Direct access to novel chromeno-pyrimidine-N-oxides via tandem base catalyzed double nucleophilic addition/dehydration reaction

Article abstract of DOI:10.1016/j.tetlet.2013.01.044

A facile protocol for direct access to chromeno-pyrimidine-N-oxides is reported by the reaction of 4-chloro-3-formylcoumarin and aromatic carboximide oximes via tandem double nucleophilic addition and dehydration reactions. The one-pot reaction serves as an alternative protocol for achieving regioselective pyrimidine mono-N-oxide products as pure precipitates in good to excellent yields. The structure of the product was confirmed by X-ray analysis. Copyright

Full text of DOI:10.1016/j.tetlet.2013.01.044

Accepted Manuscript
Direct access to novel chromeno-pyrimidine-N-oxides via tandem base cata‐
lyzed double nucleophilic addition/dehydration reaction
Venkata Prasad Jalli, Satyanarayana Reddy Jaggavarapu, Anand Solomon
Kamalakaran, Sravan Kumar Gangisetty, Jagadeesh Babu Nanubolu,
Gopikrishna Gaddamanugu
PII:
S0040-4039(13)00080-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.01.044
TETL 42420
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
15 October 2012
8 January 2013
11 January 2013
Please cite this article as: Jalli, V.P., Jaggavarapu, S.R., Kamalakaran, A.S., Gangisetty, S.K., Nanubolu, J.B.,
Gaddamanugu, G., Direct access to novel chromeno-pyrimidine-N-oxides via tandem base catalyzed double
nucleophilic addition/dehydration reaction, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.
2013.01.044
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Direct access to novel chromeno-pyrimidine-
N-oxides via tandem base catalyzed double
nucleophilic addition/dehydration reaction
Leave this area blank for abstract info.
Venkata Prasad Jallia , Satyanarayana Reddy Jaggavarapua, Anand Solomon Kamalakarana, Sravan Kumar
Gangisettya, Jagadeesh Babu Nanubolub and Gopikrishna Gaddamanugu a, 
O
N
O
N
H2N
R
N
OH
O
O
O
NaHCO3
O
H
EtOH, 60oC
2h
+
2a-o
Cl
1
3a-o
R

