Copper(I)-mediated cascade reactions: An efficient approach to the synthesis of functionalized benzofuro[3,2-d ]pyrimidines

Article abstract of DOI:10.1021/ol300822a

A novel cascade reaction was developed for the synthesis of diverse members of a series of benzofuro[3,2-d]pyrimidine derivatives. The process utilizes readily prepared 3-chlorochromenones and various commercially available amidines and their analogues as

Full text of DOI:10.1021/ol300822a

ORGANIC
LETTERS
2012
Vol. 14, No. 9
2398–2401
Copper(I)-Mediated Cascade Reactions:
An Efficient Approach to the
Synthesis of Functionalized
Benzofuro[3,2-d]pyrimidines
Bo Chao,† Shijun Lin,† Qingdong Ma,‡ Dong Lu,† and Youhong Hu*,†
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China, and
China University of Petroleum, Qingdao 266580, P. R. China
yhhu@mail.shcnc.ac.cn
Received April 1, 2012
ABSTRACT
A novel cascade reaction was developed for the synthesis of diverse members of a series of benzofuro[3,2-d]pyrimidine derivatives. The process
utilizes readily prepared 3-chlorochromenones and various commercially available amidines and their analogues as starting materials.
This tandem reaction is promoted by using
heterocyclizationꢀintramolecular cyclization sequence.
a
simple copper(I) reagent and involves
a
chemoselective Michael additionꢀ
Benzofuro[3,2-d]pyrimidine is widely found as a core struc-
ture in a large variety of substances that exhibit important
biological activities. One example of this is found in MP-470
(1), which is a multitargeted tyrosine kinase inhibitor that
radiosensitizes several GBM cell lines.1 In addition, the
benzofuro[3,2-d]pyrimidine derivative 2 has been found to
potentiate the CREB (cAMP response element binding)
signaling pathway that is associated with the enhancement
of long-term memory.2 Members of a series of benzofuropyr-
imidine derivatives serve as modulators of the histamine H4
receptor3 and, in the case of 3, as histamine H4 receptor
Figure 1. Representative bioactive benzofuro[3,2-d]pyrimidines.
† Shanghai Institute of Materia Medica, CAS.
‡ China University of Petroleum.
(1) Welsh, J.; Mahadevan, D.; Ellsworth, R.; Cooke, L.; Bearss, D.;
inverse agonists (Figure 1). Also, benzofuropyrimidines have
been observed to be Hsp90 inhibitors,4 adenosine receptor
(A2A) antagonists,5 and E. coli primase inhibitors.6
A classical synthetic method used earlier to construct the
benzofuropyrimidine scaffold (Scheme 1) begins with
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r
10.1021/ol300822a
Published on Web 04/26/2012
2012 American Chemical Society

2-carbonyl-3-aminobenzofurans 5 and their equivalents
that are transformed to benzofurans 4, which serve as
precursors to pyrimidines 6.3,7 Recently, a new route for
construction of this scaffold was described, in which
Suzuki coupling between 2-chloropyrimidine and 2-meth-
oxyphenyl boronic acid is followed by demethylation and
intramolecular CꢀO bond formation.3a,b,8 However, both
oftheapproaches described above involve multistep routes
and reactions that require reasonably harsh conditions
(e.g., high temperatures for cyclization, toxic demethyla-
tion reagents and mositure sensitive processes). In the
Michael additionꢀeliminationꢀdouble intramolecular cy-
clization sequences that result in the formation of biaryl
phenols 9 (Scheme 1). If operable, this sequence would
generate phenols that should undergo CꢀO bond-forming
cyclization to produce benzofuro[3,2-d]pyrimidine deriva-
tives 10.
In order to explore this proposal, 3-iodochromone 7a
wastreatedwithacetamidine hydrochlorideinthe presence
of a variety of bases and solvents. Under all conditions, the
undesired (imidazolyl)(phenyl)methanone derivative 11
was produced asthe sole productthrougha route involving
Michael additionꢀeliminationꢀsubstitution.9d,10 These
results indicate that the presence of the iodo leaving group
in 7a causes a substitution pathway, which forms the five-
membered heterocyclic product, to be more affective than
condensation. In contrast, reaction of 3-bromochromone
7b with acetamidine hydrochloride in the presence of
2 equiv of DBU in DMF at room temperature results in
generation of the pyrimidine-phenol 9a albeit in a 15%
yield. This finding suggests that the chemoselectivity of the
process can be controlled by decreasing the leaving group
ability of the halide. In accord with this expectation,
3-chlorochromone 7c, easily synthesized from chromone11
or enaminoketone,12 was found to react with acetamidine
hydrochloride (2 equiv DBU, DMF, rt) to produce 9b as
the predominant product (Scheme 2).
Scheme 1. (Top) Retrosynthetic Plan Serving as Basis of the
Classical Synthetic Approach to Benzofuro[3,2-d]pyrimidines.
(Bottom) Outline of the New Strategy for the Synthesis of
Benzofuro[3,2-d]pyrimidines Starting with Halogenated
Chromones
Scheme 2. Chemoselectivity of 3-Halogenated Chromone
studies described below, we have developed a straightfor-
word method to generate members of a diverse series of
benzofuro[3,2-d]pyrimidines, starting with 3-chlorochro-
menones and involving a chemoselective cascacde process.
Recent studies in our group have foccused on the
development of new synthetic pathways for the prepara-
tion of heterocyclic scaffolds, which rely on the use of
cascade or one-pot reactions starting with substituted
chromones.9 As part of this effort, we envisioned 3-halo-
genated chromones 7 would participate with amidines 8 in
Because copper salts are broadly used in tandem pro-
cesses to induce intramolecular CꢀO bond forming
reactions13 and to serve as Lewis acids to accellerate
Michael additions,14 we believed that the proposed se-
quence for generation of benzofuro[3,2-d]pyrimidines
would take place when copper reagents are employed as
promoters. In fact, inclusion of CuI in a mixture contaning
7c and acetamidine hydrochloride caused reaction to occur
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(c) Nagamochi, M.; Fang, Y.-Q.; Lautens, M. Org. Lett. 2007, 9, 2955.
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Org. Lett., Vol. 14, No. 9, 2012
2399

