Synthesis of chromeno[2,3-d]imidazol-9(1 H)-ones via tandem reactions of 3-iodochromones with amidines involving copper-catalyzed C-H functionalization and C-O bond formation

Article abstract of DOI:10.1021/ol401966y

A novel six-membered heterocyclic skeleton of imidazochromone was prepared via an efficient one-pot reaction including a key step of copper-catalyzed aerobic C-H intramolecular cycloetherification. Notably, this process does not require the presence of st

Full text of DOI:10.1021/ol401966y

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Synthesis of Chromeno[2,3‑d]imidazol-
9(1H)‑ones via Tandem Reactions of
3‑Iodochromones with Amidines Involving
Copper-Catalyzed CÀH Functionalization
and CÀO Bond Formation
Jia Sheng, Bo Chao, Hong Chen, and Youhong Hu*
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai 201203,
People’s Republic of China
yhhu@mail.shcnc.ac.cn
Received July 22, 2013
ABSTRACT
A novel six-membered heterocyclic skeleton of imidazochromone was prepared via an efficient one-pot reaction including a key step of copper-
catalyzed aerobic CÀH intramolecular cycloetherification. Notably, this process does not require the presence of strong para electron-
withdrawing groups on the phenol component. Also, the results of this effort show that acyl phenols containing electron-rich heterocycles
participate in an efficient CÀH activation/CÀO formation process.
Structurally complex and functionally diverse hetero-
cycles play important roles as lead compounds in efforts
aimed at the discovery of new pharmaceutical agents.
Among the various synthetic approaches to these sub-
stances, those that utilize tandem reactions of readily
accessible starting materials are highly attractive, owing
to their simplicity and atom economy.1 In this regard, the
processes involving transition-metal-catalyzed, directing
CÀH activation/CÀheteroatom bond formation have
been extensively explored.2 In comparison to other late
transition metals employed for these reactions, copper is a
particularly attractive catalyst because of its low cost and
toxicity.3 Indeed, copper-catalyzed reactions that occur via
directing group guided intramolecular CÀH amination
have been developed for the synthesis of five- and six-
membered nitrogen-containing heterocyclic compounds.4
(3) For selected Cu-catalyzed CÀH activation reviews, see: (a) Campbell,
A. N.; Stahl, S. S. Acc. Chem. Res. 2012, 45, 851–863. (b) Wendlandt, A. E.;
Suess, A. M.; Stahl, S. S. Angew. Chem., Int. Ed. 2011, 50, 11062–11087. (c)
Zhang, M. Appl. Organomet. Chem. 2010, 24, 269–284.
(1) For selected reviews, see: (a) Bhanja, C.; Jena, S.; Nayak, S.;
Mohapatra, S. Beilstein J. Org. Chem. 2012, 8, 1668–1694 (No. 191). (b)
Vaxelaire, C.; Winter, P.; Christmann, M. Angew. Chem., Int. Ed. 2011,
50, 3605–3607. (c) Wang, H.; Kuang, Y.; Wu, J. Asian J. Org. Chem. 2012,
1, 302–312. (d) Zhao, W.; Chen, F.-E. Curr. Org. Synth. 2012, 9, 873–897.
(2) For CÀH functionalization by precious metals, see: (a) Arockiam,
P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112, 5879–5918. (b)
Chen, X.; Engle, K. M.; Wang, D. H.; Yu, J. Q. Angew. Chem., Int. Ed.
2009, 48, 5094–5115. (c) Li, B.-J.; Shi, Z.-J. Chem. Soc. Rev. 2012, 41, 5588–
5598. (d) Mei, T.-S.; Kou, L.; Ma, S.; Engle, K. M.; Yu, J.-Q. Synthesis
2012, 44, 1778–1791. (e) Mousseau, J. J.; Charette, A. B. Acc. Chem. Res.
2013, 46, 412–424. (f) Ohno, H. Asian J. Org. Chem. 2013, 2, 18–28.
(4) (a) Brasche, G.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47,
1932–1934. (b) Chen, L.; Li, C.; Bi, X.; Liu, H.; Qiao, R. Adv. Synth. Catal.
2012, 354, 1773–1779. (c) Guru, M. M.; Ali, M. A.; Punniyamurthy, T. Org.
Lett. 2011, 13, 1194–1197. (d) Huang, P.-C.; Parthasarathy, K.; Cheng, C.-H.
Chem. Eur. J. 2013, 19, 460–464. (e) Lu, J.; Jin, Y.; Liu, H.; Jiang, Y.; Fu, H.
