The rhodium carbenoid route to 3-aryl-4-hydroxycoumarins: Synthesis of derrusnin

Article abstract of DOI:10.1055/s-2005-864808

3-Aryl-4-hydroxycoumarins have been obtained in satisfactory yields and selectivity through a Rh(II)-mediated arylation of diazocoumarin. The utility of this approach is demonstrated by synthesis of the natural product derrusnin.

Full text of DOI:10.1055/s-2005-864808

LETTER
927
The Rhodium Carbenoid Route to 3-Aryl-4-hydroxycoumarins: Synthesis of
Derrusnin
Synthesis of
Deu
rrusnin ca Goldoni,a Giancarlo Cravotto,b Andrea Penoni,c Stefano Tollari,*c Giovanni Palmisano*c
a
b
c
Dipartimento di Chimica Inorganica Metallorganica e Analitica, Università degli Studi di Milano, Via Venezian 21, 20133 Milano, Italy
Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via Giuria 9, 10235 Torino, Italy
Dipartimento di Scienze Chimiche e Ambientali, Università degli Studi dell’Insubria, Via Valleggio 11, 22100 Como, Italy
Fax +39(031)2386449; E-mail: giovanni.palmisano@uninsubria.it.
Received 21 January 2005
tion) and ethers (onium ylide formation). In these studies
we became interested in the potential applications of (for-
mal) aromatic C–H insertion reaction, which, if success-
ful, could provide a straightforward access to 1 (Figure 1).
Abstract: 3-Aryl-4-hydroxycoumarins have been obtained in satis-
factory yields and selectivity through a Rh(II)-mediated arylation of
diazocoumarin. The utility of this approach is demonstrated by
synthesis of the natural product derrusnin.
Key words: arene, arylations, diazo compounds, rhodium, hetero-
cycles
Since the pioneering discovery of 3,3¢-methylene-bis(4-
hydroxycoumarin) as the causative agent of the hemor-
rhagic sweet clover disease of cattle, there has been a
surge of interest in the development of novel hypothrom-
binemic (anticoagulant) agents.1 Accordingly, a number
of structural modifications of the 4-hydroxycoumarin
moiety have been performed, including the introduction
of an aryl group at the 3-position (1).2,3 Furthermore, some
3-aryl-4-hydroxycoumarins [e.g., derrusnin (2)]4a that
have been isolated from Leguminosae display strong phy-
toalexin properties and have proven attractive synthetic
targets. Although a number of methods for the synthesis
Figure 1 a: G = H, b: G = 2-Me, c: G = 4-Me, d: G = 2,4-Me2, e:
G = 4-t-Bu, f: G = 4-OMe, g: G = 3,4-(OMe)2, h: G = 3,4-(OCH2O).
of 1 exist in the literature, by far the majority of them fall At the outset of our investigations there were no published
into two types: in the first, the heterocyclization to the re- reports of any 3-arylation employing 3 as an electrophilic
quired ring system is the final step; in the second, only a equivalent of 4-hydroxycoumarin subunit. However,
3-arylation process is needed, i.e. the rest of the skeleton since 2002 Zhu et al. reported the use of 3-phenyliodoni-
is already present and intact in a starting material.5–7 Some um zwitterion of 4-hydroxycoumarin as an efficient elec-
of these methods have their own limitations in terms of trophile en route to 1 via a Pd-catalyzed Suzuki-type
yields, catalyst load, accessibility, toxicity and stability of coupling reaction.7
intermediates, etc. Since we were interested in obtaining
While we preliminarily reported the Rh(II)- and Ru(II)-
1 through an highly convergent approach, we focused our
catalyzed decomposition of 3,10d we discovered that some
attention on the latter strategy which would use 3-diazo-
aromatic solvents typically employed in carbenoid reac-
tions (i.e., benzene, toluene, xylenes and chlorobenzene)
benzopyran-2,4(3H)dione 38 (hereafter called diazocou-
marin) as the crucial intermediate. This compound is a
gave what appeared to be C–H insertion products. Guided
readily prepared and easy-to-handle crystalline solid that
by this observation and to ascertain how aromatic sol-
vents, temperature, catalyst and catalyst loading affect the
is stable to ordinary light.
