Preparation of 3-(fluoroalkyl)-2-azadienes and its application in the synthesis of (fluoroalkyl)isoquinoline and -pyridine derivatives

Article abstract of DOI:10.1002/ejoc.200400770

A method for the preparation of 3-(fluoroalkyl)-substituted 2-azabutadienes 5 by aza-Wittig reaction of N-vinylic 3-(fluoro-alkyl)phosphazenes 4 and aldehydes is reported. Thermal 6π-electrocyclization of these azadienes gives 3-(fluoroalkyl)-substituted

Full text of DOI:10.1002/ejoc.200400770

FULL PAPER
Preparation of 3-(Fluoroalkyl)-2-azadienes and Its Application in the Synthesis
of (Fluoroalkyl)isoquinoline and -pyridine Derivatives
Francisco Palacios,*[a] Concepción Alonso,[a] Marta Rodríguez,[a]
Eduardo Martínez de Marigorta,[a] and Gloria Rubiales[a]
Keywords: Phosphazenes / Aza-Wittig reaction / Cycloaddition / 2-Azadienes / Fluoroalkylated compounds
A method for the preparation of 3-(fluoroalkyl)-substituted 2-
azabutadienes 5 by aza-Wittig reaction of N-vinylic 3-(fluoro-
alkyl)phosphazenes 4 and aldehydes is reported. Thermal
6π-electrocyclization of these azadienes gives 3-(fluoroalkyl)-
substituted isoquinolines 6. Also [4+2] cycloaddition of these
heterodienes 5 with enamine 8 gives fluoroalkyl-substituted
pyridine derivatives 10–16. However, the reaction of azadi-
enes 17 with azo compound 18 affords bicyclic heterocycles
19.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Introduction
The development of efficient and mild methods for the
synthesis of organofluorine compounds represents a broad
area of research in organic chemistry since the incorpora-
tion of a fluorine-containing group into an organic mole-
cule dramatically alters its physical, chemical and biological
properties.[1] Special interest has been focused on the devel-
opment of synthetic methods for the preparation of fluori-
nated building blocks which can be used in the efficient
and/or selective preparation of fluorine-containing mole-
cules with biological activity and commercial applica-
tions.[2] The synthetic methods used in the synthesis of these
compounds include the introduction of fluorine into the
preformed heterocycles or the formation of heterocyclic sys-
tems by using fluorinated precursors. Direct fluorination is
the simplest way to prepare fluorinated heterocyclic com-
pounds,[3] but usually the use of fluorinated precursors is of
more interest due to the easy and regioselective formation
of the products.[4]
Functionalized 2-azabutadiene systems have proved to be
efficient key intermediates in the synthesis of heterocy-
cles[5,6] and we have previously described new methods for
the preparation of heterocycles,[7] as well as the synthesis of
neutral azadienes I[8] or electron-poor 2-aza-1,3-butadienes
derived from β-amino esters II (Figure 1),[9] all of which are
useful in the preparation of nitrogen-containing heterocy-
clic compounds.[7–9]
Figure 1. 2-Aza-1,3-butadienes I–III.
Fluoroalkyl-substituted 2-aza-1,3-butadienes III, despite
their potential interest as synthons in the construction of
more complex fluoro-containing acyclic and cyclic com-
pounds, have not received much attention, probably as a
result of the lack of general methods available for the syn-
thesis of these compounds. Indeed, as far as we know, only
the synthesis of 4-alkoxy-1,4-bis(silyloxy)-1-(trifluoro-
methyl)-,[10a] 1,1-bis(trifluoromethyl)-[10b] and 4,4-difluoro-
and 3-(trifluoromethyl)-2-aza-1,3-butadienes[10c] have been
reported and only the reactions of 4-alkoxy-1,4-bis(silyl-
oxy)-1-(trifluoromethyl)-2-aza-1,3-butadienes with carbonyl
compounds[11a] and 1,1-bis(trifluoromethyl)-2-aza-1,3-buta-
diene with bromides, amines, mercaptans,[11b] diazometh-
ane[11c] and phosphanes[11d] have been described. As a con-
tinuation of our work in the design of new building blocks
and owing to the increasing importance of fluorine-contain-
ing heterocycles in biology, pharmacology and industry, we
report herein an easy and versatile method for the synthesis
of fluoroalkyl-substituted 2-azadienes III that involves the
aza-Wittig reaction[12] of N-vinylic phosphazenes with alde-
hydes and the use of these substrates as starting materials
for the construction of fluoroalkyl-functionalized hetero-
cycles.[13]
[a] Departamento de Química Orgánica I, Facultad de Farmacia,
Universidad del País Vasco,
Apartado 450, 01080 Vitoria, Spain
Fax: +34-945-013049
E-mail: qoppagaf@vc.ehu.es
Eur. J. Org. Chem. 2005, 1795–1804
DOI: 10.1002/ejoc.200400770
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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F. Palacios, C. Alonso, M. Rodríguez, E. Martínez de Marigorta, G. Rubiales
FULL PAPER
3
doublet at δC = 113.8 ppm with coupling constants of JPC
Results and Discussion
Synthesis of N-Vinylic Phosphazenes
3
= 11.3 Hz and JFC = 1.7 Hz, the olefinic carbon in the α
position with respect to the nitrogen atom gave a quadru-
plet at δC = 137.0 ppm with a coupling constant of JFC
21.3 Hz and the CF3 group appeared as a well-resolved
2
=
Fluoroalkyl-substituted N-vinylic phosphazenes 4 were
prepared by reaction of phosphorus ylides and perfluoroal-
kyl nitriles. Gaseous nitriles 2a (RF = CF3) and 2b (RF
double quadruplet at δC = 122.8 ppm with coupling con-
=
1
3
stants of JFC = 278.0 Hz and JPC = 24.5 Hz.
C2F5) were freshly generated[14] and bubbled through a
cooled (0 °C) solution of phosphorus ylides 1 to afford the
corresponding N-vinylic phosphazenes 4a and 4b
(Scheme 1, Table 1, entries 1 and 3) in good yield, while
commercially available nitrile 2c (RF = C7F15) was also used
in the synthesis of phosphazene 4c (Table 1, entry 5).
The formation of the conjugated (E)-phosphazenes 4 can
be explained in terms of a [2+2] cycloaddition reaction of
phosphorus ylides 1 and nitriles 2 followed by ring opening
of the unstable four-membered cyclic compounds 3[8b,15]
(Scheme 1). In this context, note that isomerization of the
(E) isomer to the (Z) isomer was observed upon thermal
treatment. 1H NMR monitoring of (E)-phosphazene 4a
upon heating at 110 °C in toluene revealed that a new sing-
let appeared at δH = 6.23 ppm for the vinylic proton while
the doublet corresponding to the (E) precursor (δH
=
4
5.70 ppm, JPH = 3.2 Hz) disappeared. The configuration
of the vinylic double bonds was determined on the basis of
heteronuclear 19F–1H HOESY experiments which showed
cross signals between fluorinated groups and vinylic pro-
tons suggesting the formation of the (Z) isomer (Table 1,
entries 2, 4 and 6). Similar isomerization reactions have
been observed previously by us[16] and by others.[17]
Aza-Wittig Reaction of Fluoroalkyl-Substituted N-Vinylic
Phosphazenes 4 with Aldehydes
The aza-Wittig reaction[12] of the (Z) isomers of the N-
vinylic (fluoroalkyl)phosphazenes 4, derived from tri-
phenylphosphane, with glyoxalate in CHCl3 at room tem-
perature (Scheme 1) gave fluoroalkyl-substituted (1E,3Z)-2-
azadienes 5b and 5h (Table 2, entries 2 and 9) in which the
(Z) configuration of the vinylic double bond was retained.
These (1E,3Z)-heterodienes 5 were unstable to distillation
and chromatography and therefore were not isolated and
therefore were used in situ for subsequent reactions. How-
ever, the presence of the nonisolable compounds was estab-
lished on the basis of the spectroscopic data of the crude
Scheme 1.
Table 1. N-Vinylic phosphazenes 4 obtained from the reaction of
phosphorus ylides and perfluoroalkyl nitriles.
