Facile approaches toward the synthesis of N4-monosubstituted quinazolin-2,4-diamines

Article abstract of DOI:10.1016/j.tetlet.2015.10.096

The amination of quinazoline-based heterocyclics is of significant interest due to its privileged structure and application in the development of bioactive compound libraries, as well as in the synthesis of readily convertible building blocks. The current approaches generally result in low yields, utilize harsh conditions, and/or rely on expensive catalysts. After examining three different approaches to synthesize N⁴-monosubstituted quinazolin-2,4-diamines, we developed an efficient and mild synthetic method to prepare quinazolin-2,4-diamines in 80-85% yields.

Full text of DOI:10.1016/j.tetlet.2015.10.096

Accepted Manuscript
Facile approaches toward the synthesis of N4 -monosubstituted quinazolin-2,4-
diamines
Tarek Mohamed, Praveen P.N. Rao
PII:
S0040-4039(15)30293-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.10.096
TETL 46925
Reference:
Tetrahedron Letters
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22 September 2015
27 October 2015
28 October 2015
Please cite this article as: Mohamed, T., Rao, P.P.N., Facile approaches toward the synthesis of N4 -monosubstituted
quinazolin-2,4-diamines, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.10.096
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Facile approaches toward the synthesis of
N4-monosubstituted quinazolin-2,4-diamines
Tarek Mohamed a, b and Praveen P. N Rao a, 

Tetrahedron Letters
1
Tetrahedron Letters
Facile approaches toward the synthesis of N4-monosubstituted quinazolin-2,4-
diamines
Tarek Mohamed a,b and Praveen P. N Rao a, 
a School of Pharmacy, University of Waterloo, 200 University Ave W., Waterloo, Ontario, N2L 3G1, Canada
b Department of Chemistry, University of Waterloo, 200 University Ave W., Waterloo, Ontario, N2L 3G1, Canada
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The amination of quinazoline-based heterocyclics is of significant interest due to its privileged
structure and application in the development of bioactive compound libraries, as well as in the
synthesis of readily convertible building blocks. The current approaches generally result in low
yields, utilize harsh conditions and/or rely on expensive catalysts. After examining three
different approaches to synthesize N4-monosubstituted quinazolin-2,4-diamines, we developed
an efficient and mild synthetic method to prepare quinazolin-2,4-diamines in 80–85% yield.
Available online
Keywords:
Quinazoline
Amination
Urea
©2015 Elsevier Ltd. All rights reserved.
Azide
———
 Corresponding author. Tel.: +1-519-888-4567; e-mail: praopera@uwaterloo.ca (P. P. N. Rao_