Org. Lett. 2011, 13, 3694–3697. (f) Ma, D.; Geng, Q.; Zhang, H.; Jiang, Y.
Angew. Chem., Int. Ed. 2010, 49, 1291–1294. (g) Ueda, S.; Nagasawa, H.
J. Am. Chem. Soc. 2009, 131, 15080–15081. (h) Wang, H.; Wang, Y.; Peng,
C.; Zhang, J.; Zhu, Q. J. Am. Chem. Soc. 2010, 132, 13217–13219. (i) Wang,
X. Q.; Jin, Y. H.; Zhao, Y. F.; Zhu, L.; Fu, H. Org. Lett. 2012,14, 452–455. (j)
Zhou, W.; Liu, Y.; Yang, Y.; Deng, G.-J. Chem. Commun. 2012, 48, 10678–
10680.
r
10.1021/ol401966y
XXXX American Chemical Society

In addition, new processes devised for the preparation
of five-membered oxygen-containing heterocycles take
advantage of amide carbonyl oxygen, which directs intra-
molecular CÀH etherification promoted by a copper salt
along with oxygen as the terminal oxidant.5 Nevertheless,
the use of phenols as oxygen donors in copper-catalyzed
CÀH etherification processes is rare, due to the instability
of these substances at high temperature in the presence of
strong oxidants6 and competitive phenol homocoupl-
ing reactions.7 In 2012, Zhu et al. demonstrated that
Cu-catalyzed oxidative annulation of ο-arylphenols could
facilitate this process to form dibenzofuran when an
electron-withdrawing group was present at the para posi-
tion of the phenol moiety.8 Inspired by the success of the
investigations described above and the results of our recent
studies focusing on methods for the synthesis of highly
reactive substituted chromones,9 we designed a new
approach to the preparation of chromeno[2,3-d]imidazol-
9(1H)-ones from 3-iodochromones, which involved a cop-
per-catalyzed CÀH functionalization and CÀO bond for-
mation reaction (Scheme 1).
we postulated that(imidazolyl)(phenyl)methanones 3a
would be converted to chromeno[2,3-d]imidazol-9(1H)-
ones 4a (Scheme 2) through a tandem, copper-catalyzed
CÀH functionalization and CÀO bond formation process.
Scheme 2. Copper-Catalyzed CÀH Activation/CÀO
Formation
In order to determine if the proposed one-pot process
happened, reactions of 3-iodochromone 1a with acetami-
dine hydrochloride 2a were carried out by using different
bases, solvents, and copper catalysts. To our delight, we
smoothly obtained the new title class of six-membered ring
with an imidazochromone framework which had not been
Table 1. Optimization of Reaction Conditionsa
Scheme 1. Reactions of Substituted 3-Halogenated Chromones
entry
cat.
CuI
base
solvent
yield (%)b
1
DBU
DMF
DMF
DMF
DMF
DMF
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
trace
82
70
65
77
33
20
86
30
33
41
52
38
45
80
0
2
CuI
K2CO3
Cs2CO3
KOAc
3
CuI
4
CuI
In an earlier study, we observed that 3-chlorochromones
reacted with amidines in a copper(I)-promoted process
under basic conditions, which proceeded via a tandem
pathway involving a chemoselective Michael additionÀ
eliminationÀdouble intramolecular cyclization sequence
(Scheme 1).9a In contrast, we observed that 3-iodochro-
mone, containing the superior iodine leaving group, re-
acted with acetamidine hydrochloride under basic con-
ditions to form the (imidazolyl)(phenyl) methanone 3a. A
consideration of both processes suggested the potential of a
new approach for the preparation of a previously unknown
class of six-membered heterocycles possessing the structure
of chromeno[2,3-d]imidazol-9(1H)-one 4a.10 Specifically,
5
CuI
CsOPiv
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
6
CuI
7c
8d
9
CuI
CuI
CuCl
CuBr
CuCl2
CuBr2
CuSO4
Cu(OAc)2
Cu(OTf)2
10
11
12
13
14
15
16e
17f
18g
19h
CuI
CuI
trace
80
0
a General conditions: mixture of 1a (0.4 mmol), 2a (0.4 mmol), base
(1.2 mmol), and copper salts (10 mol %) in solvent (3 mL). b Isolated
yield. c Reaction was carried out under an Ar atmosphere. d 20 mol %
CuI was used. e Only 3a remained. f 1.0 equiv of K2CO3 was used. g 1.2
equiv of TEMPO (radical scavenger) was added into the reaction system.
h 1.2 equiv of TEMPO was added without copper; only 3a remained.
