Synthesis of 4-arylcoumarins via Cu-catalyzed hydroarylation with arylboronic acids

Article abstract of DOI:10.1021/ol802239n

(Chemical Equation Presented) In the presence of 2-4 mol % of CuOAc, methyl phenylpropiolates having a MOM-protected hydroxy group at the ortho position underwent hydroarylation with various arylboronic acids in MeOH at ambient temperature, resulting in the formation of 4-arylcoumarins in high yields after the acidic workup. This method was effectively used for the synthesis of biologically active natural and artificial compounds.

Full text of DOI:10.1021/ol802239n

ORGANIC
LETTERS
2008
Vol. 10, No. 24
5513-5516
Synthesis of 4-Arylcoumarins via
Cu-Catalyzed Hydroarylation with
Arylboronic Acids
Yoshihiko Yamamoto* and Naohiro Kirai
Department of Applied Chemistry, Graduate School of Science and Engineering, Tokyo
Institute of Technology, Ookayama, Meguro-ku, Tokyo 152-8552, Japan
omyy@apc.titech.ac.jp
Received September 26, 2008
ABSTRACT
In the presence of 2-4 mol % of CuOAc, methyl phenylpropiolates having a MOM-protected hydroxy group at the ortho position underwent
hydroarylation with various arylboronic acids in MeOH at ambient temperature, resulting in the formation of 4-arylcoumarins in high yields
after the acidic workup. This method was effectively used for the synthesis of biologically active natural and artificial compounds.
Coumarin (2H-1-benzopyran-2-one) is a privileged oxygen
heterocycle widely distributed throughout the plant kingdom.1
Among naturally occurring coumarins, 4-aryl derivatives
(neoflavones), which constitute a subgroup of flavonoids,
have received considerable attention since they exhibit
important biological activities2 such as anti-HIV,3 antima-
larial,4 antibacterial,5 and cytotoxic.6 In addition, several
natural and synthetic polyoxygenated 4-arylcoumarins have
been evaluated as the nonisomerizable analogues of com-
bretastatin A-4, which is an important antitubulin agent that
interacts with the binding site of colchicine.7 Conventionally,
4-arylcoumarins have been obtained from phenols by means
of condensation reactions with carbonyl compounds such as
Pechmann or Perkin reactions,8 while they are also synthe-
sized currently through catalytic hydroarylations with pro-
piolates.9 However, devising new synthetic routes that yield
various types of derivatives in a divergent manner would be
highly useful in terms of discovery of new drugs.10 In this
respect, the transition-metal-catalyzed coupling reactions are
highly promising tools since they effectively introduce
various arene rings into the coumarin framework at a later
(1) (a) Murray, R. D. H. Nat. Prod. Rep. 1995, 12, 477–505. (b) Este´vez-
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2003, 39, 47–82.
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Piao, D.; Kitamura, T.; Fujiwara, Y. J. Org. Chem. 2000, 65, 7516–7522.
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Y. Bull. Chem. Soc. Jpn. 2003, 76, 1889–1895. (d) Kotani, M.; Yamamoto,
K.; Oyamada, J.; Fujiwara, Y.; Kitamura, T. Synthesis 2004, n/a, 1455–
1470. (e) Oyamada, J.; Kitamura, T. Tetrahedron 2006, 62, 6918–6925. (f)
Shi, Z.; He, C. J. Org. Chem. 2004, 69, 3669–3671. (g) Li, K.; Zeng, Y.;
Neuenswander, B.; Tunge, J. A. J. Org. Chem. 2005, 70, 6515–6518.
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sky, S. J. J. Org. Chem. 2006, 71, 8329–8351.
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10.1021/ol802239n CCC: $40.75
Published on Web 11/18/2008
2008 American Chemical Society

