Synthesis of 2-substituted quinazolines by CsOH-mediated direct aerobic oxidative cyclocondensation of 2-aminoarylmethanols with nitriles in air

Article abstract of DOI:10.1039/c7gc00977a

By using air as the superior oxidant, a highly atom-efficient synthesis of 2-substituted quinazolines is developed by a CsOH-mediated direct aerobic oxidative reaction of the readily available and stable 2-aminoarylmethanols and nitriles. Effectively working as the promoter in the alcohol oxidation, nitrile hydration, and cyclocondensation steps, CsOH is the best base for the reaction. A similar method can also be extended to the synthesis of substituted quinolines starting from methyl ketones instead of nitriles.

Full text of DOI:10.1039/c7gc00977a

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Synthesis of 2‐Subsitituted Quinazolines by CsOH‐Mediated
Direct Aerobic Oxidative Cyclocondensation of 2‐
Aminoarylmethanols with Nitriles in Air†
Received 00th January 20xx,
Accepted 00th January 20xx
Song Yao,a,b Kaijing Zhou,b Jiabing Wang,a Hongen Cao,c Lei Yu,c Jianzhang Wu,a*Peihong Qiu,a*
DOI: 10.1039/x0xx00000x
Qing Xua,b,c
*
By using air as the superior oxidant, a highly atom‐efficient metal catalysts, ligands, environment‐unfriendly solvents, or
synthesis of 2‐subsitituted quinazolines is developed by a CsOH‐ large amounts of bases or oxidants that can lead to metal
mediated direct aerobic oxidative reaction of the readily available contamination in products, generation of wastes and low atom
and stable 2‐aminoarylmethanols and nitriles. Effectively working economy. These limitations largely impeded the applications
as the promoter in the alcohol oxidation, nitrile hydration, and of quinazoline derivatives in pharmaceutical synthesis.
cyclocondesation steps, CsOH is the best base for the reaction. The
similar method can also be extended to the synthesis of
substituted quinolines starting from methyl ketones instead of
nitriles.
Quinazoline derivatives are a class of fused heterocycles
frequently present in various alkaloids and functional
molecules having
a diverse range of biological and
pharmacological activities such as anticancer, antimalaria, anti‐
inflammatory, antibacterial, anticonvulsant, antituberculosis,
and antihypertensive properties.1 Due to their increasing
importance, various methods have been developed for
quinazoline construction,2‐12 which mainly include the
oxidative condensation of o‐aminobenzylamines with aldehyde
equivalents such as aldehydes3 and alcohols4 (Scheme 1A), the
reactions of o‐amino‐ or o‐haloarylcarbonyl equivalents with
amine equivalents5 or ammonia and carbon sources such as
aldehydes6 and DMF/DMA7 (Scheme 1B), the coupling of
amidines with o‐halobenzylamines8 or o‐halobenzyl halides9
(Scheme 1C), the condensation of arylamidines with aldehyde
equivalents10‐11 or functionalized alkynes12 (Scheme 1D), as
well as a novel Cu‐catalyzed [2+2+2] cascade annulation
reaction of diaryliodonium salts with nitriles.13 Despite these
advances in developing different synthetic strategies,2‐13 many
methods still have drawbacks such as harsh reaction
conditions, the use of not readily available substrates, noble
Scheme 1. General Methods for Synthesis of Substituted
Quinazolines.
