Palladium-catalyzed paraformaldehyde insertion: A three-component synthesis of benzofurans

Article abstract of DOI:10.1039/c6ob00198j

An efficient procedure for 2-aroylbenzofuran preparation from 2-bromophenols, phenacyl bromides and paraformaldehyde is described. The cheap and stable paraformaldehyde served as the carbon source via an in situ formylation reaction.

Full text of DOI:10.1039/c6ob00198j

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Palladium-Catalyzed Paraformaldehyde Insertion: A
Three-Component Synthesis of Benzofurans
Received 00th January 20xx,
Accepted 00th January 20xx
Xiufang Cheng,a Yi Peng,a Jun Wu,a Guo-Jun Denga*
DOI: 10.1039/x0xx00000x
www.rsc.org/
formylation procedure using various formylating reagens.12
An efficient procedure for 2-aroylbenzofuran preparation
from 2-bromophenols, phenacyl bromides and
paraformaldehyde is described. The cheap and stable
paraformaldehyde served as the carbon source via an in
situ formylation reaction.
Paraformaldehyde is an abundant, easy to handle, and
inexpensive one carbon source. In recent years, various
methods have been developed to introduce paraformaldehyde
into more complex molecules as carbonyl or carbon source.13
Most of the developed methods are based on the condensation
of paraformaldehyde with active amino group or enamides.14, 15
Formylation of aromatic ring with paraformaldehyde is less
studied. Very recently, the Beller and Wu groups developed
palladium-catalyzed carbonylation of aryl bromides to
selectively afford aromatic aldehydes or heterocycles using
paraformaldehyde as the carbonyl source.16 We also developed
Benzofuran is one of the commonly encountered structural
motifs in natural products.1 In recent years, benzofuran
derivatives have seen numerous applications in the
development of pharmaceutical drugs and functionalized
materials.2 Particularly, the 2-aroylbenzofuran structural motifs
have displayed
a
range of biological activities.3 These
a
palladium-catalyzed phthalazinone synthesis using
heterocyclic compounds can be used as tubulin polymerization
inhibitors,4 antimitotic agents,5 and antimicrobials.6 Meanwhile,
2-aroylbenzofurans also could be used as key precursors for the
preparation of multisubstituted benzofurans such as 2-aroyl-3-
arylbenzofurans and 2-aroyl-3-alkylbenzofurans which both
showed important biological activities.7 Therefore, the
development of efficient methods for rapid construction of 2-
aroylbenzofurans attracted considerable interests. The classic
method for the synthesis of these compounds depends on the
Rap-Stoermer condensation of salicylaldehydes with α-
bromoketones.8 Recently, this reaction has been extensively
investigated and could be carried out under microwaves9 or
solvent-free conditions10 with good functional group tolerance.
Besides the Rap-Stoermer condensation reaction, few other
methods are also available to prepare 2-aroylbenzofuran
derivatives, including palladium-catalyzed arylation of
benzofuran-2-carbaldehydes with aryl boronic acids, acylation
of benzofurans and oxidative dehydrogenation of 2-aroyl
dihydrobenzofurans.11
paraformaldehyde as the carbon source via an in situ ortho
formylation of 2-halomethylbenzoates.17 It is highly desirable
to use paraformaldehyde as the carbon source for construction
of heterocyclic compounds. Based on our continuous interest in
heterocyclic compound preparation using readily available
materials,18 herein, we disclose an alternative route for the
three-component synthesis of 2-aroylbenzofurans from 2-
bromophenols, phenacyl bromides and paraformaldehyde under
palladium-catalyzed reaction conditions.
Scheme 1 2-Aroylbenzofurans formation using paraformaldehyde as carbon source.
