Syntheses of 3,4- and 1,4-dihydroquinazolines from 2-aminobenzylamine

Article abstract of DOI:10.3762/bjoc.13.145

A straightforward strategy for the synthesis of dihydroquinazolines is presented, which allows for the preparation of 3,4- and 1,4-dihydroquinazolines with different substitution patterns from 2-aminobenzylamine (2-ABA) as common precursor. The required functionalization of both amino groups present in 2-ABA was achieved by different routes involving selective N-acylation and cesium carbonate-mediated N-alkylation reactions, avoiding protection/deprotection steps. The heterocycles were efficiently synthesized in short reaction times by microwave-assisted ring closure of the corresponding aminoamides promoted by ethyl polyphosphate (PPE).

Full text of DOI:10.3762/bjoc.13.145

Syntheses of 3,4- and 1,4-dihydroquinazolines from
2-aminobenzylamine
Jimena E. Díaz1, Silvia Ranieri1,2, Nadia Gruber1 and Liliana R. Orelli*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 1470–1477.
1Universidad de Buenos Aires. CONICET. Departamento de Química
Orgánica. Facultad de Farmacia y Bioquímica. Junín 956, (1113)
Buenos Aires, Argentina and 2Department of Industrial Chemistry
“Toso Montanari”, University of Bologna, Viale Risorgimento 4, 40136
Bologna, Italy
doi:10.3762/bjoc.13.145
Received: 20 April 2017
Accepted: 30 June 2017
Published: 27 July 2017
Email:
Associate Editor: I. R. Baxendale
Liliana R. Orelli* - lorelli@ffyb.uba.ar
© 2017 Díaz et al.; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
dihydroquinazolines; microwaves; N-acylations; N-alkylations; PPE
Abstract
A straightforward strategy for the synthesis of dihydroquinazolines is presented, which allows for the preparation of 3,4- and 1,4-
dihydroquinazolines with different substitution patterns from 2-aminobenzylamine (2-ABA) as common precursor. The required
functionalization of both amino groups present in 2-ABA was achieved by different routes involving selective N-acylation and
cesium carbonate-mediated N-alkylation reactions, avoiding protection/deprotection steps. The heterocycles were efficiently syn-
thesized in short reaction times by microwave-assisted ring closure of the corresponding aminoamides promoted by ethyl polyphos-
phate (PPE).
Introduction
Nitrogen heterocycles are part of many drugs and represent tivity as anthelmintics used in medical practice (pyrantel,
structures with wide therapeutic potential. Therefore, much morantel and oxantel) [5,6], nicotinic agonists [7], antidepres-
effort has been devoted to the development of efficient, general sants [8] and selective inhibitors of M1 acetylcholine receptors
and expeditious methods for their synthesis [1,2]. Cyclic [9,10], among others. Their benzannulated analogues, dihydro-
amidines are compounds of interest due to their multiple phar- quinazolines, also represent heterocyclic cores of pharmacologi-
macological properties, some of which derive from their inter- cal interest. Some derivatives containing this motif have shown
action with a specific receptor [3,4]. Six-membered heterocylic antimicrobial [11] and antifungal properties [12]. Their activity
amidines (1,4,5,6-tetrahydropyrimidines) display biological ac- as selective T-type calcium channel blockers [13-15] and as in-
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hibitors of β-secretase (an important target for Alzheimer’s 2-nitrobenzyl bromide, among others, which require an addi-
disease) has been reported [16]. They have also been studied as tional reduction step [17,18,29,49-51].
inhibitors of trypanothione reductase [17], an essential enzyme
of the parasite Trypanosoma brucei, and as neuroprotective Ethyl polyphosphate (PPE) and trimethylsilyl polyphosphate
agents [18].
