Pyridazine derivatives. Part 38: Efficient Heck alkenylation at position 5 of the 6-phenyl-3(2H)-pyridazinone system

Article abstract of DOI:10.1016/j.tetlet.2004.03.005

Several 6-phenyl-3(2H)-pyridazinones bearing different alkenyl groups at position 5 have been prepared in the search for novel antiplatelet agents. The target compounds were synthesised by a palladium-catalysed Heck cross-coupling reaction. Variable amounts of 4-phenyl-6-substituted-2-phthalazinones were isolated as by-products during these experiments. The crucial issues for successful Heck coupling in these systems concern the protection of position 2 of the heterocyclic ring and the use of tris(o-tolyl)phosphine as a ligand.

Full text of DOI:10.1016/j.tetlet.2004.03.005

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3459–3463
Pyridazine derivatives. Part 38: Efficient Heck alkenylation at
position 5 of the 6-phenyl-3(2H)-pyridazinone systemq
a
Alberto Coelho, Eddy Sotelo, Hector Novoa, Oswald M. Peeters, Norbert Blaton and
a
b
b
b
ꢀ
a,
*
~
Enrique Ravina
a
ꢀ
ꢀ
ꢀ
ꢀ
Departamento de Quımica Organica, Laboratorio de Quımica Farmaceutica, Facultad de Farmacia,
Universidad de Santiago de Compostela, 15782Santiago de Compostela, Spain
bKatholieke Universiteit Leuven, Laboratorium voor Analytische Chemie en Medicinale Fysicochemie,
Faculteit Farmaceutische Wetenschappen, B-3000 Leuven, Belgium
Received 17 February 2004; accepted 2 March 2004
Abstract—Several 6-phenyl-3(2H)-pyridazinones bearing different alkenyl groups at position 5 have been prepared in the search for
novel antiplatelet agents. The target compounds were synthesised by a palladium-catalysed Heck cross-coupling reaction. Variable
amounts of 4-phenyl-6-substituted-2-phthalazinones were isolated as by-products during these experiments. The crucial issues
for successful Heck coupling in these systems concern the protection of position 2 of the heterocyclic ring and the use of
tris(o-tolyl)phosphine as a ligand.
Ó 2004 Elsevier Ltd. All rights reserved.
Low molecular weight heterocycles have gained a cen-
tral role in the high throughput synthesis of libraries of
drug-like compounds.1 The tremendous variety of nat-
urally occurring heterocycles and their wide range of
biological activities continue to encourage the develop-
ment of elegant and efficient synthetic routes to these
substances.2 In this context, the significant pharmaco-
logical activities described for pyridazine derivatives in
recent decades3 have inspired researchers from academia
and industry to explore the usefulness of this hetero-
cyclic template in the search for new drugs. As a con-
sequence, the considerable efforts directed towards the
synthesis of these derivatives have allowed the devel-
opment of new promising entities that act on numerous
important targets.4
OR) and the discovery of several 5-alkylidene-6-phenyl-
3(2H)-pyridazinones III (Fig. 1, X ¼ COOR, CN,
COR), which represent a new family of potent anti-
platelet agents.7 In an effort to elucidate structure–
activity relationships for this type of derivative we
became interested in preparing the 5-alkenyl-6-phenyl-
3(2H)-pyridazinones II (Fig. 1, X ¼ COOR, COR, CN),
which can be considered as vinyl analogues of I and/or
simple derivatives of III.
All possible retrosynthetic schemes to access the target
compounds II, starting from precursors of type I,
require one C–C bond disconnection. A first approach
could involve Wittig condensation of phosphorus ylides
with the appropriate 5-formyl derivative, but this route
is limited by the synthetic accessibility of the required
heterocyclic carbaldehyde.8 The second option is to
In recent years we have been involved in developing
novel pyridazinone-based antiplatelet agents.5 For
example, we recently reported the antiplatelet activity of
compounds I6 (Fig. 1, X ¼ CHO, COR, COOR, CN,
O
O
O
H
H
H
N
N
N
N
N
N
Y
X
X
X
Keywords: Pyridazinones; Heck coupling; Phthalazinones.
q For the previous paper in this series see: Sotelo, E. Facile solution
phase combinatorial synthesis of highly substituted pyridazin-3-ones,
Mol. Diversity 2004.