Initial reaction optimization was performed with 2-
bromophenol
phenylethanone
(
1a),
paraformaldehyde,
2-bromo-1-
(2a), 1,1'-bis(diphenylphosphino)ferrocene
o
(dppf) and K2CO3 in toluene at 120 C under air atmosphere
(Table 1). Catalyst screening showed that Pd(COD)Cl2 gave the
best yield of the desired product (Table 1, entry 5). Then
various ligands were screened using Pd(COD)Cl2 as the catalyst.
The yield could be improved to 41% when dpppy (diphenyl-2-
The aforementioned procedures for the synthesis of 2-
aroylbenzofurans are mainly based on 2-hydroxybenzaldehydes
which could be prepared from phenols via an ortho-selective
aKey Laboratory of Environmentally Friendly Chemistry and Application of pyridylphosphine) was used (Table 1, entry 9). Notably, the
Ministry of Education, College of Chemistry, Xiangtan University, Xiangtan,
base played an important role in this kind of transformation.
411105, China. Fax: (+86)-731-58292251; Tel: (+86)-731-58298280; E-mail:
Among the various bases screened, K2CO3 showed the best
efficiency (Table 1, entries 9−13). Besides toluene, DMF and
DMSO are also good reaction media for this kind of reaction to
gjdeng@xtu.edu.cn
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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provide 3a in 46% and 65% yield, respectively (Table 1, entries (Table 2, entry 8). Hindered substrate such as 2i could smoothly
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DOI: 10.1039/C6OB00198J
15 and 16). Other organic solvents such as 1,2-dichloroethane react with 1a to give the product 3i in 45% yield (Table 2, entry
(DCE) and dioxane were much less efficient (Table 1, entries 9). To our delight, hetero ketones such as 2-bromo-1-(thiophen-
14 and 17). The reaction yield could be improved to 80% when 2-yl)ethanone (2j) also participated in the reaction to provide
o
the reaction temperature was increased to 140 C (entry 18). the corresponding benzofuran product 3j in moderate yield
The product 3a could be further improved to 86% yield when (Table 2, entry 10).
1.5 equiv of 2a was employed to the reaction (Table 1, entry
Table 2 Reactions of 1a with various ketones 2a
19).
Table 1 Optimization of the reaction conditionsa
a Conditions: 1a (0.2 mmol), 2a (0.24 mmol), paraformaldehyde (0.5 mmol),
a
Conditions: 1a (0.2 mmol), 2 (0.3 mmol), paraformaldehyde (0.5 mmol),
Pd(COD)Cl2 (5 mol %), dpppy (10 mol %), K2CO3 (0.6 mmol), DMSO (0.8
mL), 24 h, 140 oC under air. b Isolated yields based on 1a.
catalyst (5 mol %), ligand (10 mol %), base (0.6 mmol), solvent (0.8 mL), 24
h, 120 oC under air. b GC yield. c At 140 oC. d 2a (0.3 mmol).
With the optimized reaction conditions in hand, we then
investigated the scope of the reaction with respect to 2-
bromophenol (1a) and various phenacyl bromides (2) in the
To further explore the scope of the reaction, a number of
substituted 2-halophenols (1) were employed to react with 2a
and paraformaldehyde (Table 3). Moderate to good yields were
obtained when electron-donating groups such as methyl, ethyl,
propyl, methoxy and electron-withdrawing groups such as
fluoro, chloro, cyano and trifluoromethyl were present at the
para position of the hydroxy group (Table 3, entries 1-7, 9-11).
When 2-bromo-4,5-dimethylphenol (1m) was used, the desired
product 3v could be obtained in 68% yield (Table 3, entry 12).
presence of paraformaldehyde (Table 2). The model reaction of
1a with 2a and paraformaldehyde gave the desired product 3a
in 81% isolated yield (Table 2, entry 1). Substituents on the
phenyl ring of 2-bromo-1-arylethanone significantly affected
the reaction yields (Table 2, entries 2-8). When a methoxy
group was present, the corresponding product 3b was obtained
in 64% yield. Good yield could be achieved when a phenyl
group was located at the phenyl ring of 1a (Table 2, entry 3).