(PPSE) are mild irreversible dehydrating agents of the Lewis
acid type. They have found application for synthetically useful
Different strategies have been used for the preparation of transformations like conversion of amides into nitriles [52,53]
dihydroquinazolines. Some of them involve cyclic precursors or the Beckmann rearrangement [52,54]. They have also been
such as quinazolinones, quinazolines or tetrahydroquinazolines, widely employed in heterocyclic synthesis, including micro-
which can be reduced or oxidized to yield dihydroquinazolines wave-assisted reactions. The recognized wide functional group
[17,19-25]. Heterocyclization of acyclic precursors has also tolerance, stability and low environmental impact are addition-
been applied for the synthesis of these heterocycles. Many al advantages of these reagents. Cyclocondensation is a funda-
methods use 2-aminobenzylamine (2-ABA) that reacts with mental tool in heterocycles synthesis, and microwave (MW)
amidines, carboxylic acids, orthoformates, or aldehydes in heating has found interesting applications in this area [55,56],
oxidative conditions to yield N-unsubstituted dihydroquinazo- overcoming limitations arising from low reactivity and side
lines [11,16,26-35]. A different approach is based on the hetero- reactions typical of conventional heating [57].
cyclization of functionalized 2-aminobenzylamines [36,37] such
as the cyclization of N-(2-aminobenzyl)amides, which in We had previously reported the MW-assisted synthesis of
general requires drastic conditions or long reaction times 1,4,5,6-tetrahydropyrimidines and their homologues by
[17,18,21,22,29,38-40]. Miscellaneous methods include the cyclodehydration reactions promoted by polyphosphoric acid
nucleophilic addition of secondary amines to carbodiimides (PPA) esters PPE and PPSE [58-60]. This strategy was
followed by an intramolecular conjugate addition to successfully applied to the synthesis of 1-aryl-2-imino-1-aza-
an α,β-unsaturated ester [12-15] or copper-catalyzed cycloalkanes [61], 2-oxazolines, 5,6-dihydro-4H-1,3-oxazines
annulation of N-arylamidines [41], among others and 4,5,6,7-tetrahydro-1,3-oxazepines [62].
[42]. Most of the already mentioned methods have
been applied to the synthesis of 3,4-dihydroquinazolines. In continuation of this work we herein present an efficient
Among them, only a few were used for the preparation of strategy for the synthesis of dihydroquinazolines starting from
1,4-dihydroquinazolines, a heterocyclic framework quite unex- the easily available 2-ABA as common precursor. The route
plored.
allows for the preparation of 3,4-dihydroquinazolines 1 and 1,4-
dihydroquinazolines 2 with different substitution patterns
In addition to the heterocyclization itself, the preparation of the (Figure 1).
acyclic precursors for the synthesis of dihydroquinazolines
remains challenging as in some cases it includes a selective
N-functionalization of the amino groups of 2-ABA. For exam-
ple, the selective acylation of the aliphatic amino group was
achieved by the treatment of the diamine with benzoic acid in
the presence of Zr(azobenzene-4,4´-dicarboxylate) [43], with
tert-butylperoxybenzoate [44] and with isopropenyl acetate
Figure 1: 3,4-Dihydroquinazolines 1 and 1,4-dihydroquinazolines 2.
[45], or by a DCC-mediated coupling with a carboxylic acid
[38]. To our knowledge, selective acylations of N1-alkyl-2-
ABAs have not been reported yet.
Results and Discussion
The general synthetic pathways leading to the desired dihydro-
Alkylations of the aliphatic amino group of 2-ABA using quinazolines 1 and 2 are depicted in Scheme 1.
triflates, halogen or CCl3 derivatives have also been reported.
However, these reactions are frequently associated with long N-Alkyl-substituted 2-aminobenzylamines 3a–c were readily
reaction times, poor yields and low selectivity [46,47]. The synthesized by reduction of the amides 4a–c employing a THF
selective monofunctionalization of 2-ABA was achieved by solution of borane (yields 82–93%; see Supporting Information
using protective groups such as 9-BBN [48] or Boc [39], which File 1 and Scheme 2).
require subsequent removal. Other alternative synthetic strate-
gies use substrates like 2-nitrobenzoyl chloride, 2-nitrobenz- The synthesis of N-(2-aminobenzyl)amides 4a–k was achieved
aldehyde, 2-aminobenzamides, 2-aminobenzophenone, by selective N-acylation of 2-ABA or its N-substituted deriva-
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Scheme 1: Synthetic pathways for the preparation of 3,4-dihydroquinazolines 1 and 1,4-dihydroquinazolines 2.
