A facile and versatile protocol for the one-pot PhI(OAc)2 mediated divergent synthesis of quinazolines from 2-aminobenzylamine

Article abstract of DOI:10.1016/j.tetlet.2017.04.036

In this present work iodobenzenediacetate (PIDA) has been found to be the key reagent in absence or presence of catalytic amount of molecular iodine (I₂)/zinc chloride (ZnCl₂) to construct quinazoline scaffold from 2-aminobenzylamine and a variety of easily available aldehydes, aryl and aliphatic amines, aliphatic and aryl alcohols and nitriles. This protocol provides mild and robust conditions along with great versatility to synthesize 2-substituted quinazolines from diverse starting materials in good to excellent yields. The developed protocol is also well applicable to reactants containing ease to oxidation prone functional groups.

Full text of DOI:10.1016/j.tetlet.2017.04.036

Accepted Manuscript
A facile and versatile protocol for the one-pot PhI(OAc)2 mediated divergent
synthesis of quinazolines from 2-aminobenzylamine
Moumita Saha, Prasun Mukherjee, Asish R. Das
PII:
S0040-4039(17)30463-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.04.036
TETL 48828
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
28 February 2017
4 April 2017
8 April 2017
Please cite this article as: Saha, M., Mukherjee, P., Das, A.R., A facile and versatile protocol for the one-pot
PhI(OAc)2 mediated divergent synthesis of quinazolines from 2-aminobenzylamine, Tetrahedron Letters (2017),
doi: http://dx.doi.org/10.1016/j.tetlet.2017.04.036
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A facile and versatile protocol for the one-
pot PhI(OAc)2 mediated divergent synthesis
of quinazolines from 2-aminobenzylamine
Moumita Saha, Prasun Mukherjee, Asish R. Das*

1
Tetrahedron Letters
journal homepage: www.els evier.com
A facile and versatile protocol for the one-pot PhI(OAc)2 mediated divergent
synthesis of quinazolines from 2-aminobenzylamine
Moumita Saha, Prasun Mukherjee, Asish R. Das*
Department of Chemistry, University of Calcutta, Kolkata-700009, India
*Corresponding author: Tel.: +913323501014, +919433120265; fax:913323519754;
E-mail address: ardchem@caluniv.ac.in , ardas66@rediffmail.com
ARTICLE INFO
ABSTRACT
Article history:
Received
In this present work iodobenzenediacetate (PIDA) has been found to be the key reagent in
absence or presence of catalytic amount of molecular iodine (I2)/zinc chloride (ZnCl2) to
construct quinazoline scaffold from 2-aminobenzylamine and a variety of easily available
aldehydes, aryl and aliphatic amines, aliphatic and aryl alcohols and nitriles. This protocol
provides mild and robust conditions along with great versatility to synthesize 2-substituted
quinazolines from diverse starting materials in good to excellent yields.The developed protocol
is also well applicable to reactants containing ease to oxidation prone functional groups.
Received in revised form
Accepted
Available online
Keywords:
2-substituted quinazoline
iodobenzenediacetate
2009 Elsevier Ltd. All rights reserved
.
diverse starting materials
well tolerance of oxidant prone functional groups
1. Introduction
protocols to synthesize quinazoline derivatives require either very
strong, hazardous oxidizing agent or expensive transition metal
catalysts along with long reaction time and elevated temperature.
Recently, Li et al, have established the synthesis of quinazolines
from 2-aminobenzylamine and nitrile derivatives in presence of
Hypervalent iodine reagents have gained significant
consideration over the past decades as eco-friendly and robust
oxidants for numerous valuable organic transformations.1 In
particular, several protocols have been developed where these
reagents have been successfully employed instead of using
expensive metal catalysts and strong oxidizing agents.2 The
ability to provide a metal free reaction condition has made
hypervalent iodine reagents important in medicinal field to
construct biologically relevant heterocycles. Among them
iodobenzene diacetate (PIDA) has employed in numerous organic
transformations as the key oxidant due to its ready availability
and less toxicity.3 In our previous work, we have established the
synthesis of 2-substituted benzimidazoles through ring distortion
strategy by reacting 2-aminobenzylamine with aldehydes and
arylamines employing PIDA and molecular iodine reagent
combination to generate the key reagent IOAc in-
situ.4Interestingly, during the study of optimization of reaction
conditions, 2-phenylquinazoline was obtained in a considerable
amount when PIDA and molecular iodine was taken in 1.5:0.5
ratio along with the ring distorted product 2-
phenylbenzimidazole.
o
copper cinnamate as catalyst in toluene at 110 C (Scheme 1,
entry 1).9d
Quinazoline is the key structural motif of several biologically
significant natural products.5Besides, they are well known for
their broad spectrum of bioactivity, such as, sedative,
anticonvulsant, antitussive, hypotensive, antidiabetic, anticancer,
antiviral, antitubercularproperties.6 In addition, there are several
quinazoline derivatives marketed as potent drugs.7Consequently,
several protocols have been developed over the past decades to
access these particular heterocycles.8 However, the established
Scheme 1.Synthesis of 2-substitutedquinazolines

