Synthesis of 4-substituted oxazolo[4,5-c]quinolines by direct reaction at the C-4 position of oxazoles

Article abstract of DOI:10.1039/c4ob02224f

A facile synthesis of 4-aryl substituted oxazolo[4,5-c]quinolines has been described via a modified Pictet-Spengler method and using Cu(TFA)₂ as a catalyst. The developed methodology directly functionalizes the C-4 position of oxazoles without

Full text of DOI:10.1039/c4ob02224f

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Synthesis of 4-substituted oxazolo[4,5-c]quinolines by
direct reaction at C-4 position of oxazole
Cite this: DOI: 10.1039/x0xx00000x
Mahesh Akula,a Yadagiri Thigulla,a Connor Davis,b Mukund Jhab and Anupam
Bhattacharya*a
Received 00th January 2012,
Accepted 00th January 2012
A facile synthesis of 4-aryl substituted oxazolo[4,5-
c
]quinolines has been described via
catalyst. The developed
modified Pictet-Spengler method and using Cu(TFA)2 as
a
DOI: 10.1039/x0xx00000x
methodology directly functionalizes C-4 position of oxazoles without the aid of any
prefunctionalization, in presence of more reactive C-2 position in good yields. The versatility
of the established method has been demonstrated by its application in the synthesis of 4-
substituted oxazolo-[1, 8]naphthyridine ring systems.
www.rsc.org/
Introduction
Oxazoles and fused-oxazoles are found in many bioactive natural
products.1 These heterocycles play an important role in medicinal
chemistry as anti-tubercular, antibacterial, TRPV1 antagonist and
DNA intercalating agents.2-5 Substituted oxazoles have also been
used as fluorescent organic materials.6 These properties of oxazole
derivatives have made them an attractive target for synthetic
chemists.
Scheme 1: Retrosynthetic analysis of 4-substituted oxazolo[4,5-
c]quinolines
Recently, we have reported the synthesis pyrrolo-quinoline
compounds as anti-tubercular and selective metal sensors based on
modified Pictet-Spengler approach.7 In continuation of our studies
on fused-heterocycles, synthesis of 4-substituted oxazolo[4,5-
c]quinolines was conceived to further explore their properties. Only
few papers pertaining to the synthesis of substituted oxazolo[4,5-
c]quinoline are reported in the literature.8 Moreover, these methods
are based only on the formation of the oxazole ring in the final step
of the sequence, leading to oxazolo[4,5-c]quinoline skeleton.
However, for our work, we were interested in synthesizing fused-
oxazoles with diverse substitution at position 4. Based on our
previous experience,7a we envisaged the application of modified
Pictet-Spengler approach would be appropriate to access 4-
substituted oxazolo[4,5-c]quinoline 4. A reterosynthetic analysis of
our target structure is depicted in Scheme 1. The oxazolo-quinoline
ring 4 can be assembled from oxazole 2 upon C-4 functionalization
of the oxazole ring. Intermediate 2 can be synthesized from 2-
nitrobenzaldehyde (1) in two steps using van Leusen oxazole
synthesis.13
While designing this synthesis we were aware of the synthetic
challenge posed by the functionalization of oxazole at C-4 position
in presence of more reactive C-2 position. Most literature examples
related to C-4 functionalization of oxazole ring are initiated by
lithiation, followed by reaction with suitable electrophiles. If both C-
2 and C-4 positions are available, lithiation happens at oxazole C-2
position selectively with subsequent equilibration to ring opened
lithium enolate.9 It is the ambident nucleophilicity of ring opened
lithium enolate which results in reaction with electrophiles to give C-
4 substituted oxazoles at low temperatures. When both C-2 and C-5
positions are blocked, lithiation happens directly on C-4 position.10
Other known methods for functionalization of C-4 position includes
Heck, Negishi, Stille, Sonagashira and Suzuki couplings, which also
require prior activation of the aforementioned site.11 Antilla et.al. has
reported functionalization of C-4 position via C-H activation using
Pd(OAc)2 as catalyst.12 However, in their work the C-4
functionalization was carried out when more reactive C-2 and C-5
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C4OB02224F
positions were blocked. To the best of our information no method screened for the desired transformation to take place. The reaction
has been reported in the literature demonstrating direct temperatures were usually kept high due to low reactivity of C-4
o
functionalization of C-4 position without aid of any supporting step, position. The reactions were initiated at 150 C using hexamethyl
when more reactive C-2 position is also available in the molecule. phosphoramide (HMPA) as solvent and monitored by TLC. Failure
For our work, lithiation or other methods for C-4 activation did not to see any conversion from aldimine to the desired compound
appeared to be viable as side reactions are likely to happen. prompted us to increase the temperature further to 200 oC.