Moderate to good yields were obtained when fluoro and chloro
substituents were present (Table 2, entries 4 and 5). The
position of substituent profoundly affected the reaction yield.
When 2-bromo-1-(2-chlorophenyl)ethanone (2f) and 2-bromo-
Lower yield was obtained when 3-bromonaphthalen-2-ol (1n
)
was used as the substrate (Table 3, entry 13). To our delight, 2-
bromopyridin-3-ol (1p) could smoothly react with 2a to provide
the corresponding product 3x in 70% yield (Table 3, entry 15).
Similar yield could be achieved when 2-iodopyridin-3-ol (1q
)
was employed (Table 3, entry 16). However, much lower yield
was obtained when 2-chloropyridin-3-ol (1o) was used as the
substrate due to the low reactivity (Table 3, entry 14). It should
be noted that when 3-bromo-(1,1'-biphenyl)-4-ol (1i) and 1-
((1,1'-biphenyl)-4-yl)-2-bromoethanone (2c) were used as the
1-(3-chlorophenyl)ethanone
(
2g
)
were employed, the
corresponding product 3f and 3g were obtained in only 40%
and 41% yields, respectively (Table 2, entries 6 and 7). Under
the optimized reaction conditions, trifluoromethyl group was
well tolerated to give the corresponding product in 60% yield
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absence of palladium catalyst, reaction intermediate A was obtained
substrates, bioactive (1,1'-biphenyl)-4-yl(5-phenylbenzofuran-
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DOI: 10.1039/C6OB00198J
in 72% yield after 18 h (Scheme 2, a). Compound A could further
2-yl)methanone (3y) was obtained in 65% yield (Table 3, entry
17).6c The low reaction yields obtained in these reactions react with paraformaldehyde under the standard reaction conditions
mainly due to low conversions of substrates
1
.
to convert into the desired products 3a in 82% yield (Scheme 2, b).
No desired product was observed when chemical A was treated with
the optimized reaction conditions in the absence of
paraformaldehyde (Scheme 2, c). These control experiments showed
that A is a key intermediate and paraformaldehyde serves as an one
carbon source in the whole process.
Table 3 Reactions of 2a with various phenols 1a
Scheme 3 Possible reaction mechanism.
On the basis of the above observation and previous works done by
our group17 and others,16 a plausible mechanism for the three-
component reaction is proposed in Scheme 3. Substitution reaction
of 1a with 2a in the presence of base forms an intermediate A.
Oxidative addition of the C-Br bond of A to the Pd(0) species
affords intermediate B. Then,
a
migratory insertion of
paraformaldehyde into the Ar-Pd bond provides intermediate C, with
a subsequent -hydrogen elimination to produce a formylation
product D. Cyclization reaction of compound D in the presence of
base affords intermediate E which can provide the final product 3a
by loss H2O. The catalytic active Pd(0) is regenerated through
reductive elimination of the Pd(II)HBr complex to complete the
catalytic cycle. In another possible reaction pathway,
paraformaldehyde is decomposed into CO and H2. Subsequently, H2
is used as the hydride source reduces acyl palladium(II) complex
(similar to intermediate C) to the corresponding aldehyde D.16a
In summary, we have developed a straightforward and
efficient access to 2-aroylbenzofurans from 2-bromophenols,
phenacyl bromides and paraformaldehyde through palladium-
a
Conditions: 1 (0.2 mmol), 2a (0.3 mmol), paraformaldehyde (0.5 mmol),
Pd(COD)Cl2 (5 mol %), dpppy (10 mol %), K2CO3 (0.6 mmol), DMSO (0.8
mL), 24 h, 140 oC under air. b Isolated yields based on 1.
catalyzed
transformations.
