Efficient one-pot synthesis of dibenzopyranones via a decarboxylative cross-coupling and lactonization sequence

Article abstract of DOI:10.1002/adsc.201100338

A highly selective palladium bis(acetoacetonate)/copper(I) chloride [Pd(acac)₂/CuCl] catalytic system for the preparation of dibenzopyranones has been developed. Tandem decarboxylative coupling and lactonization can be realized in one pot using commercially available starting materials. The reaction proceeded well for a range of different substrates. Copyright

Full text of DOI:10.1002/adsc.201100338

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DOI: 10.1002/adsc.201100338
Efficient One-Pot Synthesis of Dibenzopyranones via a
Decarboxylative Cross-Coupling and Lactonization Sequence
Jiaying Luo,a Youling Lu,a Saiwen Liu,a Jing Liu,a and Guo-Jun Denga,*
a
Key Laboratory of Environmentally Friendly Chemistry and Application of Ministry of Education, College of Chemistry,
Xiangtan University, Xiangtan 411105, Peopleꢀs Republic of China
Fax : (+86)-731-5829-2251; phone: (+86)-731-5829-8601; e-mail: gjdeng@xtu.edu.cn
Received: May 1, 2011; Revised: June 26, 2011; Published online: October 10, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100338.
Abstract: A highly selective palladium bis(acetoa-
cetonate)/copper(I) chloride [Pd(acac)2/CuCl] cata-
synthesis using widely available starting materials and
fewer steps is highly desirable. Very recently, Visnu-
murthy and co-workers developed a microwave-pro-
moted one-step parallel synthesis of dibenzopyra-
nones via Suzuki–Miyaura cross-coupling from bro-
moarylcarboxylates and o-hydroxyarylboronic acids,
followed by lactonization. Various dibenzopyranones
can be prepared by this method in high yields
[Scheme 1, Eq. (2)].[13] However, most of the starting
materials used for this transformation are not com-
mercially available.
AHCTUNGTRENNUNG
lytic system for the preparation of dibenzopyra-
nones has been developed. Tandem decarboxylative
coupling and lactonization can be realized in one
pot using commercially available starting materials.
The reaction proceeded well for a range of different
substrates.
Keywords: copper; decarboxylation; dibenzopyra-
nones; lactonization; palladium; tandem reactions
Carboxylic acids are easy to store, simple to handle,
and when necessary, are accessible preparatively by
means of a large number of well-established methods.
The ready availability of carboxylic acids makes them
Dibenzopyranone motifs are present in many natural extremely promising raw materials for chemical syn-
products and biologically active molecules.[1] Dibenzo- thesis.[14] In the 1960s, Nilsson et al. observed that
pyranones are of great importance as intermediates biaryls could be obtained from aryl iodides and aro-
for the synthesis of various pharmaceutically interest- matic carboxylic acids.[15] However, this reaction has
ing compounds such as glucocorticoids,[2] progester- not attracted much attention for a long time due to
one,[3] endothelial cell proliferation inhibitors[4] and the low reaction yield, high reaction temperature and
androgen receptor ligands.[5] Common lactone synthe- large amount of copper salt used. Recently, transition
sis mainly relies on lactonization from the corre- metal-catalyzed decarboxylative cross-couplings have
sponding carboxylic acids and alcohols.[6] There are received much attention and have evolved as an ad-
several methods available for the synthesis of diben- vantageous alternative for biaryls synthesis. Using cat-
zopyranones which usually require several steps.[7] alytic amounts of metal catalysts, various biaryls can
The most used method involves Suzuki–Miyaura be prepared from aromatic carboxylic acids and aryl
[17]
cross-coupling followed by Lewis acid-[8] or metal[9]- halides[16] or even C H bonds.