Entry
RF
Time [h] Solvent Yield [%][a] M.p. [°C]
1
1
2
3
4
5
6
(E)-4a CF3
(Z)-4a CF3
(E)-4b C2F5
(Z)-4b C2F5
12
Et2O
toluene 98
Et2O 61
toluene 98
Et2O 83
toluene 98
90
134–135
121–122
105–106
97–98
oil
product mixtures. Thus, in the H NMR spectrum of the
12[b]
24
crude product of (1E,3Z)-heterodiene 5b the olefinic hydro-
gen atom appeared as a singlet at δH = 7.04 ppm and the
iminic hydrogen as a quadruplet at δH = 7.90 ppm with a
12[b]
(E)-4c C7F15 12
5
(Z)-4c C7F15 12[b]
oil
coupling constant of JFH = 2.4 Hz. The structures of 5b
and 5h were also studied by heteronuclear 19F–1H HOESY
experiments which showed cross signals between the fluori-
nated groups and the vinylic and iminic protons confirming
[a] Yield of isolated compounds. [b] Obtained from the (E) isomer
by heating at 110 °C.
Crystalline compounds 4 were characterized as exclu- the (1E,3Z) configuration of heterodienes 5b and 5h, which
sively pure E isomers by analysis of their spectroscopic means that the vinylic double bond retained the (Z) config-
data. The mass spectrum of compound 4a gave the molecu- uration of the starting phosphazenes.
lar-ion peak m/z = 447 as the base peak. The 31P NMR
spectrum of compound 4a showed an absorption at δP
7.94 ppm, in the H NMR spectrum of 4a the vinylic pro- phosphazenes 4 and glyoxalate at room temperature
ton resonated at δH = 5.70 ppm as a well-resolved doublet (Scheme 1) to give fluoroalkyl (1E,3E)-2-azadienes 5b, 5f
with a long-range coupling constant of 4JPH = 3.2 Hz, while and 5h (Table 2, entries 3, 7 and 10). In these cases, the
in the 13C NMR spectrum of 4a the olefinic CH (in the β permanence of the (E) configuration of the vinylic double
position with respect to the nitrogen atom) gave a double bond was corroborated by heteronuclear 19F–1H HOESY
Similar behaviour was observed when this reaction was
performed with the (E) isomers of fluoroalkyl N-vinylic
=
1
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Eur. J. Org. Chem. 2005, 1795–1804

3-(Fluoroalkyl)azadienes in the Synthesis of (Fluoroalkyl)isoquinoline and -pyridine Derivatives
Table 2. Azadienes 5 obtained from the aza-Wittig reaction of fluoroalkyl-substituted N-vinylic phosphazenes 4.
FULL PAPER
Entry
R1
RF
Time [h]
Solvent
Yield [%]
[a]
1
2
3
4
5
6
7
8
9
10
(1E,3Z)-5a
(1E,3Z)-5b
(1E,3E)-5b
(1E,3Z)-5c
(1E,3Z)-5d
(1E,3Z)-5e
(1E,3E)-5f
(1E,3Z)-5g
(1E,3Z)-5h
(1E,3E)-5h
2,4-(NO2)2-C6H3
CO2Et
CO2Et
CF3
CF3
CF3
C2F5
C2F5
C2F5
C2F5
C7F15
C7F15
C7F15
12
1
1
96
24
96
2
144
0.5
0.5
xylenes
CHCl3
CHCl3
xylenes
toluene
xylenes
CHCl3
xylenes
CHCl3
CHCl3
–
[a]
–
[a]
–
C6H5
72[b]
62[b]
58[b]
2,4-(NO2)2-C6H3
3-Pyridyl
CO2Et
2,4-(NO2)2-C6H3
CO2Et
[a]
–
[a]
–
[a]
–
[a]
CO2Et
–
[a] Not isolated, used in situ. [b] Yield of isolated compounds.
experiments; in these experiments no cross signals were ob-
served between the fluorinated groups and the vinylic pro-
ton. No aza-Wittig reaction was observed when the (E) iso-
mers of N-vinylic (fluoroalkyl)phosphazenes 4 were treated
with aromatic aldehydes at room temperature. However,
thermal treatment of these (E) isomers with aromatic alde-
hydes gave (1E,3Z)-(fluoroalkyl)- 2-azadienes 5a, 5c–e and
g (Scheme 1, Table 2, entries 1, 4–6 and 8). The formation
of these (1E,3Z)-2-azadienes can be explained in terms of
an initial isomerization of the (E)-phosphazene to the (Z)
isomer followed by aza-Wittig reaction with the corre-
sponding aldehydes.
6π-Electrocyclization of (1E,3Z)-3-(Perfluoroalkyl)-2-
azadienes 5
Scheme 2.
Isoquinoline nuclei are widespread in the alkaloid family
and constitute an important class of compound in pharma-
ceuticals.[18] For this reason, in order to test the synthetic
usefulness of the new fluoroalkyl-substituted azadienes 5 as
key intermediates in organic synthesis and especially in the
preparation of new nitrogen-containing heterocycles, their
electrocyclic ring-closure was explored. Thus, heating 3-
fluoroalkyl-substituted (1E,3Z)-azadienes 5d and 5e, which
contain an aryl and heteroaryl group at the 1-position [R1
= 2,4-(NO2)2-C6H3, 3-pyridyl, respectively], in refluxing xy-
lenes afforded the corresponding fluoroalkyl-substituted
isoquinolines 6a and 6b in good yields (Scheme 2, Table 3,
entries 1 and 2). The formation of the heterocycles 6 can be
explained in terms of a 1,6-electrocyclic ring closure of the
(1E,3Z) isomers of azadienes 5 followed by dehydrogena-
tion of the nonisolable annelated compound 7 under the
reaction conditions. Isoquinolines 6a–e can also be pre-
pared in a one-pot synthesis from (Z)-phosphazenes 4a–c
on heating with aldehydes without the isolation of the
(1E,3Z)-azadienes 5b, 5d, 5e, 5g and 5h (Table 3).
Table 3. Synthesis of isoquinolines 6.
Entry
RF
R1
Yield[a] [%]
1
2
3
4
5
6a
6b
6c
6d
6e
C2F5
C2F5
C7F15
CF3
2,4-(NO2)2-C6H3
3-Pyridyl
2,4-(NO2)2-C6H3
CO2Et
54[b]/70[c]
51[b]/62[c]
51[c]
63[c]
C7F15
CO2Et
68[c]
[a] Yield of isolated compounds. [b] Obtained by heating the iso-
lated azadienes. [c] Prepared by one-pot synthesis of (Z)-phosphaz-
enes 4 and aldehydes.
several fluorine-substituted isoquinolines have been pre-
pared,[7a,19] to the best of our knowledge this is the first
report of the preparation of fluoroalkyl-substituted isoqui-
nolines.
[4+2] Cycloaddition Reaction of 3-(Perfluoromethyl)-2-
azadienes 5 Derived from α-Imino Esters
In order to check that the configuration of the carbon–
Owing to the interest in pyridine derivatives as pharma-
carbon double bond of the azadienes 5 plays an important ceuticals, agrochemicals and dyestuffs,[20] we explored the
role in the process and that only the (3Z) isomers of the 2- cycloaddition reactions of these heterodienes 5 with elec-
azadienes 5 were precursors of the isoquinolines 6, (1E,3E)- tron-rich olefins such as enamines. Initially, we studied the
2-azadiene 5b [generated in situ from (E)-phosphazene 4a reaction of the 2-azadiene 5b because this substrate would
and ethyl glyoxalate] was heated in refluxing xylenes until be an interesting starting material for the preparation of
total decomposition of the starting material had occurred pipecolic acid derivatives.[21] Thus, when the reaction of
with no formation of isoquinoline 6. Note that although (1E,3E)-2-azadiene 5b (RF = CF3) with N-(3-methyl)but-1-
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FULL PAPER
enylpyrrolidine 8 in CHCl3 was performed at room tem- selective saturation at δH = 2.41–2.46 ppm (pyrrolidine
perature a mixture of cycloaddition compounds was de- CH2) afforded significant NOEs with 3-H at δH = 2.98–
1
tected by H NMR analysis of the crude product mixture 3.00 ppm (2%), with 6-H at δH = 4.79–4.84 ppm (2%) and
from which tetrahydropyridine 10 and pyridine 11a with the aromatic protons of the phenyl group (1%) con-
(Table 4, entries 1 and 2) were isolated. In order to simplify firming the cis relationship between 3-H, pyrrolidine, the
this mixture, an oxidant such as p-benzoquinone was added phenyl group and 6-H. The 13C NMR spectrum of 11a
to the crude reaction mixture to afford only aromatic pyri- showed a quadruplet at δC = 161.4 ppm with a coupling
2
dine 11a in good yield (Scheme 3, Table 4, entry 2).
constant of JFC = 32.0 Hz, which indicates that C-2 is the
iminic carbon atom. The configurations of the C-3, C-4 and
C-5 atoms of the tetrahydropyridine 10 are consistent with
an endo approach of the enamine to the heterodiene to give
cycloadduct 9 followed by tautomerization to 10. This reac-
tion can be extended to (1E,3E)-2-azadiene 5h (RF = C7F15)
and in this case only aromatic pyridine 11b was obtained
regioselectively and in good yield (Scheme 3, Table 4, en-
try 3). As far as we know, this strategy describes the first
synthesis of 2-(trifluoromethyl)pyridines derived from pipe-
colic esters 10 and 11.
