
for 40 hours. Purification of the reaction mixture by dry-
synthesized by a Neber reaction in excellent yield and re-
flash chromatography afforded the adduct 16 as reddish
acted with various dienes. This new azirine was able to
form cycloadducts in reaction with nucleophilic dienes in-
oil in 58% yield.
The azirine 8 was also subjected to reaction with 2-meth- cluding with cyclopentadiene in good yield and high ste-
ylbutadiene and 2,3-dimethylbutadiene but no cycload- reoselectivity; cycloaddition with other less electron-rich
ducts were formed after heating the reaction mixture in alkenes and furan or 2,5-dimethylfuran failed. Cycload-
toluene at 70 °C (16 h). 2-Methylbutadiene was refluxed ducts were formed by an endo approach of reactants, ex-
in Et2O (20 h) or heated in toluene at 70 °C in the presence cept for the cycloadduct with 1,3-diphenylisobenzofuran,
of BF3·Et2O as catalyst (19 h), leaving the azirine un- which was obtained by exo cycloaddition. The synthesis
touched. Furan and 2,5-dimethylfuran also did not react of other 2H-azirines with different (and more electro-
with azirine 8 after stirring at room temperature for some philic) heteroaromatic substituent at the C=N bond and its
days or by heating at 50 °C for several hours in presence reactivity towards conjugated dienes and furans are under
of ZnCl2, leaving the azirine untouched.
investigation.
These results are in contrast with those reported by Som-
fai et al.2d,5 First we were unable to achieve cycloaddition,
either thermally or by Lewis acid catalysis (BF3·Et2O,
ZnCl2), with simpler and/or less nucleophilic dienes; on
the other side we isolated a cycloadduct in very good yield
with cyclopentadiene, which has not been observed before
(Scheme 3).
1H NMR spectra were recorded on a Varian Unity Plus 300 (300
MHz) spectrometer. J values are in Hz and d in ppm. IR spectra
were recorded on a Bomem MB 104 or on a Perkin-Elmer 1600 FT-
IR spectrometer. Solid samples were run as Nujol mulls, and oils as
thin films. Mass spectra were recorded on a VG Autospec M. spec-
trometer. Microanalyses were performed in a LECO-CHNS-932
analyzer. Melting points were determined on a Gallenkamp block
N
N
15
(82%)
CO2Et
H
Ph
H
10
Ph
O
OMe
O
N
N
CO2Et
N
12
Ph
8
CO2Et
Ph
N
TMSO
H
16
OMe
(58%)
17
(54%)
11
9
OMe
OMe
OMe
N
N
N
+
N
CO2Et
CO2Et
O
TMSO
H
H
(26%)
14
13 (41%)
Scheme 3
Synthesis 2005, No. 4, 555–558 © Thieme Stuttgart · New York

PAPER
Ethyl 3-(2-Pyridyl)-2H-azirine-2-carboxylate
557
and are uncorrected. Dry-column flash chromatography was carried
out using Kieselgel 60 (<0.063 mm) and water pump vacuum. TLC
was carried out using 0.25 mm silica gel layer 60DC-Fertigplatten
Durasil-25 UV254. Et2O and THF were dried over sodium using
benzophenone as indicator. Et3N was distilled before use. Petro-
leum ether (bp 40–60 °C) was distilled before use.
IR (neat): 1583, 1679, 1728 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.29 (t, J = 7.2 Hz, 3 H, CH3),
3.04 (s, 1 H, CH), 4.23 (m, 2 H, OCH2CH3), 7.55 (m, 1 H, ArH),
7.95 (dt, J = 1.8, 7.8 Hz, 1 H, ArH), 8.09 (dt, J = 1.2, 7.8 Hz, 1 H,
ArH), 8.87 (m, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 14.1 (CH3), 31.0 (CH), 61.4 (CH2),
126.4 (CH), 127.2 (CH), 137.1 (CH), 142.8 (C), 151.0 (CH), 160.1
(C), 171.1 (C=O).
