Copper(I)-mediated and microwave-assisted Caryl-O carboxylic coupling: Synthesis of benzopyranones and isolamellarin alkaloids

Article abstract of DOI:10.1021/jo701599g

(Chemical Equation Presented) A simple and highly effective C-O _carboxylic coupling reaction catalyzed by copper(I) salts has been developed to synthesize benzopyranones. The reaction of various 2-halobiarylcarboxylic acids was examined using m

Full text of DOI:10.1021/jo701599g

copper(I) thiophene carboxylate (CuTC) have been used for
C-O bond formation. The latter has been developed and used
in the Liebeskind group.4 Recently, CuTC has been used in
asymmetric synthesis and macrocyclic molecules.5
Copper(I)-Mediated and Microwave-Assisted
Caryl-Ocarboxylic Coupling: Synthesis of
Benzopyranones and Isolamellarin Alkaloids
Since their isolation by Faulkner in 1985,6 the lamellarin
alkaloids have attracted much attention from various research
groups7 including our laboratory.8 The lamellarins, in particular
lamellarin D 4, exhibit various biological activities and thus
may be developed into potential drug candidates for treatment
of some forms of cancer and AIDS.9 In addition, the benzopy-
ranone substructure is one of the most important heterocycles
because it has been found in several natural compounds. Not
only the lamellarins but also the benzopyranones represent
components of pharmacologically active compounds including
gilvocarcin V 1,10 alternariol 2,11 and coumestrol 312 (Figure
1). Various synthetic methodologies have been devised for the
synthesis of benzopyranone derivatives.13
Nopporn Thasana,*,†,‡ Rattana Worayuthakarn,†
Phithakpong Kradanrat,† Elliot Hohn,† Lauren Young,† and
Somsak Ruchirawat†,‡,§
Laboratory of Medicinal Chemistry, Chulabhorn Research
Institute, Laksi, Bangkok 10210, Thailand, Program on
Chemical Biology, Chulabhorn Graduate Institute,
Laksi, Bangkok 10210, Thailand, and Program on Research and
DeVelopment of Synthetic Drugs, Institute of Science and
Technology for Research and DeVelopment, Mahidol UniVersity,
Salaya Campus, Nakhon Pathom, Thailand
nopporn@cri.or.th
ReceiVed August 1, 2007
(4) For selected publications on CuTC, see: (a) Liebeskind, L. S.; Srogl,
J. Org. Lett. 2002, 4, 979-981. (b) Kusturin, C. L.; Liebeskind, L. S.;
Neumann, W. L. Org. Lett. 2002, 4, 983-985. (c) Savarin, C.; Liebeskind,
L. S. Org. Lett. 2001, 3, 91-93. (d) Savarin, C.; Liebeskind, L. S. Org.
Lett. 2001, 3, 2149-2152. (e) Shen, R.; Porco, J. A. Org. Lett. 2000, 2,
1333-1336. (f) Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122,
11260-11261. (g) Srogl, J.; Liebeskind, L. S. Org. Lett. 2000, 2, 3229. (h)
Zhang, S.; Zhang, D.; Liebeskind, L. S. J. Org. Chem. 1997, 62, 2312-
2313. (i) Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118,
2748-2749.
(5) (a) d’Augustin, M.; Palais, L.; Alexakis, A. Angew. Chem., Int. Ed.
2005, 44, 1376-1378. (b) Wehlan, H.; Dauber, M.; Fernaud, M. T. M.;
Schuppan, J.; Mahrwald, R.; Ziemer, B.; Carcia, M. E. J.; Koert, U. Angew.
Chem., Int. Ed. 2004, 43, 4597-4601. (c) Nicolaou, K. C.; Kim, D. W.;
Baati, R. Angew. Chem., Int. Ed. 2002, 41, 3701-3704.
