Formation of pyridin-4(1H)-one versus 1H-azepin-4(7H)-one by treatment of 4-tert-butyldimethylsilyloxy-2-amino-1-aza-bicyclo[4.1.0]hept-3-enes with tetrabutylammonium fluoride

Article abstract of DOI:10.1016/j.tet.2007.08.007

Cycloadducts 3 and 4 were treated with tetrabutylammonium fluoride and rapidly suffer cleavage on the three-membered ring to form either pyridin-4(1H)-one or 1H-azepin-4(7H)-one. When R¹ is an oxycarbonyl or a 2-pyridyl group and R²

Full text of DOI:10.1016/j.tet.2007.08.007

Tetrahedron 63 (2007) 11167–11173
Formation of pyridin-4(1H)-one versus 1H-azepin-4(7H)-one by
treatment of 4-tert-butyldimethylsilyloxy-2-amino-1-aza-
bicyclo[4.1.0]hept-3-enes with tetrabutylammonium fluoride
a,
M. Jose Alves, A. Gil Fortes, F. Teixeira Costa and Vera C. M. Duarte
a
b
a
*
ꢀ
aDepartamento de Quꢀımica, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal
bFaculdade de Cie^ncias da Sauꢀde, Universidade Fernando Pessoa, R. Carlos da Maia 298, 4200-150 Porto, Portugal
Received 7 June 2007; revised 27 July 2007; accepted 2 August 2007
Available online 8 August 2007
Abstract—Cycloadducts 3 and 4 were treated with tetrabutylammonium fluoride and rapidly suffer cleavage on the three-membered ring to
form either pyridin-4(1H)-one or 1H-azepin-4(7H)-one. When R1 is an oxycarbonyl or a 2-pyridyl group and R2 is a negative charge-
stabilizing group (cases 3a,b and 4f) the C–C bond cleaves forming products 5. However, when R2¼H (case 3c) the ring expands to seven
members. When R1 is an acyl group the pyridin-4(1H)-one formation includes an unexpected shift of the carbonyl group.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
anion formed can be rapidly neutralized by migration of
a proton. When an aroyl group is present at C-6 of 1-aza-
bicyclo[4.1.0]hept-3-ene, C–C cleavage of the fused aziri-
dine and development of the anion can be noticed by an
unusual carbonyl migration.
During our work on cycloadditions of 2H-azirines with the
Danishefsky diene we have been observing the easy forma-
tion of azepinones, by treating the cycloadducts with silica.1
4-tert-Butyldimethylsilyloxy-2-azoyl-1-aza-bicyclo[4.1.0]-
hept-3-enes were shown to be less sensitive to silica, but at
lower pH the aziridine ring opened after nucleophilic attack
to form tetrahydropyridinones.2 To form a picture of the re-
activity of these cycloadducts in basic medium, as we had in
acidic medium, we decided to treat them with tetrabutyl-
ammonium fluoride as a privileged base. The C–N cleavage
of the aziridine moiety forming part of a fused system (five-
or six-membered rings) is well documented in the litera-
ture.2,3 Simple aziridines also readily undergo C–N opening
to relieve ring strain allowing access to amines,4 but C–C
cleavage to form azomethine ylides occurs at high tempera-
tures. Hudlicky observed the C–C breakage in an aziridine
fused to a five-membered ring by heating the sample at
520 ꢀC, ca. 10ꢁ4 Torr.5 Takano et al. also observed a similar
reaction by thermolysis of aziridines at 200 ꢀC.6 On the other
hand, aziridinyl anions are well known7 and can be obtained,
e.g., by desulfinylation,8 desilylation9 or deprotonation10 of
aziridines. An aziridinyllithium species was even stable at
ꢁ78 ꢀC and could be quenched with a range of electro-
philes.11 We observed now an easy C–C ring opening assis-
ted by the formation of a highly conjugated system; the
2. Results and discussion
Cycloadducts 3 and 4 are formed by Diels–Alder cycloaddi-
tion of electrophilic 2H-azirines 2 to dienes I and II. Prod-
ucts 4a, 4c and 4f are known compounds,2 4e was
prepared according to the procedure described for the syn-
thesis of the other compounds 4, products 3a–d are preferred
now, specially for the cost reasons. The starting 3-(tert-
butyldimethylsilyloxy)-1-(pyrazol-1-yl)-1,3-butadiene I is
obtained pure in 80% overall yield. Cycloadditions of diene
I with the 2H-azirines 2a–d are complete within several days
at rt in moderate yields (41.5–59%). Also cycloaddition
of diene II with 2H-azirine 2e to form compound 4e
(yield¼50%) occurs in 3 days under similar reaction condi-
tions. In accordance with previous results of Diels–Alder cy-
cloadditions of 2H-azirines to 1,3-dienes,12 cycloadducts are
isolated as single isomers and are estimated to have been
formed by endo approach of reagents (Scheme 1). The
main evidence for such selectivity was driven from the
chemical shifts of H-7. Values are dH¼3.94–3.66 ppm for
compounds in which R2¼Ar, dH¼2.10 ppm, when R2¼H,
and dH ca. 2.50 ppm when R2¼aliphatic. The only exception
to the endo rule in Diels–Alder reactions involving 2H-
azirines occur with furan and its derivatives. In those cases,
Keywords: Azepinones; Pyridinones; Aziridines; Tetrabutylammonium
fluoride.
