A catalyst-free rapid, practical and general synthesis of 2-substituted quinazolin-4(3H)-ones leading to luotonin B and E, bouchardatine and 8-norrutaecarpine

Article abstract of DOI:10.1039/c5ra10928k

A remarkably rapid but microwave/ultrasound/catalyst-free method has been developed for the construction of a quinazolin-4(3H)-one ring using formamide as an efficient ammonia precursor and PEG-400 as an effective solvent. The methodology afforded various 2-substituted quinazolin-4(3H)-one derivatives in good yield via a three-component reaction of isatoic anhydride, aldehydes and formamide in air. This single methodology was extended successfully to the synthesis of several alkaloids e.g. leutonin B and E, bouchardatine and 8-norrutaecarpine.

Full text of DOI:10.1039/c5ra10928k

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Adv., 2015, DOI: 10.1039/C5RA10928K.
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Luotonin B
and
Luotonin E
O
N
O
R =
2-quinolinyl
NH2
CHO
O
NH
R =
2-indolyl
Bouchardatine
and
8-Norrutaecarpine
air
heat
N
H
O
R
+
RCHO
26 examples
74-91% yield
Formamide has been identified as an ammonia surrogate in the construction of quinazolin-
4(3H)-one ring leading to several alkaloids.

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DOI: 10.1039/C5RA10928K
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COMMUNICATION
A catalyst-free rapid, practical and general synthesis of 2-substituted
quinazolin-4(3H)-ones leading to Luotonin B and E, Bouchardatine and
8-Norrutaecarpine
K. Raghavendra Rao,a Ramamohan Mekala,a Akula Raghunadh,a Suresh Babu Meruva,a S. Praveen
5
Kumar,a Dipak Kalita,a Eppakayala Laxminarayana,b Bagineni Prasad,c and Manojit Palc,*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
A remarkably rapid but microwave / ultrasound / catalyst-
free method has been developed for the construction of
OH
OMe
O
O
10 quinazolin-4(3H)-one ring using formamide as an efficient
ammonia precursor and PEG-400 as an effective solvent. The
methodology afforded various 2-substituted quinazolin-
4(3H)-one derivatives in good yield via a three-component
reaction of isatoic anhydride, aldehydes and formamide
15 under open air. This single methodology was extended
successfully to the synthesis of several alkaloids e.g. Leutonin
B and E, Bouchardatine and 8-Norrutaecarpine.
N
N
N
N
N
N
A
Luotonin B ( )
Luotonin E (B)
O
N
O
O
NH
N
N
N
HN
Synthetic methodologies that allow a quicker and economical
access to known and bioactive natural products are of great
20 demand in modern organic synthesis as they can facilitate the
research in medicinal/pharmaceutical and natural products
chemistry.
H
D
8-Norrutaecarpine ( )
C
Bouchardatine ( )
50
Fig. 1. Quinazolinꢀ4(3H)ꢀone based alkaloids.
In spite of their remarkable pharmacological properties not
many methods have been reported for the synthesis of
Leutonin B1 and E,1dꢀg Bouchardatine2,3 and 8ꢀ
The pyrroloꢀquinazolinoquinoline alkaloids such as Luotonin
B, and E1 (A and B, Fig. 1) isolated from the aerial parts of a
25 Chinese medicinal plant (i.e. Peganum nigellastrum Bunge)
are used for the cure of several disease conditions like
rheumatism, inflammation, abscesses, hepatitis etc. The
quinazoline type alkaloid Bouchardatine2,3 (C, Fig. 1) is from
the rutaecarpine family whereas 8ꢀNorrutaecarpine3 (D, Fig.
30 1), a hybrid of rutaecarpine and luotonin A, contains the
indoloꢀpyrroloquinazolinone ring. These quinazolinꢀ4(3H)ꢀ
one based alkaloids attracted our attention not only due to
their promising pharmacological properties but also their
intriguing chemical structures. Moreover, as part of our
35 ongoing medicinal chemistry related programs we required a
robust and continuous supply of these alkaloids and their
analogues for the inꢀhouse pharmacological screening.