Therefore we sought to device a methodology to functionalize C-4 Gratifyingly, the increase in temperature did result in the formation
position of oxazole leading to fused oxazolo-quinoline ring system of desired product in case of Cu(TFA)2, Cu(acac)2 and Cu(OAc)2.
(4). Herein, we wish to report the synthesis of 4-substituted The best yields were obtained using Cu(TFA)2. Because the role of
oxazolo[4,5-c]quinolines by direct functionalization of C-4 position nitrobenzene is also well documented as an oxidizing agent in
of the oxazole ring.
Skraup synthesis of quinoline,14 we thought its use might lead to
improved yields of 4. Additional solvents, such as ethylene glycol
and nitrobenzene were screened for further improvement in the
yields. Indeed, better yields of 4 were obtained in nitrobenzene
compared to HMPA (Table 1, Entry 11). Furthermore, additives such
as 1, 10-phenanthroline known to facilitate reactions catalyzed by
Cu(TFA)2 were utilized.15 The reactions were then carried out in the
presence of Cu(TFA)2 with 1, 10-phenathroline as additive in
various combinations (Table 1, entries 13-16). Thus, after a thorough
screening, best results were obtained with the use of 30 mol% of
both Cu(TFA)2 and 1, 10-phenathroline in nitrobenzene at 200 oC.
Results and discussions
The synthesis of target molecules 4 commenced with a general
synthesis of amino oxazole 2 (Scheme-2). o-Nitrobenzaldehyde was
converted to 5-(2-nitrophenyl)oxazole 1 in the presence of TosMIC
and potassium carbonate in methanol using literature procedure.13
Subsequently, a Fe mediated reduction of the nitro functionality was
carried out to obtain compound 2.7a
Table 1: Screening of catalysts for synthesis of quinoline ring
Scheme 2: Synthesis of 2-(oxazol-5-yl)aniline (2)
Having accomplished the synthesis of 2-(oxazol-5-yl)aniline 2, we
set out to explore the condensation-cyclization reaction of 2 with
various aldehydes, as outlined in the retrosynthetic analysis (Scheme
1). Taking a cue from Pictet-Spengler, initial attempts were carried
out in presence of acids (Lewis and Bronsted acids), using 2-
(oxazol-5-yl)aniline (2) and benzaldehyde (3a) as the model
reactants. Preliminary investigations were carried out with acetic
acid / trifluoroacetic acid / ZnCl2 / FeCl3 / BF3.OEt2. Inspired from
our previous experience with 2-(1H-pyrrol-3-yl)aniline,7a at first, the
reactions were carried out in ethanol as a solvent at 80 oC, except for
BF3.OEt2, which was used in solvent THF. However, only the
formation aldimine 5 was observed under these conditions (Scheme
3). No further cyclization of imine at C-4 position of oxazole was
observed. These results reflect the low reactivity of C-4 position of
oxazole towards the desired cyclization. Despite increasing the
Catalyst (mol %)/
Entry
Solvent
Yield
Additive(mol%)
Cu(TFA)2 (20)
Pd(OAc)2 (20)
Pd(TFA)2 (20)
Yb(OTf)3 (20)
Cu(acac)2 (20)
CuI (20)
1
2
HMPA
HMPA
25
0
3
HMPA
0
4
HMPA
0
5
HMPA
22
0
6
HMPA
7
Cu(OAc)2 (20)
Fe(acac)2 (20)
Cu(TFA)2 (10)
Cu(TFA)2 (20)
Cu(TFA)2 (20)
Cu(TFA)2 (30)
Cu(TFA)2 (20)/1,10
HMPA
10
0
8
HMPA
9
HMPA
7
o
reaction temperature to 140 C (in xylene), further cyclization of 5
10
11
12
13
ethylene glycol
nitrobenzene
nitrobenzene
nitrobenzene
4
could not be achieved.
