Microwave-accelerated coupling-isomerization-enamine addition-aldol condensation sequences to 1-acetyl-2-amino-cyclohexa-1,3-dienes

Article abstract of DOI:10.1055/s-2006-947352

The microwave-accelerated consecutive reaction of electron deficient (hetero)aryl bromides 1, (hetero)aryl propargyl alcohols 2, and enamino carbonyl compounds 6 or 8 furnishes 1-acetyl-2-amino-cyclohexa-1,3-dienes 7 or 6-N,N-dimethyl carbamoyl-cyclohexen

Full text of DOI:10.1055/s-2006-947352

LETTER
1841
Microwave-Accelerated Coupling–Isomerization–Enamine Addition–Aldol
Condensation Sequences to 1-Acetyl-2-amino-cyclohexa-1,3-dienes
C
oupling–Isomeriz
a
ation–Enam
n
ine Additio
a
n–Aldol Condens
G
a
tion Sequences . Schramm (née Dediu), Thomas J. J. Müller*
Organisch-Chemisches Institut der Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
Fax +49(6221)546579; E-mail: Thomas.J.J.Mueller@oci.uni-heidelberg.de
Received 26 April 2006
dienes 7 are formed in low yields under conductive
Abstract: The microwave-accelerated consecutive reaction of elec-
heating.
tron deficient (hetero)aryl bromides 1, (hetero)aryl propargyl alco-
hols 2, and enamino carbonyl compounds 6 or 8 furnishes 1-acetyl-
2-amino-cyclohexa-1,3-dienes 7 or 6-N,N-dimethyl carbamoyl-cy-
clohexenones 9, respectively, in good yields in the sense of a one-
pot coupling–isomerization–enamine addition–aldol condensation
sequence.
Since Sonogashira alkynylations can be considerably
accelerated by dielectric heating, i.e., under microwave
irradiation,12a,12e,13 we decided to optimize either the for-
mation of the dihydropyridine 4 or the cyclohexadiene 7
upon performing both steps of the sequence in a micro-
wave cavity. Interestingly, the optimization of the reac-
tion of p-bromo benzonitrile (1a), 1-phenylpropargyl
alcohol (2a), and enaminone 6a exclusively gave rise to
the formation of the cyclohexadiene 7a (Scheme 2,
Table 1).
Key words: alkynes, condensations, cross-couplings, cyclizations,
microwave reactions
One-pot multicomponent processes address very funda-
mental principles of synthetic efficiency and reaction de-
sign, and therefore have recently gained a considerable
and steadily increasing academic, economic, and ecologi-
cal interest.1,2 They are diversity-oriented syntheses3 and
can be often developed into combinatorial and solid-phase
strategies2d,4 promising manifold opportunities for gener-
ating novel lead structures of pharmaceuticals, catalysts,
and even novel molecule based materials. As part of our
program designed to develop new multicomponent meth-
odologies initiated by transition-metal-catalyzed C–C
bond formation, we have developed a coupling–isomer-
ization reaction (CIR),5 which can be considered as a So-
nogashira coupling6 of electron-deficient (hetero)aryl
halides and (hetero)arylpropargyl alcohols or N-tosyl
amines as a mild and efficient route to chalcones5 or en-
imines,7 respectively. In the past years this new chalcone
synthesis has been applied as an entry to novel three- and
four-component syntheses of various heterocycles5,8–11 in
the sense of consecutive one-pot processes. Here, we
communicate an unexpected outcome of the coupling–
isomerization–enamine addition–cyclocondensation se-
quence under microwave irradiation,12 in particular, in the
second step that leads to the formation of cyclohexadienes
or cyclohexanones.
