Expedient Synthesis of Highly Substituted Fused Heterocoumarins

Article abstract of DOI:10.1021/ol0362461

(Matrix presented) Highly substituted fused coumarins can be prepared in two steps starting from the appropriate boronic acids and enol triflates. The synthesis of fused pyrano[2,3-d]pyrimidin-7-one (1) is a key example to demonstrate the potential of the method in the elaboration of new coumarin scaffolds.

Full text of DOI:10.1021/ol0362461

ORGANIC
LETTERS
2004
Vol. 6, No. 2
277-279
Expedient Synthesis of Highly
Substituted Fused Heterocoumarins
P. Selle`s* and U. Mueller
Research Department, Lead Finding Chemistry, SYNGENTA Crop Protection AG,
CH-4002, Basel, Switzerland
patrice.selles@syngenta.com
Received November 17, 2003
ABSTRACT
Highly substituted fused coumarins can be prepared in two steps starting from the appropriate boronic acids and enol triflates. The synthesis
of fused pyrano[2,3-d]pyrimidin-7-one (1) is a key example to demonstrate the potential of the method in the elaboration of new coumarin
scaffolds.
Over the past decades palladium-mediated cross-coupling
reactions have repeatedly proven their efficiency in the
synthesis of heterocycles.1 Recently, Hesse and Kirsch2
reported the use of the Suzuki cross-coupling reaction for
the preparation of fused coumarins. In light of our interest
in an efficient preparation of complex coumarins or hetero-
coumarins under mild conditions, their methodology was
particularly interesting for us. The well-known Pechmann
condensation3a is often used to get direct access to the
coumarin scaffold, but the harsh reaction conditions (sulfuric
acid, POCl3) are not suitable for the preparation of highly
functionalized coumarins.3b Although the biological activities
shown by coumarins4 are wide ranging, our interest focused
on the preparation of novel tricyclic derivatives of the general
formula 2 by virtue of their fungicidal activity seen in our
biological screens.5
coumarino-pyrimidines (pyrano[2,3-d]pyrimidin-7-one; 2
with X ) Y ) N).
The classical Pechmann condensation (Scheme 1) was
employed for the preparation of the coumarin 6 using â-keto
Scheme 1. Pechmann Condensationa
Herein is reported a short and efficient access to highly
functionalized fused coumarins, coumarino-pyridines (pyrano-
[2,3-b]pyridin-2-one; 2 with X ) N and Y ) C) and
(1) Undheim, Kjell. Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, Ei-ichi, Eds.; John Wiley & Sons: New York,
2002; pp 409-492.
(2) Hesse, S.; Kirsch, G. Tetrahedron Lett. 2002, 43, 1213-1215.
(3) (a) Horning, E. C. Organic Syntheses; Wiley: New York, 1955;
Collect. Vol. III, p 281. (b) For recent modifications of the Pechmann
condensation under microwave condition allows milder conditions, see:
Sugino, T.; Tanaka, K. Chem. Lett. 2001, 110-111.
(4) Murray, R.; Mendez, J.; Brown, S. The Natural Coumarins: Occur-
rence, Chemistry and Biochemistry; Wiley: New York, 1982.
(5) Whittingham, W. G. WO patent 02/28183 A1, 2002.
a Reagents and conditions: (i) POCl3, toluene, 80 °C. (ii) tert-
Butylammonium tribromide (2.2 equiv), MeOH-CH2Cl2, rt.
10.1021/ol0362461 CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/18/2003

