A palladium-catalyzed three-component reaction for the preparation of quinazolin-4(3H)-imines

Article abstract of DOI:10.1039/c2cc18001d

A novel and efficient route for the preparation of quinazolin-4(3H)-imines via a palladium-catalyzed three-component reaction of carbodiimide, isocyanide, and nucleophile is described. The palladium-catalyzed isocyanide insertion is believed to be the key step during the reaction process. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc18001d

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COMMUNICATION
A palladium-catalyzed three-component reaction for the preparation of
quinazolin-4(3H)-iminesw
Guanyinsheng Qiu,a Gang Liu,ab Shouzhi Pu*b and Jie Wu*ac
Received 22nd December 2011, Accepted 25th January 2012
DOI: 10.1039/c2cc18001d
A novel and efficient route for the preparation of quinazolin-
4(3H)-imines via a palladium-catalyzed three-component reaction
of carbodiimide, isocyanide, and nucleophile is described. The
palladium-catalyzed isocyanide insertion is believed to be the key
step during the reaction process.
Among the strategies used in diversity-oriented synthesis,7
the multicomponent reaction has been recognized as a powerful
tool for the generation of molecular diversity and complexity.8
Recently, the palladium-catalyzed isocyanide insertion9 has
been widely used for the synthesis of heterocycles. Prompted
by the advancement of multicomponent reactions and the
chemistry involving isocyanide insertion, we envisioned that
the scaffold of quinazolin-4(3H)-imine could be constructed
via a palladium-catalyzed three-component reaction of carbodi-
imide 1,10 isocyanide 2, and nucleophile 3 (Scheme 1). Therefore,
we started to explore the feasibility for the synthesis of quinazolin-
4(3H)-imine as presented in Scheme 1.
The importance of N-heterocycles in natural products, pharma-
ceuticals, and synthetic materials is well known, thus continuous
efforts have been made for the generation of N-heterocycles in
organic synthesis.1 As a prominent structural motif, the
quinazolin-4(3H)-imine core (Scheme 1) can be found in many
compounds with promising biological activities.2 For example,
quinazolin-4(3H)-imine derivatives have been reported as selective
butyrylcholinesterase inhibitors for Alzheimer’s disease.3 So far,
synthesis of quinazolin-4(3H)-imines has been achieved.4,5 For
example, Rayat and co-workers developed a three-step synthesis of
2-halo-3-aryl-4(3H)-quinazoliniminium halides, which underwent
an intramolecular cyclization to afford quinazolin-4(3H)-imines.4a
However, most of the reported methods suffered from harsh
reaction conditions and long reaction times. As part of a program
in our laboratory for the construction of natural product-like
compounds,6 we consider that a general and efficient pathway
for the generation of diverse quinazolin-4(3H)-imines is highly
desirable.
The initial studies were carried out for the palladium-
catalyzed three-component reaction of carbodiimide 1a, n-butyl
isocyanide 2a, and pyrrolidine 3a. In the first attempt, the
reaction was catalyzed by palladium chloride (10 mol%) in
the presence of DPPF (20 mol%) and Cs2CO3 (3.0 equiv.) in
toluene under reflux (Table 1, entry 1). To our delight, the
expected product 4a was isolated and obtained in 32% yield.
The yield was increased to 44% when the catalyst was changed
to Pd(OAc)2 (Table 1, entry 2). A similar outcome was obtained
when PdCl2(PPh3)2 was employed as the catalyst (Table 1, entry
3). No reaction occurred without the addition of palladium
catalyst in a control experiment. The reaction was complex
when Pd2(dba)3 was used (Table 1, entry 4). Considering the
solubility issue, palladium acetate was used for further screening.