With a long term interest in heterocycles14 and alcohols,15
we have previously utilized aerobic alcohol oxidation with air
(Scheme 1E, left)15f‐i in benzazole synthesis.14f We also
observed that CsOH can catalyze the nitrile hydration and
aminolysis reactions for clean synthesis of primary to tertiary
amides (Scheme 1E, right).16 We thus envisioned a one‐step
approach for quinazoline construction starting from 2‐
aminoaryl alcohols and nitriles via a base‐catalyzed in situ
generation of the key 2‐aminoaryl aldehydes/ketones and
a Chemical Biology Research Center, College of Pharmaceutical Sciences, Wenzhou
Medical University, Wenzhou, Zhejiang 325035, China. E‐mail: wjzwzmu@163.com;
wzqph@163.com; Tel: (+)‐86‐158‐25672558
b College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou,
Zhejiang 325035, P. R. China. E‐mail: qing‐xu@wzu.edu.cn; Fax: (+)‐86‐577‐
86689302; Tel: (+)‐86‐138‐57745327
c Institute of Pesticide, School of Horticulture and Plant Protection and School of
Chemistry and Chemical Engineering, Yangzhou University, Yangzhou, Jiangsu
225002, China
† Electronic Supplementary Information (ESI) available: Experimental details,
condition screening tables, and characterization and copies of 1H and 13C NMR
spectra of the products. See DOI: 10.1039/x0xx00000x
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amides (Scheme 1E).17 If achieved, this process might be a using pure O2 as the oxidant also gave a low yield of 3aa (run
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DOI: 10.1039/C7GC00977A
greener, more practical, and atom‐efficient method than many 14). Analysis of the reaction mixture showed that complex
of the known quinazoline construction strategies2‐13 and the reaction occurred with generation of known and unknown
Ru3(CO)12/Xantphos‐catalyzed anaerobic dehydrogenation byproducts, possibly due to the instable nature of the 2‐
method,17 because: 1) 2‐aminoaryl alcohols are more available, aminobenzaldehyde intermediate. This suggested that a mild
more stable, and cheaper than the frequently used instable 2‐ oxidant like air is more preferable than the more oxidative O2
aminoaryl aldehydes, 2) no transition metal catalysts/ligands in the present reaction, which is to our knowledge rare in
other than the water soluble inorganic bases are used in the aerobic oxidative reactions.
reactions, and 3) no other additives and oxidants were
required other than the air, which is readily available,
Table 1. Base Screening and Conditions Optimization.a
economic, and safe to use, and produces water as the only
byproduct.
Based on our previous results,14‐16 the reaction of 2‐
aminophenylmethanol (1a) and benzonitrile (2a) was initially
heated at 100 oC in air (employing an air balloon) using either
water or DMSO as the solvent or additive in the presence of
0.5~1.0 equiv. of CsOH (Table1, runs 1‐2).18 However, no or
only trace amount of the target 2‐phenyl quinazoline (3aa) was
run base (equiv.)
solvent (mL)
H2O (3)
T
3aa%b
0d,e
tracee,f
10~75
80
1c
CsOH (0.50~1.0)
CsOH (0.50~1.0)
CsOH (1.0)
CsOH (1.0)
basesh (1.0)
CsOH (1.0)
CsOH (1.0)
CsOH (0.5)
CsOH (2.0)
CsOH (1.0)
CsOH (1.0)
CsOH (1.0)
CsOH (1.0)
100 oC
100 oC
2
DMSO (3)
solventsg (3) 100 oC
3
detected with observation of variant amounts of unreacted 1a
,
4
dioxane (3)
dioxane (3)
dioxane (3)
dioxanej (3)
dioxane (3)
dioxane (3)
dioxane (3)
dioxane (3)
dioxane (3)
dioxane (3)
dioxane (3)
100 oC
100 oC
100 oC
100 oC
100 oC
100 oC
80 oC
120 oC
100 oC
120 oC
120 oC
intermediates 2‐aminobenzaldehyde (4a) and benzamide (5a),
and byproduct benzoic acid (6a). Obviously, 5a and 6a were
generated by hydration and over hydrolysis of 2a in the
presence of a base;16 whereas 4a and 5a were detected due to
their incomplete conversion to 3aa. Therefore, reaction
conditions that can both ensure efficient oxidation of 1a to 4a
and its conversion to 3aa, and avoid over hydrolysis of 2a is
the key to the success of the reaction. Different parameters of
the reaction conditions were then screened to obtain the best
one.