Palladium and
À
mediated lactonization of ester and methoxy groups copper are the most used catalysts for decarboxylative
[Scheme 1, Eq. (1)]. For the lactonization step, other coupling reactions. Electron-withdrawing groups such
alternative synthetic routes have also been developed, as nitro group at the ortho-position of the carboxylic
for example, the direct lactonization of carboxylic acid can significantly increase the reactivity.
acid to an aromatic ring,[10] the displacement of a
Based on this knowledge, we hypothesized that an
nitro group with carboxylic acid[11] and the displace- alternative procedure using commercially available
ment of a benzyl group.[12] However, these methods starting materials for dibenzopyranone preparation
generally include several steps and require the purifi- might be possible via a decarboxylative coupling reac-
cation of the intermediates. Also, relatively expensive tion and lactonization sequence using 2-nitrobenzoic
reagents such as boronic acids and boron tribromide acid and methyl 2-bromobenzoate as starting materi-
are needed. Thus, the search for a dibenzopyranone als. The decarboxylative coupling of these substrates
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Efficient One-Pot Synthesis of Dibenzopyranones via a Decarboxylative Cross-Coupling
Scheme 1. Methods for the synthesis of dibenzopyranones.
will generate a methyl 2’-nitrobiphenyl-2-carboxylate ladium salts tested, PdACTHNUTRGNEUNG(acac)2 showed the best yield,
intermediate, and hydrolysis of the methyl carboxyl- and the desired product was obtained in 30% yield
ate will generate the corresponding carboxylic acid (entry 7). The combination of PdACTHNURTGNENUG(acac)2 and CuCl
which will undergo a displacement reaction between gave the desired product in 40% yield (entry 9). The
the carboxylic acid and the nitro group.[11] To get the reaction was inefficient in the absence of a copper
methyl 2’-nitrobiphenyl-2-carboxylate intermediate, catalyst (entry 10). However, the desired product
we started our investigation by using similar reaction could be achieved in 21% yield when CuCl was used
conditions to those developed by Goossen and co- as the sole catalyst (entry 11). Various ligands were
workers for decarboxylative preparation of 2-nitrobi- screened using PdACTHUNRGTNEUNG(acac)2 and CuCl as catalysts (en-
phenyl derivatives using a Pd/Cu catalytic system.[16a] tries 12–19). Among the nitrogen-containing ligands
To our surprise, we did not get the intermediate investigated, bipyridine exhibited the best efficiency
methyl 2’-nitrobiphenyl-2-carboxylate. Instead, the (entry 13). Various phosphines were also tested as li-
final product, dibenzopyranone, was observed as dete- gands and were more efficient than nitrogen-contain-
1
mined by GC-MS and H NMR methods in low yield. ing ligands (entries 15–19). The desired product could
This unexpected reaction inspired us to re-optimize be achieved in 88% yield when DPEphos {bis[(2-di-
the reaction conditions to get a satisfying yield for phenylphosphino)phenyl] ether} was used as ligand
substituted dibenzopyranones in one pot using com- (entry 19). The reactions in other solvents were also
mercially available starting materials. Herein we investigated (entries 20–22). DMSO (dimethyl sulfox-
report a one pot synthesis of dibenzopyranones by ide) and DMA (N,N-dimethylacetamide) are good
palladium/copper-catalyzed decarboxylative coupling solvents for this reaction.
and lactonization of esters with a nitro group
[Scheme 1, Eq. (3)].