The
cheap
and
stable
paraformaldehyde served as the carbon source via in situ
formylation reaction. Functional groups such as halogen and
trifluoromethyl were well tolerated under the optimized
reaction conditions. This three-component approach affords an
efficient route for the rapid synthesis of 2-aryl substituted
benzothiophenes. The scope, mechanism, and synthetic
application of this reaction are under investigation.
Scheme 2 Control experiments.
To have a better understanding of the reaction, several control
experiments were performed. When 1a reacted with 2a in the
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12 For reviews on formylation, see: (a) G. A. Olah, L. Ohannesian, M.
Acknowledgements
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Arvanaghi, Chem. Rev., 1987, 87, 671; (b) W. Kantlehner, Eur. J.
DOI: 10.1039/C6OB00198J
This work was supported by the National Natural Science
Foundation of China (21372187, 21572194), the Program for
Innovative Research Cultivation Team in University of Ministry of
Education of China (1337304) and the Hunan Provincial Innovative
Foundation for Postgraduate (CX2014B264).
Org. Chem., 2003, 2530. For selected examples on formylation of
phenols, see: (c) K. Chiba, T. Arakawa, M. Tada, Chem. Commun.,
1996, 1763; (d) S. P. Cook, A. Polara, S. J. Danishefsky, J. Am.
Chem. Soc., 2006, 128, 16440; (e) S. Tang, Y. Xu, J. He, Y. He, J.
Zheng, X. Pan, X. She, Org. Lett., 2008, 10, 1855; (f) K. B. Bahnck,
S. D. Rychnovsky, J. Am. Chem. Soc., 2008, 130, 13177; (g) D. H. T.
Phan, B. Kim, V. M. Dong, J. Am. Chem. Soc., 2009, 131, 15608.
13 For recent selected reviews on applications of paraformaldehyde, see:
Notes and references
(a) B. Sam, B. Breit, M. J. Krische, Angew. Chem. Int. Ed., 2015, 54
,
3267; (b) L. P. Wu, Q. Liu, R. Jackstell, M. Beller, Angew. Chem. Int.
Ed., 2014, 53, 6310; (c) W. F. Li and X. F. Wu, Adv. Synth. Catal.,
2016, 357, 3393.
1
(a) R. E. Ziegert, J. Toräng, K. Knepper, S. Bräse, J. Comb. Chem.,
2005, , 147; (b) B. F. Abdel-Wahab, H. A. Abdel-Aziz, E. M.
Ahmed, Eur. J. Med. Chem., 2009, 44, 2632; (c) C. Kirilmis, M.
Ahmedzade, S. Servi, M. Koca, A. Kizirgil, C. Kazaz, Eur. J. Med.
Chem., 2008, 43, 300.
(a) A. R. Katritzky, S. Rachwal, Chem. Rev., 2011, 111, 7063; (b) S.
B. Bharate, S. D. Sawant, P. P. Singh, R. A. Vishwakarma, Chem.
Rev., 2013, 113, 6761; (c) S. O. Simonetti, E. L. Larghi, A. B. J.
Bracca, T. S. Kaufman, Nat. Prod. Rep., 2013, 30, 941; (d) U. K. U.
Kucklaender, R. Bollig, W. Frank, A. Gratz, J. Bioorg. Med. Chem.,
2011, 19, 2666; (e) O. Saku, M. Saki, M. Kurokawa, K. Ikeda, T.
Takizawa, N. Uesaka, Med. Chem. Lett., 2010, 20, 1090.
(a) J. Y. Yeh, M. S. Coumar, J. T. Horng, H. Y. Shiao, F. M. Kuo, H.
L. Lee, I. C. Chen, C. W. Chang, W. F. Tang, S. N. Tseng, H. P.
Hsieh, J. Med. Chem., 2010, 53, 1519; (b) S. H. Wang, Y. Wang, Y.
Y. Zhu, J. Han, Y. F. Zhou, D. Koirala, D. W. Li, C. Hu, Arkivoc,
2010, 204.