* Corresponding author. E-mail: mja@quimica.uminho.pt
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.08.007

11168
M. J. Alves et al. / Tetrahedron 63 (2007) 11167–11173
TBSO
R1
R2
TBSO
N
R1
1N
N
N
I
2
7
R2
3a, 59%
3b, 55%
3c, 41.5 %
3d, 58%
N
N
toluene, rt, N2, 4-5 days
2a, R1 CO2Me, R2= 2,6-Cl2C6H3
=
2b, R1= CO2Me, R2= C6H4-4-Me
2e, R1= COC6H4-4-Br, R2= Me
2f, R1= 2-Pyridyl, R2= CO2Et
TBSO
R1
N
TBSO
R2
O
R1
II
R1
O
N
2
4a2
R2
toluene, rt, N2, 4-5 days
N
N
R2
N3
4c
O
4e, 50%
4f
2c
2
O
1c, R1= CO2Bn, R2= H
1d, R1= COC6H5, R2= Et
2d
Scheme 1.
O
R1
O
R2
TBAF
TBSO
CO2Et
TBAF
2
2
1
1
N
3a
3b
4f
3c
N
R1
N
H
R3
R2
5a, R1=CO2Me, R2= 2,6-Cl2-C6H3, 37 %
5b, R1=CO2Me, R2= 4-Me-C6H4, 38 %
5f, R1=pyridyl, R2= CO2Et, 30 %
6c, 55 %
3a,3b (R3= 1-pyrazolyl)
4f (R3= 1-oxazolidinyl)
Scheme 2.
the primary cycloadducts are transformed into the thermo-
dynamically more favoured products resulting from the
exo approach of the reagents.13
Cleavage of the tert-butyldimethylsilyl group in compounds
4 had been observed before in acidic non-nucleophilic me-
dium: a conjugative elimination occurs with breakage of
C2–N1 bond or the C2–N-oxazolidone bond. Treatment of
compounds 3 and 4 with tetrabutylammonium fluoride solu-
tion consistently eliminates the heterocyclic group (oxazo-
lidinyl or pyrazolyl) at C-2. Most probably the major
responsibility for silyl group elimination was not the fluoride
ion but H2O present in wet solvents used in the reactions.
The amount of fluoride ion seemed not to be critical either
in the formation of compounds 5 or 6/7. Both reactions go
to completion with 0.3 equiv of tetrabutylammonium fluo-
ride, which indeed shows that fluoride could not be con-
sumed in the formation of a fluor–silicon bond. The role
played by the fluoride ion possibly starts its action as
a base, attacking H-5 in the intermediate compound, and
continuing by carrying the proton to the developing negative
charge with regeneration of the fluoride ion and formation of
both products 5 and 6/7 (Scheme 4).
When adducts 3 and 4 are treated with tetrabutylammonium
fluoride they rapidly suffer cleavage of the three-membered
ring to form either pyridin-4(1H)-one or 1H-azepin-4(7H)-
one. When R1 is an oxycarbonyl or a 2-pyridyl group and
R2 a negative charge-stabilizing group (cases 3a,b and 4f),
compounds 5 are formed as exclusive products, rendered
by the C6–C7 cleavage. But when the negative charge to
be formed at the adjacent carbon atom to R2 cannot be dis-
persed (case 3c), the cleavage of C6–N1 occurs, installing
the developing charge at the nitrogen atom and thus, the
ring expanding to seven members (Scheme 2).
When R1 is an aroyl group and R2 is an aliphatic group, 1H-
azepin-4(7H)-one 6 and pyridin-4(1H)-one 7 are formed
simultaneously (Scheme 3). In one case, product 7 (7d)
1
was not isolated, but it was unequivocally identified by H
NMR spectroscopy in the crude sample of the reaction.
In Scheme 5 a possible mechanism for the formation of com-
pounds 7 is envisaged. The ionic intermediate 9 is proposed
to cyclize to a four-membered ring by attack of the carbanion
to the nearby ketone group. The ring opening that follows is
possibly assisted by the conjugation of the insipient charge
with the a,b-unsaturated endocyclic ketone.
O
O
R1
R2
R1
TBSO
R2
TBAF
+
2
1
N
N
H
N
R3
R1
R2
Rearrangements of carbonyl derivatives via enolate anion
shift have been described before in the chemistry of the
half-cage ketone 11 to the iso-half-cage ketone 13.14 The
phenomenon starts by homoenolization of proton Ha/Hb,
3d (R3= 1-pyrazolyl)
6d, 46 %
6e, 22 %
7d, not isolated,
4e (R3= 1-oxazolidinyl)
7e, 55%
Scheme 3.

M. J. Alves et al. / Tetrahedron 63 (2007) 11167–11173
11169
_
F
H
H
R1
R1
_
R2=Ar, CO2Et
O
O
R2
5
R2
N
N
N
R1
R2
Si O
8
9
R1=CO2Me, Pyridyl
-R3
N
_
R3
F
H
R1
H
3 or 4
R1
O
R2=H
O
6
N
_
8
10
Scheme 4.
and a higher value for C-2 in compound 5f, where 2-pyridyl
is directly attached to C-2.
_
F
O
O
_
H
H
O
Ar
O
O
O
Ar
R2
R2
Ar
R2
5
Compounds 7 showed H-5 and H-6 at dH in the same range of
those in compounds 5, but the signal integrals showed two
protons under each signal. The conclusive feature for the as-
signment of structure 7 was H-1 in the carbon chain attached
to the nitrogen pyridinone. Compound 7e showed H-1 at
dH¼5.57 ppm as a quartet, J¼7.2 Hz, coupling with the ad-
jacent methyl group (R2) and compound 7d showed H-1 at
dH¼5.18 ppm, as a doublet of doublets, J¼5.1 and 10.5 Hz
by coupling with the two adjacent protons of the ethyl group
(R2). For compound 7e 13C signals appeared at the expected
dC: C-3 and C-5 are coincident at dC¼118.8 ppm and also C-
2 and C-6 at dC¼139.0 ppm; C-1 is in the aliphatic region
(dC¼63.9 ppm), deshielded both by the nitrogen and the
aroyl group.