With the optimized conditions in hand, the scope of
the reaction with respect to the substituted aryl esters
To begin our study, the reaction of commercially (1) and 2-nitrobenzoic acid (2a) was investigated
available methyl 2-bromobenzoate (1a) and 2-nitro- (Table 2). The desired product could be achieved in
benzoic acid (2a) was chosen as a model using Pd- 76% yield when methyl 2-bromobenzoate (1a) was
ACHTUNGTRENNUNG(OAc)2 and CuI as catalysts. When methyl 2-bromo- used (entry 1). The reaction yield decreased signifi-
benzoate was reacted with 1.2 equivalents of 2-nitro- cantly when ethyl 2-bromobenzoate was used, and
benzoic acid, the desired product was observed in only 34% yield was obtained (entry 2). Methyl 2-
16% yield (Table 1, entry 1). The reaction showed chlorobenzoate (1c) and methyl 2-iodobenzoate (1d)
very poor selectivity and homo-coupling by-products also could be successfully coupled with 2a and gave
of 1a and 2a were obtained in 22% and 24% yields, the desired products in 70% and 65% yields, respec-
respectively. To improve the reaction yield and selec- tively (entries 3 and 4). Electron-donating groups
tivity, various palladium and copper salts were tested present on the aryl esters favored the reaction and
for this transformation (entries 2–9). Among the pal- good yields were obtained when 1e and 1f were used
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Table 1. Optimization of reaction conditions.[a]
Table 2. . Reaction of 2-nitrobenzoic acid 2a with various es-
ters[a]
[a]
Conditions: 1a (0.2 mmol), 2a (1.2 equiv.), Pd
[a]
Conditions: 1 (0.2 mmol), 2a (0.24 mmol), PdACHTUNGTRENNUNG(acac)2
(2.5 mol%), Cu (25 mol%), ligand (10 mol%), K2CO3
(2.5 equiv.), solvent (0.5 mL), 4 ꢂ molecular sieves
(150 mg), 1658C, 16 h under argon.
(2.5 mol%), CuCl (25 mol%), DPEphos (10 mol%),
K2CO3 (2.5 equiv.), 4 ꢂ molecular sieves (150 mg), NMP
(0.5 mL), 1658C, 16 h under argon.
Isolated yield.
Reaction was carried out at 1458C.
[b]
GC-MS yield based on 1a.
[b]
[c]
(entries 5 and 6). However, electron-withdrawing sub-
stituted groups resulted in lower yields (entries 7 and zoate and gave the desired product 3g in 76%, 65%
8). Substrate with a methyl group ortho to the bro- and 63% yield, respectively (Table 3, entries 1–3). 5-
mide also reacted smoothly with 2a and gave the de- Methoxy-2-nitrobenzoic acid (2c) also reacted with 1
sired product in moderate yield (entry 9).
and gave the desired product 3h in 83%, 74% and
Other substituted 2-nitrobenzoic acids were also in- 68% yield, respectively (entries 4–6). Electron-with-
vestigated under the same conditions. 5-Methyl-2-ni- drawing substituent groups such as fluoride at the
trobenzoic acid (2b) reacted with methyl 2-bromoben- para-position of the nitro group resulted in lower
zoate, methyl 2-chlorobenzoate, methyl 2-iodoben- yields (entries 7–9). Functional groups such as chlo-
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Efficient One-Pot Synthesis of Dibenzopyranones via a Decarboxylative Cross-Coupling
Table 3. Reaction of 1 with various substituted 2-nitrobenzo-
ic acids 2.[a]
Scheme 2. Lactonization of 5’-methoxy-2’-nitrobiphenyl-2-
carboxylate.
difluoro-2-nitrobenzoic acid (2h) was used (entries 12
and 13).
When methyl 5’-methoxy-2’-nitrobiphenyl-2-carbox-
ylate was treated with palladium/copper catalysts
under the standard reaction conditions, the desired
product 3h was obtained in 62% yield (Scheme 2).
When the amount of molecular sieves was increased
to 500 mg, the desired product was obtained in a simi-
lar yield. This means the displacement occurred di-
rectly between the ester group and the nitro group
without hydrolysis. The mechanism for the direct dis-
placement reaction is not clear at this stage.[18]
In summary, we have developed a highly selective
palladium/copper-catalyzed tandem reaction for the
formation of substituted dibenzopyranones. The de-
carboxylative cross-coupling and cyclization were re-
alized in one pot. The reaction proceeded well for a
range of different substrates. This research affords a
short cut for the preparation of substituted dibenzo-
pyranones. Further investigations including studies on
the scope and mechanism are in progress in our labo-
ratory.