2
Tetrahedron Letters
Introduction
Substituted quinazolin-2,4-diamines (Fig. 1) and related ring
scaffolds, have substantial utility in medicinal chemistry and
drug development. From cancer to diabetes to microbiology and
more, there is an ever-growing list of quinazoline-based
derivatives with a wide range of bioactive profile.1-4
Figure 1. N2, N4-Disubstituted quinazolin-2,4-diamine ring scaffold.
Synthetically, substituted quinazolin-2,4-diamines are
generally prepared from a monocyclic starting precursor such as
anthranillic acid, that is first converted to a bicyclic quinazoline
ring template using urea to obtain quinazolin-2,4(1H, 3H)-dione.
Subsequently, it is chlorinated to afford 2,4-dichloroquinazoline
(2,4-DCQ), which can be functionalized at the C2 and C4
Scheme 3. Common synthetic approaches toward C2-amine functionalized
quinazolines.
Results and discussion
positions to synthesize diverse compound libraries (Scheme 1).5-
10
As part of our on-going efforts to develop C2-amine-based
quinazolines, we herein present three viable approaches toward
achieving this functionalization in moderate to good yields. In the
evolution of our method development, we utilized 2-chloro-N4-
In another approach, cyanoimidation and tandem reductive
cyclization of 2-nitrobenzaldehyde was used to prepare N4-
substituted-2,4-diaminoquinazolines.11
monosubstituted quinazolin-4-amines 1–4 (R
=
benzyl-,
phenethyl, 3,4-dimethoxybenzyl and 3,4-dimethoxyphenethyl,
Scheme 4) as starting precursors that were synthesized in-house.
In the first C2 amination approach using aqueous ammonia,
we explored the utility of copper iodide (CuI) as a catalyst. The
reaction conditions employed 20 mol.% CuI with 1,4-dioxane
and aqueous ammonia (1:3 ratio v/v) heated at 130 °C in a sealed
pressure vial for 24 h (Scheme 4, Method 1A, Supporting
Information).18
Scheme 1. Typical retrosynthetic approach toward 2,4-DCQ scaffold.
Due to its chemical nature, the quinazoline carbons at the C2
and C4 positions are electron deficient. This property is exploited
in functionalizing 2,4-DCQ template by employing nucleophilic
aromatic substitution (NAS) conditions to replace the C4 halogen
with alkyl/aromatic amines (2-chloro-N4-monosubstituted
quinazolin-4-amines). This is
a relatively straightforward
approach that requires moderate reaction conditions (Scheme
2).10, 12, 13
Scheme 4. C2 Amination using CuI to obtain C2-amine functionalized
quinazolines.
Scheme 2. Commonly utilized approach toward C-4 functionalization of 2,4-
DCQ.
While the approach was successful in facilitating the reaction
(although not when attempted with sodium iodide), the yields
were generally low (quinazolines 5–8, 20–25%). In addition, we
encountered difficulty in preventing ammonia escaping from the
pressure vial during the reaction time period of 24 h due to seal
breaking. An improved variation of this preliminary reaction is
based on the work described by Renaud and co-workers, where
CuI is replaced with copper (I) oxide (Cu2O) and equimolar
amounts of a diamine ligand, such as dimethylethylenediamine
(DMEDA). This reaction was run under highly basic conditions
(20 eq. potassium carbonate and 40 eq. aqueous ammonia) and
heated in ethylene glycol at 100 °C in a sealed pressure vial for
24 h (Scheme 5, Method 1B, Supporting Information).18 This
modified approach was more successful in facilitating the
reaction and provided better yields (35–40%) compared to
Scheme 4, although the overall yield was still moderate. While
we didn’t encounter any ammonia leaks, the workup was more
elaborate and time-consuming.
However, amination at the C2 position, to obtain N2,N4-
disubstituted
conditions due to the inherent electrochemical nature of the
carbon at that position. The deactivation of that position toward
nucleophilic attack when the C4 halogen is substituted with
quinazolin-2,4-diamines,
requires
harsher
electron-donating
groups
prevents
its
efficient
functionalization.14,
Generally, C2 amination using alkyl or
15
arylamines in an aprotic, high-boiling point solvent along with a
quenching base under high temperature (at or above 150°C) and
pressure, yields the desired C2 amine-functionalized quinazolines
in moderate to good yields. That being said, a similar approach
using ammonia is not readily transferable to prepare N4-
monosubstituted quinazolin-2,4-diamines (C2 = NH2) which are
desirable compounds in biological activity screening studies
(Scheme 3).16, 17

Tetrahedron Letters
3
conditions (maximum temperature of 90 C, under reflux with
no pressure vial set-up), with shortest reaction time (3 h) and
provided the best yield (≥80%). Initially, the starting 2-chloro-
N4-monosubstituted quinazolin-4-amine (1–4) was heated with
sodium azide (NaN3) in 3:1 ethanol and glacial acetic acid for 2 h
at 90 C. After allowing the contents to cool to room
temperature, 10 mol.% of Pd/C (10%) was added to the solution
followed by slow addition of 1.5 eq. hydrazine (H2NNH2•H2O)
before re-heating the contents at 90 C for 2 h (Scheme 8). To
our satisfaction, this one-pot condition, gave very good yields
(80–85%, Scheme 8, Method 3, Supporting Information).19-24
Scheme 5. Modified Cu2O-based approach toward C2-amine functionalized
quinazolines.
Our second approach, utilizing urea, was more promising. The
reaction conditions used were straightforward. The starting 2-
chloro-N4-monosubstituted quinazolin-4-amines (1–4) were
heated with 6 equivalents of urea in anhydrous 1,4-dioxane at
160 °C in a sealed pressure vial for 24 h (Scheme 6, Method 2,
Supporting Information).
Scheme 8. One-pot synthesis of N4–monosubstituted quinazoline-2,4-
diamines
Scheme 6. Urea-based pressure vial approach toward C2-amine
In order to explore the C2 selectivity of this method in the
presence of quinazoline substrates with susceptible functional
groups, we used ethyl 2-chloroquinazoline-4-carboxylate 9,
which possess an ethyl ester group at C4 position. Treatment of 9
under similar conditions provided the desired C2 amine 10 in
lower yield (45-50%, Scheme 9). Interestingly, we were able to
isolate the C2 azide 11 in 20% yield which supports the proposed
mechanism shown in Scheme 7.
functionalized quinazolines.
While this condition was initially intended for the synthesis of
C2-urea-based quinazolines, we were pleasantly surprised to
observe a good amount of hydrolyzed C2-amine products (5–8,
50–55% yield, Scheme 6). Interestingly, the symmetry of urea is
one of the driving forces in this reaction, as similar attempts with
asymmetric amides (e.g. acetamide and methylcarbamate) were
not successful in producing similar outcomes. The proposed
mechanism of quinazoline-urea hydrolysis via an addition-
elimination pathway to afford compounds 5–8 is shown in
Scheme 7.
It is very evident that this one-pot approach carries many
advantages compared to the other approaches used to synthesize
N4-monosubstituted-quinazolin-2,4-diamines. The conditions are
milder and the reaction time is drastically reduced. Furthermore,
the C2-azide intermediate can be isolated if needed in structure-
activity relationship (SAR) studies. The significantly higher
yields are attributed to straightforward workup step that involves
simple filtration of the Pd/C catalyst, followed by removal of the
ethanol/acetic acid in vacuo without the need for further
purification using column chromatography. Importantly, the
reaction can be carried out to isolate C2-azides in the presence of
susceptible functional groups such as C4 esters. Some limitations
to utilizing this approach, particularly the second step involving
Pd/C based reduction, is that these conditions may not be suitable
to halogen-containing quinazoline substrates which can
potentially lead to dehalogenation during azide reduction.
Scheme 9. One-pot synthesis of ethyl 2-aminoquinazoline-4-carboxylate (10)
Scheme 7. Proposed mechanism of C2-urea-based quinazoline hydrolysis to
obtain C2-amine functionalized quinazolines.
Our final approach, utilizes a two-step, one-pot reaction
process that goes via a C2-azide (-N3) intermediate (Scheme 8).
Of the three methods discussed, this utilized the mildest

