Superelectrophilic intermediates in the synthesis of novel indenole derivatives via 1,5-cyclization reactions of 5-aryl-1-azapenta-1,4-dien-3-ones

Article abstract of DOI:10.1055/s-0028-1083188

Oximes of 5,5-disubstituted 1-azapenta-1,4-dien-3-ones 3 underwent 1,5-cyclization reactions yielding indenole derivatives 4 in moderate to good yields upon treatment with an excess of trifluoromethanesulfonic acid. Similarly, the hydrazone 3g led to indenole 4f upon protonation. The reaction could also be successfully applied to the synthesis of benzo[b]cyclopenta[d] thiophene 5 starting from 3f. Products of a competing aza-Nazarov reaction were not observed. The reaction mechanism is explained by assuming the involvement of dicationic intermediates, generated by superelectrophilic solvation, similar to that of known Nazarov and aza-Nazarov-type transformations. Quantum chemical calculations of reaction energies and activation barriers are discussed with respect to the experimental results. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083188

PAPER
3397
Superelectrophilic Intermediates in the Synthesis of Novel Indenole
Derivatives via 1,5-Cyclization Reactions of 5-Aryl-1-azapenta-1,4-dien-3-ones
A
cid-Induce
d
1,5-
u
C
yclization
R
g
eactions of
z
a
apenta-1,4
r
Organisch-Chemisches Institut, Universität Münster, Corrensstr. 40, 48149 Münster, Germany
Fax +49(251)8339772; E-mail: wurthwe@uni-muenster.de
Received 19 May 2008; revised 9 July 2008
Dedicated to Prof. A. R. Katritzky FRS on the occasion of his 80th birthday
Abstract: Oximes of 5,5-disubstituted 1-azapenta-1,4-dien-3-ones
EO
Ph
3 underwent 1,5-cyclization reactions yielding indenole derivatives
4 in moderate to good yields upon treatment with an excess of tri-
fluoromethanesulfonic acid. Similarly, the hydrazone 3g led to in-
denole 4f upon protonation. The reaction could also be successfully
applied to the synthesis of benzo[b]cyclopenta[d]thiophene 5 start-
ing from 3f. Products of a competing aza-Nazarov reaction were not
observed. The reaction mechanism is explained by assuming the in-
volvement of dicationic intermediates, generated by superelectro-
philic solvation, similar to that of known Nazarov and aza-Nazarov-
type transformations. Quantum chemical calculations of reaction
energies and activation barriers are discussed with respect to the ex-
perimental results.
O
E+
OE
+
+
H
X
Ph
Ph
Ph
Ph
Ph
X
X
X = Br, NR2
E+ = electrophile
Scheme 1 Synthesis of 1,3-diphenylindenoles according to Kohler
et al.6a,b and Cromwell et al.6c
De Lera et al. studied the nature of the ring closure reac-
tion of 1-hydroxypentadienyl cations (Scheme 2)7 theo-
retically and showed, that the observed conrotatory mode
of the pericyclic reaction and the negative NICS value8
(–11.35) for the transition state indicate a certain degree of
4p-electron Möbius aromaticity with a helical struc-
ture.9,10 On the other hand, the large charge separation on
the terminal atoms (0.58e) was taken as an alternative
view of the process as an ionic reaction (an intramolecular
Prins reaction).7
Key words: cyclization, carbocations, penta-1,4-dien-3-ones, inde-
noles, quantum chemical calculations
In recent years several publications appeared reporting on
Nazarov and related aza-Nazarov transformations involv-
ing the so-called superelectrophilic conditions with dicat-
ions as intermediates affording carbo- and heterocyclic
five-membered ring systems.1–3 Among those, indenes
and indenoles represent interesting molecules, as the in-
dene moiety is frequently found in natural products with
valuable pharmacological properties.4 However, not
many methods are known for the synthesis of functional-
ized derivatives. In the majority of these publications tran-
sition-metal-catalyzed carbocyclizations of alkynes with
ortho-carbonylated arylaldehydes or arylboron com-
pounds have been reported as efficient methods for the
preparation of 1-indenoles. 5 Acid-induced cyclizations of
2-substituted 3,3-diphenylacrylophenones to yield substi-
tuted 1,3-diphenylindenones under the influence of Brøn-
sted acids were described by Kohler et al.6a,b and later by
Cromwell et al.6c The following mechanism was proposed
by Cromwell (Scheme 1).6c Protonation/coordination of
the carbonyl oxygen atom by the acid generates a carben-
ium ion, which undergoes an intramolecular electrophilic
aromatic substitution to form an indene derivative. This
mechanism resembles the classical Nazarov cyclization,
involving now a protonated a,b,g,d-unsaturated carbonyl
compound in place of an penta-1,4-dien-3-one as known
from the Nazarov cyclization. Here, one of the double
bonds is part of an aromatic moiety.
[13.0]
+
+
OH
OH
[0.0]
[6.3]
Scheme 2 Calculated relative energies and activation energy (above
arrow) for the 1,5-cyclization of the 1-hydroxypentadienylium ion as
calculated by de Lera et al.7 [B3LYP/6-311G(d)//B3LYP/6-311G(d)
including zero point correction (ZPE)] [kcal/mol].
Our present interest is focused on 1-azapenta-1,4-dien-3-
ones, as quantum chemical calculation have shown that
this system is able to undergo various types of cyclization
reactions. Recently, we have demonstrated that 1-azapen-
ta-1,4-dien-3-ones can successfully be applied to the syn-
thesis of substituted 1H- and 2H-pyrroles via the aza-
Nazarov route.11 In the course of these studies on acid me-
diated aza-Nazarov-type reactions, we have discovered
that 1-alkoxy-substituted 5-aryl-1-azapenta-1,4-dien-3-
ones yield indenole derivatives upon treatment with an ex-
cess of very strong acid via ring-closure reactions of the
respective cationic intermediates. In the light of the publi-
cations mentioned above, the experimental conditions of
our experiments suggest the involvement of superelectro-
philic species also in this formation of indenoles.1–3
SYNTHESIS 2008, No. 21, pp 3397–3406
x
x.
x
x
.
2
0
0
8
Advanced online publication: 16.10.2008
DOI: 10.1055/s-0028-1083188; Art ID: T08108SS
© Georg Thieme Verlag Stuttgart · New York

3398
N. Ghavtadze et al.
PAPER
Preconditions for this indenole formation are such 5,5-di- was necessary to obtain stable products. Careful product
substituted 1-azapenta-1,4-dien-3-ones 3, which bear an analysis showed that treatment of such aza-dienones 3
aryl ring and additionally the very strong electron with- with strong acids does not give the aza-Nazarov products.
drawing substituent CF3 group in 5-position. This substi- Instead, we found that the aryl fragment was involved in
tution pattern precludes the final aromatization step of the the reaction and indenole derivatives 4 have been pro-
aza-Nazarov ring closure product by deprotonation. We duced via an 1,5-cyclization reaction (Scheme 4). Since
were interested to learn whether alternative reaction chan- the intermediate hydroxyindenes are rather unstable the
nels might be opened if such 1-azapenta-1,4-dien-3-ones trapping of them by anhydrides was advantageous. Simi-
3 were treated with strong acid.
lar observations were made for the aza-Nazarov reac-
tion,11a where very sensitive 3-hydroxypyrroles form the
initial reaction products. The use of weaker acids [trifluo-
roacetic acid, polyphosphoric acid (PPA)] did not induce
the cyclization reaction. In these cases, the starting mate-
rials 3 were recovered.
5,5-Disubstituted 1-amino- and 1-alkoxy-1-azapenta-1,4-
dien-3-ones 3 were accessible from hydrazones or oximes
of pyruvates 1, subsequent formation of the corresponding
phosphonates 2 and finally Horner–Wadsworth–Emmons
reaction using trifluoromethyl ketones (Scheme 3). As
other unactivated ketones did not react easily in this olefi-
nation reaction, we have restricted our study presently on
trifluormethyl systems. Furthermore, we expected the
electron-withdrawing effect of the CF3 group to enhance
the reactivity of the intermediate cationic species obtained
by protonation.
R1
R1
TfOH
N
O
O
N
R2
R2
O
O
O
O
R2
CF3
CF3
Experimentally, the protonation reactions of 1-alkoxy-1-
azapenta-1,4-dien-3-ones (oximes) 3 were carried out in
dichloromethane by treatment with an excess of the triflic
acid at –10 to 0 °C. Addition of an excess of acyl anhy-
dride (acetic acid anhydride or benzoic acid anhydride)
3
4
Scheme 4
In order to determine the scope and limitations of this re-
action we investigated differently substituted 5-aryl-1-
azapenta-1,4-dien-3-ones 3 as cyclization precursors. The
reaction was tolerant with respect to various substituents
R1. The results of the cyclization reactions are summa-
rized in Table 1.