Ethyl 3-Oxo-3-(2-pyridinyl)propanoate (3)
To a three-necked round bottom flask was added a 60% dispersion
of NaH in mineral oil (3.22 g, 80.22 mmol, 3 equiv) in anhyd cyclo-
hexane (150 mL) and the mixture was heated to reflux. 2-Acetylpy-
ridine (26.74 mmol, 3.24 g, 1 equiv) was added dropwise and the
mixture was left to react for 10 min, and then diethyl carbonate
(12.63 g, 107 mmol, 4 equiv) was slowly added. The mixture was
refluxed for 5 h followed by stirring for 20 h at r.t. A solution of
AcOH–H2O (1:5, 75 mL) was slowly added under stirring in an ice-
water bath, forming two phases with a reddish color. The organic
phase was collected and the aqueous phase was extracted with Et2O
(2 × 100 mL). The organic extracts were combined, dried (MgSO4),
and the solvent was evaporated. Purification by dry flash chroma-
tography on silica gel using increasing polarity gradient of petro-
leum ether–Et2O afforded compound 3; yield: 4.57g (84%); pale
yellow oil.
HRMS (FAB): m/z calcd for C10H11N2O2 [M + H+]: 191.0821;
found: 191.0821.
Ethyl 2-Methoxy-6-(pyridin-2-yl)-4-trimethylsilyloxy-1-azabi-
cyclo[4.1.0]hept-3-ene-7-carboxylate (13) and Ethyl 2-Methoxy-
6-(pyridin-2-yl)-4-oxo-1-azabicyclo[4.1.0]heptane-7-carboxy-
late (14)
To a solution of the azirine 8 (0.20 g, 1.05 mmol) in anhyd toluene
(5 mL), was added 1-methoxy-2-trimethylsilyloxybuta-1,3-diene
(9; 0.35 mL, 1.7 equiv) at r.t. and the mixture was stirred at 65 °C
for 12 h. The solvent was then removed in a rotary evaporator to
give a brownish oil. Flash chromatography gave 13 (Et2O–petro-
leum ether) as an oil; yield: 0.16 g (41%); and 14 (EtOAc–Et2O) as
an oil; yield: 0.08 g (26%).
IR (neat): 1570, 1583, 1648, 1702, 1736 cm–1.
13
1H NMR (300 MHz, CDCl3): d = 1.24 (t, J = 7.2 Hz, 3 H, CH2CH3),
4.19 (s, 2 H, COCH2CO), 4.20 (q, J = 7.2 Hz, 2 H, OCH2CH3), 7.50
(ddd, J = 1.2, 4.8, 7.2 Hz, 1 H), 7.86 (dt, J = 1.8, 7.8 Hz, 1 H), 8.08
(dt, J = 1.2, 7.8 Hz, 1 H), 8.68 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 13.8 (CH3), 44.6 (CH2), 60.9
(CH2), 121.8 (CH), 127.4 (CH), 136.8 (CH), 148.8 (CH), 152.0 (C),
168.1 (C=O), 194.4 (C=O).
IR (Nujol): 1376, 1463, 1749, 2929 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.23 [s, 9 H, Si(CH3)3], 1.01 (t,
J = 7.2 Hz, 3 H, CH3), 2.49 (dt, J = 2.1, 18.3 Hz, 1 H, CH), 3.10 (s,
1 H, CH), 3.21 (d, J = 18.3 Hz, 1 H, CH), 3.69 (s, 3 H, OCH3), 3.89–
4.01 (m, 2 H, CH2CH3), 4.67 (t, J = 1.8 Hz, 1 H, CH), 5.14 (s, 1 H,
CH), 7.14–7.19 (m, 1 H, CH), 7.65–7.67 (m, 2 H, 2 CH), 8.53 (dt,
J = 1.5, 4.5 Hz, 1 H, CH).
13C NMR (75 MHz, CDCl3): d = 0.1 (3 CH3), 13.9 (CH3), 31.0
(CH2), 40.0 (CH3), 49.7 (C), 56.4 (CH), 60.5 (CH2), 87.7 (CH), 99.8
(CH), 122.2 (CH), 122.3 (CH), 136.1 (CH), 148.4 (C) 148.8 (CH),
158.5 (C), 168.6 (C=O).
HRMS (FAB): m/z calcd for C15H19N2O4 [M – TMS + H+]:
291.1345; found: 291.1334.
Ethyl 3-{[(Mesitylsulfonyl)oxy]imino}-3-(2-pyridinyl)pro-
panoate (7)
o-Mesitylenesulfonylhydroxylamine (6; 3.15 g, 14.65 mmol, 1.3
equiv) in THF was added to a stirred solution of b-keto ester 3 (2.18
g, 11.27 mmol, 1 equiv) in anhyd THF (20 mL) under N2 in an ice
bath. The mixture was stirred for a further 30 min and then the cool-
ing bath was removed. The stirring was continued at r.t. for 60 h.