4
Tetrahedron Letters
Conclusion
In summary, we investigated three approaches (summarized in
Table 1) toward the synthesis of N4,N2-disubstituted quinazolin-
2,4-diamines. Among them, the one-pot reaction via an azide
intermediate provided very good yields (80–85%) and was
identified as a mild and efficient method to prepare novel
quinazoline-based compound libraries for drug screening.
5. Yoo, E.; Salunke, D. B.; Sil, D.; Guo, X.; Salyer, A. C.;
Hermanson, A. R.; Kumar, M.; Malladi, S. S.; Balakrishna,
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David, S. A. J. Med. Chem. 2014, 57, 7955.
Table 1. Summary of three potential routes to C2-amine-
based quinazolines
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Parameters
a. Copper-
Catalyzed
b. Urea-
based
c. Azide
reduction
11. Yin, P.; Liu, N.; Deng, Y. X.; Chen, Y.; Deng, Y.; He, L.
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Hydrolysis
24 h
Time
24 h
4 h
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Zhao, S. X.; Soglia, J. R.; Aspnes, G. E.; Kung, D. W.;
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Oliver, R.; Dunn, M.; Li, J. C.; Richter, D. T.; Cooper, B.
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Ung, E. J.; Roberts, W. G.; Bonnette, P. C.; Buckbinder,
L.; Mistry, A.; Griffor, M. C.; Han, S.; Guzman-Perez, A.
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Temp. (°C)
Setup
130 or 100
Sealed
160
90, reflux
RB flask
Sealed
pressure vial pressure
vial
Solvent
Dioxane or
Ethylene
glycol
Dioxane
Ethanol and
Glacial acetic
acid
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C. a.; Meeson, M. L.; Parsons, M. E.; Theobald, C. J. J
Med. Chem. 1995, 38, 2763.
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Amine source
Purification
% Yield
Aq.
Urea
Sodium azide
No column
80–85
Ammonia
Column
Column
50–55
Easy
20–25
Workup
Elaborate
Easy
17. Aubin, Y.; Fischmeister, C.; Thomas, C. M.; Renaud, J. L.
Chem Soc Rev 2010, 39, 4130.
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The authors would like to thank the Faculty of Science, the
School of Pharmacy, University of Waterloo, the Ontario Mental
Health Foundation (TM), NSERC-Discovery (RGPIN: 03830-
2014), Canada Foundation of Innovation, CFI-JELF and Early
Researcher Award, Ministry of Research and Innovation,
Government of Ontario, Canada (PR) for financial support of this
research project.
Supplementary data
24. Cellier, P. P.; Spindler, J.-F.; Taillefer, M.; Cristau, H.-J.
Tetrahedron Lett. 2003, 44, 7191.
Supplementary data associated with this article including
complete experimental procedures and product characterization
data can be found, in the online version, at http://
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