Efficient Synthesis of Quinazolinones by Transition-Metal-Free Direct Aerobic Oxidative Cascade Annulation of Alcohols with o-Aminoarylnitriles

Article abstract of DOI:10.1002/cssc.201900265

A mild and atom-economic method was developed for direct and efficient synthesis of quinazolinones through a transition-metal-free aerobic oxidative cascade annulation reaction of widely available o-aminoarylnitriles and alcohols. Air could be employed as an effective oxidant under mild conditions, generating water as the only byproduct. Possibly owing to the “cesium effect”, the water-soluble base CsOH was found to be crucial in all key steps of the reaction mechanism. Because a wide range of substrates can be used to prepare substituted quinazolinones without contamination by transition-metal residues, this method may be of interest for application in pharmaceutical synthesis. Possible reaction paths were also proposed according to control reactions.

Full text of DOI:10.1002/cssc.201900265

Accepted Article
Title: Efficient Synthesis of Quinazolinones by Transition Metal-Free
Direct Aerobic Oxidative Cascade Annulation of Alcohols with o-
Aminoarylnitriles
Authors: Qing Xu, Qi Wang, Miao Lv, Jianping Liu, Yang Li, Hongen
Cao, and Xu Zhang
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To be cited as: ChemSusChem 10.1002/cssc.201900265
Link to VoR: http://dx.doi.org/10.1002/cssc.201900265
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10.1002/cssc.201900265
ChemSusChem
COMMUNICATION
Efficient Synthesis of Quinazolinones by Transition Metal-Free
Direct Aerobic Oxidative Cascade Annulation of Alcohols with o-
Aminoarylnitriles
Qi Wang,[a] Miao Lv,[a] Jianping Liu,[b] Yang Li,[b] Hongen Cao,*[a] Xu Zhang,[a] and Qing Xu*[a,b]
Abstract: A mild and atom-economic method is developed for direct
and efficient synthesis of quinazolinones via a transition metal-free
aerobic oxidative cascade annulation reaction of the widely available
o-aminoarylnitriles and alcohols. Air can be employed as an effective
oxidant under mild conditions, generating water as the only
byproduct. Possibly owing to the “cesium effect”, the water soluble
CsOH is the best base as it’s found crucial in all the key steps of the
reaction mechanism. Since a wide range of substrates can be used
to prepare substituted quinazolinones without contamination by
transition metal residues, this method may be of potential
applications in pharmaceutical synthesis. Possible reaction paths
were also proposed according to the control reactions.
toxic chemicals,[15] using alcohols instead of the above
mentioned aldehydes, aldehyde equivalents, or acid derivatives
in annulation reactions of o-aminoarylamides through transition
metal-catalyzed dehydrogenative,[16] oxidative,[17] or aerobic
oxidative[18] strategies (Scheme 1F) have also aroused much
interest in recent years. Similarly, the reactions of alcohols with
o-nitroarylamides[19] or o-nitroarylnitriles[20] were also described
recently. Although various quinazolinones and derivatives can
be obtained by above methods, many still have inherent
drawbacks difficult to overcome. For example, some require
tedious multi-step procedures,[2,3] some require rather harsh
reaction conditions,[2,3,19,20] some require transition metal
catalysts/ligands[4-9,11,13,16] that can lead to metal residue
contaminant in the products and limit their applications in drug
synthesis, and some require excess amounts of bases,[10,13]
oxidants,[5,8,17] or reactants[19,20] that can lead to production of
large amounts of wastes. Therefore, developing direct, efficient,
atom-economic, and transition metal- and waste-free methods
that can employ greener substrates and O2 or even air as the
oxidant are still of great importance in the field.
