Iodine promoted dual oxidative C(sp3)-H amination of 2-methyl-3-arylquinazolin-4(3H)-ones: A facile route to 1,4-diarylimidazo[1,5- a] quinazolin-5(4 H)-ones

Article abstract of DOI:10.1039/c7ob02677c

An iodine promoted tandem oxidative condensation of benzylamines and 2-methylquinazolin-4-(3H)-ones was developed to yield imidazo[1,5-a]quinazolin-5(4H)-ones via dual C(sp³)-H amination under metal free conditions in a greener way using molecu

Full text of DOI:10.1039/c7ob02677c

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Iodine promoted dual oxidative C (sp3) –H amination of 2-methyl-
3-arylquinazolin-4(3H)-ones: A facile route to 1,4-diarylimidazo
[1,5-a]quinazoline-5(4H)-ones
Kavitha Donthiboina,a,b Namballa Hari Krishna,a,b Siddiq Pasha Shaik,b Jagadeesh Babu Nanubolu,c
Nagula Shankaraiah,*a Ahmed Kamal*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
An iodine promoted tandem oxidative condensation of benzyl amines and 2-methylquinazolin-4-(3H)-ones was developed
to yield imidazo[1,5-a]quinazolin-5(4H)-ones via dual C (sp3)−H aminaꢀon under metal free condiꢀons in a greener way
using molecular oxygen as terminal oxidant. This tandem transformation provides an efficient approach to construct
various functionalized imidazo[1,5-a]quinazolin-5(4H)-ones in a straightforward manner via a sequential amination-
oxidation-annulation-aromatisation.
as prefunctionalisation of substrates, harsh reaction
conditions, limited substrate scope or of multi-step
procedures. Therefore, more straightforward method for the
Introduction
Nitrogen-containing fused heterocycles are valuable structural
motifs in numerous biologically active compounds and
pharmaceuticals.1 In particular, imidazoquinazolinones and
their derivatives are among the fused heterocycles that
represent an important class of compounds which exist in wide
variety of natural as well as synthetic drug molecules.2 This
privileged motif is gifted with a wide range of biological
activities such as anti-thrombotic, anticonvulsant, antitumor,
antihypertensive, GABAA receptor ligand and cardiotonic etc.3
Thus, the development of synthetic methodologies towards
these imidazoquinazolinones is a prominent area towards drug
discovery and development. Consequently, a great deal of
attention has been diverted towards the construction of these
important and attractive scaffolds. Singh and co-workers
developed a route for the synthesis of imidazoquinazolinones
from 2-methylquinazolin-4-(3H)-ones by converting it into
preparation of imidazoquinazolinones from easily available
substrates is highly desirable.
In the past few decades a great deal of progress has been
achieved in the transition-metal-catalysis. Particularly,
transition-metal-catalyzed C-N bond formation by the
oxidative amination of C (sp3)-H has attracted considerable
attention for the construction of azaheterocycles.5 However,
the cost effectiveness and limited substrate scope are the
major concerns associated with the practical applicability in
the organic synthesis. Thus, alternative metal-free approaches
are highly desirable for C-H amination. Recently, iodine has
certainly attracted the researchers and appeared to be an
alternative for a numerous transition-metals because of its
versatility and ability to perform an array of synthetic
transformations.6 Accordingly, the versatility of iodine in
activating both C (sp2)-H and C (sp3)-H to form C-N bond, eco-
friendly nature has established and received much attention,
and is appealing due to high atom economy and easy access of
starting materials.7
aminomethyl derivative and then into corresponding
carboxamide, followed by intramolecular cyclodehydration.4a
N
Recently, Lebegue et al., has reported a microwave-assisted
two-step
synthesis
of
1,3-disubstituted-imidazo[1,5-
a]quinazolin-5-(4H)-ones via formation of quinazolinone from
anthranilamide and various Boc- or acylamino acids, followed
by intramolecular cyclodehydration under acidic conditions.4b
Eventhough, many synthetic methods have been developed
for the synthesis of imidazoquinazolinones,4 most of the
conventional methods suffer from various disadvantages such
a.Department of Medicinal Chemistry, National Institute of Pharmaceutical
Education and Research (NIPER), Hyderabad - 500 037, India
b.Department of Medicinal Chemistry and Biotechnology, CSIR-Indian Institute of
Chemical Technology, Hyderabad-500007, India
Scheme
1 Synthesis of imidazo[1,5-a]quinazolin-5(4H)-ones via dual C
(sp3)−Hamination of 2-methyl-quinazolin-4-(3H)-ones and benzyl amines.
c.Laboratory of X-ray Crystallography, CSIR-Indian Institute of Chemical
Technology, Hyderabad-500007, India
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
Recently 2-alkylarenes and 2-alkylazaarenes has been
recognized and widely exploited as important frameworks for
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C
(sp3)-H oxidative amination because of their broad iodine as a catalyst and O2 as oxidant at 110 oC, which resulted
availability and inexpensive nature.8 Chang9a and Zhu9b et al., in formation of no desired product even after stirring for more
independently reported iodine promoted benzylic C-H than 24 h (entry1, Table 1). To our delight, increase in the
amination. Muniz9c and co-workers achieved allylic C-H amount of iodine to 0.5 equiv. lead to formation of desired
amination in the presence of hypervalentiodine(III) reagents. product albeit in lesser yields (entry 2, Table 1). The structure
However, these approaches are limited to sulphonamides. In of the compound was unambiguously confirmed by the X-ray
spite of considerable progress by many research groups analysis. This inspiring result forced us to focus on the yields of
towards the development of synthetic methodologies based the product. A fair improvement in the yields of the product
on intramolecular and intermolecular oxidative C (sp3)-H was observed with the increase in the stoichiometry of iodine
amination, their application in the construction of diverse aza up to 1.5 equiv. (entry 3, 4 & 5, Table 1). However, no further
heterocycles remain scarce. In continuation of our interest in increase in the yields was observed beyond 1.5 equiv. At this
developing
domino
reactions
to
access
various juncture, we thought to study the effect of oxidant on the
pharmacologically active heterocycles,10 we envisioned that reaction conditions. It is clear that O2 was the best oxidant
isomerized nonaromatic enamine intermediate of 2-methyl- among the tested oxidants and inferior results were obtained
quinazolin-4-(3H)-one can be assembled into imidazo[1,5- with oxidants such as TBHP, DTBP and DDQ (entry 7, 8 & 9,
a]quinazolin-5(4H)-ones with various benzyl amines utilizing Table 1). DMF stood as optimal solvent of choice among the
iodine and molecular oxygen as green oxidant. Herein, we studied solvents like DMSO, PhMe and EtOH (entry 10, 11 &12,
report iodine promoted domino oxidative condensation of Table 1). Alternate iodine sources were then investigated and
benzyl amines and 2-methylquinazolin-4-(3H)-ones via dual C it is found that NIS, KI and TBAI (entry 13, 14 & 15, Table 1)
(sp3)−H aminaꢀon using oxygen as a sole oxidant to yield were comparably less effective under otherwise identical
imidazo[1,5-a]quinazolin-5(4H)-ones.