The solvent was evaporated and the crude product was subjected to
dry flash chromatography on silica gel using increasing polarity
gradient of petroleum ether–Et2O, giving compound 7; yield: 2.24
g (51%); white solid; mp 98–99 °C.
14
1H NMR (300 MHz, CDCl3): d = 1.21 (t, J = 7.2 Hz, 3 H, CH3),
2.80 (dd, J = 2.7, 16.8 Hz, 1 H, CH), 3.15 (dd, J = 4.5, 16.8 Hz, 1
H, CH), 3.46 (s, 3 H, OCH3), 4.08 (d, J = 18.3 Hz, 1 H, CH), 4.11
(m, 2 H, OCH2CH3), 4.50 (d, J = 18.3 Hz, 1 H, CH), 4.79 (dd,
J = 2.7, 4.5 Hz, 1 H, CH), 5.36 (d, J = 0.9 Hz, 1 H, CH), 7.35 (ddd,
J = 0.9, 4.8, 7.5 Hz, 1 H, CH), 7 .55 (d, J = 7.5 Hz, 1 H, CH), 7.79
(dt, J = 1.8, 7.8 Hz, 1 H, CH), 8.66 (d, J = 4.8 Hz, 1 H, CH).
IR (Nujol): 1567, 1583, 1602, 1735, 3452 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.21 (t, J = 7.5 Hz, 3 H,
OCH2CH3), 2.32 (s, 3 H, ArCH3), 2.70 (s, 6 H, 2 × ArCH3), 4.13 (q,
J = 7.2 Hz, 2 H, OCH2CH3), 4.14 (s, 2 H, CH2), 7.0 (m, 2 H, ArH),
7.31 (ddd, J = 1.2, 4.8, 7.2 Hz, 1 H, ArH), 7.67 (dt, J = 1.8, 7.5 Hz,
1 H, ArH), 7.78 (dt, J = 1.2, 8.1 Hz, 1 H, ArH), 8.57 (m, 1 H, ArH).
HRMS (FAB): m/z calcd for C14H15N2O3 [M – OCH3 + H+]:
259.1083; found: 259.1078.
13C NMR (75 MHz, CDCl3): d = 13.9 (CH3), 21.1 (CH3), 22.8
(CH3), 31.9 (CH2), 61.3 (CH2), 121.4 (CH), 125.2 (CH), 130.1 (C),
131.7 (CH), 136.5 (CH), 140.9 (C), 143.9 (C), 149.0 (CH), 150.5
(C), 159.4 (C), 167.6 (C=O).
Ethyl 4-(Pyridin-2-yl)-2-azatricyclo[3.2.1.02,4]oct-6-ene-3-car-
boxylate (15)
The azirine 8 (0.10 g, 0.54 mmol) and cyclopentadiene (10; 5 mL,
large excess) were stirred at r.t. for 3.5 h. Flash chromatography
(Et2O–petroleum ether) gave 15; yield: 0.11 g (82%); pale yellow
oil.
Anal. Calcd for C19H22N2O5S: C, 58.44; H, 5.68; N, 7.17; S, 8.21.
Found: C, 58.40; H, 5.79; N, 7.19; S, 8.30.
IR (Nujol): 1567, 1589, 1722, 1745 cm–1.
Ethyl 3-(2-Pyridyl)-2H-azirine-2-carboxylate (8)
A mixture of oxime 7 (519 mg, 1.33 mmol, 1 equiv), Et3N (131 mg,
1.33 mmol, 1 equiv) and K2CO3 (1.83 g, 10 equiv) was stirred at 55
°C in anhyd toluene (7 mL). The reaction was monitored by H
NMR spectroscopy and completed in 16 h. H2O was added and the
mixture extracted with Et2O (3 × 30 mL). The organic extracts were
combined, dried (MgSO4), and the solvent evaporated, affording
azirine 8, which was used without further purification in Diels–Al-
der reactions; yield: 0.24 g (94%); pale yellow oil.