Heterocycle derivatives have broad utilities in many fields
especially the organic, pharmaceutical, and natural product
synthesis, agrochemistry, materials and life science. For
example, quinazolinone motif and derivatives are abundant in
numerous synthetic compounds and natural alkaloids having
diverse biological and pharmacological activities such as
antimalarial, antimicrobial, anti-inflammatory, anticonvulsant,
O
O
antihypertensive,
anti-diabetic,
anticancer,
antitumor,
CO2H
R2CN
or [R2COX] + [NH3]
R2
NH
R2
or
cholinesterase inhibitory, dihydrofolate reductase inhibitory, and
kinase inhibitory properties.[1,2] Hence, a variety of methods have
been developed for quinazolinone skeleton construction.[2-19]
Among the methods reported, annulation reactions of o-
aminoaryl acids and derivatives may be the most employed
strategies, which include the condensation of o-aminoaryl acids
with amides, nitriles, or acid derivatives plus a nitrogen source
(Scheme 1A),[2,3] the dehydrogenative or oxidative annulation of
o-aminoarylamides with aldehydes,[4] masked aldehydes,[5]
ketones,[6] imines,[7] or amines[8] (Scheme 1B), the carbonylative
annulation of o-aminoarylamides with a CO source and aryl
halides (Scheme 1C),[9] and annulation of o-aminoarylnitriles
with acid derivatives,[10] aldehydes,[11] or ketones[12] (Scheme 1D).
Moreover, transition metal-catalyzed coupling reactions of o-
haloarylamides with amides, nitriles, amines, or aldehyde
equivalents plus a nitrogen source (Scheme 1E)[13] as well as
other annulation reactions[2,14] have also received much attention
recently. Meanwhile, since alcohols are known as a class of
greener, more available, more economic, more stable, and less
R1
H2N
(A)
(refs. 2-3)
+
R1
NH2
N
[R2COX] = R2CO2H, R2COCl, R2CO2R, (R2CO)2O, R2C(OR)3, etc.
O
O
CNH2
[O]
NH
R2
R1
R1
[R2CHO]
+
(refs. 4-8)
(B)
N
NH2
[R3CHO] = R2CHO, R2CO-FG, R2COR, R2CH2=NR, R2CH2NH2, etc.
O
O
CNH2
NH
Ar
cat. TM/L
base
(C)
(D)
R1
R1
(ref. 9)
+ [CO] + ArX
NH2
CN
N
O
NH
R2
(refs. 10-12)
R1
[R2COX]
+
R1
NH2
N
[R3COX] = R2COX, R2CHO, R2COR, etc.
O
O
O
R2CN
CNH2
or
H2N
R2
NH
R2
cat. TM/L
base
(E)
R1
(ref. 13)
R1
or R2CH2NH2
or [R2COX] + [NH3]
+
N
X
[R2COX] = R2CH2OH, R2CHO, R2CH3, etc.
O
O
cat. TM/L
CNH2
i) -H2 or H-acceptor
ii) oxidant
iii) O2 or air
(F)
NH
R2
R1
R2CH OH
R1
(refs. 16-18)
+
2
NH2
N
[a]
Miss Q. Wang, Miss M. Lv, Mr. H. Cao, Dr. X. Zhang, Prof. Dr. Q. Xu
School of Chemistry and Chemical Engineering, Yangzhou
University
O
CN
cat. base, air
R2CH2OH
+
This work
NH
R2
R1
(G)
R1
- 2H2O
NH2
Yangzhou, Jiangsu 225002, China
N
air
cat. base
- H2O
E-mail: xuqing@yzu.edu.cn; hecao@yzu.edu.cn
Dr. J. Liu, Mr. Y. Li, Prof. Dr. Q. Xu
cat. CsOH
(refs. 24f-g,25g)
+ H2O
O
(ref. 22)
[b]
College of Chemistry and Materials Engineering, Wenzhou
University
Wenzhou, Zhejiang 325035, China
air
- 2H2O
H
+
NH2
R1
R2
O
NH2
E-mail: qing-xu@wzu.edu.cn
Scheme 1. General methods for quinazolinone skeleton construction.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
On the other hand, it is well known amides can be readily
obtained by nitrile hydration reaction,[21,22] which, also due to the
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10.1002/cssc.201900265
ChemSusChem
COMMUNICATION
higher stability of nitriles than the corresponding amides, is
known kinetically slower than amide hydrolysis to acids.[21] In this