reaction conditions. Finally performing a reaction under inert
atmosphere did not result in formation of any desired product.
Temperature showed obvious effect on reaction where no
product was detected at room temperature or even when the
temperature was decreased to 90 oC (entry 16, Table 1).
Table 1 Optimization of the reaction conditions.a
Table 2 Substrate scope of benzyl aminesa,b
Entr Catalys Equival Oxida
Solvent
Tempera
ture(oC)
110
Yield(%
b
y
1
t
I2
ents
0.2
0.5
1.0
1.2
1.5
2
nt
O2
)
DMF
DMF
nd
26
2
I2
O2
110
3
I2
O2
DMF
110
55
4
I2
O2
DMF
110
60
5
I2
O2
DMF
DMF
110
89
6
I2
O2
110
88
7
I2
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
TBHP
DTBP
DDQ
O2
DMF
110
50
8
I2
DMF
110
76
9
I2
DMF
110
40
10
11
12
13
14
15
16
I2
DMSO
toluene
ethanol
DMF
110
trace
nd
nd
nd
nd
nd
nd
I2
O2
110
I2
O2
110
NIS
KI
TBAI
I2
O2
110
O2
DMF
110
O2
DMF
110
O2
DMF
90
aReaction conditions: 1a (0.5 mMol), 2 (0.6 mMol), solvent 1.5 mL, 110 oC, 24
h.bIsolated yield.
aReaction conditions: 1a (0.5 mMol), 2a (0.6 mMol), solvent 1.5 mL, 110 oC, 24 h.
bIsolated yield.nd = not detected.
With the optimal reaction conditions in hand, we next
investigated the generality and substrate scope of the present
Results and discussion
protocol. As shown in Table 2, various benzylamines (2a-f
)
)
Our journey towards the exploration of optimal reaction
conditions for the dual C (sp3)−H aminaꢀon commenced by
taking 2-methyl-3-phenylquinazolin-4-(3H)-one 1a and benzyl
amine 2a as model substrates. Accordingly, 2-methyl-3-
were treated with 2-methyl-3-arylquinazoline-4(3H)-one (1a
under the optimized reaction conditions to deliver
corresponding products 3a-f in good yields. It is observed that
benzyl amines substituted with electron-withdrawing CF3
substituent 3c, 3e gave superior yields 85% and 80%
respectively. However, comparably lesser yields were
phenylquinazolin-4-(3H)-one
(1a) is treated with benzyl
amine(2a) in DMF in the presence of 0.2 equiv. of molecular
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observed when electron-donating methyl substituted benzyl
amine was used as amine partner 3d (75% yield, Table 2). It is
worth mention that steric factors have great influence on the
reaction. Notably, ortho-substituted benzyl amine such as 2-
chlorobenzylamine is amenable to optimized conditions and
delivered corresponding products 3b in comparably lesser
yields 70%. However, as imagined, bulky methyl group at ortho
position of benzylamine blocked the roll-over process and did
not react at all even after stirring for more than 24 h.
With these fruitful results, we next focused on scope of
quinazolones (with various substitutions on 3rd position) as
summarized in Table 3. To our delight, electron donating and Fig .1 ORTEP diagram of 3i
electron withdrawing substituents on phenyl ring substituted
phenyl ring at 3rd position of quinazolines (3k-n
& 3s-v) than
at 3rd position of quinazolones were successfully utilized in the
reaction to deliver the corresponding products in good yields
unsubstituted ones (Table 3). The decrease in yields is directly
proportional to the electronic donating nature of the
substituents as OMe substituent gave lesser yields than Me
substituent. In contrast, mono and di-halo substitutions on the
(
3c-d & 3g-h, 3k-l, 3o-p, 3s-t and 3v) the electronic effects of
these groups slightly influenced the reaction efficacy.
Comparably lesser yields were obtained with electron
donating OMe and Me substituents at para position of the
phenyl ring at 3rd position of quinazolones (3g-j
& 3o-r) gave
better yields. In addition, quinazolones substituted with
electron withdrawing chlorine and fluorine at 8th position
were also well tolerated with benzyl amines under the
optimized reaction conditions and the corresponding products
Table 3 Scope of quinazolinonesa, b
(
3w, 3x & 3y) were afforded in 60, 70 and 79% respectively.
Moreover, 2-methyl-3-phenylbenzo[g]quinazolin-4(3H)-one is
also a suitable substrate for this dual C (sp3)-H amination
cascade process to give the desired product (3z) in descent
yields (79%).
To get insight in to the reaction mechanism, few control
experiments were conducted (Scheme 2). Initially, 1a in the
absence of benzyl amine under optimized reaction conditions
did not result in any expected aldehyde indicating that an in
situ aldehyde intermediate based oxidative condensation
process was excluded. Moreover, replacing the iodine with
stoichiometric amounts of PhI(OAc)2 did not result in any
desired product 3a, suggesting that the in situ generated
hypervalent iodine intermediates are not catalyzing the
reaction pathway. Finally assuming that the reaction may
proceed via
a free radical mechanism, radical trapping
experiments were performed by employing 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO) or
O
O
I2, 1.5 equiv.