55 Norrutaecarpine.3 While efforts have been devoted to
establish various synthetic routes towards Leutonin B and E,
only few are known for the remaining two alkaloids.
Moreover, though several of these methods are elegant and
interesting some of them are either not convenient or suitable
60 for the quicker access to A-D (Fig. 1) due to the involvement
of relatively longer synthetic routes and low overall yields.
Notably, oꢀamino benzamide has been used as a key starting
material in some of these syntheses that afforded the
appropriate quinazolinꢀ4(3H)ꢀone intermediate for further
65 reactions.1d,e,g,3 This prompted us to design and explore a
common and shorter route to A-D (Fig. 1) via constructing the
required quinazolinꢀ4(3H)ꢀone ring in
a straightforward
manner followed by subsequent cyclization / other reactions
(Scheme 1). Accordingly, we now report shorter syntheses of
70 AꢀD via a new strategy involving the direct construction of
quinazolinꢀ4(3H)ꢀone ring using isatoic anhydride (1),
appropriate aldehydes (2) and formamide as an ammonia
surrogate. While the use of a general strategy like this towards
the synthesis of all these alkaloids has not been reported
75 earlier, the strategy of constructing quinazolinꢀ4(3H)ꢀone ring
using formamide as an ammonia surrogate is also not common
in the literature.
ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ
aTechnology Development Centre, Custom Pharmaceutical Services, Dr.
40 Reddy’s Laboratories Ltd, Miyapur, Hyderabad, 500 049, India
bDepartment of Physics and Chemistry, Mahatma Gandhi Institute of
Technology, Chaitanya Bharati, Gandipet, Hyderabad, 500 075 , India.
cDr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus,
Gachibowli, Hyderabad 500 046, India
45 E-mail: manojitpal@rediffmail.com; Tel: +91 40 6657 1500
†Electronic Supplementary Information (ESI) available: Experimental
procedures, spectral data for all new compounds, and copies of spectra.
For ESI see DOI: 10.1039/b000000x/
This journal is © The Royal Society of Chemistry [year]
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Luotonin B
and E
Table 1). We were delighted with this catalystꢀfree rapid
55 synthesis of 3a without using any microwave or ultrasound
irradiation. To reduce the reaction time further the reaction
was performed in neat under microwave irradiation (entry 10,
Table 1). However the yield of 3a was decreased (entry 9 vs
10, Table 1) due to the formation of an unknown side product.
60 Since (i) the reaction rate was enhanced significantly in PEG
and (ii) being an inexpensive, nontoxic and high boiling
solvent, PEG has several advantages over other commonly
used organic solvents, hence the reaction condition of entry 9
of Table 1 was used for further studies.
O
N
O
R =
2-quinolinyl
RCHO
2
NH
O
R
N
H
O
R =
2-indolyl
Bouchardatine
and
8-Norrutaecarpine
HCONH2
3
1
Scheme 1. Anticipated route to alkaloids AꢀD via construction of
quinazolinꢀ4(3H)ꢀone ring
Various approaches have been reported for the synthesis of
quinazolinꢀ4(3H)ꢀones over the past few years,4ꢀ8 the popular
one being the reaction of anthranilamides with an aldehyde or
orthoester in the presence of various promoting agents, such
as NaHSO3,9 pꢀtolueneꢀsulfonic acids / DDQ,10 I2,11 CuCl2
(3.0 equiv),12 FeCl3 (2.0 equiv),13 and Yb(OTf)3.14 On other
5
65 Table 1. Effect of conditions on the reaction of 1, 2a and formamide.a
O
O
NH2CHO
NH
Ph
10 hand, oneꢀpot threeꢀcomponent reactions of isatoic anhydride
/ anthranilic acid, orthoesters / aldehydes and amines /
ammonium acetates in the presence of various catalysts
leading to quinazolinꢀ4(3H)ꢀones have been reported.15ꢀ20
These catalysts include NafionꢀH,15 (αꢀFe2O3)ꢀMCMꢀ41ꢀlꢀ
O
PhCHO
Solvent
Temp
N
N
O
H
2a
3a
1
Entry
Solvent
Temp (ºC) Time (h)
Yieldb (%)
15 prolinium nitrate,16
I2,17 gallium trifluoroꢀmethaneꢀ
1
2
65
MeOH
EtOH
48ꢀ50
Trace
22c
56
sulfonate,18 ceric ammonium nitrate,19 100 U laccase from
trametes versicolor,20a ultrasound based copper oxide20b etc.
