Glyoxylic acid in the reaction of isatoic anhydride with amines: A rapid synthesis of 3-(un)substituted quinazolin-4(3H)-ones leading to rutaecarpine and evodiamine

Article abstract of DOI:10.1016/j.tetlet.2014.09.011

A dual reactant/catalyst role of glyoxylic acid in the reaction of isatoic anhydride with various amines afforded a novel, robust and rapid synthesis of 3-(un)substituted quinazolin-4(3H)-ones. This metal catalyst-free reaction proceeds via an unusual and unexpected cleavage of C-C bond. A shorter and common route to two alkaloids, that is, rutaecarpine and evodiamine is also accomplished.

Full text of DOI:10.1016/j.tetlet.2014.09.011

Tetrahedron Letters xxx (2014) xxx–xxx
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Tetrahedron Letters
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Glyoxylic acid in the reaction of isatoic anhydride with amines: a
rapid synthesis of 3-(un)substituted quinazolin-4(3H)-ones leading
to rutaecarpine and evodiamine
K. Raghavendra Rao a, Akula Raghunadh a, Ramamohan Mekala a, Suresh Babu Meruva a, T. V. Pratap a,
T. Krishna a, Dipak Kalita a, Eppakayala Laxminarayana b, Bagineni Prasad c, Manojit Pal c,
⇑
a Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Limited, Bollaram Road Miyapur, Hyderabad 500 049, India
b Sreenidhi Institute of Science and Technology (Autonomous), Yamnampet, Ghatkesar, Hyderabad 501 301, India
c Dr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A dual reactant/catalyst role of glyoxylic acid in the reaction of isatoic anhydride with various amines
afforded a novel, robust and rapid synthesis of 3-(un)substituted quinazolin-4(3H)-ones. This metal
catalyst-free reaction proceeds via an unusual and unexpected cleavage of C–C bond. A shorter and
common route to two alkaloids, that is, rutaecarpine and evodiamine is also accomplished.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 31 July 2014
Revised 2 September 2014
Accepted 3 September 2014
Available online xxxx
Keywords:
Glyoxylic acid
Isatoic anhydride
Amine
Rutaecarpine
Evodiamine
Development of shorter routes to the known and bioactive nat-
ural products via newly established methodologies is of high
demand in modern organic synthesis. Indeed, these strategies
allow quicker and economical access to these compounds for
medicinal and other uses.
Since the isolation of these alkaloids, a number of methods have
been reported for the synthesis of rutaecarpine1b,4 and evodi-
amine.5 While many of these methods are elegant and interesting
several of them however, are either not convenient or not suitable
for scale-up preparation due to the involvement of relatively
longer synthetic routes and low overall yields. Notably, tryptamine
has been used as a key starting material in some of these synthe-
ses. Accordingly, we wondered if a new, shorter and common route
to both A and B starting from common reactants, that is, isatoic
anhydride (1) and tryptamine (2a) can be developed (Scheme 1).
Indeed, the synthesis of A and B via a common intermediate is
not known in the literature.
Rutaecarpine1a (A, Fig. 1), an indolopyridoquinazolinone alka-
loid isolated from Evodia rutaecarpa and related herbs has shown
a range of pharmacological properties including anti-thrombotic,
anticancer, anti-inflammatory and anti-obesity activities.1b,c Evodi-
amine (B, Fig. 1) on the other hand belongs to quinazolin-carboline
alkaloid isolated from the fruit of Evodia rutaecarpa and possesses
diverse pharmacological properties such as resisting tumour, anti-
nociception, weight losing, protecting heart and reducing blood
pressure etc.2 Both these alkaloids attracted our attention due to
their promising anti-cancer properties. Indeed, evodiamine has
shown strong cytotoxic effects against human cancer cells in addi-
tion to apoptosis induction, suppression of invasion and metasta-
sis. In continuation of our efforts on identification of novel
inducers of apoptosis3 we required robust and continuous supply
of these two alkaloids for our in-house pharmacological screen.