OH
Ar1 Br
+
Ph
2% (Ph3P)2PdCl2
1% CuI
Et3N or Et2HN, ∆
O
Ar1
Ph
R1
NH2
O
NH
O
then:
(3)
then:
(6)
R2
OEt
AcOH, ∆
under N2
AcOH, ∆
under N2
O
Ar1
Ar1
Ar1
N
EtO2C
EtO2C
R2
or
R1NH
Ph
N
H
Ph
Ph
7 (15–20%)
4 (37–45%)
5 (26–50%)
Scheme 1 CI–enamine addition–cyclocondensation sequences
under conductive heating
Recently, we have established a one-pot three-component
reaction of electron-deficient (hetero)aryl halides 1, 1-
phenylpropargyl alcohol (2a), and b-amino crotonate (3)
furnishing in the sense of an unsymmetrical Hantzsch syn-
thesis dihydropyridines 4 and pyridines 5 (Scheme 1).11a
However, if enamino carbonyl compounds 6, arising from
the condensation of primary amines and b-dicarbonyl
compounds are applied, 1-acetyl-2-amino-cyclohexa-1,3-
The optimization study under dielectric heating reveals
that not only an excess of the enaminone 6a is favorable
(entries 2, 5, and 6) but also that acetic acid has to be
present in the second step (entry 4). Therefore, the forma-
tion of the cyclohexadiene by a cyclocondensation of the
intermediate chalcone with enaminone can be interpreted
as a sequence of a Diels–Alder reaction with inverse
electron demand7,11a followed by an acid-catalyzed aldol
condensation. These findings now pave the way to a
synthetic exploration of this unusual outcome of the
enaminone addition under dielectric heating.
SYNLETT 2006, No. 12, pp 1841–1846
0
1
.0
8
.2
0
0
6
Advanced online publication: 24.07.2006
DOI: 10.1055/s-2006-947352; Art ID: G13606ST
© Georg Thieme Verlag Stuttgart · New York

1842
O. G. Schramm, T. J. J. Müller
LETTER
Ar2
2% (Ph3P)2PdCl2, 1% CuI
THF, Et3N, MW (150 °C)
15 min
NC
Br
+
2a
Ar1 Br
+
Ar1
O
1a
R
then:
O
HN
2% (Ph3P)2PdCl2, 1% CuI
THF, Et3N, MW (150 °C)
15 min
OH
Ar2
NH R
(6)
3 equiv AcOH
MW (150 °C), 10 min
H
N
7 (30–74%)
then:
Scheme 3 One-pot three-component synthesis of 1-acetyl-2-amino-
cyclohexa-1,3-dienes 7 by dielectric heating
O
HN
(6a)
The structures of the 1-acetyl-2-amino-cyclohexa-1,3-
dienes 7 were unambiguously supported by 1H NMR, 13C
NMR and DEPT, COSY, NOESY, HETCOR and HMBC
NMR experiments, IR, mass spectrometry and/or com-
bustion analyses. Most characteristically for the 1-acetyl
cyclohexadienes 7 the carbonyl resonances are found in
the 13C NMR spectra between d = 192.4 and 195.8 ppm.
In the IR spectra the dominant carbonyl valence vibrations
are found between 1628 and 1634 cm–1. Furthermore, the
structure of the CI–cyclocondensation products 7 was un-
ambiguously corroborated by an X-ray crystal structure
analysis of compound 7a (Figure 1).16
AcOH, MW (150 °C), t
Ph
NC
NH
O
HN
7a
Scheme 2 Optimization of the formation of 1-acetyl-2-amino-
cyclohexa-1,3-diene (7a) by dielectric heating
Table 1 Optimization of the CI–Enamine Addition–Cycloconden-
sation Sequence of 1a, 2a, and Enaminone 6a under Microwave
Heating at 150 °Ca
Entry
Equiv of 6a Acetic acid
Reaction time Yield of 7a
(mL)
(min)
(%)b
40
52
40
0
1
2
3
4
5
6
1.1
2
0.5
0.5
2
20
20
2
20
2
0
20
3
0.75
0.75
20
60
68
3
10
a Reaction conditions: (hetero)aryl halide 1a (1.0 equiv), propargyl
alcohol 2a (1.05 equiv), Pd(PPh3)2Cl2 (0.02 equiv), CuI (0.01 equiv),
Et3N (0.5 mL) , THF (1.5 mL), heating in a sealed vessel at 150 °C in
a Smith Synthesizer single mode microwave cavity for 15 min, then
after adding enaminone 6a and AcOH heating in a sealed vessel at
150 °C in the microwave cavity.