Table 4. Pyridine derivatives 10–12, 16 and bicyclic heterocycles 19
obtained from [4+2] cycloaddition reactions of azadienes 5 and 17.
Entry
RF
Time [h] Solvent
Yield [%]
1
2
3
4
5
6
7
10
CF3
CF3
C7F15 24
CF3 24
C2F5 24
CF3 12
C3F7 12
24
24
CHCl3
CHCl3
CHCl3
toluene
toluene
90[a] (36)[b]
90[a] (54)[b] (48)[c]
60[b]
11a
11b
12
56[b]
16
19a
19b
48[b]
acetonitrile 40[b]
acetonitrile 50[b]
However, different behaviour was observed when azadiene
5a with an aryl group in the 1-position [R1 = 2,4-(NO2)2-
C6H3] was heated with the same enamine 8. At room tem-
perature the starting materials were recovered, whilst re-
fluxing heterodiene (1E,3Z)-5a and enamine 8 in toluene
gave pyridine 12 (Scheme 4, Table 4, entry 4). The structure
of compound 12 was determined on the basis of its 1D and
[a] Consumption [%] of the starting material determined by NMR
analysis of the crude product mixture. [b] Isolated yield. [c] Ob-
tained from the crude product mixture of 5 and 8 by oxidation with
p-benzoquinone in dioxane at 80 °C.
1
2D NMR data. In H–13C HMBC 2,3-bond correlation of
compound 12, proton 5-H of the pyridine ring showed cross
signals with the same quaternary carbon as protons of the
2,4-(NO2)-C6H3 group, while the CH of the isopropyl sub-
stituent and the aromatic protons of the phenyl substituent
showed cross signals with the same quaternary carbon (C-
3). Therefore, these data are in agreement with the proposed
structure of 12 in which the fluoroalkyl, phenyl and isopro-
pyl groups are substituents on C-2, C-3 and C-4, respec-
tively. The substituent in the 1-position of the starting azad-
iene seems to play an important role, not only decreasing
the reactivity of the heterodiene, but also changing its re-
gioselectivity. The formation of compound 12 can be ex-
plained in terms of a [4+2] cycloaddition reaction of both
substrates − heterodiene 5a and dienophile 8 − with forma-
tion of cycloadduct 13 and subsequent aromatization. The
regioselectivity of these processes can be controlled by sub-
Scheme 3.
The structure of compound 10 was elucidated on the ba- stituents (FMO theory).[22] Analogous regioselectivity was
sis of its 1D and 2D NMR spectroscopic data. The 13C observed in the reaction of (1E,3Z)-3-(perfluoroethyl)-2-
NMR spectrum provided enough evidence for the proposed azadiene 5d with enamine 8. However, the spectroscopic
structure of 10 because in this case the iminic carbon atom data for the adducts showed that defluorinated compound
appeared as a singlet at δC = 171.6 ppm while the fluorine 16 was obtained (Scheme 4, Table 4, entry 5) instead of the
effect of the CF3 substituent was observed in a CH carbon expected perfluorinated compound. The mass spectra of
2
at δC = 63.0 ppm with a coupling constant of JFC
=
isolated compound 16 showed a molecular ion [m/z = 463
1
26.4 Hz, which was assigned to the C-6 of the tetrahy- (100%)] that corresponds to the loss of HF, while the H
dropyridine ring on the basis of HMQC and HMBC experi- and 13C NMR spectra showed a proton (carbon) coupled
ments. The relative configurations of the stereogenic centers to a CF–CF3 moiety instead of a CF2–CF3 group. For in-
1
C-3, C-4, C-5 and C-6 were assigned on the basis of the stance, the H NMR spectrum of compound 16 showed a
observed 1D-NOESY correlations. Selective saturation at double quadruplet at δH = 5.45 ppm for this proton with
2
3
δH = 1.91–2.02 ppm (isopropyl CH) afforded significant coupling constants of JHF = 44.4 and JHF = 5.8 Hz, and
NOEs (6%) with the proton (4-H) of the adjacent carbon the 13C NMR spectrum showed a double quadruplet at δC
1
atom at δH = 4.96 ppm confirming the trans relationship = 84.8 ppm with coupling constants of JCF = 188.4 and
between 3-H and 4-H in the tetrahydropyridine ring, while 2JCF = 34.4 Hz for the methane carbon atom directly
1798
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3-(Fluoroalkyl)azadienes in the Synthesis of (Fluoroalkyl)isoquinoline and -pyridine Derivatives
FULL PAPER
Scheme 4.
bonded to the fluorine atom. The formation of this fluo- as 4-phenyl-1,2,4-triazoline-3,5-dione 18 in the presence of
roalkyl heterocycle 16 can be explained in terms of intra- ytterbium triflate at room temperature. These bicyclic com-
molecular cyclocondensation of adduct 14 with the loss of pounds 19 were characterized on the basis of their spectro-
HF and the formation of the polycyclic aziridine 15, fol- scopic data. The mass spectrum of compound 19a gave the
lowed by ring opening of the aziridine and migration of the molecular ion m/z = 374 (54%). The 19F NMR spectrum
proton to the adjacent carbon atom bonded to the fluorine of compound 19a showed an absorption at δF = –72.8 ppm,
atom to give polysubstituted 2-(1,2,2,2-tetrafluoroethyl)pyr- and in the 1H NMR spectrum of 19a the methylene protons
idine 16 (Scheme 4). An exocyclic enaminic intermediate of the six-membered heterocycle resonated at δH = 4.40 and
from dehydrofluorination of 14 could also justify the for- 4.80 ppm as well-resolved double doublets, while the 13C
mation of compound 16. To the best of our knowledge, cyc- NMR spectrum of 19a revealed CF3 as a quadruplet at δC
1
lization reactions that afford heterocycles such as 16 have = 118.7 ppm with a coupling constant of JFC = 279 Hz
no precedent and therefore this is the first synthesis of fluo- and the carbon atom directly bonded to this as a quadru-
2
roalkyl-substituted pyridines.
plet at δC = 152.4 ppm with a coupling constant of JFC
=
37 Hz. The formation of these bicyclic heterocycles 19 can
be explained in terms of a [4+2] cycloaddition reaction of
heterodienes 17 and dienophile 18.
Reaction of 3-(Perfluoroalkyl)-2-azadienes 17 with 4-Phen-
yl-1,2,4-triazoline-3,5-dione 18
To further explore the behavior of fluoroalkyl-substi-
tuted 2-azadienes, we also studied the reactivity of heterodi-
enes with no substituents at the 4-position. Nevertheless,
the cycloaddition reaction of fluoroalkyl-substituted 2-aza-
dienes 17 with a range of electron-rich (enamines, norbor-
nadiene) and electron-poor dienophiles (maleic anhydride,
tetracyanoethylene, diethyl acetylenedicarboxylate and ethyl
glyoxalate) were inefficient at room temperature and, even
on extended heating complex product mixtures and decom-
position products were obtained. Cycloadducts 19
(Scheme 5, Table 4, entries 6 and 7) were isolated only when
azadienes 17a (RF = CF3)[10c] and 17b (RF = C3F7) were
Scheme 5.