sense, the widely available o-aminoarylnitriles[23] may be a class
of more preferable substrates, as the reaction efficiency may be
enhanced by avoiding hydrolytic side-reactions of substrate o-
aminoarylamides through in situ generation of intermediate o-
aminoarylamides by nitrile hydration. With a long term interest in
heterocycle construction[24] and developing alcohol-based green
synthetic methods,[25] we have previously observed that base
can catalyze the aerobic oxidation of alcohols[24f-g,25g] and that
“cesium effect”[26] can lead to efficient and controllable CsOH-
catalyzed nitrile hydration and aminolysis reactions.[22] We thus
envisioned a new strategy for quinazolinone construction, i.e., a
base-catalyzed aerobic oxidative annulation reaction of o-
aminoarylnitriles with alcohols (Scheme 1G). Beside the
advantages of using alcohols and o-aminoarylnitriles as the
substrates, this reaction may also features high atom-economy,
no transition metal contaminants in the products, and waste-free
if O2 or even air can be successfully used as effective oxidant as
water would be the only by-product. To our knowledge, such a
promising method has not been reported yet. Herein we report
the detail of our findings.
We started the research by investigating the model reaction
of o-aminobenzonitrile (1a) and benzyl alcohol (2a) (Table 1).
The reaction was initially heated in xylenes at different
temperatures using CsOH (1 equiv.) as the base and air (using
an air balloon) as the oxidant (entries 1-3). The results showed
that, with the increase of the reaction temperature, the yield of
product 3aa could be improved accordingly (entries 1-2), with 80
oC giving the highest yield of 3aa (entry 2, 82%). At even higher
temperatures, the product yield began to drop (entry 3), which
may be due to over hydrolysis[21,22] of the nitrile substrate at
higher temperatures. Then, the reaction was directly sealed
under air without using the balloon (entry 4). Without adequate
air, the reaction gave a lower yield of 3aa, showing that the air
amount is key to the reaction. Pure oxygen was also tested, but
gave a slightly lower yield of 78% (entry 5). This indicates that
air is even more effective than the more oxidative O2. Therefore,
the reaction can be safer, more economic, and more operable
by employing air as the oxidant. Contrary to above conditions,
the reaction under nitrogen gave no product at all (entry 6),
suggesting this is indeed an aerobic reaction. Without CsOH, no
reaction occurred either (entry 7), showing that base is crucial to
the reaction. Then, various bases (NaOH, KOH, etc.) were
screened to obtain the best one (entry 8), but gave only inferior
product yields than CsOH, suggesting that CsOH is still the best
base. The loading of CsOH was then investigated hoping to
obtain a catalytic method. However, the reaction using less
CsOH was much less effective (entry 9); while the reaction with
more CsOH also gave a lower yield of 3aa (entry 10), possibly
due to nitrile over hydrolysis caused by excess amounts of the
base.[21,22] The reaction was also investigated with higher
concentration of the reactants using less solvent to enhance the
reaction rate, but the results was not satisfactory (entry 11).
Finally, a variety of solvents was also screened (entry 12). In
comparison, xylenes were still the best solvent (entry 2).