(5) (a) Cheung, C. W.; Buchwald, S. L. J. Org. Chem. 2012, 77, 7526–
7537. (b) Guin, S.; Ghosh, T.; Rout, S. K.; Banerjee, A.; Patel, B. K. Org.
Lett. 2011, 13, 5976–5979. (c) Ueda, S.; Nagasawa, H. Angew. Chem.,
Int. Ed. 2008, 47, 6411–6413.
(6) Hewgill, F. R. J. Chem. Soc. 1962, 4987–95.
(7) (a) Li, X. L.; Yang, J.; Kozlowski, M. C. Org. Lett. 2001, 3, 1137–
1140. (b) Nakajima, M.; Kanayama, K.; Miyoshi, I.; Hashimoto, S.
Tetrahedron Lett. 1995, 36, 9519–9520.
(8) (a) Zhao, J.; Wang, Y.; He, Y.; Liu, L.; Zhu, Q. Org. Lett. 2012, 14,
1078–1081. (b) Zhao, J.; Wang, Y.; Zhu, Q. Synthesis 2012, 44, 1551–1555.
(9) (a) Chao, B.; Lin, S.; Ma, Q.; Lu, D.; Hu, Y. Org. Lett. 2012, 14,
2398–2401. (b) Cheng, M.; Yan, J.; Hu, F.; Chen, H.; Hu, Y. Chem. Sci.
2013, 4, 526–530. (c) Yan, J.; Cheng, M.; Hu, F.; Hu, Y. Org. Lett. 2012,
14, 3206–3209. (d) Zhao, L.; Xie, F.; Cheng, G.; Hu, Y. Angew. Chem.,
Int. Ed. 2009, 48, 6520–6523.
reported in early literature. The result (Table1) showed that
the use of DBU in DMF and a catalytic amount of copper
iodide promoted a very inefficient CÀH functionalization/
CÀO formation process (Table 1, entry 1). However, when
inorganic bases were employed for this convertion, 4a was
(10) Costa, M.; Proenca, M. F. Tetrahedron 2011, 67, 8622–8627.
B
Org. Lett., Vol. XX, No. XX, XXXX

generated in 65À82% yields (Table 1, entries 2À5). The
results led to the identification of K2CO3 as the optimal base
and showed that DMSO was not an ideal solvent. More-
over, the reaction that was performed under an Ar atmo-
sphere resulted in the formation of 4a in a low (20%) yield
along with remaining acyl phenol 3a (Table 1, entry 7). This
was an expected result, because oxygen was generally the
primary oxidant in copper-catalyzed oxidative CÀH func-
tionalization reactions. Further studies showed that increas-
ing the amount of CuI (0.2 equiv) caused a comparably
higher product yield (Table 1, entry 8). The results of
screening of other copper sources, including Cu(OTf)2,
demonstrated that both copper(I) and copper(II) salts
could accelerate this process in variable yields (Table 1,
entries 9À15). In addition, it was noteworthy that the
cyclization from 3a to 4a would not take place in the
absence of either base or copper salts (Table 1, entries
16 and 17). In addition, a radical scavenger barely had
an effect on the whole reaction (Table 1, entry 18) and
TEMPO was added without CuI to give 3a only (Table 1,
entry 19). Certainly we also divided the reaction into two
parts, in which the copper catalyst was added into the
bottle after former process was finished. This gave a
satisfying result as well, which also proved the occurrence
of a copper-catalyzed direct CÀO coupling process during
the transformation of 3a into 4a.
Table 2. Scope of the Cascade Reaction of 1 with 2a
Consequently, the scope of substrates for this one-pot
tandem reaction was explored under the optimized condi-
tions. The results (Table 2) showed that the electronic
nature of substituents on the chromone ring had a pro-
nounced effect on the efficiency of the copper-catalyzed
annulation reaction. For example, the 3-iodochromone
containing a OMe group at C-7 underwent a more efficient
reaction process (Table 2, entry 4). In contrast, the pre-
sence of an electron-donating OMe group at C-6 of the
chromone ring system delivered the corresponding pro-
duct in diminished yield for uncertain reasons; perhaps it
weakened the stability of the intermediate during the
cyclization process or it was liable to be oxidated to
quinones (Table 2, entry 3).11 In addition, the presence of
a mild electron-withdrawing fluoro substituent at either
C-6 or C-7 of the chromone ring system had an obvious
impact on the efficiency of this reaction. The results of the
exploration probing the effect of changing the amidine
reactant showed that both sterically encumbered alkyl and
mild electron-withdrawing substituents on the amidine
carbon did not greatly impact the yield of the reaction.