O
P
O
O
O
O
R1NH2
EtOH
n-BuLi
THF
O
O
In the cases of t-Bu and benzyl derivatives 3c,d, these
groups were replaced by the acetyl group under the very
strong acidic conditions to give 4c (Scheme 5).
N
O
R1
1a–e (49–95%)
We found that the reaction was unsuccessful if the aryl
fragment contained any deactivating substituents. Reac-
tion with p-Br, p-Cl, m-CF3, and p-NMe2H+ substituent
containing substrates and the corresponding naphthalene-
1-yl derivative showed either formation of the cyclic
product 4 – but in a complex mixture and low yield – or
only unidentified products. Introducing a phenyl substitu-
t-BuOK
O
Ar
O
O
CF3
O
Ar
P
CF3
O
O
N
N
R1
THF
R1
3a–g (56–97%)
2a–e (45–73%)
major isomer
Scheme 3
Table 1 Substitution Pattern of Compounds 3, 4 and Yields of 4
Compounds
R1
R2
Aryl
Yield (%)
3a, 4a
OMe
Me
Me
Me
Me
Ph
Ph
75
80
39
49
38
39
40
89
3b, 4b
OEt
Ph
3c, 4c
OBn → OAca
Ph
3d, 4c
Ot-Bu → OAca
Ph
3a, 4d
OMe
Ph
3e, 4e
OMe
Me
Me
Me
2,4-dimethylphenyl
2-benzothienyl
Ph
3f, 5
OMe
3g, 4f
2,6-dimethylpiperidin-1-yl
a See text and Scheme 5.
Synthesis 2008, No. 21, 3397–3406 © Thieme Stuttgart · New York

PAPER
Acid-Induced 1,5-Cyclization Reactions of 5-Aryl-1-azapenta-1,4-dien-3-ones
3399
R1
N
TfOH
Ac2O
OAc
N
AcO
O
CF3
CF3
3c,d (R1 = Ot-Bu, OBn)
4c
Scheme 5
ent instead of the methyl group in 2-position of the 1-aza-
penta-1,4-dien-3-one furnished no products at all, and the
starting aza-dienone was quantitatively recovered. If a
benzothienyl group was introduced as aromatic moiety
into the cyclization precursor 3f, the tricyclic product 5
was formed in 40% yield (Scheme 6).
O
N
TfOH
Ac2O
OAc
O
O
N
S
S
CF3
CF3
Figure 1 Molecular structures of 4e and 5 in the solid state (X-ray)
5 (40 %)
3f
Scheme 6
ed species (superelectrophiles) in equilibrating mix-
tures.3b However, this does not imply that protosolvation
de facto leads to these dications in any appreciable con-
centration. According to quantum chemical calculations
many of such dications correspond to energy minima.3d
This cyclization reaction could be extended to sterically
demanding hydrazones like 3g, leading to the correspond-
ing indenole derivative 4f having a 1-amino-2,6-di-
methylpiperidinecarbhydrazone moiety (Scheme 7). In
contrast, sterically unhindered hydrazones gave tricyclic
products.11b
On the basis of kinetic studies and theoretical calculations
it has been shown that superacid-induced Nazarov cy-
clization reactions involve dicationic or superelectrophilic
intermediates.1b Dicationic superelectrophilic species
may also be involved in aza-Nazarov reactions.1a In the
light of these findings we suggest that the reaction report-
ed here also proceeds via superelectrophilic intermediates
and the following mechanism is proposed (Scheme 8).
N
N
AcO
N
TfOH
Ac2O
N
O
Protonation, at least in equilibrium, at the carbonyl oxy-
gen and imine nitrogen atoms leads to highly reactive
dicationic species, which subsequently undergo the cy-
CF3
(89%)
CF3
3g
4f
Scheme 7
R1
R1
+
N
HN
O
All products 4 and 5 were fully characterized by spectro-
scopic methods. In two cases the molecular structures in
the solid state were confirmed by X-ray diffraction
(Figure 1).12–19
+
HO
+ 2 H
+
CF3
CF3
3
The fact that the reactions studied necessarily required an
excess of very strong Brønsted acid clearly indicates that
in these transformations superelectrophilic solvation
plays an important role. This phenomenon was thoroughly
investigated by Olah et al.3 Triflic acid with an Hammett’s
acidity function equal to –14.11b is qualified as a super
acid and is able to interact with n-donor as well as with p-
donor systems easily. This kind of interactions allows the
formation of protonated and subsequently also diprotonat-
R1
R1
+
N
HN
HO
HO
+
+
– 2 H
CF3
CF3
4
Scheme 8
Synthesis 2008, No. 21, 3397–3406 © Thieme Stuttgart · New York

3400
N. Ghavtadze et al.
PAPER
OH
+
clization reaction to produce the observed indenole deri-
vatives 4 after workup.
HO
[11.5]
CF3
In order to demonstrate the effect of superelectrophilic
activation SCS-MP2/6-311G(d,p)//B3LYP/6-311G(d,p)
quantum chemical calculations20 [including zero point
correction (ZPE)]21 were performed (Scheme 9). Such
calculations, however, do not take solvent effects into ac-
count, but simulate gas-phase reactions.
N
+
CF3
O
N
O
[–14.5]
[3.6]
OH
+
HO
+
[39.0]
CF3
+
O
O
+
NH
O
CF3
N
N
N
O
N
HO
+
HO
+
HO
O
H
+
[32.6]
[8.0]
CF3
CF3
CF3
Scheme 10 Calculated relative energies of mono (upper line) and
dicationic species (lower line) as intermediates of the aza-Nazarov
cyclizations. The data refer to the values given in Scheme 9. [SCS-
MP2/6-311G(d,p)//B3LYP/6-311G(d,p) including zero point correc-
tion (ZPE)][kcal/mol].
[18.4]
[15.7]
[0.0]
+
O
+
+
O
O
HN
HN
HN
HO
+
HO
+
HO
+
studied here proceed synchronously via helical transition
states without intermediates.
CF3
CF3
CF3
[15.7]
In summary, we have disclosed that upon treatment with
triflic acid oximes and hydrazone derivatives of 5,5-di-
substituted 1-azapenta-1,4-dien-3-ones 3 undergo 1,5-cy-
clization reactions affording indenole derivatives 4. The
reaction could also be successfully applied for the synthe-
sis of a benzo[b]cyclopenta[d]thiophene 5. Products of a
competing aza-Nazarov reaction were not observed. The
reaction mechanism is explained by dicationic intermedi-
ates, which are generated in situ by superelectrophilic sol-
vation, similarly to that of known Nazarov and aza-
Nazarov-type transformations. The possibility of dica-
tionic intermediates in the cyclization reaction is also dis-
cussed on the basis of quantum chemical calculations.
[1.3]
[0.0]
Scheme 9 Calculated relative energies of mono (upper line) and di-
cationic species (lower line) as intermediates in the 1,5-cyclization
[SCS-MP2/6-311G(d,p)//B3LYP/6-311G(d,p) including zero point
correction (ZPE)][kcal/mol].
In the case of the dicationic mechanism, the cyclization
reaction is slightly endothermic (~1.3 kcal/mol) with a
calculated barrier of 15.7 kcal/mol. This is in sharp differ-
ence to the monocationic mechanism, which is quite en-
dothermic (15.7 kcal/mol) with a calculated barrier of
18.4 kcal/mol. We have determined a low negative NICS
value (–6.6) and a large charge separation between the ter-
minal carbon atoms (0.63e) for the helical transition state
of the dicationic 1,5-cyclization reaction.
Melting points: Büchi Melting Point B-540; melting points are un-
1
corrected. H, 13C, 19F, 31P, GCOSY, GHSQC, GHMBC, and 1D-
NOE NMR spectroscopy: Varian INOVA 500, AMX 400, Bruker
WM 300 spectrometer. TMS (1H) (0.00 ppm), CDCl3 (13C) (77.0
ppm), CFCl3 (19F) (0.0 ppm) were used as internal references, 85%
H3PO4 (31P) (0.0 ppm) was used as external reference; IR: Nicolet
FT-IR 5DXC spectrometer. Electron ionization mass spectra (EI):
Finnigan MAT C 312 spectrometer (70 eV). MS: mass spectra were
recorded on a Finnigan MAT 4200S, or Bruker Daltonics
micrOTOF, or Waters-Micromass Quatro LCZ (ESI) spectrometer;
elemental analysis: automated Elementar Vario EL III CHNS ana-
lyzer. All solvents (tert-butyl methyl ether: TBME) and reagents
were rigorously dried and purified by standard methods or were
used as received from Aldrich, Acros or Fluka. When necessary, the
experiments were carried out with complete exclusion of moisture.
Column chromatography: silica gel Merck 60 (0.040–0.063 mm).
TLC: Merck silica gel plates (silica gel 60 F254), detection with UV
light.