1H NMR (300 MHz, CDCl3): d = 0. 92 (t, J = 7.2 Hz, 3 H, CH3),
1.67 (d, J = 8.1 Hz, 1 H, CH), 2.19 (d, J = 8.1 Hz, 1 H, CH), 2.45
(s, 1 H, CH), 3.60 (s, 1 H, CH), 3.89 (m, 2 H, OCH2CH3), 4.43 (s, 1
H, CH), 5.84 (dd, J = 2.7, 5.4 Hz, 1 H, CH), 6.42 (m, 1 H, CH), 7.19
(m, 1 H, CH), 7.67 (m, 2 H, 2 CH), 8.57 (dd, J = 1.5, 3.6 Hz, 1 H,
CH).
1
Synthesis 2005, No. 4, 555–558 © Thieme Stuttgart · New York

558
M. J. Alves et al.
PAPER
13C NMR (75 MHz, CDCl3): d = 13.8 (CH3), 50.4 (CH), 52.0 (CH),
52.1 (C), 58.1 (CH2), 60.6 (CH2), 67.2 (CH), 122.2 (CH), 123.6
(CH), 128.0 (CH), 134.0 (CH), 136.0 (CH), 148.9 (CH), 157.2 (C),
167.2 (C=O).
127.0 (CH), 127.4 (CH), 127.6 (CH), 128.4 (CH), 128.4 (CH),
128.9 (CH), 129.2 (CH), 129.3 (CH), 132.3 (C), 133.1 (C), 135.5
(CH), 144.9 (C), 148.1 (C), 148.4 (CH), 153.5 (C), 167.4 (C=O).
HRMS (FAB): m/z calcd for C30H25N2O3 [M + H+]: 461.1865;
HRMS (FAB): m/z calcd for C15H16N2O2 [M + H+]: 257.1290;
found: 461.1850.
found: 257.1294.
Acknowledgment
Ethyl 2-Methoxy-6-(pyridin-2-yl)-1-azabicyclo[4.1.0]hept-3-
ene-7-carboxylate (16)
Thanks are expressed to Dr. Thomas L. Gilchrist for helpful discus-
sions. The authors also thank Fundação para a Ciência e Tecnologia
and FEDER for financial support (POCTI/QUI/32723/2000).
To a solution of the azirine 8 (0.24 g; 1.25 mmol) in anhyd Et2O (10
mL) was added 1-methoxybuta-1,3-diene (11; 0.26 mL, 2.0 equiv)
dropwise at r.t. and the mixture was stirred at 75 °C for 40 h. The
solvent was then removed in a rotary evaporator to give a reddish
oil. Flash chromatography (Et2O–petroleum ether) gave 16; yield:
0.20 g (58%); reddish oil.
References
(1) For reviews, see: (a) Palacios, F.; Ochoa de Retana, A. M.;
Marigorta, E. M.; Santos, J. M. Org. Prep. Proced. Int. 2002,
34, 219. (b) Gilchrist, T. L. Aldrichimica Acta 2001, 34, 51.
(c) Palacios, F.; Ochoa de Retana, A. M.; Marigorta, E. M.;
Santos, J. M. Eur. J. Org. Chem. 2001, 2401.
1H NMR (300 MHz, CDCl3): d = 1. 01 (t, J = 7.2 Hz, 3 H, CH3),
2.43 (dq, J = 2.8, 19.2 Hz, 1 H, CH), 3.14 (s, 1 H, CH), 3.28 (dd,
J = 6.0, 19.2 Hz, 1 H, CH), 3.70 (s, 3 H, OCH3), 3.89–4.00 (m, 2 H,
CH2CH3), 4.96 (d, J = 1.5 Hz, 1 H, CH), 5.56–5.60 (dm, J = 10.5
Hz, 1 H, CH), 5.83–5.89 (m, 1 H, CH), 7.15–7.19 (m, 1 H, CH),
7.66–7.68 (m, 2 H, 2 CH), 8.51–8.54 (m, 1 H, CH).
13C NMR (75 MHz, CDCl3): d = 13.8 (CH3), 25.9 (CH2), 39.3
(CH3), 48.7 (C), 56.3 (CH), 60.4 (CH2), 84.9 (CH), 122.1 (CH),
122.2 (CH), 123.7 (CH), 124.4 (CH), 136.1 (CH), 148.6 (CH),
158.7 (C), 168.6 (C=O).
(2) For recent contributions, see: (a) Timen, A. S.; Somfai, P. J.