However, the use of expensive or complex metal or nonꢀmetal
catalysts and longer reaction times are the major drawbacks of
20 many of these methods. Moreover, some of the catalysts used
are not easily accessible. Thus, development of an
operationally simple, straightforward, and catalystꢀfree
method was expected to be highly advantageous. Recently, we
80
48ꢀ50
3
115
nꢀBuOH
CHCl3
8ꢀ10
4
60
48ꢀ50
ꢀꢀ
Toluene
20ꢀ22
53c
65c
32c
25c
91
5
110
6
105
1,4ꢀDioxane
2ꢀ Propanol
2ꢀMeꢀTHF
PEGꢀ400
Neatd
20ꢀ24
7
85
20ꢀ24
8
85
20ꢀ22
have demonstrated21a
a catalystꢀfree synthesis of 2,3ꢀ
9
120ꢀ125
35 min
25 dihydroquinazolinꢀ4(1H)ꢀones21b,c and quinazolinꢀ4(3H)ꢀones
via the reaction of isatoic anhydride, aldehyde, and urea as a
ammonia surrogate in EtOH under open air conditions.22
However, the method lacked in selectivity of product
formation. We therefore decided to explore formamide as an
30 ammonia surrogate in the selective synthesis of quinazolinꢀ
4(3H)ꢀones. Indeed, the earlier reports disclosing formamide
as a source of ammonia in the synthesis of primary amides23
prompted us to perform our study.
10
120
15ꢀ20 min
68
aReaction was performed by using a mixture of 1 (1.0 equiv), 2a (1.0
equiv) and formamide (1.0 equiv) in a solvent (4 mL) under open air.
bIsolated yield. cNo complete conversion of starting material observed.
70 dThe reaction was performed under microwave (300 W).
To check the generality of the present catalystꢀfree
environmental friendly reaction a range of aliphatic, aryl and
heteroaryl aldehydes were reacted with 1 under the optimized
conditions (Table 2). The aliphatic aldehydes may contain
Several reactions were performed using isatoic anhydride (1),
35 benzaldehyde (2a) and formamide as model substrates under 75 groups like alkyl, cycloalkyl, alkylaryl etc (entries 7, 16, 17,
various conditions to establish the optimal reaction conditions
(Table 1). Initially, the reaction was performed in MeOH at 65
°C when trace of desired product 3a was formed (entry 1,
Table 1). Change of solvent to higher boiling EtOH or nꢀ
21 and 23, Table 2) whereas the aromatic aldehydes may
contain various substituents like hydroxy, alkoxy, amine,
halogens, phenyl, cyano, benzyloxy, etc on the aromatic ring
(entries 2ꢀ6, 8, 9, 11ꢀ13, 15 and 18, Table 2). The aromatic
40 BuOH improved the product yield (entries 2 and 3, Table 1). 80 aldehyde may be a simple benzaldehyde or αꢀnaphthyl
Though the reaction did not proceed in chloroform (entry 4,
Table 1), 3a was isolated in 53 and 65% yield when toluene
(entry 5, Table 1) and 1,4 dioxane (entry 6, Table1) was used.
The use of other relatively low boiling solvents such as 2ꢀ
aldehyde (entry 1 and 14, Table 2). The heteroaryl ring of
heteroaryl aldehydes may be furan, pyrrole, pyridine,
thiophene, quinoline and indole (entries 10, 19, 20, 22, 24 and
25, Table 1). The reaction proceeded well in all these cases
45 propanol and 2ꢀMeꢀTHF afforded 3a in poor yield (entries 7 85 affording the desired quinazolinꢀ4(3H)ꢀones (3) in good to
and 8, Table 1). Notably, the duration of reaction was 8ꢀ50 h
in all these cases. We then examined the use of a further high
boiling solvent such as PEGꢀ400 and to our surprise the
reaction reached to completion within 35 min affording the
excellent yields within short reaction time. Notably, the
reaction afforded quinazolinꢀ4(3H)ꢀone (3z) when performed
in the absence of an aldehyde for 90 min (entry 26, Table 2).