Ph
Ph
N
(Not detected)
H
N
(i)
O2, DMF,
110 oC, 12 h
N
N
O
O
O
Ph
N
Ph
PhI(OAc)2
N
N
(No reaction)
(ii)
Ph
NH2
O2, DMF,
N
110 oC, 12 h
N
O
N
Ph
O
Ph
I2, 1.5 equiv.
O2, DMF,
110 oC, 12 h
Radical quencher
TEMPO/
BHT
N
Ph
Ph
72 %
(iii)
(iv)
NH2
N
N
N
Ph
O
O
Ph
I
2, 1.5 equiv.
N
Ph
N
2 DMF, 110 oC, 12 h
Ph
NH
N
N
No oxygen
N
Ph
nd
aReaction conditions: 1 (0.5 mMol), 2 (0.6 mMol), solvent 1.5 mL, 110 oC, 24 h.
bIsolated yield.
Scheme 2 Control experiments for proposed mechanism. nd = not detected.
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2,6-di-tert-butyl-4- methylphenol (BHT). This possibility was spectrometer at 25 °C. Chemical shifts values are given in ppm and
ruled out as the reaction did not retard in the presence of calibrated relative to the residual signal of the TMS solvent. The
radical scavengers yielding the required product in good yields. peak patterns are defined as follows: s, singlet; d, doublet; t, triplet;
These results conclude that reaction presumably undergoes q, quartet; m, multiplet and dd, doublet of doublets. The coupling
through an in situ generated iodo intermediate which was constants J are reported in Hertz (Hz). Column chromatography was
generated via ionic pathway.
performed over silica gel (100−200 mesh) using a mixture of n-
Based on the reported literature11 and our observations, a hexane and ethyl acetate (EtOAc) as an eluent. TLC plates (Silica gel
plausible reaction mechanism for this domino oxidative GF254) were visualized by exposure to ultraviolet light. High
condensation via dual C (sp3)-H amination was outlined in resolution mass spectrometry (HRMS) was obtained on a QTOF
Scheme 3. Since aldehyde was not formed in the reaction it is micro spectrometer. Melting points were determined with electro
assumed that an aromatic enamine intermediate
from 2-Methyl-3-arylquinazoline-4(3H)-one via iodine- solutions were concentrated by rotary evaporation below 45 °C in
promoted isomerization (1,3-H shift).12 The intermediate
vacuum.
then transforms into iodo-intermediate Moreover, as
toluene is not reactive under these conditions, it is clear that General procedure for synthesis of substituted 1,4-diphenyl
nitrogen is crucial for the formation of this intermediate C 13
imidazo[1,4-a]quinazolin-5 (4H)-one
Subsequent nucleophilic amination of benzyl amine 2a onto
the intermediate generates intermediate which further 2-Methyl-3-phenylquinazolin-4(3H)-one (1 equiv.), benzyl amine
oxidises to intermediate . The intermediate
converts into product 3a via intermediate
promoted intramolecular cyclization
A is formed thermal melting point apparatus without corrections. Organic
A
B
.
.
B
C
D
D
then directly (1.2 equiv.) and iodine (1.5 equiv.) in DMF (5 mL) were taken in a
E
through iodine sealed tube and capped with rubber septum, bubbled with O2 via a
followed
by cannula and then the septa was replaced with Teflon cap and
dehydrogenation (oxidative aromatization) in the presence of refluxed at 110 oC. After completion of the reaction (monitored
molecular oxygen14 in a tandem process.
with TLC), reaction mixture was quenched with saturated solution
of sodium thiosulphate (10 mL) and extracted with ethyl acetate (20
mL). Combined organic layers were dried over anhydrous sodium
sulphate, filtered through funnel and solvent was removed under
reduced pressure. Product obtained was further purified by column
chromatography with 100-200 mesh silica gel using hexane and
ethyl acetate as an eluent in increasing polarity to yield the desired
imidazoquinazolinones.
O
O
O
Ph
Ph
Ph
[1, 3] H shift
I2
N
N
N
NH2
O
I
I2
N
N
N
H
2a
B
A
O
N
O
O
Ph
Ph
N
Ph
Ph
N
I2
N
N
O2
O2
N
H
N
N
N
Ph
Ph
NH
NH
N
Ph
Ph
C
D
E
1,4-Diphenylimidazo[1,5-a]quinazolin-5(4H)-one (3a): 3a was
obtained as white solid; M.p: 216-217 oC; Rf = 0.4 (30 % ethyl
Scheme 3 Plausible reaction mechanism.
1
acetate/n-hexane); H NMR (400 MHz, CDCl3): δ 8.38-8.36 ( m, 1H),
7.64-7.60 (m, 4H), 7.59-7.57 (m, 2H), 7.55-7.52 (m, 3H), 7.45-7.43
(m, 4H), 7.24 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 158.5,
142.2, 135.0, 134.4, 133.8, 131.7, 131.5, 130.5, 130.3, 130.1, 129.8,
129.7, 129.5, 129.1, 126.3, 117.9, 116.5 ppm; HRMS calculated for
[M+H]+ C22H16N3O: 338.1293 found: 338.1303.
Conclusion
In summary, we have developed an iodine promoted domino
oxidative condensation of benzyl amines and 2-
methylquinazolin-4-(3H)-ones using oxygen as sole oxidant to
yield imidazo[1,5-a]quinazolin-5(4H)-ones under metal free
1-(2-Chlorophenyl)-4-phenylimidazo[1,5-a]quinazolin-5(4H)-one
(3b): 3b was obtained as white solid; M.p: 225-226 oC; Rf = 0.4 (30%
conditions.