38
46
48
phenanthroline (20)
Cu(TFA)2 (30)/ 1,10
14
nitrobenzene
61
Scheme 3: Proposed synthesis of 4-substituted oxazolo[4,5-
c]quinolines using various Lewis and bronsted acids
phenanthroline (30)
Cu(TFA)2 (40)/ 1,10
phenanthroline (40)
15
16
nitrobenzene
nitrobenzene
42
46
Subsequently, we expanded our search of a Lewis acid suitable to
catalyse the formation of the oxazolo-quinoline ring. As shown in
Table 1, a number of potential transition metal catalysts were
Cu(TFA)2 (30)/ 1,10
phenanthroline (30)
2 | J. Name., 2012, 00, 1-3
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After having the optimized conditions for the formation of
oxazolo[4,5-c]quinoline in hand, we set out to demonstrate the
substrate scope of the newly developed methodology. As listed in
Table 2, wide array of aromatic aldehydes were examined in the
synthesis of oxazolo-quinoline 4a-l. In general, aldehydes possessing
electron donating groups (such as -OMe, -OH) resulted in good
yields of the corresponding fused-oxazole products. On the other
hand, substrates with electron-withdrawing substitutions (e.g. CF3, -
NO2) yielded the cyclized products in moderate yields. Interestingly,
the yields in the cases of halo-substituted reactants were found to be
effected by the electronegativity of the halogens. Improved yield was
obtained using bromobenzaldehyde, whereas, the yield was
compromised in the case of fluorobenzaldehyde. Remarkably, the
use of thiophenecarboxaldehyde in place of benzaldehyde also
resulted in the corresponding quinoline substituted product 4d in
moderate yields under the optimized conditions. Reactions were also
attempted with aliphatic aldehydes but no product formation was
observed.
4l (40%)
4d (42%)
4h (55%)
aReaction condition: 1.25 mmol of 2, 1.25 mmol of aldehyde,
Cu(OCOCF3)2(30 mol%), 1,10-phenathroline(30 mol%) and
nitrobenzene(1ml).
Based on the above observations a plausible mechanism for the
formation of oxazolo[3,2-c]quinoline systems is proposed (Scheme-
4). It is assumed that Cu(TFA)2 forms complex with the imine
nitrogen which is followed by attack of oxazole C-4 on imine
carbon. The resulting cyclic intermediate then undergoes
aromatization to a more stable fused oxazolo-quinoline system.
Higher yields of 4 with electron rich aldehydes further support the
proposed mechanism. However, given the low reactivity of oxazole
C-4 position there is also a possibility of involvement of C-H
activation. A detailed investigation is required in future to fully
understand the mechanism involved.
Table 2: Synthesis of various 4-substituted oxazolo[4,5-
c]quinolinesa
O
O
N
N
N
N
Cu
5
4a (61%)
4i (44%)
4e (70%)
O
O
N
N
[O]
N
N
H
4a
Scheme 4: Initial attempt to synthesize 4-substituted oxazolo[4,5-
c]quinolines using various Lewis and bronsted acids
4j (61%)
4b (41%)
4f (77%)
Next, in order to further demonstrate the synthetic utility of the
developed methodology we attempted the synthesis of fused
oxazolo-[1,8]-naphthyridine system. We began with the conversion
of commercially available 2-amino-3-formylpyridine to 3-(oxazol-5-
yl)pyridine-2-amine (6) by reaction under basic condition with
TosMIC. To our delight, the amine 6 reacted with aromatic
aldehydes analogous to 2-(oxazol-5-yl)aniline (2), resulting in the
formation of 4-aryl substituted oxazolo[4,5-c][1,8]naphthyridine (7a-
d; Table 3) in good yields.
O
N
NO2
N
4g (60%)
4c (43%)
4k (46% )
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Table 3: Synthesis of various 4-aryl substituted oxazolo[4,5- 2-(oxazol-5-yl)aniline or 3-(oxazol-5-yl)pyridin-2-amine (1.25
c][1,8]naphthyridinesa
mmol), aldehyde(1.25 mmol), Cu(OCOCF3)2(30 mol%), 1,10-
phenathroline(30 mol%) and nitrobenzene(1ml) were added in a 25
ml round bottam flask under nitrogen atmosphere. The reaction
mixture was heated at 200 0C for 8h and then cooled to room
temperature. The reaction mixture was diluted with EtOAc (5mL)
adsorbed on silica gel and purified by a column chromatography on
silica gel using hexane/ethyl acetate or hexane/Et2O as the eluent to
give the corresponding product.