All these observations clearly highlight the utility and
50 high yield of 3a (entry 9, Table 1). This observation clearly 90 robustness of formamide as an ammonia surrogate in the
indicated that not only a polar protic solvent but elevated
reaction temperature was necessary for the present reaction to
proceed successfully in the forward direction (entries 1ꢀ3 vs 9,
present catalystꢀfree and efficient synthesis of quinazolinꢀ
4(3H)ꢀones.
2
|
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Table 2. Catalystꢀfree rapid synthesis of 2ꢀsubstituted quinazolinꢀ4(3H)ꢀ
one derivatives (3).a
The Scheme 2 represents a plausible mechanism for the
present 3ꢀcomponent reaction leading to the compound 3. The
10 generation of intermediate E-1 appeared to be the initial step
of this reaction.24a Subsequent tautomerization of E-1 to the
enol E-2 was facilitated by the intramolecular Hꢀbonding in a
six membered cyclic form. The amino group of E-2 then
reacts with the aldehyde24b 2 to give the imine E-3 which on
15 intramolecular cyclization afforded the intermediate E-4. The
cleavage of –NꢀC(=O)ꢀ bond aided by H2O (formed during the
conversion of E-2 to E-3) at elevated temperature afforded E-
5. The ability of PEG to form Hꢀbond with water is known in
the literature and that its Hꢀbond acceptor ability is similar to
20 MeOH (though its Hꢀbond donor ability is less than
MeOH).24c Thus, the nucleophilicity of water molecule was
greatly enhanced by the presence of PEGꢀ400 via formation of
Hꢀbond between the oxygen atom of PEG and hydrogen atom
of H2O. Next, the oxidation of E-5 in the presence of air
25 afforded 3. To gain further evidence on the intermediacy of E-
5 the MCR (multicomponent reaction) of 1, 2a and formamide
was performed under inert atmosphere (in the absence of air)
in PEGꢀ400 at 120ꢀ125 ºC for 10 min (cf entry 9, Table 1).
The isolation of 2ꢀphenylꢀ2,3ꢀdihydroquinazolinꢀ4(1H)ꢀone
30 (4a), in addition to 3a as a major product (4a : 3a ~ 7:3)
clearly indicated the intermediacy of E-5 in the present
reaction. Moreover, 4a was converted to 3a when the reaction
was allowed to proceed for additional 25 min. This also
suggested that formation of E-5 is relatively a faster process
35 whereas its oxidation to 3 is a slower one. Notably, the
oxidative aromatization of 2,3ꢀdihydroquinazolinꢀ4(3H)ꢀones
to the corresponding quinazolinꢀ4(3H)ꢀone analogues is a
known process9,12,25 and PEGꢀ400 has been used as an
effective solvent in several aerobic oxidation reactions.24c
40 Overall, the role of PEG in the (i) deformylation step of E-4
and (ii) aerobic oxidation of E-5 at an elevated reaction
temperature was the possible reason for the observed
remarkable rate enhancement of the present catalyst free MCR
in PEGꢀ400.24d,26
O
O
NH2CHO
O
NH
RCHO
+
PEG-400
120-125°C
N
H
O
N
R
1
2
3
Aldehyde (2);
Time
(min)
Product
(3)
Yieldb
(%)
Entry
R =
1
2a; Ph
35
43
30
42
45
56
18
40
42
55
27
50
47
32
40
15
20
32
60
55
20
46
55
45
32
90
3a
3b
3c
3d
3e
3f
91
84
87
85
92
81
88
83
89
74
84
81
87
88
79
93
92
85
76
85