I
II
III
*Corresponding author. Tel.: +34-981594628; fax: +34-981594912;
e-mail: qofara@usc.es
Figure 1.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.005

3460
A. Coelho et al. / Tetrahedron Letters 45 (2004) 3459–3463
carry out the well-established Heck reaction9 on the
readily obtained 5-bromo-6-phenyl-3(2H)-pyridazinone
1.10 Palladium-catalysed cross-coupling reactions in
heterocyclic chemistry,11 and especially in pyridazine
chemistry,12 have become widely studied in recent years
but curiously very few references describe Heck olefin-
ations on a 1,2-diazine.13
The formation of 2-substituted-3-pyridazinones 2 can be
rationalised in terms of a Michael addition between the
3(2H)-pyridazinone and the highly activated sterically
unhindered ethyl acrylate.17 Other typical Michael
acceptors such as acrylonitrile, methyl acrylate or
butenone reacted similarly. Analogous experiments
using styrene (a nonactivated olefin) led to recovery of
unreacted pyridazinone 1.The reactivity of 1 toward
Heck alkenylation (Scheme 1) is not dissimilar to that
described in previous works on palladium-catalysed
reactions of pyridazinones18 and confirms the advanta-
ges of protecting position 2 of the heterocyclic ring
before performing cross-coupling reactions.
As a continuation of our work into the development of
new and versatile palladium-assisted syntheses of phar-
macologically useful pyridazinones, we describe here the
preliminary results obtained during the study the scope
and limitations of a Heck alkenylation methodology as
a simple entry to 5-functionalised pyridazinones and
phthalazinones.
Isolation of compounds 3 under these conditions
(Scheme 1) can be explained by subsequent Heck alken-
ylation at position 5 of compounds 2 (once the tauto-
meric carbonyl group at position 3 has been blocked as a
consequence of the Michael addition). The low yields
obtained for compounds 3 (including the case where a
larger excess of acrylate (2.5–3 equiv) was used) could
suggest that the catalytic system employed is not opti-
mal for such a transformation.
Initial experiments were performed using 5-bromo-6-
phenyl-3(2H)-pyridazinone
1 with a slight excess
(1.5 equiv) of ethyl acrylate as a model reaction under
the classical Heck conditions9 (Scheme 1).14 Despite the
fact that various catalytic systems were used [e.g.,
Pd[Ph3]4, Pd(PPh3)2Cl2, Pd2(dba)3 or Pd(OAc)2 in
combination with P(Ph)3, P(2-tolyl)3, dppe, bases (Et3N,
Na2CO3, NaOAc) and solvents (acetonitrile, toluene,
DMF)], all attempts to obtain the desired 5-alkenyl-6-
phenyl-3(2H)-pyridazinones 8 from 1 failed and a vari-
able mixture of compounds 215 and 316 was always iso-
lated (Scheme 1, Table 1).
The drawback outlined above was circumvented by
blocking position 2 of compound 1 by the introduction
of a methoxymethyl (MOM) group.18 We then pro-
ceeded to study the palladium-catalysed Heck alkenyl-
ation of 4 (Scheme 2).
Treatment of 4 with ethyl acrylate (2 equiv), PPh3 as
ligand, Et3N as base and Pd(OAc)2 as the palladium
source in DMF led to the formation of debrominated
pyridazinone 5 (50%) along with a very small amount of
the desired 5-alkenyl-3-pyridazinone 7a (10%) (Scheme
2). Surprisingly, a compound that was identified as the
phthalazinone 6a (28%) was also isolated from the
reaction mixture (Scheme 2). Analogous results were
obtained on applying these conditions to different olefins
(Table 2), with compound 5 (45–50%) and phthalazi-
nones 6 isolated in yields in the range 25–30%. It is
noteworthy that during these experiments, the use of
styrene as the alkene component did not lead to the
formation of the corresponding phthalazinone.