ester 5 and 5-methyl-benzene-1,3-diol 4. Bromination of 6
with tert-butylammonium tribromide afforded 7, which could
be further substituted via cross-coupling reactions. The
absence of convergence, as well as the lack of selectivity in
the introduction of halogen6 in the coumarin scaffold, forced
us to find a more convenient approach. To render the
synthesis more convergent, we retrosynthetically proposed
that coumarin 2 could be prepared via deprotection of 8
followed by an in situ lactonization reaction.7 Preparation
of compound 8 could then be envisaged by cross-coupling
between boronic acid 9 and the enol triflate 108 (Scheme
2).
commercially available boronic acid 9a. Deprotection of the
methoxy group with a slight excess of BBr3 furnished the
fused coumarin 12 in 62% yield.
2-Hydroxycoumarins 14 (n ) 0 or 1) were both obtained
in high yields by reacting the corresponding enol triflate of
cyclopentanone or cyclohexanone (10a or 10b) and the
commercially available boronic acid 9b. The two-step
synthesis was not dependent on the nature of the triflate used
for the preparation of our fused coumarins (Scheme 4).
Scheme 4 a
Scheme 2. Retrosynthetic Analysis of Coumarins 1
a Reagents and conditions: (i) 10a or 10b; Pd(TPP)4 (5 mol %)
in toluene/ethanol/Na2CO3 (2 M in water) 3/1/1, reflux 80 min.
(ii) BBr3 (1 M in CH2Cl2; 1.4 equiv), CH2Cl2, rt.
The highly functionalized coumarin 16 was obtained under
the same conditions in moderate yield by coupling the
boronic acid 9c10a with enol triflate 10b (Scheme 5). The
Scheme 5 a
The proposed C-C bond disconnection and the appropri-
ate choice of the o-methoxyboronic acid9 9 provides a very
convergent route to coumarin 2 and more generally to
substituted coumarin scaffolds in only two steps.
We could first exemplify our approach by the straight-
forward synthesis of the 2-fluorocoumarin 12 (Scheme 3).
a Reagents and conditions: (i) 10b, Pd(TPP)4 (5 mol %) in
toluene/ethanol/Na2CO3 (2 M in water) 3/1/1, reflux 3 h. (ii) BBr3
(1 M in CH2Cl2; 2.1 equiv), CH2Cl2, rt.
Scheme 3 a
Suzuki cross-coupling reaction afforded the coumarin precur-
sor 15 in 51% yield, as well as 46% of unreacted 9c.
Treatment with BBr3 finally provided coumarin 16 with the
protected nitrogen and the free phenol group.
We rationalized the moderate yield of the lactonization
step by comparing the previous synthesis of coumarins 12
and 14. In the case of 16, the presence of the o-pivaloyl
amide is certainly responsible for the lower yield (50% of
recovered material is bis demethylated but not cyclized). The
bulky pivaloyl group can generate steric interactions with
the cyclohexane moiety disturbing the intermediate required
a Reagents and conditions: (i) Pd(TPP)4 (5 mol %) in toluene/
ethanol/Na2CO3 (2 M in water) 3/1/1, reflux 80 min. (ii) BBr3
(1 M in CH2Cl2; 1.4 equiv), CH2Cl2, rt. TPP ) triphenylphosphine.
The ester 11 was prepared by a Suzuki cross-coupling
reaction between the enol triflate 10b8 (n ) 1) and the
(6) The coumarin 7 can be prepared with an excess of tert-butylammo-
nium tribromide, but the use of only 1 equiv of the brominating agent
provides mixture of regioisomers in positions 2 and 4.
(7) Dubuffet, T.; Loutz, A.; Lavielle, G. Synth. Commun. 1999, 29, 929-
936.
(8) Synthesis and chemical stability of cyclic enol triflate described by
Crisp, G. T.; Meyer, A. G. J. Org. Chem. 1992, 57, 6972-6975.
(9) Based on SciFinder, around 200 o-methoxy boronic acids are
registered and more than 20 commercially available.
(10) (a) The pivaloyl-protected 4-chloro-2,5-dimethoxy-phenylamine is
treated with n-BuLi in THF followed by addidtion of B(OMe)3. After
aqueous workup and chromatography, the boronic acid 9c is obtained in
50% yield. (b) The 2-chloro-4,6-dimethoxy-pyrimidine was treated in the
same condition as in (a) (nBuLi, B(OMe)3) and afforded 9d in 75% yield
(see Supporting Information) (c) The 2-fluoro-pyridine was treated in the
same condition as in (a) (nBuLi, B(OMe)3) and afforded 9e in 80% yield.
278
Org. Lett., Vol. 6, No. 2, 2004