Scheme 2: Synthesis of compounds 3a–c.
tives 3a–c, whose preparation is depicted in Scheme 2. In spite group present in compounds 4 using alkyl halides. In a previous
of the different nucleophilicity of both amino groups, the work [63], we developed a methodology for the selective
predictable formation of a hydrogen bond between the aromatic N-alkylation of anilines with ω-halonitriles in the presence of
amino group (hydrogen bond donor) and the aliphatic NHR cesium carbonate and potassium iodide. There the use of the
(hydrogen bond acceptor) could increase the nucleophilicity of cesium base prevented N-dialkylation and therefore it was not
the former and decrease the reactivity of the latter, favoring the necessary to use an excess of the amine. This led us to test the
chance for N,N´-diacylation. To avoid this, the reaction was per- same reaction conditions for the synthesis of compounds 5. In
formed employing a diluted solution of the amine in a biphasic this case, the presence of the amide functionality was regarded
system (CHCl3/aqueous NaOH), low temperature (0 °C) and the as an additional problem, as Cs2CO3-mediated alkylation of
use of anhydrides as acylating agents, if commercially avail- cyclic amides had already been reported in the literature [64]. In
able. The results are shown in Table 1.
spite of this, compounds 5 were obtained in good to high yields
(Table 2) employing the same experimental conditions [63].
For R3 = H, products 4a–e were obtained in excellent yields The reaction times and temperatures were individually adjusted
when 2-ABA was treated with acid anhydrides as the acylating taking into account the boiling points of the alkylating agents
agents (Table 1, entries 1–5). Replacing anhydrides by acyl and the reactivity of each substrate.
chlorides in the reaction the yields were slightly lower, and in
some cases small amounts of the N,N’-diacylated products were As expected, the reaction was selective toward the N-mono-
also obtained (Table 1, entries 6 and 7). Under the same reac- alkylation of the arylamino group in the presence of the amide.
tion conditions, the N-substituted derivatives 3 (R3 ≠ H) were Satisfactory results were also obtained using the more hindered
selectively acylated with very good yields (Table 1, entries isopropyl iodide (Table 2, entries 4 and 8).
8–11). Thus, precursors 4 were efficiently prepared by a se-
quence of N-acylation–reduction–N-acylation.
Next, the conversion of N-(2-aminobenzyl)acetamide (4a) into
2-methyl-3,4-dihydroquinazoline (1a) was chosen for the opti-
The acyclic precursors 5, necessary for the synthesis of dihydro- mization of the reaction conditions for the synthesis of com-
quinazolines 2, were prepared by N-alkylation of the arylamino pounds 1. No background reaction was observed when heating a
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Table 1: Selective N-acylation of 2-ABA and its derivatives.
Entry
4
R3
R2
Acylation agent
Yield (%)a
1
2
a
b
c
d
e
f
H
CH3
CH2CH3
CH(CH3)2
C(CH3)3
C6H5
anhydride
anhydride
anhydride
anhydride
anhydride
acyl chloride
acyl chloride
anhydride
anhydride
anhydride
anhydride
90
93
94
93
94
83
70
81
80
72
79
H
3
H
4
H
5
H
H
6
2-CH3C6H4
2-FC6H4
CH3
7
g
h
i
H
8
CH2CH3
CH2CH3
CH2CH2CH3
CH2CH(CH3)2
9
CH2CH3
CH2CH3
CH2CH3
10
11
j
k
aYields correspond to pure compounds.
Table 2: Synthesis of compounds 5.