Conclusions
In summary, (E) and (Z) fluoroalkyl N-vinylic phosphaz-
treated with a very reactive electron-poor dienophile such enes 4 can be prepared readily from fluoroalkyl nitriles 2
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F. Palacios, C. Alonso, M. Rodríguez, E. Martínez de Marigorta, G. Rubiales
FULL PAPER
3
3
13C NMR (100 MHz, CDCl3): δ = 113.8 (dd, JCP = 11.3, JCF
=
and phosphorus ylides 1. These conjugated phosphazenes 4
react cleanly and in good yields with aldehydes by means
of an aza-Wittig reaction to afford (1E,3E) and (1E,3Z)
fluoroalkyl-functionalized 2-azadienes 5 which are excellent
building blocks for the preparation of fluorinated heterocy-
cles. For instance, fluoroalkylated heterocycles such as iso-
quinolines 6 were obtained by 6π-electrocyclization of het-
erodienes 5, while pyridines derived from pipecolic esters 10
and 11, as well as polysubstituted pyridines 12 and 16 and
bicyclic heterocycles 19, can be prepared through a [4+2]
cycloaddition strategy involving the reaction of heterodi-
enes 5 or 17 with dienophiles. Most of these heterocycles
have been prepared for the first time, thus showing that
these fluoroalkylated 2-aza-1,3-butadienes may be impor-
tant synthons in organic synthesis and in the preparation
of fluoroalkyl-substituted acyclic and heterocycles.[1,5]
1.7 Hz), 122.8 (dq, 1JCF = 278.0, 3JCP = 24.5 Hz), 125.5–133.7 (m),
2
137.0 (q, JCF = 21.3 Hz) ppm. 31P NMR (120 MHz, CDCl3): δ =
7.94 ppm. 19F NMR (282 MHz, CDCl3): δ = –64.1 ppm. MS (EI):
m/z = 447 (100) [M]+. C27H21F3NP (447): calcd. C 72.48, H 4.73,
N 3.13; found C 72.02, H 4.68, N 3.10.
(3E)-3-(Perfluoroethyl)-1,1,1,4-tetraphenyl-2-aza-1λ5-phosphabuta-
1,3-diene (4b): The general procedure was followed, bubbling per-
fluoropropanenitrile in excess (C2F5CN) and the mixture was
stirred for 24 h. Crystallization from ethyl acetate gave a yellow
solid (2.01 g, 81%); m.p. 105–106 °C (ethyl acetate). IR (KBr): ν =
˜
1
1608, 1203 cm–1. H NMR (300 MHz, CDCl3): δ = 5.73 (s, 1 H),
6.91–7.8 (m, 20 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 112.4
(tq, JCP = 259.9, JCF = 40.8 Hz), 119.3 (tq, JCF = 286.6, JCF
1
2
1
2
=
40.8 Hz), 125.9–136.6 (m) ppm. 31P NMR (120 MHz, CDCl3): δ =
7.46 ppm. 19F NMR (282 MHz, CDCl3): δ = –64.3, –94.5 ppm. MS
(EI): m/z = 497 (100) [M]+. C28H21F5NP (497): calcd. C 67.61, H
4.25, N 2.82; found C 67.72, H 4.21, N 2.81.
(3E)-3-(Perfluoroheptyl)-1,1,1,4-tetraphenyl-2-aza-1λ5-phospha-
buta-1,3-diene (4c): The general procedure was followed using per-
fluorooctanenitrile (C7F15CN) (1.97 g, 5 mmol) and the mixture
was stirred at room temperature for 12 h to give a yellow oil (83%);
Experimental Section
General Remarks: Chemicals were purchased from Aldrich Chemi-
cal Company. Solvents for extraction and chromatography were
technical grade. All the solvents used in the reactions were freshly
distilled from appropriate drying agents before use. All other rea-
gents were recrystallized or distilled as necessary. All reactions were
performed under dry nitrogen. Analytical TLC was performed with
Merck silica gel 60 F254 plates; visualization was accomplished with
UV light. Flash chromatography was carried out using Merck silica
gel 60 (230–400 mesh ASTM). Melting points were determined
with an Electrothermal IA9100 Digital Melting Point Apparatus
R = 0.41 (ethyl acetate/hexane. 1:10). IR (KBr): ν = 1611,
˜
f
1206 cm–1. H NMR (300 MHz, CDCl3): δ = 5.74 (s, 1 H), 6.89–
1
7.81 (m, 20 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 109.3–115.8
(m), 125.9–136.6 (m) ppm. 31P NMR (120 MHz, CDCl3): δ =
7.03 ppm. 19F NMR (282 MHz, CDCl3): δ = –81.2 (t, JFF
=
3
9.2 Hz), –107.1 to –126.5 (m) ppm. MS (EI): m/z = 747 (40) [M]+.
C33H21F15NP (747): calcd. C 53.03, H 2.83, N 1.87; found C 53.20,
H 2.80, N 1.82.
General Procedure for the Preparation of (Z)-Phosphazenes 4: A
solution of (E)-phosphazene 4 (2 mmol) in toluene under N2 was
stirred at reflux (110 °C) overnight until 1H NMR indicated the
disappearance of the (E) isomer of the phosphazene.
1
and are uncorrected. H (400, 300 MHz), 13C (100, 75 MHz), 19F
(376, 282 MHz) and 31P NMR (120 MHz) spectra were recorded
with a Bruker Avance 400 MHz and a Varian Unity 300 MHz spec-
trometer using CDCl3 or CD3OD solutions with TMS as an in-
ternal reference (δ = 0.00 ppm) for 1H and 13C NMR spectra,
CFCl3 as an internal reference (δ = 0.00 ppm) for 19F NMR spec-
tra, and phosphoric acid (85%) (δ = 0.00 ppm) for 31P NMR spec-
tra. Chemical shifts (δ) are reported in ppm and coupling constants
(J) are in Hertz. Low-resolution mass spectra (MS) were obtained
at 50–70 eV by electron impact (EIMS) with a Hewlett–Packard
5971 or 5973 spectrometer. Data are reported in the form m/z (in-
tensity relative to base peak = 100). Infrared spectra (IR) were
recorded with a Nicolet IRFT Magna 550 spectrometer and were
obtained as solids in KBr or as neat oils. Peaks are reported in
cm–1. Elemental analyses were performed in a LECO CHNS-932
apparatus. Azadiene 17a was prepared according to the literature
procedure.[10c]
(Z)-3-(Trifluoromethyl)-1,1,1,4-tetraphenyl-2-aza-1λ5-phosphabuta-
1,3-diene (4a): The general procedure was followed using (3E)-3-
(trifluoromethyl)-1,1,1,4-tetraphenyl-2-aza-1λ5-phosphabuta-1,3-
diene (4a). Evaporation of the solvent and crystallization from
ethyl acetate gave a yellow solid; m.p. 121–122 °C (ethyl acetate).
1
IR (KBr): ν = 1613, 1467 cm–1. H NMR (400 MHz, CDCl ): δ =
˜
3
6.23 (s, 1 H), 7.05–7.81 (m, 20 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 112.6–112.8 (m), 122.5 (dq, JCF = 279.0, JCP
1
3
=
3.7 Hz), 125.9–133.7 (m), 133.7 (q, 2JCF = 29.5 Hz) ppm. 31P NMR
(120 MHz, CDCl3): δ = 2.13 ppm. 19F NMR (282 MHz, CDCl3):
δ = –68.2 ppm. MS (EI): m/z = 447 (100) [M]+. C27H21F3NP (447):
calcd. C 72.48, H 4.73, N 3.13; found C 72.22, H 4.70, N 3.10.
(Z)-3-(Perfluoroethyl)-1,1,1,4-tetraphenyl-2-aza-1λ5-phosphabuta-
1,3-diene (4b): The general procedure was followed using (3E)-3-
(perfluoroethyl)-1,1,1,4-tetraphenyl-2-aza-1λ5-phosphabuta-1,3-
diene (4b). Evaporation of the solvent and crystallization from
General Procedure for the Preparation of (E)-Phosphazenes 4: A
1.6 m solution of methyllithium in diethyl ether (3.125 mL, 5 mmol)
was added dropwise to a solution of benzyltriphenylphosphonium
iodide (2.40 g, 5 mmol) in diethyl ether (20 mL) cooled to 0 °C un-
der N2. The clear red solution was heated at reflux for 1 h. Fluoro-
alkylated nitrile was added dropwise or bubbled into the ylide solu-
tion at 0 °C and the mixture was stirred at room temperature. The
mixture was filtered and concentrated to afford an oil.
ethyl acetate gave a yellow solid; m.p. 97–98 °C (ethyl acetate). IR
1
(KBr): ν = 1626, 1328, 1150 cm–1. H NMR (400 MHz, CDCl ): δ
˜
3
= 6.17 (s, 1 H), 7.08–7.67 (m, 20 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 112.4 (tq, 1JCP = 259.8, 2JCF = 36.7 Hz), 115.3 (t, 3JCF
1
2
= 7.3 Hz), 119.4 (tq, JCF = 287.0, JCF = 39.8 Hz), 125.8–132.9
(m), 133.5 (t, JCF = 21.9 Hz) ppm. 31P NMR (120 MHz, CDCl3):
2
(3E)-3-(Trifluoromethyl)-1,1,1,4-tetraphenyl-2-aza-1λ5-phospha-
buta-1,3-diene (4a): The general procedure was followed, bubbling
trifluoroacetonitrile in excess (CF3CN). Crystallization from ethyl
acetate gave a yellow solid (2.01 g, 90%); m.p. 134–135 °C (ethyl
δ = 2.35 ppm. 19F NMR (282 MHz, CDCl3): δ = –66.3, –96.5 ppm.