Our proposed strategy was mainly based on the elegant con-
struction of 3-substituted quinazolin-4(3H)-one ring as a key step
O
O
N
N
N
N
HN
HN
B
A
⇑
Corresponding author. Tel.: +91 40 6657 1500; fax: +91 40 6657 1581.
E-mail address: manojitpal@rediffmail.com (M. Pal).
Figure 1. Rutaecarpine (A) and ( )-evodiamine (B).
http://dx.doi.org/10.1016/j.tetlet.2014.09.011
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Rao, K. R.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.09.011

2
K.R. Rao et al. / Tetrahedron Letters xxx (2014) xxx–xxx
O
(entries 1–3, Table 1). The reaction was almost suppressed in chlo-
not
successful
earlier
roform (entry 4, Table 1) but proceeded well in toluene (entry 5,
Table 1). In all these cases the duration of the reaction was 8–
50 h. We then examined the use of PEG-400 and to our surprise
the reaction reached to completion within 12 min affording the
high yield of 3b (entry 6, Table 1). The reaction time was margin-
ally reduced to 10 min when the reaction was performed under
neat microwave irradiation (entry 7, Table 1). However the yield
of 3b was decreased (entry 6 vs 7, Table 1) due to the formation
of an unknown side product. Being an inexpensive, polar, nontoxic
and high boiling solvent, PEG has several advantages over other
commonly used organic solvents. We therefore used the reaction
condition of entry 6 in Table 1 for further studies.
A range of aliphatic and aromatic amines as well as ammonia
were reacted with 1 under optimized conditions (Table 2). The ali-
phatic amines may contain groups like alkyl, cycloalkyl, alkylaryl
etc., (entries 1–3 and 5–12, Table 2) whereas the aromatic amines
may contain various substituents like alkyl, haloalkyl, alkoxy, mor-
pholino etc., on the aromatic ring (entries 13–19, Table 1). The
reaction proceeded well in all these cases affording the desired
3-substituted quinazolin-4(3H)-ones (3) in good yields.
A plausible mechanism for the step-wise formation of 3-substi-
tuted quinazolin-4(3H)-ones (3) is shown in Scheme 2. The reac-
tion of isatoic anhydride (1) with amine (2) affords the o-amino
benzamide intermediate E-1 which on reaction with glyoxylic acid
gives the cyclic intermediate E-2. This step seemed to proceed via
an imine formation between the –NH2 group of E-1 and the alde-
hyde moiety of glyoxylic acid16 followed by intramolecular cycliza-
tion. The glyoxylic acid seemed to play a dual role, that is, as a
reactant and a catalyst in this step. An oxidative decarboxylation
of E-2 in the presence of aerial oxygen affords the desired product
3.17
O
A
N
O
CHO
CO2H
O
O
known
N
H
HN
N
N
intramolecular
1
+
aerial
cyclization
HN
NH2
oxidation
B
?
not
N
N
H
H
common
intermediate
explored
earlier
3a
2a
Scheme 1. Proposed synthesis of rutaecarpine (A) and evodiamine (B).
followed by a subsequent cyclization leading to the common
precursor for A and B. A literature search revealed that the
proposed strategy of constructing quinazolin-4(3H)-one ring using
glyoxylic acid was not only an unknown fact but also unusual and
unexpected as it involved the cleavage of a C–C bond. We therefore
decided to expand the scope and generality of this novel
methodology further. Herein we report our preliminary results
on the rapid synthesis of 3-(un)substituted quinazolin-4(3H)-ones
leading to rutaecarpine and evodiamine.