As indicated, five-membered heterocycles as products of
a competing aza-Nazarov cyclization of the 5,5-disubsti-
tuted 1-azapenta-1,4-dien-3-ones were not observed un-
der the present reaction conditions (Scheme 10). The
impossibility to produce an aromatic pyrrole system by
deprotonation may render such a reaction pathway inef-
fective. We can not exclude the formation of cationic pyr-
role intermediates in equilibrium with the indenole
systems, but this reaction channel was not productive un-
der our reaction conditions. Quantum chemical calcula-
tions preclude the dicationic pathway for the aza-Nazarov
route for thermodynamic reasons (very endothermic cy-
clization). For monocationic species, the aza-Nazarov cy-
clization step is kinetically and thermodynamically
favored over the indenole reaction pathway, but this route
might not be followed under the equilibrium conditions
within the reaction mixture. IRC-calculations indicate that
all cyclization reactions of mono- and dicationic species
Iminoesters 1; General Procedure
Iminoesters 1 were prepared from ethyl pyruvate and the corre-
sponding hydroxylamine hydrochloride or hydrazine. Ethyl pyru-
vate (1.16 g, 10 mmol) was dissolved in anhyd EtOH (20 mL) and
hydroxylamine or hydrazine (11 mmol) in anhyd EtOH (5 mL) was
Synthesis 2008, No. 21, 3397–3406 © Thieme Stuttgart · New York

PAPER
Acid-Induced 1,5-Cyclization Reactions of 5-Aryl-1-azapenta-1,4-dien-3-ones
3401
added slowly at 0 °C. AcOH (0.572 mL, 600 mg, 10 mmol) and a
small amount of NaOAc were added to the mixture in order to main-
tain pH 5–6. The mixture was stirred at r.t. for 4 h. Then, the mixture
was filtered and the solvent was evaporated. The iminoesters 1 were
purified by distillation at reduced pressure.
IR (film): 3090 (w), 3065 (w), 3034 (w), 2982 (m), 2937 (m), 2882
(w), 1719 (s), 1612 (w), 1497 (w), 1466 (m), 1454 (m), 1396 (w),
1367 (s), 1319 (s), 1300 (m), 1209 (w), 1175 (s), 1151 (s), 1113 (w),
1096 (w), 1082 (w), 1016 (s), 959 (m), 924 (w), 858 (m), 822 (w),
793 (w), 756 (m), 737 (w), 717 (m), 698 (m), 665 (w), 608 cm–1 (w).
1H NMR (300 MHz, CDCl3): d = 0.79 (d, J = 6.2 Hz, 6 H, CH3),
1.25–1.73 (m, 9 H), 2.25 (s, 3 H, CH3), 2.41–2.72 (m, 2 H, CH),
4.36 (q, J = 6.9 Hz, 2 H, CH2).
13C NMR (75 MHz, CDCl3): d = 14.2, 17.0, 18.6, 20.9, 21.0, 24.1,
33.6, 33.7, 59.4, 60.5, 61.8, 165.1, 165.6.
2-Methoxyiminopropionic Acid Ethyl Ester (1a)22
Prepared from ethyl pyruvate and O-methylhydroxylamine accord-
ing to the general procedure. The subsequent distillation (60 °C/3
mbar) gave 2.18 g (15 mmol, 60%) of 1a as colorless oil.
1H NMR (400 MHz, CDCl3): d = 1.35 (t, J = 7.1 Hz, 3 H, CH3),
2.05 (s, 3 H, CH3), 4.06 (s, 3 H, OCH3), 4.33 (q, J = 7.1 Hz, 2 H,
CH2).
HRMS (ESI): m/z calcd for C12H22N2O2 + Na: 249.1573; found:
249.1564.
13C NMR (100 MHz, CDCl3): d = 11.2 (CH3), 14.2 (CH3), 61.7
(CH2), 63.1 (OCH3), 149.1 (C=N), 163.7 (COO).
Anal. Calcd for C12H22N2O2: C, 63.69; H, 9.80; N, 12.38. Found: C,
63.39; H, 9.92; N, 12.26.
Ketophosphonates 2; General Procedure23
2-Ethoxyiminopropionic Acid Ethyl Ester (1b)23
Dimethyl methylphosphonate (1.241 g, 10 mmol) was dissolved in
anhyd THF (15 mL), cooled to –78 °C and n-BuLi (1.6 M in hex-
anes, 6.25 mL, 10 mmol) was added slowly. The mixture was stirred
at –78 °C for 1 h. Then, iminoester 1 (10 mmol) in anhyd THF (5
mL) was added. The mixture was stirred for 4 h at –78 °C, and then
quenched with AcOH (0.6 mL) and H2O (5 mL). After evaporation
of the solvent, the residue was dissolved in CH2Cl2 (40 mL) and the
CH2Cl2 layer was washed first with H2O (30 mL), and then with sat.
aq NaHCO3 (30 mL) and again with H2O (30 mL). The residue was
dried (MgSO4) and purified by column chromatography.
Prepared from ethyl pyruvate and O-ethylhydroxylamine according
to the general procedure. The subsequent distillation (64 °C/6 mbar)
gave 1.98 g (12.5 mmol, 49%) of 1b as colorless oil.
1H NMR (300 MHz, CDCl3): d = 1.34 (t, J = 7.1 Hz, 6 H, CH3),
2.05 (s, 3 H, CH3), 4.33 (q, J = 7.1 Hz, 4 H, CH2).
13C NMR (75 MHz, CDCl3): d = 11.3 (CH3), 14.1 (CH3), 14.5
(CH3), 61.6 (CH2), 71.1 (CH2), 148.6 (C=N), 163.8 (COO).
2-Benzyloxyiminopropionic Acid Ethyl Ester (1c)23
Prepared from ethyl pyruvate and O-benzylhydroxylamine accord-
ing to the general procedure. The subsequent distillation (145 °C/
7 × 10–3 mbar) gave 1.59 g (7.21 mmol, 72%) of 1c as a colorless
oil.
1H NMR (300 MHz, CDCl3): d = 1.34 (t, J = 7.1 Hz, 3 H, CH3),
2.08 (s, 3 H, CH3), 4.31 (q, J = 7.1 Hz, 2 H, CH2), 5.30 (s, 2 H, CH2),
7.31–7.39 (m, 5 Harom).
3-Methoxyimino-2-oxobutylphosphonic Acid Dimethyl Ester
(2a)
Prepared from 1a according to the general procedure. The subse-
quent chromatographic purification (TBME–acetone, 2:1) gave
0.450 g (2.02 mmol, 45%) of 2a as a pale yellow oil.
IR (film): 3543 (s), 3483 (s), 3370 (s), 2990 (m), 2957 (m), 2855 (s),
2828 (s), 2640 (s), 1962 (s), 1846 (s), 1693 (w), 1607 (m), 1460 (m),
1448 (m), 1394 (m), 1367 (m), 1323 (w), 1263 (w), 1213 (m), 1188
(m), 1159 (m), 1045 (w), 924 (m), 880 (w), 843 (w), 810 (w), 779
(m), 754 (s), 741 (s), 692 (s), 665 (m), 598 cm–1 (w).
13C NMR (75 MHz, CDCl3): d = 11.6 (CH3), 14.2 (CH3), 61.7
(CH2), 77.5 (CH2), 128.1 (CHarom), 128.2 (CHarom), 128.4 (CHarom),
136.7 (Cipso), 149.5 (C=N), 163.8 (COO).
2-tert-Butoxyiminopropionic Acid Ethyl Ester (1d)
Prepared from ethyl pyruvate and O-tert-butylhydroxylamine ac-
cording to the general procedure. The subsequent distillation
(34 °C/1 mbar) gave 0.773 g (4.13 mmol, 52%) of 1d as a colorless
oil.
1H NMR (400 MHz, CDCl3): d = 1.94 (s, 3 H, CH3), 3.58 (d,
J = 22.3 Hz, 2 H, CH2P), 3.79 (d, J = 11.2 Hz, 6 H, CH3O), 4.09 (s,
3 H, CH3ON).
13C NMR (75 MHz, CDCl3): d = 8.6 (CH3), 34.8 (d, J = 132.0 Hz,
CH2P), 52.9 (d, J = 6.2 Hz, CH3O), 63.5 (CH3ON), 155.1 (d, J = 2.3
Hz, C=N), 189.9 (d, J = 7.0 Hz, C=O).
IR (film): 2980 (vs), 2936 (s), 2909 (m), 2876 (m), 1740 (s), 1719
(s), 1612 (m), 1512 (w), 1475 (m), 1466 (m), 1449 (s), 1391 (s),
1367 (s), 1321 (s), 1300 (s), 1263 (m), 1244 (m), 1190 (s), 1175 (s),
1151 (s), 1115 (m), 1097 (m), 1030 (s), 1007 (s), 966 (s), 922 (m),
899 (m), 860 (s), 797 (m), 777 (m), 756 (s), 683 (m), 559 cm–1 (m).