A
domino process to construct valuable
azaheterocycles by forming 2 C-N bonds via dual C (sp3)−H
amination. Absence of metal catalyst, operational simplicity,
commercially available starting materials and avoidance of
substrate prefunctionalization is the distinguished feature of
the present protocol. Further studies based on iodine
promoted C-H aminations for the construction of various
heterocycles are underway.
1
ethyl acetate/n-hexane); H NMR (400 MHz, CDCl3): δ 8.34-8.30 (m,
1H), 7.85-7.79 (m, 2H), 7.61-7.52 (m, 3H), 7.51-7.47 (t, J = 6.9 Hz,
1H), 7.39-7.37 (d, J = 7.5 Hz, 1H), 7.35-7.31 (d, J = 7.0 Hz, 2H), 7.23-
7.19 (d, J = 9.0 Hz, 2H), 7.17-7.14 (d, J = 7.0 Hz, 1H), 6.4 (d, J =15.0
Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 162.3, 151.2, 147.7,
136.9, 135.8, 134.6, 133.6, 130.3, 129.9, 129.4, 128.7, 127.7, 127.5,
127.1, 126.9, 126.8, 122.6, 121.0 ppm; HRMS calculated for [M+H]+
C22H15ClN3O: 372.0903 found: 372.0912.
Experimental section
4-Phenyl-1-(4-(trifluoromethyl)phenyl)imidazo[1,5-a]quinazolin-
5(4H)-one (3c): 3c was obtained as creamish white solid; M.p: 170-
171 oC; Rf = 0.4 (40% ethyl acetate/n-hexane); 1H NMR (500 MHz,
CDCl3): δ 8.43 (dd , J = 1.5, 7.7 Hz, 1H), 7.80 (s, 4H), 7.62 (t, J = 7.3
Hz, 2H), 7.56 (d, J = 7.3Hz, 1H), 7.50 (dd, J = 1.5, 8.3 Hz, 3H), 7.45 (t,
J = 7.7 Hz, 1H), 7.30 (d, J = 8.3 Hz, 1H), 6.33 (s, 1H) ppm; 13C NMR
Materials and General Methods.
Starting materials, reagents and solvents were purchased as
reagent grade and used without further purification. 1H and 13C
NMR spectra were recorded on
a 300, 400 and 500 MHz
4 | J. Name., 2012, 00, 1-3
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(125 MHz, CDCl3): δ 157.6, 138.4, 136.0, 135.4, 134.6, 133.9, 131.5
ARTICLE
(q, J = 32.3 Hz, 1C), 130.5, 130.1, 129.9, 129.5, 128.9, 128.4, 128.1, 4-(4-Chlorophenyl)-1-(4-(trifluoromethyl)phenyl)imidazo[1,5-
126.3, 125.9 (q, J = 2.9Hz, 1C), 125.1 (q, J = 272.8 Hz, 1C), 116.5, a]quinazolin-5(4H)-one (3i): 3i was obtained as white solid; M.p:
110.4 ppm; HRMS calculated for [M+H]+ C23H14F3N3O: 406.1167 207-208 oC; Rf = 0.4 (30% ethyl acetate/n-hexane); 1H NMR (500
found: 406.1153.
MHz, CDCl3): δ 8.42 (dd, J = 1.4, 7.7 Hz, 1H), 7.80 (s, 4H), 7.59 (d, J =
8.8 Hz, 2H), 7.55-7.43 (m, 4H), 7.30 (d, J = 8.2 Hz, 1H), 6.36 (s, 1H)
4-Phenyl-1-p-tolylimidazo[1,5-a]quinazolin-5(4H)-one (3d): 3d was ppm; 13C NMR (100 MHz, CDCl3): 157.5, 138.6, 135.8, 135.4, 134.4,
obtained as creamish white solid; M.p: 238-239 oC; Rf = 0.5 (40% 134.2, 134.0, 131.9 (q, J = 32.7 Hz, 1C), 130.4, 130.3, 129.8, 129.3,
1
ethyl acetate/n-hexane); H NMR (500 MHz, CDCl3): δ 8.36 (dd, J = 126.3, 125.9 (q, J = 2.7 Hz, 1C), 124.8 (q, J = 272.4 Hz, 1C), 122.7,
1.5, 7.4 Hz, 1H), 7.62-7.55 (m, 3H), 7.50 (d, J = 7.9 Hz, 2H), 7.44-7.38 118.0, 116.5, 110.3 ppm; HRMS calculated for [M+H]+
(m, 4H), 7.32 (d, J = 7.7 Hz, 2H), 7.30-7.26 (m, 2H), 2.47 (s, 3H) ppm; C23H14ClF3N3O: 440.0772 found: 440.0791.
13C NMR (125 MHz, CDCl3): δ 158.5, 142.4, 140.2, 35.1, 134.4, 133.8,
131.4, 130.5, 130.2, 129.8, 129.8, 129.7, 129.4, 128.7, 127.9, 126.2, 4-(4-Chlorophenyl)-1-p-tolylimidazo[1,5-a]quinazolin-5(4H)-one
117.8, 116.5 ppm; HRMS calculated for [M+H]+ C23H18N3O: 352.1444 (3j): 3j was obtained as white solid; M.p: 235-236 oC; Rf = 0.4 (40%
found: 352.1445.
ethyl acetate/n-hexane); 1H NMR (500 MHz, CDCl3): δ 8.38 (d, J =
7.2 Hz, 1H), 7.57 (d, J = 7.5 Hz, 2H), 7.51-7.43 (m, 5H), 7.41-7.33 (m,
4H), 6.29 (s, 1H), 2.48 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ
4-Phenyl-1-(3-(trifluoromethyl)phenyl)imidazo[1,5-a]quinazolin-
5(4H)-one(3e): 3e was obtained as creamish white solid; M.p: 238- 15.7, 140.4, 140.0, 135.9, 135.2, 134.6, 133.9, 133.5, 131.8, 130.3,
239 oC; Rf = 0.5 (40% ethyl acetate/n-hexane); 1H NMR (500 MHz, 130.2, 129.7, 129.4, 129.4, 129.4, 125.9, 117.8, 116.6, 109.5, 21.5
CDCl3): δ 8.33-8.30 (d, J = 7.8 Hz, 1H), 8.01-7.95 (d, J = 15.5 Hz, 1H), ppm ; HRMS calculated for [M+H]+ C23H17ClN3O: 386.1060 found:
7.85-7.77 (m, 2H), 7.63-7.52 (m, 5H), 7.49-7.41 (m, 2H), 7.36-7.31 386.1067.