A simple and highly effective C-Ocarboxylic coupling reaction
catalyzed by copper(I) salts has been developed to synthesize
benzopyranones. The reaction of various 2-halobiarylcar-
boxylic acids was examined using microwave irradiation. A
new class of pyrroloisoquinoline alkaloid, isolamellarin, was
synthesized based on the annulation of dihydroisoquinoline
with aryl pyruvates under basic condition and Cu-mediated/
MW-assisted C-Ocarboxylic lactonization.
(6) Andersen, R. J.; Faulkner, D. J.; Cun-Heng, H.; Van Duyne, G. D.;
Clardy, J. J. Am. Chem. Soc. 1985, 107, 5492-5495.
(7) (a) Pla, D.; Marchal, A.; Olsen, C. A.; Francesch, A.; Alvarez, M. J.
Org. Chem. 2005, 70, 8231-8234. (b) Handy, S. T.; Zhang, Y.; Bregman,
H. J. Org. Chem. 2004, 69, 2362-2366. (c) Ishibashi, F.; Tanabe, S.; Oda,
T.; Iwao, M. J. Nat. Prod. 2002, 65, 500-504. (d) Diaz, B.; Guitian, E.;
Castedo, L. Synlett 2001, 1164-1166. (e) Peschko, C.; Winklhofer, C.;
Steglich, W. Chem. Eur. J. 2000, 6, 1147-1152. (f) Boger, D. L.; Soenen,
D. R.; Boyce, C. W.; Hedrick, M. P.; Jin, Q. J. Org. Chem. 2000, 65, 2479-
2483. (g) Banwell, M.; Flynn, B.; Hockless, D.; Longmore, R. W.; Rae, A.
D. Aust. J. Chem. 1998, 52, 755-765 and references therein.
(8) (a) Ploypradith, P.; Petchmanee, T.; Sahakitpichan, P.; Litvinas, N.
D.; Ruchirawat, S. J. Org. Chem. 2006, 71, 9440-9448. (b) Ploypradith,
P.; Kagan, R. K.; Ruchirawat, S. J. Org. Chem. 2005, 70, 5119-5125. (c)
Ploypradith, P.; Mahidol, C.; Sahakitpichan, P.; Wongbundit, S.; Ruchirawat,
S. Angew. Chem., Int. Ed. 2004, 43, 866-868. (d) Ploypradith, P.;
Jinaglueng, W.; Pavaro, C.; Ruchirawat, S. Tetrahedron Lett. 2003, 44,
1363-1366. (e) Ruchirawat, S.; Mutarapat, M. Tetrahedron Lett. 2001, 42,
1205-1208.
(9) (a) Kluza, J.; Gallego, M. A.; Loyenz, A.; Beauvillian, J. C.; Sousa-
Faro, J. M.; Cuevas, C.; Marchetti, P.; Bailly, C. Cancer Res. 2006, 66,
3177-3187. (b) Bailly, C. Curr. Med. Chem. Anticancer Agents. 2004, 4,
363-378. (c) Ridley, C. P.; Reddy, M. V.; Rocha, G.; Bushman, F. D.;
Faulkner, D. J. Bioorg. Med. Chem. 2002, 10, 3285-3290. (d) Reddy, M.
V.; Rao, M. R.; Rhodes, D.; Hansen, M. S.; Rubins, K.; Bushman, F. D.;
Venkateswarlu, Y.; Faulkner, D. J. J. Med. Chem. 1999, 42, 1901-1907
and references therein.
During the past 10 years, many research groups have
developed Cu-mediated reactions to form C-O bonds using
various copper salts in catalytic and/or stoichiometric amounts.1
The classical Ullmann reaction2 requires harsh conditions, high
temperature, strong base, and long reaction times in high polar
solvents with stoichiometric quantities of copper. Buchwald has
reported Caryl-O bond formation using the modern Ullmann
reaction.3 Various copper(I) salts such as copper iodide (CuI),
copper bromide (CuBr), and copper chloride (CuCl) as well as
† Chulabhorn Research Institute.
‡ Chulabhorn Graduate Institute.
§ Mahidol University.
(1) For the reviews on organocopper, see: (a) Ley, S. V.; Thomas, A.
