An unexpected copper(ii)-catalyzed three-component reaction of quinazoline 3-oxide, alkylidenecyclopropane, and water

Article abstract of DOI:10.1039/c4cc04341c

An unexpected copper(ii)-catalyzed three-component reaction of quinazoline-3-oxide, alkylidenecyclopropane and water under mild conditions is reported. This transformation including [3+2] cycloaddition and intramolecular rearrangement leads to N-(2-(5-oxa

Full text of DOI:10.1039/c4cc04341c

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An unexpected copper(II)-catalyzed three-
component reaction of quinazoline 3-oxide,
alkylidenecyclopropane, and water†
Yuanyuan An,a Danqing Zhenga and Jie Wu*ab
Cite this: Chem. Commun., 2014,
50, 9165
Received 7th June 2014,
Accepted 27th June 2014
DOI: 10.1039/c4cc04341c
www.rsc.org/chemcomm
An unexpected copper(II)-catalyzed three-component reaction of
quinazoline-3-oxide, alkylidenecyclopropane and water under mild
conditions is reported. This transformation including [3+2] cyclo-
addition and intramolecular rearrangement leads to N-(2-(5-oxa-6-
azaspiro[2.4]hept-6-en-7-yl)phenyl)formamides in good yields.
It is well known that nitrogen-containing heterocycles occupy an
important position among pharmaceuticals and natural products.1
In the last decade, N-heterocycles with molecular complexity and
diversity have been used broadly in the studies of chemical genetics.2
Therefore, continuous efforts have been devoted to explore efficient
approaches for access to N-heterocycles. Among the developed
strategies, tandem reactions3 have been utilized as an efficient
method for the preparation of N-heterocycles, due to its well-
known advantages, such as atom economy and high efficiency.
Scheme 1 A proposed reaction of quinazoline 3-oxide with alkylidene-
cyclopropane.
Recently, we have been interested in the construction of small block as well for accessing diverse quinazoline derivatives.
libraries of natural product-like compounds with privileged scaf- The characteristics of quinazoline-3-oxide indicated that it
folds.4 The quinazoline derivatives attracted our attention, due could be easily involved in a [3+2] cycloaddition reaction to
to their biological importance in many natural products and provide fused quinazoline derivatives. Recently, strained alkyl-
pharmaceuticals.5 Additionally, quinazoline derivatives have idenecyclopropanes have been widely utilized for the construc-
involved in the total synthesis of alkaloids.6 In the past few years, tion of carbocycles and heterocycles.8,9 We also developed a
we have developed efficient methods for the assembly of complex facile route to benzo-7-azabicyclo[4.2.2]dec-7-en-4-ones via a
molecules using 2-alkynylbenzaldoximes as the starting materials.7 silver(I)-catalyzed reaction of isoquinoline N-oxide with alkyl-
During the process, isoquinoline N-oxide was identified as the idenecyclopropane (Scheme 1, eqn (1)).7d Prompted by this
key intermediate, which was generated through 6-endo cycliza- result and the chemistry of quinazoline-3-oxide and alkyl-
tion of 2-alkynylbenzaldoxime. Due to the structural similarity idenecyclopropane, we conceived that under appropriate con-
of isoquinoline N-oxide and quinazoline-3-oxide, we envisioned ditions, the fused quinazoline derivative A would be generated
that quinazoline-3-oxide could be used as a useful building through a reaction of quinazoline-3-oxide 1 with alkylidene-
cyclopropane 2 (Scheme 1, eqn (2)).
To verify the feasibility of this hypothesis, we first evaluated
the reaction using quinazoline-3-oxide 1a and 1-(cyclopropyl-
a Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433,
China. E-mail: jie_wu@fudan.edu.cn; Fax: +86 21 6564 1740;
idenemethyl)-4-methylbenzene 2a as the model substrates.
The preliminary results are shown in Table 1. Initially, the
reaction occurred in the absence of a metal catalyst at 80 1C in
1,4-dioxane (AR: Analytical Reagent) (entry 1). This transforma-
tion did not take place at all. Only a trace amount of product
was detected when palladium(II) chloride or silver(I) triflate was
used as a catalyst (entries 2 and 3). Interestingly, an unexpected
Tel: +86 21 6510 2412
