Retro-Cheletropic ene reactions with 2-carbena-1,3-dioxolane as chelefuge

Article abstract of DOI:10.1016/j.tet.2011.05.119

N[β-(Hetero)arylvinyl] ketenimines and carbodiimides bearing adequately positioned 1,3-dioxolane functions experience a new class of tandem process consisting of a 6π electrocyclic ring closure followed by a rare retro-cheletropic ene reaction, the extrusion of 2-carbena-1,3-dioxolane. This mechanistic sequence is supported by a computational study using DFT methods, showing that the simultaneous recovery of aromaticity at two rings is the clue for the low energy barrier of the retro-cheletropic step. Moreover, the highly exergonic decomposition of 2-carbena-1,3-dioxolane into CO₂ plus ethylene contribute to the success of the tandem sequences.

Full text of DOI:10.1016/j.tet.2011.05.119

Tetrahedron 67 (2011) 5590e5595
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
retro-Cheletropic ene reactions with 2-carbena-1,3-dioxolane as chelefuge
*
*
Mateo Alajarin, Marta Marin-Luna, Maria-Mar Ortin, Pilar Sanchez-Andrada , Angel Vidal
Departamento de Quimica Organica, Facultad de Quimica, Universidad de Murcia, Campus de Espinardo, 30100 Murcia, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
N[
functions experience a new class of tandem process consisting of a 6
lowed by a rare retro-cheletropic ene reaction, the extrusion of 2-carbena-1,3-dioxolane. This mecha-
nistic sequence is supported by computational study using DFT methods, showing that the
simultaneous recovery of aromaticity at two rings is the clue for the low energy barrier of the retro-
cheletropic step. Moreover, the highly exergonic decomposition of 2-carbena-1,3-dioxolane into CO2 plus
ethylene contribute to the success of the tandem sequences.
b
-(Hetero)arylvinyl] ketenimines and carbodiimides bearing adequately positioned 1,3-dioxolane
Received 3 March 2011
Received in revised form 27 May 2011
Accepted 29 May 2011
p
electrocyclic ring closure fol-
a
Available online 2 June 2011
Keywords:
retro-Cheletropic ene reactions
Dioxocarbenes
Ó 2011 Elsevier Ltd. All rights reserved.
Ketenimines
Carbodiimides
DFT computations
1. Introduction
excellent H donor fragment and these rearrangements were char-
acterized as intramolecular hydride-like transfers by means of
The translocation of a hydrogen atom along a polyene chain is
a well recognized event in organic chemistry. Woodward and
Hoffmann characterized and classified this type of sigmatropic
rearrangement, the hydrogen shift. Orbital symmetry rules estab-
lish in which cases these reactions are either thermally or photo-
chemically allowed, as well as the suprafacial or antarafacial
trajectory that the hydrogen atom follows from the atom to which
is initially bonded to the migration terminus.1 Sigmatropic hydro-
gen shifts are reactions that play an important role in some sig-
nificant biosynthetic transformations. Probably the most typical
example is the one occurring in the biosynthesis of the biologically
active form of vitamin D3: previtamin D3 converts into vitamin D3
by thermal isomerization involving an antarafacial 1,7 hydrogen
shift.2 Also in the biosynthesis of Giffordene, an olefinic hydrocar-
bon [(2Z,4Z,6E,8Z)-2,4,6,8-undecatetraene] isolated from the
brown alga Giffordia mitchellae, evidences of a [1,7]-H migration
have been found.3
computational studies. The resulting ortho-azaxylylene in-
termediates 2 further undergo 6 electrocyclic ring closure (6p-
ERC) to give quinolines 3 (X¼CR2) and quinazolines 3 (X¼NAr).
p
O
O
O
H
N C X
O
O
X
1,5-H
6 -ERC
O
X
N
N
H
R1
R1
R1
H
1
3
2
X = CR2, NAr
Scheme 1. Cyclization of acetal-ketenimines and -carbodiimides 1.