MS (EI): m/z = 497 (76) [M]+. C28H21F5NP (497): calcd. C 67.61,
H 4.25, N 2.82; found C 67.70, H 4.29, N 2.79.
acetate). IR (KBr): ν = 1600, 1341 cm–1
.
1H NMR (400 MHz,
(Z)-3-(Perfluoroheptyl)-1,1,1,4-tetraphenyl-2-aza-1λ5-phosphabuta-
˜
CDCl3): δ = 5.70 (d, J = 3.2 Hz, 1 H), 6.98–7.85 (m, 20 H) ppm. 1,3-diene (4c): The general procedure was followed using (3E)-3-
1800 © 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
Eur. J. Org. Chem. 2005, 1795–1804

3-(Fluoroalkyl)azadienes in the Synthesis of (Fluoroalkyl)isoquinoline and -pyridine Derivatives
FULL PAPER
(perfluoroheptyl)-1,1,1,4-tetraphenyl-2-aza-1λ5-phosphabuta-1,3-
diene (4c). Chromatographic separation (hexane/ethyl acetate, 10:1)
raphy on neutral aluminium oxide (ethyl acetate/hexane, 1:20) to
give 2-azadiene 5d (0.51 g, 62%) as a yellow oil; Rf = 0.55 (ethyl
gave a yellow oil; Rf = 0.13 (ethyl acetate/hexane, 1:10). IR (KBr):
acetate/hexane, 1:5). IR (KBr) ν = 1539, 1339, 1213 cm–1. 1H NMR
˜
1
ν = 1612, 1438, 1206 cm–1. H NMR (300 MHz, CDCl ): δ = 6.07
(400 MHz, CDCl3): δ = 6.80 (s, 1 H), 7.07–8.61 (m, 7 H), 8.94 (s,
˜
3
(s, 1 H), 6.93–7.82 (m, 20 H) ppm. 13C NMR (75 MHz, CDCl3):
1 H), 8.95 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 120.4,
δ = 107.2–119.1 (m), 125.8–137.3 (m) ppm. 31P NMR (120 MHz, 102.9–124.1 (m), 127.1–149.3 (m), 159.7 ppm. MS (70 eV): m/z =
CDCl3): δ = 1.44 ppm. 19F NMR (282 MHz, CDCl3): δ = –81.15 415 (20) [M]+. C17H10F5N3O4 (415): calcd. C 49.17, H 2.43, N
to –82.3 (m), –109.8 (t, 3JFF = 15.2 Hz), –117.0 to –127.2 (m) ppm. 10.12; found C 49.11, H 2.39, N 10.16.
MS (EI): m/z = 747 (69) [M]+. C33H21F15NP (747): calcd. C 53.03,
(1E,3Z)-2-Azadiene 5e: The general procedure was followed using
H 2.83, N 1.87; found C 52.90, H 2.86, N 1.86.
(3E)-3-(perfluoroethyl)-1,1,1,4-tetraphenyl-2-aza-1λ5-phospha-
General Procedure for Preparation of 2-Azadienes 5: The appropri-
ate aldehyde (2 mmol) was added to a solution of phosphazene 4
(2 mmol) in CHCl3, toluene or xylenes at 0–10 °C under N2, and
the mixture was stirred at room temperature or reflux until TLC
indicated the disappearance of the phosphazene.
buta-1,3-diene (4b) (0.99 g) and 3-pyridylcarboxaldehyde (0.92 g)
for 96 h at 135 °C in xylenes. Evaporation of the solvent under
reduced pressure afforded an oil that was purified by chromatog-
raphy on neutral aluminium oxide (ethyl acetate/hexane, 1:10) to
give 2-azadiene 5e (0.38 g, 58%) as a yellow oil; Rf = 0.31 (ethyl
acetate/hexane, 1:2). IR (KBr) ν = 1636, 1202 cm–1
.
1H NMR
˜
(1E,3Z)-2-Azadiene 5a: The general procedure was followed using
(3E)-3-(trifluoromethyl)-1,1,1,4-tetraphenyl-2-aza-1λ5-phospha-
buta-1,3-diene (4a) (0.89 g) and 2,4-dinitrobenzaldehyde (0.39 g)
for 12 h at 110 °C in xylenes. The reaction product was unstable to
distillation and chromatography and therefore was not isolated and
used in subsequent reactions. 1H NMR (300 MHz, CDCl3) of
crude reaction mixture (5a + Ph3PO): δ = 7.04 (s, 1 H), 7.12–8.17
(m, 6 H), 8.47 (s, 1 H), 8.55–9.04 (m, 2 H) ppm.
(300 MHz, CDCl3): δ = 6.58 (s, 1 H), 7.21–8.22 (m, 7 H), 8.39 (s,
3
3
3
1 H), 8.70 (dd, JHH = 4.7, JHH = 1.7 Hz), 8.70 (d, JHH
=
=
1.7 Hz) ppm. 13C NMR (75 MHz, CDCl3): δ = 111.0 (tq, JCF
1
2
1
2
255.9, JCF = 38.6 Hz), 118.8 (tq, JCF = 285.5, JCF = 38.1 Hz),
120.1 (t, 3JCF = 7.1 Hz), 123.8–135.0 (m), 137.7 (t, 2JCF = 19.3 Hz),
150.9, 152.8, 163.4 ppm. 19F NMR (282 MHz, CDCl3): δ = –60.5,
–94.0 ppm. MS (70 eV): m/z = 326 (90) [M]+. C16H11F5N2 (326):
calcd. C 58.90, H 3.40, N 8.59; found C 59.12, H 3.48, N 8.63.
(1E,3Z)-2-Azadiene 5b: The general procedure was followed using
(3Z)-3-(trifluoromethyl)-1,1,1,4-tetraphenyl-2-aza-1λ5-phospha-
buta-1,3-diene (4a) (0.89 g) and ethyl glyoxalate (0.20 g) for 1 h at
room temperature in CHCl3. The reaction product was unstable to
distillation and chromatography and therefore was not isolated and
used in subsequent reactions. 1H NMR (400 MHz, CDCl3) of
crude reaction mixture (5b + Ph3PO): δ = 1.26 (t, J = 7.1 Hz, 3 H),
4.26 (q, J = 7.1 Hz, 2 H), 7.04 (s, 1 H), 7.11–7.79 (m, 5 H), 7.90
(q, J = 2.4 Hz, 1 H), 7.92–7.94 (m, 1 H) ppm.
(1E,3E)-2-Azadiene 5f: The general procedure was followed using
(3E)-3-(perfluoroethyl)-1,1,1,4-tetraphenyl-2-aza-1λ5-phospha-
buta-1,3-diene (4b) (0.99 g) and ethyl glyoxalate (0.20 g) for 2 h at
room temperature in CHCl3. The reaction product was unstable to
distillation and chromatography and therefore was not isolated and
used in subsequent reactions. 1H NMR (400 MHz, CDCl3) of
crude reaction mixture (5f + Ph3PO): δ = 1.46 (t, J = 7.2 Hz, 3 H),
4.45 (q, J = 7.2 Hz, 2 H), 6.85 (s, 1 H), 7.40–7.80 (m, 5 H), 7.90
(s, 1 H) ppm.
(1E,3E)-2-Azadiene 5b: The general procedure was followed using
(3E)-3-(trifluoromethyl)-1,1,1,4-tetraphenyl-2-aza-1λ5-phospha-
buta-1,3-diene (4a) (0.89 g) and ethyl glyoxalate (0.20 g) for 1 h at
room temperature in CHCl3. The reaction product was unstable to
distillation and chromatography and therefore was not isolated and
used in subsequent reactions. 1H NMR (400 MHz, CDCl3) of
crude reaction mixture (5b + Ph3PO): δ = 1.26 (t, J = 7.1 Hz, 3 H),
4.26 (q, J = 7.1 Hz, 2 H), 6.89 (s, 1 H), 7.20–7.60 (m, 5 H), 7.82
(s, 1 H) ppm.
