Simple synthesis of versatile coumarin scaffolds

Article abstract of DOI:10.1080/00397910600638937

We describe an approach using ring-closing metathesis (RCM) to synthesize versatile coumarin derivatives that present appropriate substitutions both at the aromatic and at the α,β-unsaturated lactone ring. The obtained compounds can be used as molecular scaffolds suitable for further diversifications through a combinatorial approach. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600638937

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Simple Synthesis of Versatile Coumarin
Scaffolds
Laura Polito a , Massimiliano Cravini a , Laura Poletti a & Luigi Lay a
a Department of Organic and Industrial Chemistry, Interdisciplinary Center
for Bio‐molecular Studies and Industrial Applications (CISI), University of
Milan, Milan, Italy
Published online: 16 Feb 2007.
To cite this article: Laura Polito , Massimiliano Cravini , Laura Poletti & Luigi Lay (2006) Simple Synthesis of
Versatile Coumarin Scaffolds, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 36:15, 2203-2209, DOI: 10.1080/00397910600638937
To link to this article: http://dx.doi.org/10.1080/00397910600638937
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Synthetic Communicationsw, 36: 2203–2209, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600638937
Simple Synthesis of Versatile
Coumarin Scaffolds
Laura Polito, Massimiliano Cravini, Laura Poletti,
and Luigi Lay
Department of Organic and Industrial Chemistry, Interdisciplinary Center
for Bio-molecular Studies and Industrial Applications (CISI),
University of Milan, Milan, Italy
Abstract: We describe an approach using ring-closing metathesis (RCM) to synthesize
versatile coumarin derivatives that present appropriate substitutions both at the
aromatic and at the a,b-unsaturated lactone ring. The obtained compounds can be
used as molecular scaffolds suitable for further diversifications through a combinatorial
approach.
Keywords: Coumarins, lactones, oxygen heterocycles, ring-closing metathesis
Coumarins form an important class of benzopyrones that are found in nature as
independent compounds and as structural subunits of more complex natural
products.[1,2] These compounds possess interesting biological activities,
such as antifungal, anticoagulant, antispasmodic, and anticholerostatic
activity, including anticancer and HIV-1–specific reverse transcriptase
inhibitor properties.[2,3] For these reasons, we became interested in the
synthesis of scaffolds apt to prepare libraries of coumarin derivatives to be
submitted for biological screening. During the past years, a number of
coumarin derivatives have been obtained through a combinatorial approach
on coumarin scaffolds. Coumarins were obtained by classical methods (such
as Michael,[4] Knoevenaegel,[5] Pechmann,[6] and Wittig[7] reactions and
Received in the UK August 16, 2005
Address correspondence to Luigi Lay, Dipartimento di Chimica Organica e Indus-
triale, Centro Interdisciplinare Studi bio-molecolari e applicazioni Industriali (CISI),
`
Universita degli Studi di Milano, via G. Venezian, 21-20133, Milan, Italy.
Fax: þ39-025031-4061; E-mail: luigi.lay@unimi.it
2203

2204
L. Polito et al.
their variations[8]) and converted into the corresponding scaffolds suitable for
palladium-catalyzed,[9,10] nickel-catalyzed,[11] and Suzuki[12] cross-coupling
reactions.[13] However, the classical strategies suffer major shortcomings,
such as strongly acidic conditions due to the use of stoichiometric amounts
of mineral or Lewis acid,[8] the use of toxic reagents,[6a] and often high
reaction temperatures.[6a,7] Very little work was concerned with completely
novel synthesis of substituted coumarins[14–16] to be used directly as
coumarin scaffolds.
In this communication, we describe an approach via ring-closing meta-
thesis (RCM) to synthesize versatile coumarin scaffolds. Although two
examples of the synthesis of coumarins based on RCM[17,18] have been
recently reported, the obtained derivatives are not useful as scaffolds for the
synthesis of a library of compounds. Moreover, the previous papers
describe the synthesis of coumarins only substituted on the aromatic ring[17]
or only substituted at the a,b-unsaturated bond.[18] Coumarins reported
herein are suitable building blocks for further diversification through a combi-
natorial approach, because they present appropriate substitutions both at the
aromatic and at the a,b-unsaturated lactone ring. The mild conditions of
every step, the commercial availability of starting materials, the good
overall yields of the products, and the flexibility of this method make it
very useful for the synthesis of a variety of coumarin derivatives. Our route
toward coumarin scaffolds 5a–h is described in Scheme 1.
It should be emphasized that the high versatility of our strategy derives
from the installation of the diversity sites on the diolefin precursors 4a–h,
Scheme 1. Synthesis of coumarin scaffolds. Procedure A: 3, K2CO3, dry DMF, rt.
Procedure B: 3, Et3N, dry toluene, 2108C. Procedure C: 3, DMAP, DCC, CH2Cl2,
08C ! rt.