O
O
O
H
X
X
N
N
N
N
N
N
CH2=CH-X
+
Heck Conditions
Br
Br
X
1
2
3
Scheme 1. Heck conditions: method A: Pd(OAc)2, PPh3, Et3N, DMF,
120 °C, sealed tube; method B: PdCl2(PPh3)2, Et3N, DMF, 120 °C,
sealed tube.
Table 1
Entry
X
Yield (%) of 2a Yield (%) of 3a
The structures of compounds 5, 6 and 7 were unam-
biguously established on the basis of their analytical and
spectroscopic data.20 The unexpected phthalazinones 6
were also completely characterised by NMR experi-
ments and by single crystal X-ray analysis of compound
6a (Fig. 2).21
1
2
3
4
COOEt
COOMe
CN
70
63
65
––
20
15
18
––
Ph
a Reported yield corresponds to data obtained using method A.
O
O
O
O
O
N
N
O
N
N
O
N
N
O
N
N
CH2=CH-X
Method A
+
+
X
Br
X
4
5
7a X = COOEt
7b X = COOMe
7c X = CN
6a X = COOEt
6b X = COOMe
6c X = CN
Scheme 2. Reagents and conditions: method A: Pd(OAc)2, PPh3, Et3N, DMF, 120 °C, sealed tube.19

A. Coelho et al. / Tetrahedron Letters 45 (2004) 3459–3463
3461
Table 2
Since we were unable to prepare target compounds 7 by
the procedures described above, a detailed study of this
transformation was initiated. The fact that debromi-
nated pyridazinone 5 was obtained as the main product
during Heck alkenylation of 4 suggests that migratory
insertion of the olefin to the r-heteroarylpalladium(II)
complex is not a favoured process. For this reason
experiments were aimed at finding appropriate condi-
tions to accelerate the olefin migratory insertion.
Pyridazinone 4 was used as the electrophile and the
Heck reaction was performed using different catalysts,
phosphines and solvents from the plethora of protocols
and catalytic systems described for the successful Heck
alkenylation.9 The ultimate aim was to find optimal
experimental conditions to obtain compounds 7.
Entry
Olefin
Yield (%) Yield (%) Yield (%)
of 5
of 6
of 7
1
2
3
4
CH2@CHCOOEt
CH2@CHCOOMe
CH2@CHCN
50
45
48
65
28
25
30
––
10
8
10
5
CH2@CHPh
These screening experiments revealed that the formation
of debrominated pyridazinone 5 and phthalazinone 6 is
usually associated with the presence of acetates in the
coupling cocktails (provided by the palladium acetate).
Indeed, the use of catalytic systems that did not contain
these anions [e.g., Pd2(dba)3 and Pd(Ph3)2Cl2] gave the
expected 5-alkenyl-3-pyridazinones 7 in moderate yields
(35–50%) and the formation of compounds 5 and 6 was
minimal. Although the role of acetate proved to be
critical in the coupling behaviour, another important
issue that needed to be taken into account was the
phosphine; it was observed that the nature of the phos-
phine can dramatically change the results obtained in
reactions performed in the presence of acetates. For in-
stance, replacement of triphenylphosphine by the bulky
tris(o-tolyl)phosphine [PdCl2[P(o-tolyl)3]2 or Pd(OAc)2/
P(o-tolyl)3] in cocktails generated a remarkable increase
in the yield (50–70%) of the 5-alkenyl-3-pyridazinones 7.
