A divergent synthesis of 1,8-naphthyridines and hydropyridopyrimidinones by the reactions of o-aminonitriles with ketones

Article abstract of DOI:10.1002/cjoc.201201247

An efficient divergent synthesis of substituted 1,8-naphthyridine and hydropyridopyrimidinone derivatives was developed by the reactions of o-aminocyanopyridines and ketones based on different catalytic conditions. Catalyst-controlled cyclization pathways

Full text of DOI:10.1002/cjoc.201201247

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DOI: 10.1002/cjoc.201201247
A Divergent Synthesis of 1,8-Naphthyridines and
Hydropyridopyrimidinones by the Reactions of
o-Aminonitriles with Ketones
Liupan Yang, Jiarong Li, Hongxin Chai, Hongyan Lu, Qi Zhang, and Daxin Shi*
School of Chemical Engineering and Environment, Beijing Institute of Technology, Beijing 100081, China
An efficient divergent synthesis of substituted 1,8-naphthyridine and hydropyridopyrimidinone derivatives was
developed by the reactions of o-aminocyanopyridines and ketones based on different catalytic conditions.
Keywords Friedländer annulations, divergent synthesis, 1,8-naphthyridine, hydropyridopyrimidinone
Introduction
ous research,[12d,12j] further investigating the scope as
well as controlling of divergent reactions are still desir-
able. Herein we wish to report the divergent synthesis of
1,8-naphthyridine and hydropyridopyrimidinone deriva-
tives through controlled cyclization pathways of
o-aminocyanopyridines with ketones.
Among the various synthetic strategies, divergent
reactions are particularly attractive because they can
synthesize a variety of heterocyclic motifs from a single
class of precursor. In order for this strategy to be of
synthetic utility, many efforts have dealt with the con-
trol of divergent reactions to provide one of several
products selectively,[1] for examples, Fan et al.[1b] re-
ported a solvent-controlled oxidative cyclization for a
divergent synthesis of highly functionalized oxetanes
and cyclopropanes, Liang et al.[2] developed a palla-
dium-catalyzed divergent reaction of α-diazocarbonyl
compounds with allylic esters. However, metal catalysts
are always used in the control of divergent reactions,
thus the control of divergent reactions based solely on
catalyst selection especially metal-free and ligand-free is
still one of the challenges in modern synthetic commu-
nity.[3]
1,8-Naphthyridine derivatives have been extensively
investigated and remain an ongoing interest because of
their wide biological activities including antibacterials,[4]
anticonvulsants,[5] and antihypertensives[6] and have
appeared as a key core in numerous compounds and
drugs over the past few decades. The fused pyrido[2,3-
d]pyrimidiones ring system has also received consider-
able interest because of its wide range of biological and
pharmacological properties such as antihistaminic,[7]
antibacterial,[8] antifolate,[9] and PED4 inhibiting activi-
ties[10] as well as diuretic activity.[11] During studying
Friedländer cyclocondasation of aryl o-aminonitrile and
ketone possessing an active α-methylene group, the
formations of new skeleton products have been reported
by us and other groups.[12] Although synthesis of some
hydropyridopyrimidinones was mentioned in our previ-
Results and Discussion
To standardize the reaction conditions for the differ-
ent way of this divergent conversion,[12e] we selected
compound 1a and cyclohexanone as the model sub-
strates for the optimization of the reaction conditions.
Based on the possible mechanism of Friedländer con-
densation, the direction of the designed divergent con-
version depends on dehydration of the key intermediate
I. Various catalysts such as Brønsted and Lewis acids,
and base were evaluated for the reaction. The data indi-
cated that PPA was the most effective catalyst for the
formation of Friedländer product 3b (Scheme 1, Route
A) and only a single product 4b was obtained in high
yield in the presence of strong bases such as NaOH,
NaOCH3 (Scheme 1, Route B). Screening of other cata-
lyst gave 1,8-naphthyridine 3b along with varying
amounts of hydropyridopyrimidinone 4b. The effect of
solvents was also investigated, and cyclohexanone itself
was the best choice for the formation of 4b. The func-
tion of PPA and NaOCH3 can be explained as follows:
PPA, as a common dehydrant strongly favors Friedlän-
der conversion resulting in the formation of
1,8-naphthyridine whereas NaOCH3 leads the intra-
molecular Pinner reaction to give pyrido[2,3-d]-
oxazine II (Pinner reaction[13]), which subsequently re-
arranges to afford the final product (Dimroth rear-
rangement[14]). And this conversion is called PDF
*
E-mail: shidaxin@bit.edu.cn
Received December 23, 2012; accepted February 1, 2013; published online March 1, 2013.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201201247 or from the author.
Chin. J. Chem. 2013, 31, 443—448
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Yang et al.
COMMUNICATION
Scheme 1 Proposed mechanism for the divergent conversion
Cl
Cl
N
Cl
N
O
NH2
N
O
CN
Route B
NH
Route A
+
N
N
NH2
H
4b
Dimroth
Cl
3b
Cl
Cl
Cl
NaOCH3
Pinner
NH
-H2O
PPA
N
CN
OH
O
CN
N
O
N
N
N
N
N
N
H
N
H
II
H
I
Table 1 Evaluation of reaction conditionsa
conversion which means a transformation from Pinner
to Dimroth rearrangement in the Friedländer reac-
tion.[12c]
Cl
O
With the optimized reaction conditions in hand, we
investigated the substrate scope of the reaction (Table 2).
Under the catalysis of PPA, most ketones were reacted
with o-aminocyanopyridines to give the corresponding
1,8-naphthyridines via Friedländer conversion. In the
case of acetone and 3-methylbutan-2-one without an
active α-methylene group only PDF conversion oc-
curred, and the products 4f and 4l were isolated in 85%
and 87% yields, respectively. It was noted that the elec-
tronic influence of o-aminocyanopyridines has a pro-
found impact on the reaction pathway. Hence, substrates
with electron withdrawing groups adjacent to phenyl
ring strongly favor PDF pathway resulting in the forma-
tion of hydropyridopyrimidinone, the method underwent
well for most cyclic and branched ketone tested except
cycloheptanone (Table 2, Entries 1－14), whereas those
substituted with electron-donating groups only favor
formation of 1,8-naphthyridine (Table 2, Entries 15 and
16).
CN
conditions
N
NH2
1a
Cl
Cl
N
O
NH2
N
NH
+
N
N
H
3b
4b
Yieldc/%
3b 4b
Entry
Catalystb
Solvent
Temp./℃
1
AlCl3
DCE
none
80
55
7
0
2
CuCl2
140
140
140
140
120
140
140
140
140
140
160
120
130
32
3
ZnCl2
none
10 75
47 13
24 10
The structures of all products were established on
the basis of spectroscopic data such as IR, NMR, and
ESI spectra and elemental analyses. A couple structures
of the divergent products 3b and 4b were determined
unambiguously by X-ray crystallography (Figure 1).[15]
4
p-PSA
HCl
none
5
none
6
PPA
toluene
none
80
0
0
7
Na2CO3
Pyridine
NaOH
0
8
none
0
0
Conclusions
9
none
0
77
83
73
65
0
In summary, we have developed the first example of
a PPA and NaOCH3 promoted cyclization of o-amino-
cyanopyridines and readily available ketones to selec-
tively achieve 1,8-naphthyridines and fused pyrido[2,3-
d]pyrimidines. Compared with the traditional used
catalysts of Friedländer cyclization for the synthesis of
tacrine analogues, the PPA-catalyzed process can be
performed at fast reaction rates, no special precautions
were required such as N2 or argon to carry out the reac-
10
11
12
13
14
NaOCH3
NaOCH3
NaOCH3
NaOCH3
NaOCH3
none
0
DMF
DMSO
toluene
xylne
0
0
0
0
12
a Reaction conditions: 1a (2 mmol), solvent (3 mL). b For Entry 1
－6, 1.5 equiv. based on 1a; Entry 7－12, 0.5 equiv. based on 1a.
c Isolated yield.
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Chin. J. Chem. 2013, 31, 443—448