(1E,3Z)-2-Azadiene 5g: The general procedure was followed using
(3E)-3-(perfluoroheptyl)-4-phenyl-1,1,1-triphenyl-2-aza-1λ5-phos-
phabuta-1,3-diene (4c) (1.50 g) and 2,4-dinitrobenzaldehyde
(0.39 g) for 144 h at 135 °C in xylenes. The reaction product was
unstable to distillation and chromatography and therefore was not
isolated and used in subsequent reactions. 1H NMR (300 MHz,
CDCl3) of crude reaction mixture (5g + Ph3PO): δ = 7.25 (s, 1 H),
7.37–8.12 (m, 6 H), 8.22 (s, 1 H), 8.01–9.07 (m, 2 H) ppm.
(1E,3Z)-2-Azadiene 5h: The general procedure was followed using
(3Z)-3-(perfluoroheptyl)-4-phenyl-1,1,1-triphenyl-2-aza-1λ5-phos-
phabuta-1,3-diene (4c) (1.50 g) and ethyl glyoxalate (0.20 g) for
0.5 h at room temperature in CHCl3. The reaction product was
unstable to distillation and chromatography and therefore was not
isolated and used in subsequent reactions. 1H NMR (400 MHz,
CDCl3) of crude reaction mixture (5h + Ph3PO): δ = 1.38 (t, J =
7.1 Hz, 3 H), 4.37 (q, J = 7.1 Hz, 2 H), 6.75 (s, 1 H), 7.09–7.70 (m,
5 H), 7.80 (s, 1 H) ppm.
(1E,3Z)-2-Azadiene 5c: The general procedure was followed using
(3E)-3-(perfluoroethyl)-1,1,1,4-tetraphenyl-2-aza-1λ5-phospha-
buta-1,3-diene (4b) (0.99 g) and benzaldehyde (0.20 mL) for 96 h at
135 °C in xylenes. Evaporation of the solvent under reduced pres-
sure afforded an oil that was purified by chromatography on neu-
tral aluminium oxide (ethyl acetate/hexane, 1:20) to give 2-azadiene
5c (0.47 g, 72%) as a yellow oil; Rf = 0.46 (ethyl acetate/hexane,
1:2). IR (KBr) ν = 1627, 1454, 1209 cm–1. 1H NMR (300 MHz,
˜
CDCl3): δ = 6.51 (s, 1 H), 7.21–7.86 (m, 10 H), 8.34 (s, 1 H) ppm.
1
2
13C NMR (75 MHz, CDCl3): δ = 111.4 (tq, JCF = 254.7, JCF
=
=
(1E,3E)-2-Azadiene 5h: The general procedure was followed using
(3E)-3-(perfluoroheptyl)-4-phenyl-1,1,1-triphenyl-2-aza-1λ5-phos-
phabuta-1,3-diene (4c) (1.50 g) and ethyl glyoxalate (0.20 g) for
0.5 h at room temperature in CHCl3. The reaction product was
unstable to distillation and chromatography and therefore was not
isolated and used in subsequent reactions. 1H NMR (400 MHz,
CDCl3) of crude reaction mixture (5h + Ph3PO): δ = 1.22 (t, J =
7.2 Hz, 3 H), 4.21 (q, J = 7.2 Hz, 2 H, CH2), 6.63 (s, 1 H), 7.16–
7.59 (m, 5 H), 7.70 (s, 1 H) ppm.
3
1
2
38.5 Hz), 118.9 (t, JCF = 7.5 Hz), 119.0 (tq, JCF = 285.5, JCF
2
38.5 Hz), 128.1–135.2 (m), 137.7 (t, JCF = 23.0 Hz), 166.3 ppm.
19F NMR (282 MHz, CDCl3): δ = –60.4, –94.2 ppm. MS (70 eV):
m/z = 325 (90) [M]+. C17H12F5N (325): calcd. C 62.77, H 3.69, N
4.31; found C 67.06, H 4.41, N 3.71.
(1E,3Z)-2-Azadiene 5d: The general procedure was followed using
(3E)-3-(perfluoroethyl)-1,1,1,4-tetraphenyl-2-aza-1λ5-phospha-
buta-1,3-diene (4b) (1.00 g) and 2,4-dinitrobenzaldehyde (0.39 g)
for 24 h at 110 °C in toluene. Evaporation of the solvent under
reduced pressure afforded an oil that was purified by chromatog-
General Procedure A for the Preparation of Isoquinolines 6: A solu-
tion of the (1E,3Z) isomer of 2-azadiene 5 (1 mmol) was heated in
Eur. J. Org. Chem. 2005, 1795–1804
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1801

F. Palacios, C. Alonso, M. Rodríguez, E. Martínez de Marigorta, G. Rubiales
FULL PAPER
xylenes (10 mL) at reflux under N2 until TLC indicated the disap-
pearance of the azadiene.
of the solvent under reduced pressure and chromatographic separa-
tion (hexane/ethyl acetate, 10:1) gave 0.17 g (63 %) of 6d as an
orange oil; R = 0.29 (ethyl acetate/hexane, 1:5). IR (KBr): ν =
˜
f
General Procedure B for the Preparation of Isoquinolines 6: The ap-
propriate aldehyde (1 mmol) was added to a solution of phosphaz-
ene 4 (1 mmol) in xylenes at 0–10 °C under N2, and the mixture
was stirred at reflux until TLC indicated the disappearance of 2-
azadiene.
1727, 1146 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.53 (t, J =
7.1 Hz, 3 H), 4.62 (q, J = 7.1 Hz, 2 H), 7.81–8.40 (m, 5 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 14.2, 62.5, 117.7–150.9 (m),
165.4 ppm. 19F NMR (282 MHz, CDCl3): δ = –67.5 ppm. MS (EI):
m/z = 269 (5) [M]+. C13H10F3NO2 (269): calcd. C 58.00, H 3.74, N
5.20; found C 57.97, H 3.50, N 5.17.
1-(2,4-Dinitrophenyl)-3-(perfluoroethyl)isoquinoline (6a): The gene-
ral procedure A was followed by using (1E,3Z)-2-azadiene 5d
(0.42 g) and by heating for 72 h. Evaporation of the solvent under
reduced pressure and chromatographic separation (hexane/ethyl
acetate, 10:1) gave 0.22 g (54%) of 6a as a yellow solid. The general
procedure B was followed using (3Z)-3-(perfluoroethyl)-1,1,1,4-tet-
raphenyl-2-aza-1λ5-phosphabuta-1,3-diene 4b (0.50 g) and 2,4-dini-
trobenzaldehyde (0.19 g) and by stirring for 90 h. Evaporation of
the solvent under reduced pressure and chromatographic separa-
tion (hexane/ethyl acetate, 10:1) gave 0.29 g (70%) of 6a as a yellow
Ethyl 3-(Perfluoroheptyl)isoquinoline-1-carboxylate (6e): The gene-
ral procedure B was followed using (3Z)-3-(perfluoroheptyl)-4-
phenyl-1,1,1-triphenyl-2-aza-1λ5-phosphabuta-1,3-diene 4c (0.75 g)
and ethyl glyoxalate (0.10 g) and by stirring for 144 h. Evaporation
of the solvent under reduced pressure and chromatographic separa-
tion (hexane/ethyl acetate, 10:1) gave 0.39 g (68%) of 6e as a white
solid; m.p. 39–40 °C (ethyl acetate/hexane). IR (KBr): ν = 1734,
˜
1
1135 cm–1. H NMR (400 MHz, CDCl3): δ = 1.37 (t, J = 7.1 Hz,
3 H), 4.49 (q, J = 7.1 Hz, 2 H), 7.72–7.94 (m, 5 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 14.1, 62.4, 102.0–120.0 (m), 123.3–150.6
(m), 165.5 ppm. 19F NMR (282 MHz, CDCl3): δ = –81.6 (t, J =
10.8 Hz), –113.6 to –127.0 (m) ppm. MS (EI): m/z = 569 (2) [M]+.
C19H10F15NO2 (569): calcd. C 40.09, H 1.77, N 2.46; found C
40.18, H 1.80, N 2.12.
solid; m.p. 97–98 °C (ethyl acetate/hexane). IR (KBr): ν = 1540,
˜
1
1354 cm–1. H NMR (400 MHz, CDCl3): δ = 7.28–8.14 (m, 6 H),
8.65 (dd, J = 8.4, J = 2.3 Hz, 1 H), 8.66 (d, J = 2.3 Hz, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 108.7–120.1 (m), 120.4–155.9
(m) ppm. 19F NMR (282 MHz, CDCl3): δ = –82.0, –113.6 ppm.
MS (EI): m/z = 413 (100) [M]+. C17H8F5N3O4 (413): calcd. C 49.41,
H 1.95, N 10.17; found C 49.38, H 1.90, N 10.15.