a-Diazo carbonyl compounds are recognized precursors insertion efficiency, we carried out the decomposition of
to carbenoid species when exposed to many metal com- 3 in benzene at different temperatures by employing a va-
plexes or salts.9 Over the past several years we10 and Lee11 riety of metal transition complexes. A brief comparison
have been developing methods for the synthesis of poly- study with commercially available Cu(I)-, Pd(II)-, Ru(II)-
heterocyclic frameworks taking advantage of the metal- and Rh(II)-based catalysts led to the identification of
promoted decomposition of 3 in the presence of p-bonds Rh2(OAc)4 as the most promising candidate for the C–H
([2+1] and/or [3+2] cycloaddition), alcohols (O–H inser- insertion. Initially, heating of 3 in benzene for 4 hours at
reflux in the presence of Rh2(OAc)4 (2 mol%) led to about
a 35% yield of 3-phenyl-4-hydroxycoumarin (1a)5 along
with 56% of unreacted starting material. Under these con-
ditions the refluxing temperature of benzene was not high
SYNLETT 2005, No. 6, pp 0927–0930
Advanced online publication: 23.03.2005
DOI: 10.1055/s-2005-864808; Art ID: G03605ST
© Georg Thieme Verlag Stuttgart · New York
0
6.
0
4.
2
0
0
5

928
L. Goldoni et al.
LETTER
enough to trigger efficiently the decomposition of 3. The Both positional isomers 1b2 and 1c5 along with the benzyl
reaction run in a sealed vessel at 130 °C (external)12 ef- derivative 4a14 were obtained in a respective ratio of
fected a clean conversion of 3 after 3 hours, producing 1a 5:10:1 (83%) when 3 was thermolyzed in the presence of
in 68% isolated yield. No evidence of cyclopropanation to toluene in C6F6 solution (method B, entry 3). Positional
a norcaradiene (and/or its valence tautomer cyclohep- substitution of toluene was inferred by analysis of the
tatriene) was observed, although similar products have aromatic splitting pattern in the 1H NMR spectra and the
been reported with other diazo compounds and aromatics results of NOEDS experiments on 1b and 1c.
(Büchner-type reaction).13
Anisole yielded 81% of 3-(4-methoxyphenyl)-4-hydroxy-
To examine the generality of this reaction further, we pro- coumarin (1e)5 as the sole isomer (entry 8). The mild elec-
ceeded to study the Rh(II)-catalyzed transformation of 3 tron-withdrawing halogen substituents in chloro- and
in the presence of differently substituted arenes. With liq- bromobenzene should enable them to participate in elec-
uid compounds, the reaction was performed simply using trophilic substitution reactions. However, attempts to
an excess of arene as solvent reagent (method A) or in the react both aromatics with 3 in the presence of Rh(II)
presence of a co-solvent (method B). Working with high catalysts have so far failed to produce synthetically useful
boiling or solid aromatics, a suitable solvent must be inert results (isolated yields £15%).
and capable of dissolving reasonably 3. The use of the
most common organic solvents can lead to product de-
As expected, extension of Rh(II)-catalyzed decomposi-
tion of 3 to other EW-substituted aromatics, viz. nitro-
rived from C-H insertion but such transformation can be
benzene, trifluoromethylbenzene and methyl benzoate,
severely curtailed if a perfluorinated solvent (viz. C6F6) is
led to messy reactions and did not appear to give any
used. Less satisfactory results were achieved in other
coupled products.
commercial perfluorinated solvents [e.g., perfluorodeca-
Two major trends can be observed. First, it is evident that
line, perfluoro(butyltetrahydrofuran) and perfluoro(1,3-
efficient 3-arylation reactions require the use of arenes
dimethylcyclohexane)], even at higher temperatures, ow-
substituted with electron-donating groups, thereby sup-
ing to the low solubility of 3. Optimally, reactions (10
equiv of arene) were run in C6F6 as a solvent at 130 °C (in
an heavy-walled Pyrex tube sealed with screw cap fitted
porting the electrophilic character of metallo-carbenoid
intermediate RhII(3-N2)Ln. Second, when benzylic CH are
Teflon® septum) in the presence of 2 mol% of catalyst re-
quiring 3–7 hours to reach acceptable conversions
(£85%). Under these conditions, the products were readily
isolated by silica gel column chromatography after evap-
oration of the solvent and examples are gathered in
Table 1.