However, when the amidine contained strong electron-
withdrawing groups such as p-nitrophenyl and 4-pyridyl,
the efficiency of the process was greatly influenced and the
reaction product was complex with a mixture of side
products and a large amount of noncyclized products 3n
and 3o, respectively (Table 2, entries 14 and 15). As an
a Unless noted, the reactions were conducted under the optimized
conditions. b Yields of isolated compounds. c reaction time required 36 h.
d large amount of noncyclized product remained.
aside, the structure of 4h was unambiguously determined
by using X-ray crystallographic analysis (Figure 1).12
A further investigation probing the synthetic utility of
the copper-catalyzed CÀH functionalization and CÀO
bond formation was carried out by using intermediate acyl
phenols derived from other five-membered heterocycles
(Scheme 3).13 The observations made in this effort demon-
strated that the more electron-rich pyrrole 5a14 underwent
cyclization efficiently to give6a in 68% yield. However, the
(11) Ali, M. H.; Niedbalski, M.; Bohnert, G.; Bryant, D. Synth.
Commun. 2006, 36, 1751–1759.
(12) CCDC 928999 (4h) contains supplementary crystallographicda-
ta for this paper. The data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data-request/cif.
(13) Figueiredo, A. G. P. R.; Tome, A. C.; Silva, A. M. S.; Cavaleiro,
J. A. S. Tetrahedron 2006, 63, 910–917.
(14) St, J. D. J.; Fotsch, C. J. Med. Chem. 2012, 55, 6002–6020.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Possible Pathway for Copper-Catalyzed CÀH
Cycloetherification
Figure 1. X-ray structure of 4h.
N-methylpyrrole analogue 5b reacted under identical con-
ditions to form a complicated mixture. In addition, the
pyrrole substrate 5e containing a phenyl group at C-2
underwent efficient cyclization, while the 2-methoxycar-
bonyl species 5f bearing an electron-withdrawing group
reacted to form 6f in an attenuated yield (23%). Finally,
the reactant 5c containing a thiophene ring and the rela-
tively more electron deficient furan 5d both went through a
highly inefficient process to give rise to complicated pro-
duct mixtures.
basic conditions, combines with Cu(I) catalyst to form
complex A. Rapid oxidation of A then generates the more
electrophilic Cu(II) complex precursor, which is prone to
undergo an agostic CÀHinteraction15 owing to the electron-
rich nature of the heterocycle and following carbonate-
assisted formation of a six-membered cyclic transition state
gives the Cu(II) complex B. Also, it is possible that Cu(II)
complex B can be directly generated by the reaction of
Cu(II) species with 3a. Finally, disproportionation of the
Cu(II) complex B16 produces aryl- Cu(III) complex C,
which affords the final cyclization product 4a and recycl-
able Cu(I) via direct reductive elimination.
Scheme 3. CÀH Activation/CÀO Bond Formation of Other
Heterocycle-Substituted Acyl Phenols
In summary, we have developed a simple and efficient
one-pot copper-catalyzed direct CÀO coupling method to
form a novel imidazochromone scaffold. Only a catalytic
amount of CuI and 3.0 equiv of K2CO3 were employed to
promote the whole reaction efficiently. To broaden the
application of Cu-catalyzed aerobic CÀH activation, we
attempted to use other heterocycles as the substrates of the
cyclization reaction and found that electron-rich hetero-
cycles can facilitate the cycloetherification remarkably.
Acknowledgment. This work was supported by a grant
from the National Natural Science Foundation of China
(21172232 and 81225022)
Supporting Information Available. Text and figures
giving 3xperimental procedures and full spectroscopic
data for all new compounds above. This material is
available free of charge via the Internet at http://pubs.
acs.org.
On the basis of the preliminary results described above,
including the fact that the whole reaction is not susceptible
in the presence of TEMPO, which rules out the probability
of a radical mechanism such as SET,3b and oxidant with-
out copper reagent also has no impact on the reaction,
which excludes an addition/oxidation mechanism. We
hypothesize a copper catalytic cycle of this transformation
(Scheme 4). In the cycle, the phenolic hydroxy group of
intermediate3a, formedby the reaction of 1awith2aunder
(15) Lapointe, D.; Fagnou, K. Chem. Lett. 2010, 39, 1118–1126.
(16) King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.;
Stahl, S. S. J. Am. Chem. Soc. 2010, 132, 12068–12073.
The authors declare no competing financial interest.
D
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