W. Angew. Chem., Int. Ed. 2003, 42, 5400-5499. (b) Kunz, K.; Scholz,
U.; Ganzer, D. Synlett 2003, 2428-2439. (c) Sawyer, J. S. Tetrahedron
2000, 56, 5045-5065.
(2) (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1904, 37, 853-857. (b)
Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2389-2391.
(3) For selected publications on Cu(I)-catalyzed C-O bond formations,
see: (a) Wolter, M.; Nordmann, G.; Job, G. E.; Buchwald, S. L. Org. Lett.
2002, 4, 973-976. (b) Marcoux, J.-F.; Doye, S.; Buchwald, S. L. J. Am.
Chem. Soc. 1997, 119, 10539-10540. see also (c) Lipshutz, B. H.; Unger,
J. B. Org. Lett. 2007, 9, 1089-1092. (d) He, H.; Wu, Y.-J. Tetrahedron
Lett. 2003, 43, 3445-3446.
(10) Hosoya, T.; Takashiro, E.; Matsumoto, T.; Suzuki, K. J. Am. Chem.
Soc. 1994, 116, 1004-1015.
(11) Koch, K.; Podlech, J.; Pfeiffer, E.; Metzler, M. J. Org. Chem. 2005,
70, 3275-3276.
(12) (a) Yao, T.; Yue, D.; Larock, R. C. J. Org. Chem. 2005, 70, 9985-
9989. (b) Kraus, G. A.; Zhang, N. J. Org. Chem. 2000, 65, 5644-5646.
(c) Chuder, B. A.; Kalinin, A. V.; Taylor, N. J.; Snieckus, V. Angew. Chem.,
Int. Ed. 1999, 38, 1435-1438.
(13) (a) Palencia, H.; Garcia-Jimenez, F.; Takacs, J. M. Tetrahedron Lett.
2004, 45, 3849-3853. (b) Langer, P.; Saleh, N. N. R.; Freifeld, I. Chem.
Commun. 2002, 168-169. (c) Muraki, T.; Togo, H.; Yokoyama, M. J.
Chem. Soc., Perkin Trans. 1 1999, 1713-1716.
10.1021/jo701599g CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/02/2007
J. Org. Chem. 2007, 72, 9379-9382
9379

TABLE 1. Synthesis of Dibenzo[b,d]pyran-6-one 5a Using
Cu(I)-Mediated and MW-Assisted Lactonizationa
entry
acid
Cu(I)
solvent
yield (%)
1
2
3
4
5
6
7
8
6a
6b
6a
6b
6a
6b
6a
6b
CuI
CuI
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
58
53
88
84
65
81
94
97
CuBr
CuBr
CuCl
CuCl
CuTC
CuTC
FIGURE 1. Biologically active compounds (1-4) containing aromatic
lactone.
a Unless otherwise noted, the reactions were performed in a 10 mL
microwave vessel: compound 6 (0.2 mmol), Cu(I) salts (0.4 mmol) in DMF
(3 mL), 200 °C, 20 min.
Herein, we report a new efficient synthesis of benzopyranones
and isolamellarin alkaloids, isomeric with the marine lamellarin
alkaloids. Our strategy is based on the Cu(I)-mediated and
microwave-assisted14 intramolecular Caryl-Ocarboxylate lactone
bond formation under ligand- and base-free conditions. A series
of copper(I) salts including CuI, CuBr, CuCl, and CuTC as well
as ligands and bases were examined for the model study. We
note that the successful preparation of benzopyranones, to the
best of our knowledge, is the first metal-catalyzed coupling of
Caryl-Ocarboxylate lactone bond formation using a combination
of Cu(I)-mediated and microwave-assisted reactions. We have
extended our work to synthesize various lactone systems.
