A Novel Copper-Catalyzed Preparation of Pyrido[1,2- a ]pyrimidine Derivatives

Article abstract of DOI:10.1055/s-0035-1561352

A copper-catalyzed reaction of 2-amino-1-(prop-2-yn-1-yl)pyridinium bromide derivatives and aromatic sulfonyl azides has been demonstrated under mild condition.

Full text of DOI:10.1055/s-0035-1561352

SYNLETT
0
9
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6
-
5
2
1
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1
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3
7
-
2
0
9
6
©
Georg Thieme Verlag Stuttgart · New York
2015, 27, A–D
A
letter
Synlett
M. Mahdavi et al.
Letter
A Novel Copper-Catalyzed Preparation of Pyrido[1,2-a]pyrimidine
Derivatives
Mohammad Mahdavia
Roxana Fazli Estabragha
Setareh Moghimia
Mohammad Hosein Sayahib
Abbas Shafieea
Alireza Foroumadi*a,c
R1
R1
SO2N3
CuI, Et3N
R2
+
N
+
NH2
DMF, r.t.
– N2
N
N
O
S
Br–
R2
N
O
9
examples
71–93%
a
Department of Medicinal Chemistry, Faculty of Pharmacy and
Pharmaceutical Sciences Research Center, Tehran University of
Medical Sciences, Tehran, Iran
Department of Chemistry, Payame Noor University (PNU),
b
P.O. Box 19395-3697, Tehran, Iran
aforoumadi@yahoo.com
Drug Design and Development Center, Tehran University of
c
Medical Sciences, Tehran, Iran
Received: 17.08.2015
Accepted after revision: 12.01.2016
Published online: 04.03.2016
The synthetic utility of sulfonyl azides as highly ener-
getic species in versatile organic reactions has become a
powerful tool towards nitrogen-rich heterocycles. One of
the most interesting and near perfect transformations is
copper-catalyzed cycloaddition between azides and
DOI: 10.1055/s-0035-1561352; Art ID: st-2015-b0640-l
Abstract A copper-catalyzed reaction of 2-amino-1-(prop-2-yn-1-
yl)pyridinium bromide derivatives and aromatic sulfonyl azides has
been demonstrated under mild condition.
11
alkynes, called CuAAC, resulting in 1-sulfonyltriazoles A.
Despite the stability of triazoles, the presence of strong
electron-withdrawing group like sulfonyl at N-1 led to the
destabilization of this intermediate and increased reactivity
Key words copper-catalyzed, ketenimine, pyrido[1,2-a]pyrimidine,
sulfonyl azide, 2-amino pyridine
in ketenimines. Upon the loss of N and after protonation or
2
Pyrimidine ring system, appear in DNA, RNA, and in di-
verse synthetic and natural bioactive compounds as sub-
ring-chain isomerization, copper(І) alkynamide B and cu-
1
12
prated diazoimine C furnish ketenimine D (Scheme 1). N-
stituted or ring fused forms, comprises an opportunistic
class of biologically active compounds. Pyrido[1,2-a]pyrim-
idines are an important subgroup of hybrid heterocycles
and have attracted much attention in medicinal fields due
to their wide range of functions like agonists of ERRα recep-
Sulfonyl ketenimines13 are characterized as a reactive enti-
ty, containing highly electron-deficient carbon atom which
led to the increased capturing possibility of this compound
by various nucleophiles.1
4,15
This useful synthetic interme-
16
diate was also utilized in different types of reactions.
2
3
4
tor, antimalarial, antioxidant, and stress-protecting
While significantly less number of reports concerning in-
5
17
agents. Until now, the repertoire of synthetic efforts have
tramolecular trapping of ketenimines have been reported,
been revealed, mainly based on the cyclization of 2-amino
herein, we introduce a new and streamlined synthetic
pathway based on the integrating terminal alkyne and nu-
cleophilic center into one molecule to construct new pyri-
do[1,2-a]pyrimidine derivatives.
6–
pyridine with several types of bifunctional electrophiles.
10
Despite the amply recognized methods for the synthesis
of this valuable core, there is still a lot of space for finding
more ideal approaches in terms of both interesting chemis-
try and novel structures.
[
Cu]
N
2
R O2S
N
N
R1
H
R1
R1
H
[
Cu]
SO2R2
B
N
+
•
NSO2R2
–
H+
R1
R2 SO2N3
[
Cu]
2
D
R O2SN
N2
R1
A
[
Cu]
C
Scheme 1 Possible pathways leading to ketenimine intermediate
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 27, A–D