5
6i
0~26
traced,e,f
83
7
8
21
9
75
26e,f
10d,e,f
58d,e,f
tracee
40e,f
10
11
12k
13l
As shown in Table 1, using directly the commercial solvents
(THF, toluene, etc.) without addition of water seemed to be
more preferable as up to 75% isolated yields of 3aa could be
obtained in the presence of 100% CsOH (run 3).18 Among the
solvents tested, 1,4‐dioxane was found to be the best one as
the highest 80% yield of 3aa could be obtained (run 4). Other
usual bases like NaOH, KOH, or t‐BuONa were also investigated
under the same conditions in dioxane, but no good results
could be obtained (run 5).18 CsOH is thus still the best base for
the reaction, most likely due to the cesium effect.19 Addition of
water to the best solvent dioxane was found again an
unfavorable operation, for only trace yield of 3aa was
generated with formation of considerable amounts of 5a and
6a (run 6). Dry dioxane was then tested. A slightly enhanced
83% yield of 3aa was obtained under the same conditions (run
7). The above results (runs 1‐4, 6) suggested that the existing
water in the substrates and base is adequate for the reaction,
and thus additional water is not necessary. Screening of the
base loading showed that less CsOH is ineffective and excess
CsOH is also unnecessary (runs 8‐9). Temperature screening
showed that lower temperature was ineffective and higher
temperature led to side reactions and formation of byproducts
5a and 6a (runs 10‐11). Besides, a reaction directly sealed in
the reaction tube without the air balloon (with less air) gave a
lower yield of 3aa (run 12). Similarly, a reaction under N2 (with
even less air) gave only trace amounts of 3aa (run 13). These
results (runs 12‐13) clearly revealed that the amount of air is
also significant to the product’s yield. Surprisingly, the reaction
14m CsOH (1.0)
a Unless otherwise noted, the mixture of 1a (1.0 mmol), 2a (1.2 equiv.),
and a base (CsOH∙H2O is abbreviated as CsOH) in a solvent (3 mL) was
sealed under air in a 100 mL Schlenk tube equipped with an air balloon
and then heated and monitored by GC‐MS/TLC. b Isolated yields based
c
on 1a
.
With or without DMSO (2 equiv.). d Variant amounts of 1a
remained not oxidized. e Considerable amounts of PhCONH2 (5a) and
f
PhCOOH (6a) were observed. Trace amount of 2‐aminobenzaldehyde
g
(
4a) was observed. Usual solvents such as THF, toluene, etc. h Usual
bases like NaOH, KOH, t‐BuONa, etc. i 1 equiv. H2O added. j Dry dioxane
was used. k Directly sealed in the tube without air balloon. l Under N2. m
With an O2 balloon.
Since the commercial dioxane gave a close result with the
dry one (Table 1, runs 4 and 7), it was used as the solvent in
reactions of more substrates for convenience’s sake to extend
the scope of the method. As shown in Table 2, similar to
benzonitrile (run 1), both p‐ and m‐methylbenzonitrile gave
good yields of the target products (runs 2‐3); while the
reaction of sterically more bulky o‐methylbenzonitrile was not
effective under the same conditions (run 4). Then, by heating
o
at 120 C in the presence of more CsOH, the reaction of o‐
methylbenzonitrile afforded the target product in a moderated
yield of 51% (run 4). In contrast, the reactions of the most
bulky 2,4,6‐trimethylbenzonitrile were all ineffective under a
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variety conditions due to the great steric hindrance derived also a good leaving group in electron deficient aromatic and
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DOI: 10.1039/C7GC00977A
from the two adjacent methyl groups (run 5). Similar to p‐ heteroaromatic compounds.20
methylbenzonitrile, p‐methoxylbenzonitrile gave a good yield
Table 2. CsOH‐Mediated Aerobic Oxidative Synthesis of Subsitituted
of the product under the standard conditions (run 6); while the
m‐ and o‐substituted ones required slightly harsher conditions
such as 120 oC (run 7) and also more CsOH (run 8). This can be
attributed, in addition to steric effect, to the relatively strong
electron‐donating effect of the methoxyl group in deactivation
of the nitrile moiety. This is the same with the electron‐
donating p‐amino‐ and p‐hydroxyl substituted benzonitriles
that also require higher temperatures to obtain good results
(run 9‐10). In the latter case, most possibly because the slightly
acidic hydroxyl group can consume at least 1 equiv. of the base,
an excess amount of CsOH is needed (run 10).
