A simple and efficient approach for the synthesis of 2-aminated quinazoline derivatives via metal free oxidative annulation

Article abstract of DOI:10.1016/j.tetlet.2017.02.033

A simple and efficient approach for the synthesis of 2-aminoquinazoline derivatives in moderate to good yields. This reaction employs mild reaction conditions, is metal-free and utilizes readily available starting materials making it a more viable reaction for scale up synthesis and ligand diversity. Notably, this methodology allows for the synthesis of 2-aminoquinazolines using a free amine or cyclic amine enabling structural diversity and good atom economy.

Full text of DOI:10.1016/j.tetlet.2017.02.033

Accepted Manuscript
A Simple and Efficient Approach for the Synthesis of 2-Aminated Quinazoline
Derivatives via Metal Free Oxidative Annulation
Amit N. Pandya, Eric M. Villa, E. Jeffrey North
PII:
S0040-4039(17)30201-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.02.033
TETL 48644
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
2 January 2017
2 February 2017
9 February 2017
Please cite this article as: Pandya, A.N., Villa, E.M., Jeffrey North, E., A Simple and Efficient Approach for the
Synthesis of 2-Aminated Quinazoline Derivatives via Metal Free Oxidative Annulation, Tetrahedron Letters (2017),
doi: http://dx.doi.org/10.1016/j.tetlet.2017.02.033
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A Simple and Efficient Approach for the Synthesis of 2-Aminated Quinazoline Derivatives
via Metal Free Oxidative Annulation
*
Amit N. Pandya, 1 Eric M. Villa, 2 E. Jeffrey North 1
1Department of Pharmacy Sciences, School of Pharmacy and Health Professions, Creighton
University, Omaha, Nebraska.
2Department of Chemistry, Creighton University, Omaha, NE 68178, USA
Corresponding Author email: jeffreynorth@creighton.edu
Abstract
A simple and efficient approach for the synthesis of 2-aminoquinazoline derivatives in moderate
to good yields. This reaction employs mild reaction conditions, is metal-free and utilizes readily
available starting materials making it a more viable reaction for the scale up synthesis and ligand
diversity. Notably, this methodology allows the synthesis of 2-aminoquinazolines using a free
amine or cyclic amine enabling structural diversity and good atom economy.
Keywords: Quinazolines / Oxidative Annulation / Metal Free / Heteroaromatic
Designing a simple and efficient chemical reaction sequence that provides maximum structural
diversity with few synthetic steps to yield small heterocyclic molecules with interesting
biological function is a challenge to both medicinal and synthetic chemists.1 As a representative
of heterocyclic molecules, 2-aminoquinazolines are drug-like scaffolds and exhibit wide range of
biological activities such as potent, selective, and orally efficacious inhibitors of receptor
tyrosine kinase c-Kit, represented by the 5,6-dihydro-pyridinone 12 along with a 2¢-
deoxynucleotide analogue 23 (figure 1). The 2-aminoquinazoline and quinazoline scaffold is also
represented in FDA-approved pharmaceuticals including the antihypertensive agent Prazosin (3)
and the anti-cancer agent Gefitinib (4) (figure 1).

Figure 1. Selected examples of tyrosine kinase receptor inhibitors (1), 2¢-deoxynucleotide
analogue (2) and pharmaceutical drugs Prazosin (3) and Gefitinib (4), possessing the quinazoline
scaffold.
Diverse ranges of pharmacological activities of 2-aminoquinazoline derivatives have sparked
considerable interest in their synthesis using versatile and scalable methods.4-6 There are very
few approaches that describe the construction of 2-aminoquinazolines (scheme 1). For example,
2-aminoquinazoline derivatives have been developed using arylboronic acids as a precursor
(scheme 1, A).4 In 2005, Mahajan reported a microwave-promoted synthesis of quinazolines
from N-arylamidines and aldehydes (scheme 1, B).5 Alternatively, the reaction of 2-halophenyl
ketone with guanidine derivatives in the presence of copper catalyst yielded 2-aminoquinazoline
derivatives (scheme 1, C).6 These reactions suffer from harsh reaction conditions using
microwaves, use of reactive metal catalysts and expensive boronated pre-functionalized starting
materials, which limits ligand diversity and scale up processes.