Table 1. Condition screening and optimization.[a]
3aa%[
entry
base (mol%)
atm. (oxid.)
solv. (mL), temp.
b]
1
CsOH (100)
CsOH (100)
CsOH (100)
CsOH (100)
CsOH (100)
CsOH (100)
-
air balloon
air balloon
air balloon
air[c]
xylenes (3), 40~60 oC
36~73
82
xylenes (3), 80 o
C
2
The optimized conditions were then applied to various
substrates to extend the scope of the method. As shown in
Table 2, like the model reaction (entry 1), electron-rich benzylic
alcohols including the sterically more bulky ortho-substituted
ones (entries 4 and 7) generally gave good to high yields of the
products (entries 2-7). The reactions of electron-deficient
benzylic alcohols seemed to be less efficient. Thus, benzylic
alcohols with more inert para-substituted fluoro, chloro, and
trifluoromethyl groups could still give satisfactory yields of the
products (entries 8-9, 13); whereas, those bearing sterically
more bulky ortho-substituted ones and those with more reactive
bromo and iodo groups gave lower yields of the products
(entries 10-12). Modified conditions such as prolonged reaction
time, elevated temperature, and increased loading of the
substrates could improve the product yields obviously (entries 9-
13). In contrast, para-nitrobenzyl alcohol did not gave any target
product under a variety of conditions (entry 14), which may be
due to the reactive nature of the nitro group under the basic
conditions.[27] The reactions of the bulky naphthylmethanols
were more sluggish, but afforded higher yields of the products in
xylenes (3), 100~120 oC
xylenes (3), 80 oC
xylenes (3), 80 oC
xylenes (3), 80 oC
xylenes (3), 80 oC
xylenes (3), 80 oC
xylenes (3), 80 oC
xylenes (3), 80 oC
xylenes (1.5), 80 oC
solvents (3),[e] 80 oC
72~75
67
3
4
5
O2 balloon
N2
78
6
0
7
air balloon
air balloon
air balloon
air balloon
air balloon
air balloon
0
base (100)[d]
CsOH (50)
CsOH (150)
CsOH (100)
CsOH (100)
0~69
46
8
9
10
11
12
71
64
0~79
[a] The mixture of 1a (1 mmol), 2a (1.2 mmol), and a base (CsOH·H2O
abbreviated as CsOH) in a solvent was sealed in a 100 mL Schlenk tube
equipped with an air or O2 balloon, heated for 24 h, and monitored by
TLC/GC-MS. [b] Isolated yields based on 1a. [c] Directly sealed without
balloon. [d] NaOH: 59%; KOH: 64%; t-BuONa: 54%; t-BuOK: 69%; Cs2CO3:
0%. [e] Toluene: 78%; CH3CN:58%; EtOH: 0%; DCM: trace; DMSO: 66%;
dioxane: 79%.
prolonged
reaction
time
(entries
15-16).
Similarly,
heteroarylmethanols such as 2-pyridylmethanol and 2-
thienylmethanol also afforded moderate yields of the products
under the standard conditions and afforded higher yields of the
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10.1002/cssc.201900265
ChemSusChem
COMMUNICATION
products under modified conditions (entries 17-18) as dioxane
was also found as a good solvent for the reaction (Table 1, entry
12). In the case of allyl alcohols such as cinnamyl alcohol, its
reaction required a higher temperature to achieve a satisfactory
yield (entry 19). Aliphatic alcohols were then investigated.
However, except the more reactive cyclopropylmethanol that
afforded the product (entry 20), other aliphatic alcohols were
found not reactive (entry 21), possibly due to their inactive
nature toward the aerobic oxidation under the present conditions.
[a] See entry 2 of Table 1 for detail. Isolated yields based on 1. [b] 36 h. [c]
120 oC. [d] 48 h. [e] 2 equiv. 1 added. [f] Dioxane used as the solvent.