4-Phenyloxazolo[4,5-c]quinoline (4a): Yield: 61%. Light yellow
o
solid, m.p. 134-138 C; Rf 0.5 [hexane-Et2O (9:1)]; νmax (KBr)/cm-1
3068, 1507, 1049; 1H NMR (300 MHz, DMSO) δ 7.58 (d, J = 7.4
Hz, 3H), 7.72 (d, J = 6.6 Hz, 1H), 7.80 (d, J = 7.2 Hz, 1H), 8.20 (d, J
= 5.5 Hz, 2H), 8.69 (d, J = 5.6 Hz, 2H), 9.09 (d, J = 3.7 Hz, 1H); 13
C
NMR (75 MHz, DMSO) δ 115.62, 120.60, 127.93, 128.99, 129.47,
130.04, 130.63, 131.86, 136.80, 145.38, 149.85, 152.20, 154.23;
HRMS-ESI (m/z): Calcd for C16H11N2O [M+H]+ 247.0871, found
247.0865.
4-(4-Nitrophenyl)oxazolo[4,5-c]quinoline (4b): Yield: 41%.
o
Yellow solid, m.p. 184-186 C; Rf 0.5 [hexane-EtOAc (8:2)]; νmax
(KBr)/cm-1 3067, 1515, 1350, 1065; H NMR (300 MHz, DMSO) δ
1
aReaction condition: 1.25 mmol of 6, 1.25 mmol of aldehyde,
Cu(OCOCF3)2(30 mol%), 1,10-phenathroline(30 mol%) and
nitrobenzene(1ml).
7.84 (t, J = 7.4 Hz, 1H), 7.92 (t, J = 7.7 Hz, 1H), 8.32 (t, J = 7.9 Hz,
2H), 8.48 (d, J = 8.7 Hz, 2H), 8.99 (d, J = 8.6 Hz, 2H), 9.22 (s, 1H);
13C NMR (75 MHz, DMSO) δ 115.96, 120.79, 124.24, 128.95,
130.33, 130.42, 130.51, 132.18, 142.51, 145.31, 147.21, 148.60,
152.51, 154.79; HRMS-ESI (m/z): Calcd for C16H10N3O3 [M+H]+
292.0722, found 292.0704.
Conclusions
In conclusion, we have developed a Cu(TFA)2-catalyzed
synthesis of substituted oxazolo[4,5-c]quinoline from 2-
4-(4-(Trifluoromethyl)phenyl)oxazolo[4,5-c]quinoline (4c): Yield:
43%. Light yellow solid, m.p. 122-126 oC; Rf 0.5 [hexane-Et2O
(8:2)]; 1H NMR (300 MHz, DMSO) δ 7.89 – 7.64 (m, 2H), 7.93 (d,
J = 7.5 Hz, 2H), 8.21 (d, J = 6.0 Hz, 2H), 8.85 (d, J = 7.4 Hz, 2H), δ
9.12 (s, 1H); 13C NMR (75 MHz, DMSO) δ 115.83, 120.69, 125.85,
125.88, 125.93, 128.58, 129.97, 130.20, 130.32, 131.98, 140.38,
145.26, 147.96, 152.37, 154.57; HRMS-ESI (m/z): Calcd for
C17H10F3N2O [M+H]+ 315.0745, found 315.0733.
(oxazol-5-yl)aniline with various aldehydes via modified Pictet-
Spengler reaction. In the course of this synthesis we have also
demonstrated, for the first time, a method that does not require
any prefunctionalization of unreactive C-4 position of oxazole.
The developed methodology is amenable to a wide range of
functional groups and allows the formation of fused oxazolo-
quinoline/oxazolo-1,8-naphthyridine systems in good to
moderate yields. Since many natural products containing
oxazole are C-4 substituted, the method developed in this paper
will open up the possibility of synthesizing these molecules
without aid of any additional activation or prefunctionalization
step.
4-(Thiophen-2-yl)oxazolo[4,5-c]quinoline (4d): Yield: 42%. Light
brown solid, m.p. 178-182 oC; Rf 0.4 [hexane-EtOAc (9:1)]; νmax
(KBr)/cm-1 3090, 1521, 1053; 1H NMR (300 MHz, CDCl3) δ 7.28
(t, J = 4.2 Hz, 1H), 7.62 (dd, J = 15.2, 6.4 Hz, 2H), 7.76 (t, J = 7.3
Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H), 8.26 (d, J = 8.0 Hz, 1H), 8.33 (s,
1H), 8.69 (d, J = 2.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 115.65,
120.18, 126.83, 128.52, 129.53, 129.58, 131.02, 141.65, 145.81,
146.20, 151.64, 152.21; HRMS-ESI (m/z): Calcd for C14H9N2OS
[M+H]+ 253.0436, found 253.0428.
