One-pot synthesis of biaryl lactones by Sonogashira cross-coupling reactions of 4-chloro-3-formylcoumarin and subsequent domino [5+1] cyclization/deacetylation reactions with 1,3-dicarbonyl compounds

Article abstract of DOI:10.1002/adsc.201100621

Biaryl lactones were prepared by a new palladium(0) and base-catalyzed one-pot reaction of 4-chloro-3-formylcoumarin with alkynes and 1,3-dicarbonyl compounds. Copyright

Full text of DOI:10.1002/adsc.201100621

COMMUNICATIONS
DOI: 10.1002/adsc.201100621
One-Pot Synthesis of Biaryl Lactones by Sonogashira
Cross-Coupling Reactions of 4-Chloro-3-formylcoumarin and
Subsequent Domino [5+1]Cyclization/Deacetylation Reactions
with 1,3-Dicarbonyl Compounds
Viktor O. Iaroshenko,a,b,* Muhammad S. A. Abbasi,a Alexander Villinger,b
and Peter Langera,c,*
a
Institut fꢀr Chemie, Universitꢁt Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
Fax : (+49)-381-498-6412; e-mail: viktor.iaroshenko@uni-rostock.de or peter.langer@uni-rostock.de
National Taras Shevchenko University, 62 Volodymyrska st., Kyiv-33, 01033, Ukraine
Leibniz-Institut fꢀr Katalyse e. V. an der Universitꢁt Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
b
c
Received: August 3, 2011; Revised: December 1, 2011; Published online: March 6, 2012
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100621.
Abstract: Biaryl lactones were prepared by a new
palladium(0) and base-catalyzed one-pot reaction
of 4-chloro-3-formylcoumarin with alkynes and 1,3-
dicarbonyl compounds.
(Figure 1),[1] as well as molecules containing two lac-
tone moieties, e.g., ellagic and coruleoellagic acid,[2]
and benzo[d]naphthopyran-6-ones, such as the gilvo-
carcins, chrysomycins and ravidomycins and defuco-
gilvocarcin V. Benzo[d]naphthopyran-6-ones show
a wide range of pharmacological properties, such as
antibiotic and antitumor activities.[3]
Keywords: biaryl lactones; 4-chloro-3-formylcou-
marin; cyclization; domino reactions; heterocycles
Biaryl lactones have been prepared by several
methods which are based on Pd-catalyzed coupling
reactions[4] and are also available by building block
syntheses. Examples include the TiCl4-mediated [3+
Biaryl lactones (benzo[c]chromen-6-ones) are phar- 3]cyclization of 1,3-bisACTHNUTRGNEUNG(silyloxy)-1,3-butadienes with
macologically important core structures that occur in 3-(2-methoxyphenyl)-3-silyloxy-2-en-1-ones and sub-
several natural products. Examples include autumnar- sequent BBr3-mediated lactonization,[5] the reaction
iol, autumnariniol, alternariol, and altenuisol of 1,3-bis
and the cyclization[7] of 4-chloro-2-oxo-2H-chromene-
3-carbaldehyde[8]
with 1,3-bis(silyloxy)-1,3-buta-
(silyloxy)-1,3-butadienes with chromones,[6]
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
dienes.[9] Mꢀller and co-workers reported the synthe-
sis of various heterocycles by consecutive multicom-
ponent reactions initiated by Sonogashira reactions.[10]
Herein, we report a new one-pot synthesis of biaryl
lactones by Sonogashira reactions of 4-chloro-2-oxo-
2H-chromene-3-carbaldehyde and subsequent cyclo-
condensation with 1,3-dicarbonyl compounds. The
cyclization step proceeds by a domino [5+1]cycliza-
tion/deacetylation process which has, to the best of
our knowledge, not been reported so far.[11] The sub-
stitution pattern of the products reported herein is
not readily accessible by other methods.
4-Chloro-2-oxo-2H-chromene-3-carbaldehyde
(1)
was prepared, according to a literature procedure, by
formylation of commercially available 4-hydroxycou-
marin with POCl3 and DMF.[12] The Sonogashira reac-
Figure 1. Natural products with benzo[c]chromen-6-one sub-
unit.
tion of 1 with arylacetylenes 2a–i, using PdCl2ACHTUNGTRENNUNG(PPh3)2
Adv. Synth. Catal. 2012, 354, 803 – 806
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
803