Figure 1 Molecular structure of 7a in the crystal
In accordance with the CIR the acceptor substituents in
the halide 1 and the (hetero)aryl substituents in the prop-
argyl alcohol 2 can be varied in the expected range. As a
consequence of their electron richness aliphatic substitu-
ents on the nitrogen atom of the enaminones 6 are better
suited in the cyclocondensation step than aniline deriva-
tives (entries 7, 8).
b Yields refer to isolated yields of compound 7a after flash chroma-
tography on silica gel to be ≥ 95% pure as determined by NMR
spectroscopy.
Therefore, after the reaction of electron-deficient (hete-
ro)aryl halides 1 with 1-(hetero)aryl propargyl alcohols 2
in the presence of catalytic amounts of Pd(PPh3)2Cl2 and
CuI in THF in a microwave cavity at 150 °C for 15 min-
utes, the subsequent addition of enaminones 6 and acetic
acid followed; heating in a microwave cavity at 150 °C for
10 minutes gave rise to the formation of the 1-acetyl-2-
aminocyclohexa-1,3-dienes 7 in moderate to good yields
(Scheme 3, Table 2).14,15
However, upon applying b-amino crotonamide 8a as
enamine compound not the 2-amino cyclohexadienes 7
were isolated but 6-N,N-dimethylcarbamoyl cyclohex-
enones 9, i.e. the hydrolysis product, in moderate to good
yields (Scheme 4, Table 3).15,17
The structures of the 6-N,N-dimethylcarbamoyl-cyclo-
hexenones 9 were unambiguously supported by 1H NMR,
13C NMR and DEPT, COSY, NOESY, HETCOR and
HMBC NMR experiments, IR, mass spectrometry and/or
combustion analyses. Interestingly, in the NMR spectra
Synlett 2006, No. 12, 1841–1846 © Thieme Stuttgart · New York

LETTER
Coupling–Isomerization–Enamine Addition–Aldol Condensation Sequences
1843
2% (Ph3P)2PdCl2, 1% CuI
THF, Et3N, MW (150 °C)
15 min
Ph
11.5–12.0, 11.8–12.3 Hz) between d = 3.93 and 4.09 ppm.
Furthermore, the enone methine protons are detected at
d = 6.29–6.59 with characteristic allylic coupling con-
stants (J = 2.0 Hz). Additionally, in the 13C NMR spectra
of 9 the diagnostic keto carbonyl resonances appear
between d = 194.2 ppm and d = 195.5 ppm, whereas the
amide carbonyl nuclei are found between d = 168.3 ppm
and d = 169.5 ppm. Finally, also in the IR spectra the
presence of two carbonyl groups is strongly supported by
the characteristic intense appearances of enone carbonyl
valence vibrations at 1640 cm–1 and of the amide carbonyl
vibration at 1608–1620 cm–1. Furthermore, an X-ray
crystal structure analysis of 9d16 (Figure 2) clearly shows
that the substituents at the chiral centers are arranged in a
pseudo-equatorial orientation. Therefore, the relative
configuration is trans.
Ar1
O
2a
1
+
nBu
then:
O
HN
O
(8a)
Me2N
NMe2
3 equiv AcOH
MW (150 °C), 10 min
9 (48–70%)
Scheme 4 One-pot three-component synthesis of 6-N,N-dimethyl-
carbamoyl cyclohexenones 9 by dielectric heating
only a single set of signals is detected indicating that only
one diastereomer (as a pair of enantiomers) is formed.