Scheme 1. Retrosynthetic analysis of the 2-aminoquinazoline scaffold.
Pandya et al have explored the metal catalyzed transformation of small heterocycles including
the C-H functionalization.7,8 Herein, we report a metal-free and simple reaction scheme for the
synthesis of 2-aminated (primary and tertiary amines) quinazoline derivatives using readily
available starting materials producing moderate to high yields. Our initial efforts commenced by
designing unsubstituted 2-amino derivatives of the quinazoline scaffold using unsubstituted
cynamide (1 eq.) and 2-aminobenzophenone (1eq.). To identify suitable reaction conditions, we
started our investigation with PTSA (p-toluene sulfonic acid) (1 eq.) as a catalyst for the reaction
in THF (table 1, entry 1). These conditions produced the desired product (7a) in moderate yields
(61%). To our delight, the yield was increased to 75% when changing the solvent to DMF, also
in the presence of PTSA (table 1, entry 2). Decreasing the reaction temperature to 70oC
produced the desired product in a low yield (table 1, entry 5) and at room temperature the
reaction did not produce product (table 1, entry 6). Notably, after basifying reaction conditions
using KOtBu, the reaction produced moderate yields (table 1, entry 3 & 4).
Table 1. Optimization of reaction conditions for the unsubstituted 2-aminoquinazoline
derivatives.
entry
1
2
acid/base
PTSA
PTSA
KOtBu
KOtBu
PTSA
equivalent
solvent
THF
DMF
DMF
DMF
DMF
DMF
yields (%)c
1
1
0.5
1
1
1
61
75
55
65
8
3
4
5a
6b
PTSA
0
aReaction Carried out at 700 C. bReaction carried out at room temperature. cIsolated yields
(flash chromatography). PTSA: para toluene sulfonic acid
The reaction of 4-morpholinecarbonitrile (1 eq.) with 2-aminobenzophenone (1eq.) produced a
cyclic amine at the 2-position of the quinazoline core. To our surprise, the reaction gave good
yield when KOtBu used over the PTSA. (table 2, entry 1 & 2).

Table 2. Optimization of reaction conditions for substituted cyclic 2-aminoquinazoline
derivatives.
entry
1
2
acid/base
PTSA
KOtBu
equivalent
solvent
DMF
DMF
yields (%)a
1
1
66
78
aIsolated Yields (Flash Chromatography).
With the optimized reaction conditions in hand, further exploration for the scope of substrate and
functional group tolerance was explored. The reaction with strong electron withdrawing groups
(7b, 9b, 9e) present on the aromatic ring of the acyl phenyl ring resulted in the good yield
compared to weak electron withdrawing (7c, 9c, 9f) and unsubstituted aromatic ring (7a, 9a, 9d)
shown in scheme 2.

Scheme 2. Substrate scope used in the synthesis of 2-aminoquinazoline derivatives.

1
13
Structure conformation of the synthesized compounds was confirmed by H & C NMR and
mass spectrometry (supplemental information). Lastly, to dually confirm the synthesis of 2-
aminoquinazolines, overnight evaporation of the compound 9e dissolved in ethyl acetate and
hexane (3:1) gave a single crystal for the x-ray analysis illustrated in figure 2.
Figure 2. X-ray crystal structure of 2-aminoquinazoline 9e.
Plausible reaction mechanism for 2-aminoquinazoline formation mediated by acid or base is
shown in scheme 3. Weak acid PTSA carried out the protonation of the cyano group’s nitrogen,
which increases the electrophilic nature of the cyanamide carbon.9 This allows the amine to
attack the electrophilic carbon forming the amidine intermediate. This intermediate undergoes
cyclization followed by elimination of a water molecule to produce the 2-aminoquinazoline.
Conversely, base-mediated proton removal of the amine yields a strong nucleophile capable of
reacting with the cyanamide carbon, followed by ring closure afforded product. In summary, acid
increases cyanamide carbon electrophilicity, while base increases nucleophilicity, which is one
of the key steps in the reaction kinetics.

Scheme 3. Plausible reaction mechanism for a metal free cascade cyclization.
In conclusion, we have developed a simple and efficient approach for the synthesis of 2-
aminoquinazoline derivatives in moderate to good yields. The advantage of this reaction is its
mild and metal free reaction conditions. This methodology allows the synthesis of a 2-
aminoquinazoline core functionalized with a free amine as chemical handle for the further
structural diversity generating a potentially biologically important compound library.
Acknowledgments
This project was supported by the National Institutes of Health / National Institute of Allergy and
Infectious Diseases research grant AI116525, American Associations of Colleges of Pharmacy
(AACP) New Investigator Award and Creighton University (LB692) to EJN.
Supplementary data
General experimental procedures, Mass and NMR spectral data for compounds are provided in
supporting information.
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A Simple and Efficient Approach for the Synthesis of 2-Aminated Quinazolines Derivatives
via Metal Free Oxidative Annulation
*
Amit N. Pandya, 1 Eric M. Villa, 2 E. Jeffrey North 1
1Department of Pharmacy Sciences, School of Pharmacy and Health Professions, Creighton
University, Omaha, Nebraska.
2Department of Chemistry, Creighton University, Omaha, NE 68178, USA
Corresponding Author email: jeffreynorth@creighton.edu
Highlights




Metal-free reaction conditions for the synthesis of 2-aminoquinazolines
Mild reaction conditions for the synthesis of 2-aminoquinazolines
Functionalization of the biologically relevant quinazoline scaffold
Scalable synthesis for 2-aminoquinazolines