(d, J = 6.5 Hz, 2H), 6.48-6.40 (d, J = 15.6 Hz, 1H) ppm; 13C NMR (125
MHz, CDCl3): 162.1, 151.0, 147.6, 138.0, 136.8, 134.7, 131.8 (q, J = 4-(4-Methoxyphenyl)-1-phenylimidazo[1,5-a]quinazolin-5(4H)-one
o
32.3 Hz, 1C), 130.2, 130.0, 129.3, 128.6, 127.4, 127.2, 126.9, 125.9, (3k): 3k was obtained as white solid; M.p: 233-234 C; Rf = 0.4 (50%
125.1 (q, J = 272.1 Hz, 1C), 124.7 (q, J = 2.9 Hz, 1C), 121.7, 121.0 ethyl acetate/n-hexane); 1H NMR (500 MHz, CDCl3): δ 8.37 (s, 1H),
ppm; HRMS calculated for [M+H]+ C23H14F3N3O: 406.1167 found: 7.64-7.49 (m, 5H), 7.44-7.22 (m, 6H), 7.10 (d, J = 8.2 Hz, 2H), 3.90 (s,
406.1153.
3H) ppm; 13C NMR (100 MHz, CDCl3): δ 160.7, 158.7, 142.2, 135.0,
133.8, 131.8, 131.5, 130.3, 130.1, 130.0, 129.5, 129.1, 127.0, 126.3,
4-Pheny-1-(pyridin-2-yl)imidazo[1,5-a]quinazolin-5(4H)-one (3f): 3f 117.9, 114.8, 130.1, 55.6 ppm; HRMS calculated for [M+H]+
was obtained as creamish white solid; M.p: 228-229 oC; Rf = 0.4
C23H18N3O2: 368.1399 found: 368.1409.
1
(40% ethyl acetate/n-hexane); H NMR (500 MHz, CDCl3): δ 8.82 (d,
J = 4.5 Hz, 1H), 8.43 (d, J = 7.8 Hz, 1H), 8.06 (d, J = 7.9 Hz, 2H), 8.04- 1-(2-Chlorophenyl)-4-(4-methoxyphenyl)imidazo[1,5-a]quinazolin-
8.0 (m, 1H), 7.93-7.86 (m, 3H), 7.75 (d, J = 3.9 Hz, 2H), 7.55 (t, J = 8.0 5(4H)-one (3l): 3l was obtained as white solid; M.p: 228-229 oC; Rf =
Hz, 1H), 7.48 (d, J = 7.2 Hz, 2H), 7.44-7.40 (m, 1H), 6.97 (t, J = 2.8 Hz, 0.4 (40% ethyl acetate/n-hexane); 1H NMR (500 MHz, CDCl3): δ
1H) ppm; 13C NMR (125 MHz, CDCl3): δ 150.7, 148.1, 136.6, 135.2, 8.34-8.29 (m, 2H), 7.83-7.77 (m, 2H), 7.50-7.46 (m, 1H), 7.39 (dd, J =
135.1, 132.8, 126.1, 126.0, 121.9, 121.7, 120.4, 120.4, 118.0, 113.8 1.2, 7.9 Hz, 1H), 7.27-7.21 (m, 5H), 7.19-7.15 (m, 1H), 7.09-7.06 (m,
ppm; HRMS calculated for [M+H]+ C21H14N4O: 339.1246 found: 2H), 6.48 (d, J = 15.4 Hz, 1H), 3.89 (s, 3H) ppm; 13C NMR (100 MHz,
352.1252.
CDCl3): δ 160.8, 158.6, 146.4, 138.7, 135.0. 134.5, 134.3, 132.4,
131.7, 131.5, 130.2, 130.0, 128.1, 127.6, 127.5, 127.1, 127.0, 126.4,
114.8, 55.6 ppm; HRMS calculated for [M]+ C23H16ClN3O2: 401.0925
4-(4-Chlorophenyl)-1-phenylimidazo[1,5-a]quinazolin-5(4H)-one
o
(3g): 3g was obtained as creamish white solid; M.p: 229-230 C; Rf = found: 401.0928.
0.4 (40% ethyl acetate/n-hexane); 1H NMR (500 MHz, CDCl3): δ 8.35
(d, J = 8.3 Hz, 1H), 7.62-7.57 (m, 4H), 7.56-7.51 (m, 3H), 7.44-7.38 4-(4-Methoxyphenyl)-1-(4-(trifluoromethyl)phenyl)imidazo[1,5-
(m, 4H), 7.26-7.23 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3):δ 158.4, a]quinazolin-5(4H)-one (3m): 3m was obtained as white solid; M.p:
142.4, 135.9, 135.0, 134.0, 132.8, 131.8, 131.5, 131.2, 130.2, 130.2, 178-179 oC; Rf = 0.4 (50% ethyl acetate/n-hexane); 1H NMR (500
129.9, 129.4, 129.1, 126.4, 117.6, 116.5 ppm; HRMS calculated for MHz, CDCl3): δ 8.43 (d, J = 7.0 Hz, 1H), 7.79 (s, 3H), 7.52-7.39 (m,
[M+H]+ C22H15ON3Cl: 372.0898 found: 372.0892.