2
Tetrahedron
Su and co-workers have employed carbazolic conjugated
reaction time (Table 1, entry 4-8). To explore the necessity of a
base during the reaction; triethylamine, K2CO3 and Cs2CO3 were
employed in conjunction. However, presence of a base was found
to be ineffective to increase the product yield in this particular
reaction (Table 1, entry 9-11).
microporous polymers as visible-light photocatalyst to synthesize
quinazoline scaffolds from tetrahydroquinazolines (Scheme 1,
entry 2).9a Yamaguchi’s group has reported magnesium iodide-
catalyzed synthesis of quinazolines from aldehydes and 2-
aminobenzylamine under visible light and oxygen atmosphere
(scheme 1, entry 3).9b In addition, Sen et al, have reported IBX
promoted synthesis of quinazolines from aldehydes and 2-
aminobenzylamine (scheme 1, entry 3).9a However, no protocol
has been developed so far which can afford quinazolines from the
reaction of 2-aminobenzylamine with either aldehydes, aryl
amines, aryl alcohols or aromatic nitriles by employing a
common oxidant as the key reagent. Thus the synthesis of
quinazolines is still seeking a mild, competent and versatile
methodology with a broad range of substrate scope.
Having the optimized reaction condition in hand, we have then
investigated the scope and limitation of this protocol. Various
aromatic, heteroaromatic and aliphatic aldehydes along with 2-
aminobenzylamine were treated with 2.0 equiv PIDA in 3 mL
DCM at rt. In all cases the reaction proceeded with equal
efficiency to provide the functionalized quinazoline derivatives in
good to excellent yield (Table 2, entry 3a-u). The reaction is
greatly product selective affording no side products after
completion of the reaction. Importantly, in this protocol also the
oxidant sensitive functional groups were able to survive during
the reaction (Table 2, entry 3j, 3k, 3o, 3t and 3u).
Following our latest efforts in hypervalent iodine mediated
formation of carbon-carbon and carbon-heteroatom bond to
synthesize bioactive heterocycles,10 herein we wish to report a
hypervalent iodine promoted mild and robust synthesis of
quinazoline derivatives by reacting 2-aminobenzylamine with
aldehydes, arylamines, arylalcohols and aromatic nitriles, using
DCM as solvent at room temperature (Scheme 1, entry 5).
Table 2. Substrate scope for the synthesis of quinazolinesa
2. Results and Discussion
Initially, to optimize the reaction conditions for the synthesis
ofquinazoline scaffold 1a (1.0 mmol) and benzaldehyde (1.0
mmol) were treated with 2.0 mmol PIDA in 3 mL of DCM at
room temperature. To our satisfaction, the product 3a was
obtained in 92% yield after 0.7 h (Table 1, entry 1). The reaction
was then
Table 1. Optimization of the reaction condition to synthesize
quinazolinea
PIDA
additive
(2mmol)
time
(h)
yieldb
(%)
entry
solvent
(mmol)
1
2.0
1.8
2.1
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
DCM
DCM
DCM
DCE
-
0.7
1.0
1.0
1.5
2.0
4.0
3.0
2.0
1.0
1.0
1.0
92
82
91
88
86
70
76
80
91
90
92
2
-
3
-
4
-
5
CH3CN
EtOAc
THF
-
a
reaction conditions: 1a (1.0mmol), aldehyde (1.0mmol), DCM
(3 mL), PIDA (2.0mmol) were stirred for 0.7h. b yield.
In view of the above impressive results, we have then tried to
extend the scope of these protocols in realizing
6
-
7
-
8
toluene
DCM
DCM
DCM
-
Table 3.Synthesis of quinazolines from arylaminesa
9
Et3N
K2CO3
Cs2CO3
10
11
aIn each case 1a (1.0mmol), benzaldehyde (1.0mmol), 3 mL
solvent were used. b yield.
carried out by using PIDAin different amounts. Significant
decrease in the product yield was observed when 1.8 mmol of
PIDA was employed (Table 1, entry 2). However, use of 2.1
mmol of PIDA was found to be fruitless to increase the product
yield (Table 1, entry 3). Replacement of DCM with other
solvents results in a decrease in product yield along with a longer