Viktor O. Iaroshenko et al.
COMMUNICATIONS
Figure 2. Molecular structure of 5f.
Scheme 1. Reagents and conditions: i, 1) 2a–i, PdCl2ACTHNUTRGEN(UNG PPh3)2
(4 mol%), CuI (7 mol%), THF, K2CO3, 208C, 8–10 h; 2) 4a–
e, 508C, 5–6 h
The best yields were obtained when PdCl
was used as the catalyst. The use of Pd(PPh3)4 or
Pd(OAc)2 in the presence of XPhos or SPhos resulted
2ACHTUNGTRENNUNG(PPh3)2
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
as the catalyst (CuI, K2CO3, THF, 208C, 8–10 h), and in lower yields. In addition, we have found that
subsequent addition of 1,3-dicarbonyl compounds 4a– longer reaction times were required when less than
e (508C, 5–6 h) afforded the biaryl lactones 5a–x in 4 mol% of the catalyst and less than 7 mol% of CuI
a one-pot process (Scheme 1, Table 1). In the first were employed. Equally successful results were ob-
step, the (unstable) 4-alkynyl-2-oxo-2H-chromene-3- tained when (dry) potassium carbonate or triethyla-
carbaldehydes 3a–i were formed which were, without mine was used as the base. The structure of 5f was in-
isolation, directly transformed to products 5a–x. The dependently confirmed by X-ray crystal structure
formation of intermediate 3a was proven by its isola- analysis (Figure 2).[13]
tion and characterization and subsequent transforma-
tion into the corresponding product 5a.
The formation of the products can be explained by
base-mediated attack of the 1,3-dicarbonyl compound
onto the aldehyde (Knoevenagel reaction) to give in-
termediate A, base-mediated cyclization to give inter-
mediate B, and subsequent base-mediated deacetyla-
tion (Scheme 2). The overall process can be regarded
as a formal [5+1]cyclization. Both b-ketoesters and
acetylacetone and both aryl- and alkyl-substituted al-
kynes could be successfully employed as the starting
materials.
Table 1. Yields of pyrroloACTHNUTRGNEUGN[2,3-b]pyridines 5a–x.
2
4
5
R1
R2
Time [h] Yield [%][a]
a
a
a
b
b
b
b
c
c
c
c
d
d
d
e
e
e
e
f
a
b
c
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
4-MeC6H4
4-MeC6H4
4-MeC6H4
Ph
Ph
Ph
Ph
n-Pr
n-Pr
n-Pr
CO2Me
CO2Et
COMe
COMe
CO2Et
CO2Me
8+5
8+5
8+5
8+5
8+5
8+5
48
47
43
42
46
47
44
41
38
43
41
43
45
44
50
47
45
44
44
46
54
52
55
54
c
b
a
d
d
a
b
c
CO2-i-Pr 8+5
CO2-i-Pr 10+6
CO2Me
CO2Et
COMe
COMe
CO2Me
CO2Et
CO2Me
CO2Et
CO2-t-Bu 8+5
CO2Allyl 8+5
CO2Me
CO2Me
CO2Me
CO2Et
10+6
10+6
10+6
10+6
10+6
10+6
8+5
n-Pr
c
n-Pent
n-Pent
n-Pent
t-BuC6H4
t-BuC6H4
t-BuC6H4
t-BuC6H4
2-MeC6H4
4-n-PrC6H4
4-FC6H4
4-FC6H4
a
b
a
b
d
e
a
a
a
b
a
b
8+5
s
t
u
v
w
x
8+5
8+5
8+5
8+5
8+5
8+5
g
h
h
i
4-(MeO)C6H4 CO2Me
4-(MeO)C6H4 CO2Et
i
[a]
Yields of isolated products.
Scheme 2. Possible mechanism for the formation of 5a–x.
804
asc.wiley-vch.de
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 803 – 806