4H), 7.31-7.28 (m, 2H), 7.10 (d, J = 8.0 Hz, 2H), 6.35 (s, 1H), 3.90 (s,
3H) ppm; 13C NMR (100 MHz, CDCl3): δ 160.0, 157.9, 138.4, 136.0,
135.4, 134.9, 133.8, 131.6, 130.5, 129.8, 128.9, 128.5, 126.2, 125.9
1-(2-Chlorophenyl)-4-(4-chlorophenyl)imidazo[1,5-a]quinazolin-
o
5(4H)-one (3h): 3h was obtained as white solid; M.p: 230-231 C; Rf (q, J = 3.7 Hz, 1C), 125.1 (q, J = 272.1 Hz, 1C), 118.3, 116.5, 115.3,
= 0.4 (40% ethyl acetate/n-hexane); 1H NMR (500 MHz, CDCl3): δ 110.4, 55.5 ppm; HRMS calculated for [M+H]+ C24H17F3N3O2:
8.37 (dd, J = 1.7, 7.6 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 8.7 436.1267 found: 436.1263.
Hz, 2H), 7.57-7.55 (m, 2H), 7.50-7.47 (m, 3H), 7.46-7.41 (m, 3H),
7.01 (d, J = 8.8 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 158.4, 4-(4-Methoxyphenyl)-1-p-tolylimidazo[1,5-a]quinazolin-5 (4H)-one
o
138.9, 135.9, 135.0,134.9, 132.8, 132.4, 131.8, 131.4, 130.9, 130.2, (3n): 3n was obtained as white solid; M.p: 221-222 C; Rf = 0.4 (40%
130.0,129.9, 127.7, 126.5, 117.3, 115.0 ppm; HRMS calculated for ethyl acetate/n-hexane); 1H NMR (500 MHz, CDCl3): δ 8.36 (d, J =
[M+H]+ C22H14ON3Cl 2: 406.0508 found: 406.0504.
7.2 Hz, 1H), 7.49 (d, J = 7.8 Hz, 2H),7.44-7.36 (m, 2H), 7.34-7.31 (m,
J. Name., 2013, 00, 1-3 | 5
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Method
Organic Chemistry Frontiers
4H), 7.28-7.26 (m, 2H), 7.10 (d, J = 8.7 Hz, 2H), 3.90 (s, 3H), 2.47 (s,
3H) ppm; 13C NMR (100 MHz, CDCl3): δ 160.7, 158.8, 142.4, 140.2, 1-(2-Chlorophenyl)-4-(p-tolyl)imidazo[1,5-a]quinazolin-5(4H)-one
o
135.1, 133.7, 131.7, 131.5, 130.2, 129.7, 129.4, 128.8, 127.0, 126.2, (3t): 3t was obtained as white solid; M.p: 252-253 C; Rf = 0.4 (40%
117.9, 116.5, 114.8, 55.6, 21.5 ppm; HRMS calculated for [M+H]+ ethyl acetate/n-hexane); 1H NMR (500 MHz, CDCl3): δ 8.39 (d, J =
C24H20N3O2: 382.1556 found: 382.1567.
8.8 Hz, 1H), 7.64 (d, J = 7.1 Hz, 1H), 7.58-7.52 (m, 2H), 7.50-7.27 (m,
8H), 7.02 (s, 1H), 2.47 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ
158.5, 140.0, 138.6, 135.0, 134.9, 134.3, 132.4, 131.7, 131.6, 131.5,
4-(3,4-Dichlorophenyl)-1-phenylimidazo[1,5-a]quinazolin-5(4H)-
o
one (3o): 3o was obtained as white solid; M.p: 222-223 C; Rf = 0.4 131.3, 130.3, 130.2, 130.0, 128, 127.7, 126.4, 117.6, 115 ppm;
(30% ethyl acetate/n-hexane); 1H NMR (500 MHz, CDCl3): δ 8.37- HRMS calculated for [M+H]+ C23H17ClN3O: 386.1054 found:
8.33 (s, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.65-7.55 (m, 4H), 7.56-7.52 (m, 386.1061.
2H), 7.46-7.39 (m, 2H), 7.32 (dd, J = 2.4, 8.4 Hz, 1H), 7.27-7.22 (m, 1,4-Di-p-tolylimidazo[1,5-a]quinazolin-5(4H)-one (3u): 3u was
2H) ppm; 13C NMR (100 MHz, CDCl3): δ 158.3, 145.0, 142.5, 135.0, obtained as white solid; M.p: 204-205 oC; Rf = 0.5 (30% ethyl
134.9, 134.4, 134.2, 133.7, 133.5, 132.5, 131.5, 131.2, 130.8, 130.3, acetate/n-hexane); 1H NMR (500 MHz, CDCl3): δ 8.39 (dd, J = 1.6,
130.2, 19.9, 129.5, 126.5, 117.4, 116.5 ppm; HRMS calculated for 7.6 Hz, 1H), 7.51 (d, J = 8.0 Hz, 2H), 7.46-7.40 (m, 2H), 7.39-7.35 (m,
[M+H]+ C22H14N3OCl2: 406.0508 found: 406.0507.
4H), 7.33 (d, J = 7.9Hz, 3H), 6.28 (s, 1H), 2.48 (s, 3H), 2.47 (s, 3H)
ppm; 13C NMR (100 MHz, CDCl3): δ 157.8, 140.1, 139.8, 139.3,
135.8, 134.0, 133.6, 130.6, 130.2, 129.7, 129.5, 127.6, 125.8, 118.1,
1-(2-Chlorophenyl)-4-(3,4-dichlorophenyl)imidazo[1,5-
a]quinazolin-5(4H)-one (3p): 3p was obtained as white solid; M.p: 116.6, 109.6, 21.5, 21.3 ppm; HRMS calculated for [M+H]+
205-206 oC; Rf = 0.5 (40% ethyl acetate/n-hexane); 1H NMR (500 C24H20N3O: 366.1606 found: 366.1600.