91
78
76
74
80
81
2
2b; C6H4OHꢀp
2c; C6H4OMeꢀp
2d; C6H4NMe2ꢀp
2e; C6H4Fꢀp
3
4
5
6
2f; C6H4Phꢀp
2g; nꢀPentyl
7
3g
3h
3i
8
2h; C6H4Clꢀp
2i; C6H3Me2ꢀo,p
2j; Furyl
2k; C6H4Butꢀp
2l; C6H4CNꢀp
2m; C6H4OBnꢀm
2n; αꢀNapthyl
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
2o; C6H2(OMe)2m,OMeꢀp
2p; Ethyl
2q; Cyclohexyl
2r; C6H4Meꢀm
2s; 2ꢀPyrrolyl
2t; 4ꢀPyridinyl
2u; iꢀButyl
3t
3u
3v
3w
3x
3y
2v; 2 Thienyl
ꢀ
2w; PhCH2CH2
2x; 2ꢀQuinolinyl
2y; 2ꢀIndolyl
45 Having developed
a catalyst free rapid synthesis of
quinazolinꢀ4(3H)ꢀones we then applied this methodology for
the synthesis of our target natural products i.e. Luotonin B
and E (Scheme 3), and then Bouchardatine and 8ꢀ
No aldehyde
3z (R = H)
Norrutaecarpine (Scheme 4). Thus, the compound 3x obtained
50 via the reaction of isatoic anhydride (1), quinolineꢀ2ꢀ
carbaldehyde (2x) and formamide in PEGꢀ400 at 120ꢀ125 °C
for 45 min under open air (entry 24, Table 2) was treated with
mesityllithium at ꢀ80 to ꢀ78 °C followed by DMF at ꢀ30 °C to
afford the Luotonin B (A) in 71% yield.1d Luotonin E (B) was
55 then prepared by treating Luotonin B with pꢀTSA in methanol
at refluxing temperature for 3 h.1d Notably, the alkaloid A can
also be transformed into Luotonin A via mesylation of the
hydroxyl group of A followed by removal ot the resulting –
OMs group in the presence of Pd/C.27
60 Similarly, the compound 3y prepared via the reaction of
isatoic anhydride (1) with 1Hꢀindoleꢀ2ꢀcarbaldehyde (2y) and
formamide in PEGꢀ400 at 120ꢀ125 °C (entry 24, Table 2) was
allowed to undergo VilsmeierꢀHaak reaction3 to provide
Bouchardatine in 84% yield. Reduction of Bouchardatine with
65 NaBH4 followed by acid mediated dehydration produced 8ꢀ
aReaction was performed by using 1 (1.0 equiv), 2 (1.0 equiv) and
5
formamide (1.0 equiv) in PEGꢀ400 (4 mL) under open air. bIsolated yield.
H
O
O
O
O
O
RCHO
( )
2
N
H
O
H2N
H
N
H
H
1
NH2
E-1
NH2
H2O
E-2
CO2
HO(CH2CH2O)nH
H
O
O
O
R
O
H
O
H
NH
N
H
N
N
H
N
H
R
N
H
R
E-5
E-4
E-3
HCO2H
air
[O]
3
Scheme 2. The proposed reaction mechanism for the formation of 3.
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and 13C NMR respectively that were compared with the
25 corresponding NMR values (i.e. δ 10.48 and 187.5 ppm)
reported for Bouchardatine.3 The CH2 moiety of D appeared
OH
O
1. Mesityllithium,
-80 to -78 °C
N
3x
1
at δ 5.03 and 57.0 ppm in H and 13C NMR respectively were
2. DMF -30°C ,
aqNH4Cl (sat)
71%
N
N
compared with corresponding NMR values (i.e. δ 5.12 and
47.5 ppm) reported for 8ꢀNorrutaecarpine.3
A
Luotonin B (
)
30 In conclusion, we have identified formamide as an efficient
ammonia surrogate and PEGꢀ400 as an effective solvent in the
rapid construction of quinazolinꢀ4(3H)ꢀone ring for the first
time. This strategy accomplished a practical and catalystꢀfree
synthesis of various 2ꢀsubstituted quinazolinꢀ4(3H)ꢀone
OMe
O
p-TSA
(5 equiv)
MeOH
N
N
N
reflux, 3h,
64%
Luotonin E (B)
35 derivatives via
a
threeꢀcomponent reaction of isatoic
Scheme 3. Synthesis of Luotonin B (A) and Luotonin E (B) from
quinazolinꢀ4(3H)ꢀone 3x.