Based on these interesting 1/3 tandem processes, we targeted
the preparation of several ketenimines and carbodiimides of gen-
eral structure 4 (Scheme 2), in which that of substrates 1 has been
modified by inserting a carbonecarbon double bond between the
heterocumulenic function and the fragment bearing the dioxolane
ring. In these new species the carbonecarbon double bond con-
necting the 1,3-dioxolane with the vinylheterocumulenic function
is part of an aromatic or heteroaromatic ring. Our main aim was to
examine the suitability of heterocumules 4 for experiencing a 1,7
hydride-like transfer6 from the acetalic carbon atom to the electron
deficient central carbon atom of the ketenimine or carbodiimide
fragment. The putative 3-aza-1,3,5,7-octatetraenic intermediates 5,
resulting from such H shift, could further cyclize by two alternative
Within the frame of our long-lasting efforts on the chemistry of
heterocumulenes,4 we have recently reported a study on 1,5 hy-
drogen shifts in acetal-ketenimines
1
(X¼CR2) and acetal-
carbodiimides 1 (X¼NAr) in which the acetalic H atom migrates
to the electrophilic carbon atom of the heterocumulenic function
(Scheme 1).5 The 1,3-dioxolane function was demonstrated to be an
* Corresponding authors. Tel.: þ34 868 887418; fax: þ34 868 364149 (P.S.-A.);
tel.: þ34 868 887525; fax: þ34 868 364149 (A.V.); e-mail addresses: andrada@
um.es (P. Sanchez-Andrada), vidal@um.es (A. Vidal).
6p
-ERC modes, either by closure of the X1eC2eN3eC4eC5eC6
3-azatriene system via X1eC6 bond formation or by cyclization of
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.119

M. Alajarin et al. / Tetrahedron 67 (2011) 5590e5595
5591
the N3eC4eC5eC6eC7eC8 1-azatriene fragment through N3eC8
bond formation, to give diverse pyridines. An alternative cyclization
mode is the 8 -ERC with X1eC8 bond formation to afford azocines.
The potential periselectivity of this cyclization step adds further
interest to the study of this type of 1,7-H shift.
a
62%
O
b
O
O
O
O
89%
p
Br
6
CHO
7
c
85%
d
O
O
O
O
9
8
N PPh3
f
N3
O
EtO2C
EtO2C
O
H
O
X
8 O
7
1,7-H
C
H
O
O
2
N
N
3
X
O
5
1
R
R
Ph
10
12
N C C
N C N
4 X = CR2, NAr
5
EtO2C
44%
Ph
EtO2C
81%
Scheme 2. N-[b-(Hetero)arylvinyl] ketenimines and carbodiimides bearing 1,3-
dioxolane functions.
g
e
CH3
CH3
Herein we report our results on the thermal treatment of some
examples of ketenimines and carbodiimides of general structure 4.
We show that they experience an unexpected 6p-ERC/retro-che-
letropic ene reaction tandem process, instead of any of the above
Ph
Ph
H
N
N
N
11
13
CO2Et
CO2Et
sequences involving as the first step a [1,7]-H shift.
Scheme 3. Reagents and conditions: (a) n-BuLi, DMF, Et2O, ꢀ78 ꢁC/rt, 16 h. (b)
N3CH2CO2Et, Na, EtOH, ꢀ15 ꢁC 3 h, then rt 12 h. (c) PPh3, Et2O, rt, 16 h. (d) Ph2C]C]O,
toluene, rt, 30 min. (e) Toluene, reflux, 1 h. (f) 4-CH3eC6H4eN]C]O, toluene, rt, 1 h.
(g) Toluene, 170 ꢁC, sealed tube, 24 h.
2. Results and discussion
We first prepared ketenimine 10 and carbodiimide 12. Bromo-
lithium exchange in 2-(1-bromo-2-naphthyl)-1,3-dioxolane 6 using
n-butyllithium, in diethyl ether at ꢀ78 ꢁC, and further reaction with
DMF provided 2-(1,3-dioxolan-2-yl)-1-naphthaldehyde 7 in 62%
yield. Condensation of aldehyde 7 with ethyl azidoacetate in the
azidoacetate and subsequent Staudinger reaction of the azide 15
with triphenylphosphine provided iminophosphorane 16. Keteni-
mine 17 was generated in toluene solution by reaction of com-
pound 16 with diphenylketene and activated by heating at 80 ꢁC for
converting into the 4-diphenylmethylthieno[3,2-c]pyridine 18 (79%
yield) (Scheme 4). Carbodiimide 19, synthesized by reacting 16
with 4-methylphenylisocyanate experienced cyclization to the
4-(4-methylphenyl)aminothieno[3,2-c]pyridine 20 (55% yield) by
thermal treatment in toluene solution at 160 ꢁC in a sealed tube.
presence of sodium ethoxide in ethanol at ꢀ15 ꢁC led to
b-(1-
naphthyl)vinyl azide 8 (89% yield). The imination reaction of triphe-
nylphosphine with the azide 8, in anhydrous diethyl ether at room
temperature, yielded the triphenyliminophosphorane 9 (85% yield).