Experimental Section
Typical Procedure
A 10-mL oven-dried reaction vessel was charged with
PdACTHNUTRGEN(UGN acac)2 (1.53 mg, 0.005 mmol), DPEphos (10.76 mg,
0.02 mmol), CuCl (4.95 mg, 0.05 mmol), K2CO3 (69.0 mg,
0.5 mmol), 4 ꢂ molecular sieves (150 mg), 2-nitrobenzoic
acid (2a, 40.1 mg, 0.24 mmol) and purged with argon three
times. Methyl 2-bromobenzoate (1a, 28.7 mL, 0.2 mmol) and
NMP (0.5 mL) were added by syringe. The resulting solution
was stirred at 1658C for 16 h. After cooling to room temper-
ature, the volatiles were removed under vacuum and the res-
idue was purified by column chromatography (silica gel, pe-
troleum ether/ethyl acetate=20:1) to give 3a as white solid;
yield: 29.8 mg (76%).
[a]
Conditions: 1 (0.2 mmol), 2 (0.24 mmol), Pd (acac)2
(2.5 mol%), CuCl (25 mol%), DPEphos (10 mol%),
K2CO3 (2.5 equiv.), 4 ꢂ molecular sieves (150 mg), NMP
(0.5 mL), 1658C, 16 h under argon.
Isolated yield based on 1.
GC-MS yield.
[b]
[c]
ride could survive under the optimized reaction con-
ditions and a moderate reaction yield was obtained
when 5-chloro-2-nitrobenzoic acid was used
(entry 10). A methyl group at the ortho-position of
the nitro group did not significantly affect the reac-
tion yield (entry 11). An excellent yield was obtained
when 4,5-dimethoxy-2-nitrobenzoic acid (2g) was
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (20902076, 21172185), the Hunan Pro-
vincial Natural Science Foundation of China (11JJ1003) and
the One Hundred Talent Project of Hunan Province
used whereas only 6% yield was obtained when 4,5- (11QDZ28).
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References
Ratajczyk, D. P. Larson, S. W. Elmore, J. K. Pratt,
M. A. Stashko, H. Douglass Falls, C. W. Lin, M.
Nakane, L. Miller, C. M. Tyree, J. N. Miner, P. B. Jacob-
son, D. M. Wilcox, P. Nguyen, B. C. Lane, J. Med.
Chem. 2003, 46, 1016; e) B. I. Alo, P. A. Patil, M. J.
Sharp, M. A. Siddiqui, V. Snieckus, J. Org. Chem. 1991,
56, 3763.
[1] a) K. Koch, J. Podlech, E. Pfeiffer, M. Metzler, J. Org.
Chem. 2005, 70, 3275; b) H. Abe, K. Nishioka, S.
Takeda, M. Arai, Y. Takeuchi, T. Harayama, Tetrahe-
dron Lett. 2005, 46, 3197; c) C. Garino, F. Bihel, N. Pie-
trancosta, Y. Laras, G. Quelever, I. Woo, P. Klein, J.
Bain, J. L. Boucher, J. L. Kraus, Bioorg. Med. Chem.
Lett. 2005, 15, 135; d) W. Sun, L. D. Cama, E. T. Birzin,
S. Warrier, L. Locco, R. Mosley, M. L. Hammond, S. P.
Rohrer, Bioorg. Med. Chem. Lett. 2006, 16, 1468;
e) R. W. Pero, D. Harvan, Tetrahedron Lett. 1973, 945;
f) W. T. L. Sidwell, H. Fritz, C. Tamm, Helv. Chim. Acta
1971, 54, 207; g) H. Raistrick, C. E. Stilkings, R.
Thomas, Biochemistry 1953, 55, 421.
[2] a) M. J. Coghlan, P. R. Kym, S. W. Elmore, A. X. Wang,
J. R. Luly, D. Wilcox, M. Stshko, C. W. Lin, J. Miner, C.
Tyree, M. Nakane, P. Jacobsen, B. C. Lane, J. Med.