anhydride, aldehydes and formamide under open air. The
notable advantages of this protocol include (i) simple
operational procedure, (ii) shorter reaction time (iii) free from
the use of microwave or ultrasound irradiation and (iv) good
40 yields of products. This single methodology was extended
successfully to the synthesis of several alkaloids e.g. Leutonin
B and E, Bouchardatine and 8ꢀNorrutaecarpine highlighting
its immense utility in organic synthesis. Overall, this
methodology is amenable not only for the generation of
45 library of small molecules based on quinazolinꢀ4(3H)ꢀone
framework but also for the synthesis of bioactive alkaloid
natural products and their analogues.
O
O
NH
DMF/POCl3
3y
N
0-5°C
HN
84%
Bouchardatine (C)
O
NaBH4/MeOH
N
30%H2SO4,
N
EtOH, reflux,1h
52%
N
K. R. Rao thanks Dr. H. Ramamohan for his encouragement
and Department of Chemistry, JNTU, Hyderabad, India for
50 support. Authors thank Analytical Department of DRL,
Hyderabad, India for spectra.
H
D
)
8-Norrutaecarpine (
5
Scheme 4. Synthesis of Bouchardatine (C) and 8ꢀNorrutaecarpine (D)
from 3y.
Norrutaecarpine in 52% yield.3
Notes and references
All the natural products synthesized e.g. alkaloids A-D were
characterized by spectral data and compared with that
10 reported earlier (see Table Sꢀ2 in the ESI). The selected 1H
and 13C NMR signals of synthesized alkaloids A-D are shown
1. (a) T. Harayama, Y. Morikami, Y. Shigeta, H. Abe, and Y.
Takeuchi, Synlett 2003, 847. (b) Z. Ma, Y. Hano, T. Nomura,
55
60
65
70
75
80
85
and Y. Chen, Biorg. Med. Chem. Lett. 2004, 14, 1193. (c) M.
C. Tseng, Y. W. Chu, H. P. Tsai, C. M. Lin, J. Hwang, and Y.
H. Chu, Org. Lett. 2011, 13, 920. (d) S. B. Mhaske, and N. P.
Argade, J. Org. Chem. 2004, 69, 4563. (e) S. P. Chavan, and
R. Sivappa, Tetrahedron 2004, 60, 9931. (f) M. B. Wagh, R.
Shankar, U. K. S. Kumar, and C. H. Gill, Synlett 2011, 84. (g)
L. Nagarapu, and H. K. Gaikwad, and R. Bantu Synlett 2012,
23, 1775.
1
in Fig.2. Thus, the H and 13C NMR signal appeared at δ 6.97
and 80.4 ppm in the respective spectra of A due to the –
CH(OH)ꢀ moiety was correlated to that reported (i.e. δ 6.98
15 and 80.5 ppm) for Luotonin B.1f Similarly, B showed 1H
signals at δ 6.95 (CH) and 3.61 (OMe) due to the ꢀCH(OMe)ꢀ
group and 13C signals at δ 87.0 (CH) and 56.3 (OMe) ppm for
the same group that were correlated with the reported values
2. (a) N. H. Naik, T. D. Urmode, A. K. Sikder, and R. S.
Kusurkar, Aust. J. Chem. 2013, 66, 1112; (b) M. Vili and R.
Nagarajan, J. Chem. Sci 2014, 126, 1075.
3. M. Bubenyák, M. Pálfi, M. Takács, S. Béni, É. Szöko, B.
Noszál, J. Kökösi, Tetrehedron Lett. 2008, 49, 4937.
4. C. L. Yoo, J. C. Fettinger, M. J. Kurth, J. Org. Chem. 2005,
70, 6941.