In a preliminary investigation, the synthesis of dibenzo[b,d]-
pyran-6-one 5a was studied. Synthesis of the required 2-halo-
biarylcarboxylic acid 6 was prepared by the Suzuki cross-
coupling reaction between the iodoaryl carboxylate esters and
2-haloarylboronic acids to form the C-C bond of the biaryl
compounds 7. The reaction involved the use of Pd(PPh3)4 as a
catalyst and 10% Na2CO3 in solvent mixtures of toluene and
EtOH.15 To obtain the hydrolyzed products 6, compounds 7 were
saponified using potassium hydroxide as a base in methanol.
The reaction was quenched with 2 N hydrochloric acid, and
compounds 6 were obtained in good to excellent yields (89-
96% yield).
Lactonization was carried out in DMF and/or solvent mixtures
of DMF either with EtOH or water using a series of copper(I)
salts under microwave irradiation. Among the various copper
salts examined, CuTC provided the desired product 5a in the
best yields (Table 1, entries 7 and 8) using microwave irradiation
with ligand- and base-free conditions. Our endeavor to use a
single solvent, either EtOH or water, failed. However, the yields
were moderate when mixtures of DMF/EtOH or DMF/water
were used as solvents. This C-Ocarboxylic bond formation
represents the first reported copper-mediated lactonization.
However, using CuI gave the lowest yields as shown in Table
1, and stoichiometric amounts of copper salts (2 equiv) were
necessary.
FIGURE 2. Ligands and differing amounts of CuI for the lactonization.
MW heating conditions: 2-chlorobiphenylcarboxylic acid 6b (0.2
mmol), Cs2CO3 (0.3 mmol), DMF, 200 °C, 20 min.
We next turned our attention to investigate the reaction
conditions which may require only catalytic amount of Cu(I)
salts for lactonization. CuI was used to study the Cu-catalyzed/
microwave-assisted lactonization of biarylcarboxylic acid 6b by
varying the type and amount of ligands. A set of bidentate
ligands including N,N,N′,N′-tetramethylethylenediamine (TME-
DA), bipyridine (Bip), and phenanthroline (Phen) was examined
together with different substoichiometric amounts (10-50 mol
%) of CuI as catalyst and Cs2CO3 as base in the three-component
reaction in DMF using microwave irradiation. The effectiveness
of several ligands was evaluated by comparing the ratio of CuI.
However, no ligands were found to promote lactonization. The
most effective condition was found to be 50 mol % of CuI
without ligand (Figure 2, 91% yield).
Based on the above observations, we then examined the best
conditions with various bases using 50 mol % of CuI under the
optimized conditions. The most effective base for lactonization
was found to be Na2CO3, which gave the best yield (Table 2,
entry 2). The yield dramatically decreased without base under
substoichiometric lactonization conditions.
To extend the scope of this methodology toward the synthesis
of benzopyranone derivatives, the reaction of several biaryl-
carboxylic acids was studied under substoichiometric conditions
using 50 mol % of CuI and Na2CO3 as base (method B). We
also examined the lactonization using CuTC (method A) which
gave the best result in stoichiometric amounts to compare Cu-
mediated lactonization with Cu-catalyzed lactonization.
(14) For microwave irradiation, see: (a) Kappe, C. O.; Stadler, A. In
MicrowaVes in Organic and Medicinal Chemistry; Mannhold, R., Kubinyi,
H., Folkers, G., Eds.; Wiley-VCH: Weinheim, 2005. (b) Hayes, B. L.
MicrowaVe Synthesis: Chemistry at the Speed of Light; CEM Publishing:
Matthews, 2002. (c) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 44, 6250-
6284.
(15) Sahakitpichan, P.; Thasana, N.; Ruchirawat, S. Synthesis 2005,
2934-2938.
9380 J. Org. Chem., Vol. 72, No. 24, 2007

TABLE 2. Base Screening for the Lactonizationa
TABLE 3. Synthesis of Benzopyranone Derivatives 5 Using
CuTC-Mediated (Method A) and CuI-Catalyzed (Method B)
Lactonizationa
entry
base
yield (%)
1
2
3
4
5
NaOAc
Na2CO3
K2CO3
Cs2CO3
no base
93
99
92
91
43
a MW heating conditions: 2-chlorobiphenylcarboxylic acid 6b (0.2
mmol), 50 mol % of CuI, base (0.3 mmol), DMF, 200 °C, 20 min.