7
1 N
N
N
_
9
8
Scheme 5.
taken by a base, followed by four-membered ring closure to
form the alcohol 12 and finally C–C bond opening to the re-
arranged half-cage ketone structure 13 (Scheme 6). The pro-
cess occurs in BuOH, in the presence of BuOK, 0.9 M, at
175–200 ꢀC. The extremely mild conditions under which
the formation of compounds 7 occur are certainly due to
the developing negative charge that spontaneously is formed
at C-4, after elimination of the H-5 proton from the amino-
enone 8 (compare Schemes 5 and 6).
t
t
In compounds 6 the aliphatic proton(s) vicinal to NH appear
at dH¼4.15–4.62 ppm coupling with the mobile proton at the
nitrogen atom and other vicinal protons if existing. When
R2¼H, no geminal coupling is observed. The NH appeared
at dH¼5.58–6.22 ppm as a broad singlet that disappears after
D2O exchange. In the aminoenone moiety, H-b to the
carbonyl showed up at dH¼6.90–7.06 ppm and H-a at
dH¼5.27–5.29 ppm. The coupling constant between these
protons is J¼8.4–9.3 Hz. The other H-a to the endocyclic
carbonyl shows up as a doublet with a small coupling con-
stant J¼2.1–2.4 Hz at dH¼6.51–7.17 ppm.
Ha
O
HO
O
Hb
11
12
13
Scheme 6.
The same kind of intermediate 9 was suggested in the syn-
thesis of compounds 5. In those cases no migration was as-
signed to the carbonyl group (R1), which can be understood
in view of the poor reactivity of esters compared to ketones.
3. Conclusion
The main point of this work is the exploitation of the
reactivity of 4-tert-butyldimethylsilyloxy-2-amino-1-aza-
bicyclo[4.1.0]hept-3-enes in the presence of tetrabutylam-
monium fluoride and the mechanistic understanding of their
reactions. The fused aziridine ring opens in two different
ways according to the nature of the R2 groups attached at
C-7: a pyridin-4(1H)-one is formed when R2 is aromatic
and 1H-azepin-4(7H)-one forms as a sole product when R2
is H. When R2 is aliphatic two types of compounds are
formed simultaneously. An unusual rearrangement of an
acyl group at C-6 takes place in the formation of the pyri-
din-4(1H)-one compound.
Major features of compounds 5 in 1H NMR spectra are the
expected dH for H-5 and H-6, coupling together with
J¼7.5/7.8 Hz. The chemical shifts take into account the pro-
tective effect of the endocyclic nitrogen by conjugation over
H-5 (dH¼6.3–6.5 ppm), and the deprotective effect at b posi-
tion of the unsaturated ketone moiety H-6 (dH¼7.1–
7.4 ppm). H-3 appears as a doublet with a long range
coupling (J¼2.7–3.0 Hz) to H-5. In compounds 5a and 5b
1H–13C NMR correlation spectra indicate C-5 at
dC¼118.2–119.8 ppm, C-3 at dC¼120.6–122.5 ppm, C-6 at
dC¼140.0–143.2 ppm and C-2 at dC¼140.0–140.9 ppm

11170
M. J. Alves et al. / Tetrahedron 63 (2007) 11167–11173
4. Experimental
4.3. Synthesis of cycloadducts 3
4.1. General
4.3.1. Methyl 4-(tert-butyldimethylsilyloxy)-7-(2,6-di-
chorophenyl)-2-(1H-pyrazol-1-yl)-1-aza-bicyclo[4.1.0]-
hept-3-ene-6-carboxylate 3a. To a solution of diene I
(0.85 g; 0.00316 mol) in toluene (15 mL) was added 2H-
azirine 2a (0.63 g; 0.00316 mol) and the resulting mixture
was stirred at rt for 5 days under nitrogen. The solvent was
removed to afford a yellow oil, which was subjected to dry
flash chromatography (silica; pet. ether/diethyl ether; polar-
ity gradient) giving the title adduct 3a as an oil (0.82 g;
1H NMR spectra were recorded on a Varian Unity Plus 300
(300 MHz) spectrometer. Multiplicities are recorded as
broad peaks (br), singlets (s), doublets (d), triplets (t), dou-
blets of doublets (dd), doublets of doublets of doublets
(ddd), doublets of triplets (dt), triplets (t), quartets (q) and
multiplets (m). J values are in Hertz and d in parts per mil-
lion. Infrared spectra were recorded on a Bomem MB 104
or on a Perkin–Elmer spectrophotometer. Samples were
run as Nujol mulls and oils as thin films. MS spectra were
recorded on a VG Autospec M. spectrometer. Microanalyses
were performed in a LECO-CHNS-932 analyser. Melting
points (mp) were determined on a Gallenkamp block and
are uncorrected. Dry column flash chromatography was car-
ried out using Kieselgel 60 and water pump vacuum. Tolu-
ene was dried over sodium followed by distillation.
