Synthesis of Substituted Quinazolin-4(3H)-imines from Aryldiazonium Salts, Nitriles and 2-Cyanoanilines via A Metal-Free Tandem Approach

Article abstract of DOI:10.1021/acs.orglett.7b02822

A transition metal-free synthesis of multisubstituted quinazolin-4(3H)-imines has been realized by the direct reaction of aryldiazonium salts, nitriles, and 2-cyanoanilines in a one-pot fashion. This strategy utilizes the in situ formation of reactive N-arylnitrilium intermediate, which undergoes further tandem cyclization with consecutive formation of N-C bonds. Broad functional group compatibility, mild conditions, shorter time, and operational simplicity are the notable features of this report.

Full text of DOI:10.1021/acs.orglett.7b02822

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Synthesis of Substituted Quinazolin-4(3H)‑imines From
Aryldiazonium Salts, Nitriles and 2‑Cyanoanilines via A Metal-Free
Tandem Approach
Mani Ramanathan, Yi-Hung Liu, Shie-Ming Peng, and Shiuh-Tzung Liu*
Department of Chemistry, National Taiwan University, Taipei 106, Taiwan
S
* Supporting Information
ABSTRACT: A transition metal-free synthesis of multisubsti-
tuted quinazolin-4(3H)-imines has been realized by the direct
reaction of aryldiazonium salts, nitriles, and 2-cyanoanilines in a
one-pot fashion. This strategy utilizes the in situ formation of
reactive N-arylnitrilium intermediate, which undergoes further
tandem cyclization with consecutive formation of N−C bonds.
Broad functional group compatibility, mild conditions, shorter
time, and operational simplicity are the notable features of this report.
synthesis of 3-aryl-2-halo-4(3H)-quinazoliniminium halides
from heteroenyne-allenes (Scheme 1a).7a A base promoted
one-step synthesis of 3-aryl-4-imino-3,4-dihydroquinazolin-2-
carbonitriles from 2-amino-N′-arylbenzamidines and 4,5-
dichloro-1,2,3-dithiazolium chloride (Appel salt) was achieved
by Koutentis’ group (Scheme 1b).7b A multicomponent
synthesis of quinazolin-4(3H)-imines via Pd-catalyzed reaction
of isocyanide, carbodiimide in the presence of a cyclic amine or
alcohol was developed by Wu’s group, in which the insertion of
isocyanide was illustrated to be the key step (Scheme 1c).7c
Recently, Chen and co-workers described an efficient synthesis
of 2-aminoaryl substituted quinazolin-4(3H)-imines via Cu-
(OTf)2 catalyzing the tandem reaction of diaryliodonium salts
with 2 equiv of o-cyanoanilines at an elevated temperature
(Scheme 1d).7d In addition, Rojas and co-workers reported that
quinazolin-4(3H)-imines could be also prepared by reaction of
phenylchloroimines with 2-aminobenzonitrile (Scheme 1e).7e
Finally, Szczepankiewicz’s group reported the preparation of
desired imines from from 2-amino-N′-arylbenzamidines and
triethyl orthoformate.7h
uinazolin-4(3H)-imines represent a privileged class of
Q annulated six-membered aza-heterocycles with diverse
biological activities such as antimicrobial,1 antihypertensive,2
antiproliferative,3 cholinesterase,4 and cMET kinase inhibitory
properties.5 Furthermore, these molecules could serve as
precursors for quinazolin-4(3H)-one derivatives.6 Because of
their biological portfolio, several appealing synthetic approaches
were reported in recent years and are summarized in Scheme
1.7 Rayat et al. demonstrated a Lewis acid mediated three-step
Scheme 1. Recent Works in Preparation of Quinazolin-
4(3H)-imines
Despite the proven advancements, there are limitations due
to the complicated prefunctionalized sites, multistep proce-
dures, metal catalysts, harsh conditions, and the formation of
waste byproduct. Thus, development of a convenient and atom-
economical synthetic route from easily available precursors
under mild conditions is highly desirable.