Most characteristically, the methine resonances at a-posi-
tion of the amide appear as doublets (J = 11.8–12.3 Hz) at
d = 4.08–4.35 ppm and the b-methine resonances are
found as doublets of doublets of doublets (J = 4.5–6.0,
Table 2 CI–Enamine Addition–Cyclocondensation Synthesis of 1-Acetyl-2-amino-cyclohexa-1,3-dienes 7a
Entry
Ar1–Br 1
Propargyl alcohol 2
Enaminone 6
6a:
1-Acetyl-2-amino cyclohexadiene 7 (yield, %)b
Ph
NC
1
1a: Ar1 = 4-NCC6H4
2a: Ar2 = Ph
NH
NH
O
O
O
HN
HN
HN
O
HN
7a (68)
S
2
1a
2b: Ar2 = 3-thienyl
6a
NC
NH
7b (64)
OMe
3
1a
2c: Ar2 = p-MeOC6H4 6a
NC
NH
7c (68)
Ph
F3C
4
5
1b: Ar1 = 4-F3CC6H4
2a
2a
6a
6a
NH
O
HN
7d (47)
Ph
N
1c: Ar1 = 2-pyridyl
NH
O
HN
7e (70)
Synlett 2006, No. 12, 1841–1846 © Thieme Stuttgart · New York

1844
O. G. Schramm, T. J. J. Müller
LETTER
Table 2 CI–Enamine Addition–Cyclocondensation Synthesis of 1-Acetyl-2-amino-cyclohexa-1,3-dienes 7a (continued)
Entry
6
Ar1–Br 1
Propargyl alcohol 2
Enaminone 6
1-Acetyl-2-amino cyclohexadiene 7 (yield, %)b
Ph
N
1d: Ar1 = 2-pyrimidyl
2a
6a
N
NH
O
HN
7f (74)
Ph
6b:
Ph
NC
7
8
9
1a
1a
1a
2a
2a
2a
O
HN
O
O
O
HN Ph
Ph
7h (0)
6c:
OMe
NC
O
HN
HN
HN
Ph
OMe
7g (30)
6d:
nBu
NC
O
HN nBu
7h (54)
Ph
N
10
1c
2a
6d
O
HN nBu
7i (52)
a Reaction conditions: (hetero)aryl halide 1 (1.0 equiv), propargyl alcohol 2 (1.05 equiv), Pd(PPh3)2Cl2 (0.02 equiv), CuI (0.01 equiv), Et3N
(0.5 mL), THF (1.5 mL), heating in a sealed vessel at 150 °C in a Smith Synthesizer single mode microwave cavity for 15 min, then after adding
enaminone 6 and AcOH (3 equiv) heating in a sealed vessel at 150 °C in the microwave cavity for 10 min.
b Yields refer to isolated yields of compound 7 after flash chromatography on silica gel to be ≥ 95% pure as determined by NMR spectroscopy.
ro)aryl halide 1 and the propargyl alcohol 2 furnishes the
enone 10 that reacts with the enamino carbonyl com-
pounds 6 or 8 in the sense of [4+2] cycloaddition11a giving
rise to the formation of the dihydropyran 11. In presence
of protons the dihydropyran 11 opens to give an iminium
carbonyl compound 12, which in turn is a suitable inter-
mediate for an intramolecular iminium aldol condensation
furnishing the 2-amino-cyclohexa-1,3-diene 7. In case of
dimethylamino carbamoyl substitution the enamino func-
tionality is prone to hydrolysis and cyclohexenones 9 are
isolated instead.
In conclusion, upon microwave irradiation not only the
rate of the CIR is considerably enhanced but also an aldol-
type condensation in the second step is favored over the
dihydropyridine formation. Therefore, we have developed
a novel microwave-accelerated CI–enamine addition–
aldol condensation sequence that furnishes 1-acetyl-2-
amino-cyclohexa-1,3-dienes, if enaminones are applied,
whereas 6-N,N-dimethyl carbamoyl cyclohexenones are
Figure 2 Molecular structure of 9d in the crystal
Mechanistically, these novel CI–enamine addition–cyclo-
condensation sequences rationalize as follows
(Scheme 5). The microwave accelerated CIR of the (hete-
Synlett 2006, No. 12, 1841–1846 © Thieme Stuttgart · New York

LETTER
Coupling–Isomerization–Enamine Addition–Aldol Condensation Sequences
1845
Ar2
Table 3 CI–Enamine Addition–Cyclocondensation Sequence of
Ar2
(Hetero)aryl halides 1, 1-Phenyl Propargyl Alcohol 2a, and b-Amino
Crotonamide 8a to 6-N,N-Dimethyl Carbamoyl-cyclohexenones 9a
[Pd, Cu]
Et3N, MW
Ar1
O
Ar1
O
or
+
1
2
then:
6 or 8
AcOH
MW
Entry
Ar1–Br 1
6-N,N-Dimethyl carbamoyl-
cyclohexenones 9 (yield, %)b
O
HN
R
R1
NMe2
9
7
Ph
solvolysis, if
1 = NMe2
NC
1c
1a
R
CIR
O
O
– H2O
NMe2
Ar2
9a (66)
Ar2
O
Ph
[4+2]
6 or 8
O
Ar1
O
O
H+
Ar1
O
Ar1
Ar2
F3C
2c
1b
1c
N+
R
HN
R
R1
12
H
O
O
R1
11
NMe2
Ph
10
9b (70)
Scheme 5 Mechanistic rationale of the one-pot three-component
synthesis of 1-acetyl-2-amino-cyclohexa-1,3-dienes 7 and 6-N,N-di-
methyl carbamoyl-cyclohexenones 9 by dielectric heating
3d
N
O
O
formed if b-amino crotonamide is the chosen enamine
component. In both cases new reactive functionalities are
generated that could be the starting point for further se-
quential processes. Studies addressing the scope of these
novel sequences and related sequential transformations to
enhance the molecular diversity are currently underway.