The above method was then extended to substituted o-
aminobenzonitriles. Even more efficient than unsubstituted 1a
(Table 2, entry 1), the electron-rich p-methyl-o-aminobenzonitrile
1b afforded high yields of the products in reactions with
unsubstituted alcohol 2a, both electron-rich and –deficient
benzylic alcohols, as well as the heteroarylmethanols (entries
22-26). In great contrast, the reaction of the sterically more bulky
o-methyl-o-aminobenzonitrile 1c was much ineffective, affording
only the product in a moderate yield at a higher temperature
using dioxane as the solvent (entry 27). This may be attributed
to the hindered nitrile hydration step by the adjacent Me group in
the reaction mechanism (vide infra). On the other hand,
electron-deficient o-aminobenzonitriles could also afford the
target products in satisfactory yields under the standard or
modified conditions (entries 28-31). In addition to above o-
aminoarylnitriles, an aliphatic nitrile (2-aminopropane nitrile) was
also tested, but no product was obtained under the present
conditions (entry 32).
Table 2. Substrate Extension for CsOH-mediated aerobic oxidative
annulation of o-aminoarylnitriles and alcohols.[a]
Control reactions were then investigated to probe the
reaction mechanism and the role of CsOH in the reaction.[28]
Firstly, o-aminobenzonitrile 1a and benzyl alcohol 2a effectively
afforded o-aminobenzamide 4a and benzaldehyde 5a
respectively by hydration and aerobic oxidation reactions in the
presence of CsOH (eqs. 1-2). The reaction of 4a and 2a also
afforded 3aa under the standard conditions (eq. 3). In contrast,
all the above reactions did not occur without CsOH, suggesting
the key role of CsOH in the nitrile hydration[22] and aerobic
alcohol oxidation[24f-g,25g,29] steps. Then, the reaction of 1a and 5a
under the standard conditions effectively afforded 3aa in a high
yield of 97% (eq. 4); whereas, in the absence of CsOH, the
reaction afforded only the condensed imine 6aa in a moderate
yield (eq. 5). This suggests that condensation of 1 and 5 can
readily take place to give imine intermediates 6, but CsOH is key
to facilitate its annulation to product 3.
O
CN
CsOH (1.0 equiv.)
NH
(4)
+
Ph
O
air balloon
xylenes, 80 oC, 24 h
NH2
N
Ph
5a
1a
3aa, 97%
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10.1002/cssc.201900265
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COMMUNICATION
The reaction of 4a and 5a was then investigated in the
presence of CsOH, which afforded 3aa in 40% yield (eq. 6).
Herein the yields of 3aa obtained from the reactions of o-
aminobenzamide 4a (eqs. 3 and 6) are clearly much lower than
those from o-aminobenzonitrile 1a (the standard reaction in
Table 1 and eq. 4), which may be due to the amide hydrolysis to
acid in the presence of a base, a difficult-to-avoid side reaction
of nitrile hydration.[21] This further suggests that o-
aminobenzonitriles 1 are more advantageous substrates than o-
aminobenzamides 4 in the present reaction. In contrast, without
CsOH, instead of producing 3aa, a considerable amount of a
new product was observed in an incomplete reaction of 4a and
5a, which, possibly via formation imine intermediate 7aa, was
determined to be annulated 8aa as confirmed by GC-MS and
NMR analysis (eq. 7).[4,28] As we have also observed, the low
yield of 8aa in this reaction may be attributed to the incomplete
reaction of 4a and 5a, 8aa’s easy decomposition to reactants 4a
and 5a and slow oxidation to 3aa in the presence of air (eq. 8).[28]
Therefore, it may be concluded from above contrastive reactions
(eqs. 6-8) that, without CsOH, the blank reaction of 4 and 5
giving 8 is an equilibrium[4] and further aerobic oxidation of 8 to 3
is a slow process. In contrast, the annulation of 4 and 5 can be
greatly facilitated by CsOH to finally afford product 3 via a
CsOH-promoted aerobic oxidation of intermediate 8.
intermeiate 8. Although the blank reaction of 4 and 5 may be an
equilibrium and 8 tends to decompose back to 4 and 5, in the
presence of CsOH, fast aerobic oxidation of 8 to 3 can drive the
reaction go forward and finally afford the quinazolinones 3.