MHz, CDCl3): δ 8.37 (d, J = 6.6 Hz, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.63
(d, J = 6.9 Hz, 2H), 7.59-7.53 (m, 3H), 7.52-7.41 (m, 4H), 7.01 (d, J = 4-(p-Tolyl)-4-(trifluoromethyl)phenyl)imidazo[1,5-a]quinazolin-
o
7.3, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 158.2, 139.1, 139.0, 5(4H)-one (3v): 3v was obtained as white solid; M.p: 198-199 C; Rf
135.0, 134.9, 134.8, 134.4, 133.7, 133.4, 132.5, 132.3, 131.9, 131.3, = 0.5 (40% ethyl acetate/n-hexane); 1H NMR (500 MHz, CDCl3): δ
131.2, 130.6, 130.2, 130.1, 129.9, 127.7, 126.6, 117.1, 115.0 ppm; 8.43 (dd, J = 1.6, 7.7 Hz, 1H), 7.79 (s, 4H), 7.52-7.41 (m, 3H), 7.40-
HRMS calculated for [M+H]+ C22H13Cl3N3O: 440.0119 found: 7.35 (m, 3H), 7.30 (d, J = 7.3 Hz, 1H), 6.34 (s, 1H), 2.47 (s, 3H) ppm;
440.0116.
13C NMR (100 MHz, CDCl3): δ 157.7, 139.5, 138.3, 136.0, 135.4,
134.7, 133.8, 133.3, 132.1 (q, J = 33.0 Hz, 1C), 130.7, 130.5, 129.8,
127.5, 126.2, 125.9 (q, J = 3.3 Hz, 1C) 125.6 (q, J = 272.3 Hz, 1C)
4-(3,4-Dichlorophenyl)-1-(4-(trifluoromethyl)phenyl)imidazo[1,5-
a]quinazolin-5(4H)-one (3q): 3q was obtained as white solid; M.p: 118.3, 116.4, 110.4, 21.3 ppm; HRMS calculated for [M+H]+ C24H16
182-183 oC; Rf = 0.5 (40% ethyl acetate/n-hexane); 1H NMR (500 F3N3O: 420.1318 found: 420.1316.
MHz, CDCl3): δ 8.41 (dd, J = 1.4, 7.7 Hz, 1H), 7.80 (t, J = 8.8 Hz, 4H),
7.72-7.64 (m, 2H), 7.56-7.43 (m, 2H), 7.39 (dd, J = 2.5, 8.5Hz, 1H), 8-Chloro-1,4-diphenylimidazo[1,5-a]quinazolin-5(4H)-one (3w): 3w
7.32-7.27 (m, 1H), 6.40 (s, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ was obtained as white solid; M.p: 210-211 oC; Rf = 0.5 (40% ethyl
1
157.4, 138.8, 135.7, 135.4, 135.0, 134.3, 134.1, 134.0, 133.8, 131.8, acetate/n-hexane); H NMR (500MHz, CDCl3): δ 8.22 (d, J = 8.4 Hz,
131.6, 130.5, 130.2, 129.8, 127.4, 126.5, 126.0 (q, J = 2.7 Hz, 1C), 1H), 7.98 (d, J = 15.5 Hz, 1H), 7.79 (s, 1H), 7.62-7.54 (m, 3H), 7.41
124.8 (q, J = 272.4Hz, 1C), 117.8, 116.5, 110.3 ppm; HRMS (dd, J = 1.7, 8.4 Hz, 1H), 7.34-7.28 (m, 6H), 6.37 (d, J = 15.5Hz, 1H)
calculated for [M+H]+ C23H13Cl2F3N3O: 474.0387 found: 474.0393.
ppm; 13C NMR (100 MHz, CDCl3): δ 161.7, 152.9,148.8, 140.7, 136.7,
135.1, 130.0, 129.9, 129.5, 128.8, 128.6, 127.9,127.1, 126.8, 119.5,
119.3 ppm; HRMS calculated for [M+H]+ C22H15ON3Cl: 372.0898
4-(3,4-Dichlorophenyl)-1-p-tolylimidazo[1,5-a]quinazolin-5(4H)-
one (3r): 3r was obtained as white solid; M.p: 229-230 oC; Rf = 0.5 found: 372.0892.
1
(30% ethyl acetate/n-hexane); H NMR (500 MHz, CDCl3): δ 8.34 (d,
J =7.6 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H),7.57 (s, 1H), 7.48 (d, J =7.8, 8-Chloro-4-pheny-1-(4-(trifluoromethyl)phenyl)imidazo[1,5-
2H), 7.45-7.39 (m, 2H), 7.33 (d, J = 7.6 Hz, 3H), 7.31-7.27 (m, 2H), a]quinazolin-5(4H)-one (3x): 3x was obtained as white solid; M.p:
2.47 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 158.3, 142.7, 140.4, 220-221 oC; Rf = 0.5 (50% ethyl acetate/n-hexane); 1H NMR (400
135.1, 134.3, 134.2, 133.6, 133.5, 132.5, 131.2, 130.7, 130.2, 129.9, MHz, CDCl3): δ 8.23 (d, J = 8.5Hz, 1H), 7.98 (d, J = 15.5Hz, 1H), 7.81
129.8, 129.3, 128.5, 126.4, 117.4, 116.5, 21.5 ppm; HRMS (d, J = 1.9Hz, 1H), 7.63-7.55 (m, 4H), 7.44 (dd, J = 2.0, 8.5 Hz, 1H),
calculated for [M+H]+ C23H16Cl2N3O: 420.0664 found: 420.0672.
7.40 (d, J = 8.1Hz, 2H), 7.32 (dd, J = 1.9, 8.1 Hz, 2H), 6.43 (d, J =
15.5Hz , 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 161.6, 152.2, 148.5,
1-Phenyl-4-(p-tolyl)imidazo[1,5-a]quinazolin-5(4H)-one (3s): 3s 141, 138.8, 138.4, 136.4, 130.1, 129.7, 128.6, 128.5, 127.9, 126.9,
was obtained as white solid; M.p: 243-244 oC; Rf = 0.5 (40% ethyl 125.8, 125.8, 121.9, 119.4 ppm; HRMS calculated for [M+H]+
acetate/n-hexane); 1H NMR (500 MHz, CDCl3): δ 8.36 (dd, J = 1.3, C23H14ClF3N3O: 440.0772 found: 440.0791.