NMe2
9c (68)
Ph
N
N
4c
1d
O
O
NMe2
Acknowledgment
9d (48)
Financial support of the Deutsche Forschungsgemeinschaft, the
Fonds der Chemischen Industrie and the Dr.-Otto-Röhm Gedächt-
nisstiftung is gratefully acknowledged. We also cordially thank Ms
Annette Loos for experimental assistance and BASF AG for the
generous donation of chemicals.
a Reaction conditions: (hetero)aryl halide 1 (1.0 equiv), propargyl
alcohol 2a (1.05 equiv), Pd(PPh3)2Cl2 (0.02 equiv), CuI (0.01 equiv),
Et3N (0.5 mL), THF (1.5 mL), heating in a sealed vessel at 150 °C in
a Smith Synthesizer single mode microwave cavity for 15 min, then
after adding b-amino crotonamide (8a) and of AcOH (3 equiv) heat-
ing in a sealed vessel at 150 °C in the microwave cavity for 10 min.
b Yields refer to isolated yields of compound 9 after flash
chromatography on silica gel to be ≥ 95% pure as determined by
NMR spectroscopy.
References and Notes
(1) For a recent monography, see for example: Multicomponent
Reactions; Zhu, J.; Bienaymé, H., Eds.; Wiley-VCH:
Weinheim, 2005.
(2) For reviews, see for example: (a) Bienaymé, H.; Hulme, C.;
Oddon, G.; Schmitt, P. Chem. Eur. J. 2000, 6, 3321.
(b) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39,
3168. (c) Ugi, I.; Dömling, A.; Werner, B. J. Heterocycl.
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Endeavour 1994, 18, 115. (g) Posner, G. H. Chem. Rev.
1986, 86, 831.
(3) For reviews on diversity-oriented syntheses, see for
example: (a) Schreiber, S. L.; Burke, M. D. Angew. Chem.
Int. Ed. 2004, 43, 46. (b) Burke, M. D.; Berger, E. M.;
Schreiber, S. L. Science 2003, 302, 613. (c) Arya, P.; Chou,
D. T. H.; Baek, M. G. Angew. Chem. Int. Ed. 2001, 40, 339.
(d) Cox, B.; Denyer, J. C.; Binnie, A.; Donnelly, M. C.;
Evans, B.; Green, D. V. S.; Lewis, J. A.; Mander, T. H.;
Merritt, A. T.; Valler, M. J.; Watson, S. P. Progr. Med.
Chem. 2000, 37, 83. (e) Schreiber, S. L. Science 2000, 287,
1964.
(4) Kobayashi, S. Chem. Soc. Rev. 1999, 28, 1.
(5) Müller, T. J. J.; Ansorge, M.; Aktah, D. Angew. Chem. Int.
Ed. 2000, 39, 1253.
(6) For lead reviews on Sonogashira couplings, see for
example: (a) Takahashi, S.; Kuroyama, Y.; Sonogashira, K.;
Hagihara, N. Synthesis 1980, 627. (b) Sonogashira, K. In
Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.;
Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998, 203.
(c) Sonogashira, K. J. Organomet. Chem. 2002, 653, 46.
(d) Negishi, E.-I.; Anastasia, L. Chem. Rev. 2003, 103, 1979.
(7) Dediu, O. G.; Yehia, N. A. M.; Müller, T. J. J. Z.
Naturforsch., B: Chem. Sci. 2004, 59, 443.
(8) Müller, T. J. J.; Braun, R.; Ansorge, M. Org. Lett. 2000, 2,
1967.