Aryldiazonium salts, an important class of readily available
and inexpensive precursors, have been used in various organic
reactions.8 In continuation of our recent studies on the use of
aryldiazonium salt as the precursor for the preparation of
various heterocycles,9 herein, we report a general, mild, and
transition metal-free synthesis of quinazolin-4(3H)-imines
(Scheme 2). We envision that the reactive N-arylnitrilium
Received: September 8, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02822
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Our Proposed Synthetic Approach
Scheme 3. Reactions of Various Aryldiazonium Salts with 3a
in MeCN
a
intermediate (2), generated in situ from the reaction of the
arenediazonium salt with a nitrile molecule,9,10 could further
react with o-cyanoanilines via amination/tandem cyclization to
afford quinazolin-4(3H)-imines directly.
To probe our hypothesis, the reaction of phenyldiazonium
tetrafluoroborate (1a) with anthralonitrile (3a) in anhydrous
MeCN was carried out at room temperature for 12 h. To our
delight, the expected 2-methyl-3-phenylquinazolin-4(3H)-imine
was obtained in 78% isolated yield. When the reaction was
carried out at 80 °C for 2 h, the desired compound 4a was
isolated in 92% yield as a sole product. Lowering or raising the
reaction temperature resulted in diminished yields (Table 1,
entries 3−4). Performing the reaction in the presence of base
or in organic solvents, such as toluene, THF, DMSO, and DCE,
led to inferior results (Table 1, entries 5−9).
a
+
Reaction conditions: ArN2 BF4− (0.52 mmol) and 3a (0.52 mmol) in
MeCN (2 mL) were heated at 80 °C for 2 h; isolated yields.
methods would be challenging and may demand multistep
synthesis. Multiple substituted and fused aryldiazonium salts
were also viable and provided the desired compounds in
excellent yields (Scheme 3, 4k−4m). Notably, 2,4,6-trimethyl
phenyldiazonium salt with distinct steric substituents afforded
4k in good yield. Pleasingly, the use of 1-naphthyl and 2-
naphthyl diazonium salts also produced the corresponding
naphthyl bound quinazolin-4(3H)-imines in excellent yields
(Scheme 3, 4n,4o). To further demonstrate the practicality and
efficiency of the developed method, a gram-scale synthesis of
quinazolin-4(3H)-imine 4a was performed. Typically, reaction
of 1a (1.1 g) with 3a (0.68 g) in acetonitrile (20 mL) delivered
4a (1.16 g, 87%) [Caution: The aryldiazonium tetrafluoroborates
are potentially explosive upon heating and reactions should be
performed using appropriate precautions.]
Next, the limitation of this method with various nitriles was
investigated (Scheme 4). A series of differently substituted
benzonitriles was successfully used in this tandem reaction to
furnish N-aryl substituted quinazolin-4(3H)-imines in yields
ranging from 48−79% (Scheme 4, 5a−5e). The use of 1°, 2°,
3° aliphatic nitriles gave the desired products in reasonable
a
Table 1. Reaction Optimization
b
entry
solvent
temp
rt
t (h)
yield (%)
1
2
3
4
MeCN
MeCN
MeCN
MeCN
MeCN
12
2
78
80 °C
60 °C
110 °C
80 °C
reflux
92(95)
(88)
(79)
trace
2
1
c
5
2
d
e
6
7
8
9
MeCN/toluene
12
12
12
12
ND
d
e
MeCN/THF
reflux
ND
d
e
MeCN/dmso
100 °C
reflux
ND
d
MeCN/ClCH2CH2Cl
trace
a
Scheme 4. Reaction Scope of Various Nitriles
a
Reaction conditions: a mixture of 1a (0.52 mmol), 3a (0.52 mmol),
b
and acetonitrile (2 mL) in a reaction tube. Yields given in parentheses
were determined by H NMR; others refer to isolated yields. K2CO3
(1 equiv) was added in the reaction mixture. MeCN (2.6 mmol) in
solvent (2 mL). ND = not detected.
c
1
d
e
With the optimized conditions in hand, the scope of the
aryldiazonium salts for this reaction was studied, and the results
are summarized in Scheme 3. The reaction tolerated a variety of
electronically distinct substituents on the aryl ring (Scheme 3,
4b−4j). All desired products were isolated with moderate to
excellent yields. To our delight, varieties of functional groups
such as ester, nitrile, arylketone, amide, bromo, ether, and
thioether were compatible under the reaction conditions and
furnished the expected compounds in synthetically useful
yields. However, it was noticed that aryldiazonium salts bearing
p-F and p- NO2 substituents furnished the desired products 4g
and 4h, respectively, in acceptable yields. Preparation of such
functionalized quinazolin-4(3H)-imines through other existing
a
Reaction conditions: diazonium salt (0.52 mmol) and 3a (0.52
mmol) in RCN (2 mL) were heated at 80 °C for 2 h; isolated yields.