allowed to compete with aromatic system (entries 3–6) a
mixture of products from aromatic substitution and
benzylic C–H insertion were uneventfully obtained. The
presence of both products will decrease the efficiency of
this method and might seriously limit the scope of these
reactions.15
Table 1 3-Arylation of Diazocumarin 3 with Arenes under Various Conditionsa,b
Entry
Arene
Catalyst
Time (h)c
Products (yield, %)d
1a5 (35)
1
2
PhHa
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(pfb)4
Rh2(tfac)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
4
3
7
7
7
7
6
6
5
5
PhHb
1a5 (68)
3
PhMeb
1b2 (25), 1c5 (53), 4a14 (5)
1d2 (35), 4c14 (32)
1d (63), 4c (5)
1d (51), 4c (4)
1e2 (66)
b
b
b
4
1,4-Me2C6H4
1,4-Me2C6H4
1,4-Me2C6H4
t-C4H9Phb
PhOMeb
5
6
7
8
1f5 (81)
b
9
1,2-(OMe)2C6H4
1g5 (78)
b
10
1,2-(OCH2O)C6H4
1h5 (65)
a Method A: 3 (0.01 M in the respective arene as a solvent), Rh(II) catalysts (2 mol%) at reflux.
b Method B: Reactions were carried out at 130 °C (sealed tube) in C6F6 with 1.0 equiv of 3, 10 equiv of arene and 2 mol% Rh(II) catalyst.
Concentration: 3 mmol of 3/mL of C6F6.
c Reaction times have not been fully optimized.
d Yield of isolated products after column chromatography.
Synlett 2005, No. 6, 927–930 © Thieme Stuttgart · New York

LETTER
Synthesis of Derrusnin
929
In the excellent seminal studies begun by Padwa, Doyle the possibility of tautomerism for 10, the presence of the
and their respective collaborators,16 it has been demon- 2-methoxy-chromen-4-one derivative was not detected
strated that ligands of dirhodium(II) catalysts play a (1H NMR) in the methylation reaction mixture.
crucial role in determining product distribution in compet-
itive metallo-carbenoid transformation of diazo carbon-
yls. In the event, thermolysis of 3 in C6F6 in the presence
In conclusion, apart from failure with electron-deficient
arenes, we disclose a synthetic route to 1 (and 2) where the
3-substituent is introduced (and varied) at a late stage of
the synthesis to produce a wide variety of 3-aryl-4-hy-
of Rh2(OAc)4 and p-xylene (entry 4) produced a mixture
of 1d2 and 4c.14 A switch of Rh(II) ligand to perfluorobu-
droxycoumarins substructures found in a number of bio-
tanoate (pfb)17 (entry 5) caused the regioselectivity for
logically active compounds. Importantly, this method25
isomers 1d/4c to be changed [from 35:32 to 55:5 (by
obviates the preparation of costly starting materials and
avoids toxic reagents. Future work will be directed at
HPLC), respectively], which suggests a significant en-
hancement of electrophilic character of metallo-car-
expanding the potential synthetic utility and at the im-
benoid. Furthermore,
a
change of ligand to
provement of the regioselectivities obtained to date.
trifluoroacetamidate (tfac), as suggested by Moody,18 was
again beneficial as the regioselectivity increased to 51:4
although with slightly lower yields (entry 6).
Acknowledgment
We acknowledge the fruitful cooperation and many stimulating
discussions and helpful suggestions in the field of diazocarbonyl
chemistry with Professor. S. Cenini (University of Milan) and his
group throughout the course of this work.
Having established an effective method for the regioselec-
tive arylation of 4-hydroxycoumarin ring system, we set
out the synthesis of the more elaborate derrusnin (2) start-
ing from 3,5-dimethoxy phenol 5 by way of 6 (Scheme 1).
References
(1) Overman, R. S.; Stahmann, M. A.; Huebner, C. F.; Sullivan,
W. R.; Spero, L.; Doherty, D. G.; Ikawa, M.; Graf, L.;
Roseman, S.; Link, K. P. J. Biol. Chem. 1944, 153, 5.
(2) Van Zanten, B.; Nauta, W. Th. Arzneim.-Forsch. 1964, 14,
29.
(3) Van Zanten, B.; Nauta, W. Th. Recl. Trav. Chim. Pays-Bas
1960, 79, 1211.
(4) (a) East, A. J.; Ollis, W. D.; Wheller, R. E. J. Chem. Soc. C
1969, 365. (b) For related naturally occurring 3-aryl-4-
hydroxycoumarins, see: Yankep, E.; Fomum, Z. T.; Bisrat,
D.; Dagne, E.; Hellwig, V.; Steglich, W. Phytochemistry
1978, 49, 2521.
(5) Barton, D. H. R.; Donnelly, D. M. X.; Finet, J.-P. J. Chem.
Soc., Perkin Trans. 1 1992, 1365.
(6) Combes, S.; Finet, J.-P.; Siri, D. J. Chem. Soc., Perkin
Trans. 1 2002, 38.