for the cyclization. Nevertheless, with sufficient quantity of
16 in our hands, synthesis of new libraries of fused coumarins
was undertaken.
Hence, δ-lactonization resulting from the nucleophilic attack
of the carboxylate at the pyridine C2 position was expected
to be straightforward (Figure 1).
The functional group tolerance of our approach was further
exemplified by the preparation of fused aza-coumarins such
as pyrano[2,3-d]pyrimidin-7-one11a (1). Related pyrimidine
derivatives can be prepared from barbituric acid11a,b but
usually are limited by the choice of substituents. The
preparation of the coumarino-pyrimidine 1 is shown in
Scheme 6. The boronic acid 9d is readily accessible from
the commercially available pyrimidine.10b
Figure 1. Lactonization by fluorine displacement at C2.
Scheme 6 a
The cross-coupling reaction of boronic acid 9e followed
by saponification of the ester 18e provided the seco-acid 19e
and not the expected aza coumarin 20e. During the saponi-
fication, the fluorine atom is readily displaced by water. This
limitation was overcome by treating 19e with oxalyl chloride
in dichloromethane, which afforded the coumarin 20e (R )
H) in 90% yield. Attempts to realize the one-step cyclization
from the carboxylate failed by other methods such as
saponification with potassium trimethylsilanolate.16 Interest-
ingly, the alkyne-substituted compound 19f was readily
transformed into the chlorovinyl derivative 20f under the
same conditions, providing a very useful scaffold for further
coupling reactions. In summary, we report a short and
a Reagents and conditions: (i) 10b, Pd(TPP)4 (5 mol %) in
toluene/ethanol/Na2CO3 (2 M in water) 3/1/1, reflux 2 h. (ii) BBr3
(1 M in CH2Cl2; 5 equiv), CH2Cl2, reflux.
Following the Suzuki cross-coupling reaction between 9d
and 10b, the lactonization of 17 failed using the conditions
that were successful for the synthesis of 12 and 14.12
However, refluxing 17 overnight in the presence of 5 equiv
of BBr3, gave methoxy-diazacoumarin 1. Unexpectedly, even
by forcing the conditions (BBr3 10 equiv, refluxing 48 h in
CH2Cl2) the second methoxy group was not cleaved.
Compound 1 was submitted to cross-coupling reactions
to replace the chlorine atom successfully with CN, aromatics,
and acetylene derivatives. This family of compounds showed
weak but interesting broad spectrum in vivo fungicidal
activities in our screens.13
In addition, fused coumarino-pyridines14 or pyrano-
[2,3-b]pyridin-2-one were prepared following a slightly
different process starting from the boronic acid 9e.15a,10c
Nucleophilic displacement of a fluorine ortho to the
nitrogen in the pyridine ring is precedented in the literature.15b
Scheme 7 a
a Reagents and conditions: (i) 10b, Pd(TPP)4 (5 mol %) in
toluene/ethanol/Na2CO3 (2 M in water) 3/1/1, reflux 2 h. (ii) LiOH,
THF/H2O, rt. (iii) (COCl)2 in CH2Cl2, 0 °C to rt.
efficient synthetic access to highly functionnalized coumarins
combining two reliable methodologies. This method has been
successfully applied for the two-step preparation of various
substituted novel aromatic or heteroaromatic coumarins.
(11) (a) Habib, N. S.; Kappe, T. Monatsh. Chem. 1984, 115, 1459-
1466. (b) Harris, R. L. N.; Huppatz, J. L.; Teitei, T. Aus. J. Chem. 1979,
32, 669-679 (coumarino-pyridine described only as unwanted compound).
(12) After 24 h at room temperature, only 5% of the corresponding
Acknowledgment. We are grateful to the Analytic
Service of Syngenta and especially Dr. T. Winkler for useful
structure elucidation.
1
coumarin could be detected by NMR H.
(13) Compound 1 was submitted to Sonogashira coupling reaction (2
mmol of 1 in 8 mL of dimethylformamide was treated with 4 mmol of
ethynyltrimethylsilane in the presence of 5% Pd(TPP)2Cl2 and 10% CuI at
room temperature for 1 h. The crude compound was deprotected with tert-
butylammonium fluoride in THF to afford 1 mmol of ethynyl analogue of
1 (2-ethynyl-4-methoxy-5,6,7,8-tetrahydro-10-oxa-1,3-diaza-phenanthren-
9-one). Leaf spots and rust such as Septoria, Pyricularia oryzae, Pyreno-
phora teres, and Puccina recondita were 90% controlled in vivo by this
compound at 200 ppm.
Supporting Information Available: Experimental pro-
cedures and analytical data for the preparation of 1 and 12.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Trecourt, F.; Marsais, F.; Gungor, T.; Queguiner, G. J. Chem. Soc.,
Perkin Trans. 1 1990, 9, 2409-2415.
(15) (a) Sutherland, A.; Gallagher, T. J. Org. Chem. 2003, 68, 3352-
3355 for the preparation of the boronic acid. (b) Cherng, Y. Tetrahedron
2002, 58, 4931-4935.
OL0362461
(16) Laganis, E. D.; Chenard, B. L. Tetrahedron Lett. 1984, 25, 5831-
5834.
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