B
Synlett
M. Mahdavi et al.
Letter
R2 SO2Cl + NaN3
4
5
R1
Br-
R1
R1
Br
CuI, Et3N
DMF, r.t.
MeCN
2
+
R SO2N3
+
N
+
NH2
•
+
N
reflux
NH2
N
NH2
Br–
7
O
3
6
N
2
1
S
R2
O
R1
R1
+
N
N
N
NH
O
O
R2
R2
Br-
S
S
N
N
O
O
9a–i
8
Scheme 2 Copper-catalyzed pyrido[1,2-a]pyrimidine synthesis
In continuation of our burgeoning program for the syn-
thesis of N-rich cycles and new heterocyclic compounds,
we started with 2-aminopyridine derivatives as a tradition-
al substrate for the synthesis of pyridopyrimidines.
ing dimethyl formamide (DMF). The reaction proceeded via
ketenimines 7, which converted into 9a–i by intramolecular
attack of nitrogen, 1,3-H-shift and the subsequent aromati-
zation (Scheme 2).
18
19
In order to insert terminal alkyne moiety into our start-
ing material, we performed the reaction of 2-amino pyri-
dine derivatives 1 with propargyl bromide 2 in acetonitrile.
We succeeded in separating the resultant salt 3 as a pure
solid containing methyl substituent at different positions.
Sulfonyl azide derivatives can be easily prepared from di-
verse commercially available sulfonyl chlorides 4 and sodi-
um azide 5, according to the literature (Scheme 2).20
Then, the substrate scope of this reaction was investi-
gated (Scheme 3). The annulation of 2-amino-1-(prop-2-
yn-1-yl)pyridinium bromide derivatives 3a–d with un- and
para-substituted sulfonyl azides 6a–d bearing electron-do-
nating and electron-withdrawing groups was carried out
and N-(2H-pyrido[1,2-a]pyrimidin-2-ylidene)benzenesul-
21
fonamides 9a–i were obtained in good to excellent yields.
The presence of methyl group at the 3, 4, and 5 positions
did not affect the reaction significantly. Electronically neu-
tral and poor sulfonyl azides afforded the cyclized product
in higher yields.
In summary, a novel application of ketenimine to form
pyrido[1,2-a]pyrimidine under mild condition has been es-
tablished. This reaction proceeded in the presence of cop-
per iodide affording a range of structurally diverse deriva-
tives in high yields via an operationally simple procedure.
Next, we examined the reaction of 2-amino-1-(prop-2-
yn-1-yl)pyridinium bromide (3a) and benzenesulfonyl
azide 6a with a catalytic amount of different copper salts
like CuI, CuBr, CuCl and Cu O (10 mol%) and Et N (1 equiv)
2
3
at room temperature (Table 1, entries 1–4). Employing CuI
as the optimal catalyst, various solvents were screened (Ta-
ble 1, entries 5–7) and 9a was obtained in 79% yield utiliz-
Table 1 Optimization of Reaction Conditions for the Formation of 9a
Acknowledgment
Entry
Catalysta
Solvent
Yield (%)b
This work was supported and funded by the Research Council of Teh-
ran University of Medical Sciences (TUMS) and the Iran National Sci-
ence Foundation (INSF).
1
2
3
4
5
6
Cu
2
O
MeCN
MeCN
MeCN
MeCN
THF
44
58
52
39
60
79
31
CuI
CuBr
CuCl
CuI
References and Notes
(1) (a) Stevens, C. L.; Nagarajart, I. C.; Hoskell, T. H. J. Org. Chem.
1962, 27, 2991. (b) Schwan, T. J.; Tieekelmann, H.; Holland, J. F.;
CuI
DMF
Bryant, B. J. Med. Chem. 1965, 8, 750. (c) Takia, T.; Muraoka, Y.;
Nakatani, T.; Fujii, A.; Urnezaweg, Y.; Naganawa, H.; Umezava,
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Bull. Chem. Soc. 1966, 39, 1901.
7
CuI
2 2
CH Cl
a
Amount of catalyst: 10 mol%.
Reaction time: 12 h.
b
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 27, A–D