Our choice for the coupling experiments on 4 therefore
involved heating in DMF in the presence of 5%
PdCl2P[(o-tolyl)3]2 with 2 equiv of triethylamine. The
application of these optimised conditions22 to a variety of
olefins gave the corresponding 5-alkenyl-6-phenyl-2-
methoxymethyl-3-pyridazinones 7a–d23 in moderate to
good yields (Scheme 3, Table 3).
Figure 2. ORTEP diagram of compound 6a, obtained by single crystal
X-ray diffraction, showing the molecular conformation and numbering
scheme.
The unexpected isolation of phthalazinones 6 under
these conditions is a very interesting finding and could
open a new entry to functionalised phthalazinones
starting form 5-substituted-3-pyridazinones. The estab-
lished structures of compounds 6 (with the X group at
position 6 of the phthalazinone ring) suggest that a
highly regioselective processes could be operating during
their formation. Preliminary mechanistic proposals to
explain phthalazinone formation are based on a tandem
reaction. This process would initially involve a Heck sp2
cascade due to a second insertion of another olefin
molecule into the previously formed r-alkylpalladium
complex, which could be arylated through intramolec-
ular C–H activation (to yield palladacycle intermedi-
ates). The final steps in the proposed sequence are
reductive elimination, oxidative addition, b-elimination
and then aromatisation to yield compounds 6. The
excellent results obtained have led us to carry out new
experiments aimed at improving the yields of phthala-
zinones 6 and these are currently under way.
Table 3
Compound
X
Yield (%)
of 7
Deprotection
(HCl) Yield (%)
7a
7b
7c
7d
COOEt
COOMe
CN
73
70
40
50
75
78
77
70
Ph
O
O
O
H
N
N
AlCl3
Toluene
O
N
N
O
N
N
CH2=CH-X
Method B
Br
X
X
4
7a-d
8a-d
Scheme 3. Reagents and conditions: method B: PdCl2[P(o-tolyl)3]2, Et3N, DMF, 120 °C, sealed tube.22

3462
A. Coelho et al. / Tetrahedron Letters 45 (2004) 3459–3463
~
ꢀ
8. Sotelo, E.; Ravina, E.; Estevez, I. J. Heterocycl. Chem.
1999, 36, 985; Sotelo, E., Ph.D. Thesis; University of
Santiago de Compostela, Spain, 2000.
Cleavage of the methoxymethyl group at position 2 in 7
was successfully performed using 6 N HCl or, alterna-
tively, under mild conditions by employing aluminium
chloride24 to obtain the target 5-alkenyl-6-phenyl-3(2H)-
pyridazinones 825 (Scheme 3, Table 3).
9. Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000,
3009; Brase, S.; de Meijere, A. In Metal-Catalyzed Cross-
Coupling Reactions; Diedrich, F., Stang, P. J., Eds.; Wiley-
VCH: New York, 1998; p 99; Cabri, W.; Candiani, I. Acc.
Chem. Res. 1995, 28, 2; de Meijere, A.; Meyer, F. E.
Angew Chem. Int. Ed. Engl. 1994, 33, 2379.
ꢀ ~
10. Estevez, I.; Ravina, E.; Sotelo, E. J. Heterocyclic. Chem.
1998, 35, 1421.
11. Li, J. J.; Gribble, G. W. Palladium in Heterocyclic
Chemistry; Elsevier: Amsterdam, 2000; p 3.
12. Riedl, Z.; Maes, B. U. W.; Monsieurs, K.; Lemiere, G. L.
In summary, we have developed a straightforward pal-
ladium-catalysed route to several pharmacologically
interesting 5-alkenyl-6-phenyl-3(2H)-pyridazinones 8.
The crucial points for the successful Heck coupling in this
series concern the protection of position 2 of the hetero-
cyclic ring and the use of tris(o-tolyl)phosphine as ligand.
Further investigations into the application of the Heck
reaction as an alternative synthetic entry to substituted
phthalazinones and the study of the antiplatelet activity
of the resulting compounds are in progress.