Benzopyranones 5a-d were obtained in good to excellent
yields from all biarylcarboxylic acids (Table 3, entries 1-6).
Surprisingly, microwave irradiation provided powerful energy
for the CuTC-mediated lactonization of 2-halophenylindole
carboxylic acids to give indolactone 5e,f in good to excellent
yields. In contrast, using conventional heating under CuTC-
mediated conditions16 or CuI-mediated catalytic conditions using
microwave irradiation (method B), the lactonization either
proceeded in poor yield or resulted in no desired product (Table
3, entries 7-10). Under these basic and substoichiometric
conditions, adducts from decarboxylation were obtained as major
products. Coumestan 5g was also obtained in good yield using
CuTC-mediated lactonization from 2-(2-bromophenyl)benzo-
furan-3-carboxylic acid.17 However, treatment of this acid under
substoichiometric conditions afforded lactone 5g in poor yield
(Table 3, entry 11). The lactonization of 2-haloaryl aliphatic
acids failed using either method, and oxidative decarboxylation
adducts were observed (Table 3, entries 12-14).
Based on these results, the versatility of the procedure was
illustrated, and it is shown that copper-mediated Caryl-Ocarboxylic
coupling lactonization reactions of dibenzopyranone derivatives
work very well under both stoichiometric/base-free and subs-
toichimetric/basic conditions from biarylcarboxylic acids. In-
dolecarboxylic acids and benzofurancarboxylic acids also gave
lactones in good yields from stoichiometric/base-free conditions;
however, the yield was decreased under substoichimetric/basic
conditions. Both conditions failed to give the lactones from the
2-haloarylaliphatic acids.
Having successfully developed a route for the synthesis of
benzopyranones, we then applied the above approach to the
synthesis of isolamellarins 12. In order to study the effect of
substitution on the biological activity of the lamellarins and other
closely related compounds, we have initiated synthetic studies
for isolamellarin 12 where the R-carboxylic group and the â-aryl
groups are transposed.
The synthesis of isolamellarin with a more complex oxygen-
ation pattern in the lactone ring as normally found in natural
lamellarin alkaloids was then studied as shown in Scheme 1.
Toward this end, our first target was the isolamellarin 12a,
isomeric with lamellarin G trimethyl ether.8e The condensation
of 8 with R-chloro-3-(4,5-dimethoxyphenyl) pyruvate18 9a in
the presence of K2CO3 in acetonitrile afforded pyrrolo[2,1-a]-
isoquinoline carboxylate 10a in moderate yield (49%). The
a Unless otherwise noted, the reactions were performed in a 10 mL
microwave vessel: biarylcarboxylic acid (0.2 mmol) in DMF (3 mL).
b Stoichiometric condition: CuTC (0.4 mmol), 200 °C, 20 min. c Substo-
ichiometric conditions: 50 mol % of CuI, Na2CO3 (1.5 equiv), 200 °C, 20
min. d The reactions were performed in a 10 mL microwave vessel: 2-(2-
bromophenyl)benzofuran-3-carboxylic acid (0.1 mmol) in DMF (2 mL).
reaction presumably involves the intramolecular reaction of the
enamine derived from the isoquinolinium salt and the ketone
as found in the Knorr pyrrole synthesis.19 Ester compound 10a
was hydrolyzed with KOH in aqueous i-PrOH to give the
pyrrolo[2,1-a]isoquinoline carboxylic acid 11a in excellent yield
(16) Lactone 5e was obtained in only 3% yield from 3-(2-chlorophenyl)-
indole-2-carboxylic acid under conventional heating, refluxing DMF
overnight,and lactone 5f was obtained in 7% yield from 2-(2-chlorophenyl)-
indole-3-carboxylic acid. Reaction with (2-bromophenyl)indole carboxylic
acid derivatives showed no lactone formation under the same conditions.