Table 1. Optimization of Reaction Conditions for Formation of
Benzofuropyrimidine 10aa
Table 2. Scope of the Cascade Reaction of 7 with 8a,b
entry
copper promoters
base
DBU
solvent
yield (%)
1
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
dioxane
tolunene
DME
CH3CN
DMSO
DMF
DMF
DMF
DMF
DMF
0
2
CuI
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
Cs2CO3
K2CO3
Et3N
t-BuONa
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
62
76
41
26
0
3
CuBr
4
CuCl
5
Cu
6
CuBr2
7
CuBr (0.1 equiv)
CuBr (0.2 equiv)
CuBr (0.5 equiv)
CuBr
27
50
65
20
18
0
8
9
10
11
12
13
14
15
16
17
18
19b
20c
21d
22e
23f
CuBr
CuBr
CuBr
0
CuBr
trace
trace
trace
trace
34
49
72
9
CuBr
CuBr
CuBr
CuBr
CuBr(0.2 equiv)
CuBr(0.2 equiv)
CuBr(0.2 equiv)
CuBr(0.2 equiv)
CuBr(0.2 equiv)
53
35
a Reaction conditions: mixtures of substrate 7c (0.55 mmol), acet-
amidine hydrochloride 8a (0.61 mmol), copper promoters (0.55 mmol),
and bases (1.2 mmol) in solvents (3 mL) were heated at 90 °C for 10 h.
b N,N-Dimethylglycine (0.6 equiv) was added. c 1,10-Phen (0.6 equiv)
was added. d DMEDA (0.6 equiv) was added. e \TMHD (0.6 equiv) was
added. f Bipy (0.6 equiv) was added.
that forms benzofuropyrimidine 10a in 62% yield (Table 1,
entry 2). The results of an exploration of different copper
reagents demonstrated that only copper(I) salts bring
about generation of 10a (Table 1, entries 2ꢀ6), and Cu(II)
salt did not promote the final CꢀO bond-forming step to
givetheintermediate9bonly(Table1, entry6). Probingthe
use of different amounts of CuBr for this process (Table 1,
entries 7ꢀ9) led to the observation that a stoichiometric
amount of this salt is optimal. When changing to inorganic
bases such as Cs2CO3 and K2CO3, the desired product 10a
(14) (a) Harutyunyan, S. R.; Lopez, F.; Browne, W. R.; Correa, A.;
~
Pena, D.; Badorrey, R.; Meetsma, A.; Minnaard, A. J.; Feringa, B. L.
J. Am. Chem. Soc. 2006, 128, 9103. (b) Howell, G. P.; Fletcher, S. P.;
Geurts, K.; ter Horst, B.; Feringa, B. L. J. Am. Chem. Soc. 2006, 128,
14977. (c) Li, K.; Alexakis, A. Angew. Chem., Int. Ed. 2006, 45, 7600.
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(e) Palais, L.; Mikhel, I. S.; Bournaud, C.; Micouin, L.; Falciola, C. A.;
Vuagnoux-d’Augustin, M.; Rosset, S.; Bernardinelli, G.; Alexakis, A.
Angew. Chem., Int. Ed. 2007, 46, 7462. (f) De Roma, A.; Ruffo, F.;
Woodward, S. Chem. Commun. 2008, 5384. (g) Jerphagnon, T.; Pizzuti,
M. G.; Minnaard, A. J.; Feringa, B. L. Chem. Soc. Rev. 2009, 38, 1039.
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2011, 50, 12335. (i) Takatsu, K.; Shintani, R.; Hayashi, T. Angew.
Chem., Int. Ed. 2011, 50, 5548. (j) Gremaud, L.; Alexakis, A. Angew.
Chem., Int. Ed. 2012, 51, 794.
a Reaction conditions: mixtures of 7c (0.55 mmol), 8 (0.61 mmol),
CuBr (0.55 mmol), and DBU (1.2 mmol) in DMF (3 mL) were heated at
90 °C for 10 h. b Yields by catalyzed CuBr (0.11 mmol) with 1,10-Phen
(0.33 mmol) are given in parentheses. c DBU (1.8 mmol) was used. d 8h,
8i, or 8l (0.30 mmol) was used, respectively.
2400
Org. Lett., Vol. 14, No. 9, 2012