One-Pot Synthesis of Biaryl Lactones by Sonogashira Cross-Coupling Reactions
70 eV): m/z (%)=288 ([M]+, 100), 260 (41), 231 (51), 203
In conclusion, we have reported the one-pot syn-
thesis of biaryl lactones by Sonogashira reaction of 4-
chloro-2-oxo-2H-chromene-3-carbaldehyde and subse-
quent cyclocondensation with 1,3-dicarbonyl com-
pounds. The cyclization proceeds by a novel domino
[5+1]cyclization/deacetylation reaction. From a prep-
arative viewpoint, the substitution pattern of the
products is not readily available by other methods.
From a methodology viewpoint, the domino process
reported has, to the best of our knowledge, not been
reported so far and might be of general interest. At
present, we are exploring the scope of the reaction re-
ported herein and its application to other halogenated
enals.
(42), 189 (43), 101 (14); HR-MS (EI): m/z=288.0789, calcd.
for C19H12O3 ([M]+): 288.0781.
Acknowledgements
Financial support by the State of Mecklenburg-Vorpommern,
by the DAAD (scholarship for M.S.A.A.) and by the BMBF
(Remedis-Verbundprojekt, Grant No. 03IS2081A) is grateful-
ly acknowledged.
References
[1] a) H. W. T. Sidwell, L. Fritz, C. Tamm, Helv. Chim.
Acta 1971, 54, 207; b) C. Tamm, Arzneim.-Forsch. 1972,
22, 1776; c) H. Raistrick, C. E. Stilkings, R. Thomas,
Biochemistry 1953, 55, 421; d) R. Pero, W. D. M.
Harvan, C. Blois, Tetrahedron Lett. 1973, 945;
Experimental Section
General Procedure for the Synthesis of 5a–n
To a solution of 1 (0.20 g, 1.0 mmol) in THF (7–8 mL) was
e) Rçmpp – Lexikon NaACHTNUGTREGtNUNN urACHTUNRTEGNGsNUN tofACTHNUGTRENfGUNN e, (Eds.: W. Steglich, B.
added K2CO3 (0.20 g, 1.5 equiv.). Under a continuous supply
of argon were added PdCl2ACHTNUGTRNEUNG(PPh3)2 (4 mol%) and CuI
Fugmann, S. Lang-Fugmann), Thieme, Stuttgart, 1997.
[2] a) J. M. Sayer, Y. Haruhiko, A. W. Wood, A. H.
Conney, D. M. Jerina, J. Am. Chem. Soc. 1982, 104,
5562; b) Y. A. G. P. Gunawardana, N. S. Kumar,
M. U. S. Sultanbawa, Phytochemistry 1979, 18, 1017.
[3] For antibiotic and antitumor activity, see: a) B. I. Alo,
A. Kandil, P. A. Patil, M. J. Sharp, M. A. Siddiqui, V.
Snieckus, J. Org. Chem. 1991, 56, 3763, and refs.[6–10]
cited therein. For the inhibition of endothelic cells, see:
b) J. M. Schmidt, G. B. Tremblay, M. Page, J. Mercure,
M. Feher, R. Dunn-Dufault, M. G. Peter, P. R. Redden,
J. Med. Chem. 2003, 46, 1289. For the inhibition of oes-
trogen receptor growth, see: c) J. Pandey, A. K. Jha, K.
Hajela, Bioorg. Med. Chem. 2004, 12, 2239.
[4] For intramolecular Pd(II)-catalyzed coupling reactions
of aryl benzoates, see: a) G. Bringmann, H. Reuscher,
Tetrahedron Lett. 1989, 30, 5249. For the combination
of directed ortho-metalations (DoM) with Suzuki reac-
tions, see: b) B. I. Alo, A. Kandil, P. A. Patil, M. J.
Sharp, M. A. Siddiqui, V. Snieckus, J. Org. Chem. 1991,
56, 3763. For the Pd-catalyzed reaction of boroxarenes,
prepared from ortho-hydroxybiaryls, with carbon mon-
oxide, see: c) Q. J. Zhou, K. Worm, R. E. Dolle, J. Org.
Chem. 2004, 69, 5147.
(7 mol%), followed by dropwise addition (an interval of
2 min) of 2 (1.5 equiv.). The reaction mixture was allowed to
stir at room temperature for 8 to 10 h and monitored by
TLC. To the same reaction vessel was dropwise added the
1,3-dicarbonyl compound (1.5 equiv.). The reaction mixture
was then stirred at 508C for 5 to 6 h. After completion of
the reaction, the reaction mixture was acidified by addition
of a few drops of hydrochloric acid (1M). The mixture was