A Divergent Synthesis of 1,8-Naphthyridines and Hydropyridopyrimidinones
Table 2 Catalyst-controlled cyclization of o-aminocyanopyridines with ketones
O
Ar
N
Ar NH2
Ar
1 (1 mmol), 2 (4 mL),
NaOCH3 (0.5 equiv.), 4 h
1 (1mmol), 2 (1.5mmol),
PPA (1.5 equiv.), 4 h
R2
R1
CN
O
NH
R1
R2
R1
+
R2
condition A
condition B
N
H
N
N
N
NH2
2
n
n
n
3a - 3p
1
4a - 4n
Condition A
Product
Condition B
Product
Entry
n, Ar
2
Yielda/%
Yielda/%
Cl
Cl
O
O
NH2
N
1
1, p-Cl-Ph
76
78
NH
N
N
H
N
3a
Cl
4a
Cl
O
O
NH2
N
2
1, p-Cl-Ph
80
83
NH
N
N
H
N
4b12d,12 j
3b
F
F
O
O
NH2
N
3
1, p-F-Ph
81
84
NH
N
N
N
H
3c
4c12d,12 j
Cl
O
NH2
N
4
5
6
1, p-Cl-Ph
1, p-F-Ph
1, p-Cl-Ph
72
－
trace
trace
85
N
3d
Cl
O
NH2
N
72
－
N
3e
Cl
O
O
trace
NH
N
N
H
4f
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Yang et al.
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Continued
Condition A
Product
Condition B
Product
Entry
n, Ar
2
Yielda/%
Yielda/%
Cl
Cl
O
O
NH2
N
7
1, p-Cl-Ph
88
87
NH
N
N
H
N
3g
4g
F
F
O
NH2
N
O
8
1, p-F-Ph
1, p-Cl-Ph
1, p-Cl-Ph
1, p-F-Ph
1, p-Cl-Ph
88
82
85
88
86
86
84
82
NH
N
N
4h
N
H
3h
Cl
Cl
O
O
NH2
9
NH
N
N
H
N
N
4i
3i
Cl
Cl
O
O
NH2
N
10
11
12
NH
N
N
N
H
3j
4j
F
F
O
O
NH2
N
NH
N
N
H
N
3k
4k
Cl
O
O
－
trace
87
NH
N
N
H
4l
Cl
N
Cl
O
O
NH2
N
13
0, p-Cl-Ph
80
80
NH
N
N
H
3m
4m[12d,12j]
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Chin. J. Chem. 2013, 31, 443—448