Dichloromethane (DCM) was dried over CaH2. Acetonitrile
(ACN) used was not dried. Petroleum ether 40–60 ꢀC
was distilled before use. 2H-Azirines 2a,14 b,14 f,15 benzyl
a-azidoacrylate 1c16 and diene II2 were obtained according
to the literature. 2H-Azirines 2e and 2d were obtained by
adapting the method of Hemetsberger for the synthesis of
carbonyl 2H-azirines.17,18 4-(1H-Pyrazol-1-yl)but-3-en-
2-one was obtained by repeating the procedure described
in the literature.19 Diene I was obtained by adapting the
methodology described for the synthesis of diene II.2 Com-
pounds 4a, 4c and 4f are known compounds and their syn-
theses were carried out according to the literature.2
Tetrabutylammonium fluoride was used as 1.0 M solution
in tetrahydrofuran (THF), sodium bis-(trimethylsilyl)amide
(NaHMDS), 1.0 M in THF and TBDMSCl, and were
purchased from Aldrich.
1
1.86 mmol; 59%). H NMR (CDCl3, 300 MHz) dH¼0.23
(s, 3H, Me), 0.25 (s, 3H, Me), 0.96 (s, 9H, 3ꢂMe), 2.97
(dt, J¼18.6, 2.4 Hz, 1H, H-5), 3.12 (d, J¼18.6 Hz, 1H,
H-5), 3.40 (s, 3H, OMe), 3.94 (s, 1H, H-7), 4.88 (t,
J¼2.1 Hz, 1H, H-3), 6.29–6.31 (m, 2H, H-2, 1H, Py), 7.01
(m, 1H, Ar), 7.14 (d, J¼7.5 Hz, 2H, Ar), 7.55 (d,
J¼1.5 Hz, 1H, Py), 7.73 (d, J¼2.1, 1H, Py). 13C NMR
(CDCl3, 75.5 MHz) dC¼ꢁ4.5 (Me), ꢁ4.4 (Me), 17.9 (C),
25.5 (Me), 27.6 (C-5), 42.1 (C-7), 45.7 (C-6), 52.3 (Me),
72.3 (C-2), 98.2 (C-3), 105.7 (CH, Py), 128.1 (CH, Ph),
130.1 (CH, Ph), 131.1 (CH, Py), 135.6 (C, Ph), 140.1 (CH,
Py), 149.5 (C-4), 170.0 (CO). IR (neat) nmax (cmꢁ1) 3007,
1749, 1726, 1679, 1582, 1561, 1504. HRMS (ESI) calcd
516.1253 [M+Na]; found 516.1247.
4.3.2. Synthesis of methyl 4-(tert-butyldimethylsilyloxy)-
7-(p-tolyl)-2-(1H-pyrazol-1-yl)-1-aza-bicyclo[4.1.0]hept-
3-ene-6-carboxylate 3b. A solution of azirine 2b (0.83 g;
4.44 mmol) in dry DCM (35 mL) was added to diene I
(1.21 g; 4.84 mmol). The reaction mixture was stirred under
nitrogen for 17 h at rt. The solvent was removed and the
crude oil subjected to dry flash chromatography (silica;
pet. ether/diethyl ether; polarity gradient) to give the product
as a yellow solid (1.06 g; 2.42 mmol; 55%); mp 99.8–
1
103.8 ꢀC. H NMR (CDCl3, 300 MHz) dH¼0.22 (s, 3H,
4.2. Synthesis of 1-(3-(tert-butyldimethylsilyloxy)buta-
1,3-dienyl)-1H-pyrazole I
Me), 0.25 (s, 3H, Me), 0.97 (s, 9H, 3ꢂMe), 2.24 (s, 3H,
Me), 2.69 (dt, J¼18.6, 2.1 Hz, 1H, H-5), 3.07 (d,
J¼18.6 Hz, 1H, H-5), 3.42 (s, 3H, OMe), 3.66 (s, 1H, H-
7), 5.02 (t, J¼1.8 Hz, 1H, H-3), 6.25 (t, J¼2.1 Hz, 1H,
Py), 6.31 (br s, 1H, H-2), 6.89 (d, J¼8.1 Hz, 2H, Ar), 6.96
(d, J¼8.1 Hz, 2H, Ar), 7.51 (d, J¼1.5 Hz, 1H, Py), 7.70
(d, J¼2.1 Hz, 1H, Py). 13C NMR (CDCl3, 75.5 MHz)
dC¼ꢁ4.6 (Me), ꢁ4.4 (Me), 17.9 (C), 21.0 (Me), 25.5
(Me), 28.2 (C-5), 42.4 (C-7), 47.8 (C-6), 51.9 (Me), 72.0
(C-2), 98.3 (C-3), 105.9 (CH, Py), 127.1 (CH, Ph), 128.4
(CH, Ph), 128.6 (CH, Ph), 131.8 (CH, Py), 136.6 (C, Ph),
140.0 (CH, Py), 148.8 (C-4), 169.8 (CO). IR (Nujol mull)
nmax (cmꢁ1) 3132, 3114, 1740, 1688, 1410. Anal. Calcd
for C24H33N3O3Si: C, 65.57; H, 7.57; N, 9.56. Found: C,
5.54; H, 7.58; N, 9.36.