Quinazolines.a
As to electron‐deficient nitriles, although 1 equiv. of strong
basic CsOH was employed as the best promoter for the
present reaction, screening of the halo‐substituted nitriles
showed that the halo groups can be well tolerated under the
basic conditions. Thus, except the more bulky o‐
chlorobenzonitrile that required harsher conditions (run 13),
the p‐ and m‐chloro‐ and bromobenzonitriles all gave good
results under the standard conditions (runs 11‐12, 14‐15). The
iodobenzonitriles could also afford the target products under
the standard conditions, but the yields were much lower (runs
16‐17). Certain yields of the deiodonation product 3aa were
also observed in these reactions, which may be attributed to
the reactive nature and good leaving ability of the iodo group.
In great contrast with above halobenzonitriles, only trace
amounts of the target product could be observed in the
reactions of p‐fluorobenzonitrile under the standard and a
variety modified conditions (run 18). Analysis of the reaction
mixtures showed that the O‐ and N‐arylation byproducts of
CsOH or 1a with p‐fluorobenzonitrile, such as p‐
hydroxybenzonitrile, were generated in considerable amounts.
This is mostly due to the highest reactivity and the best leaving
ability of the fluoro group among the electron‐deficient
haloarenes in nucleophilic aromatic substitution (SNAr)
reactions.20
Moreover,
electron
deficient
p‐
trifluorobenzonitrile was also investigated, which gave a
moderate yield of the product under the standard conditions
but could afford a better result under modified conditions (run
19). In the cases of nitrobenzonitriles, all the p‐, m‐, o‐
substituted ones were found not good substrates in this
method (run 20), most possibly because the nitro is a sensitive
group under the basic conditions.21
a Unless otherwise noted, see run 4 of Table 1 for conditions. Isolated yields
based on 1. b 120 oC. c 2.0 equiv. CsOH∙H2O. d 3.0 equiv. CsOH∙H2O. e 150 oC. f
2.0 equiv. nitrile (2) used.
The same with benzonitriles, the reaction of β‐naphthayl
nitrile was also efficient under the standard conditions to give
a good yield of the product (run 21); while the sterically more
bulky α‐naphthayl nitrile required a higher temperature and
more CsOH to obtain a better result (run 22). In the case of
heteroaryl nitriles, 2‐thienylnitrile could afford a moderate
yield of the product under the modified conditions (run 23);
while p‐pyridyl nitrile was found not a suitable substrate in this
reaction (run 24). It gave only trace amount of the target
product with observation of the O‐ and N‐pyridation
byproducts of CsOH or 1a with p‐pyridylnitrile since cyano is
The less reactive aliphatic nitriles were then investigated to
obtain alkyl‐substituted quinazolines. Acetonitile was firstly
tested, but only trace product was observed under the
standard and modified conditions (run 25). Similarly,
valeronnitrile and phenylacetonitrile were also less reactive
than the arylnitriles and gave only low yields of the product
under modified harsher reaction conditions (runs 26‐27).
Attempts to enhance the product yields of these aliphatic
nitriles were also made by adding 4.0 or even 8.0 equiv. of the
nitriles in the presence of 2.0 or even 4.0 equiv. of CsOH, but
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no better results could be obtained. In great contrast, isolated yield of 70%. Thus, self‐condensation of
9
was
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cyclopropylnitrile seems to be a much more reactive aliphatic investigated and by reducing the volumeDoOfIt:h10e.1s0o3l9v/eCn7Gt Cto00197m7AL
nitrile and gave a satisfactory yield of the product under the only, the yield of 10a could be improved to 85% (eq. 4).
standard conditions (run 28).
As to substituted 2‐aminophenylmethanols, as shown in
Table 2, electron‐rich 2‐amino‐5‐methylphenyl‐methanol gave
generally lower yields of the products than unsubstituted 2‐
aminophenylmethanol 1a (runs 29‐32). In contrast, the
reactions
of
electron‐deficient
2‐amino‐5‐
Since both the alcohols can be oxidized to aldehydes by
air14f,15 and the nitriles hydrated to primary amides16 under
base‐catalyzed conditions, we reckon the reactions most
possibly proceeded via a reaction path involving the aldehyde
and amide intermediates as shown in Scheme 1E. Control
reactions were then investigated to confirm this hypothesis.
Indeed, 2‐aminophenylmethanol (1a) could be oxidized to 2‐
aminobenzaldehyde (4a) by air under the standard conditions
(eq. 5), albeit the yield was not high due to its unstable nature.