The aza-Wittig reaction of iminophosphorane 9 with diphenylketene
in toluene solution at room temperature led to the ketenimine 10. Its
formation was confirmed by an IR spectrum of the reaction mixture
showing averystrong absorption band close to 2000 cmꢀ1 associated
to the N]C]C grouping. This compound was used in the following
step without purification. When the toluene solution containing
ketenimine 10 was heated at reflux temperature for 1 h the 4-
diphenylmethylbenz[f]isoquinoline 11 was formed and isolated in
moderate yield (44%) (Scheme 3). The reaction of iminophosphorane
9 with 4-methylphenylisocyanate in toluene at room temperature
gave carbodiimide 12, as evidenced the IR spectrum of the reaction
mixture showing a strong absorption band close to 2270 cmꢀ1 as-
sociated to the N]C]N grouping. Under severe thermal conditions
(toluene,170 ꢁC, sealedtube, 24 h)carbodiimide 12 convertedintothe
4-(4-methylphenyl)aminobenz[f]isoquinoline 13 (81% yield).
O
O
H
O
O
a
65%
H
N3
CO2Et
b 80%
S
S
CHO
15
14
O
O
H
c
e
PPh3
N
S
16
CO2Et
Ph
C
Ph
Benz[f]isoquinolines 11 and 13 were characterized following
O
H
O
H
O
N
C
N
CH3
O
their analytical and spectroscopic data. In their 1H NMR spectra the
C
N
C(1)H proton resonates as a singlet at
d
d
¼9.25 ppm for 11 and
S
S
¼8.79 for 13. The 13C NMR spectrum of benz[f]isoquinoline 11
CO2Et
19
CO2Et
17
shows the signal of the aliphatic methine carbon atom of the
diphenylmethyl substituent at
d
¼55.9 ppm.
d
79%
f
55%
The outcome of the conversions of heterocumulenes 10 and 12
into 11 and 13, respectively, was striking as the 1,3-dioxolane
fragment was absent from the structure of the reaction products.
One H atom of such fragment, presumably the most labile acetalic
proton, becomes incorporated into 11 and 13, apparently at the
exocyclic C and N atoms linked to C(4) of the benz[f]isoquinoline
ring system. In order to prove that this outcome is not privative of
the 1,2-disubstituted naphthalene scaffolding linking the vinyl-
heterocumulene and dioxolane fragments, we next aborded the
H3C
Ph Ph
N
NH
N
S
S
CO2Et
CO2Et
18
20
Scheme 4. Reagents and conditions: (a) N3CH2CO2Et, Na, EtOH, ꢀ15 ꢁC 3 h, then rt
12 h. (b) PPh3, Et2O, rt, 16 h. (c) Ph2C]C]O, toluene, rt, 30 min. (d) Toluene, 80 ꢁC, 2 h.
(e) 4-CH3eC6H4-N]C]O, toluene, rt, 1 h. (f) Toluene, 160 ꢁC, sealed tube, 24 h.
We have envisaged a reasonable mechanism for explaining the
conversion of ketenimines 10 and 17 and carbodiimides 12 and 19
into the corresponding fused pyridines 11, 13, 18 or 20.7 It involves
study of two new similar heterocumulenes built on
disubstituted thiophene nucleus. Thus, the condensation of
3-(1,3-dioxolan-2-yl)thiophene-2-carbaldehyde 14 with ethyl
a 2,3-

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M. Alajarin et al. / Tetrahedron 67 (2011) 5590e5595
a 6
p
-ERC of the heterocumulenic acetals at the first step to give
species acting as the chelefuge, 2-carbena-1,3-dioxolane instead of
the habitual carbon monoxide in the previously disclosed instances
represented in Scheme 6. We aimed to compare, by computational
evaluation, these two chelefuges. DFT calculations at the B3LYP/6-
31þG** theoretical level predict an energy barrier of 22.7 kcal molꢀ1
for the transformation of 1-methyl-6-methylenecyclohexa-2,4-
diene-1-carbaldehyde 24 into ortho-xylene and carbon monoxide,
whereas that calculated for the conversion of 1-methyl-6-
methylenecyclohexa-2,4-dienyl-1,3-dioxolane 25 into ortho-xy-
lene and ethylenedioxycarbene is higher (32.2 kcal molꢀ1) (see
Scheme 7). However, as the first reaction is considerably more
exergonic than the latter (e20.3 vs ꢀ45.7 kcal molꢀ1), we have used
the Marcus theory12 for excluding the effects of the different
thermodynamic contributions to the magnitude of these energy
intermediates 21 (Scheme 5). These species would then experience
a retro-cheletropic ene reaction8 with extrusion of 2-carbena-1,3-
dioxolane to provide the final fused pyridines, a process, that is,
probably favoured because the newly formed double bond com-
pletes an aromatic system (the pyridine ring). As being previously
disclosed, the generated ethylenedioxycarbene should immediately
fragment into carbon dioxide and ethylene.9,10
O
H
O
H
O
X
C
O
X
6 -ERC
N
N
CO2Et
CO2Et
10, 12, 17, 19
barriers by calculating the intrinsic
D
Gs
barrier. The calcu-
21
Marcus
lated
D
Gs values are 45.6 and 42.4 kcal molꢀ1, respectively,
Marcus
retro-cheletropic
ene reaction
showing that the ability of 2-carbena-1,3-dioxolane as chelefuge is
intrinsically comparable, even slightly better, than that of carbon
monoxide in these transformations.