Experimental
All starting materials were purchased from Spectrochem, SRL,
Aldrich, and Sd Fine(India) and used directly without further
purification. Solvents were dried using standard methods and
distilled before use. Melting points were recorded on a Stuart SMP
30 melting point apparatus and are uncorrected. 1H NMR (300 MHz)
and 13C (75 MHz) spectra were recorded in CDCl3 and DMSO using
(CH3)4Si as internal standard. IR spectra were recorded as KBr
plates on Jasco FT/IR-4200 instrument. High resolution mass spectra
were obtained at the Department of Chemistry, Dalhousie
University, Canada, by Mr. Xiao Feng.
4-(4-Methoxyphenyl)oxazolo[4,5-c]quinoline (4e): Yield: 70%.
o
Light yellow solid, m.p. 108 C. Rf 0.45 [hexane-EtOAc (9:1)]; νmax
(KBr)/cm-1 2934, 1507, 1030; 1H NMR (300 MHz, CDCl3) δ 3.93
(s, 2H), 7.12 (d, J = 8.7 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.78 (t, J =
7.7 Hz, 1H), 8.21 (d, J = 8.1 Hz, 1H), 8.30 (d, J = 9.8 Hz, 1H), 8.74
(d, J = 8.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 55.42, 114.05,
115.55, 120.16, 126.68, 129.37, 129.57, 129.87, 131.00, 131.67,
General procedure for the preparation of 4-substituted
oxazolo[4, 5-c]quinolones/[1, 8]naphthyridines
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145.90, 150.67, 151.28, 152.45, 161.31; HRMS-ESI (m/z): Calcd for 4-(3-Nitrophenyl)oxazolo[4,5-c]quinoline (4k): Yield: 46%. Light
C17H13N2O2 [M+H]+ 277.0977, found 277.0976.
yellow solid, m.p. 200-202 oC; Rf 0.6[hexane-EtOAc(7:3)]; νmax
1
(KBr)/cm-1 2926, 1524, 1347,1064; H NMR (300 MHz, DMSO) δ
2-(Oxazolo[4,5-c]quinolin-4-yl)phenol (4f): Yield: 77%. Yellow
solid, m.p. 164-168 oC; Rf 0.5 [hexane-EtOAc(7:3)]; νmax (KBr)/cm-1
3123, 2701, 1513, 1302; 1H NMR (300 MHz, DMSO) δ 6.96 (t, J =
7.7 Hz, 2H), 7.38 (t, J = 7.5 Hz, 1H), 7.69 (t, J = 7.5 Hz, 1H), 7.79
(t, J = 7.5 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H),
9.12 (s, 1H), 9.20 (d, J = 7.9 Hz, 1H), 14.91 (s, 1H); 13C NMR (75
MHz, DMSO) δ 115.19, 118.10, 118.16, 119.03, 120.69, 127.71,
7.75 (t, J = 7.4 Hz, 1H), 7.83 (t, J = 7.8 Hz, 2H), 8.22 – 8.12 (m,
2H), 8.33 (d, J = 8.0 Hz, 1H), 9.06 (d, J = 7.7 Hz, 1H), 9.12 (s, 1H),
9.46 (s, 1H);13C NMR (75 MHz, DMSO) δ 115.93, 120.77, 123.68,
125.20, 128.73, 130.20, 130.47, 130.80, 131.87, 135.29, 138.08,
145.20, 148.58, 152.48, 152.50, 152.52, 154.77; HRMS-ESI (m/z):
Calcd for C16H10N3O3 [M+H]+ 292.0722, found 292.0728.
128.23, 130.87, 131.31, 132.99, 142.20, 151.65, 152.42, 154.38, 4-(3-(Trifluoromethyl)phenyl)oxazolo[4,5-c]quinoline (4l): Yield:
160.98; HRMS-ESI (m/z): Calcd for C16H11N2O2 [M+H]+ 263.0821, 40%. Light yellow solid, m.p. 118-120 oC; Rf 0.5[hexane-Et2O(9:1)];
1
found 263.0809.