To
a
solution of 4-(1H-pyrazol-1-yl)but-3-en-2-one
(0.69 g; 5.07 mmol) in recently dried THF (40 mL) was
slowly added a diluted solution of NaHMDS (1.0 M in
THF; 5.58 mL; 1.1 equiv) in dry THF (12 mL) under
magnetic stirring at ꢁ78 ꢀC for 1 h. After 1 h a solution
of TBDMSCl (0.84 g; 5.07 mmol) in dry THF (5 mL)
was added, and the reaction mixture was left to stir for
1 h at rt. The reaction mixture was poured into diethyl
ether (40 mL), passed through a pad of Celite and the
filtrate evaporated to give a brown oil that proved to be
virtually pure 3-(tert-butyldimethylsilyloxy)-1-(pyrazol-1-
yl)-1,3-butadiene I (1.25 g; 5.00 mmol; 98.6%) by 1H
NMR, which was used for further reactions without puri-
fication. 1H NMR (CDCl3, 300 MHz) dH¼0.24 (s, 6H,
2ꢂMe), 1.02 (s, 9H, 3ꢂMe), 4.38 (s, 1H, H-4), 4.42
(s, 1H, H-4), 6.37 (t, J¼2.4 Hz, 1H, Py), 6.56 (d,
J¼13.5 Hz, 1H, H-2), 7.28 (d, J¼13.5 Hz, 1H, H-1),
7.58 (d, J¼2.4 Hz, 1H, Py), 7.63 (s, 1H, Py). 13C
NMR (CDCl3, 75.5 MHz) dC¼ꢁ4.6 (Me), 18.3 (C),
25.8 (Me), 96.1 (C-4), 107.3 (CH, Py), 115.2 (C-2),
127.1 (C-1), 128.1 (CH), 128.2 (CH), 141.2 (CH, Py),
153.1 (CH, Py). IR (neat) nmax (cmꢁ1) 2956, 2930,
2886, 2859, 1658, 1598. HRMS (ESI) calcd 251.1580
[M+1]; found 251.1578.
4.3.3. Synthesis of benzyl 4-(tert-butyldimethylsilyloxy)-
2-(1H-pyrazol-1-yl)-1-aza-bicyclo[4.1.0]hept-3-ene-6-
carboxylate 3c. A solution of benzyl a-azido acrylate 1c
(1.20 g; 5.91 mmol) in dry toluene (180 mL) was heated un-
der reflux for 5 h. The reaction mixture was cooled, the diene
I (1.20 g; 5.91 mmol) added and the mixture stirred at rt for
8 days. The volume was reduced to half and a new portion of
freshly prepared azirine, obtained from benzyl a-azido acry-
late (1.20 g; 5.91 mmol) in toluene (180 mL), was added af-
ter being cooled. The reaction was continued for another
24 h and the solvent removed to give a dark oil that was

M. J. Alves et al. / Tetrahedron 63 (2007) 11167–11173
11171
subjected to dry flash chromatography [pet. ether (3)/ether
(1)] giving an yellow oil (1.04 g; 2.45 mmol; 41.5%). H
(Ar), 131.9 (Ar), 134.2 (Ar), 149.5 (C-4), 157.4 (CO-ox),
196.9 (CO). IR (Nujol mull) nmax (cmꢁ1) 3062, 2962,
2887, 1753, 1664, 1584. HRMS (ESI) calcd 507.1315
[M+1]; found 507.131.
1
NMR (CDCl3, 300 MHz) dH¼0.19 (s, 3H, Me), 0.20 (s,
3H, Me), 0.94 (s, 9H, 3ꢂMe), 2.10 (s, 1H, H-7), 2.41 (s,
1H, H-7), 2.68 (dd, J¼0.9, 18.0 Hz, 1H, H-5), 2.94 (dm,
J¼18.0 Hz, 1H, H-5), 4.85 (t, J¼2.1 Hz, 1H, H-3), 5.10 (d,
J¼12.3 Hz, 1H, CH2Ph), 5.29 (d, J¼12.3 Hz, 1H, CH2Ph),
6.10 (br s, 1H, H-2), 6.30 (dd, J¼1.8, 2.4 Hz, 1H, Py),
7.35 (s, 5H), 7.59 (d, J¼2.1 Hz, 1H, Py), 7.62 (d,
J¼2.1 Hz, 1H, Py). 13C NMR (CDCl3, 75.5 MHz)
dC¼ꢁ4.6 (Me), ꢁ4.4 (Me), 17.9 (C), 25.5 (Me), 27.1 (C-
5), 30.0 (C-7), 39.4 (C-6), 65.8 (CH2Ph), 72.2 (C-2), 97.6
(C-3), 105.9 (CH, Py), 128.2 (CH), 128.3 (CH), 128.5
(CH), 128.7 (CH), 135.5 (C), 140.1 (CH, Py), 149.2 (C-4),
171.1 (CO). IR (neat) nmax (cmꢁ1) 3054, 2986, 1739.
HRMS (ESI) calcd 448.2032 [M+Na]; found 448.2027.
4.4. Treatment of the cycloadducts 3 and 4 with tetra-
butylammonium fluoride
4.4.1. Synthesis of pyridines 5.
4.4.1.1. Synthesis of methyl 1-(2,6-dichlorobenzyl)-4-
oxo-1,4-dihydro-pyridine-2-carboxylate 5a. To a solution
of cycloadduct 3a (233 mg; 0.46 mmol) in ACN (5 mL) was
added Bu4N+Fꢁ in THF (1 M, 146 mL, 0.15 mmol;
0.32 equiv) at 0 ꢀC. The reaction mixture was stirred for
2 h at rt. The solvent was evaporated, DCM (10 mL) was
added and then a multiple washing with water (3ꢂ15 mL)
was carried out. The organic layers were combined and dried
over MgSO4. The solvent was removed to afford a yellow oil
that spontaneously crystallize (54 mg; 0.17 mmol; 37%); mp
4.3.4. Synthesis of (4-(tert-butyldimethylsilyloxy)-7-
ethyl-2-(1H-pyrazol-1-yl)-1-aza-bicyclo[4.1.0]hept-3-en-
6-yl)(phenyl)methanone 3d. a-Azido acrylate 1d (0.54 g;
2.69 mmol) was solubilized in dry toluene (20 mL) and
heated under reflux for 3 h. The solution was concentrated
to half of its volume and diene I (0.53 g; 2.12 mmol) was
added. The reaction mixture was stirred for 4 days at rt.