This may also account for the abnormal finding that air is a
more advantageous oxidant than pure O2 in this reaction
(Table 1, run 13), probably because the instable 4a tends to be
oxidized or decompose under the more oxidative atmosphere
of O2. Secondly, benzonitrile (2a) readily afforded benzamide
chlorophenylmethanol were generally more efficient and gave
closer results to those of unsubstituted 1a (runs 33‐36).
To our surprise, the reaction of another electron‐deficient
p‐acetylbenzonitrile (7a) did not afford the target quinazoline
derivative as other nitriles, but a 30% isolated yield of the
quinoline derivative 8a as determined by NMR analysis (eq. 1).
This indicated that the reaction is more selective with the
methyl ketone moiety than the nitrile moiety under the
present conditions, leading to selective formation of
quinolines. This result intrigued us to further investigate the
reaction of 2‐aminophenylmethanol with methyl ketones.
(
5a) in a good yield under the same conditions (eq. 6). These
results suggested that aldehydes and amides are both
potential intermediates in the reaction.
4
5
As shown in eq. 2, the reaction of 1a and acetophenone
(
7b) was firstly optimized.18 Under the preceding optimized
o
conditions with 1 equiv. of CsOH at 100 C (eq. 2, run 1), the
reaction gave only 40% yield of the target 2‐phenyl quinoline
(
8b). By elevating the reaction temperature (run 2), increasing
the loading of CsOH (run 3), the reaction afforded a good yield
o
of 8b at 120 C. Under these optimized conditions, electron‐
rich and –deficient acetophenones also reacted smoothly with
1a to give 2‐substituted quinolines in moderate yields (runs 4‐
6). However, the reaction of 1a and 7a under the optimized
conditions did not afford the target 8a, but a low yield of the
hydrated 8a’ (run 7), most possibly due to the ready hydration
of the CN group under the basic conditions.
Cross reactions of 1a or 4a with 2a or 5a were then
investigated to confirm the generation of products from the
potential and . As shown in eq. 7, the reaction of 1a and 5a
3
4
5
indeed afforded the target 3aa with observation of both 4a
and benzoic acid as the byproduct. The low yield of 3aa in this
reaction is understandable because aldehydes
4 are unstable
and amides
5 are prone to undergo over hydrolysis in the
In addition to above reactions that gave 2‐
monosubstituted quinazolines (Tables 1‐2), we also
investigated the reaction of 2‐aminoacetophenone (9) with
nitriles in order to obtain 2,4‐disubstituted quinazoline
derivatives becasue 1‐(2‐aminophenyl)ethanols are not readily
presence of bases to give acids,16a which can neutralize the
base in some extent and consequetnly lead to an ineffective
reaction between the amide and aldehyde intermediates,
resulting in the observation of unreacted 4 and a lower yield of
the target quinazoline product. As shown in eq. 8, the reaction
of 4a and 2a also afforded a low yield of 3aa under the
standard conditions, with observation of amide intermediate
available. As shown in eq. 3, surprisingly the reaction of
benzonitrile 2a did not give the target quinazoline derivative
but the self‐condensed 2,4‐disubstituted quinoline 10a in an
9 with
9
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5a and byproduct 6a, confirming that aldehyde
intermediate in the reaction. However, the reaction of intermediate (
4
is the key aerobic oxidation of the starting alcohols (
1) to the aldehyde
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4
) (Scheme 2). OtherwisDeO, Ia: 1d0d.1i0ti3o9n/C7oGfCe0x0c9e77sAs
intermediates 4a and 5a did not afford 3aa in the absence of water can lead to considerable yields of the hydration and
CsOH (eq. 9, run 1), suggesting that CsOH may be needed in over hydrolysis byproducts such as amides and acids (Table 1,
this cyclocondensation step. The reaction was then runs 1, 2, and 6).
investigated under the standard conditions, and it did
successfully afford 30% yield of the target 3aa in the presence
of 1 equiv. CsOH (eq. 9, run 2), revealing unambiguously the
crucial role of CsOH in the cyclocondensation step. All the
Conclusions
In conclusion, we developed a facile and atom‐efficient
method for direct synthesis of the useful 2‐subsitituted
quinazolines from the readily available and stable 2‐aminoaryl
methanols and nitriles by using air as an advantageous oxidant
above results (eqs. 5‐9) clearly demonstrated that aldehydes (
and amides ( ) are indeed reactive intermediates in the
reaction and CsOH plays crucial roles in the alcohol oxidation
(eqs. 5 and 7), nitrile hydration (eqs. 6 and 8), and
cyclocondensation (eqs. 7‐9) steps.