31P NMR (121.5 MHz, CDCl3): d = 21.7.
HRMS (ESI): m/z calcd for C7H14NO5P + Na: 246.502; found:
246.507.
1H NMR (400 MHz, CDCl3): d = 1.33 (t, J = 7.1 Hz, 3 H, CH3),
1.34 [s, 9 H, (CH3)3C], 2.01 (s, 3 H, CH3), 4.28 (q, J = 7.1 Hz, 2 H,
CH2).
13C NMR (100 MHz, CDCl3): d = 11.2 (CH3), 14.2 (CH3), 27.5
(CH3), 61.9 (CH2), 80.7 [C(CH3)3], 147.4 (C=N), 164.4 (COO).
Anal. Calcd for C7H14NO5P: C, 37.67; H, 6.32; N, 6.28. Found: C,
37.49; H, 6.35; N, 6.19.
3-Ethoxyimino-2-oxobutylphosphonic Acid Dimethyl Ester (2b)
Prepared from 1b according to the general procedure. The subse-
quent chromatographic purification (Et2O–acetone, 3:1) gave 0.370
g (1.56 mmol, 52%) of 2b as a pale yellow oil.
MS (EI): m/z = 187 ([M]+), 142, 131, 114, 103, 85, 57.
Anal. Calcd for C9H17NO3: C, 57.73; H, 9.15; N, 7.48. Found: C,
57.71; H, 9.01; N, 7.59.
IR (film): 3483 (m), 3370 (w), 1655 (w), 2984 (m), 2957 (s), 2901
(m), 2855 (m), 1693 (s), 1605 (m), 1460 (m), 1447 (m), 1389 (m),
1369 (m), 1323 (s), 1263 (s), 1211 (m), 1184 (m), 1121 (m), 1042
(s), 945 (m), 880 (s), 843 (s), 810 (s), 772 (w), 750 (w), 741 (w), 690
(w), 665 (w), 600 cm–1 (m).
2-(2,6-Dimethylpiperidin-1-yl)iminopropionic Acid Ethyl Ester
(1e)
Prepared from ethyl pyruvate and N-amino-2,6-dimethylpiperidine
(mixture of stereoisomers) according to the general procedure. The
subsequent distillation (60 °C/2.5 × 10–2 mbar) gave 1.51 g (6.67
mmol, 95%) of 1e as a yellow oil as a mixture of stereoisomers. 1H
data are given for the main isomer.
1H NMR (300 MHz, CDCl3): d = 1.36 (t, J = 7.1 Hz, 3 H, CH3),
1.94 (s, 3 H, CH3), 3.59 (d, J = 22.3 Hz, 2 H, CH2P), 3.79 (d,
J = 11.2 Hz, 6 H, CH3O), 4.34 (q, J = 7.1 Hz, 2 H, CH2O).
Synthesis 2008, No. 21, 3397–3406 © Thieme Stuttgart · New York

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N. Ghavtadze et al.
PAPER
13C NMR (75 MHz, CDCl3): d = 8.6 (CH3), 14.5 (CH3), 34.7 (d,
J = 132.0 Hz, CH2P), 52.9 (d, J = 6.2 Hz, CH3O), 71.6 (CH2O),
154.8 (C=N), 190.1 (d, J = 6.8 Hz, C=O).
1300 (m), 1261 (s), 1205 (m), 1153 (w), 1103 (w), 1038 (s), 978
(w), 941 (w), 881 (m), 845 (m), 808 (m), 737 (m), 679 (w), 590 (m),
507 cm–1 (w).
31P NMR (121.5 MHz, CDCl3): d = 21.1.
1H NMR (300 MHz, CDCl3): d = 0.89 (d, J = 6.4 Hz, 6 H, CH3),
1.49–1.84 (m, 6 H, CH2), 2.11 (s, 3 H, CH3), 3.01 (m, 2 H, CH), 3.72
(d, J = 22.6 Hz, 2 H, CH2P), 3.78 (d, J = 11.2 Hz, 6 H, CH3O).
13C NMR (75 MHz, CDCl3): d = 13.7 (CH3), 20.6 (CH3), 21.2
(CH2), 32.5 (CH2), 34.4 (d, J = 131.1 Hz, CH2P), 52.8 (d, J = 6.3
Hz, CH3O), 141.7 (C=N), 193.2 (d, J = 6.8 Hz, C=O).
HRMS (ESI): m/z calcd for C8H16NO5P + Na: 260.0658; found:
260.0654.
Anal. Calcd for C8H16NO5P: C, 40.51; H, 6.80; N, 5.91. Found: C,
40.37; H, 6.87; N 6.04.
3-Benzyloxyimino-2-oxobutylphosphonic Acid Dimethyl Ester
(2c)
Prepared from 1c according to the general procedure. The subse-
quent chromatographic purification (TBME–acetone, 2:1) gave
1.09 g (3.65 mmol, 73%) of 2c as a pale yellow oil.
31P NMR (121.5 MHz, CDCl3): d = 22.6.
HRMS (ESI): m/z calcd for C13H25N2O4P + Na: 327.1444; found:
327.1434.
Anal. Calcd for C13H25N2O4P: C, 51.31; H, 8.28; N, 9.21. Found: C,
50.79; H, 7.97; N, 9.07.
IR (film): 3530 (w), 3476 (w), 3090 (w), 3063 (w), 3032 (w), 2995
(w), 2957 (w), 2885 (w), 2853 (w), 1693 (s), 1655 (w), 1607 (w),
1497 (w), 1456 (w), 1394 (w), 1366 (w), 1321 (m), 1261 (m), 1211
(m), 1184 (w), 1161 (w), 1030 (s), 972 (w), 924 (w), 880 (m), 843
(m), 810 (m), 787 (w), 741 (m), 700 (m), 665 cm–1 (w).
1H NMR (300 MHz, CDCl3): d = 1.97 (s, 3 H, CH3), 3.56 (d,
J = 22.4 Hz, 2 H, CH2P), 3.71 (d, J = 11.3 Hz, 6 H, CH3O), 5.30 (s,
2 H, CH2), 7.28–7.43 (m, 5 Harom).
13C NMR (75 MHz, CDCl3): d = 8.8 (CH3), 34.9 (d, J = 131.5 Hz,
CH2P), 52.8 (d, J = 6.0 Hz, CH3O), 77.8 (CH2), 128.2 (CHarom),
128.4 (CHarom), 136.5 (CHarom), 155.5 (C=N), 189.9 (d, J = 6.9 Hz,
C=O).
Azadienones 3; General Procedure
t-BuOK (1.12 g, 10 mmol) was dissolved in anhyd THF (100 mL)
and a solution of ketophosphonate 2 (10 mmol) in anhyd THF (20
mL) was added. The mixture was stirred for 1 h at r.t. and the appro-
priate trifluoroacetyl ketone (10 mmol) was added. The mixture was
stirred for 4 h at r.t. and the solvent was evaporated. The residue was
dissolved in CH2Cl2 (80 mL), the CH2Cl2 layer was washed with
brine (60 mL), dried (MgSO4), concentrated, and the residue was
purified by column chromatography. In all cases the E-isomers
1
were the main products. H and 13C signals were assigned for the
main E-product. The stereochemistry and the ratios of E- and Z-iso-
mers were determined by comparing the 19F chemical shifts to com-
pounds with known stereochemistry from the crude reaction
mixtures.11b
31P NMR (121.5 MHz, CDCl3): d = 21.5.
HRMS (ESI): m/z calcd for C13H18F3NO5P + Na: 322.0815; found:
322.0817.
6,6,6-Trifluoro-5-phenylhex-4-ene-2,3-dione 2-(O-Methyl-
oxime) (3a)
Prepared from ketophosphonate 2a and 2,2,2-trifluoroacetophe-
none according to the general procedure. The subsequent chromato-
graphic purification (pentane–Et2O, 6:1) gave 0.577 g (2.13 mmol,
89%) of 3a as a yellow oil.
Anal. Calcd for C13H18F3NO5P: C, 52.17; H, 6.02; N, 4.68. Found:
C, 51.50; H, 6.26; N, 4.84.
3-tert-Butoxyimino-2-oxobutylphosphonic Acid Dimethyl Ester
(2d)
Prepared from 1d according to the general procedure. The subse-
quent chromatographic purification (TBME–acetone, 4:1) gave
0.535 g (2.02 mmol, 73%) of 2d as a pale yellow oil.
IR (film): 3356 (w), 3088 (w), 3063 (w), 3026 (w), 2943 (m), 2856
(w), 2826 (w), 1686 (s), 1655 (w), 1639 (w), 1605 (m), 1578 (w),
1543 (w), 1499 (w), 1460 (w), 1445 (w), 1367 (m), 1308 (m), 1267
(s), 1177 (s), 1132 (s), 1069 (m), 1047 (s), 1001 (w), 972 (w), 953
(w), 926 (w), 912 (w), 874 (w), 827 (w), 777 (w), 756 (w), 739 (w),
698 (m), 665 cm–1 (m).