Chem. 2001, 44, 2879; b) Y. Y. Ku, T. Grieme, P. Raje,
P. Sharma, S. A. King, H. E. Morton, J. Am. Chem.
Soc. 2002, 124, 4282.
[3] a) J. P. Edwards, S. J. West, K. B. Marschke, D. E. Mais,
M. M. Gottardis, T. K. Jones, J. Med. Chem. 1998, 41,
303; b) L. Zhi, C. M. Tegly, K. B. Marschke, D. E. Mais,
T. K. Jones, J. Med. Chem. 1999, 42, 1466.
[4] 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.
[5] a) L. G. Hamann, R. I. Higuchi, L. Zhi, J. P. Edwards,
X. N. Wang, K. B. Marchke, J. W. Kong, L. J. Farmer,
T. K. Jones, J. Med. Chem. 1998, 41, 623.
[6] For a review on lactonization in total synthesis of natu-
ral products, see: A. Parenty, X. Moreau, J. M. Cam-
pagne, Chem. Rev. 2006, 106, 911.
[7] a) M. E. Jung, D. A. Allen, Org. Lett. 2009, 11, 757;
b) R. Sanz, Y. Fernandez, M. P. Castroviejo, A. Perez,
F. J. Fananas, Eur. J. Org. Chem. 2007, 1, 62; c) J. A.
Teske, A. Deiters, Org. Lett. 2008, 10, 2195; d) Y. Y.
Ku, T. Grieme, P. Raje, H. E. Morton, M. Rozema,
S. A. King, J. Org. Chem. 2003, 68, 3238; e) T. Pundt,
M. Lau, I. Hussain, M. A. Yawer, H. Reinke, P. Langer,
Tetrahedron Lett. 2007, 48, 2745; f) I. Hussain, M. A.
Yawer, M. Lau, T. Pundt, C. Fischer, H. Goerls, P.
Langer, Eur. J. Org. Chem. 2008, 503; g) H. Palencia, F.
Garcia-jiminez, J. Takcs, Tetrahedron Lett. 2004, 45,
3849; h) V. Nguyen, P. Langer, Tetrahedron Lett. 2005,
46, 1013; i) S. Qi, K. Kawagoe, S. Miyano, Chem. Lett.
1993, 79; j) O. Boye, Y. Itoh, A. Brossi, Helv. Chim.
Acta 1989, 72, 1690; k) A. D. Khanolkar, D. Liu, M.
Ibrahim, R. Duclos Jr, G. A. Thakur, T. P. Malan Jr, F.
Porreca, V. Veerappan, X. Tian, C. George, D. A. Par-
rish, D. P. Papahatjis, A. Markriyannis, J. Med. Chem.
2007, 50, 6493.
[9] N. Thasana, R. Worayuthakarn, P. Kradanrat, E. Hohn,
L. Young, S. Ruchirawat, J. Org. Chem. 2007, 72, 9379.
[10] a) H. Togo, T. Muraki, M. Yokoyama, Tetrahedron Lett.
1995, 36, 7089; b) T. Muraki, H. Togo, M. Yokoyama, J.
Chem. Soc. Perkin Trans. 1 1999, 1713.
[11] a) D. H. Hey, J. A. Leonard, C. W. Rees, J. Chem. Soc.
1962, 4579; b) G. A. Val’kova, T. V. Sakhno, D. N. Shi-
govin, A. M. Andriecskii, A. Nn. Poplavskii, Russ. J.
Phys. Chem. 1981, 55, 459; c) C. Finzi, V. Bellavita,
Gazz. Chim. Ital. 1936, 66, 421.
[12] W. J. Zhang, B. I. Wilke, J. X. Zhan, K. Watanable,
C. N. Boddy, Y. Tang, J. Am. Chem. Soc. 2007, 129,
9304.