XH
N
CO2
CH2 CH2
+
+
O
O
CO2Et
11, 13, 18, 20
Scheme 5. Proposed mechanism for the conversions 10/11, 12/13, 17/18 and
19/20.
Obviously the main interest of the conversions of hetero-
cumulenes 10, 12, 17 and 19 into their corresponding fused pyri-
dines 11,13,18 and 20 is not synthetic but mechanistic. In fact, these
final heterocyclic products should reasonably result from similar
reaction sequences by starting from less elaborated materials, the
respective (hetero)aromatic aldehydes lacking the 1,3-dioxolane
functions [H instead of CH(OCH2)2 in the structures 7 and 14]. In-
deed, compound 20 has been previously prepared in this way.11 By
contrast the herein disclosed synthetic sequences are relevant on
mechanistic grounds as they belong to a new class of tandem
processes and involve the scarcely reported retro-cheletropic ene
reaction as the key step. As far as we are aware, no examples of
cheletropic ene reactions are known, whereas only a few frag-
mentations that can be interpreted as the reversal of these pro-
cesses have been reported: the decarbonylation of 2,2-dimethyl-3-
butenal 228b,d (Eq. 1 in Scheme 6) and those of the structurally
related 3,4-pentadienal 238c (Eq. 2) and 6-methylenecyclohexa-
2,4-diene-1-carbaldehyde 248a,b (Eq. 3).
Scheme 7. Comparison of carbon monoxide and ethylenedioxacarbene as chelefuges.
On the other hand, the fragmentation of 2-carbena-1,3-
dioxolane into carbon dioxide plus ethylene is a well-known pro-
cess. Several computational studies have concluded that this
reaction takes place in a concerted pathway with a small energy
barrier.13 Our calculations show that 2-carbena-1,3-dioxolane
fragments into ethylene and carbon dioxide via the transition
state TSfrag involving an energy barrier of 7.8 kcal molꢀ1 (slightly
higher than that computed at the CASPT2 level13b), and a reaction
energy of ꢀ60.5 kcal molꢀ1 at the B3LYP/6-31þG**. This notable
exergonic and irreversible second step of the conversion
25/ortho-xyleneþcarbon dioxideþethylene should be the major
driving force for the success of the retro-cheletropic ene step.
We also targeted to investigate by computations the trans-
formations of the heterocumulenes used in the experimental study
into the corresponding fused pyridines, trying to discern why these
molecules do not experience the initially planned [1,7]-H shift but
instead electrocycle and further extrude the dialkoxycarbene. We
first chose the structurally simplest N-[(1Z,3Z)-4-(1,3-dioxolan-2-
yl)buta-1,3-dienyl] ketenimine 26 as a model of the hetero-
cumulenes used in the experimental work (Scheme 8). We
located the transition state TSc1,7 connecting 26 with the
3-azaoctatetraenic system 27 by [1,7]-H shift of the acetalic proton.
TSc1,7 shows a nice helical geometry as expected for this class of
O
O
H
eq 1
+
CO
CO
H
H
22
O
O
O
MeO
H
H
eq 2
+
H
O
MeO
O
MeO
·
23
O
O
H
eq 3
+ CO
H
H
24
Scheme 6. Decarbonylation of 2,2-dimethyl-3-butenal (Eq. 1), 3,4-pentadienal (Eq. 2)
and 6-methylenecyclohexa-2,4-diene-1-carbaldehyde (Eq. 3).
The transformations in Eqs. 1 and 3 have been computationally
studied by DFT methods and shown to proceed by asynchronous
concerted mechanisms via five-membered cyclic transition
states.8b A differentiating fact of the retro-cheletropic ene reactions
involved in the herein reported experiments is the new divalent
sigmatropic rearrangement. The alternative 6p electrocyclic ring
closure of 26 leading to 3-(1,3-dioxolan-2-yl)-2,3-dihydro-2-

M. Alajarin et al. / Tetrahedron 67 (2011) 5590e5595
5593
methylenepyridine (28) takes place via the transition structure
considerably more exergonic,
D
Grxn¼e34.2 kcal molꢀ1, than that of
14
TSc6
,
slightly below in energy than TSc1,7 (18.6 vs
28,
D
Grxn¼e17.8 kcal molꢀ1
.
p
-ERC
21.9 kcal molꢀ1, respectively). In addition, the 2-methylenepyridine
28 is thermodynamically more stable than the azaoctatetraene 27.