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Direct access to novel chromeno-pyrimidine-N-oxides via tandem base catalyzed
double nucleophilic addition/dehydration reaction
Venkata Prasad Jallia , Satyanarayana Reddy Jaggavarapua, Anand Solomon Kamalakarana, Sravan Kumar
Gangisettya, Jagadeesh Babu Nanubolub and Gopikrishna Gaddamanugu a, 
a Department of Chemistry, Sankar Foundation Research Institute, Naiduthota, Vishakapatnam 530047, India
bX-ray crystallography division, Indian Institute of Chemical Technology, Hyderabad 500076, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A facile protocol for direct access to chromeno-pyrimidine-N-oxides is reported by the reaction
of 4-chloro-3-formylcoumarin and aromatic carboximide oximes via tandem double nucleophilic
addition and dehydration reactions. The one-pot reaction serves as an alternative protocol for
achieving regioselective pyrimidine mono-N-oxide products as pure precipitates in good to
excellent yields. The structure of the product was confirmed by X-ray analysis.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Pyrimidine-N-oxides
4-Chloro-3-formylcoumarin
Carboximide oxime
Chromeno-pyrimidine-N-oxide
Tandem
Pyrimidines are substructures of essential building blocks of
nucleotides which make the composition of DNA and RNA.
Their wide range of applications in medicinal chemistry make
them a class of highly admired privileged structures.1 Derivatives
of pyrimidines such as pyrimidine-N-oxides are versatile class of
compounds which like their precursors have gained ample
importance in recent years. A well known pyrimidine-N-oxide,
Minoxidil is an efficient vasodilator and anti-hypertensive
molecule.2 It is popularly used to treat the male baldness
associated with androgenic or androgenetic alopecia.3
Additionally, they account for potential applications as growth
regulators and herbicides.4 Apart from biological applications
pyrimidine-N-oxides are employed as intermediates for the
synthesis of several heterocyclic scaffolds.5
methylene 1,3-dicarbonyl compounds in presence of Lewis
acids.10 Similar synthesis of trifluoromethylated pyridine-N-
oxides was achieved by reaction of 3-amino-5-methyl-1,2,4-
oxadiazoles and 1,2-diketones under perchloric acid conditions
albeit in poor yields.11 Imidazole aminooximes and orthoformates
were successfully exploited as precursors to afford purine mono-
N-oxides.12 Ring rearrangement of oxadiazolyl-enamino
ketones13 and DBU catalyzed reaction of nitroarenes with ethyl
isocyanoacetates14 were also reported as elegant methodologies
to access the privileged N-oxide compounds. However most of
the methods suffer either from limited substrate scope, poor
yields or employs high temperatures up to 200 °C to achieve the
target molecules.
Application of tandem methodologies has witnessed enormous
surge in recent times for the generation of several complex
heterocyclic molecular targets of biological interest.15 This would
be a highly attractive approach where synthesis of pyrimidine-N-
oxides can be accomplished using easily accessible starting
materials which evade the disadvantages of isolation of the
intermediates and generation of waste solvents. We have earlier
reported the synthesis of novel 2-benzazepines via tandem
Most familiar straightforward approach to access pyrimidine-
N-oxides is N-oxidation of pyrimidines with hydrogen peroxide.6
Organic peracids and their complexes have also been used
successfully for the N-oxidation of pyrimidines.7 However,
unlike pyridines, the N-oxidation of pyrimidines is relatively
complicated as the reaction is susceptible to low yields due to
ring-carbon oxidation, ring opening reactions and formation of
isomeric products.8 Alternative methods other than direct N-
oxidation of pyrimidines have also been developed which employ
ring closure, ring transformations and substitution reactions of a
variety of starting materials to access the pyrimidine-N-oxides.9
One of the simple methods for generation of pyrimidine-N-oxides