stage of the synthetic sequence. Palladium-, rhodium-, or
nickel-catalyzed cross couplings of coumarin scaffolds with
a coupling point at the 4 position have been developed by
several research groups.11 Cacchi and co-workers have
recently devised the domino Heck coupling/cyclization
method.12 This method is useful since readily available
cinnamates and aryl halides can be coupled together to form
4-arylcoumarins directly.
Our study commenced with the preparation of phenol-
derived propiolate substrates (Scheme 2). Cacchi et al.
reported that the Sonogashira coupling of o-iodophenol with
ethyl propiolate gave protection-free o-alkynylphenol 6 in
30% yield, while a similar coupling of the THP-protected
analogue led to a mixture of 6 and its THP ether (P )
We have previously reported that the syn hydroarylation
of propiolates with arylboronic acids proceeds even at
ambient temperature without additives upon treatment with
an inexpensive copper catalyst in methanol.13 As a continu-
ation of this study, we herein synthesize 4-arylcoumarins 3
via the Cu-catalyzed hydroarylation of phenol-derived pro-
piolates 1 with arylboronic acids 2 and subsequent cyclization
(Scheme 1).
Scheme 2
Scheme 1
THP).15c Hence, we examined the alternative route reported
by Sato and co-workers.17 Readily available MOM-protected
salicylaldehyde 4 was treated with CBr4 (1.3 equiv), PPh3
(2.6 equiv), and Et3N (1 equiv) in CH2Cl2 at 0 °C overnight
to obtain dibromoalkene 5 in 95% yield. The isolated 5 was
then converted into propiolate 1a in 68% yield upon
n
treatment with BuLi (2.2 equiv) in THF and subsequently
The catalytic hydroarylation of alkynes and their subse-
quent cyclization have been employed thus far for the
syntheses of butenolides,14 chromenes,15 and quinolines;16
however, no example of the direct synthesis of 4-arylcou-
marins along this line has been reported as far as we know.
with ClCO2Me (1.5 equiv). Finally, deprotection under acidic
conditions uneventfully gave 6 in 88% yield.
Having secured a reliable route to the alkyne substrates,
we then attempted the synthesis of 4-arylcoumarins via Cu-
catalyzed hydroarylation/cyclization. In our previous report,
we described that the Cu-catalyzed hydroarylation of methyl
4-hydroxy-2-butynoate with phenylboronic acid gave 3-phe-
nylbutenolide in 61% yield.13 Similarly, 6 was first subjected
to hydroarylation conditions (Scheme 3). As a result,
(11) (a) Wattanasin, S. Synth. Commun. 1988, 18, 1919–1925. (b)
Ciattini, P. G.; Morera, E.; Ortar, G. Synth. Commun. 1995, 25, 2883–
2894. (c) Boland, G. M.; Donnelly, D. M. X.; Finet, J.-P.; Rea, M. D.
J. Chem. Soc., Perkin Trans. 1 1996, n/a, 2591–2597. (d) Schio, L.;
Chatreaux, F.; Klich, M. Tetrahedron Lett. 2000, 41, 1543–1547. (e) Wu,
J.; Liao, Y.; Yang, Z. J. Org. Chem. 2001, 66, 3642–3645. (f) Wu, J.; Yang,
Z. J. Org. Chem. 2001, 66, 7875–7878. (g) Wu, J.; Wang, L.; Fathi, R.;
Yang, Z. Tetrahedron Lett. 2002, 43, 4395–4397. (h) Lei, J.-G.; Xu, M.-
H.; Lin, G.-Q. Synlett 2004, n/a, 2364–2368.
Scheme 3
(12) (i) Tang, Z.-Y.; Hu, Q.-Y. AdV. Synth. Catal. 2004, 346, 1635–
1637. (j) Wu, J.; Zhang, L.; Xia, H.-G. Tetrahedron Lett. 2006, 47, 1525–
1528. (k) Wu, J.; Zhang, L.; Luo, Y. Tetrahedron Lett. 2006, 47, 6747–
6750. (l) Wu, J.; Zhang, L.; Gao, K. Eur. J. Org. Chem. 2006, n/a, 5260–
5263. (m) Zhang, L.; Meng, T.; Fan, R.; Wu, J. J. Org. Chem. 2007, 72,
7279–7286. Battistuzzzi, G.; Cacchi, S.; Salve, I. D.; Fabrizi, G.; Parisi,
L. M. AdV. Synth. Catal. 2005, 347, 308–312.
(13) Yamamoto, Y.; Kirai, N.; Harada, Y. Chem. Commun. 2008, 2010–
2012.
(14) (a) Arcadi, A.; Bernocchi, E.; Burini, A.; Cacchi, S.; Marinelli, F.;
Pietroni, B. Tetrahedron 1988, 44, 481–490. (b) Oh, C. H.; Park, S. J.;
Ryu, J. H.; Gupta, A. K. Tetrahedron Lett. 2004, 45, 7039–7042. (c) Alfonsi,
M.; Arcadi, A.; Chiarini, M.; Marinelli, F. J. Org. Chem. 2007, 72, 9510–
9517.
(15) (a) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Pace, P. Eur.
J. Org. Chem. 2000, n/a, 4099–4108. (b) Arcadi, A.; Cacchi, S.; Fabrizi,
G.; Marinelli, F.; Verdecchia, M. Synlett 2006, n/a, 909–915. Also see: (c)
Cacchi, S.; Fabrizi, G.; Moro, L.; Pace, P. Synlett 1997, n/a, 1367–1370.
In this report, they synthesized 3-(p-anisyl)-2-hydroxychromene, which was
then transformed into the corresponding coumarin via CrO3 oxidation. For
a related synthesis of dihydrocoumarins, see: Kobayashi, K.; Nishikata, T.;
Yamamoto, Y.; Miyaura, N. Bull. Chem. Soc. Jpn. 2008, 81, 1019–1025.
(16) (a) Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L.; Pace, P.
Tetrahedron 1996, 52, 10225–10240. (b) Cacchi, S.; Fabrizi, G.; Goggia-
mani, A.; Moreno-Man˜as, M.; Vallribera, A. Tetrahedron Lett. 2002, 43,
5537–5540. (c) Abbiati, G.; Arcadi, A.; Marinelli, F.; Rossi, E.; Verdecchia,
M. Synlett 2006, n/a, 3218–3224. (d) Arcadi, A.; Aschi, M.; Marinellim,
F.; Verdecchia, M. Tetrahedron 2008, 64, 5354–5361.
4-phenylcoumarin 3aa was obtained in 54% yield; however,
unexpectedly, 4-methoxycoumarin 7 was also formed in 37%
yield. Although the details are unclear, it is reasonable to
assume that the o-hydroxy group played some role in
facilitating the addition of methanol because no such
methoxylation product was observed in the corresponding
o-methoxyphenylpropiolate in our previous study.13 In this
(17) Sato, Y.; Tamura, T.; Kinbara, A.; Mori, M. AdV. Synth. Catal.
2007, 349, 647–661.
5514
Org. Lett., Vol. 10, No. 24, 2008