The 3-substituted quinazolin-4(3H)-ones are generally synthe-
sized via a 3-component reaction of anthranilic acid, amines and
ortho esters. The reaction proceeds in the presence of a range of
catalysts such as NaHSO4 or Amberlyst-15,6 Yb(III)-resin,7
Yb(OTf)3,8 Bi(TFA)3-[nbp]FeCl4 ionic liquid,9 La(NO3)3Á6H2O or
p-toluenesulfonic acid,10 Keggin-type heteropoly acid under micro-
wave irradiation,11 SnCl4Á4H2O,12 SiO2–FeCl3 and Al(NO3)3Á6H2-
13
O.14 However, the use of expensive metal or non-metal catalysts
and longer reaction times are the main drawbacks of many of these
methods. A catalyst-free synthesis of 3-aryl quinazolin-4(3H)-ones
via the reaction of isatoic anhydride, formic acid and anilines under
solvent-free conditions has been reported.15 However, the method
involved microwave heating and yields of products were not par-
ticularly high. We anticipated that the commercially available
50% aqueous glyoxylic acid could be a cheaper alternative to the
formic acid (neat) used earlier. Moreover, like formic acid the gly-
oxylic acid also could play a dual role, that is, as a reactant as well
as a catalyst. Accordingly, the reaction of isatoic anhydride (1),
cyclohexyl amine (2b) and glyoxylic acid was used as a model reac-
tion to establish the optimized reaction condition (Table 1). The
reaction was initially performed in polar and protic solvents such
as MeOH, EtOH and n-BuOH at their refluxing temperatures when
the desired product 3b was isolated in moderate to good yields
Table 2
Synthesis of 3-substituted quinazolin-4(3H)-ones (3)a
O
O
50% aqueous
OHC-COOH
R
O
N
+
RNH2
N
H
O
PEG-400
N
110-120 o
C
1
2b-t
3b-t
air
Entry
Amine (2); R=
Time (min)
Products (3)
Yieldb (%)
1
2
3
4
5
6
7
2b; Cyclohexyl
2c; Cyclopropyl
2d; Cycloheptyl
2e; Hc,d
12
15
12
8
8
10
18
3b
3c
3d
3e
3f
94
92
90
96
96
94
93
2f; Mec,e
Table 1
2g; n-Buc
2h; CH2(CH2)2OMe
3g
3h
Reaction of 1, 2b and glyoxylic acid under various conditionsa
O
O
N
NH2
O
50% aqueous
OHC-COOH
2i;
8
20
3i
85
O
N
+
9
2j; CH2Ph
22
25
22
25
20
20
25
30
30
25
30
3j
3k
3l
86
81
91
88
82
84
89
78
76
88
83
Solvent
air
N
H
O
10
11
12
13
14
15
16
17
18
19
2k; CH2C6H4F-p
2l; CH2C6H4OMe-p
2m; CH(Me)Ph-(S)
2n; Ph
2o; C6H4Me-p
2p; C6H4But-p
2q; C6H4CF3-p
2r; C6H4Cl-p
3b
2b
1
3m
3n
3o
3p
3q
3r
3s
3t
Entry
Solvent/temp
Time
Yieldb (%)
1
2
3
4
5
6
7
MeOH/65 °C
EtOH/80 °C
n-BuOH/115 °C
CHCl3/60 °C
48–50 h
48–50 h
8–10 h
48–50 h
20–22 h
12 min
10 min
44
52
76
10
70
94
82
2s; C6H4OMe-p
2t; C6H4(morpholino)-p
Toluene/110 °C
PEG-400/110–120 °C
Neatc/120 °C
a
Reaction was performed by using a mixture of 1 (1.0 equiv), 2b–t (1.1 equiv)
and glyoxylic acid (50% w/w in water) (1.1 equiv) in PEG-400 (3 mL) under open air.
a
b
Reactions were performed by using a mixture of 1 (1.0 equiv), 2b (1.1 equiv)
and glyoxylic acid (50% w/w in water) (1.1 equiv) in a solvent (3 mL) under open air.
Isolated yield.
c
Reaction was performed in a closed vessel without removing air.
28% aqueous NH4OH was used.
40% aqueous MeNH2 was used.
b
d
Isolated yield.
c
e
Reaction was performed under microwave irradiation (300 W).