R. Romagnoli, P. G. Baraldi, T. Sarkar, M. D. Carrion, O. Cruz-
Lopez, C. L. Cara, M. Tolomeo, S. Grimaudo, A. D. Cristina, M. R.
Pipitone, J. Balzarini, R. Gambari, L. Ilaria, R. Saletti, A. Brancale, E.
Hamel, Bioorg. Med. Chem., 2008, 16, 8419.
R. Romagnoli, P. G. Baraldi, T. Sarkar, M. D. Carrion, C. L. Cara, O.
Cruz-Lopez, D. Preti, M. A. Tabrizi, M. Tolomeo, S. Grimaudo, A. D.
Cristina, N. Zonta, J. Balzarini, A. Brancale, H. P. Hsieh, E. Hamel, J.
Med. Chem., 2008, 51, 1464.
(a) K. Bonjean, M. C. De Pauw-Gillet, M. P. Defresne, P. Colson, C.
Houssier, L. Dassonneville, C. Bailly, R. Greimers, C. Wright, J.
Quetin-Leclercq, M. Tits, L. Angenot, Biochemistry, 1998, 37, 5136;
(b) J. Lavrado, K. Gani, P. A. Nobre, S. A. Santos, P. Figueiredo, D.
Lopes, V. do Rosário, J. Gut, P. J. Rosenthal, R. M.oreira, A. Paulo,
7
14 For recent selected examples on applications of paraformaldehyde,
see: (a) J. M. Carcía, G. O. Jones, K. Virwani, B. D. McCloskey, D. J.
Boday, G. Huurne, H. W. Horn, D. J. Coady, A. M. Bintaleb, A.
Alaldulrahman, F. Alsewailem, H. Almegren, J. L. Hedrick, Science,
2014, 344, 732; (b) A. Khan, R. Zheng, Y. Kan, J. Ye, J. Xing, Y. J.
Zhang, Angew. Chem. Int. Ed., 2014, 53, 6439; (c) K. Park, Y. Heo, S.
Lee, Org. Lett., 2013, 15, 3322; (d) Z. Quan, W. Hu, Z. Zhang, Y. Da,
X. Jia, X. C. Wang, Adv. Synth. Catal., 2013, 355, 891; (e) C. Bausch,
2
R. Patman, B. Breit, M. J. Krische, Angew. Chem. Int. Ed., 2011, 50
5687; (f) A. Köpfer, B. Sam, B. Breit, M. J. Krische, Chem. Sci.,
2013, , 1876; (g) T. Smejkal, H. Han, B. Breit, M. J. Krische, J. Am.
Chem. Soc., 2009, 131, 10366; (h) Q. Liu, L. Wu, R. Jackstell, M.
Beller, ChemCatChem., 2014, , 2805; (i) Z. G. Ke, Y. Zhang, X. J.
,
3
4
6
Cui, F. Shi, Green Chem., 2016, DOI: 10.1039/c5gc01992c; (j) D. M.
Kaphan, F. D. Toste, R. G. Bergman, K. N. Raymond, J. Am. Chem.
Soc., 2015, 137, 9202.
4
5
6
15 For selected examples on using paraformaldehyde for aromatic
heterocycle construction, see: (a) X. D. Tang, L. B. Huang, J. D.
Yang, Y. L. Xu, W. Q. Wu, H. F. Jiang, Chem. Commun., 2014, 50
,
14793; (b) H. F. Jiang, J. D. Yang, X. D. Tang, J. X. Li, W. Q. Wu, J.
Org. Chem., 2015, 80, 8763; (c) T. Morimoto, K. Yamasaki, A.
Hirano, K. Tsutsumi, N. Kagawa, K. Kakiuchi, Y. Harada, Y.
Fukumoto, N. Chatani, T. Nishioka, Org. Lett., 2009, 11, 1777.