[13] K. Visnumurthy, A. Makriyannis, J. Comb. Chem. 2010,
12, 664.
[14] L. J. Goossen, N. Rodrꢃguez, K. Goossen, Angew.
Chem. 2008, 120, 3144; Angew. Chem. Int. Ed. 2008, 47,
3100.
[15] a) M. Nilsson, Acta Chem. Scand. 1966, 20, 423; b) M.
Nilsson, C. Ullenius, Acta Chem. Scand. 1968, 22, 1998.
[16] For selected decarboxylative biaryl synthesis, see:
a) L. J. Goossen, G. J. Deng, L. M. Levy, Science 2006,
313, 662; b) P. Forgione, M. St-Onge, K. H. Thesen,
M. D. Bailey, F. Bilofeu, J. Am. Chem. Soc. 2006, 128,
11350; c) L. J. Goossen, N. Rodrꢃguez, B. Melzer, C.
Linder, G. J. Deng, L. M. Levy, J. Am. Chem. Soc.
2007, 129, 4824; d) L. J. Goossen, B. Zimmermann, T.
Knauber, Angew. Chem. 2008, 120, 7211; Angew.
Chem. Int. Ed. 2008, 47, 7103; e) L. J. Goossen, N. Ro-
drꢃguez, C. Linder, J. Am. Chem. Soc. 2008, 130, 15248;
f) L. J. Goossen, F. Rudolphi, C. Oppel, N. Rodrꢃguez,
J. Am. Chem. Soc. 2008, 130, 15240; g) J. Cornella, P. F.
Lu, I. Larrosa, Org. Lett. 2009, 11, 5506; h) R. Shang,
Q. Xu, Y. Y. Jiang, Y. Wang, L. Liu, Org. Lett. 2010, 12,
1000; i) J. M. Becht, C. Catala, C. Drian, A. Wagner,
Org. Lett. 2007, 9, 1781; j) M. Miyasaka, A. Fukushima,
T. Satoh, K. Hirano, M. Miura, Chem. Eur. J. 2009, 15,
3674; k) P. P. Lange, L. J. Goossen, P. Podmore, T. Un-
derwood, N. Sciammetta, Chem. Commun. 2011, 47,
3628; l) L. J. Goossen, B. Melzer, J. Org. Chem. 2007,
72, 7473.
[17] a) C. Y. Wang, I. Piel, F. Glorius, J. Am. Chem. Soc.
2009, 131, 4194; b) A. Voutchkova, A. Coplin, N. E.
Leadbeater, R. H. Crabtree, Chem. Commun. 2008,
6312; c) H. Q. Zhao, Y. Wei, J. Xu, J. Kan, W. P. Su,
M. C. Hong, J. Org. Chem. 2011, 76, 882; d) K. Xie, Z.
Yong, X. L. Zhou, X. J. Li, S. Z. Wang, Z. Tan, C. C.
Guo, Org. Lett. 2010, 12, 1564; e) W. Y. Yu, N. Sit,
Z. Y. Zhou, A. S. C. Chan, Org. Lett. 2009, 11, 3174.
[18] When 2-nitrobenzoic acid (2a) was replaced by 2-fluo-
robenzoic acid, the desired product 3a was obtained in
56% yield.
[8] a) I. Hussain, V. T. H. Nguyen, T. T. Yawer, C. Fiscer,
H. Reinke, P. Langer, J. Org. Chem. 2007, 72, 6255;
b) G. J. Kemperman, B. Ter Horst, D. Van de Goor, T.
Roeters, J. Bergwerff, R. Van der Eem, J. Basten, Eur.
J. Org. Chem. 2006, 14, 3169; c) Q. J. Zhou, K. Worm,
R. E. Dolle, J. Org. Chem. 2004, 69, 5147; d) P. R. Kym,
M. E. Kort, M. J. Coghlan, J. L. Moore, R. Tang, J. D.
2608
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