Please cite this article in press as: Rao, K. R.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.09.011

K.R. Rao et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
convert 4 directly to A using oxidative coupling reagents such as
Hg(OAc)2, FeCl3 and Pb(OAc)4 were not successful as complex reac-
tion mixtures were obtained in all these cases.1a Thus the present
effort represents the first example of successful conversion of 4
into A and the method does not require the use of any metal cata-
lyst. It is also mention worthy that our approach of converting 4
into B has not been explored earlier. Overall, our strategy of syn-
thesizing A and B via a common intermediate 4 seemed to be
attractive and may find a wide usage.
In conclusion, we have demonstrated for the first time the use
of glyoxylic acid in the reaction of isatoic anhydride with various
amines to furnish a novel and metal catalyst-/microwave-free
rapid synthesis of 3-(un)substituted quinazolin-4(3H)-ones. The
glyoxylic acid played a dual reactant/catalyst role in this reaction
which proceeded via the cleavage of a C–C bond. The potential of
this methodology has been realized in developing a shorter, com-
mon and economical route to two known alkaloids, for example,
rutaecarpine and evodiamine.
O
N
O
O
CHO
CO2H
R-NH2
R
2
( )
NH
R
O
N
H
N
H
O
NH2
1
E-1
CO2H
O
O
R
R
N
air
-CO2
N
N
H
COOH
N
3
E-2
Scheme 2. Proposed reaction mechanism for the formation of 3.
To gain further evidence on the proposed mechanism, the isa-
toic anhydride 1 was reacted with the amine 2g in PEG-400 at
room temp for 10 min (Scheme 3) when the amino amide interme-
diate E-1g was formed that was isolated and characterized by 1H
NMR, MS and HRMS. Then the glyoxylic acid was added and the
mixture was stirred at room temp for 5 h. We were able to detect
the formation of the intermediate E-2g that was supported by MS
and HRMS data (see ESI). However, we failed to isolate pure E-2g
due to its quick conversion to 3g during the removal of PEG-400
at elevated temperature. Nevertheless, all these studies indicated
the intermediacy of E-1 and E-2 in the present reaction.
Having developed a novel and catalyst-free rapid synthesis of
3-substituted quinazolin-4(3H)-ones we then applied this
methodology for the synthesis of our target natural products, that
is, rutaecarpine (A) and evodiamine (B) (Scheme 4). Thus isatoic
anhydride (1) was reacted with tryptamine (2a) and glyoxylic acid
in PEG-400 at 110–120 °C for 15 min under open air to give the
desired product 3a in 85% yield. The compound 3a on treatment
with TFAA followed by KOH afforded 13b,14-dihydrorutaecarpine
4 in 82% yield.1a,18 Treatment of 4 with alkaline H2O2 afforded A
in 88% yield whereas reaction of 4 with MeI in the presence of
Cs2CO3 provided B in 62% yield. Notably, earlier attempts to
Acknowledgment
The author (KRR) thanks Dr. Upadhya Timmanna for his encour-
agement and the Department of Chemistry, JNTU, Hyderabad for
support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.09.
011.
References and notes
1. (a) Bergman, J.; Bergman, S. J. Org. Chem. 1985, 50, 1246. For reviews, see:; (b)
Lee, S. H.; Son, J.-K.; Jeong, B. S.; Jeong, T.-C.; Chang, H. W.; Lee, E.-S.; Jahng, Y.
Molecules 2008, 13, 272; (c) Jia, S.; Hu, C. Molecules 2010, 15, 1873.
2. Yu, H.; Jin, H.; Gong, W.; Wang, Z.; Liang, H. Molecules 2013, 18, 1826.
3. Prasad, B.; Sreenivas, B. Y.; Sushma, A.; Yellanki, S.; Medisetti, R.; Kulkarni, P.;
Pal, M. Org. Biomol. Chem. 2014, 12, 2864.
4. For recent examples, see: (a) Zhang, C.; De, C. K.; Mal, R.; Seidel, D. J. Am. Chem.
Soc. 2008, 130, 416; (b) Tseng, M. C.; Cheng, H.-T.; Shen, M.-J.; Chu, Y.-H. Org.