respect, the MOM-protected 1a was a promising substrate
as the MOM protection probably suppressed the methoxy-
lation and was readily removed after hydroarylation. In fact,
1a underwent smooth hydroarylation within 6 h under the
same conditions, and upon treatment with 6 M HCl in
refluxing MeOH in the same pot, the desired coumarin 3aa
was formed in 89% yield as an exclusive product (Table 1,
entry 1).
First, alkynoate 1b was coupled with known 3-(tert-
butyldimethylsilyloxy)-4-methoxyphenylboronic acid 2k18
Table 1. Cu-Catalyzed Hydroarylation/Cyclization of 1aa
Figure 1. Coupling components for the synthesis of natural
4-arylcoumarins.
entry
2, Ar
2a, C6H5
2b, p-MeC6H4
2c, m-MeC6H4
2d, o-MeC6H4
2e, p-MeOC6H4
2f, p-ClC6H4
Cu (mol %) time (h) 3, yield (%)
1
2
3
4
5
6
7
8
9
2
2
6
6
6
6
2
6
6
3
6
6
3aa, 89
3ab, 90
3ac, 93
3ad, 89
3ae, 90
3af, 88
3ag, 89
3ah, 89
3ai, 87
3aj, 75
under standard conditions to obtain volubolin 3bk in 93%
yield (Table 2, entry 1).19 Next, dalbergin 3ca, which is the
oldest known and most common 4-arylcoumarin constitu-
ent,20 was obtained in 92% yield from alkynoate 1c and
phenylboronic acid 2a (entry 2). Similarly from 1c, melan-
nein21 3ck and melanettin22 3cl were synthesized in high
yields using the TBS-protected phenolic boron reagents 2k
and 2l, respectively (entries 3 and 4). Other types of natural
neoflavones isolated from Coutarea hexandra were also
synthesized from alkynoate 1d.23 The combination of 1d with
arylboronic acids 2k-m gave 3dk-3dm, respectively, in
good yields although increased catalyst loadings of 4 mol
% were required under the steric effect of the 5-methoxy
group (entries 5-7). The formation of 3dk, which has also
been isolated from other plant origins, is of particular
importance since it has been reported to exhibit interesting
biological activities such as cytotoxic activities against human
tumor cell lines,24 antiplasmodial activity against Plasmo-
dium falciparum,4a and inhibition of microtubule assembly
without influencing human topoisomerases I and II.7
2
4
2
4
4
4
10
2
2g, p-IC6H4
2h, p-OHCC6H4
2i, m-O2NC6H4
2j, 2-naphthyl
10
a 1a (0.5 mmol), 2 (3 equiv), MeOH (1 mL, 0.5 M); 6 M HCl (4 mL)/
MeOH (4 mL).
We further checked the scope of this method in terms of
arylboronic acids as summarized in Table 1. All tolylboronic
acids 2b-d having a methyl group at the para, meta, or ortho
positions, respectively, gave the desired coumarins 3ab-ad
in high yields, although higher catalyst loading was required
for 2d (entries 2-4). Neither electron-donating nor electron-
withdrawing groups gave a deleterious effect on the forma-
tion of coumarins 3ae and 3af-ai (entries 5 and 6-9). More
importantly, this protocol could be applied to arylboronic
acids having a labile functional group, such as 2g and 2h,
efficiently affording the corresponding coumarins 3ag and
3ah without the loss of the reactive C-I bond or the formyl
group (entries 7 and 8). These functional groups are useful
synthetic handles for further derivatizations (vide infra).
Further illustrations of the synthetic utility are outlined in
Scheme 4. Tunge et al. have reported the elegant one-pot
tandem Pd(II)-catalyzed cyclization/Pd(0)-catalyzed cross
coupling process that efficiently provides highly substituted
4-arylcoumarins.25 With the 4-arylcoumarin products 3ag and
(18) Banwell, M. G.; Hamel, E.; Hockless, D. C. R.; Verdier-Pinard,
P.; Willis, A. C.; Wong, D. J. Bioorg. Med. Chem. 2006, 14, 4627–4638.
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2626. (b) Chawla, H. M.; Johny, C. J.; Mittal, R. S. Bull. Soc. Chim. Fr.
1989, 82–87.
To demonstrate the synthetic utility of our method, we
have applied the method to the synthesis of natural products.
The plants belonging to the Dalbergia family have been
known to possess unique medicinal properties. Naturally, the
identification of their constituents relevant to the biological
activities is highly important. Thus far, various 4-arylcou-
marins have been isolated, and their structures have been
characterized by their phenyl rings multiply oxygenated in
several substitution patterns.1c Their synthesis is hence an
attractive testing ground for our flexible method: the
combinations of only three arylpropiolates 1b-d with readily
available arylboronic acids 2a,k-m would cover the syn-
thesis of seven natural products (Figure 1 and Table 2).
(20) Ahluwalia, V. K.; Seshadri, T. R. J. Chem. Soc. 1957, 970–972.
Also see refs 19 and 21–23.
(21) (a) Donnelly, B. J.; Donelly, D. M. X.; O’Sullivan, A. M. Chem.
Ind. (London) 1966, n/a, 1498. (b) Donnelly, B. J.; Donelly, D. M. X.;
O’Sullivan, A. M. Tetrahedron 1968, 24, 2617–2622.
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2290.
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Phytochemistry 1983, 22, 1657–1658. (b) Monache, G. D.; Botta, B.; de
Lima, R. A. Phytochemistry 1984, 23, 1813.
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2005, 70, 6515–6518.
Org. Lett., Vol. 10, No. 24, 2008
5515