(17) Thasana, N.; Prachyawarakorn, V.; Tontoolarug, S.; Ruchirawat,
S. Tetrahedron Lett. 2003, 44, 1019-1021.
(18) (a) Coutrot, P.; Grison, C.; Coutrot, F. Synlett 1998, 393-395. (b)
Coutrot, P.; Grison, C.; Tabyaoni, M.; Czernecki, S.; Valery, J.-M. J. Chem.
Soc., Chem. Commun. 1988, 1515-1516.
(19) (a) Casagrande, C.; Invernizzi, A.; Ferrari, G.; Ferrini, R. J. Med.
Chem. 1968, 11, 765-770. (b) Alberola, A.; Ortega, A. G.; Sa´daba, M. L.;
San˜udo, C. Tetrahedron 1999, 55, 6555-6566.
J. Org. Chem, Vol. 72, No. 24, 2007 9381

SCHEME 1. Synthesis of Isolamellarins 12
silica gel and washed with EtOAc (4 × 25 mL). The solvent was
concentrated under reduced pressure to give a pale yellow solid
which was then recrystallized with EtOAc/hexane to give ben-
zopyran-6-one 5 (e.g., 5a; 36.7 mg, 94% yield)20 as a white solid.
General Procedure for Lactonization Reaction (Method B).
Dibenzo[b,d]pyran-6-one (5a). In a 10 mL microwave vessel, 2′-
halobiphenyl-2-carboxylic acid (e.g., 6b; 46.5 mg, 0.2 mmol, 1.0
equiv), CuI (19.4 mg, 0.1 mmol, 0.5 equiv), and Na2CO3 (33 mg,
0.3 mmol, 1.5 equiv) were dissolved in DMF (3 mL) followed by
sealing of the vessel and heating to 200 °C for 20 min in a
microwave reactor. The reaction temperature increased from 25 to
200 °C in 120 s and was maintained at 200 °C for the duration.
The yellow-brown precipitate was filtered through silica gel and
washed with EtOAc (4 × 25 mL). The solvent was concentrated
under reduced pressure to give a pale yellow solid which was then
recrystallized with EtOAc/hexane to give benzopyran-6-one 5 (e.g.,
5a; 38.4 mg, 98% yield)20 as a white solid.
General Procedure for Synthesis of Isolamellarin. 2,3,8,9-
Tetramethoxy-13-(3,4-dimethoxyphenyl)-5H,6H-11-oxa-6a-aza-
dibenzo[a,g]fluoren-12-one (12a). In a 10 mL microwave vessel,
pyrrolo[2,1-a]isoquinolinecarboxylic acid (e.g., 11c; 25 mg, 0.04
mmol, 1.0 equiv) and CuTC (18 mg, 0.08 mmol, 2.0 equiv) were
dissolved in DMF (1 mL) followed by sealing of the vessel and
heating to 200 °C for 20 min in a microwave reactor. The reaction
temperature increased from 25 to 200 °C in 120 s and was
maintained at 200 °C for the duration. The yellow-brown precipitate
was filtered through silica gel and washed with EtOAc (4 × 25
mL). The solvent was concentrated under reduced pressure to give
a pale yellow solid which was then recrystallized with EtOAc/
hexane to give isolamellarin 12 (e.g., 12a; 18.7 mg, 86% yield) as
a gray solid: mp >235 °C (ethyl acetate-hexane); IR (KBr) νmax
1713, 1515, 1465, 1267, 1101 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.36 (s, 1H), 7.08 (dd, J ) 8.0, 1.0 Hz, 1H), 7.06 (d, J ) 1.0 Hz,
1H), 7.01 (s, 1H), 6.94 (d, J ) 8.0 Hz, 1H), 6.74 (s, 1H), 6.67 (s,
1H), 4.62 (t, J ) 6.4 Hz, 2H), 4.01 (s, 3H), 3.95 (s, 3H), 3.92 (s,
3H), 3.90 (s, 3H), 3.85 (s, 3H), 3.39 (s, 3H), 3.18 (t, J ) 6.3 Hz,
1H); 13C NMR (100 MHz, CDCl3): δ 158.5, 149.8, 148.7, 148.4,
148.1, 147.7, 147.5, 145.5, 133.9, 129.8, 126.3, 124.1, 123.2, 120.8,
119.7, 114.1, 111.0, 110.4, 108.6, 106.3, 104.4, 104.3, 101.6, 56.8,
56.1, 55.9 (3C), 55.3, 43.3, 29.0; HRMS (posFAB) calcd for C31H30-
NO8 (M + H)+ 544.1971, found 544.1973.