Entry
5
R2
R1
X
Time (h)
Temperature (°C)
Yield (%)a
1
2
a
b
c
d
e
f
CH3
CH3
CH2CH2CH3
CH2CH=CH2
CH2C6H5
I
Br
Cl
I
5
4.5
5
75
65
90
85
85
85
90
85
85
85
81
68
64
60
67
69
60
75
55
71
3
CH3
4
CH3
CH(CH3)2
6
5
CH(CH3)2
C(CH3)3
C(CH3)3
C(CH3)3
C6H5
CH2CH2CH3
CH2CH2CH3
CH2C6H5
I
6.5
6
6
I
7
g
h
i
Cl
I
3
8
CH(CH3)2
7
9
CH2CH2CH3
CH2CH2CH3
I
7
10
j
2-CH3C6H4
I
10
aYields correspond to pure compounds.
solution of compound 4a in chloroform for 10 minutes at preparation and the inexpensive reagents required for its synthe-
130 °C under MW irradiation in a closed vessel. Using a solu- sis [65], PPE was chosen as cyclodehydrating agent for the
tion of PPSE in DCM as cyclodehydrating agent, after preparation of compounds 1. Results and optimized experimen-
30 minutes of reaction under reflux using conventional heating tal conditions of the MW-assisted ring-closure reaction are
compound 1a was obtained in 86% yield. Analogous results depicted in Table 3. Due to the different reactivity of each sub-
were obtained using either PPE/CHCl3 or PPSE/CH2Cl2 under strate, irradiation times and temperatures were individually
microwave irradiation at 110 ºC for 4 minutes. Due to the easier adjusted.
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Table 3: Synthesis of 3,4-dihydroquinazolines 1.
Entry
Product 1
R3
R2
Time (min)
Temperature (°C)
Yield (%)a
1
2
a
b
c
d
e
f
H
CH3
CH2CH3
CH(CH3)2
C(CH3)3
C6H5
4
4
110
110
120
130
130
130
130
100
115
115
115
86
84
76
73
71
79
60
98
79
86
80
H
3
H
9
4
H
12
12
15
15
4.5
8
5
H
H
6
2-CH3C6H4
2-FC6H4
CH3
7
g
h
i
H
8
CH2CH3
CH2CH3
CH2CH2CH3
CH2CH(CH3)2
9
CH2CH3
CH2CH3
CH2CH3
10
11
j
8
k
8
aYields correspond to pure compounds.
For the synthesis of compounds 1 the reaction conditions from spontaneous benzylic oxidation of 2a. An analogous reac-
mainly depended on the steric and electronic features of the tion had been previously reported for 3,4-dihydroquinazolines
amido group present in the substrates. Acetamides and propi- upon exposure to air (Scheme 3, (b)) [19,24,40,66].
onamides 4a,b,h–k reacted readily under mild reaction condi-
tions (Table 3, entries 1, 2, and 8–11), while for isobutyramide The fact that quinazolin-4(1H)-ones 6, which are fully conju-
4c a higher temperature was necessary (Table 3, entry 3). gated push–pull molecules, are more resonance stabilized than
Finally, the more sterically hindered pivalamide 4d and the less their isomeric counterparts quinazolin-4(3H)-ones 7, would
reactive benzamides 4e–g required harsher reaction conditions explain the differential behavior of N-substituted 3,4- and 1,4-
to achieve complete conversion of the substrates and the prod- dihydroquinazolines toward spontaneous oxidation.
ucts were afforded in generally lower yields (Table 3, entries
4–7).
By the same procedure used for 2a, a series of novel 1,4-
dihydroquinazolines were synthesized. The results and opti-
In order to widen the scope of the method, we examined next mized reaction conditions are reported in Table 4. Due to the
the applicability of the PPE/MW system to the synthesis of 1,4- different reactivity of each substrate, irradiation times and tem-
dihydroquinazolines 2. Treatment of precursor 5a with PPE/ peratures were individually adjusted.
CHCl3 under microwave irradiation led to 1,4-dihydroquinazo-
line 2a, accompanied by a low percentage of a collateral prod- Generally the yields for compounds 2 were good to excellent
uct. This compound was identified as 2-methyl-1-propylquina- and the experimental conditions and reaction outcome varied
zolin-4(1H)-one (6a) (Scheme 3, (a), R1 = Pr, R2 = Me), arising depending on the electronic and steric features of the substitu-
Scheme 3: Benzylic oxidation of 1,4-dihydroquinazolines (a) and 3,4-dihydroquinazolines (b).
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Table 4: Synthesis of 1,4-dihydroquinazolines 2.