1H NMR (500 MHz, CDCl3): d = 1.82 (s, 3 H, CH3), 4.08 (s, 3 H,
CH3O), 7.23–7.25 (m, 2 Harom), 7.35–7.41 (m, 3 Harom), 7.44 (q,
J = 1.4 Hz, 1 H, =CH).
13C NMR (100 MHz, CDCl3): d = 8.5 (CH3), 63.6 (CH3O), 122.8 (q,
J = 274.6 Hz, CF3), 127.8 (q, J = 5.4 Hz, =CH), 128.2 (CHarom),
128.8 (CHarom), 129.1 (CHarom), 131.5 (Cipso), 140.0 (q, J = 30.6 Hz,
=C), 156.1 (C=N), 187.4 (C=O).
19F NMR (282 MHz, CDCl3): d (E-isomer) = –67.6; d (Z-isomer) =
–59.8; E/Z ratio: 13:1.
IR (film): 3483 (w), 3368 (w), 2980 (m), 2959 (m), 2855 (w), 1692
(s), 1605 (w), 1458 (m), 1450 (w), 1391 (m), 1367 (s), 1323 (m),
1263 (s), 1188 (s), 1034 (s), 953 (m), 880 (m), 841 (m), 810 (m),
729 (m), 679 (m), 665 cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 1.34 [s, 9 H, (CH3)3C], 1.93 (s, 3
H, CH3), 3.59 (d, J = 22.3 Hz, 2 H, CH2P), 3.78 (d, J = 11.2 Hz, 6
H, CH3O).
13C NMR (75 MHz, CDCl3): d = 8.6 (CH3), 27.5 (CH3), 35.0 (d,
J = 132.5 Hz, CH2P), 52.9 (d, J = 6.4 Hz, CH3O), 81.7 [C(CH3)3],
154.2 (C=N), 190.4 (d, J = 6.9 Hz, C=O).
31P NMR (121.5 MHz, CDCl3): d = 22.0.
HRMS (ESI): m/z calcd for C10H20NO5P + Na: 288.0971; found:
288.0971.
HRMS (ESI): m/z calcd for C13H12NF3O2 + Na: 294.0712; found:
Anal. Calcd for C10H20NO5P: C, 45.28; H, 7.60; N, 5.28. Found: C,
44.87; H, 7.72; N, 5.50.
294.0712.
6,6,6-Trifluoro-5-phenylhex-4-ene-2,3-dione 2-(O-Ethyloxime)
(3b)
Prepared from ketophosphonate 2b and 2,2,2-trifluoroacetophe-
none according to the general procedure. The subsequent chromato-
graphic purification (pentane–Et2O, 10:1) gave 0.420 g (1.47 mmol,
74%) of 3b as a yellow oil.
3-(2,6-Dimethylpiperidin-1-yl)imino-2-oxobutylphosphonic
Acid Dimethyl Ester (2e)
Prepared from 1e according to the general procedure. The subse-
quent chromatographic purification (TBME–acetone, 5:1) gave
0.860 g (2.83 mmol, 56%) of 2e as a pale yellow solid; mp 46.5–
47 °C.
IR (film): 3356 (w), 3088 (w), 3063 (w), 3038 (w), 2984 (w), 2899
(w), 1686 (m), 1643 (w), 1603 (w), 1497 (w), 1464 (w), 1445 (w),
1385 (w), 1369 (w), 1360 (w), 1308 (m), 1267 (s), 1176 (m), 1130
IR (KBr): 3466 (m), 2959 (m), 2932 (m), 2853 (w), 2829 (w), 1701
(s), 1663 (w), 1628 (w), 1553 (w), 1456 (m), 1373 (w), 1366 (w),
Synthesis 2008, No. 21, 3397–3406 © Thieme Stuttgart · New York

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Acid-Induced 1,5-Cyclization Reactions of 5-Aryl-1-azapenta-1,4-dien-3-ones
3403
(m), 1090 (m), 1069 (m), 1043 (m), 970 (w), 943 (w), 912 (w), 874
(w), 824 (w), 775 (w), 754 (w), 737 (w), 698 (m), 642 (m), 615 (w),
588 cm–1 (w).
1H NMR (400 MHz, CDCl3): d = 1.35 (t, J = 7.1 Hz, 3 H, CH3),
1.83 (s, 3 H, CH3), 4.33 (q, J = 7.1 Hz, 2 H, CH2O), 7.24–7.26 (m,
2 Harom), 7.36–7.38 (m, 3 Harom), 7.45 (q, J = 1.4 Hz, 1 H, =CH).
13C NMR (100 MHz, CDCl3): d = 8.5 (CH3), 14.6 (CH3), 71.7
(CH2O), 122.8 (q, J = 274.6 Hz, CF3), 128.1 (q, J = 5.3 Hz, =CH),
128.2 (CHarom), 128.9 (CHarom), 129.1 (CHarom), 131.6 (Cipso), 139.6
(q, J = 30.5 Hz, =C), 156.0 (C=N), 187.6 (C=O).
19F NMR (282 MHz, CDCl3): d (E-isomer) = –67.5; d (Z-isomer) =
–60.0; E/Z ratio: 13.7:1.
HRMS (ESI): m/z calcd for C16H18F3NO2 + Na: 336.1182; found:
336.1190.
Anal. Calcd for C16H18F3NO2: C, 61.33; H, 5.79; N, 4.47. Found: C,
61.71; H, 5.89; N, 4.40.
5-(2,4-Dimethylphenyl)-6,6,6-trifluorohex-4-ene-2,3-dione
2-(O-Methyloxime) (3e)
Prepared from ketophosphonate 2a and trifluoromethyl 2,4-dimeth-
ylphenyl ketone according to the general procedure. The subsequent
chromatographic purification (pentane–Et2O, 5:1) gave 0.154 g
(0.52 mmol, 86%) of 3e as a yellow oil.
IR (film): 3358 (w), 2980 (m), 2943 (m), 2880 (w), 2826 (w), 1686
(s), 1641 (w), 1605 (m), 1504 (m), 1460 (m), 1445 (m), 1336 (m),
1306 (s), 1265 (s), 1234 (w), 1173 (s), 1132 (s), 1069 (m), 1047 (s),
972 (m), 920 (m), 908 (m), 878 (m), 818 (m), 781 (w), 756 (w), 735
(w),723 (w), 710 (w), 665 (w), 652 (w), 642 cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 1.83 (s, 3 H, CH3), 2.18 (s, 3 H,
CH3), 2.33 (s, 3 H, CH3), 4.12 (s, 3 H, CH3O), 7.03 (d, J = 7.6 Hz,
1 Harom) 7.06 (s, 1 Harom), 7.14 (d, J = 7.6 Hz, 1 Harom), 7.65 (q,
J = 1.4 Hz, 1 H, =CH).
HRMS (ESI): m/z calcd for C14H14F3NO2 + Na: 308.0869; found:
308.0869.
Anal. Calcd for C14H14F3NO2: C, 58.95; H, 4.95; N, 4.91. Found: C,
58.86; H, 4.83; N, 4.72.
6,6,6-Trifluoro-5-phenylhex-4-ene-2,3-dione 2-(O-Benzyl-
oxime) (3c)
Prepared from ketophosphonate 2c and 2,2,2-trifluoroacetophenone
according to the general procedure. The subsequent chromato-
graphic purification (pentane–Et2O, 2:1) gave 0.150 g (0.43 mmol,
86%) of 3c as a yellow oil.
13C NMR (100 MHz, CDCl3): d = 8.5 (CH3), 19.5 (CH3), 21.3
(CH3), 63.6 (CH3O), 122.9 (q, J = 274.9 Hz, CF3), 126.25 (CHarom),
128.3 (CHarom), 130.8 (CHarom), 134.90 (q, J = 3.2 Hz, =CH), 136.8,
138.7, 140.2 (q, J = 30.5 Hz, =C), 156.2 (C=N), 186.2 (C=O).
IR (film): 3356 (w), 3090 (w), 3065 (w), 3034 (w), 2939 (w), 2883
(w), 1686 (s), 1605 (w), 1497 (w), 1454 (w), 1445 (w), 1366 (m),
1306 (s), 1267 (s), 1175 (s), 1130 (s), 1076 (w), 1015 (s), 972 (m),
914 (w), 872 (w), 827 (w), 777 (w), 756 (w), 735 (w), 698 (m), 644
(w), 604 cm–1 (w).
19F NMR (282 MHz, CDCl3): d (E-isomer) = –68.5; d (Z-isomer) =
–61.9; E/Z ratio: 5.5:1.
HRMS (ESI): m/z calcd for C15H16F3NO2 + Na: 370.1025; found:
370.1035.