Lett. 2011, 13, 4434; (c) Pin, F.; Comesse, S.; Daich, A. Tetrahedron 2011, 67,
5564; (d) Fang, J.; Zhou, J. Org. Biomol. Chem. 2012, 10, 2389.
5. For selected and recent examples, see: (a) Nakayama, A.; Kogure, N.; Kitajima,
M.; Takayama, H. Heterocycles 2008, 76, 861; (b) Chvana, S. P.; Sivappa, R.
Tetrahedron Lett. 2004, 45, 997; (c) Mhaske, S. B.; Argade, N. P. Tetrahedron
2004, 60, 3417; (d) Mohnata, P. K.; Kim, K. Tetrahedron Lett. 2002, 43, 3993.
6. Das, B.; Banerjee, J. Chem. Lett. 2004, 33, 960.
O
O
n-BuNH2
CHO
CO2H
Bu-n
Bu-n
(2g)
N
H
N
1
PEG-400
rt, 10 min
NH2
N
H
COOH
rt, 5h
E-1g
E-2g
air
3g
7. Jiang, Z. D.; Chen, R. F. Synth. Commun. 2005, 35, 503.
110 o
C
8. Wang, L. M.; Xia, J. J.; Qin, F.; Qian, C. T.; Sun, J. Synthesis 2003, 1241.
9. Khosropour, A. R.; Mohammadpoor-Baltork, I.; Ghorbankhani, H. Tetrahedron
Lett. 2006, 47, 3561.
Scheme 3. Reaction of isatoic anhydride 1 with amine 2g.
10. Narasimhulu, M.; Mahesh, K. C.; Reddy, T. S.; Rajesh, K.; Venkateswarlu, Y.
Tetrahedron Lett. 2006, 47, 4381.
11. Ighilahriz, K.; Boutemeur, B.; Chami, F.; Rabia, C.; Hamdi, M.; Hamdi, S. M.
Molecules 2008, 13, 779.
12. Oskooie, H. A.; Baghernezhad, B.; Heravi, M. M. Indian J. Heterocycl. Chem. 2007,
17, 95.
NH2
O
50% aqueous
OHC CO2H
O
N
NH
13. Chari, M. A.; Mukkanti, D. S. K. Catal. Commun. 2006, 7, 787.
14. Wang, M.; Song, Z.; Zhang, T. Synth. Commun. 2011, 41, 385.
15. Rad-Moghadam, K.; Mamghani, M.; Samavi, L. Synth. Commun. 2006, 36, 2245.
16. While the participation of carboxylic acid moiety (as described under
microwave irradiation earlier, see Ref. 15) of glyoxylic acid in this step cannot
be ruled out completely, this appeared to be less likely due to the (a) higher
reactivity of the aldehyde moiety, (b) detection of E-2 in the reaction mixture
(see the text) and (c) absence of microwave irradiation.
17. In an alternative pathway the reaction may proceed via an initial formation of
imine (resulted from the reaction of amine 2 with the glyoxylic acid) which on
subsequent reaction with 1 may furnish 3. However, we failed to detect the
formation of this imine during the reaction even after several attempts.
18. While the synthesis of 4 was claimed by Horvath-Dora and Clauder earlier
[see: Horvath-Dora, K.; Clauder, O. Acta Chim. Acad. Sci. Hung. 1975, 84, 93
(Chem. Abstr. 1975, 82, 171273)] the real structure of the 4 was corrected by
Bergman and Bergman later (see: Bergman, J.; Bergman, S. Heterocycles 1981,
16, 347, see also Ref. 1a).
NH
O
+
N
PEG
O
N
H
110-120°C
(under open air)
3a (yield 85%)
1
2a
H2O2/KOH
A (yield 88%)
O
EtOH
reflux, 45 min
1) TFAA
2) KOH
N
CH3I
N
H
Cs2CO3
B (yield 62%)
HN
MeCN
rt, 45h
4 (yield 82%)
Scheme 4. Synthesis of rutaecarpine (A) and evodiamine (B).
Please cite this article in press as: Rao, K. R.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.09.011