C
Synlett
M. Mahdavi et al.
Letter
R1
R1
+
N
+
N
N
NH2
R2 SO2N3
O
S
Br–
R2
N
O
3a–d
6a–d
9a–i
N
N
N
N
N
N
O
O
O
S
S
S
N
N
N
O
O
O
9a (79%)
9b (76%)
9c (78%)
Br
Br
NO2
N
N
N
N
N
N
O
S
O
S
O
S
N
O
N
O
N
O
9d (81%)
9e (80%)
9f (91%)
NO2
OMe
OMe
N
N
N
N
N
N
O
S
O
S
O
S
N
O
N
O
N
O
9g (93%)
9h (71%)
9i (74%)
Scheme 3 Structures and yields of compounds 9a–i. Reagents and conditions: 3 (1 mmol), 6 (1 mmol), CuI (10 mol%), and Et N (1 mmol) in DMF (3 mL)
3
stirred at r.t. for 12 h. Isolated yields.
(
(
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(
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(
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 27, A–D

D
Synlett
M. Mahdavi et al.
Letter
(
18) (a) Rasouli, M. A.; Mahdavi, M.; Firoozpour, L.; Shafiee, A.;
(21) General Procedure for the Preparation of Pyrido[1,2-
a]pyrimidines 9a–i: To the stirred solution of alkyne (1 mmol),
Foroumadi, A. Tetrahedron 2014, 70, 3931. (b) Mahdavi, M.;
Najafi, R.; Saeedi, M.; Alipour, E.; Shafiee, A.; Foroumadi, A. Helv.
Chim. Acta 2013, 96, 419.
azide (1 mmol), CuI (10 mol%) in DMF (3 mL), Et N (1 mmol)
3
was added under N . The mixture was stirred at r.t. for 12 h.
2
(
19) (a) Shafii, B.; Saeedi, M.; Mahdavi, M.; Foroumadi, A.; Shafiee, A.
Synth. Commun. 2014, 44, 215. (b) Farzipour, S.; Saeedi, M.;
Mahdavi, M.; Yavari, H.; Mirzahekmati, M.; Ghaemi, N.;
Foroumadi, A.; Shafiee, A. Synth. Commun. 2014, 44, 481.
After dilution with CH Cl , the aqueous solution of NH Cl was
2
2
4
added and the stirring was continued for 30 min. The aqueous
layer was extracted with CH Cl and dried over Na SO . The
2
2
2
4
solvent was removed under reduced pressure and the residue
was purified by column chromatography (EtOAc–EtOH, 10:1) to
afford the pure product.
(
c) Mahdavi, M.; Asadi, M.; Saeedi, M.; Tehrani, M. H.; Mirfazli,
S. S.; Shafiee, A.; Foroumadi, A. Synth. Commun. 2013, 43, 2936.
d) Ebrahimi, S. M.; Mahdavi, M.; Emami, S.; Saeedi, M.; Asadi,
(
N-(2H-Pyrido[1,2-a]pyrimidin-2-ylidene)benzenesulfon-
amide (9a): yield: 0.23 g (79%); pale yellow powder; mp 254–
M.; Firoozpour, L.; Khoobi, M.; Divsalar, K.; Shafiee, A.;
Foroumadi, A. Synth. Commun. 2014, 44, 665. (e) Asadi, M.;
Ebrahimi, M.; Mahdavi, M.; Saeedi, M.; Ranjbar, P. R.; Yazdani,
F.; Shafiee, A.; Foroumadi, A. Synth. Commun. 2013, 43, 2385.
–
1
256 °C. IR (KBr): 3283, 1644, 1463, 1321, 1130, 763, 692 cm
.
1
H NMR (500 MHz, DMSO-d ): δ = 6.94 (d, J = 7.5 Hz, 1 H), 7.25
6
(dt, J = 6.8, 1.0 Hz, 1 H), 7.40 (d, J = 9.0 Hz, 1 H), 7.45–7.49 (m, 3
H), 7.92–7.95 (m, 3 H), 8.41 (d, J = 6.6 Hz, 1 H), 8.53 (d, J = 7.5 Hz,
(
20) (a) Xing, Y.; Sheng, G.; Wang, J.; Lu, P.; Wang, Y. Org. Lett.
014, 16, 1244. (b) Waser, J.; Gasper, B.; Nambu, H.; Carreira,
E. M. J. Am. Chem. Soc. 2006, 128, 11693.
13
2
1 H). C NMR (125 MHz, DMSO-d ): δ = 114.8, 123.9, 124.3,
6
127.6, 129.1, 133.7, 135.6, 139.3, 143.8, 148.1, 149.5, 160.9.
Anal. Calcd for C14H11N O S: C, 58.94; H, 3.89; N, 14.73. Found:
3
2
C, 58.73; H, 3.75; N, 14.99.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 27, A–D