General Procedure for the [4+2] Cycloaddition Reactions: The dien-
ophile (5 mmol) was added to a solution of azadiene 5 (5 mmol) in
CHCl3 or toluene (15 mL) at 0–10 °C under N2 and the mixture
was stirred at an adequate temperature until TLC indicated the
disappearance of the azadiene.
3-(Perfluoroethyl)-1-(3-pyridyl)isoquinoline (6b): The general pro-
cedure A was followed using (1E,3Z)-2-azadiene 5e (0.326 g) and
by heating for 144 h. Evaporation of the solvent under reduced
pressure and chromatographic separation (hexane/ethyl acetate,
10:1) gave 0.20 g (62%) of 6b as a yellow solid. The general pro-
cedure B was followed using (3Z)-3-(perfluoroethyl)-1,1,1,4-tet-
raphenyl-2-aza-1λ5-phosphabuta-1,3-diene (4b) (0.50 g) and 3-pyri-
dylcarboxaldehyde (0.46 g) and by stirring for 240 h. Evaporation
of the solvent under reduced pressure and chromatographic separa-
tion (hexane/ethyl acetate, 10:1) gave 0.16 g (51%) of 6b as a yellow
Ethyl 3-Isopropyl-6-(perfluoromethyl)-5-phenyl-4-pyrrolidinyl-
3,4,5,6-tetrahydropyridine-2-carboxylate (10) and Ethyl 3-Isopropyl-
6-(perfluoromethyl)-5-phenylpyridine-2-carboxylate (11a): The gene-
ral procedure was followed using (1E,3E)-2-azadiene 5b prepared
in situ and trans-3-methyl-1-pyrrolidinylbut-1-ene (0.67 g) at room
temperature and by stirring for 24 h in CHCl3. Chromatographic
separation (hexane/ethyl acetate, 15:1) gave 0.63 g (31%) of 10 as
a yellow oil [Rf = 0.16 (ethyl acetate/hexane, 1:10)] and 0.82 g
(49%) of 11a as a yellow oil [Rf = 0.35 (ethyl acetate/hexane, 1:10)].
solid; m.p. 98–99 °C (ethyl acetate/hexane). IR (KBr): ν = 1739,
˜
1
1189 cm–1. H NMR (400 MHz, CDCl3): δ = 7.28–8.20 (m, 7 H),
8.80 (dd, J = 4.8, J = 1.7 Hz, 1 H), 9.02 (dd, J = 2.2, J = 0.8 Hz,
1
1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 111.7 (tq, JCF
=
For compound 10: IR (KBr): ν = 1719, 1121 cm–1 1H NMR
.
˜
2
1
2
254.4, JCF = 37.8 Hz), 119.1 (tq, JCF = 286.8, JCF = 37.9 Hz),
119.9 (t, 3JCF = 4.2 Hz), 121.0–137.6 (m), 140.8 (t, 2JCF = 25.7 Hz),
150.2, 150.7, 158.2 ppm. 19F NMR (282 MHz, CDCl3): δ = –83.2,
–117.0 ppm. MS (EI): m/z 324 (67) [M]+. C16H9F5N2 (324): calcd.
C 59.27, H 2.80, N 8.64; found C 59.09, H 2.82, N 8.61.
(400 MHz, CDCl3): δ = 1.06 (d, J = 6.8 Hz, 3 H), 1.10 (d, J =
6.8 Hz, 3 H), 1.41 (t, J = 7.2 Hz, 3 H), 1.61–1.67 (m, 4 H), 1.91–
2.02 (m, 1 H), 2.26–2.31 (m, 2 H), 2.41–2.46 (m, 2 H), 2.98–3.00
(m, 1 H), 3.10 (s, 1 H), 3.12–3.14 (m, 1 H), 4.27–4.50 (m, 2 H),
4.79–4.84 (m, 1 H), 7.25–7.34 (m, 5 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 14.0, 20.8, 21.6, 23.6, 31.1, 40.4, 41.8, 50.7, 58.3, 62.3,
1-(2,4-Dinitrophenyl)-3-(perfluoroheptyl)isoquinoline (6c): The gene-
ral procedure B was followed using (3Z)-3-(perfluoroheptyl)-4-
phenyl-1,1,1-triphenyl-2-aza-1λ5-phosphabuta-1,3-diene (4c)
(0.75 g) and 2,4-dinitrobenzaldehyde (0.20 g) and by stirring for
250 h. Evaporation of the solvent under reduced pressure and chro-
matographic separation (hexane/ethyl acetate, 10:1) gave 0.34 g
(51%) of 6c as a yellow solid; m.p. 119–120 °C (ethyl acetate/hex-
2
1
63.0 (q, JCF = 26.4 Hz), 125.3 (q, JCF = 286.6 Hz), 126.7–139.9
(m), 165.4, 171.6 ppm. 19F NMR (282 MHz, CDCl3): δ =
–72.1 ppm. MS (70 eV): m/z = 410 (5) [M]+. C22H29F3N2O2 (410):
calcd. C 64.37, H 7.12, N 6.82; found C 64.31, H 7.16, N 6.79. For
compound 11a: IR (KBr): ν = 1734 cm–1. 1H NMR (400 MHz,
˜
CDCl3): δ = 1.33 (d, J = 6.9 Hz, 6 H), 1.47 (t, J = 7.1 Hz, 3 H),
3.51–3.55 (m, 1 H), 4.51 (q, J = 7.1 Hz, 2 H), 7.28–7.50 (m, 5 H),
7.74 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.2, 23.4,
ane). IR (KBr): ν = 1540, 1348 cm–1. 1H NMR (400 MHz, CDCl ):
˜
3
δ = 7.66–8.13 (m, 6 H), 8.23 (s, 1 H), 8.65 (dd, J = 8.4, J = 2.3 Hz,
1
1 H), 9.09 (d, J = 2.3 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
29.1, 62.1, 121.3 (q, JCF = 275.8 Hz), 126.8–138.8 (m), 142.3 (q,
2JCF = 33.4 Hz), 145.6, 147.3, 166.1 ppm. 19F NMR (282 MHz,
CDCl3): δ = –61.5 ppm. MS (70 eV): m/z = 337 (35) [M]+.
C18H18F3NO2 (337): calcd. C 64.09, H 5.38, N 4.15; found C 64.13,
H 5.39, N 4.19.
δ = 110.6–120.3 (m), 120.5–141.0 (m), 148.3, 149.3, 155.9 ppm. 19
F
NMR (282 MHz, CDCl3): δ = –81.1 (t, J = 11 Hz), –109.8. to
–126.4 (m) ppm. MS (EI): m/z = 663 (50) [M]+. C22H8F15N3O4
(663): calcd. C 39.84, H 1.22, N 6.34; found C 39.58, H 1.19, N
6.15.
Ethyl 3-Isopropyl-6-(perfluoroheptyl)-5-phenylpyridine-2-carboxyl-
ate (11b): The general procedure was followed using (1E,3E)-2-aza-
diene 5h prepared in situ and trans-3-methyl-1-pyrrolidinylbut-1-
ene (0.67 g) in CHCl3 at room temperature and by stirring for 24 h.
Chromatographic separation (hexane/ethyl acetate, 15:1) gave
Ethyl 3-(Trifluoromethyl)isoquinoline-1-carboxylate (6d): The gene-
ral procedure B was followed using (3Z)-3-(trifluoromethyl)-
1,1,1,4-tetraphenyl-2-aza-1λ5-phosphabuta-1,3-diene (4a) (0.45 g)
and ethyl glyoxalate (0.10 g) and by stirring for 24 h. Evaporation
1802
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Eur. J. Org. Chem. 2005, 1795–1804

3-(Fluoroalkyl)azadienes in the Synthesis of (Fluoroalkyl)isoquinoline and -pyridine Derivatives
FULL PAPER
1.91 g (60%) of 11b as a yellow oil; Rf = 0.53 (ethyl acetate/hexane,
1,2,4-triazoline-3,5-dione (about 1 mmol) was added to a solution
of an equimolecular amount of azadiene 17 and a catalytic amount
of ytterbium triflate in acetonitrile (5 mL) under N2 and the mix-
ture was stirred at room temperature until TLC indicated the disap-
pearance of the starting azadiene. The reaction mixture was treated
with water, extracted with dichloromethane, dried and the solvent
removed under reduced pressure to yield a residue that was crys-
tallized from hexane.