ꢀ
F.; Matyus, P.; Hajos, G. Tetrahedron 2002, 58, 5645;
Kosmrlj, J.; Maes, B. U. W.; Lemiere, G. L. F.; Haemers,
H. Synlett 2000, 11, 1581; R’kyek, O.; Maes, B. U. W.;
Jonkers, T. H. M.; Lemiere, G. L. F.; Dommisse, R. A.
~
Tetrahedron 2001, 57, 10009; Coelho, A.; Ravina, E.;
Sotelo, E. Synlett 2002, 6062; Sotelo, E.; Coelho, A.;
~
Ravina, E. Tetrahedron Lett. 2003, 44, 4459; Bourotte, M.;
Pellegrini, N.; Schmitt, M.; Bourginon, J. J. Synlett 2003,
1482; Guerry, S.; Parrot, I.; Rival, Y.; Wermuth, C. G.
Tetrahedron Lett. 2001, 42, 2115.
Acknowledgements
Financial support from the Xunta de Galicia (Project
PGIDT 01PX20309PR) is gratefully acknowledged. We
are also grateful to Prof. Bert Maes for valuable dis-
cussions and suggestions.
13. Draper, T. L.; Bailey, Th. R. J. Org. Chem. 1995, 60, 748;
ꢀ
~
Estevez, I.; Coelho, A.; Ravina, E. Synthesis 1999, 9, 1666.
14. Representative procedure for the preparation of com-
pounds 2 and 3 (Scheme 1). A mixture of 1 (1.01 mmol),
olefin (1.5 mmol), Pd(OAc)2 (0.10 mmol) and triethyl-
amine (1.52 mmol) in DMF (10 mL) was flushed with
argon for 5 min and then deoxygenated and purged. The
mixture was stirred and heated under reflux (oil bath
120 °C) under argon until the starting material had been
consumed. The reaction mixture was cooled, filtered
through a Celite pad and the resulting solution was
concentrated to dryness under reduced pressure. The
residue was purified by column chromatography on silica
gel (AcOEt/hexane, 1:2).
References and notes
1. Orru, R. V. A.; De Greef, M. Synthesis 2003, 10, 1471;
€
Ugi, I.; Domling, A.; Werner, B. J. Heterocycl. Chem.
2000, 37, 647.
ꢀ
2. Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem.
Eur. J. 2000, 6, 3321.
15. Selected physical and spectral data for compounds 2.
Compound 2a: Yield: 70%, oil, IR (KBr): 1734; 1664;
3. Frank, H.; Heinisch, G. Pharmacologically Active Pyrid-
azines. In Progress in Medicinal Chemistry. Part 1; Ellis,
G. P., West, G. B., Eds.; Elsevier: Amsterdam, 1990; 27,
p 1; Frank, H.; Heinisch, G. Pharmacologically Active
Pyridazines. Part 2. In Progress in Medicinal Chemistry;
Ellis, G. P., Luscombe, D. K., Eds.; Elsevier: Amsterdam,
1992; 29, p 141.
4. Li, C. S.; Brideau, C.; Chan, C. C.; Savoie, C.; Claveau,
D.; Charleston, S.; Gordon, R.; Greig, G.; Gauthier, J. Y.;
Lau, K.; Riendeau, D.; Thierien, M.; Wong, E.; Prasit, P.
Bioorg. Med. Chem. Lett. 2003, 13, 597; Giovannoni, M.
P.; Vergelli, C.; Ghelardini, C.; Galeotti, N.; Bartolini, A.;
Dal Piaz, V. J. Med. Chem. 2003, 46, 1055; Costantino, L.;
Rastelli, G.; Gamberini, M. C.; Giovannoni, M. P.;
DalPiaz, V.; Vianello, P.; Barlocco, D. J. Med. Chem.