B
DOI: 10.1021/acs.orglett.7b02822
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Organic Letters
Letter
yields (Scheme 4, 5f−5h). Notably, α-chloroacetonitrile was
also applicable for this reaction to provide the desired
compound 5i in 76% yield (Scheme 4, 5i). The chloro group
remains intact on the aliphatic side chain, providing a potential
handle for further transformation. Other nitriles such as benzyl,
naphthyl, and heteroaryl nitriles also led to the products in
moderate to excellent yields (Scheme 4, 5j−5l). X-ray
crystallography of 5k was determined to support the structure
of the compound (Figure 1). Malonic mononitrile, with an
Scheme 5. Isolation of Quinazolin-4(3H)-iminium Salts
a
Scheme 6. Reaction Scope of Various 2-Cyanoanilines
a
Reaction conditions: 1a (0.52 mmol) and 3 (0.52 mmol) in MeCN
(2 mL) were heated at 80 °C for 2 h; isolated yields.
Figure 1. ORTEP Plot of 5k (30% probability ellipsoids).
active methylene unit in the molecule, reacted with 1a and 3a
smoothly to render a mixture of tautomers (5m and 5m′) as an
inseparable mixture (eq 1):
(Scheme 6, entries 13a−13c). The use of 5-aryl-2-amino-
benzonitrile delivered the desired product 13d in 79% isolated
yield. However, reaction of 1a with 2-amino-1H-indene-3-
carbonitrile in MeCN led to a mixture of unidentified products
with no formation of the expected product.
In summary, we have reported a facile and sustainable
method for the preparation of quinazolin-4-(3H)-imines via an
intermolecular amination/tandem cyclization from readily
available aryldiazonium salts, nitriles, and 2-cyanoanilines. A
wide range of typical functional groups are tolerated, and the
corresponding products are isolated in high yields under
transition-metal free conditions. Experimental simplicity and
mild reaction conditions are the advantage of this method.
Intriguingly, when aryldiazonium salt 6 bearing an adjacent
benzoyl group was employed in this reaction, an intramolecular
arylation took place to yield 9H-fluoren-9-one as the sole
product (eq 2). In contrast to our previous observations,9a,b,d
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02822.
Experimental procedures; details of characterization of all
new compounds; complete bond distances and bond
angles of 5k (PDF)
aryldiazonium salt 8 reacted with 3a in acetonitrile to give 9 in
excellent yield instead of the formation of 6-methylphenan-
thridine (10) (eq 3). Evidently, the rate of intermolecular
Crystal data (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: stliu@ntu.edu.tw
ORCID
amination/tandem cyclization appears to be faster than that of
intramolecular arylation of N-arylnitrilium ion. Moreover, stable
quinazolin-4(3H)-iminium salts could be conveniently obtained
by simple trituration of crude reaction residue with ether, thus
making the overall procedure more sustainable (Scheme 5):
The scope of this method was further applied to various
substituted 2-cyanoanilines (3b−3e). As shown in Scheme 6, o-
cyanoanilines with bromo and chloro substitutents at different
positions were smoothly reacted with 1a and produced the
corresponding quinazolin-4(3H)-imines in good yields
Shiuh-Tzung Liu: 0000-0002-0544-006X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Ministry of Science and Technology, Taiwan for
the financial support (MOST103-2113-M-002-MY3). We also
thank “National Taiwan University Mass Spectrometry-based
Proteomics Core Facility” for the measurement of SI mass data.
C
DOI: 10.1021/acs.orglett.7b02822
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Organic Letters
Letter
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DOI: 10.1021/acs.orglett.7b02822
Org. Lett. XXXX, XXX, XXX−XXX