The 2-methylenepyridine 28 further fragments into 2-carbena-1,3-
3. Conclusions
dioxolane and 2-methylpyridine via the transition structure TScchel
.
In summary, we here disclosed some examples of a new type of
tandem process involving as key step the rare pericyclic fragmen-
tation known as the retro-cheletropic ene reaction. The
experimentally-assayed processes are thermally-activated tandem
The calculated energy barrier for this step is 32.5 kcal molꢀ1, and
the reaction energy ꢀ17.8 kcal molꢀ1. The overall process, including
the fragmentation of 2-carbena-1,3-dioxolane, i.e., the conversion
of ketenimine 26 into 2-methylpyridine, CO2 and ethylene, is highly
exergonic (ꢀ90.0 kcal molꢀ1). Consequently, on the basis of kinetic
and thermodynamic grounds, the 1,7-H shift via TSc1,7 leading to 27
is predicted to be non competitive with the experimentally-
observed reaction channel, the electrocyclization/extrusion tan-
dem processes of the (het)arene fused analogous of 26.15
6p-electrocyclization/fragmentation reactions of N-(hetero)aryl-
vinyl substituted ketenimines and carbodiimides, bearing a 1,3-
dioxolane ring at 2 position of the (hetero)aryl fragment, which
were initially designed for testing potential [1,7]-H shifts. A com-
putational DFT study predicts surmountable energy barriers at the
experimental reaction conditions, gives account of the peri-
selectivity towards the electrocyclization versus the competitive H
shift in the first mechanistic step, and also shows that the retro-
cheletropic ene fragmentation benefits, as presumed, from the
simultaneous gain of aromatic stabilization at two nuclei. The un-
precedented chelefuge in the retro-cheletropic ene step is a dia-
lkoxycarbene, 2-carbena-1,3-dioxolane, which in turn should
decompose to carbon dioxide and ethylene as soon as formed in
a further fragmentation. This latter concerted step, with a low en-
ergy barrier and highly exergonic, should decisively contribute to
the success of the experimental processes.
4. Experimental section
4.1. General methods
All melting points are uncorrected. Infrared (IR) spectra were
recorded as Nujol emulsions. 1H NMR spectra were recorded in
CDCl3 at 300 or 400 MHz. 13C NMR spectra were recorded in CDCl3
at 75 or 100 MHz. The chemical shifts are expressed in parts per
million, relative to Me4Si at
d
¼0.00 ppm for 1H, while the chemical
shifts for 13C are reported relative to the resonance of CDCl3 d¼77.1.
2-(1-Bromo-2-naphthyl)-1,3-dioxolane 6,16 3-(1,3-dioxolan-2-
yl)thiophene-2-carbaldehyde 1417 and diphenylketene18 were
prepared following published experimental procedures.
Scheme 8. Mechanistic paths found for the conversion of ketenimine 26 into the
azaoctatetraene 27 and into 2-methylpyridineþ2-carbena-1,3-dioxolane.
4.2. Preparation of benz[f]isoquinolines 11 and 13
Finally, in a closer approximation to the experimental processes,
we have also computed the fragmentation of the slightly simplified
model 3-(1,3-dioxolan-2-yl)-3,4-dihydro-4-methylenethieno[3,2-
c]pyridine (29) into 4-methylthieno[3,2-c]pyridine (30) plus
2-carbena-1,3-dioxolane by a similar concerted process (Scheme 9).
The value of the energy barrier calculated for this retro-cheletropic
ene reaction, 17.2 kcal molꢀ1, is notably lower than the one calcu-
lated for the previous conversion of 28 into 2-methylpyridine and
the dialkoxycarbene, 32.5 kcal molꢀ1. This low energy barrier is
reasonably interpreted in terms of the gain in aromatization energy
occurring not only at the pyridine ring but also at the thiophene
fragment. For the same reason, the fragmentation of 29 is also
n-BuLi [4 mL, 2.5 M in hexane] was added dropwise to a solution
of 2-(1-bromo-2-naphthyl)-1,3-dioxolane 6 (2.79 g, 10 mmol) in
anhydrous diethyl ether (50 mL) at ꢀ78 ꢁC under an atmosphere of
nitrogen. The mixture was stirred at ꢀ78 ꢁC for 30 min, after which
a precipitate came out. Then, N,N-dimethylformamide (1.46 g,
22 mmol) was added. The mixture was stirred at ꢀ78 ꢁC for 15 min,
warmed to room temperature and stirred for 16 h. Saturated aque-
ous sodium hydrogen carbonate (50 mL) was added and the solvent
was removed under reduced pressure. The aqueous phase was
extracted with dichloromethane (4ꢂ50 mL), and the combined or-
ganic extracts were washed with brine (100 mL) and dried over
anhydrous magnesium sulfate, filtered and concentrated under re-
duced pressure The crude product was purified by column chro-
matography [silica gel; eluting with hexanes/diethyl ether (7:3, v/v)]
to give 2-(1,3-dioxolan-2-yl)-1-naphthaldehyde 7 [yield 62% (1.41 g)].