Entry
Product 2
R2
R1
Time (min)
Temperature (°C)
Yield (%)a
1
2
a
b
c
d
e
f
CH3
CH3
CH2CH2CH3
CH2CH=CH2
CH2C6H5
11
11
11
12
21
20
25
25
13
5
80
90
67
75
72
91
79
68
–
3
CH3
90
4
CH3
CH(CH3)2
130
110
130
130
130
90
5
CH(CH3)2
C(CH3)3
C(CH3)3
C(CH3)3
C6H5
CH2CH2CH3
CH2CH2CH3
CH2C6H5
6
7
g
h
i
8
CH(CH3)2
–
9
CH2CH2CH3
CH2CH2CH3
25b
39b
10
j
2-CH3C6H4
100
aYields correspond to pure compounds. bThe reported yield is approximate and was estimated by integration of suitable 1H NMR signals (see Sup-
porting Information File 1).
ents R1 and R2 present in precursors 5. The cyclodehydration of reduced due to steric effects, was higher than for the phenyl-
acetamides 5a–c proceeded under mild reaction conditions substituted derivative reinforces this hypothesis.
(Table 4, entries 1–3), while acetamide 5d required a higher
temperature probably due to the steric hindrance produced by Conclusion
the N-isopropyl moiety (Table 4, entry 4). A higher tempera- We have developed novel, general and straightforward strate-
ture and a longer reaction time were necessary in order to gies for the synthesis of 3,4-dihydroquinazolines with different
achieve cyclodehydration of isobutyramide 5e, and even harsher substitution patterns, starting from 2-ABA as common precur-
conditions were required for pivalamide 5f (Table 4, entries 5 sor. An extension of the method allowed for the preparation of
and 6). In the case of precursors 5g,h, instead of the expected N-alkyl-1,4-dihydroquinazolines, a heterocyclic nucleus almost
1-substituted-2-tert-butyl-1,4-dihydroquinazolines, cyclodehy- unexplored. To our knowledge, this is the first general method
dration led to 2-tert-butyl-3,4-dihydroquinazoline (1d, Table 4, available for synthesis of these compounds. The products were
entries 7 and 8), with loss of one N-substituent. A possible ex- synthesized by microwave-assisted ring closure of different
planation is that the reaction conditions required in those cases aminoamides promoted by PPE. The yields and reaction times
due to steric hindrance bring about a competitive elimination involved in the heterocyclization step compare favorably with
reaction. Finally, as already mentioned, 1,4-dihydroquinazo- the reported methodologies. The preparation of the required
lines 2 are prone to spontaneous oxidation leading to 4(1H)- aminoamides involves N-acylation and N-alkylation reactions,
quinazolinones (Scheme 3a) and dihydroquinazolines 2i,j which were optimized to achieve selective monofunctionaliza-
showed a comparatively higher lability toward this side reac- tion thus avoiding additional protection/deprotection steps. A
tion. For this reason, the cyclodehydration of the substrates 5i,j judicious combination of these steps into different sequences,
was carried out at lower temperatures in order to avoid benzylic allowed for the preparation of both 3,4- and 1,4-dihydroquina-
oxidation. In spite of this, partial oxidation during workup and zolines with the desired N-substitution starting from a single
purification could not be avoided accounting for the lower precursor.
yields obtained for the 2-aryl derivatives 2i,j (Table 4,
entries 9 and 10). The higher sensitivity of compounds 2i,j The protocols are operationally simple and involve easily avail-
towards oxidation may be a consequence of the enhanced able and inexpensive reagents. Due to their widespread use in
resonance stabilization of the resulting 2-arylquinazolin-4(1H)- organic synthesis, the selective N-functionalization reactions
ones 6i,j (Scheme 3). The fact that the yield of the o-methyl- described herein may find application in many different molec-
phenyl-substituted derivative 2j, in which this stabilization is ular contexts.
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Beilstein J. Org. Chem. 2017, 13, 1470–1477.
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Supporting Information
Supporting Information File 1
Experimental procedures and characterization of new
compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-13-145-S1.pdf]
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Acknowledgements
This work was supported by the University of Buenos Aires
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