Org. Chem. 2003, 68, 9958. (b) Alves, M. J.; Almeida, I. G.;
Gil Fortes, A.; Freitas, A. P. Tetrahedron Lett. 2003, 44,
6561. (c) Alves, M. J.; Durães, M. M.; Gil Fortes, A.
Tetrahedron Lett. 2003, 44, 5079. (d) Ray, C. A.; Risberg,
E.; Somfai, P. Tetrahedron 2002, 58, 5983. (e) Davis, F. A.;
Wu, Y.; Yan, H.; Prasad, K. R.; McCoull, W. Org. Lett.
2002, 4, 655. (f) Bickley, J. F.; Gilchrist, T. L.; Mendonça,
R. Arkivoc 2002, vi, 192; www.arkat-usa.org. (g) Álvares,
Y. S. P.; Alves, M. J.; Azoia, N. G.; Bickley, J. F.; Gilchrist,
T. L. J. Chem. Soc., Perkin Trans. 1 2002, 1911.
(3) (a) Anderson, D. J.; Hassner, A. Synthesis 1975, 483.
(b) Anderson, D. J.; Hassner, A. J. Org. Chem. 1974, 39,
2031.
(4) Hemetsberger, H.; Knitell, D. Monatsh. Chem. 1972, 103,
205.
(5) Ray, C. A.; Risberg, E.; Somfai, P. Tetrahedron Lett. 2001,
42, 9289.
(6) Verstappen, M. M. H.; Ariaans, G. J. A.; Zwanenburg, B. J.
Am. Chem. Soc. 1996, 118, 8491.
(7) Krause, J. G. Synthesis 1972, 140.
HRMS (FAB): m/z calcd for C15H19N2O3 [M + H+]: 275.1396;
found: 275.1396.
Ethyl 3,8-Diphenyl-8a-(pyridin-2-yl)-1,3,8,8a-tetrahydro-3,8-
epoxyazirin[1,2-b]isoquinoline-1-carboxylate (17)
To a solution of the azirine 8 (0.24 g, 1.25 mmol) in anhyd THF (10
mL) was added 1,3-diphenylisobenzofuran (12; 0.34 g, 1.25 mmol,
1.0 equiv) and the mixture was refluxed for 20 h. The solvent was
then removed in a rotary evaporator to give a solid. Recrystalliza-
tion from CH2Cl2–Et2O–petroleum ether gave 17; yield: 0.31 g
(54%); white solid; mp 168–169 °C.
IR (Nujol): 1569, 1590, 1727 cm–1.
1H NMR (300 MHz, CDCl3): d = 0. 99 (t, J = 7.2 Hz, 3 H, CH3),
3.69–3.98 (m, 1 H, OCH2CH3), 4.04–4.15 (m, 1 H, OCH2), 4.11 (s,
1 H, CH), 6.07 (d, J = 7.8 Hz, 1 H, CH), 6.99–7.10 (m, 3 H, 3 CH),
7.21 (dt, J = 1.8, 7.2 Hz, 1 H, CH), 7.27–7.32 (m, 2 H, 2 CH), 7.45–
7.51 (m, 6 H, 6 CH), 7.84–7.88 (m, 4 H, 4 CH), 8.45 (dm, J = 4.5
Hz, 1 H, CH).
13C NMR (75 MHz, CDCl3): d = 13. 8 (CH3), 46.9 (CH), 59.7 (C),
61.0 (CH2), 92.0 (C), 101.8 (C), 120.1 (CH), 120.7 (CH), 122.3
(CH), 122.6 (CH), 124.7 (CH), 125.1 (CH), 125.1 (C), 126.8 (CH),
(8) (a) Alves, M. J.; Bickley, J. F.; Gilchrist, T. L. J. Chem. Soc.,
Perkin Trans. 1 1999, 1399. (b) Alves, M. J.; Gilchrist, T. L.
J. Chem. Soc., Perkin Trans. 1 1998, 299. (c) Alves, M. J.;
Gilchrist, T. L. Tetrahedron Lett. 1998, 39, 7579.
(9) Alves, M. J.; Azoia, N. G.; Bickley, J. F.; Gil Fortes, A.;
Gilchrist, T. L.; Mendonça, R. J. Chem. Soc., Perkin Trans.
1 2001, 2969.
Synthesis 2005, No. 4, 555–558 © Thieme Stuttgart · New York