A mixture of ethyl azidoacetate (5.16 g, 40 mmol) and 2-(1,3-
dioxolan-2-yl)-1-naphthaldehyde 7 (2.28 g, 10 mmol) was added
dropwise to a well-stirred solution containing sodium (0.92 g) in
anhydrous ethanol (50 mL), under nitrogen at ꢀ15 ꢁC. The reaction
mixture was stirred at ꢀ15 ꢁC for 3 h, allowed to warm to room
temperature, and the stirring continued for 12 h. The mixture was
poured into aqueous 30% ammonium chloride (100 mL) and
extracted with diethyl ether (3ꢂ80 mL). The combined organic
layers were washed with water (3ꢂ100 mL) and dried over
Scheme 9. Computed retro-cheletropic ene fragmentation of 29.

5594
M. Alajarin et al. / Tetrahedron 67 (2011) 5590e5595
anhydrous magnesium sulfate. The solvent was removed under
reduced pressure and the crude material was chromatographed on
silica gel, using dichloromethane as eluent to give ethyl 2-azido-3-
[2-(1,3-dioxolan-2-yl)-1-naphthyl]propenoate 8 [yield 89% (3.02 g)].
A solution of triphenylphosphine (1.97 g, 7.5 mmol) in anhy-
drous diethyl ether (20 mL) was added dropwise, under nitrogen, at
layers were washed with water (3ꢂ100 mL) and dried over anhy-
drous magnesium sulfate. The solvent was removed under reduced
pressure and the crude material was chromatographed on silica gel,
using dichloromethane as eluent to give ethyl 2-azido-3-[3-(1,3-
dioxolan-2-yl)-2-thienyl]propenoate 15 [yield 65% (1.92 g)].
A solution of triphenylphosphine (1.97 g, 7.5 mmol) in anhy-
drous diethyl ether (20 mL) was added dropwise, under nitrogen, at
room temperature, to
a solution of ethyl 2-azido-3-[2-(1,3-
dioxolan-2-yl)-1-naphthyl]propenoate 8 (2.54 g, 7.5 mmol) in the
same solvent (15 mL). The reaction mixture was stirred at room
temperature for 16 h. The precipitated ethyl 3-[2-(1,3-dioxolan-2-
room temperature, to a solution of ethyl 2-azido-3-[3-(1,3-
dioxolan-2-yl)-2-thienyl]propenoate 15 (2.21 g, 7.5 mmol) in the
same solvent (15 mL). The reaction mixture was stirred at room
temperature for 16 h. The precipitated ethyl 3-[3-(1,3-dioxolan-2-
yl)-1-naphthyl]-2-triphenylphosphoranylideneaminopropenoate
was filtered and air dried [yield 85% (3.65 g)].
9
yl)-2-thienyl]-2-triphenylphosphoranylideneaminopropenoate
was filtered and air dried [yield 80% (3.18 g)].