Mannich reaction/Ir-catalyzed cycloisomerization process.27
Gratifyingly, we could obtain the pyrrole-substituted product
9 in 58% yield from 3ah, N-benzylallylamine, and 1-hexyne.
Table 2. Synthesis of Coumarins from Arylalkynoates 1b-ca
Scheme 4
In conclusion, we have established an efficient Cu-
catalyzed coupling to synthesize 4-arylcoumarins. This
protocol is compatible with phenylboronic acids having
various functional groups including carbon-halogen bonds
as well as an aldehyde. By applying this protocol, we have
synthesized seven naturally occurring neoflavones in good
yields. Further, the present Cu-catalyzed hydroarylation/
cyclization was combined with Cu-catalyzed Ullmann cou-
pling or Cu-catalyzed Mannich reaction/Ir-catalyzed cyclo-
isomerization to produce N-heterocycle-substituted 4-arylcou-
marins with interesting applications.
a 1 (0.5 mmol), 2 (3 equiv), MeOH (1 mL, 0.5 M), 28 °C, 6 h; 6 M
HCl (4 mL)/MeOH (4 mL), reflux, 3 h.
Acknowledgment. This research was partially supported
by the MEXT, Grant-in-Aid for Scientific Research (B),
20350045, Scientific Research on Priority Area “Chemistry
on Concerto Catalysis” (20037018). We thank Prof. K.
Tomooka (Kyushu University) for use of a NMR spectrom-
eter and Profs. H. Suzuki, T. Takao, T. Ikariya, and S.
Kuwata (Tokyo Institute of Technology) for use of mass
spectrometers.
3ah having the C-I bond or the formyl group on the
4-phenyl ring in hand, we have attempted to realize
sequential processes that provide nitrogen heterocycles. First,
3ag was subjected to Ullmann coupling with indole using
the Cu(I)/N,N′-dimethylethylenediamine (dmeda) catalyst
system developed by Buchwald et al.26 to obtain 8 in 98%
yield. We then applied our own sequential Cu-catalyzed
Supporting Information Available: Experimental pro-
cedures and analytical data for products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(26) Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 11684–11688.
(27) (a) Yamamoto, Y.; Hayashi, H.; Saigoku, T.; Nishiyama, H. J. Am.
Chem. Soc. 2005, 127, 10804–10805. (b) Yamamoto, Y.; Hayashi, H.
Tetrahedron 2007, 63, 10149–10160.
OL802239N
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