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032,
China
† Electronic supplementary information (ESI) available: Experimental procedure,
characterization data, 1H and 13C NMR spectra of compounds 3. CCDC 995733
(compound 3c). For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c4cc04341c
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Table 1 Initial studies for the copper(II)-catalyzed reaction of quinazoline-
N-oxide 1a with 1-(cyclopropylidenemethyl)-4-methylbenzene 2a
Encouraged by this result, several copper salts were then
employed in the reaction (entries 5–7). It was found that
copper(II) chloride was the most effective one. Further screening
of solvents did not provide any better results (entries 8–12). The
yield was lower when the reaction temperature was increased or
decreased (entries 13 and 14). A similar yield was observed when
5 mol% of copper(II) chloride was utilized (entry 15). The result
could not be improved when the amount of catalyst was
increased to 20 mol% (entry 16).
We next explored the reaction scope under the optimized
reaction conditions shown in Table 1 (5 mol% of CuCl2, 80 1C,
1,4-dioxane). The results for the evaluation of various substituted
quinazoline-3-oxides and alkylidenecyclopropanes are presented
in Table 2. This copper(II)-catalyzed reaction of quinazoline-3-
oxides 1 and alkylidenecyclopropanes 2 occurred smoothly to
generate the desired products 3 in good yields. Obviously, the
reaction was practicable with quinazoline-3-oxides bearing
electron-withdrawing and electron-donating substituents. Methyl,
methoxy, fluoro and chloro functionalities were all tolerated,
leading to the corresponding N-(2-(5-oxa-6-azaspiro[2.4]hept-6-en-
7-yl)phenyl) 3. For example, 5-fluoroquinazoline-3-oxide reacted
with 4-methyl-1-(cyclopropylidenemethyl)benzene giving rise to
the product 3c in 85% yield. The structure of compound 3c was
Entry
[M]
Solvent
T (1C)
Yielda (%)
1
2
3
4
5
6
7
8
—
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
Toluene
DMSO
MeCN
DMF
DCE
80
80
80
80
80
80
80
80
80
80
80
80
50
100
80
80
nd
PdCl2
AgOTf
CuBr
Trace
Trace
47
65
75
44
65
Trace
24
18
40
20
50
76
CuCl
CuCl2
Cu(OAc)2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
9
10
11
12
13
14
15b
16c
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
66
a
b
Isolated yield based on quinazoline-N-oxide 1a. In the presence of
c
5 mol% of CuCl2. In the presence of 20 mol% of CuCl2.
product was generated in 47% yield when copper(I) bromide
joined the reaction system (entry 4). After structural illustration, Table 2 Copper(II)-catalyzed reaction of quinazoline-N-oxide 1 with
alkylidenecyclopropane 2a
it was identified as N-(2-(4-(p-tolyl)-5-oxa-6-azaspiro[2.4]hept-6-
en-7-yl)phenyl)formamide 3a.
From the structure of compound 3a, it seemed that a molecule
of water participated in the reaction, since non-distilled 1,4-dioxane
(Analytical Reagent) was used as the solvent. Thus, a control
experiment was performed in the anhydrous solvent. As expected,
no desired product 3a was obtained. Compound A, which was
not stable, might be formed after several days. Therefore, we
proposed a possible mechanism for this copper-catalyzed reaction
of quinazoline-3-oxide 1 with alkylidenecyclopropane 2 (Scheme 2).
We reasoned that a fused 3,4-dihydroquinazoline compound A
would be formed through [3+2] cycloaddition of quinazoline-3-
oxide 1 with alkylidenecyclopropane 2. In the presence of a copper
catalyst, water would act as a nucleophile to attack the intermediate
B. After C–N bond cleavage, compound 3 would be furnished.
Scheme 2 A possible mechanism for the copper(II)-catalyzed reaction of
quinazoline-3-oxide 1 with alkylidenecyclopropane 2.
a
Isolated yield based on quinazoline-N-oxide 1.
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Fig. 1 X-ray ORTEP illustration of compound 3c (30% probability ellipsoids).
confirmed by X-ray diffraction analysis in the meantime (Fig. 1).
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Financial support from the National Natural Science Foun-
dation of China (No. 21032007 and 21372046) is gratefully
acknowledged.
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Chem. Commun., 2014, 50, 9165--9167 | 9167