nucleophilic reaction and cyclization using
4-chloro-3-
formylcoumarin (1) and aromatic benzylamines.16 Herein, we
envisaged a facile protocol for direct generation of novel fused
chromeno-pyrimidine-N-oxides by a reaction of 1 with aromatic
carboxamide oximes 2a-o. For the initial validation of the
protocol and the optimization of the reaction conditions, 1 was
was achieved by reaction of carboxamide oximes with active
———
 Corresponding author. Tel.: +91-0891-2891187; fax: +91-0891-2891186; e-mail: gkrishnagps@gmail.com

2
Tetrahedron
subjected to the reaction with N’-hydroxybenzimdamide 2a
1, entries 3-5) yields, sodium bicarbonate gave best yield of 85%
(Table 1, entry 6) in 2 hours. Similarly, the choice of solvent also
displayed profound effect on the reaction yields where solvents
such as methanol, dichloromethane, chloroform, THF and 1,4-
dioxane afforded 20-70% yields of 3a (Table 1, entries 7-10).
From the observations of the optimization studies in Table 1, it
can be surmised that sodium bicarbonate afforded the best yield
of product 3a in ethanol solvent and hence all further
experiments were conducted with this system.
under various base catalyzed conditions in different solvents
(Table 1).
Table 1. Screening studies of the reaction of 1 and 2a with various bases and
solventsa.
O
N
O
N
O
O
O
H2N
N
OH
Base
H
+
Solvent
O
Cl
1
3a
2a
The optimized reaction conditions were further utilized to
evaluate the substrate scope of the reaction. Diverse carboxamide
oxime substrates 2b-o as shown in Table 2 were thus assessed for
their reactivity under the experimental conditions. When the
carboxamide oximes with halogen substituents such as 4-F, 2-Cl,
4-Cl, 3-Cl, 2,4-dicloro, 4-Br and 3-Br (Table 2, entries 1-7) were
subjected to the reaction with 1, corresponding pyrimidine-N-
oxides were obtained in good to excellent yields (75-85%).
Similarly, carboxamide oximes 2i-n possessing electron donating
functional groups such as 4-methyl, 3,4,5-trimethoxy, 3-
methoxy, 4-methoxy, 3,4-dimethoxy, and 2-methoxy substituents
also afforded the corresponding products 3i-n in good to
excellent yields (Table 2, entries 8-13). However, in case of
electron withdrawing 4-nitro substrate 3o, the reaction afforded
only N-alkylated product despite prolonged reaction times. Hence
a reaction was attempted in 1,4-dioxane solvent with the
intention of attaining higher reaction temperatures. To our
delight, the required pyrimidine-N-oxide 3o was afforded in 65%
yield after 3 hours of reflux (Table 2, entry 14). Attempts to
expand the scope of the reaction to aliphatic substrates did not
yield fruitful results, as the reaction resulted in mixture of several
unidentified products due to the relative instability of the
aliphatic carboxamide oximes under the experimental conditions.
Entry
1
2
3
4
5
6
7
8
Base
NEt3
NEt3
DBU
DABCO
DIPEA
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
Solvent
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
DCM
CHCl3
THF
T (°C)
rt
60
60
60
60
60
60
Time(h)
Yield (%) b
24
12
2
2
2
2
2
2
2
30
50
40
40
56
85c
70
30
25
20
40
reflux
reflux
60
9
10
11
2
2
1,4-dioxane
60
aAll the reactions were performed on 1 mmol scale with 1 equiv. of base in 5
ml solvent.
bisolated yields.
cprecipitated yield.
As illustrated in Table 1, to identify the best base for the
reaction of 1 and 2a, various bases such as NEt3, DBU, DABCO,
DIPEA and sodium bicarbonate were employed as promoters in
ethanol solvent. When triethylamine was employed as base in
ethanol at room temperature the reaction afforded pyrimidine-N-
oxide 3a in 30% yield which improved to 50% when temperature
was raised to 60 °C (Table 1, entries 1 and 2). All further
optimizations were conducted at this temperature. While DBU,
DABCO and DIPEA afforded the product 3a in 40-56% (Table
Table 2. Synthesis of diverse chromeno-pyrimidine-N-oxides 3b-oa
Entry
Substrate (2b-p)
Product (3b-p)
Yield (%)b
O
O
NH2
N
N
F
O
N
OH
3b
1
77
2b
F
O
N
O
N
Cl
NH2
O
2
75
3c
Cl
N
OH
2c
O
N
O
N
O
NH2
3d
82
75
Cl
3
4
N
OH
2d
Cl
O
N
O
N
NH2
OH
O
N
3e
2e
Cl
Cl