In conclusion, we developed a mild and atom-economic
method for direct and efficient synthesis of quinazolinones via a
transition metal-free aerobic oxidative cascade annulation
reaction of the widely available and stable o-aminoarylnitriles
and alcohols. In this reaction, air can be employed as an
effective oxidant under a mild condition, generating water as the
only byproduct. Meanwhile, possibly owing to the “cesium effect”,
the water soluble CsOH is the best base as it’s found crucial in
all the key steps of the reaction mechanism. Since a wide range
of substrates can be used to prepare substituted quinazolinones
without contamination by transition metal residues, this method
may be of potential applications in pharmaceutical synthesis.
Further extensions of this transition metal-free base-catalyzed
construction of heterocycles using readily available and
economic starting materials are underway in this laboratory.
Experimental Section
Typical Procedure for CsOH-Mediated Aerobic Oxidative Casecade
Annulation of Alcohols with o-Aminoarylnitriles. The mixture of o-
aminobenzontrile (1a) (0.1181 g, 1.0 mmol), benzyl alcohol (2a) (0.1296
g, 1.2 mmol, 1.2 equiv.), and CsOH·H2O (0.1679 g, 1.0 equiv.) in xylenes
(3.0 mL) in a Schlenk tube (100 mL) equipped with an air balloon was
heated at 80 oC for 24 h and monitored by TLC and/or GC-MS. The
mixture was then quenched by aqueous HCl (1 M, 2 mL) and extracted
with ethyl acetate. The solvent was evaporated under vacuum. The
residue was then purified by flash column chromatography on silica gel
using petroleum ether and ethyl acetate (5:1) as the eluent, giving the
target 3aa in 82% isolated yield.
Acknowledgements
We thank National Natural Science Foundation of China
(21672163), National Key Research and Development Program
of China (2018YFD0200100), and Natural Science Foundation
of Zhejiang Province for Distinguished Young Scholars
(LR14B020002) for financial support.
Scheme 2. Plausible reaction paths for the CsOH-mediated aerobic oxidative
cascade annulation of alcohols with o-aminoarylnitriles.
Keywords: aerobic oxidation
•
air
•
alcohols
•
o-
aminobenzonitriles • cascade annulation • quinazolinones
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CsOH-mediated aerobic oxidative cascade annulation of
alcohols and o-aminoarylnitriles were proposed. As shown in
Scheme 2, o-aminoarylnitriles 1 and alcohols 2 may firstly be
transformed into the corresponding o-aminobenzamides 4 and
aldehydes 5 respectively via CsOH-mediated nitrile hydration
and aerobic alcohol oxidation reactions. Then, the remained
unhydrated o-aminoarylnitriles 1 or o-aminobenzamides 4 may
react with aldehydes 5 to give condensed imine intermediates 6
or 7, which may quickly undergo oxidative annulation to afford
[2]
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3
via the formation of another
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COMMUNICATION
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Entry for the Table of Contents
COMMUNICATION
Q. Wang, M. Lv, J. Liu, Y, Li, H. Cao,* X.
Zhang, and Q. Xu*
Page No. – Page No.
Efficient Synthesis of Quinazolinones
by Transition Metal-Free Direct
Aerobic Oxidative Cascade
Annulation of Alcohols with o-
Aminoarylnitriles
A mild and atom-economic method is developed for direct and efficient synthesis of
quinazolinones via a transition metal-free aerobic oxidative cascade annulation
reaction of the widely available o-aminoarylnitriles and alcohols. Air can be
employed as an effective oxidant under mild conditions, generating water as the
only byproduct. Possibly owing to the “cesium effect”, the water soluble CsOH is the
best base as it’s found crucial in all the key steps of the reaction mechanism. Since
a wide range of substrates can be used to prepare substituted quinazolinones
without contamination by transition metal residues, this method may be of potential
applications in pharmaceutical synthesis. Possible reaction paths were also
proposed according to the control reactions.
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