Next, various ligands including phosphine and N-heterocyclic
carbene were screened (Table 1, entries 5–11). From the results, it
seemed that PCy3 and IMes were the best ligands in the
transformation (50% yield). Only a trace amount of product
was detected in the absence of ligand. Different bases and
solvents were screened subsequently (Table 1, entries 12–19). It
was demonstrated that the reaction worked most efficiently in
toluene when Cs2CO3 was employed as a base. A lower yield was
obtained when the reaction was performed at 80 1C (45% yield,
Table 1, entry 20). No reaction occurred at room temperature
(Table 1, entry 21). Reducing the amount of palladium catalyst
retarded the reaction (data not shown in Table 1). The yield
could be increased to 66% when 3.0 equiv. of pyrrolidine was
used in the reaction (Table 1, entry 23).
Scheme 1 A proposed three-component reaction for the synthesis of
quinazolin-4(3H)-imines.
a Department of Chemistry, Fudan University, 220 Handan Road,
Shanghai 200433, China. E-mail: jie_wu@fudan.edu.cn;
Fax: +86 21 6564 1740; Tel: +86 21 6510 2412
b Jiangxi Key Laboratory of Organic Chemistry, Jiangxi Science &
Technology Normal University, Nanchang 330013, China
c State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China
w Electronic supplementary information (ESI) available: Experimental
procedure, characterization data, 1H and 13C NMR spectra of com-
pounds 4, and a CIF file of compound 4c. CCDC 860138. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c2cc18001d
Having defined the optimized conditions (10 mol% of
Pd(OAc)2, 20 mol% of PCy3, 3.0 equiv. of Cs2CO3, toluene,
reflux), we then investigated the generality of this palladium-
catalyzed three-component reaction of carbodiimides 1,
c
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Chem. Commun., 2012, 48, 2903–2905 2903

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Table 1 Initial studies for the palladium-catalyzed three-component
reaction of carbodiimide 1a, n-butyl isocyanide 2a, and pyrrolidine 3aa
Table 2 Synthesis of quinazolin-4(3H)-imines 4 via a palladium-
catalyzed three-component reaction of carbodiimide 1, isocyanide 2,
and amine 3a
Entry [Pd]
Ligand
Base
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
PdCl2
Pd(OAc)2
PdCl2(PPh3)2 DPPF
DPPF
DPPF
Cs2CO3 Toluene 32
Cs2CO3 Toluene 44
Cs2CO3 Toluene 43
Cs2CO3 Toluene Complex
Cs2CO3 Toluene 40
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
DPPF
Xphos
Xant-phos Cs2CO3 Toluene 30
DPPE
PtBu3
PCy3
IMes
IPr
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
Cs2CO3 Toluene 49
Cs2CO3 Toluene 18
Cs2CO3 Toluene 50
Cs2CO3 Toluene 50
Cs2CO3 Toluene 46
tBuOK Toluene 19
K3PO4 Toluene Trace
DBU Toluene Trace
Et3N Toluene NR
Cs2CO3 Dioxane 29
9
10
11
12
13
14
15
16
17
18
19
20c
21d
22e
23f
Cs2CO3 DMF
Cs2CO3 MeCN
Cs2CO3 THF
25
36
NR
Cs2CO3 Toluene 45
Cs2CO3 Toluene NR
Cs2CO3 Toluene 42
Cs2CO3 Toluene 66
a
Reaction conditions: carbodiimide 1a (1.0 equiv.), isocyanide 2a
(1.5 equiv.), pyrrolidine 3a (1.5 equiv.), palladium catalyst (10 mol%),
b
ligand (20 mol%), base (3.0 equiv.), reflux. Isolated yield based on
c
d
carbodiimide 1a. The reaction was performed at 80 1C. The reaction
occurred at room temperature. In the presence of 1.0 equiv. of
e
f
pyrrolidine 3a. In the presence of 3.0 equiv. of pyrrolidine 3a.
isocyanides 2, and amines 3. The results are presented in
Table 2. Usually, the reactions were finished in 4–6 hours. A
range of quinazolin-4(3H)-imines 4 were obtained under the
standard conditions. Not only n-butyl isocyanide but also n-pentyl
isocyanide and tert-butyl isocyanide are suitable partners in
the palladium-catalyzed reaction of carbodiimide 1a and pyrroli-
dine 3a. For instance, carbodiimide 1a reacted with tert-butyl
isocyanide and pyrrolidine leading to the corresponding
product 4c in 70% yield. The structural elucidation of compound
4c was confirmed by X-ray diffraction analysis (see the ESIw).