was obtained in low yields (Table 1, entries 10 and 11). The
weak base Et3N did not promote the reaction well to
generate 9b, with starting material recovered (Table 1,
entry 12). The strong base t-BuONa afforded the compli-
cated products (Table 1, entry 13). When the reaction was
carried out in dioxane, toluent, DME, or CH3CN, respec-
tively, only a trace amount of 10a was obtained with 9b
(Table 1, entries 14ꢀ17). Also DMSO did not improve the
yield (Table 1, entry 18). When addition of the different
ligands with catalytic copper(I) bromide such as N,N-
dimethylglycine,15 1,10-phenanthroline monohydrate (1,10-
phen),16 N,N0-dimethylenylene-1,2-diamine (DMEDA),17
2,2,6,6-teramethyle-3,5-heptanedione (TMHD),18 and
2,20-dipyridine (bipy) (Table 1, entries 19ꢀ23) was employed
in the reaction, CuBr (0.2 equiv) with 1,10-phen (0.06 equiv)
gave the comparable yield.
Further investigations revealed that ethyl 3-aminocroto-
nate (12a) and ethyl 3-amino-4,4,4-trifluorocrotonate (12b),
serving as a C,N bis-nucleophiles, react with 3-chlorochro-
mone to give the corresponding benzofuro[3,2-b]pyridines
13a or 13b in 31% and 38% respective yields (Scheme 3).
However, the catalytic conditions yielded trace amounts of the
desired products. These observations show that the new
methodology can be applied to substrates other than amidines
and used for the construction diverse molecular scaffolds.
Scheme 3. Synthesis of Benzofuro[3,2-b]pyridines
Reactions of substituted 3-chlorochromones with ami-
dines and their analogues were investigated to probe the
scope of this new reaction (Table 2). The results show that
3-chlorochromones, bearing electron-withdrawing and
electron-donating groups on the aromatic ring, react under
the optimal conditions (see above) to form the correspond-
ing benzofuropyrimidines in moderate to good yields
(Table 2, entries 1ꢀ6). In contrast, changes in the R2
amidine substituent were observed to have a profound
impact on the efficiencies of the process. Specifically,
reactions of amidines with the R2 substituent being an
alkyl group or variously substituted aryl groups (Table 2,
entries 7ꢀ11) occur in good to excellent yields. However,
when R2 is an electron-donating group, reactions take
place in low yields (Table 2, entries 12ꢀ14). Interestingly,
structurally and functionally complicated polyheterocyclic
scaffolds can be constructed by using the new process
(Table 2, entries 15ꢀ17). Under the catalyzed conditions,
reactions gave the similar results except for the formation
of 10r.
In conclusion, the studies described above resulted in the
development ofa novel cascade reaction inwhich 3-chloro-
chromones are transformed to diverse benzofuro[3,2-d]-
pyrimidines and related polycylic heterocylic scaffolds.
The process is promoted by CuBr and takes place via a
chemoselective Michael additionꢀeliminationꢀdouble in-
tramolecular cyclization sequence. Significantly, the con-
ditions utilized for the tandem process are mild and
economical. Further applications of the new methodology
and biological testing of compounds prepared in this effort
are under current investigation.
Acknowledgment. This work was supported by a grant
from National Natural Science Foundation of China
(21172232).
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Supporting Information Available. Experimental pro-
cedures and 1H and 13C NMR spectra for compounds in
Table 2 and Scheme 3. This material is available free of
charge via the Internet at http://pubs.acs.org.
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The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 9, 2012
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