(9) (a) Braun, R. U.; Müller, T. J. J. Tetrahedron 2004, 60,
9463. (b) Braun, R. U.; Zeitler, K.; Müller, T. J. J. Org. Lett.
2000, 2, 4181.
Synlett 2006, No. 12, 1841–1846 © Thieme Stuttgart · New York

1846
O. G. Schramm, T. J. J. Müller
LETTER
(10) (a) Braun, R. U.; Müller, T. J. J. Synthesis 2004, 2391.
(b) Braun, R. U.; Zeitler, K.; Müller, T. J. J. Org. Lett. 2001,
3, 3297.
(11) (a) Dediu, O. G.; Yehia, N. A. M.; Oeser, T.; Polborn, K.;
Müller, T. J. J. Eur. J. Org. Chem. 2005, 1834. (b) Yehia,
N. A. M.; Polborn, K.; Müller, T. J. J. Tetrahedron Lett.
2002, 43, 6907.
(12) For recent reviews and monographs on microwave-
accelerated syntheses, see for example: (a) Kappe, C. O.
Angew. Chem. Int. Ed. 2004, 43, 6250. (b) Nüchter, M.;
Ondruschka, B.; Bonrath, W.; Gum, A. Green Chem. 2004,
6, 128. (c) Nüchter, M.; Müller, U.; Ondruschka, B.; Tied,
A.; Lautenschläger, W. Chem. Eng. Technol. 2003, 26,
1207. (d) de la Hoz, A.; D’Waz-Ortis, A.; Moreno, A.;
Langa, F. Eur. J. Org. Chem. 2000, 3659. (e) Xu, Y.; Guo,
Q.-X. Heterocycles 2004, 63, 903. (f) Microwaves in
Organic Synthesis; Loupy, A., Ed.; Wiley-VCH: Weinheim,
2002. (g) Hayes, B. L. Microwave Synthesis: Chemistry at
the Speed of Light; CEM Publishing: Matthews, NC, 2002.
(h) Microwave-Assisted Organic Synthesis; Lidström, P.;
Tierney, J. P., Eds.; Blackwell: Oxford, 2004. (i) Kappe, C.
O.; Stadler, A. Microwaves in Organic and Medicinal
Chemistry; Wiley-VCH: Weinheim, 2005.
MHz): d = 26.6 (CH2), 26.9 (CH2), 38.6 (CH3), 34.8 (CH2),
38.2 (CH), 42.4 (CH2), 97.7 (CH) 108.9 (Cquat.), 110.9
(Cquat.), 111.5 (Cquat.), 115.7 (CH), 118.2 (Cquat.), 118.5 (CH),
118.9 (CH), 121.0 (CH), 123.7 (CH), 125.5 (CH), 127.0
(Cquat.), 128.3 (CH), 128.5 (CH), 128.8 (CH), 132.0 (CH),
136.4 (Cquat.), 138.6 (Cquat.), 145.2 (Cquat.), 146.9 (Cquat.),
151.1 (Cquat.), 156.1 (Cquat.), 192.8 (Cquat.). MS (EI, 70 eV):
m/z (%) = 457 (14) [M+], 414 (12) [M+ – CH3CO], 327 (44)
[M+ – C9H8N+], 144 (4) [C10H10N+], 130 (100) [C9H8N+].
Anal. Calcd for C31H27N3O (457.6): C, 81.40; H, 5.91; N,
9.19. Found: C, 81.02; H, 6.05; N, 9.09.
(15) All compounds have been fully characterized
spectroscopically and by correct elemental analysis or
HRMS, respectively.
(16) Crystallographic data (excluding structure factors) for the
structures reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication nos. CCDC-605608 (7a), and CCDC-605609
(9d). Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK [Fax: +44 (1223)336-033; email: deposit@ccdc.cam.
ac.uk].
(17) Typical Procedure (9a, Entry 1).
(13) For microwave-accelerated Sonogashira coupling in
homogenous media, see for example: (a) Petricci, E.; Radi,
M.; Corelli, F.; Botta, M. Tetrahedron Lett. 2003, 44, 9181.
(b) Kaval, N.; Bisztray, K.; Dehaen, W.; Kappe, C. O.; Van
der Eycken, E. Mol. Diversity 2003, 7, 125. (c) Erdelyi, M.;
Gogoll, A. J. Org. Chem. 2001, 66, 4165.