7.0 Hz, 1H), 7.62 (d, J = 6.4 Hz, 2H), 7.53 (t, J = 7.6 Hz, 3H), 7.43-7.37
(m, 3H), 7.30 (d, J = 8.0 Hz, 3H), 7.27-7.22 (m, 2H), 2.48 (s, 3H) ppm; 8-Fluoro-4-pheny-1-(4-(trifluoromethyl)phenyl)imidazo[1,5-
13C NMR (100 MHz, CDCl3): δ 158.6, 142.1, 135.0, 133.7, 131.7, a]quinazolin-5(4H)-one (3y): 3y was obtained as white solid; M.p:
131.6, 130.2, 130.1, 130.0, 129.5, 129.0, 126.2,117.9, 116.4, 21.4 202-203 oC; Rf = 0.45 (50% ethyl acetate/n-hexane); 1H NMR (500
ppm; HRMS calculated for [M+H]+ C22H13N3O: 352.1444 found: MHz, CDCl3): δ 8.42 (t, J = 8.3 Hz, 1H), 7.85-7.75 (m, 4H), 7.66-7.56
352.1445.
(m, 4H), 7.42 (d, J = 6.6 Hz, 2H), 7.15 (t, J = 8.4 Hz, 1H), 6.91 (d, J =
6 | J. Name., 2012, 00, 1-3
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Journal Name
ARTICLE
examples on SP3 C-H amination; (f) H. Wang, W. Xu, Z. Wang,
L. Yu and K. Xu, J. Am. Chem. Soc., 2012, 134, 7242; (g) A.
Ilangovan and G. Satish, Org. Lett., 2013, 15, 5726.
9.4 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 166.7 (d, J =256.1 Hz,
1C), 157.6, 140.6, 136.1, 136.0, 134.5, 134.0, 133.5, 133.4, 132.6,
130.4, 130.1, 129.9, 129.8, 126.2 (q, J =3.6 Hz, 1C), 114.8, 114.6,
104.2, 103.9 ppm; HRMS calculated for [M]+ C23H13F4N3O: 423.0989
found: 423.0998.
6
(a) Y. Z. Yan, Y. H. Zhang, Z. G. Zha and Z. Y. Wang, Org. Lett.,
2013, 15, 2274; (b) D. Zhao, T. Wang, Q. Shen and J. X. Li,
Chem. Commun., 2014, 50, 4302; (c) Q. Xue, J. Xie, H. Li, Y.
Cheng and C. Zhu, Chem. Commun., 2013, 49, 3700; (d) Q. J
iang, B. Xu, A. Zhao, J. Jia, T. Liu and C. Guo, J. Org. Chem.,
2014, 79, 8750; (e) J. T. Zhang, D. P. Zhu, C. M. Yu, C. F. Wan
and Z. Y. Wang, Org. Lett., 2010, 12, 2841; (f) M. Lamani, and
K. R. Prabhu, J. Org. Chem., 2011, 76, 7938; (g) T. Froehr, C.
P. Sindlinger, U. Kloeckner, P. Finkbeiner, and B. J.
Nachtsheim, Org. Lett., 2011, 13, 3754; (h) H. Batchu, S.
Bhattacharyya, and S. Batra, Org. Lett., 2012, 14, 6330; (i) Q.
Wang, C. F. Wan, Y. Gu, J. T. Zhang, L. F. Gao, and Z. Y. Wang,
Green Chem., 2011, 13, 578; (j) H. F. Jiang, H. W. Huang, H.
Cao, and C. R. Qi, Org. Lett., 2010, 12, 5561.
1,4-Diphenylbenzo[g]imidazo[1,5-a]quinazolin-5(4H)-one (3z): 3z
was obtained as white solid; M.p: 225-226 oC; Rf = 0.5 (50% ethyl
acetate/n-hexane); 1H NMR (500 MHz, CDCl3): δ 8.99 (s, 1H), 8.26 (s,
1H), 8.26 (s, 1H), 8.15-8.06 (m, 3H), 8.03 (d, J = 8.2 Hz, 1H), 7.65 (t, J
= 6.7 Hz, 2H), 7.58 (t, J = 7.4 Hz, 4H), 7.54-7.44 (m, 5H); 13C NMR
(100 MHz, CDCl3): δ 161.2, 145.3, 143.1, 137.6, 136.6, 132, 129.7,
129.4, 129, 128.9, 128.7, 128.1, 127.1, 126.7, 125.6 ppm; HRMS
calculated for [M+H]+ C26H18N3O: 388.1449 found: 388.1456.
7
For recent reviews, see: (a) V. V. Zhdankin and P. J. Stang,
Chem. Rev., 2008, 108, 5299; (b) T. Dohi and Y. Kita, Chem.
Commun., 2009, 2073; (c) Y. Yan, Y. Zhang, C. Feng, Z. Zha
and Z. Wang, Angew. Chem. Int. Ed., 2012, 51, 8077; (d) L.
Acknowledgements
We are thankful to DoP, the Ministry of Chemicals
&
Fertilizers, Govt. of India, New Delhi, for awarding the NIPER
fellowship. Dr. N. Shankaraiah gratefully acknowledges SERB,
DST, Govt. of India for the research grant (YSS-2015-001709).
Ma, X. Wang, W. Yu and B. Han, Chem. Commun., 2011, 47,
11333.
For recent reviews, see: (a) R. Vanjari and K. N. Singh, Chem.
Soc. Rev., 2015, 44, 8062; (b) A. Armstrong and J. C. Collins,
Angew. Chem., Int. Ed., 2010, 49, 2282; (c) D. Zhao, T. Wang
and J. X. Li, Chem. Commun., 2014, 50, 6471.
(a) H. J. Kim, J. Kim, S. H. Cho and S. Chang, J. Am. Chem.
Soc., 2011, 133, 16382; (b) Q. Xue, J. Xie, H. Li, Y. Cheng, and
C. Zhu, Chem. Commun., 2013, 49, 3700; (c) J. A. Souto, D.
Zian and K. Muniz, J. Am. Chem. Soc., 2012, 134, 7242.
8
9
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