1
i.e. δ 6.9 (CH) and 3.6 (OMe) in H and δ 87.0 (CH) and 56.3
20 (OMe) ppm in 13C NMR of Luotonin B.1f The aldehyde (ꢀ
1
CHO) group of C appeared at δ 10.48 and 187.5 ppm in H
δ
6.97 (d, J = 8.2 Hz, 1H)
6.95 (s, 1H)
3.61 (s, 3H)
MeO
5. A. Kamal, K. S. Reddy, B. R. Prasad, A. H. Babu, and A. V.
H
87.0
Ramana, Tetrahedron Lett. 2004 45, 6517.
6. F. R. Alexandre, A. Berecibar, R. Wrigglesworth, and T.
Besson, Tetrahedron 2003, 59, 1413.
7. M. Shimizu, A. Oishi, Y. Taguchi, Y. Gama, I. Shibuya,
Chem. Pharm. Bull. 2002, 50, 426.
8. A. A. Shalaby, A. M. A. EiꢀKhamry, S. A. Shiba, and A. A. A.
E. Ahmed, Arch. Pharm. Pharm. Med. Chem. 2000, 333, 365.
9. S. E. Lopez, M. E. Rosales, N. Urdaneta, M. V. Godoy, J. E.
Charris, J. Chem. Res., Synop. 2000, 6, 258.
10. J. J. Naleway, C. M. J. Fox, D. Robinhold, E. Terpetsching, N.
A. Olsen, and R. P. Haugland, Tetrahedron Lett. 1994, 35,
8569.
11. B. A. Bhat, and D. P. Sahu, Synth. Commun. 2004, 34, 2169.
12. R. J. AbdelꢀJalil, W. Voelterb, and M. Saeed, Tetrahedron
Lett. 2004, 45, 3475.
,
H
HO
N
O
80.4
56.3
O
N
N
N
N
N
A
Luotonin B (
)
Luotonin E (B)
5.03 (s, 2H)
10.48 (s, 1H)
O
O
H
H
O
H
57.0
NH
N
187.5
N
N
N
H
HN
D
8-Norrutaecarpine ( )
Bouchardatine (C)
Fig. 2. Selected 1H and 13C NMR signals of synthesized alkaloids A-D
4
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DOI: 10.1039/C5RA10928K
13. G. Wang, C. Miao, and H. Kang, Bull. Chem. Soc. Jpn. 2006,
recovered from the reaction of entry 9 of Table 1 (with the
recovery of ~ 68%, see ESI for solvent recovery) and reused.
After the first recycle of solvent it was recovered once again
(with the recovery of ~ 65%) and reused. The desired product
3a was isolated in 84% and 81% yield after the first and
second recycles of the solvent, respectively compared to 91%
yield after its first use, entry 9 of Table 1.
79, 1426.
14. L. Wang, J. Xia, F. Qin, C. Qian, and J. Sun, Synthesis 2003,
1241.
15. B. V. Lingaiaha, G. Ezikiela, T. Yakaiaha, G. V. Reddy, and
P. S. Rao, Synlett 2006, 2507.
16. S. Rostamizadeh, M. Nojavan, R. Aryan, E. Isapoor, and M.
Azad, J. Mol. Catal. A – Chemical, 2013, 374-375, 102.
17. LiꢀY. Zeng, and C. Cai, J. Heterocycl. Chem. 2010, 47, 1035.
18. J. Chen, D. Wu, F. He, M. Liu, H. Wu, J. Ding, and W. Su,
Tetrahedron Lett. 2008, 49, 3814.
19. M. Baghbanzadeh, M. Dabiri, and P. Salehi, Heterocycles
2008, 75, 2809.
20. (a) M. Heidary, M. Khoobi, S. Ghasemi, Z. Habibi, and M. A.
Faramarzi, Adv. Synth. Catal. 2014, 356, 1789; (b) J. Zhang,
D. Ren, Y. Ma, W. Wang, and H. Wu, Tetrahedron 2014, 70,
5274.
75
80
85
5
10
15
20
25
30
35
40
45
50
55
60
65
70
27. M. B. Wagh, R. Shankar, and U. K. S. Kumar, Synlett 2011,
84.
21. (a) P. P. Naidu, A. Raghunadh, K. R. Rao, R. Mekala, J. M.