The solvent was removed and the crude oil was subjected
to dry flash chromatography (silica; pet. ether/ether; polarity
gradient) to give the product as a yellow oil. Yield (0.52 g;
1
119–121 ꢀC. H NMR (CDCl3, 300 MHz) dH¼3.98 (s, 3H,
Me), 5.64 (s, 2H, CH2), 6.33 (dd, J¼3.0, 7.8 Hz, 1H, H-5),
6.94 (d, J¼3.0 Hz, 1H, H-3), 7.11 (d, J¼7.8 Hz, 1H, H-6),
7.31 (dd, J¼6.6, 9.3 Hz, 1H, Ar), 7.43–7.40 (m, 2H, Ar).
13C NMR (CDCl3, 75.5 MHz) dC¼51.1 (CH2), 53.5 (Me),
119.8 (CH, C-5), 122.0 (CH, C-3), 129.1 (CH, Ar), 131.3
(CH, Ar), 136.8 (C), 140.5 (C-6), 140.9 (C-2), 163.3 (CO),
178.5 (CO, C-4). IR (Nujol mull) nmax (cmꢁ1) 1748, 1625,
1558, 1537. HRMS (ESI) calcd 312.0194 [M+1]; found
312.0192.
1
1.23 mmol; 58%). H NMR (CDCl3, 300 MHz) dH¼0.18
(s, 3H, Me), 0.22 (s, 3H, Me), 0.38 (t, 3H, Me), 0.67–0.80
(m, 1H, CH2Me), 0.93 (s, 9H, 3ꢂMe), 1.41–1.56 (m, 1H,
CH2Me), 2.47 (dt, J¼2.4, 17.7 Hz, 1H, H-5), 2.50–2.56 (m,
1H, H-7), 2.90 (d, J¼17.7 Hz, 1H, H-5), 5.06 (t, J¼2.1 Hz,
1H, H-3), 6.30 (dd, J¼1.8, 2.1 Hz, 1H, Py), 6.35 (br s, 1H,
H-2), 7.48 (t, J¼8.1 Hz, 2H, Ar), 7.53–7.60 (m, 2H,
Py+Ar), 8.02 (d, J¼8.1 Hz, 1H, Py). 13C NMR (CDCl3,
75.5 MHz) dC¼ꢁ4.5 (Me), ꢁ4.3 (Me), 10.5 (Me), 17.9
(C), 23.9 (CH2), 25.5 (Me), 29.2 (C-5), 42.1 (C-7), 50.3 (C-
6), 72.0 (C-2), 98.8 (C-3), 106.0 (CH, Py), 128.6 (CH),
128.8 (CH), 129.5 (CH), 133.4 (CH, Py), 135.2 (C), 139.9
4.4.1.2. Synthesis of methyl 1-(4-methylbenzyl)-4-oxo-
1,4-dihydro-pyridine-2-carboxylate 5b. To a solution of
cycloadduct 3b (0.24 g; 0.55 mmol) in ACN (13 mL) was
added Bu4N+Fꢁ in THF (1 M; 550 mL; 0.55 mmol) at
0 ꢀC. The reaction mixture was stirred for 1 h at rt. The sol-
vent was evaporated, DCM (15 mL) was added and then
a multiple washing with water (3ꢂ15 mL) was carried out.
The organic layers were combined and dried over MgSO4.
The solvent was removed and a yellow oil was obtained
(54 mg; 0.21 mmol; 38%). 1H NMR (CDCl3, 300 MHz)
dH¼2.33 (s, 3H, Me), 3.80 (s, 1H, Me), 5.30 (s, 2H, CH2),
6.44 (dd, J¼3.0, 7.5 Hz, 1H, H-5), 6.91 (d, J¼3.0 Hz, 1H,
H-3), 6.99 (d, J¼7.8 Hz, 2H, Ar), 7.15 (d, J¼7.8 Hz, 2H,
Ar), 7.43 (d, J¼7.8 Hz, 2H, H-6). 13C NMR (CDCl3,
75.5 MHz) dC¼21.1 (Me), 53.3 (Me), 57.4 (CH2), 119.4
(CH, C-5), 122.5 (CH, C-3), 127.1 (CH, Ph), 129.7 (CH,
Ph), 132.3 (C, Ph), 138.5 (C, Ph), 140.0 (C-2), 143.2 (C-
(CH, Py), 148.8 (C-4), 197.1 (CO). IR (neat) nmax (cmꢁ1
)
3062, 2960, 2931, 2886, 2859, 1677, 1580, 1579, 1514.
HRMS (ESI) calcd 446.2240 [M+Na]; found 446.2234.