A magnetically stirred solution of 182 mg (1.00 mmol) of
1a, 139 mg (1.05 mmol) of 2a, 20 mg (0.02 mmol) of
Pd(PPh3)Cl2, and 2 mg (0.01 mmol) of CuI in a degassed
mixture of 0.5 mL of Et3N and 1.5 mL of THF in a sealed
microwave vial under nitrogen was heated by microwave
irradiation to 150 °C for 15 min. After cooling to r.t. 576 mg
(3.00 mmol) of enaminone 8a and 0.75 mL of AcOH were
added and the reaction mixture was heated by microwave
irradiation to 150 °C for another 10 min. After work-up and
chromatography on silica gel (toluene–acetone, 3:1) and
recrystallization from acetone 227 mg (66%) of 9a were
obtained as light yellow crystals. Mp. 164 °C. IR (KBr):
2227, 1644, 1608 cm–1.1H NMR (300 MHz, DMSO-d6):
d = 2.79 (s, 3 H), 2.96 (s, 3 H), 2.99–3.01 (m, 2 H), 3.97
(ddd, J = 6.0, 12.0, 12.0 Hz, 1 H), 4.08 (d, J = 12.0 Hz, 1 H),
6.45 (s, 1 H), 7.31–7.50 (m, 7 H), 7.53 (d, J = 8.16 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 35.3 (CH2), 35.5 (CH3),
37.4 (CH3), 43.6 (CH), 54.7 (CH), 110.6 (Cquat.), 118.5
(Cquat.), 124.2 (CH), 125.5 (CH), 128.1 (CH), 128.7 (CH),
130.4 (CH), 132.7 (CH), 137.3 (Cquat.), 147.6 (Cquat.), 158.1
(Cquat.), 168.3 (Cquat.), 194.8 (Cquat.). MS (EI, 70 eV): m/z
(%) = 344 (30) [M+], 300(7) [M+ – C2H6N+], 272 (100) [M+
– C2H6NCO], 244 (6) [M+ – C2H6NCO – CO], 72 (23)
[C2H6NCO+]. Anal. Calcd for C22H20N2O2 (344.4): C, 76.72;
H, 5.85; N, 8.13. Found: C, 76.96; H, 5.89; N, 8.15.
(14) Typical Procedure (7a, Entry 1).
A magnetically stirred solution of 182 mg (1.00 mmol) of
1a, 139 mg (1.05 mmol) of 2a, 20 mg (0.02 mmol) of
Pd(PPh3)Cl2, and 2 mg (0.01 mmol) of CuI in a degassed
mixture of 0.5 mL of Et3N and 1.5 mL of THF in a sealed
microwave vial under nitrogen was heated by microwave
irradiation to 150 °C for 15 min. After cooling to r.t. 726 mg
(3.00 mmol) of enaminone 6a and 0.75 mL of AcOH were
added and the reaction mixture was heated by microwave
irradiation to 150 °C for another 10 min. After aqueous
work-up and chromatography on silica gel (hexane–acetone,
2:1) and recrystallization from acetone 311 mg (68%) of 7a
were obtained as yellow crystals. Mp. 227 °C. IR (KBr):
2219, 1632 cm–1.1H NMR (300 MHz, DMSO-d6): d = 1.80
(s, 3 H), 2.75–2.81 (m, 1 H), 2.94–3.12 (m, 3 H), 3.68–3.89
(m, 2 H), 4.17 (d, J = 7.0 Hz, 1 H), 6.49 (d, J = 1.9 Hz, 1 H),
7.00–7.05 (m, 3 H), 7.14 (t, J = 7.4 Hz, 1 H), 7.21–7.29 (m,
4 H), 7.32 (d, J = 8.12 Hz, 2 H), 7.36 (d, J = 8.12 Hz, 1 H),
7.62 (d, J = 8.12 Hz, 1 H), 7.69 (d, J = 8.12 Hz, 2 H), 10.92
(s, 1 H), 11.72 (t, J = 6.0 Hz, 1 H). 13C NMR (CDCl3, 75.5
Synlett 2006, No. 12, 1841–1846 © Thieme Stuttgart · New York