16 (a) K. Natte, A. Dumrath, H. Neumann, M. Beller, Angew. Chem. Int.
Ed., 2014, 53, 10090; (b) W. F. Li, X. F. Wu, J. Org. Chem., 2014,
79, 10410.
17 H. M. Wang, J. H. Cai, H. W. Huang, G. J. Deng, Org. Lett., 2014,
16, 5324.
Bioorg. Med. Chem. Lett., 2010, 20
,
5634; (c) C.
18 For our recent selected examples, see: (a) H. W. Huang, J. H. Cai, X.
C. Ji, F. H. Xiao, Y. Chen, G. J. Deng, Angew. Chem. Int. Ed., 2016,
55, 307; (b) J. J. Chen, G. Z. li, Y. J. Xie, Y. F. Liao, F. H. Xiao, G. J.
Deng, Org. Lett., 2015, 17, 5870; (c) S. W. Liu, R. Chen, H. Chen, G.
J. Deng, Tetrahedron Lett., 2013, 54, 3838; (d) X. X. Cao, X. F.
Cheng, Y. Bai, S. W. Liu, G. J. Deng, Green Chem., 2014, 16, 4644;
(e) Y. F. Liao, Y. Peng, H. R. Qi, H. Gong, G. J. Deng, C. J. Li,
Chem. Commun., 2015, 51, 1031.
Aswathanarayanappa, E. Bheemappa, Y. D. Bodke, V. K. Bhovi, R.
Ningegowda, M. C. Shivakumar, S. K. Peethambar, S. Telkar, Med.
Chem. Res., 2013, 22, 78.
(a) D. J. Paymode, C. V. Ramana, J. Org. Chem., 2015, 80, 11551; (b)
M. Ionita, J. Roger, H. Doucet, ChemSusChem., 2010, 3, 367; (c) A.
Carrer, D. Brinet, J. C. Forent, P. Rousselle, E. Bertounesque, J. Org.
Chem., 2012, 77, 1316; (d) Y. Kommagalla, K. Srinivas, C. V.
Ramana, Chem. - Eur. J., 2014, 20, 7884.
7
8
9
(a) N. P. Buuhoi, G. Saintruf, T. B. Loc, N. D. Xuong, J. Chem. Soc.,
1957, 2593; (b) J. P. Bachelet, P. Demerseman, R. Royer, R. Cavier,
J. Lemoine, Eur. J. Med. Chem., 1982, 17, 323.
M. L. N. Rao, D. K. Awasthi, D. Banerjee, Tetrahedron Lett., 2007,
48, 431.
10 K. Yoshizawa, S. Toyota, F. Toda, I. Csoregh, Green Chem., 2003,
353.
5
,
11 (a) X. Lei, C. Jiang, X. Wen, Q. L. Xu, H. B. Sun, RSC Adv., 2015,
5
,
14953; (b) T. Ueyama, S. Mochida, T. Fukutani, K. Hirano, T. Satoh,
M. Miura, Org. Lett., 2011, 13, 706; (c) D. S. Black, D. C. Craig, N.
Kumar, R. Rezaie, Tetrahedron, 2002, 58, 5125; (d) T. L. Boehm, H.
Showalter, J. Org. Chem., 1996, 61, 6498; (e) R. A. Smith, J. Chen,
M. M. Mader, I. Muegge, U. Moehler, S. Katti, D. Marrero, W. G.
Stirtan, D. R. Weaver, H. Xiao, W. Carley, Bioorg. Med. Chem. Lett.,
2002, 12, 2875; (f) K. K. Park, J. Jeong, Tetrahedron, 2005, 61, 545;
(g) G. Sendi, W. Hu, S. Boominathan, J. Wang, Chem. - Eur. J., 2015,
21, 998; (h) W. Xu, Q. Li, C. Cao, F. L. Zhang, H. Zheng, Org.
Biomol. Chem., 2015, 13, 6158.
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