A Divergent Synthesis of 1,8-Naphthyridines and Hydropyridopyrimidinones
Condition A
Continued
Yielda/%
Condition B
Product
Entry
n, Ar
2
Product
Yielda/%
F
F
O
O
NH2
14
0, p-F-Ph
74
85
NH
N
N
H
N
N
4n[12d, 12j]
3n
O
O
NH2
N
15
1, p-OMe-Ph
88
－
trace
N
3o
O
O
NH2
N
16
1, p-OMe-Ph
81
－
trace
N
3p
a Isolated yield.
tion and avoid the use of silica gel column chromatog-
raphy for purify. The PDF pathway is an atom eco-
nomical process, pyrido[2,3-d]pyrimidines can be ob-
tained via simple filtration since the products directly
precipitate out of solution after cooled to room tem-
perature with good yields.
Experimental
The starting materials o-aminocyanopyridines were
synthesized from using a standard methodology re-
ported by El-Salam.[16] Toluene was distilled from P2O5
and dried over MS 4 Å. Other reagents were used as
purchased from commercial suppliers without further
purification. Melting points were determined using XT4
micro-scope melting point apparatus (uncorrected). In-
frared (IR) spectra were recorded on a Perkin Elmer
1
FT-IR spectrophotometer with KBr pellets. H and 13C
NMR spectra were recorded at a Varian mercury-plus
400 spectrometer with TMS as the internal standard.
Mass spectra were recorded on a Varian 500-MS using
ESI ionization. Elemental analyses were performed on
an Elementar Vario EL.
General procedure for the synthesis of 1,8-naph-
thyridine derivatives
PPA (1.5 mmol), o-aminocyanopyridines (1 mmol)
and the corresponding ketones (1.5 mmol) were added
to 5 mL anhydrous toluene, the reaction mixture was
Figure 1 X-ray structure of 3b (top) and 4b (bottom).
Chin. J. Chem. 2013, 31, 443—448
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447

Yang et al.
COMMUNICATION
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poured into 20 mL H2O and stirred for 30 min, the mix-
ture was extracted with ethyl ether (5 mL×3), concen-
trated ammonia liquor was added dropwise to the aque-
ous phase until the aqueous solution was basic and the
precipitate was isolated by filtration. The crude product
was recrystallized from 95% enthol to afford pure com-
pounds.
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CCDC-900015 (3b) and no. CCDC-854866 (4b). Copies of the data
can be obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK, (Fax:＋44-(0)1223-336033 or
e-mail: deposit@ccdc.cam.ac.Uk).
Acknowledgement
We are grateful for financial support from the Sci-
ence and Technology Innovation Program of Beijing
Institute of Technology (No. 2011CX0436).
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Chin. J. Chem. 2013, 31, 443—448