Scheme 1 Reaction conditions: i) MeCOCl, Sc(OTf)3, heat, PhMe,
reflux, 5 h (78%); ii) (EtO)2CO (neat), NaH, reflux, 20 min, then
10% HCl, r.t., 1 h (89%); iii) p-ABSA, DBU, MeCN, r.t., 5 h
(73%); iv) 1,3-benzodioxole, C6F6, Rh2(pfb)4, 130 °C, 7 h (70%);
v) (TMS)CHN2, MeOH, r.t., 12 h (85%).
(7) Zhu, Q.; Wu, J.; Fathi, R.; Yang, Z. Org.Lett. 2002, 4, 3333.
(8) Frimer, A. A.; Marks, V.; Gilinsky-Sharon, P.; Aljadeff, G.;
Gottlieb, H. E. J. Org. Chem. 1995, 60, 4520.
Initial attempts to promote the cyclization directly on 5
under Kappe–Stadlbauer conditions19 [bis(2,4,6-trichlo-
rophenyl)malonate, Ph2O, 250 °C, 1–5 h] resulted in
sharply attenuated yields of 7 (ca. 37%) as a result of com-
peting two-fold annulation to produce the pyrano[3,2-
c]chromene-2,5-dione (8). Optimal elaboration of 5 to 2
was instead achieved in five steps by first conversion to
the ketone 6 [MeCOCl, Sc(OTf)3, PhMe, reflux, 6 h]20 fol-
lowed by crossed-Claisen condensation (neat diethyl car-
bonate, NaH, reflux, 20 min) with enolate generation and
in situ ring-closure (10% aq HCl, r.t., 1 h) to 7. Conver-
sion of 7 to diazo carbonyl 921 was best accomplished by
diazo transfer reaction [p-acetamidobenzenesulphonyl
azide (p-ABSA), DBU, MeCN, r.t., 5 h]22 followed by
chromatographic purification. Exposure of 9 to 1,3-ben-
zodioxole and Rh2(pfb)4 (2 mol%) in C6F6 at 130 °C for a
period of 7 hours resulted in the clean production of 106
(70%) which, upon O-(4)-methylation [(TMS)CHN2 (2.0
M in n-hexane), MeOH, r.t., 12 h]23,24 gave derrusnin (2)
in 30% overall yield (for the five steps from 5). Despite
(9) (a) The Chemistry of Diazonium and Diazo Groups; Patai,
S., Ed.; Wiley: New York, 1978. (b) Burke, S. D.; Grieco,
P. A. Org. React. 1979, 26, 361. (c) Wulfman, D. S.;
Poling, B. In Reactive Intermediates, Vol. 1; Abramovitch,
R. A., Ed.; Plenum Press: New York, 1980, 321. (d) Doyle,
M. P. In Catalysis of Organic Reactions; Augustine, R. L.,
Ed.; Marcel Dekker: New York, 1985, Chapt. 4. (e) Doyle,
M. P. Chem. Rev. 1986, 86, 919. (f) Doyle, M. P. Acc.
Chem. Res. 1986, 19, 348. (g) Maas, G. Top. Curr. Chem.
1987, 137, 75. (h) Doyle, M. P.; McKervey, M. A.; Ye, T.
Modern Catalytic Methods for Organic Synthesis with Diazo
Compounds; John Wiley and Sons: Chichester, New York,
Brisbane, Toronto, Singapore, 1998.
(10) (a) Cenini, S.; Cravotto, G.; Giovenzana, G. B.; Penoni, A.;
Tollari, S.; Palmisano, G. J. Mol. Catal. A: Chem. 2000, 164,
165. (b) Cenini, S.; Cravotto, G.; Giovenzana, G. B.; Tollari,
S.; Palmisano, G. Tetrahedron 1999, 55, 6577. (c) Cenini,
S.; Cravotto, G.; Giovenzana, G. B.; Palmisano, G.; Penoni,
A.; Tollari, S. Tetrahedron Lett. 2002, 43, 3637. (d)Tollari,
S.; Palmisano, G.; Cenini, S.; Cravotto, G.; Giovenzana, G.
B.; Penoni, A. Synthesis 2001, 735.
Synlett 2005, No. 6, 927–930 © Thieme Stuttgart · New York

930
L. Goldoni et al.
LETTER
(23) Robinson, A.; Hui-Yin, L.; Feaster, J. Tetrahedron Lett.
(11) Lee, Y. R.; Suk, J. Y.; Kim, B. S. Tetrahedron Lett. 1999, 40,
6603.
1996, 37, 8321.
(12) Temperature of 130 °C was used because it represents the
right compromise between formation of Rh(II)-carbenoid
and thermal decomposition of diazocoumarin 3 (checked by
DCS-TGA analysis).