1999, 42, 1894; Matyus, P. J. Heterocycl. Chem. 1998, 35,
1075; Mylari, B. L.; Armento, S. J.; Beebe, D. A.; Conn,
1
1578 cmÀ1. H NMR (DMSO-d6 300 MHz): 7.49 (m, 2H,
aromatics), 7.44 (m, 3H, aromatics), 7.34 (s, 1H, CH), 4.46
(t, J ¼ 7:1 Hz, 2H, CH2), 4.22 (q, J ¼ 7:1 Hz, 2H, CH2),
2.83 (t, J ¼ 7:1 Hz, CH2), 1.17 (t, J ¼ 7:1 Hz, 3H, CH3).
13C NMR (DMSO-d6 300 MHz): 171.1, 158.7, 146.5,
135.1, 132.9, 130.1, 129.8, 129.5, 128.5, 61.0, 47.7, 33.1,
14.4. HRMS, m=z: calcd for C15H15BrN2O3 [Mþ]
350.0266, found 350.0270.
16. Selected physical and spectral data for compounds 3.
Compound 3a: Yield: 20%, oil, IR (KBr): 1730; 1721;
1
1658 cmÀ1. H NMR (DMSO-d6 300 MHz): 7.39 (m, 6H,
aromatics þ CH), 6.41 (d, J ¼ 15:8 Hz, 1H, CH), 4.52 (t,
J ¼ 7:1 Hz, CH2), 4.24 (q, J ¼ 7:1 Hz, 2H, CH2), 4.12 (q,
J ¼ 7:1 Hz, 2H, CH2), 2.87 (t, J ¼ 7:1 Hz, 2H, CH2), 1.29
(t, J ¼ 7:1 Hz, 3H, CH3), 1.19 (t, J ¼ 7:1 Hz, 3H, CH3).
13C NMR (DMSO-d6 300 MHz): 171.3, 165.6, 159.9,
146.2, 139.1, 138.7, 134.6, 129.3, 119.0, 126.6, 125.6,
61.5, 61.0, 47.7, 33.1, 14.5, 142. HRMS, m=z: calcd for
C20H22N2O5 [Mþ] 370.1529, found 370.1532.
ꢀ
E. L.; Coutcher, J. B.; Dina, M. S.; OaGorman, M. J.;
Linhares, M. C.; Martin, W. H.; Oates, P. J.; Tess, D. A.;
Withbroe, G. J.; Zembrowski, W. J. J. Med. Chem. 2003,
46, 2283.
17. Ismail, M. F.; Shams, N. A.; Rahman, S. E.; Fateen, A. K.
Revue Roumane de Chimie 1979, 24, 899; Sayed, A. A.;
Jahine, H.; Zaher, H. A.; Sherif, O. Indian J. Chem. 1975,
4, 1142.
5. Montero-Lastres, A.; Fraiz, N.; Cano, E.; Laguna, R.;
ꢀ
Estevez, I.; Ravina, E. Acta Pharm. Hung. 1999, 22, 1376.
6. Laguna, R.; Rodriguez-Linares, B.; Cano, E.; Estevez, I.;
~
~
ꢀ
ꢀ ~
18. Coelho, A.; Sotelo, E.; Estevez, I.; Ravina, E. Synthesis
~
Ravina, E.; Sotelo, E. Chem. Pharm. Bull. 1997, 45, 1151;
Sotelo, E.; Fraiz, N.; Yanez, M.; Terrades, V.; Laguna, R.;
~
2001, 6, 871876; Coelho, A.; Sotelo, E.; Ravina, E.
Tetrahedron 2003, 59, 2477.
~
~
Cano, E.; Ravina, E. Bioorg. Med. Chem. 2002, 10, 2873.
7. Sotelo, E.; Fraiz, N.; Yanez, M.; Brea, J. M.; Laguna, R.;
~
19. Representative procedure for the preparation of com-
pounds 5 and 6 (Scheme 2). A mixture of 4 (1.01 mmol),
olefin (2.0 mmol), Pd(OAc)2 (0.10 mmol) and triethyl-
~
Cano, E.; Ravina, E. Bioorg. Med. Chem. Lett. 2002, 10,
1575.