then extracted with ethyl acetate. The solvent was removed
under reduced pressure. The residue was purified by column
chromatography (silica gel, heptanes/EtOAc).
Methyl 6-oxo-9-phenyl-6H-benzo[c]chromene-8-carbox-
ylate (5f): Starting with 1 (0.20 g, 1.0 mmol), K2CO3 (0.20 g,
1.5 equiv.), PdCl2ACHTUNGTRENNUNG(PPh3)2 (4 mol%), CuI (7 mol%), 2d
(0.15 g, 1.5 equiv.), and 4d (0.174 g, 1.5 equiv.), 5d was isolat-
ed by chromatography as a white crystalline solid; yield:
1
0.155 g (47%); mp 185–1878C. H NMR (250 MHz, CDCl3):
d=3.66 (s, 3H, OCH3), 7.24–7.36 (m, 4H, Ar-H), 7.37–7.50
(m, 4H, Ar-H), 7.98–8.01 (m, 2H, Ar-H), 8.81 (s, 1H, Ar-
H); 13C NMR (250 MHz, CDCl3): d=52.3 (OCH3), 117.2
(C), 118.0 (CH), 119.9 (C), 123.3, 124.3, 124.8 (CH), 128.2
(2CH), 128.4 (3CH), 131.3 (C), 131.6, 132.9 (CH), 136.8,
140.0, 148.85 (C), 152.0, 160.3, 167.0 (CO); IR (ATR): n=
2947 (w), 1716 (s), 1608(m), 1228 (s), 1184 (m) 1083(m),
977(m), 751 (s), 703 cmÀ1 (m); GC-MS (EI, 70 eV): m/z
(%)=330 ([M]+, 97), 330 (100), 271 (8), 255 (20), 226 (25);
HR-MS (EI): m/z=330.0884, calcd. for C21H14O3 ([M]+):
330.0886.
[5] I. Hussain, V. T. H. Nguyen, M. A. Yawer, T. T. Dang,
C. Fischer, H. Reinke, P. Langer, J. Org. Chem. 2007,
72, 6255.
[6] B. Appel, N. N. R. Saleh, P. Langer, Chem. Eur. J. 2006,
12, 1221.
[7] O. Fatunsin, V. O. Iaroshenko, S. O. Dudkin, S.
Mkrtchyan, A. Villinger, P. Langer, Tetrahedron Lett.
2010, 51, 4693.
2-Oxo-4-(p-tolylethynyl)-2H-chromene-3-carbaldehyde
(3a): yellow crystalline solid; mp 188–1908C. 1H NMR
(300 MHz, CDCl3): d=2.36 (s, 3H), 7.19–7.37 (m, 4H, Ar-
H), 7.58–7.63 (m, 3H, Ar-H), 8.12 (dd, J=8.07 Hz, J=
[8] A. M. M. El-Saghier, M. B. Naili, B. Kh. Rammash,
N. A. Saleh, K. M. Kreddan, Arkivoc 2007, 83.
1.38 Hz, 1H, Ar-H), 10.47
N
[9] For a review, see: P. Langer, Synthesis 2002, 441.
[10] For reviews, see: a) B. Willy, T. J. J. Mꢀller, Curr. Org.
Chem. 2009, 13, 1777; b) B. Willy, T. J. J. Mꢀller, Arki-
voc 2008, 195; see also: c) E. Merkul, C. Boersch, W.
Frank, T. J. J. Mꢀller, Org. Lett. 2009, 11, 2269;
d) D. M. D’Souza, C. Muschelknautz, F. Rominger,
CDCl3): d=21.91 (CH3), 83.30, 113.41, 117.21, 117.90,
118.66, 120.59 (C), 125.07, 128.77 (CH), 129.69, (2CH),
133.22 (2CH), 134.65 (CH), 140.10, 142.34 (C), 154.23,
159.68 (CO) 187.67 (CHO); IR (ATR): n=2858 (w), 2182
(s), 1698 (m), 1268 (m), 819 (s), 747 cmÀ1 (s); GC-MS (EI,
Adv. Synth. Catal. 2012, 354, 803 – 806
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
805

Viktor O. Iaroshenko et al.
COMMUNICATIONS
T. J. J. Mꢀller, Org. Lett. 2010, 12, 3364; e) E. Merkul,
T. Oeser, T. J. J. Mꢀller, Chem. Eur. J. 2009, 15, 5006.
[11] Very recently, base-catalyzed cyclocondensations of
methyl mercaptoacetate with heteroarenes, bearing
a formyl and an alkynyl group located in a 1,2-relation-
ship, have been reported: I. Cikotiene, R. Buksnaitiene,
R. Sazinas, Tetrahedron 2011, 67, 706. This reaction can
be regarded as a formal [5+1]cyclization which pro-
ceeds by extrusion of H2S. Due to the mandatory use
of methyl thioacetate, the preparative scope of the re-
action is restricted.
[12] U. R. Saeed, H. C. Zahid, G. Farzana, T. S. Claudiu, J.
Enz. Inhib. Med. Chem. 2005, 20, 333.
[13] CCDC 864456 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif
or can be ordered from the following address: Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB21EZ, U.K.; Fax: (+44)-1223-336-033;
or deposit@ccdc.cam.ac.uk.
806
asc.wiley-vch.de
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 803 – 806