3
O
N
O
N
80
77
NH2
O
Cl
5
3f
Cl
N
OH
2f
Cl
Cl
O
N
O
N
NH2
Br
N
OH
O
2g
3g
6
Br
O
N
O
N
Br
NH2
O
7
8
N
OH
3h
85
82
2h
Br
O
N
O
N
NH2
O
3i
N
OH
2i
O
O
MeO
MeO
MeO
N
N
O
NH2
OH
3j
N
9
88
2j
MeO
OMe
OMe
O
N
O
N
NH2
OH
O
N
3k
10
11
MeO
2k
80
78
OMe
O
O
NH2
OH
N
N
MeO
O
N
3l
2l
OMe
O
O
NH2
OH
N
N
MeO
MeO
O
N
3m
12
13
85
75
2m
OMe
OMe
O
O
N
NH2
OH
N
OMe
N
O
2n
3n
OMe

4
Tetrahedron
O
O
NH2
OH
O2N
N
N
65c
O
N
14
3o
2o
NO2
aAll the reactions were performed on 1 mmol scale with 1 equiv. of NaHCO3 in 5 ml ethanol at 60°C.
bPrecipitated yields.
cReaction performed in 1,4-dioxane under reflux condition
The structure of the product was confirmed by X-ray analysis
Acknowledgments
of 3d as shown in Figure 1. The molecule was crystallized in
monoclinic system with space group C 2/c with eight molecules
in the unit cell. The crystal is stabilized by C−H···O–, C−H···O
and C−H···Cl interactions. The chloro benzene ring is tilted by
12.8° away from the plane of the pyrimidine-N-oxide moiety
(Also refer crystal data and crystal packing diagram in
supplementary data).
We thank the Managing Trustee and the Chairman (Medical
Sciences), Sankar Foundation for their kind support.
Supplementary data
General experimental section, analytical data for compounds
3a-o and the X-ray analysis of 3d can be found in supplementary
data. Crystallographic data of 3d has been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication nos. CCDC 902947. The data can be obtained free of
charge at www.ccdc.cam.ac.uk/conts/retrieving.html [or from the
Cambridge Crystallographic Data Centre (CCDC), 12 Union
Road, Cambridge CB2 1EZ, UK; fax: +44(0) 1223 336 033;
email: deposit@ccdc.cam.ac.uk].
References and notes
1. (a) Bruno, O.; Schenone, S.; Ranise, A.; Bondavalli, F.; Barocelli,
E.; Ballabeni, V.; Chiavarini, M.; Bertoni, S.; Tognolini, M.;
Impicciatore, M. Bioorg. Med. Chem. 2001, 9, 629–636; (b)
Bruno, O.; Brullo, C.; Schenone, S.; Ranise, A.; Bondavalli, F.;
Barocelli, E.; Tognolini, M.; Magnanini, F.; Ballabeni, V.
Farmaco. 2002, 57, 753–758; (c) Bruno, O.; Brullo, C.; Schenone,
S.; Bondavalli, F.; Ranise, A.; Tognolini, M.; Ballabeni, V.;
Barocelli, E. Bioorg. Med. Chem. 2004, 12, 553–61; (d) Bruno,
O.; Brullo, C.; Bondavalli, F.; Ranise, A.; Schenone, S.;
Tognolini, M.; Ballabeni, V.; Barocelli, E. Med. Chem. 2007, 3,
127–34; (e) Keche, A. P.; Hatnapure, G. D.; Tale, R. H.; Rodge,
A. H.; Birajdar, S. S.; Kamble, V. M. Bioorg Med Chem Lett.
2012, 22, 3445-3448; (f) Ji Hoon, L.; Hyum-suk, L. Org. Biomol.
Chem. 2012, 10, 4229-4235.
Fig. 1. ORTEP plot for the X-ray crystal structure of 3d at 30% probability.
In all the above reactions (Table 2, entries 1-14) a precipitate
was observed after initial 15 minutes of reaction which re-
dissolves and re-precipitates to afford products 3a-o. The first
precipitated solid was isolated in the reaction of 2a with 1 and
confirmed as N-alkylated intermediate A of primary amine
(Scheme 1). Based on the above observations, mechanism as
shown in Scheme 1 can be proposed where the initial nucleophlic
addition of the primary amine on 1 leads to an N-alkylated
Intermediate A. Intermediate A further undergoes a base
catalyzed deprotonation triggering the nucleophilic addition of
the oxime amine on the aldehyde resulting in intermediate B,
which subsequently undergoes dehydration leading to the final
chromeno-pyrimidine-N-oxide 3a.
2. Messenger, A. G.; Rundegren, J. Br. J. Dermatol. 2004, 150, 186-
194 and references cited therein.
3. (a) Johnson, G. A.; Barsuhn, K. J.; McCall, J. M. Biochem.
Pharmacol. 1982, 31, 2949; (b) Meisheri, K. D.; Cipkus, L. A.;
Taylor, C. J. J. Pharmacol. Exp. Ther. 1988, 245, 751; (c)
Winquist, R. J.; Heaney, L. A.; Wallace, A. A.; Baskin, E. P.;
Stein, R. B.; Garcia, M. L.; Kaczorowsk, G. J. J. Pharmacol. Exp.
Ther. 1989, 248, 149; (d) Meisheri, K. D.; Johnson, G. A.;
Puddington, L. Biochem. Pharmacol. 1993, 45, 271; (e)
Anderson, R. J.; Kudlacek, P. E.; Clemens, D. L. Chem. Biol.
Interact. 1998, 109, 53.
O
N
O
N
O
O
O
N
O
O
N
O
N
OH
O
O
CHO
+H+
-H2O
+NaHCO3
-HCl
H
Cl
H
:N
1
O
O
H
NH2
Base
N
OH
4. Tseng, C. P. U.S. Patent 4,411,690, Oct 24, 1983. Chem. Abstr.
1984, 100, 34561.
3a
B
2a
A
5. Yamanaka, H.; Sakamoto, T.; Niitsuma, S. Heterocycles. 1990,
Scheme 1. Mechanism for the formation of 3a intermediate A.
31, 923–967.
In summary, we have reported a facile protocol for direct
access to novel chromeno-pyrimidine-N-oxides via tandem
double nucleophilic addition and dehydration steps. The reaction
offers a complementary approach for obtaining selective mono-
N-oxides products of pyrimidines in good yields. Additionally,
all the products were afforded as pure precipitates avoiding the
necessity for tedious column purification steps. Further
investigations on structural diversification and biological
implications of the structural scaffolds are currently being
conducted.
6. (a) Jandali.; Shareef.; Low.; David, W. Ann. Plast. Surg. 2010, 65,
437-442. Chem. Abstract, 1992, 116, 135998.
7. (a) Rousseau, R. J.; Robins, R. K. J. Heterocycl. Chem. 1965, 2,
196; (b) Kim, K. M.; Chung, K. H.; Kim, J. N.; Ryu, E. K.
Synthesis. 1993, 283; (c) Cartwright, D.; Ferguson, J. R.;
Giannopouls, T.; Varvounis, G.; Wakefield, B. J. Tetrahedron.
1995, 51, 12791.
8. (a) Katritzky, A. R. Chemistry of heterocyclic N-oxides,
Academic Presee London, 1971; (b) Hiroshi, Y.; Shigeru, O,
Takao, S. Heterocycles. 1981, 16, 573-576; (c) Jovanovic, M. V.
Canadian Journal of Chemistry, 1984, 62, 1176; (d) Thomos, J. K.
J.Org. Chem. 1985, 49, 3073.