3
areaction conditions : 1a (1.0 mmol), aryl amines (1.0 mmol),
areaction conditions : 1a (1.0 mmol), nitriles (1.0 mmol),
b
PIDA (3.0 mmol), and DCM (3mL) at rt for 1.0h. yield.
reaction time was 4.0h.
c
PIDA (1.0 mmol), ZnCl2 (10 mol%) and DCM (3mL) at rt for
1.3h. b yield.
quinazolines from 2-aminobenzylamine and aryl and alkyl amine
derivatives. Initially benzylamine derivatives (1.0 mmol) were
stirred in 3 mL DCM in presence of 1.0 mmol of PIDA for 15
min and then to it 1a (1.0 mmol) and 2.0 mmol PIDA were added
at rt. Satisfyingly, the reaction proceeded well by affording the
corresponding quinazolines in excellent yield (Table 3, entry 3a,
3l, 3v, 3x and 3ag). Interestingly, quinazolinone 3ah was also
obtained in excellent yield from 2-aminobenzamide and benzyl
amine by applying this protocol (Table 3, entry 3ah)
A tentative mechanism for the formation of quinazoline is also
shown in Scheme 2. After the formation of intermediate I from
the reaction between 1a and 1b, PIDA reacts with I to generate
the intermediate II. An elimination reaction in II then leads to
In order to synthesize quinazolines from arylalcohols we have
then reacted arylalcohol derivatives (1.0 mmol) with 1.0 mmol of
PIDA and molecular iodine (10 mol%) for 15 min in 3 mL DCM
and then to it 1a (1.0 mmol) and 2.0 mmol PIDA were added at
rt. Benzyl alcohol derivatives with electron donating as well as
electron withdrawing groups have been employed and
corresponding products were obtained in excellent yield (Table 4,
entry 3a, y, l, v). Interestingly, when we have employed ethanol
in place of benzyl alcohol derivatives the reaction have
proceeded with equal efficacy affording the corresponding
quinazolines in excellent yield (Table 4, entry 3z). It is
noteworthy to mention that without the addition of catalytic
amount of I2 the formation of the desired quinazolines was not
observed.
Table 4.Synthesis of quinazolines from aryl and aliphatic
alcoholsa
Scheme3: Plausible mechanism for the synthesis of
quinazolines
the formation of III. III then gets attacked by another molecule
of PIDA to produce the product 3 following a similar course via
intermediate IV. In case of arylamines (1c) and arylalcohol
derivatives (1d), their initial oxidation takes place in presence of
PIDA and PIDA/I2 respectively to generate their corresponding
aldehydes. It is noteworthy to mention that the conversion of 1d
to 1b was not observed in absence of molecular iodine. The role
of catalytic amount of molecular iodine in this transformation is
probably the formation of IOAc which may impart the key role
in generating the intermediate 1b which then follows the desired
course of reaction and ultimately produces the product 3. For
nitrile derivatives, coordination of ZnCl2 with –CN group11
facilitates the reaction of 2-aminobenzylamine with nitrile moiety
thereby allowing the formation of V which then releases a
molecule of NH3 in presence of ZnCl2 to form III. III then
follows the similar course of mechanism to afford the product 3.
areaction conditions : 1a (1.0 mmol), alcohols (1.0 mmol),
PIDA (3.0 mmol), I2 (10 mol%) and DCM (3mL) at rt for 1.2h. b
yield.
We have further extended this protocol to construct quinazoline
scaffold from aryl, alkyl and heteroaryl nitriles by reacting 1a
(1.0 mmol) with nitrile derivatives (1.0 mmol) using PIDA as the
oxidants in presence of ZnCl2 (10 mol%) in DCM at rt. In this
particular case however the presence of Lewis acid catalyst is
essential to facilitate the attack of 2-aminobenzylamine to the
nitrile group. The reaction proceeded well at rt affording the
corresponding quinazolines in excellent yields.
3. Conclusions
In summary, PIDA has been successfully employed to
synthesize 2-substitutedquinazolinesfrom 2-aminobenzylamine
and a variety of easily available aldehydes, arylamines, aryl as
well as aliphatic alcohols and nitriles. The versatility of this
protocol is well established by exploiting PIDA in absence or
presence of different additives in order to synthesize 2-
substituted quinazolines from diverse starting materials.
Additionally, this protocol offers mild and robust conditions to
synthesize quinazoline scaffold in excellent yields by promoting
the C-N bond formation at room temperature.
Table 5.Synthesis of quinazolines from aryl and aliphatic nitrilesa
4. Acknowledgments
We acknowledge the financial support from the centre of
CAS-V (Synthesis and functional materials) (support offered by
UGC, New Delhi) of the department of Chemistry, University of
Calcutta. MS and PM are thankful to U.G.C, New Delhi, India
for the grant of their Junior and Senior Research fellowships