4.3.5. Synthesis of 3-(6-(4-bromobenzoyl)-4-(tert-butyldi-
methylsilyloxy)-7-methyl-1-aza-bicyclo[4.1.0]hept-3-en-
2-yl)oxazolidin-2-one 4e. To a solution of diene II (0.27 g;
1.0 mmol) in toluene (15 mL) was added azirine 2e (0.28 g;
1.0 mmol) and the resulting mixture was stirred at rt for
3 days under nitrogen. The solvent was removed to give
a crude oil, which was subjected to dry flash chromato-
graphy (silica; pet. ether/diethyl ether; polarity gradient) to
afford the adduct as a yellow solid (0.25 g; 0.50 mmol;
50%); mp 135–137 ꢀC. 1H NMR (CDCl3, 300 MHz)
dH¼0.16 (s, 3H, Me), 0.18 (s, 3H, Me), 0.91 (s, 9H,
3ꢂMe), 1.09 (d, J¼6.0 Hz, 3H, Me), 2.41 (dm,
J¼17.7 Hz, 1H, H-5), 2.50 (q, J¼6.0 Hz, 1H, H-7), 2.82
(d, J¼17.7 Hz, 1H, H-5), 3.62 (t, J¼7.8 Hz, 2H, CH2ox),
4.38 (m, 2H, CH2ox), 4.62 (t, J¼1.8 Hz, 1H, H-3), 5.86
(br s, 1H, H-2), 7.63 (d, J¼7.8 Hz, 2H, Ar), 7.94 (d,
J¼7.8 Hz, 2H, Ar). 13C NMR (CDCl3, 75.5 MHz)
dC¼ꢁ4.6 (Me), ꢁ4.4 (Me), 15.1 (Me), 17.9 (C), 25.5
(Me), 29.2 (C-5), 34.6 (C-7), 41.4 (CH2ox), 47.2 (C-6),
62.1 (CH2ox), 65.6 (C-2), 98.1 (C-3), 128.8 (Ar), 131.1
6), 162.9 (CO), 178.8 (CO, C-4). IR (neat) nmax (cmꢁ1
)
3395, 3028, 2955, 2925, 1738, 1632, 1567, 1515. HRMS
(ESI) calcd 258.1130 [M+1]; found 258.1126.
4.4.1.3. Synthesis of ethyl 2-(4-oxo-2-(pyridin-2-yl)-
pyridin-1(4H)-yl)acetate 5f. To a solution of adduct 4f
(0.16 g; 0.36 mmol) in ACN (5 mL) was added Bu4N+Fꢁ
in THF (1.0 M, 124 mL; 0.32 equiv) at 0 ꢀC. The resulting
mixture was stirred at rt for 2 h. DCM (20 mL) was added,
the organic phase washed with H2O (3ꢂ15 mL), dried
with MgSO4 and solvent removed to afford an oil contami-
nated with the reagent ammonium salt. The crude was dis-
solved in Et2O (20 mL) and washed with H2O (20 mL).
The aqueous phase was extracted with DCM (3ꢂ10 mL).
The organic layers were combined, dried over MgSO4 and
evaporated to give the pure title pyrimidone 5f as a yellow

11172
M. J. Alves et al. / Tetrahedron 63 (2007) 11167–11173
oil (28 mg; 0.108 mmol; 30%). 1H NMR (CDCl3, 300 MHz)
dH¼1.20 (t, J¼7.2 Hz, 3H, Me), 4.15 (q, J¼7.2 Hz, 2H,
CH2), 4.72 (s, 2H, CH2), 6.45 (dd, J¼2.7, 7.5 Hz, H-5),
6.55 (d, J¼2.7 Hz, 1H, H-3), 7.33 (d, J¼7.5 Hz, 1H, H-6),
7.37–7.41 (m, 1H, Py), 7.58 (dm, J¼7.8 Hz, 1H, Py), 7.85
(td, J¼1.5, 8.7 Hz, 1H, Py), 8.62–8.65 (m, 1H, Py). 13C
NMR (CDCl3, 75.5 MHz) dC¼14.0 (Me), 55.0 (CH2), 61.9
(CH2), 118.2 (CH, C-5), 120.6 (CH, C-3), 124.2 (CH, Py),
124.7 (CH, Py), 137.8 (CH, Py), 143.2 (C-6), 148.8 (CH,
Py), 149.0 (C-Py or C-2), 152.6 (C-2 or C-Py), 167.5
(CO), 179.3 (CO, C-4). IR (neat) nmax (cmꢁ1) 2963, 1747,
1633, 1572. HRMS (ESI) 259.1082 [M+1]; found 259.1110.
4.4.2.3. Synthesis of 6-(4-bromobenzoyl)-7-methyl-
1H-azepin-4(7H)-one 6e and 1-(1-(4-bromophenyl)-1-
oxopropan-2-yl)pyridin-4(1H)-one 7e. To a solution of
adduct 4e (0.15 g; 0.296 mmol) in ACN (5 mL) was added
Bu4N+Fꢁ in THF (1.0 M; 93 mL; 0.095 mmol; 0.32 equiv)
at 0 ꢀC. The mixture was stirred at rt for 2 h. DCM
(15 mL) was added, the organic phase washed with H2O
(3ꢂ15 mL), dried over MgSO4 and solvent was removed
to afford an oil, that spontaneously crystallizes to give the
title pyridinone 7e (50 mg; 0.163 mmol; 55%); mp 120–
123 ꢀC. The mother liquid was also recovered and the sol-
vent evaporated to afford azepinone compound 6e (20 mg;
0.065 mmol; 22%). Compound 7e: 1H NMR (CDCl3,
300 MHz) dH¼1.75 (d, J¼7.2 Hz, 3H, Me), 5.57 (q,
J¼7.2 Hz, 1H, CH), 6.41 (d, J¼7.5 Hz, 2H), 7.67 (d,
J¼7.5 Hz, 2H), 7.82 (d, J¼8.7 Hz, 2H), 7.82 (d, J¼8.7 Hz,
2H). 13C NMR (CDCl3, 75.5 MHz) dC¼18.7 (Me), 63.9
(C-10), 118.8 (C-3+C-5), 130.0 (Ar), 132.7 (Ar), 139.0 (C-
2+C-6), 178.9 (CO), 193.9 (CO). R (Nujol mull) nmax
(cmꢁ1) 2918, 2850, 1692, 1638, 1584, 1564. HRMS (ESI)
calcd 306.0130 [M+1]; found 306.0135.