16
4.2.1. 2-Ethoxycarbonyl-4-diphenylmethylbenz[f]isoquinoline 11. To
solution of ethyl 3-[2-(1,3-dioxolan-2-yl)-1-naphthyl]-2-
a
4.3.1. 6-Ethoxycarbonyl-4-diphenylmethylthieno[3,2-c]pyridine
18. To a solution of ethyl 3-[3-(1,3-dioxolan-2-yl)-2-thienyl]-2-
triphenylphosphoranylideneaminopropenoate 16 (0.53 g, 1 mmol)
in anhydrous toluene (20 mL) a solution of diphenylketene (0.19 g,
1 mmol) in the same solvent (5 mL) was added. The reaction mixture
was stirred at roomtemperature for 30 min, and then heated at 80 ꢁC
for 2 h. After cooling, the solvent was removed to dryness under
reduced pressure and the crude material was chromatographed on
silica gel, using hexanes/diethyl ether (1:1, v/v) as eluent, to give 6-
ethoxycarbonyl-4-diphenylmethylthieno[3,2-c]pyridine 18 [yield 79%
(0.29 g)]; mp 105e106 ꢁC (colourless prisms, diethyl ether); IR
(Nujol) 1728 (vs),1541 (m),1492 (m),1297 (s),1283 (s),1251 (s),1211
(m),1183 (m),1080 (m),1031 (m), 796 (w), 751 (m), 724 (m), 706 (m),
triphenylphosphoranylideneaminopropenoate 9 (0.57 g, 1 mmol)
in anhydrous toluene (20 mL) a solution of diphenylketene (0.19 g,
1 mmol) in the same solvent (5 mL) was added. The reaction
mixture was stirred at room temperature for 30 min, and then
heated at reflux for 1 h. After cooling, the solvent was removed to
dryness under reduced pressure and the crude material was
chromatographed on silica gel, using hexanes/diethyl ether (7:3, v/
v) as eluent, to give 2-ethoxycarbonyl-4-diphenylmethylbenz[f]iso-
quinoline 11 [yield 44% (0.18 g)]; mp 163e164 ꢁC (colourless prisms,
diethyl ether); IR (Nujol) 1719 (vs), 1281 (vs), 1258 (vs), 1168 (m),
1143 (s), 1029 (m), 816 (m), 758 (s), 739 (s), 702 (s) cmꢀ1; 1H NMR
(CDCl3, 300 MHz)
d
1.44 (t, 3H, J¼7.1 Hz), 4.45 (q, 2H, J¼7.1 Hz), 6.47
(s, 1H), 7.18e7.41 (m, 10H), 7.70e7.74 (m, 2H), 7.84 (d, 1H, J¼9.2 Hz),
7.87e7.90 (m, 1H), 8.10 (d, 1H, J¼9.2 Hz), 8.79 (d, 1H, J¼7.9 Hz), 9.25
690 (m) cmꢀ1; 1H NMR (CDCl3, 400 MHz)
d
1.43 (s, 3H, J¼7.2 Hz), 4.45
(q, 2H, J¼7.2 Hz), 6.19 (s, 1H), 7.22e7.37 (m, 11H), 7.55 (d, 1H,
(s, 1H); 13C NMR (CDCl3, 75 MHz)
d
14.3, 55.9, 61.5, 117.4, 122.4,
J¼5.6 Hz), 8.58 (s, 1H); 13C NMR (CDCl3, 100 MHz)
d 14.4, 58.0, 61.6,
123.7, 126.6, 127.3 (s), 127.8, 128.3, 128.7, 129.0, 129.5 (s), 129.8,
130.4, 132.9 (s), 135.8 (s), 142.4 (s), 142.7 (s), 160.8 (s), 166.3 (s);
HRMS (ESI): calcd for C29H24NO2 [MþH]þ 418.1802; found 418.1806.
118.4, 122.7, 126.7, 128.4, 129.5, 130.2, 136.7 (s), 141.2 (s), 142.0 (s),
148.3 (s), 157.8 (s), 165.7 (s); HRMS (ESI): calcd for C23H20NO2S
[MþH]þ 374.1209; found 374.1212.
4.2.2. 2-Ethoxycarbonyl-4-(4-methylphenyl)aminobenz[f]isoquino-
line 13. To a solution of ethyl 3-[2-(1,3-dioxolan-2-yl)-1-naphthyl]-
2-triphenylphosphoranylideneaminopropenoate 9 (0.57 g, 1 mmol)
in anhydrous toluene (20 mL) a solution of 4-methylpheny-
lisocyanate (0.13 g, 1 mmol) in the same solvent (5 mL) was
added. The reaction mixture was stirred at room temperature for
1 h, and then heated at 170 ꢁC in a sealed tube for 24 h. After
cooling, the solvent was removed to dryness under reduced pres-
sure and the crude material was chromatographed on silica gel,
using hexanes/diethyl ether (7:3, v/v) as eluent, to give 2-ethoxy-
carbonyl-4-(4-methylphenyl)aminobenz[f]isoquinoline 13 [yield 81%
(0.29 g)]; mp 187e189 ꢁC (yellow prisms, diethyl ether); IR (Nujol)
1698 (vs), 1611 (vs), 1577 (vs), 1512 (vs), 1403 (vs), 1270 (vs), 1250
4.3.2. 6-Ethoxycarbonyl-4-(4-methylphenyl)aminothieno[3,2-c]pyri-
dine 20. To a solution of ethyl 3-[3-(1,3-dioxolan-2-yl)-2-thienyl]-2-
triphenylphosphoranylideneaminopropenoate 16 (0.53 g,1 mmol)in
anhydrous toluene (20 mL) a solution of 4-methylphenylisocyanate
(0.13 g, 1 mmol) in the same solvent (5 mL) was added. The re-
action mixture was stirred at room temperature for 1 h, and then
heated at 160 ꢁC in a sealed tube for 24 h. After cooling, the solvent
was removed to dryness under reduced pressure and the crude
material was chromatographed on silica gel, using hexanes/diethyl
ether (3:7, v/v) as eluent, to give 6-ethoxycarbonyl-4-(4-methyl-
phenyl)aminothieno[3,2-c]pyridine 20 [yield 55% (0.17 g)].11
Acknowledgements
;
(vs), 1181 (s), 822 (s), 749 (s), 718 (m) cmꢀ1 1H NMR (CDCl3,
300 MHz)
d
1.52 (t, 3H, J¼7.2 Hz), 2.34 (s, 3H), 4.51 (q, 2H, J¼7.2 Hz),
This work was supported by the Ministerio de Ciencia e Inno-
vacion of Spain (Project CTQ2008-05827/BQU) and Fundacion
Seneca-CARM (Project 08661/PI/08). M.-M.O. thanks Fundacion
CajaMurcia for a fellowship.