4
Tetrahedron
respectively. Crystallography was performed at the DST-FIST,
India-funded Single Crystal Diffractometer Facility at the
Department of Chemistry, University of Calcutta.
5. References and notes
1. (a) Yoshimura, A. and ZhdankinV. V.Chem. Rev. 2016, 116,
3328–3435; (b) Zhdankin V. V. and StangP. J. Chem. Rev. 2008,
108, 5299–5358; (c) Banks, D. F. Chem. Rev. 1966, 66, 243–266.
2. (a) Dohi, T., Takenaga, N., Goto, A., Maruyama, A., Kita,
Y., Org. Lett. 2007, 9, 3129-3132; (b) Yoshimura, A., Middleton,
K. R., Todora, A. D., Kastern, B. J., Koski, S. R., Maskaev, A. V.,
Zhdankin V. V, Org. Lett. 2013, 15, 4010-4013.
3. (a) Liu, G.Q., Li, Y.M. J. Org. Chem. 2014 79, 10094–10109; (b)
Zhang, L.H., Kauffman, G.S., Pesti, J. A., Yin, J. J. Org.
Chem. 1997 62, 6918–6920; (c) Xu, J.H., Jiang, Q., Guo, C.C. J.
Org. Chem. 2013 78, 11881–11886.
4. Saha, M., Mukherjee, P., Das, A. R. Tetrahedron Lett. 2017, 58,
1046–1049.
5. (a) Connolly, D. J., Cusack, D., Sullivan, T. P. O., Guiry, P. J.
Tetrahedron 2005, 61, 10153; (b) Foster, B. A., Coffrey, H. A.,
Morin, M. J., Rastinejad, F. Science 1999, 286, 2507; (c) Gundla,
R., Kazemi, R., Sanam, R., Muttineni, R., Sarma, J. A. R. P.,
Dayam, R., Neamati, N. J. J. Med. Chem. 2008, 51, 3367; (d)
Lüth, A., Löwe, W. Eur. J. Med. Chem. 2008, 43, 1478.
6. (a) Selvam T. P. and Kumar P. V. Research in Pharmacy 2011, 1,
1; (b) Henderson, E. A., Bavetsias, V., Theti, D. S., Wilson, S. C.,
Clauss, R., Jackman, A. L. Bioorg. Med. Chem. 2006, 14, 5020;
(c) Chien, T.C., Chen, C.S., Yu, F.H., Chern, J.W Chem. Pharm.
Bull. 2004, 52, 1422.
7. Ravez, S., Castillo-Aguilera, O., Depreux, P., Goossens, L. Expert
OpinTher Pat. 2015, 25, 789-804.
8. (a) VandenEynde, J. J., Godin, J., Mayence, A., Maquestiau, A.,
Anders, E. Synthesis 1993, 867; (b) Peng, Y., Zeng, Y., Qiu, G.,
Cai, L., Pike, V. W. J. Heterocycl. Chem. 2010, 47, 1240; (c) C.
Maheswari, U., Kumar, G. S., Venkateshwar, M., Kumar, R. A.,
Kantam, M. L., Reddy, K. R. Adv. Synth. Catal. 2010, 352, 341;