A. Coelho et al. / Tetrahedron Letters 45 (2004) 3459–3463
3463
amine (1.52 mmol) in DMF (10 mL) was flushed with
argon for 5 min and then deoxygenated and purged. The
mixture was stirred and heated under reflux (oil bath
120 °C) under argon until the starting material had been
consumed. The reaction mixture was cooled, filtered
through a Celite pad and the resulting solution was
concentrated to dryness under reduced pressure. The
residue was purified by column chromatography on silica
gel (AcOEt/hexane, 1:2).
CH), 7.12 (s, 1H, CH), 6.42 (d, J ¼ 15:7 Hz, 1H, CH), 5.49
(s, 2H, CH2), 4.22 (q, J ¼ 7:0 Hz, 2H, CH2), 3.50 (s, 3H,
CH3), 1.28 (t, J ¼ 7:0 Hz, 3H, CH3). 13C NMR (DMSO-d6
300 MHz): 165.5, 160.6, 146.5, 140.0, 138.9, 134.4, 129.8,
129.4, 129.0, 127.5, 126.2, 81.9, 61.5, 58.3, 14.5. Com-
pound 7b: Yield: 70%, mp 124–125 °C (dec.), iso-PrOH. IR
(KBr): 1727; 1670; 1587 cmÀ1
.
1H NMR (DMSO-d6
300 MHz): 7.39 (m, 6H, 5H, aromatics þ 1H, CH), 7.11
(s, 1H, CH), 6.42 (d, J ¼ 15:7 Hz, 1H, CH), 5.48 (s, 2H,
CH2), 3.75 (s, 3H, CH3), 3.49 (s, 3H, CH3). 13C NMR
(DMSO-d6 300 MHz): 165.9, 160.5, 146.4, 139.9, 139.1,
134.4, 129.8, 129.3, 129.0, 127.5, 125.7, 125.4, 81.9, 58.3,
52.5.
20. Selected physical and spectral data for compounds 5 and
6. Compound 5: Yield: 50%, mp 113–114 °C (dec.), iso-
PrOH. IR (KBr): 1660; 1586; 1089 cmÀ1
.
1H NMR
(DMSO-d6 300 MHz): 7.80 (m, 2H, aromatics), 7.70 (d,
J ¼ 9:7 Hz, 1H, CH), 7.45 (m, 3H, aromatics), 7.04 (d,
J ¼ 9:7 Hz, 1H, CH), 5.53 (s, 2H, CH2), 3.52 (s, 2H, CH3).
13C NMR (DMSO-d6 300 MHz): 161.3, 145.0, 135.0,
131.3, 131.4, 130.0, 129.3, 126.4, 58.2, 31.3. HRMS, m=z:
calcd for C12H12N2O2 [Mþ] 216.0899, found 216.0903.
Compound 6a: Yield: 28%, mp 189–190 °C (dec.), iso-
~
24. Sotelo, E.; Coelho, A.; Ravina, E. Tetrahedron Lett. 2001,
42, 8633.