Simple Synthesis of Versatile Coumarin Scaffolds
2205
so that the final RCM step affords the multifunctionalized coumarin scaffolds
5a–h.
Syntheses of 4a–h, which present the optimal distance of the two unsa-
turated bonds for the RCM reaction, start from requisite salicylaldehydes
1a–h (Scheme 1, Table 1), which were allowed to react with methyltriphenyl-
phosphorane under Wittig conditions[19] to afford compounds 2a–h in good to
high yields (Table 1). Olefins 2a–h reacted at room temperature, in the
presence of a base, with acryloyl derivatives 3a–h to give the functionalized
esters 4a–h.[20,21] Eventually, the closure of the lactone ring was carried out
using 6 mol% of Grubbs second-generation catalyst 6 (Fig. 1), furnishing
coumarins 5a–h in satisfactory to good yields.
Table 1 reports the chemical yields of the syntheses of coumarins 5a–h
and of intermediates 2a–h and 4a–h. The efficiency of the RCM step was
clearly influenced by the electronic nature of the substituents on the aromatic
ring. Diolefin precursors containing electron-donating groups reacted
smoothly to give the corresponding coumarin derivatives in good yields (see
entries 2 and 4), whereas the presence of electron-withdrawing groups on the
aromatic ring caused a drastic drop in the chemical yields (see entries 5 and
6). Disappointingly, partial cleavage of the thexyldimethylsilyl (TDS) group
occurred during the ring-closure step of diolefins 4c and 4g (entries 3 and 7),
leading to moderate yields of the corresponding coumarins 5c and 5g.
Because most of the coumarins 5a–h were designed to be used as
molecular scaffolds, they contain various diversity sites distributed at
different positions. For example, coumarins 5c, 5d, and 5 g contain tempor-
arily protected OH groups at position 7 (5c and 5d) and 7, 8 (5g) that can
be further functionalized after O-deprotection. A versatile nitro group was
instead introduced at position 6 in coumarin 5e as a direct precursor of a
free amine.
Table 1. Chemical yields in the syntheses of coumarins 5a–h and their precursors
2a–h and 4a–h
Yield of 2a–h
(%)
Yield of 4a–h
(%)
Yield of 5a–h
(%)
Entry
Aldehydes
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
88
90
98
99
65
90
87
88
77
75
68
48
66
94
72
41
70a
81a
24a (30b)
78a
27a (50b)
33a (61b)
41a(54b)
65
1g
1h
aIsolated yield after column chromatography.
bYield corrected for recovered starting material.

2206
L. Polito et al.
Figure 1. Grubbs second-generation catalyst.
Aryl and vinyl halides are very useful substrates largely employed in C-C
bond-forming reactions via metal-catalyzed cross-couplings.[9,13] Therefore,
we synthesized coumarin 5f, which contains a bromine atom at position 6.
Scaffolds containing a diversity site on the lactone ring are also feasible
with our strategy, as demonstrated by the synthesis of coumarin 5h with a
bromine atom at position 3. To the best of our knowledge, only a few
examples of metathesis involving the participation of halogen-substituted
olefins have been reported,[22–24] and even fewer with vinyl halides contain-
ing an additional electron-withdrawing group.[25] In particular, Marhold
et al.[25] described a single example of Grubbs second-generation catalyzed
RCM reaction of a-fluoroacrylate to give 3-fluorocoumarin in 16% yield. In
our hands, the a-bromoacrylate 4h reacted readily to afford 3-bromocoumarin
5h in 65% isolated yield (Table 1, entry 8). It should be emphasized that this
result is particularly important, because literature data report that coumarins
functionalized at position 3 possess interesting and unique biological
properties.[3]
In conclusion, we have demonstrated that coumarin scaffolds are
readily accessible under mild conditions in good overall yield from
commercially available materials. The versatility of the proposed strategy is
ensured by the preliminary introduction of the diversity sites on the synthetic
precursors (the aromatic aldehyde and the acryloyl reagent). Eventually, a
simple RCM reaction affords the coumarin ring equipped with the desired
diversification.
EXPERIMENTAL
1H NMR spectra were recorded with Bruker AC 300 spectrometers at 298 K.
TLC was performed on Merck silica gel 60 F254 plates (0.25-mm thickness),
and spots were visualized by spraying with a solution of H2SO4
(31 mL), ammonium molybdate (21 g), and Ce(SO4)2 (1 g) in water
(500 mL), followed by heating at 1108C for 5 min. All the products were
purified by silica-gel chromatography, which was performed by the flash
procedure using Merck silica gel 60 (230–100.58 mesh). Solvents were
dried by standard procedures.