4.4.2. Synthesis of azepines 6 and pyridines 7.
4.4.2.1. Synthesis of benzyl 5-oxo-2,5-dihydro-1H-aze-
pine-3-carboxylate 6c. To a solution of adduct 3c (0.26 g;
0.58 mmol) in ACN (5 mL) was added Bu4N+Fꢁ in THF
(1.0 M; 185 mL; 0.32 equiv) at 0 ꢀC. The resulting mixture
was stirred at rt for 2 h. DCM (15 mL) was added, the organic
phase washed with H2O (3ꢂ15 mL), dried with MgSO4 and
the solvent was removed to afford a crude oil, which was sub-
jected to dry flash chromatography (silica; pet. ether/diethyl
ether; polarity gradient). A yellow oil was obtained (0.08 g;
1
Compound 6e: H NMR (CDCl3, 300 MHz) dH¼1.57 (d,
J¼7.2 Hz, Me), 4.62 (quint, J¼6.6 Hz, 1H, H-7), 5.27
(ddd, J¼1.5, 2.1, 8.7 Hz, 1H, H-3), 6.15 (br s, 1H, NH),
6.51 (d, J¼2.1 Hz, 1H, H-5), 6.90 (dd, J¼6.9, 8.7 Hz, 1H,
H-2), 7.61 (d, J¼8.7 Hz, 2H), 7.65 (d, J¼8.7 Hz, 2H). 13C
NMR (CDCl3, 75.5 MHz) dC¼15.3 (Me), 58.4 (C-7),
102.1 (C-3), 128.3 (C), 131.0 (CH, Ar), 131.7 (CH, Ar),
134.8 (C), 140.0 (C-5), 141.7 (C-6), 147.2 (C-2), 188.2
(CO), 195.4 (CO). R (DCM) nmax (cmꢁ1) 3230, 2962,
1653, 1584, 1534. HRMS (ESI) 3056.0129 [M+1]; found
306.012.
1
0.32 mmol; 55%). H NMR (CDCl3, 300 MHz) dH¼4.15
(d, J¼5.1 Hz, 2H, CH2, H-2),y 5.24 (s, 2H, CH2), 5.29 (dt,
J¼2.4, 8.4 Hz, 1H, H-6), 6.22 (br s, 1H, NH), 7.06 (dd,
J¼5.7, 8.4 Hz, 1H, H-7), 7.17 (d, J¼2.4 Hz, 1H, H-4), 7.36
(s, 5H). 13C NMR (CDCl3, 75.5 MHz) dC¼42.4 (CH2, C-
2), 67.4 (CH2), 103.7 (CH, C-6), 128.1 (CH, Ar), 128.5
(CH, Ar), 129.2 (C), 135.1 (C), 149.3 (CH, C-7), 142.1
(CH, C-4), 165.2 (CO), 189.2 (CO, C-5). IR (neat) nmax
(cmꢁ1) 3180, 1701, 1635, 1590, 1561, 1505. HRMS (ESI)
calcd 244.097 [M+1]; found 244.0974.
4.4.2.2. Synthesis of 6-benzoyl-7-ethyl-1H-azepin-
4(7H)-one 6d. To a solution of the adduct 3d (0.34 g;
0.80 mmol) in ACN (10 mL) was added Bu4N+Fꢁ in THF
(1 M; 260 mL; 0.26 mmol; 0.32 equiv) at 0 ꢀC. The resulting
solution was stirred at rt for 1 h. The solvent was evaporated,
and the crude materialz dissolved in ether (20 mL), washed
with water (2ꢂ20 mL), dried over MgSO4 and evaporated
to give a yellow oil, pure product 6d. Yield (0.09 g;
Acknowledgements
We thank Dr. Thomas Gilchrist for reading the manuscript
^
and Fundac¸ao para a Ciencia e Tecnologia for project
~
funding.
References and notes
1
0.37 mmol; 46%). H NMR (CDCl3, 300 MHz) dH¼0.95
(t, J¼7.5 Hz, 3H, Me), 1.85 (m, 1H, CH2Me), 2.05–2.20
(m, 1H, CH2Me), 4.45 (dt, J¼6.3, 9.3 Hz, 1H, H-7), 5.29
(ddd, J¼1.8, 2.4, 9.3 Hz, 1H, H-3), 5.58 (br s, 1H, NH),
6.62 (d, J¼2.4 Hz, 1H, H-5), 6.91 (dd, J¼7.2, 9.3 Hz, 1H,
H-2), 7.30 (t, J¼7.5 Hz, 2H, Ar), 7.60 (t, J¼6.3 Hz, 1H,
Ar), 7.80 (d, J¼6.3 Hz, 2H, Ar). 13C NMR (CDCl3,
75.5 MHz) dC¼10.7 (Me), 22.0 (CH2), 55.4 (C-7), 102.8
(C-3), 128.5 (CH, Ar), 129.6 (CH, Ar), 132.9 (CH, Ar),
136.6 (C), 141.4 (C-5), 141.7 (C-6), 145.6 (C-2), 189.1
(CO), 197.0 (CO). R (DCM) nmax (cmꢁ1) 3252, 3054,
1653, 1576, 1519. HRMS (ESI) 264.1000 [M+Na]; found
264.0996.
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