4)
5
through
a
CsOH‐mediated direct aerobic oxidative
cyclocondensation reaction. Most likely owning to the cesium
effect,19 CsOH was found to be the most suitable base for this
one‐pot cascade reaction, working as the best promoter in the
aerobic oxidation of 2‐aminoarylmethanols, aminolysis of
nitriles, as well as the cyclocondensation steps. Control
reactions also revealed that 2‐aminoarylmethanols and nitriles
are superior starting materials because the potential side
reactions of the reactive aldehyde and amide intermediates
can be greatly inhibited by the in situ generation protocol,
which then leads to good yields of the quinazoline products.
This method tolerates a wide range of nitriles and 2‐
aminoarylmethanols and can also be extended to the synthesis
of substituted quinolines starting from methyl ketones.
Further extensions of the transition metal‐free CsOH‐catalyzed
aerobic alcohol oxidation and nitrile hydration strategies as
well as their applications in the synthesis of other heterocycle
compounds are still in progress in this laboratory.
Based on the above findings, a mechanism was proposed for
this CsOH‐mediated aerobic oxidative cyclocondensation
reaction of 2‐aminoarylmethanols and nitriles. As shown in
Scheme 2, in the presence of CsOH, 2‐aminoarylmethanols (
are firstly oxidized by air to give 2‐amino arylaldehydes ( ) and
nitriles ( ) hydrated with water to give amides ( ). The in situ
generated and then undergo a CsOH‐mediated double‐
condensation reaction to give cyclized quinazoline products ( ),
1)
4
2
5
4
5
3
generating meanwhile 2 equiv. of water as the only byproduct.
The preceding findings that much higher yields of the target
quinazolines could be obtained (run 4 of Table 1 VS eqs. 7‐9)
from 2‐aminoarylmethanols (
demonstrated that and
materials than the pre‐prepared aldehydes (
but also implied that the in situ generated
more effective cyclocondensation reagents than the pre‐
prepared ones since the potential side reactions of and can
be greatly inhibited by this in situ generation protocol.
Otherwise, side reactions of the instable pre‐prepared and
1
) and nitriles (
are much superior starting
) and amides ( ),
and should be
2) not only
1
2
Acknowledgements
4
4
5
5
We thank National Natural Science Foundation of China
(21672163, 81272462), Natural Science Foundation of Zhejiang
Province (LR14B020002, Y13H300005) for financial support.
4
5
4
5
Notes and references
can readily occur to afford only low yields of the target
quinazolines (eqs. 7‐9).
1
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T. Kato, V. Gorbunova, K. H. Lee, R. Shah, D. Massey, V.
Scheme 2. Proposed mechanism for CsOH‐mediated aerobic
oxidative cyclocondensation of 2‐aminoarylmethanols and
nitriles generating 2‐subsitituted quinazolines.
Besides, the previous findings that addition of water to the
reaction is not favored (Table 1, runs 1, 2, and 6) and that dry
solvent gave a slightly better result (Table 1, run 7) may
suggest that the water needed for nitrile hydration is very
possibly compensated by the water generated from the
Zazulina, M. Shahidi and M. Schuler, J. Clin. Oncol., 2013, 31,
3327. For antihypertensive treatment: (g) On prazosin: W. Xu,
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DOI: 10.1039/C7GC00977A
Table of Contents
Synthesis of 2-Subsitituted Quinazolines by CsOH-Mediated Direct Aerobic Oxidative Cyclocondensation of
2-Aminoarylmethanols with Nitriles in Air
Song Yao, Kaijing Zhou, Jiabing Wang, Hongen Cao, Lei Yu, Jianzhang Wu,*Peihong Qiu,* Qing Xu*
An atom-efficient synthesis of 2-subsitituted quinazolines is developed by a CsOH-mediated aerobic oxidative
reaction of 2-aminoarylmethanols and nitriles in air.