(96%). Steglich has successfully utilized lead(IV) acetate for
lactone formation from the corresponding 2-pyrrolecarboxylic
acid in an elegant synthesis of the lamellarin.7e However,
treatment of 11a in refluxing ethyl acetate with 1 equiv of lead-
(IV) acetate afforded lactone 12a in a disappointing yield (7%).
Presumably, for the reaction to proceed well, strict coplanarity
of the aromatic ring and the carboxylic group is required.
An alternative method for the synthesis of the lactone was
also investigated using our methodology. In an effort to form
lactone ring in isolamellarin 12b by the aromatic C-Ocarboxylic
bond formation, we prepared the brominated analogue pyrrolo-
[2,1-a]isoquinoline 11b. Successfully, the isolamellarin 12b was
prepared from the corresponding bromopyrrolecarboxylic acid
11b in 95% yield using method A. Application of this protocol
to the formation of lactone in the formation of isolamellarin
12a furnished the desired product from the corresponding
bromopyrrole carboxylic acid 11c in 86% yield.
In conclusion, a simple and highly effective C-Ocarboxylic
lactonization method catalyzed by copper(I) salts has been
developed to synthesize benzopyranones. The reaction of various
2-halobiarylcarboxylic acids was examined using microwave
irradiation. A new class of pyrroloisoquinoline alkaloids,
isolamellarins, was synthesized on the basis of the ring
annulation of dihydroisoquinoline with aryl pyruvates under
basic conditions and Cu-mediated/MW-assisted C-Ocarboxylic
lactonization. The method developed and reported here should
be applicable to the synthesis of lactone system in natural
products, biologically active compounds, and materials.
Acknowledgment. This work is dedicated to Professor Dr.
HRH Princess Chulabhorn Mahidol on the occasion of her 50th
birthday. N.T. would like to thank Professor L. S. Liebeskind
for the procedure of preparation of CuTC. Financial support
from the Thailand Research Fund (TRF; RMU4980048 for
N.T.), from the Thailand Toray Science Foundation (TTSF) for
N.T., and from NSF-REU research fellowship (INT-0123857
for L.Y. and CHE-0453126 for E.H.) is gratefully acknowl-
edged.
Experimental Section
Supporting Information Available: General methods, experi-
mental procedures as well as spectroscopic data and copies of NMR
spectra of all new compounds (5b-g, 10a-c, 11a-c, and 12a,b).
This material is available free of charge via the Internet at
http://pubs.acs.org.
General Procedure for Lactonization Reaction (Method A).
Dibenzo[b,d]pyran-6-one (5a). In a 10 mL microwave vessel, 2′-
halobiphenyl-2-carboxylic acid (e.g., 6a; 55.4 mg, 0.2 mmol, 1.0
equiv) and CuTC (76.4 mg, 0.4 mmol, 2.0 equiv) were dissolved
in DMF (3 mL) followed by sealing of the vessel and heating to
200 °C for 20 min in a microwave reactor. The reaction temperature
increased from 25 to 200 °C in 120 s and was maintained at 200 °C
for the duration. The yellow-brown precipitate was filtered through
JO701599G
(20) For complete characterization of compound 5, see the Supporting
Information.
9382 J. Org. Chem., Vol. 72, No. 24, 2007