1H NMR (400 MHz, CDCl3): d = 1.84 (s, 3 H, CH3), 5.28 (s, 2 H,
CH2), 7.16–7.18 (m, 2 Harom), 7.31–7.40 (m, 8 Harom), 7.40 (q,
J = 1.4 Hz, 1 H, =CH).
Anal. Calcd for C15H16F3NO2: C, 60.20; H, 5.39; N, 4.68. Found: C,
60.22; H, 5.43; N, 4.56.
5-Benzo[b]thiophen-2-yl-6,6,6-trifluorohex-4-ene-2,3-dione
2-(O-Methyloxime) (3f)
Prepared from ketophosphonate 2a and 2-benzothienyl trifluoro-
methyl ketone according to the general procedure. The subsequent
chromatographic purification (pentane–Et2O, 2:1) gave 0.141 g
(0.43 mmol, 86%) of 3f as a yellow oil.
13C NMR (100 MHz, CDCl3): d = 8.8 (CH3), 78.1 (CH2O), 122.8 (q,
J = 274.8 Hz, CF3), 128.2(CHarom), 128.5 (CHarom), 128.6 (CHarom),
128.7 (CHarom), 128.9 (CHarom), 129.1 (CHarom), 131.4 (Cipso), 136.4
(Cipso), 155.5 (C=N), 187.6 (C=O).
19F NMR (282 MHz, CDCl3): d (E-isomer) = –67.6; d (Z-isomer) =
–59.9; E/Z ratio: 23:1.
IR (film): 3344 (w), 3061 (w), 2984 (w), 2943 (m), 2905 (w), 2826
(w), 1684 (s), 1638 (w), 1630 (w), 1603 (m), 1560 (w), 1543 (w),
1524 (w), 1510 (w), 1460 (m), 1439 (m), 1369 (m), 1310 (m), 1267
(s), 1177 (s), 1157 (m), 1134 (s), 1107 (m), 1047 (s), 920 (m), 864
(m), 837 (m), 818 (m), 748 (m), 727 (m), 708 (m), 665 cm–1 (m).
HRMS (ESI): m/z calcd for C19H16F3NO2 + Na: 370.1025; found:
370.1035.
Anal. Calcd for C19H16F3NO2: C, 65.70; H, 4.64; N, 4.03. Found: C,
65.73; H, 4.57; N, 4.35
1H NMR (400 MHz, CDCl3): d = 1.89 (s, 3 H, CH3), 4.07 (s, 3 H,
6,6,6-Trifluoro-5-phenylhex-4-ene-2,3-dione 2-(O-tert-Butyl-
oxime) (3d)
Prepared from ketophosphonate 2d and 2,2,2-trifluoroacetophe-
none according to the general procedure. The subsequent chromato-
graphic purification (pentane–Et2O, 2:1) gave 0.280 g (0.89 mmol,
56%) of 3d as a yellow oil.
CH3O), 7.34–7.40 (m, 4 Harom), 7.76–7.80 (m, 2 Harom and =CH).
13C NMR (100 MHz, CDCl3): d = 8.7 (CH3), 63.7 (OCH3), 122.0
(CHarom), 122.3 (q, J = 275.2 Hz, CF3), 124.3 (CHarom), 124.6
(CHarom), 125.5 (CHarom), 127.1 (CHarom), 130.7 (q, J = 5.2 Hz,
=CH), 131.3, 131.9 (q, J = 31.9 Hz, =C), 132.4, 139.0, 140.7, 156.0
(C=N), 188.1 (C=O).
IR (film): 3350 (w), 3088 (w), 3063 (w), 3028 (w), 2982 (m), 2930
(m), 2858 (w), 1686 (s), 1603 (m), 1499 (w), 1447 (w), 1391 (w),
1367 (m), 1310 (m), 1269 (s), 1178 (s), 1132 (s), 1076 (m), 1036
(m), 1016 (s), 970 (m), 953 (m), 895 (w), 870 (w), 824 (w), 787 (w),
770 (w), 743 (w), 721 (w), 698 (m), 665 (w), 638 cm–1 (m).
19F NMR (282 MHz, CDCl3): d (E-isomer) = –67.1; d (Z-isomer) =
–60.3; E/Z ratio 6:1.
HRMS (ESI): m/z calcd for C15H12F3NO2S + Na: 350.0433; found:
350.0440.
1H NMR (400 MHz, CDCl3): d = 1.37 [s, 9 H, (CH3)3C], 1.82 (s, 3
H, CH3), 7.24–7.27 (m, 1 Harom), 7.33–7.41 (m, 4 Harom), 7.44 (q,
J = 1.45 Hz, 1 H, =CH).
Anal. Calcd for C15H12F3NO2S: C, 55.04; H, 3.70; N, 4.28. Found:
C, 55.20; H, 3.71; N, 4.24.
2-(2,6-Dimethylpiperidin-1-yl)imino-6,6,6-trifluoro-5-phenyl-
hex-4-en-3-one (3g)
Prepared from ketophosphonate 2e and 2,2,2-trifluoroacetophenone
according to the general procedure. The subsequent chromato-
graphic purification (pentane–TBME, 2:1) gave 0.900 g (2.56
mmol, 97%) of 3g as a red oil.
13C NMR (100 MHz, CDCl3): d = 8.4 (CH3), 27.6 (CH3), 81.9
[C(CH3)3], 128.2 (CHarom), 128.7 (q, J = 5.9 Hz, =CH), 128.9
(CHarom), 129.1 (CHarom), 131.7 133.5, 155.4 (C=N), 194.6 (C=O).
19F NMR (282 MHz, CDCl3): d (E-isomer) = –67.5; d (Z-isomer) =
–60.3; E/Z ratio: 10.5:1.
Synthesis 2008, No. 21, 3397–3406 © Thieme Stuttgart · New York

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N. Ghavtadze et al.
PAPER
IR (film): 3368 (w), 3088 (w), 3061 (w), 3026 (w), 2966 (m), 2936
(m), 2862 (m), 1693 (m), 1659 (m), 1639 (m), 1549 (m), 1499 (w),
1450 (m), 1371 (m), 1290 (s), 1271 (m), 1258 (m), 1171 (s), 1128
(s), 1080 (m), 1059 (m), 970 (m), 941 (w), 872 (w), 841 (w), 799
(w), 773 (w), 756 (w), 698 (m), 667 (w), 636 cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 0.95 (d, J = 6.6 Hz, 6 H, CH3),
1.51–1.56 (m, 3 H), 1.76–1.79 (m, 3 H), 2.00 (s, 3 H, CH3), 3.36 (m,
2 H, CH), 7.27–7.45 (m, 5 Harom), 7.57 (q, J = 1.2 Hz, 1 H, =CH).
13C NMR (100 MHz, CDCl3): d = 13.3 (CH3), 20.6 (CH3), 31.8
(CH2), 31.9 (CH2), 58.1 (CH), 123.1 (q, J = 274.6 Hz, CF3),127.9
(CHarom), 128.2 (CHarom), 128.5 (CHarom), 128.8 (CHarom), 128.9
(CHarom), 129.8 (d, J = 26.9 Hz, =C), 130.8 (=CH), 131.9 (Cipso),
154.0 (C=N), 190.3 (C=O).
19F NMR (282 MHz, CDCl3): d = –67.1 (E-isomer); d (Z-isomer) =
–60.0; E/Z ratio: 12:1.
1384 (s), 1369 (s), 1315 (m), 1288 (m), 1248 (s), 1229 (s), 1209 (s),
1178 (s), 1130 (s), 1092 (m), 1049 (s), 951 (m), 924 (m), 910 (m),
883 (m), 802 (w), 766 (m), 758 (m), 717 (m), 656 cm–1 (m).
1H NMR (500 MHz, CDCl3): d = 1.22 (t, J = 7.1 Hz, 3 H, CH3CH2),
1.76 (s, 3 H, CH3), 2.11 (s, 3 H, CH3COO), 4.09 (q, J = 7.1 Hz, 2 H,
CH2), 7.25–7.26 (m, 1 Harom), 7.30–7.33 (m, 1 Harom), 7.37–7.40 (m,
2 Harom), 7.49–7.51 (m, 1 Harom).
13C NMR (125 MHz, CDCl3): d = 11.1 (CH3), 14.6 (CH3CH2), 21.3
(CH3COO), 69.8 (CH2), 88.0 (C–O), 121.4 (CHarom), 121.8 (q,
J = 270.6 Hz, CF3), 124.5 (CHarom), 127.9 (CHarom), 129.8 (CHarom),
136.5, 137.4 (q, J = 5.2 Hz, CH), 142.9, 151.3 (C=N), 170.0 (COO).
19F NMR (282 MHz, CDCl3): d = –65.6.
HRMS (ESI): m/z calcd for C16H16F3NO3 + Na: 350.0980; found:
350.0968.