(13) Yang, M.; Webb, T. R.; Livant, P. J. Org. Chem. 2001, 66,
4945; and references cited therein.
(14) Appendino, G.; Cravotto, G.; Tagliapietra, S.; Ferraro, S.;
Nano, G. M.; Palmisano, G. Helv. Chim. Acta 1991, 74,
1451.
(15) Rosenfeld, M. J.; Ravi Shankar, B. K.; Shechter, H. J. Org.
Chem. 1988, 53, 2699.
(24) Jain, A. C.; Rohatgi, V. K.; Seshadri, T. R. Tetrahedron
1967, 23, 2499.
(25) General Procedure (Method A).
Unless stated otherwise, diazocoumarin 3 (1 mmol), was
suspended in the aromatic compound (5 mL) and Rh(II)
catalyst (0.02 mmol) was added. The mixture was brought to
reflux under N2 and vigorous stirring for several hours,
checking by TLC (CH2Cl2–EtOAc, 97:3) or HPLC the
reaction progress. The crude reaction mixture was
evaporated to dryness by rotary evaporator and the residual
submitted to silica gel chromatography.
(16) Padwa, A.; Austin, D. J.; Price, A. T.; Semones, M. A.;
Doyle, M. P.; Protopopova, M. N.; Winchester, W. R.; Tran,
A. J. Am. Chem. Soc. 1993, 115, 8669.
(17) Drago, R. S.; Long, F. R.; Cusmano, R. Inorg. Chem. 1982,
21, 2196.
Representative Arylation Procedure (Method B;
Preparation of 10).
Diazocoumarin 9 (248 mg, 1.5 mmol), 1,3-benzodioxole
(1.72 mL, 15 mmol) and Rh2 (pfb)4 (317 mg, 0.3 mmol) were
combined in C6F6 (5 mL) in a dry 25 mL heavy-walled Pyrex
tube, equipped with a magnetic stir bar, flushed with N2 and
sealed with a screw cap fitted Teflon® septum. The reaction
was warmed to 130 °C (oil bath) with stirring behind a
protective shield until TLC (CH2Cl2– EtOAc, 97:3) or HPLC
[Symmetry C8-Waters (4.6 mm/150 mm); phosphate
buffer–TEA(pH 7)–MeCN; 1 mL/min] indicated the
disappearance of the starting 9 (7 h) [CAUTION: While we
observed no problems with the thermal stability of
diazocoumarins (viz., 3 and 9), care should be exercised].
The cooled solution was poured directly onto the top of a
silica gel column, and the column was flushed with hexane
to remove excess 1,3-benzodioxole and C6F6. Elution was
then continued with a 49:1 mixture of CH2Cl2–EtOAc to
afford 5,7-dimethoxy-4-hydroxy-3-(3,4-methylenedioxy-
phenyl)chromen-2-one (10, 359mg, 70%) as light yellow
needles after crystallization from EtOH, mp 233 °C [Lit.6
234 °C].
(18) Moody, J. C.; Doyle, K. J.; Elliott, M. C.; Mowlem, T. J.
Pure Appl. Chem. 1994, 66, 2107.
(19) (a) Kappe, Th.; Ajili, S.; Stadlbauer, W. J. Heterocycl.
Chem. 1988, 25, 463. (b) Kappe, T. Bis(2,4,6-trichloro-
phenyl) malonate, In Encyclopaedia of Reagents for
Organic Synthesis, Vol. 1; Paquette, L. A., Ed.; John Wiley
and Sons: Chichester, New York, Brisbane, Toronto,
Singapore, 1995, 577.
(20) Kobayashi, S.; Moriwaki, M.; Hachiya, I. Bull. Chem. Soc.
Jpn. 1997, 70, 267.
(21) 5,7-Dimethoxy-3-diazo-benzopyran-2,4 (3H)dione (9): pale
yellow powder. 1H NMR (400 MHz, CDCl3): d = 6.37 (d,
J = 2.5 Hz, 1 H), 6.33 (d, J = 2.5 Hz, 1 H), 3.96 (s, 3 H), 3.90
(s, 3 H) ppm. IR: n = 2168, 1720, 1643, 1612 cm–1. MS (CI,
isobutane): m/z (%) = 217 (100) [MH]+. Anal. Calcd for
C11H8N2O3 (216.2): C, 61.11; H, 3.73; N, 12.96. Found: C,
61.02; H, 3.98; N, 12.76.
(22) Taber, D. F.; You, K.; Song, J. J. Org. Chem. 1995, 60, 1093.
Synlett 2005, No. 6, 927–930 © Thieme Stuttgart · New York