5
9. (a) Vivona, N.; Buscemi, S.; Frenna, V.; Ruccia, M. Chem. Soc.,
Perkin Trans. 1. 1986, 17–19; (b) Buscemi, S.; Macaluso, G.;
Frenna, V.; Vivona, N. J. Heterocycl. Chem. 1986, 23, 1175–
1177.
10. (a) Kocevar, M.; Mlakar, B.; Perdih, M.; Petric, A.; Polans, S.;
Vercek, B. Tetrahedron. Lett. 1992, 33, 2195-2198; (b) Mlaker,
B.; Stefane, B.; Kocevar, M.; Polanc, S. Tetrahedron. 1998, 54,
4387.
11. Buscemi, S.; Pace, A.; Piccionello, A. P.; Vivona, N.; Pani, M.
Tetrahedron. 2006, 62, 1158-1164.
12. Rhie, S. Y.; Rhu, E. K. Heterocycles. 1995, 41, 323-328.
13. Goti, A.; Cicchi, S.; Cordero, F.; M.; Fedi, V.; Brandi,
A. Molecules. 1999, 4, 1-12.
14. Takashi, M.; Ken-ichi, F.; Kazuo, O.; Takuji, O.; Hidemitsu,
U.; Noboru, O. J. Chem. Soc., Perkin Trans. 1. 1996, 1403-1407.
15. (a) Bunce, R. A. Tetrahedron. 1995, 51, 13103–13159; (b)
Nicolaou, K. C.; Montagnon, T.; Snyder, S. A. Chem. Commun.
2003, 5, 551–564; (c) Padwa, A. Pure Appl. Chem. 2004, 76,
1933–1952; (d) Nicolaou, K. C.; Edmonds, E. J.; Bulger, P. G.
Angew Chem. Int Ed. 2006, 45, 7134-7186; (e) Yicheng, Z.; Min,
W.; Pinhua, L.; Lei, W. Org. Lett., 2012, 14, 2206–2209; (f)
García-Álvarez, J.; Díez, J.; Vidal, C. Green Chem. 2012,
Advance Article; (g) Weihui, Z.; Guan, W.; Kai, C. Heterocycles.
2012, 85, 43-56; (h) Devanga, K. S.; Nagarajan, R.; Rajagopal., N.
Org. Biomol. Chem. 2012, 10, 3417-3423.
16. Prasad, J. V.; Prabhakar, M.; Manjulatha, K.; Rambabu, D.;
Anand Solomon, K.; Gopikrishna, G.; Anil Kumar, K.
Tetrahedron. Lett. 2010, 51, 3109-3111.

Graphical Abstract
Leave this area blank for abstract info.
Direct access to novel chromeno-pyrimidine-
N-oxides via base catalyzed tandem double
nucleophilic addition/dehydration reaction
Venkata P J , Satyanarayana R J, Anand S K, Sravan K G, Jagadeesh B N and Gopikrishna G
O
O
H2N
N
OH
O
O
O
NaHCO3
N
N
O
H
EtOH, 60oC
2h
+
2a-o
Cl
R
1
3a-o
R
Abstract: A facile protocol for direct access to chromeno-pyrimidine-N-oxides is reported by the
reaction of 4-chloro-3-formylcoumarin and aromatic carboximide oximes via tandem double
nucleophilic addition and dehydration reactions. The one-pot reaction serves as an alternative
protocol for achieving regioselective pyrimidine mono-N-oxide products as pure precipitates in
good to excellent yields. The structure of the product was confirmed by X-ray analysis.