(d) Huang, C., Fu, Y., Fu, H., Jiang, Y.,Zhao, Y., Chem. Commun.
2008, 6333; (e) Malakar, C. C., Baskakova, A., Conrad J., Beifuss,
U. Chem. Eur. J. 2012, 18, 8882; (e) Han, B., Yang, X. L., Wang,
C.,Bai, Y. M., Pan, T. C., Chen, X., Yu, W. J. Org. Chem. 2012,
77, 1136; (f) Wang, C., Li, S., Liu, H., Jiang,Y., Fu, H. J. Org.
Chem. 2010, 75, 7936; (g) Chen, Z., Chen, J., Liu, M., Ding, J.,
Gao, W., Huang, X. and Wu, H. J. Org. Chem. 2013, 78,
11342−11348; (h) Zhao, D., Shen, Q., Zhou, Y. R., Li, J. X. Org.
Biomol. Chem. 2013, 11, 5908; (i) Truong, V. L., Morrow, M.,
Tetrahedron Lett. 2010, 51, 758–760; (j) Xu, C., Jia, F.C., Zhou,
Z.W., Zheng, S.J., Li, H. and Wu, A.X. J. Org. Chem. 2016, 81,
3000–3006; (k) Cai, Q., Li, D.K., Zhou, R.R., Zhuang, S.Y., Ma ,
J.T., Wu, Y.D and Wu, A.X.J. Org. Chem. 2016, 81, 8104–
8111;(l) Zhao, D., Zhou, Y.R., Shen, Q.and Li, J.X. RSC Adv.
2014, 4, 6486; (m) Zhang, Z., Wang, M., Zhang, C., Zhang, Z.,
Lu, J. and Wang, F. Chem. Commun. 2015, 51, 9205-9207; (n)
Tangella, Y., Manasa, K. L., Sathish , M., Alarifi , A. and
Kamal , A. Chemistry Select 2016, 1, 2895 – 2899.
9. (a) Su, C., Tandiana, R., Tian, B., Sengupta, A., Tang, W., Su, J.
and Loh, K. P. ACS Catal. 2016, 6, 3594–3599; (b) Yamaguchi,
T., Sakairi, K., Yamaguchi, E., Tada, N., Itoh, A. RSC Adv.
2016,6, 56892-56895; (c) Hati, S., Sen, S., Synthesis 2016, 48,
1389-1398; (d) Li, C., An, S., Zhang, Y. J., Kang, Y., Liu, P.,
Wang, Y. and Li, J. RSC Adv. 2014, 4, 49888.
10. Mukherjee, P. and Das, A. R. J. Org.
Chem.DOI: 10.1021/acs.joc.7b00089.
11. Vorona, S., Artamonova, T., Zevatskii, Y., Myznikov, L.
Synthesis 2014, 46, 0781–0786.
.

5
• 2-substituted
quinazolines
from
2-
aminobenzylamine.
• Diverse aldehydes, aryl and alkyl amines,
alcohols and nitriles can be employed.
• PhI(OAc)2 shows the promise in presence or
absence of ZnCl2 or I2.
• Mild and versatile protocol does not
demand high thermal or photochemical
energy.
• Protocol offers well tolerance towards
oxidation prone functional groups.