1:5). IR (KBr): ν = 1735, 1197 cm–1. 1H NMR (400 MHz, CDCl ):
˜
3
δ = 1.35 (d, J = 6.9 Hz, 6 H), 1.47 (t, J = 7.1 Hz, 3 H), 3.50–3.57
(m, 1 H), 4.52 (q, J = 7.1 Hz, 2 H), 7.28–7.48 (m, 5 H), 7.83 (s, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.1, 23.3, 29.2, 62.1,
104.5–122.3 (m), 127.1–153.8 (m), 166.1 ppm. 19F NMR
(282 MHz, CDCl3): δ = –81.2, –117.9 to –163.6 (m) ppm. MS
(70 eV): m/z = 637 (1) [M]+. C24H18F15NO2 (637): calcd. C 45.23,
H 2.85, N 2.20; found C 45.30, H 2.80, N 2.22.
7-(Perfluoromethyl)-2,5-diphenyl-5,8-dihydro[1,2,4]triazolo[1,2-a]-
[1,2,4]triazine-1,3-dione (19a): The general procedure was followed
using (1E)-3-(perfluoromethyl)-1-phenyl-2-azabuta-1,3-diene (17a)
(0.25 g, 1.26 mmol) and by stirring for 12 h. Work up of the reac-
tion and crystallization yielded 0.19 g (40%) of 19a as a white solid;
2-(2,4-Dinitrophenyl)-4-isopropyl-6-(perfluoromethyl)-5-phenyl-
pyridine (12): The general procedure was followed using (1E,3Z)-2-
azadiene 5a obtained in situ and trans-3-methyl-1-pyrrolidinylbut-
1-ene (0.21 g) in toluene at 110 °C and by stirring for 24 h. When
the 2-azadiene had disappeared (12 h), p-benzoquinone (0.16 g)
was added and the mixture was heated to 80 °C for 48 h. Chroma-
tographic separation (hexane/ethyl acetate, 1:10) gave 0.36 g (56%)
1
m.p. 115–116 °C (hexane). IR (NaCl): ν = 1724, 1601 cm–1. H
˜
NMR (300 MHz, CDCl3): δ = 4.40 (dd, J = 18.3, J = 3.0 Hz, 1 H),
4.80 (dd, J = 18.0, J = 0.9 Hz, 1 H), 6.85 (s, 1 H), 7.25–7.64 (m,
of 12 as a yellow solid; m.p. 161–162 °C. IR (KBr): ν = 1534,
1
10 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 72.9, 118.7 (q, JCF
˜
1
1348 cm–1. H NMR (300 MHz, CDCl3): δ = 1.18 (d, J = 6.9 Hz,
= 279 Hz), 125.2–129.8 (m), 130.0, 132.7, 134.4, 150.4, 152.4 (q,
2JCF = 36.7 Hz), 152.8 ppm. 19F NMR (282 MHz, CDCl3): δ =
–72.8 ppm. MS (70 eV): m/z = 374 (54) [M]+. C18H13F3N4O2 (374):
calcd. C 57.76, H 3.50, N 14.97; found C 57.66, H 3.59, N 14.33.
6 H), 2.86 (dq, J = 6.9 Hz, 1 H), 7.27–7.51 (m, 4 H), 7.69 (s, 1 H),
8.03 (d, J = 8.5 Hz, 1 H), 8.58 (dd, J = 8.5, J = 2.3 Hz, 1 H), 8.82
(d, J = 2.3 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 23.5,
1
30.0, 123.6 (q, JCF = 278.0 Hz) 120.4–151.6 (m), 161.1 ppm. 19F
7-(Perfluoropropyl)-2,5-diphenyl-5,8-dihydro[1,2,4]triazole[1,2-a]-
[1,2,4]triazine-1,3-dione (19b): The general procedure was followed
using (1E)-3-(perfluoropropyl)-1-phenyl-2-azabuta-1,3-diene (17b)
(0.25 g, 0.84 mmol) and by stirring for 12 h. Work up of the reac-
tion and crystallization yielded 0.20 g (50%) of 19b as a white solid;
NMR (282 MHz, CDCl3): δ = –62.2 ppm. MS (70 eV): m/z = 431
(5) [M]+. C21H16F3N3O4 (431): calcd. C 58.47, H 3.74, N 9.74;
found C 58.30, H 3.80, N 9.62.
2-(2,4-Dinitrophenyl)-4-isopropyl-5-phenyl-6-(1,2,2,2-tetrafluoro-
ethyl)pyridine (16): The general procedure was followed using
(1E,3Z)-2-azadiene 5d (2.08 g) and trans-3-methyl-1-pyrrolidinyl-
but-1-ene (0.21 g) at 110 °C in toluene and by stirring for 24 h.
Chromatographic separation (hexane/ethyl acetate, 20:1) gave
1.11 g (48%) of 16 as a yellow oil; Rf = 0.61 (ethyl acetate/hexane,
m.p. 110–111 °C (hexane). IR (NaCl): ν = 1727, 1602 cm–1. 1H
˜
NMR (300 MHz, CDCl3): δ = 4.30 (dd, J = 18.3, J = 3.0 Hz, 1 H),
4.60 (dd, J = 18.3, J = 1.3 Hz, 1 H), 6.77 (s, 1 H), 7.15–7.34 (m,
10 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 73.3, 104.4–119.5
(m), 125.1–129.0 (m), 132.4, 132.5, 134.2, 150.2, 152.5, 154.1 (q,
2JCF = 35.3 Hz), 152.8 ppm. 19F NMR (282 MHz, CDCl3): δ =
1:5). IR (KBr): ν = 1534, 1358 cm–1. 1H NMR (400 MHz, CDCl ):
˜
3
δ = 1.18 (d, J = 6.9 Hz, 3 H), 1.20 (d, J = 6.9 Hz, 3 H), 2.83 (dq,
J = 6.9 Hz, 1 H), 5.49 (dq, J = 44.4, J = 5.8 Hz), 7.23–7.63 (m, 5
H), 7.99 (d, J = 8.5 Hz, 1 H), 8.56 (dd, J = 8.5, J = 2.2 Hz 1 H),
8.79 (d, J = 2.3 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
2
2
–80.3, –116.4 (d, JFF = 285.3 Hz), –118.1 (d, JFF = 285.3 Hz),
–125.7 ppm. MS (70 eV): m/z = 474 (56) [M]+. C20H13F7N4O2
(474): C 50.64, H 2.76, N 11.81; found C 50.76, H 2.59, N 11.33.
1
2
23.2, 23.3, 30.2, 84.8 (dq, JCF = 188.4, JCF = 34.4 Hz), 120.4–
139.9 (m), 147.7, 147.9, 149.5, 152.6, 159.2 ppm. 19F NMR
(282 MHz, CDCl3): δ = –75.5 (d, J = 15 Hz), –190.8 (dq, J = 44,
J = 15 Hz) ppm. MS (70 eV): m/z = 463 (100) [M]+. C22H17F4N3O4
(463): calcd. C 57.02, H 3.70, N 9.07; found C 57.10, H 3.67, N
9.10.
Acknowledgments
The authors thank the Ministerio de Ciencia y Tecnología (MCYT,
Madrid DGI, PPQ2003–0910) and the Universidad del País Vasco
(UPV-GC/2002) for supporting this work. C. A. thanks the De-
partamento de Educación, Universidades e Investigación of Gobi-
erno Vasco, for a postdoctoral fellowship.
(1E)-3-(Perfluoropropyl)-1-phenyl-2-azabuta-1,3-diene (17b): This
azadiene was prepared by a modification of the method of So-
loshonok and co-workers.[10c] First, N-(3,3,4,4,5,5,5-heptafluoro-
pent-2-ylidene)benzylamine was obtained by condensation of
methyl heptafluoropropyl ketone and benzylamine. NBS bromina-
tion of this imine in CCl4 produced N-(1-bromo-3,3,4,4,5,5,5-hep-
tafluoropent-2-yliden)benzylamine which was treated (0.64 g,
2.3 mmol) with triethylamine (5 mL) at room temperature for 24 h.
Elimination of triethylamine under reduced pressure afforded an
oil that was purified by chromatography on silica gel (ethyl acetate/
hexane, 1:40) to give 2-azadiene 17b (0.27 g, 40%) as a yellow oil;
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˜
f
1657 cm–1. H NMR (300 MHz, CDCl3): δ = 5.14 (m, 2 H), 7.42–
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2
=
21.3 Hz), 161.9 ppm. 19F NMR (282 MHz, CDCl3): δ = –81.4,
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Eur. J. Org. Chem. 2005, 1795–1804
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1803

F. Palacios, C. Alonso, M. Rodríguez, E. Martínez de Marigorta, G. Rubiales
FULL PAPER
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Eur. J. Org. Chem. 2005, 1795–1804