Simple Synthesis of Versatile Coumarin Scaffolds
2207
General Procedure for the Synthesis of 1c and 1 g
Commercial aldehyde (1 eq) was dissolved in dry toluene (5 mL), and Et3N
(1.1 eq for each OH) and TDSCl (1 eq for each OH) were added slowly.
Upon disappearance of the starting material, the reaction was quenched
with H2O and diluted with EtOAc, and the organic layer was dried
(Na2SO4), filtered, concentrated under vacuum (standard workup), and
purified by silica-gel chromatography (90% yield).
General Procedure for the Synthesis of 1d
Commercial aldehyde (1 eq) was dissolved in dry CH3CN (5 mL), and dry
K2CO3 (1 eq) and methyl p-toluenesulfonate (1 eq) were added. The
mixture was refluxed for 1 h. The reaction was quenched with aq. HCl 5%,
diluted with EtOAc, and washed with H2O, and the organic layer was dried
(Na2SO4), filtered, and concentrated under vacuum. The residue was
purified by silica-gel chromatography (65% yield).
General Experimental Procedure for the Synthesis of 2a–h
A 1.6 M solution of BuLi in hexane (9 mmol) was added dropwise under argon
to a cooled solution (2788C) of Ph3PþCH3I2 (9.9 mmol) in dry THF (40 mL).
The mixture was stirred at 08C for 2 h, then cooled at 2788C, and the aldehyde
(3 mmol) was added slowly. Upon disappearance of the starting material, the
reaction was quenched with satd. aq. NH4Cl, diluted with EtOAc, and washed
with H2O, and the organic layer was dried (Na2SO4), filtered, and concentrated
under vacuum.
General Experimental Procedure for the Synthesis of 4a–h
Procedure A
K2CO3 (17 mmol) was added to a solution of olefin 2 (2 mmol) in dry DMF
(10 mL). Then acryloyl chloride 3 (3 mmol) was added dropwise. Upon disap-
pearance of the starting material, the reaction was submitted to standard
workup.
Procedure B
A solution of olefin 2 (2 mmol) and Et3N (2.4 mmol) in dry toluene (20 mL)
was added dropwise to a cooled solution (2108C) of acryloyl chloride 3

2208
L. Polito et al.
(2 mmol) in CH2Cl2 (10 mL). Upon disappearance of the starting material, the
mixture was submitted to standard workup.
Procedure C
A solution of olefin 2h (1 mmol) in CH2Cl2 (3 mL) was added to a solution of
2-bromoacrylic acid 3h (1 mmol) and DMAP (0.1 mmol) in CH2Cl2 (2 mL).
The mixture was stirred at 08C for 10 min, and then DCC (1.2 mmol) was
added slowly. After stirring for additional 2 h at room temperature, the
reaction mixture was filtered on a Celitew pad, and the residue was washed
with Et2O and concentrated under vacuum.
General Experimental Procedure for the Synthesis of 5a–h
Grubbs catalyst 6 (0.06 mmol) was added to a solution of ester 4 (1 mmol) in
CH2Cl2 (2 mL). The reaction mixture was stirred overnight at room tempera-
ture, and then the solvent was evaporated under vacuum. Silica-gel chromato-
graphy yielded coumarins 5a–h.[26]
ACKNOWLEDGMENTS
This research was financed in part by the Combigen Consortium.
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1
Coumarin 5c: H NMR (400 MHz) d(ppm) ¼ 7.65 (d, J ¼ 9.2 Hz, 1H), 7.35 (d,
J ¼ 8.4 Hz, 1H), 6.79–6.76 (m, 2H), 6.27 (d, J ¼ 9.6 Hz, 1H) 1.18–1.71 (m,
1H), 0.97–0.91 (m, 12H), 0.30 (s, 6H); 13C NMR (100 MHz) d(ppm) ¼ 143.43,
128.70, 117.55, 113.30, 107.78, 34.07, 20.07, 18.53, 22.40. For coumarin 5d,
see Trost, B.; Toste, F.; Greenman, K. J. Amer. Chem. Soc. 2003, 125, 4518–
4526. Coumarin 5g: 1H NMR (200 MHz) d(ppm) ¼ 7.60 (d, J ¼ 8.0 Hz, 1H),
9.92 (d, J ¼ 7.4 Hz, 1H), 6.76 (d, J ¼ 7.6 Hz, 1H), 6.29 (d, J ¼ 8.2 Hz, 1H),
1.89–1.66 (m, 1H), 1.09–0.85 (m, 24H), 0.34–0.18 (m, 12H); 13C NMR
(50 MHz) d(ppm) ¼ 143.52, 122.60, 118.20, 113.65, 34.55, 21.33, 19.82,
22.80. For coumarin 5h, see Kyoung-Mahn, K.; In-Hwan, P. Synthesis 2004,
16, 2641–2644.