25. Representative procedure for the cleavage of the MOM
group in compounds 7: A mixture of 7 (1.01 mmol),
MeOH (5 mL) and 6 N HCl (15 mL) was stirred and
heated under reflux (oil bath 120 °C) under argon until the
starting material had been consumed. The reaction mix-
ture was cooled and concentrated to dryness under
reduced pressure. The resulting residue was poured into
water and extracted with ethyl acetate. The organic layer
was dried (Na2SO4) and the solvent removed under
reduced pressure to give a solid, which was purified by
column chromatography (ethyl acetate/hexane 1:2) to
afford compounds 8. Selected physical and spectral data
for compounds 8. Compound 8a: Yield: 75%, mp 189–
190 °C (dec.), iso-PrOH. IR (KBr): 2851; 1720; 1669;
1
PrOH. IR (KBr): 1726; 1671; 1546, 1093 cmÀ1. H NMR
(DMSO-d6 300 MHz): 8.61 (d, J ¼ 8:2 Hz, 1H, CH), 8.42
(s, 1H, CH), 8.40 (d, J ¼ 8:2 Hz, 1H, CH), 7.58 (m, 5H,
aromatics), 5.61 (s, 2H, CH2), 4.40 (q, J ¼ 2:4 Hz, 2H,
CH2), 3.54 (s, 3H, CH3), 1.39 (t, J ¼ 2:4 Hz, 3H, CH3). 13
C
NMR (DMSO-d6 300 MHz): 165.8, 159.6, 147.5, 135.5,
135.0, 131.9, 131.7, 129.9, 129.8, 129.6, 129.2, 129.1, 128.4,
81.8, 62.3, 14.6. Anal. calcd for C19H18N2O4 requires C:
67.44; H: 5.36, N: 8.28, Found: C: 67.45; H: 5.39; N: 8.25.
21. Coelho, A.; Sotelo, E.; Novoa, H.; Peeters, M. O.; Blaton,
N.; Ravina, E. to be published.
1529 cmÀ1 1H NMR (DMSO-d6 300 MHz): 12.71 (br s,
.
~
22. Representative procedure for the preparation of com-
pounds 7 (Scheme 3). A mixture of 4 (1.01 mmol), olefin
(2.0 mmol), PdP(o-tolyl3)2Cl2 (0.10 mmol) and triethyl-
amine (1.52 mmol) in DMF (10 mL) was flushed with
argon for 5 min and then deoxygenated and purged. The
mixture was stirred and heated under reflux (oil bath
120 °C) under argon until the starting material had been
consumed. The reaction mixture was cooled, filtered
through a Celite pad and the resulting solution was
concentrated to dryness under reduced pressure. The
residue was purified by column chromatography on silica
gel (AcOEt/hexane, 1:2).
1H, NH), 7.40 (m, 6H, 5H, aromatics þ 1H, CH), 7.17 (s,
1H, CH), 6.45 (d, J ¼ 15:8 Hz, 1H, CH), 4.22 (q,
J ¼ 7:1 Hz, 2H, CH2), 1.29 (t, J ¼ 7:1 Hz, 3H, CH3). 13C
NMR (DMSO-d6 300 MHz): 165.6, 162.5, 147.5, 140.6,
139.3, 134.5, 129.9, 129.3, 129.0, 127.1, 126.3, 61.6, 14.5.
Anal. Calcd for C15H14N2O3 requires C: 66.66; H: 5.22; N:
10.36, found: C: 66.69; H: 5.24; N: 10.40. Compound 8b:
Yield: 78%, mp 203–204 °C (dec.), iso-PrOH. IR (KBr):
1724; 1663; 1585 cmÀ1 1H NMR (DMSO-d6 300 MHz):
.
12.93 (br s, 1H, NH), 7.41 (m, 6H, 5H, aromatics þ 1H,
CH), 7.17 (s, 1H, CH), 6.45 (d, J ¼ 15:9 Hz, 1H, CH), 3.77
(s, 3H, CH3). 13C NMR (DMSO-d6 300 MHz): 166.0,
162.1, 147.4, 140.5, 139.5, 134.5, 129.9, 129.3, 129.1, 129.0,
125.7, 52.5. Anal. Calcd for C14H12N2O3 requires C:
65.62; H: 4.72; N: 10.93, Found: C: 65.70; H: 4.70; N:
10.93.
23. Selected physical and spectral data for compounds 7.
Compound 7a: Yield: 70%, mp 146–147 °C (dec.), iso-
PrOH. IR (KBr): 1719; 1671; 1590 cmÀ1
.
1H NMR
(DMSO-d6 300 MHz): 7.37 (m, 6H, 5H, aromatics þ 1H,