Anal. Calcd for C16H16F3NO3: C, 58.71; H, 4.93; N, 4.28. Found: C,
58.82; H, 4.49; N, 4.13.
HRMS (ESI): m/z calcd for C19H23F3N2O + H: 353.1835; found:
353.1833.
Anal. Calcd for C19H23F3N2O: C, 64.76; H, 6.58; N, 7.95. Found: C,
65.01; H, 6.68; N, 8.01.
1-[1-(Acetoxyimino)ethyl]-3-(trifluoromethyl)-1H-inden-1-yl
Acetate (4c)
Prepared from azadienone 3c according to the general procedure.
The subsequent chromatographic purification (TBME) gave 0.070
g (0.21 mmol, 49%) of 4c as a brown oil. Compound 3d also gave
0.069 g (0.20 mmol, 37%) of 4c.
Cyclization of Azadienones Using Trifluoromethanesulfonic
Acid; General Procedure
A solution of trifluoromethanesulfonic acid (0.4 mL) in anhyd
CH2Cl2 (20 mL) was cooled to –10 °C. A solution of the appropriate
1-azapenta-1,4-dienone 3 (0.4 mmol) in anhyd CH2Cl2 (2 mL) was
added dropwise with stirring. After complete addition, the stirring
was continued for 1 h. Then, the mixture was treated with Ac2O (1
mL) and stirred at 0 °C for 1 h. Sat. aq NaHCO3 (10 mL) was added
carefully to neutralize the acidic reaction mixture. The organic layer
was washed with sat. aq NaHCO3 (10 mL) until the aqueous layer
became neutral. Then the organic layer was washed with H2O (20
mL), dried (MgSO4) and the solvent was evaporated. Products 4 and
5 were purified by column chromatography.
IR (film): 3119 (w), 3074 (w), 3020 (w), 2962 (w), 2937 (w), 1776
(s), 1757 (s), 1639 (m), 1587 (w), 1562 (w), 1474 (m), 1460 (m),
1431 (m), 1385 (m), 1369 (s), 1315 (m), 1290 (m), 1251 (s), 1229
(s), 1190 (s), 1144 (s), 1132 (s), 1090 (m), 1045 (m), 1030 (m), 1009
(m), 978 (m), 951 (w), 924 (m), 887 (w), 881 (m), 802 (w), 770 (m),
758 (m), 717 (w), 654 cm–1 (w).
1H NMR (500 MHz, CDCl3): d = 1.85 (s, 3 H, CH3), 2.16 (s, 3 H,
CH3COO), 2.19 (s, 3 H, CH3COO), 7.27–7.28 (m, 1 Harom), 7.34–
7.46 (m, 3 Harom), 7.56–7.59 (m, 1 H, CH).
13C NMR (125 MHz, CDCl3): d = 12.6 (CH3), 19.7 (CH3COO),
21.2 (CH3COO), 87.4 (C–O), 117.8 (q, J = 281.9 Hz, CF3), 121.7
(CHarom), 124.9 (CHarom), 128.5 (CHarom), 130.5 (CHarom), 135.8 (q,
J = 5.2 Hz, CH), 136.5, 138.0, 141.8, 160.7 (C=N), 168.7 (COO),
170.4 (COO).
1-[1-(Methoxyimino)ethyl]-3-(trifluoromethyl)-1H-inden-1-yl
Acetate (4a)
Prepared from azadienone 3a according to the general procedure.
The subsequent chromatographic purification (TBME) gave 0.170
g (0.54 mmol, 75%) of 4a as a red oil.
19F NMR (282 MHz, CDCl3): d = –65.7.
IR (film): 3121 (w), 3071 (w), 2963 (s), 2928 (m), 2907 (m), 2856
(w), 1755 (s), 1637 (w), 1568 (w), 1460 (m), 1447 (m), 1414 (m),
1385 (m), 1369 (m), 1313 (w), 1261 (s), 1228 (s), 1199 (m), 1091
(s), 1020 (s), 951 (w), 866 (s), 800 (s), 761 (m), 700 (m), 663 cm–1
(m).
HRMS (ESI): m/z calcd for C16H14F3NO4 + Na: 364.0767; found:
364.0773.
Anal. Calcd for C16H14F3NO4: C, 56.31; H, 4.13; N, 4.10. Found: C,
56.73; H, 4.44; N, 3.73.
1H NMR (500 MHz, CDCl3): d = 1.77 (s, 3 H, CH3), 2.11 (s, 3 H,
CH3COO), 3.85 (s, 3 H, CH3), 7.23 (q, J = 1.8 Hz, 1 H, CH), 7.38–
7.39 (m, 3 Harom), 7.49–7.50 (m, 1 Harom).
13C NMR (125 MHz, CDCl3): d = 11.1 (CH3), 21.3 (CH3COO),
62.1 (CH3), 87.8 (C-O), 121.4 (CHarom), 121.7 (q, J = 270.6 Hz,
CF3), 124.4 (CHarom), 127.9 (CHarom), 129.9 (CHarom), 136.5, 137.1
(q, J = 5.1 Hz, CH), 142.8, 151.9 (C=N), 170.0 (COO).
1-[1-(Methoxyimino)ethyl]-3-(trifluoromethyl)-1H-inden-1-yl
Benzoate (4d)
Prepared from azadienone 3a according to the general procedure,
but using benzoic anhydride for quenching the reaction. The subse-
quent chromatographic purification (pentane–Et2O, 10:1) gave
0.057 g (0.15 mmol, 38%) 4d as a colorless oil.
IR (film): 3121 (w), 3071 (w), 3036 (w), 2957 (m), 2939 (m), 2905
(m), 2853 (w), 2822 (w), 1732 (s), 1638 (w), 1601 (m), 1585 (w),
1458 (m), 1452 (m), 1385 (m), 1369 (m), 1315 (m), 1269 (s), 1250
(s), 1209 (m), 1178 (s), 1148 (s), 1130 (s), 1105 (s), 1094 (s), 1069
(s), 1051 (s), 1026 (s), 1011 (m), 1001 (m), 939 (m), 887 (s), 840
(w), 804 (w), 768 (m), 758 (m), 710 (s), 687 (w), 665 (w), 656 (w),
613 cm–1 (w).
1H NMR (300 MHz, CDCl3): d = 1.91 (s, 3 H, CH3), 3.82 (s, 3 H,
CH3O), 7.33 (q, J = 2.0 Hz, 1 H, CH), 7.35–7.46 (m, 5 Harom), 7.54–
7.62 (m, 4 Harom).
19F NMR (282 MHz, CDCl3): d = –65.6.
MS (EI): m/z = 313 ([M]+), 271, 240, 198, 172, 151, 129, 71.
Anal. Calcd for C15H14F3NO3: C, 57.51; H, 4.50; N, 4.47. Found: C,
58.04; H, 4.44; N, 4.00.
1-[1-(Ethoxyimino)ethyl]-3-(trifluoromethyl)-1H-inden-1-yl
Acetate (4b)
Prepared from azadienone 3b according to the general procedure.
The subsequent chromatographic purification (TBME) gave 0.119
g (0.36 mmol, 80%) of 4b as a brown oil.
13C NMR (75 MHz, CDCl3): d = 11.2 (CH3), 62.1 (CH3O), 88.1 (C–
O), 121.5 (CHarom), 121.8 (q, J = 270.6 Hz, CF3), 124.3 (CHarom),
127.9 (CHarom), 128.4 (CHarom), 129.6 (Cq), 129.8 (CHarom), 129.9
IR (film): 3122 (w), 3074 (w), 2980 (m), 2936 (m), 2889 (w), 1753
(s), 1638 (w), 1605 (w), 1582 (w), 1471 (w), 1460 (m), 1443 (m),
Synthesis 2008, No. 21, 3397–3406 © Thieme Stuttgart · New York

PAPER
Acid-Induced 1,5-Cyclization Reactions of 5-Aryl-1-azapenta-1,4-dien-3-ones
3405
(CHarom), 133.4 (CHarom), 136.2 (Cq), 136.6 (Cq), 137.4 (q, J = 5.3
Hz, CH), 142.8 (Cq), 152.4 (C=N), 165.4 (COO).
19F NMR (282 MHz, CDCl3): d = –65.5.
13C NMR (125 MHz, CDCl3): d = 15.5 (CH3), 20.7 (CH2), 21.0
(CH2), 21.4 (CH2), 24.3 (CH3), 33.5 (CH3), 59.8 (CHN), 59.9
(CHN), 89.3 (C–O), 121.3 (CHarom), 121.8 (q, J = 270.7 Hz, CF3),
124.6 (CHarom), 127.8 (CHarom), 129.8 (CHarom), 136.8, 136.9 (q,
J = 34.7 Hz, CCF3), 136.9 (q, J = 34.7 Hz, CCF3), 137.9 (q, J = 5.0
Hz, CH), 143.3, 167.6 (C=N), 170.1 (COO).