Babu, S. Rao and M. Pal, Synth. Commun. 2014, 44, 1475. For
our earlier synthesis of 2,3ꢀdihydroquinazolinꢀ4(1H)ꢀone
derivatives, see: (a) D. Rambabu, S. K. Kumar, B. Y.
Sreenivas, S. Sandra, A. Kandale, P. Misra, M. V. B. Rao, and
M. Pal, Tertahedron Lett. 2013, 54, 495; (b) P. V. S. Murthy,
D. Rambabu, G. R. Krishna, C. M. Reddy, K. S. R. Prasad, M.
V. B. Rao, and M. Pal, Tertahedron Lett. 2012, 53, 863.
22. For our earlier reports on the reaction of isatoic anhydride,
aldehyde, and amine, see: (a) K. S. Kumar, P. M. Kumar, K.
A. Kumar, M. Sreenivasulu, A. A. Jafar, D. Rambabu, G. R.
Krishna, C. M. Reddy, R. Kapavarapu, K. S. Kumar, K. K.
Priya, K. V. L. Parsa and M. Pal Chem. Commun. 2011, 47,
5010; (b) K. S. Kumar, P. M. Kumar, M. A. Reddy, M.
Ferozuddin, M. Sreenivasulu, A. A. Jafar, G. R. Krishna, C.
Malla Reddy, D. Rambabu, K. S. Kumar, S.Pal, and M. Pal,
Chem. Commun., 2011, 47, 10263; (c) K. S. Kumar, P. M.
Kumar, V. S. Rao, A. A. Jafar, C. L. T. Meda, R. Kapavarapu,
K. V. L. Parsa, and M. Pal, Org. Biomol. Chem. 2012, 10,
3098; (d) R. Adepu,B. Prasad,M. A. Ashfaq,N. Z. Ehtesham
and M. Pal, RSCAdv. 2014, 4, 49324; (e) G. R. Rao; T. R.
Reddy, R. G. Chary, S. C. Joseph, S. Mukherjee, and M. Pal,
Tetrahedron Lett. 2013, 54, 6744; (f) K. R. Rao, A.
Raghunadh, ,R. Mekala, S. B. Meruva, T. V. Pratap, T.
Krishna, D. Kalita, E. Laxminarayana, B. Prasad, and M. Pal,
Tetrahedron Lett. 2014, 55, 6004; (g) For a threeꢀcomponent
reactions of isatoic anhydride, aldehyde (in the form of a
cyclic acetal) and amine leading to polycyclic compounds, see:
S. Sun, C. Cheng, J. Yang, A. Taheri, D. Jiang, B. Zhang, and
Y. Gu, Org. Lett., 2014, 16, 4520.
23. (a) A. Schnyder, M. Beller, G. Mehltretter, T. Nsenda, M.
Studer, and A. F. Indolese, J. Org. Chem. 2001, 66, 4311. (b)
S. Srinivasan, and P. Manisankar, Synth. Commun. 2010, 40,
3538.
24. (a) Our attempt to isolate the intermediate E-1 was not
successful even after several trials. The isatoic anhydride (1)
remained unchanged when it was reacted with the formamide
(in the absence of aldehyde 2) at a temperature below 50 ºC.
Though, a blue colored spot (different from the product 3z)
was detected in TLC when the reaction was performed at 60
ºC for 40 min we failed to isolate it due to its unstable nature.
Prolonging the reaction time further led to the formation of 3z.
(b) In the absence of aldehyde (2) the intermediate E-2 (or its
tautomeric form E-1) undergoes intramolecular cyclization
involving the Nꢀformyl and –NH2 groups to give the
unsubstituted quinazolinꢀ4(3H)ꢀone (3z); (c) For a scholarly
review, see: J. Chen, S. K. Spear, J. G. Huddleston and R. D.
Rogers, Green. Chem. 2005, 7, 64; (d) For a review on MCR
in unconventional solvents including PEG, see: Y. Gu, Green
Chem. 2012, 14, 2091.
25. V. B. Rao, P. Hanumanthu, and C. V. Ratnam, Indian J.
Chem., Sect. B 1979, 18, 493.
26. We also examined the recovery and reuse of solvent PEGꢀ400
used in the present reaction. Accordingly, the PEGꢀ400 was
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