Reactions of carbodiimide 1a, tert-butyl isocyanide with
piperidine or morpholine worked smoothly as well. Interestingly,
azepane was a good nucleophile in the palladium-catalyzed
reaction of carbodiimide 1a and tert-butyl isocyanide, which
afforded the expected product 4g in 70% yield. Other amines
such as diisopropylamine, indoline, and methyl pyrrolidine-2-
carboxylate were examined in the reaction in the meantime, and
the corresponding products were furnished in moderate yields.
Only a trace amount of product was detected when 2,2,6,6-
tetramethylpiperidine was used as a nucleophile in the reaction of
carbodiimide 1a and tert-butyl isocyanide. This might be due to
its steric hindrance in the reaction process. Aniline was a good
reactant as well. However, a mixture of product 4l/4l0 (1 : 1)
was obtained for the reaction of carbodiimide 1a, tert-butyl
isocyanide, and p-toluidine. We also tested other carbodiimides.
a
Isolated yield based on carbodiimide 1.
Reaction of 2-bromo-N-((butylimino)methylene)benzenamine,
tert-butyl isocyanide, and azepane led to the expected product
4n in 83% yield. Reactions of fluoro- or methyl-substituted
carbodiimides also worked well, which afforded the corres-
ponding products as expected.
We next explored the reactions employing other nucleophiles,
such as alcohols and phenols. The examples are shown in
Scheme 2. Carbodiimide 1a reacted with tert-butyl isocyanide
and benzyl alcohol affording the desired product 4r in 66%
yield under the standard conditions described in Table 2. When
4-tert-butylphenol was utilized as a replacement of benzyl
alcohol, the corresponding quinazolin-4(3H)-imine 4s was
generated in 78% yield.
A possible mechanism was proposed, which is shown in
Scheme 3. We conceived that an oxidative addition of Pd(0) to
carbodiimide 1 would occur to generate an intermediate A. Then
an isocyanide insertion would be involved to afford a palladium(II)
species B. Subsequently, nucleophilic addition and reductive
elimination took place to produce the quinazolin-4(3H)-imines 4.
Another pathway could not be excluded. A nucleophilic attack on
carbodiimide 1 would happen first to generate an intermediate D,
c
2904 Chem. Commun., 2012, 48, 2903–2905
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Scheme 2 Synthesis of quinazolin-4(3H)-imines 4 via a palladium-
catalyzed three-component reaction of carbodiimide 1, isocyanide 2,
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8 (a) Multicomponent Reactions, ed. J. Zhu and H. Bienayme
´
,
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carbon monoxide.10a
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In conclusion, we have described a novel and efficient route
for the preparation of quinazolin-4(3H)-imines via a palladium-
catalyzed three-component reaction of carbodiimide, isocyanide,
and amine or alcohol. The generality of this palladium-catalyzed
three-component reaction has been demonstrated. In the reaction
process, an isocyanide insertion was believed to be the key step
for the successful transformation. Currently, using the strategy of
isocyanide insertion for the formation of other N-heterocycles
is under investigation in our laboratory, and the results will be
reported in due course.
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Financial support from the National Natural Science Founda-
tion of China (Nos. 21032007, 21172038) and Jiangxi Key
Laboratory of Organic Chemistry, Jiangxi Science & Technology
Normal University is gratefully acknowledged.
Notes and references
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c
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Chem. Commun., 2012, 48, 2903–2905 2905