HRMS (ESI): m/z calcd for C20H16F3NO3 + Na: 398.0974; found:
398.0980.
19F NMR (282 MHz, CDCl3): d = –65.6.
Anal. Calcd for C20H16F3NO3: C, 64.00; H, 4.30; N, 3.73. Found: C,
63.95; H, 4.20; N, 3.60.
HRMS (ESI): m/z calcd for C21H25N2F3O2 + H: 395.1941; found:
395.1935.
1-[1-(Methoxyimino)ethyl]-4,6-dimethyl-3-(trifluoromethyl)-
1H-inden-1-yl Acetate (4e)
1-[1-(Methoxyimino)ethyl]-3-(trifluoromethyl)-1H-benzo[b]cy-
clopenta[d]thiophen-1-yl Acetate (5)
Prepared from azadienone 3f according to the general procedure.
The subsequent chromatographic purification (pentane–Et2O, 8:1)
gave 0.152 g (0.41 mmol, 40%) of 5 as a yellowish solid; mp 134–
135 °C.
Prepared from azadienone 3e according to the general procedure.
The subsequent chromatographic purification (pentane–Et2O, 10:1)
gave 0.055 g (0.16 mmol, 39%) of 4e as a colorless solid; mp 96–
97 °C.
IR (KBr): 3145 (w), 2995 (w), 2972 (m), 2943 (m), 2907 (w), 2878
(w), 2820 (w), 1749 (s), 1626 (m), 1614 (m), 1578 (w), 1504 (m),
1472 (m), 1447 (m), 1369 (s), 1315 (m), 1302 (s), 1242 (s), 1223 (s),
1186 (s), 1161 (s), 1126 (s), 1065 (s), 1043 (s), 1018 (s), 957 (s), 912
(m), 895 (m), 880 (s), 853 (s), 820 (m), 802 (m), 766 (w), 754 (w),
735 (m), 689 (m), 660 (m), 638 (w), 604 (w), 586 (w), 555 (m), 527
cm–1 (w).
1H NMR (400 MHz, CDCl3): d = 1.69 (s, 3 H, CH3), 2.11 (s, 3 H,
CH3), 2.34 (s, 3 H, CH3), 2.42 (s, 3 H, CH3), 3.87 (s, 3 H, CH3), 6.99
(s, 1 Harom), 7.13 (s, 1 Harom), 7.29 (q, J = 1.6 Hz, 1 H, CH).
13C NMR (100 MHz, CDCl3): d = 11.0 (CH3), 19.6 (q, J = 4.7 Hz,
CH3), 21.2 (CH3), 21.3 (CH3), 62.1 (CH3), 86.6 (C–O), 122.1 (q,
J = 281.9 Hz, CF3), 122.9 (CHarom), 131.9 (Cq), 132.2 (Cq), 133.7
(CHarom), 137.06 (CHarom), 137.4 (q, J = 6.5 Hz, CH), 138.2 (Cq),
144.2 (Cq), 151.8 (C=N), 170.1 (COO).
IR (KBr): 3084 (m), 3061 (w), 3007 (w), 2968 (m), 2937 (m), 2897
(w), 2818 (w), 1755 (s), 1630 (m), 1609 (m), 1501 (m), 1470 (m),
1439 (m), 1427 (s), 1389 (m), 1367 (s), 1314 (m), 1283 (s), 1252 (s),
1217 (s), 1188 (s), 1161 (s), 1128 (s), 1045 (s), 1016 (s), 964 (s), 935
(m), 904 (m), 866 (s), 824 (m), 762 (s), 735 (s), 719 (m), 677 (m),
617 (w), 606 (w), 596 (w), 567 (w), 541 cm–1 (w).
1H NMR (400 MHz, CDCl3): d = 1.74 (s, 3 H, CH3), 2.14 (s, 3 H,
CH3), 3.88 (s, 3 H, CH3), 7.32–7.36 (m, 1 Harom), 7.37 (q, 1 H,
J = 2.2 Hz, CH), 7.40–7.44 (m, 1 Harom), 7.87 (m, 2 Harom).
13C NMR (100 MHz, CDCl3): d = 11.3 (CH3), 21.2 (CH3), 62.2
(CH3), 86.0 (C–O), 122.1 (q, J = 270.1 Hz, CF3), 122.1 (CHarom),
123.8 (CHarom), 124.6 (CHarom), 125.3 (CHarom), 133.0 (Cq), 133.9
(q, J = 37.1 Hz, CCF3), 139.4 (q, J = 5.4 Hz, CH), 141.5 (Cq), 144.5
(Cq), 150.2 (C=N), 169.7 (COO).
19F NMR (282 MHz, CDCl3): d = –62.8.
19F NMR (282 MHz, CDCl3): d = –65.5.
HRMS (ESI): m/z calcd for C17H18F3NO3 + Na: 364.1131; found:
364.1127.
HRMS (ESI): m/z calcd for C17H14F3NO3S + Na: 392.0539; found:
392.0544.
X-ray Crystal Structure Analysis of 4e12–19
Anal. Calcd for C17H14F3NO3S: C, 55.28; H, 3.82; N, 3.79. Found:
C, 55.08; H, 3.84; N, 3.68.
Molecular formula C17H18F3NO3, M = 341.32, colorless crystal,
0.45 × 0.30 × 0.10 mm, triclinic, space group: P1 (No. 2),
a = 8.2751(2), b = 8.6975(3), c = 12.8651(3) Å, a = 80.345(1),
b = 88.458(1), g = 68.512(3)°, V = 848.77(4) Å3, rcalcd = 1.336 g
cm–3, m = 0.113 mm–1, empirical absorption correction (0.951 £ T £
0.989), Z = 2, l = 0.71073 Å, T = 223(2) K, w and j scans, 8775 re-
flections collected ( h, k, l), [(sin q)/l] = 0.67 Å–1, 4013 inde-
pendent (Rint = 0.052) and 2197 observed reflections [I 2 s(I)],
222 refined parameters, R1 = 0.056, wR2 = 0.173, max (min) resid-
ual electron density 0.30 (–0.25) e Å–3, hydrogen atoms calculated
and refined as riding atoms.
X-ray Crystal Structure Analysis of 512–19
Molecular formula C17H14F3NO3S, M = 369.35, light yellow crystal
0.40 × 0.30 × 0.30
c = 16.6900(4) Å, b = 100.327(1)°, V = 1660.03(5) Å3,
calc = 1.478 g cm–3, m = 0.243 mm–1, empirical absorption correc-
mm,
a = 8.0706(1),
b = 12.5270(2),
r
tion (0.909 £ T £ 0.930), Z = 4, monoclinic, space group P21/c (No.
14), l = 0.71073 Å, T = 223(2) K, w and j scans, 12846 reflections
collected ( h, k, l), [(sin q)/l] = 0.67 Å–1, 4033 independent
(Rint = 0.036) and 3276 observed reflections [I 2 s(I)], 229 refined
parameters, R = 0.042, wR2 = 0.115, max (min) residual electron
density 0.43 (–0.36) e Å–3, hydrogen atoms calculated and refined
as riding atoms.
1-[1-(2,6-Dimethylpiperidin-1-ylimino)ethyl]-3-(trifluorometh-
yl)-1H-inden-1-yl Acetate (4f)
Prepared from azadienone 3g according to the general procedure.
The subsequent chromatographic purification (TBME) gave 0.263
g (0.67 mmol, 89%) 4f as a red solid; mp 71–73 °C.
Acknowledgment
IR (KBr): 3123 (w), 3074 (w), 2963 (m), 2932 (s), 2860 (w), 2824
(w), 2588 (w), 1749 (s), 1728 (w), 1639 (w), 1603 (w), 1443 (w),
1383 (m), 1369 (m), 1313 (m), 1288 (m), 1236 (s), 1209 (m), 1177
(m), 1148 (m), 1132 (s), 1088 (m), 1055 (m), 1028 (m), 955 (w),
934 (w), 897 (w), 866 (w), 804 (w), 758 (m), 716 (w), 665 (m), 648
cm–1 (m).
We thank Dr. Jürgen Dieker for preliminary experiments in this
field. This work was supported by the NRW Graduate School of
Chemistry Münster, the Deutsche Forschungsgemeinschaft (DFG,
Bad Godesberg), and the Fonds der Chemischen Industrie (Frank-
furt).
1H NMR (500 MHz, CDCl3): d = 0.67 (d, J = 6.2 Hz, 3 H, CH3),
0.78 (d, J = 6.2 Hz, 3 H, CH3), 1.32–1.37 (m, 3 H, CH2), 1.62–1.65
(m, 3 H, CH2), 1.86 (s, 3 H, CH3), 2.15 (s, 3 H, CH3), 2.39 (m, 1 H,
CHN), 2.53 (m, 1 H, CHN), 7.29–7.41 (m, 4 Harom), 7.54–7.57 (m,
1 Harom).
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