7.16 (d, 2H, J¼8.1 Hz), 7.18 (s, 1H), 7.68e7.74 (m, 4H), 7.79 (d, 1H,
J¼9.0 Hz), 7.86 (d, 1H, J¼9.0 Hz), 7.88e7.91 (m, 1H), 8.65e8.68 (m,
1H), 8.79 (s, 1H); 13C NMR (CDCl3, 75 MHz)
d 14.4, 20.8, 61.6, 111.6,
117.7 (s), 119.0, 119.4, 123.8, 127.7, 128.62, 128.64, 129.5, 131.9 (s),
133.1 (s), 136.2 (s), 138.4 (s), 141.3 (s), 152.3 (s), 166.4 (s); HRMS
(ESI): calcd for C23H21N2O2 [MþH]þ 357.1598; found 357.1604.
Supplementary data
1H and 13C NMR spectra of compounds 11, 13 and 18. Details of
computational procedures, cartesian coordinates, and energies for all
thestationarypoints. Supplementarydataassociatedwiththis article
can be found in the online version at doi:10.1016/j.tet.2011.05.119.
4.3. Preparation of thieno[3,2-c]pyridines 18 and 20
A mixture of ethyl azidoacetate (5.16 g, 40 mmol) and 3-(1,3-
dioxolan-2-yl)thiophene-2-carbaldehyde 14 (1.84 g, 10 mmol) was
added dropwise to a well-stirred solution containing sodium
(0.92 g) in anhydrous ethanol (50 mL), under nitrogen at ꢀ15 ꢁC. The
reaction mixture was stirred at ꢀ15 ꢁC for 3 h and then allowed to
warm to room temperature, and the stirring continued for 12 h. The
mixturewas poured intoaqueous 30% ammonium chloride (100 mL)
and extracted with diethyl ether (3ꢂ80 mL). The combined organic
References and notes
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is
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and can be calculated by applying the Marcus equation:
Ea¼ EMarcusþ½ Erxnþ( EMarcus) For early reports on the Marcus
Erxn)2/16(
DEa) is the
D
D
D
D
D
D
D
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weinePonndorfeVerley reduction of acyclic
a,b-unsaturated ketones to sec-
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14. We could locate an alternative isomeric transition state for the electrocyclic
ring closure of 26 higher in energy than TSc6
(see Supplementary data).
p-ERC
7. We also considered a second mechanistic option, the 1,3 migration of the
15. We have discarded the alternative mechanistic path involving 1,3 migration
and -elimination (see Ref. 7) on the following grounds: (i) we could not locate
acetalic fragment to the X atom of 21 followed by an
acetalic carbon atom, promoted by the basic pyridinic
a
-elimination at the
atom, yielding
a
N
a first order transition structure for the 1,3 migration of the dioxolane ring; (ii)
although we were able to locate a transition structure (see Supplementary
data) for the 1,3-[CH3] shift transforming 2,3-dihydro-3-methyl-2-
methylenepyridine into 2-ethylpyridine, whose geometry correspond to a su-
prafacial migration with inversion at the migrating group (in agreement with
the WoodwadeHoffman rules), the energy barrier for this process is very high
(57.6 kcal molꢀ1); (iii) all the attempts to optimize an analogous transition
state for the migration of a 1,3-dioxolan-2-yl fragment failed or converged into
the ethylenedioxycarbene and the final heterocycle:
the transition state corresponding to the retro-chelotropic ene reaction, TScchel
.
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This alternative mechanistic sequence, in our view less convincing than the
former one, was finally discarded on computational ground: see Ref. 14.