ν
max (KBr)/cm-1 3117, 2972, 1515, 1320, 1123; H NMR (300 MHz,
DMSO) δ 7.80 (tt, J = 19.3, 7.5 Hz, 5H), 8.19 (d, J = 8.2 Hz, 2H),
8.94 (d, J = 7.6 Hz, 1H), 9.01 (s, 1H), 9.10 (s, 1H);13C NMR (75
MHz, DMSO) δ 115.75, 120.61, 125.53, 125.58, 125.62, 127.05,
127.08, 127.11, 128.42, 129.61, 130.03, 130.12, 130.23, 131.75,
132.98, 137.50, 145.16, 147.59, 152.31, 154.52; HRMS-ESI (m/z):
Calcd for C17H10F3N2O [M+H]+ 315.0745, found 315.0747.
4-(3,4-Dimethoxyphenyl)oxazolo[4,5-c]quinoline (4g): Yield:
o
60%. Light brown solid, m.p. 138 C; Rf 0.5[hexane-EtOAc (8:2)];
νmax (KBr)/cm-1 3070, 3007, 1591, 1512, 1268, 1146; 1H NMR
(300 MHz, CDCl3) δ 4.00 (s,3H), 4.09 (s,3H), 7.08 (d, J = 8.5 Hz,
1H), 7.64 (t, J = 7.5 Hz, 1H), 7.78 (t, J = 7.7 Hz, 1H), 8.20 (d, J =
8.1 Hz, 1H), 8.31 (t, J = 4.1 Hz, 2H), 8.48 (d, J = 8.4 Hz, 1H), 8.37
(s, 1H); 13C NMR (75 MHz, CDCl3) δ 55.9, 56.0, 110.8, 111.7, 4-Phenyloxazolo[4,5-c][1,8]naphthyridine (7a): Yield: 73%. Light
115.5, 120.1, 123.1, 126.7, 129.3, 129.8, 131.7, 145.8, 149.0, 150.4, yellow solid, m.p. 168-170oC; Rf 0.5[hexane-EtOAc(5:5)]; νmax
150.8, 151.2, 152.4; HRMS-ESI (m/z): Calcd for C18H15N2O3 (KBr)/cm-1 2923, 2854, 1488, 1273, 1059; 1H NMR (300 MHz,
[M+H]+ 307.1083, found 307.1072.
DMSO) δ 7.60 (s, 3H). 7.78 – 7.70 (m, 1H), 8.72 (t, J = 5.9 Hz, 3H),
9.14 (s, 1H), 9.19 (d, J = 5.3 Hz, 1H);13C NMR (75 MHz, DMSO) δ
110.83, 123.15, 129.15, 129.76, 130.51, 131.25, 132.37, 132.38,
136.48, 152.03, 152.44, 153.40, 153.77, 155.35; HRMS-ESI (m/z):
Calcd for C15H10N3O [M+H]+ 248.0824, found 248.0812.
4-(4-Chlorophenyl)oxazolo[4,5-c]quinoline (4h): Yield: 55%.
o
Light yellow solid, m.p. 182 C; Rf 0.5[hexane-EtOAc (9:1)]; νmax
(KBr)/cm-1 2925, 1509, 1181, 1065; 1H NMR (300 MHz, CDCl3) δ
7.55 (d, J = 8.5 Hz, 2H), 7.65 (t, J = 7.5 Hz, 1H), 7.78 (t, J = 7.7 Hz,
1H), 8.19 (d, J = 8.1 Hz, 1H), 8.27 (d, J = 10.1 Hz, 2H), 8.70 (d, J =
4-(4-Methoxyphenyl)oxazolo[4,5-c][1,8]naphthyridine
(7b):
8.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 115.74, 120.17, 127.26, Yield: 60%. Yellow solid, m.p. 156-157 oC. Rf 0.5[hexane-
128.81, 129.51, 130.09, 130.68, 131.72, 135.26, 136.26, 145.76, EtOAc(4:6)]; νmax (KBr)/cm-1 2924, 1565, 1459, 1127; 1H NMR
149.46, 151.42, 152.49; HRMS-ESI (m/z): Calcd for C16H10ClN2O (300 MHz, DMSO) δ 3.87 (s, 3H), 7.15 (d, J = 8.2 Hz, 3H), 7.67 (s,
[M+H]+ 281.0482, found 281.0467.
1H), 8.19 (d, J = 8.1 Hz, 1H), 8.88 – 8.58 (m, 2H), 9.19 – 8.99 (m,
1H
13C NMR (75 MHz, DMSO) δ 55.33, 110.02, 114.06, 122.13,
);
4-(4-Fluorophenyl)oxazolo[4,5-c]quinoline (4i): Yield: 44%
Light yellow solid, m.p. 158-162 oC; Rf 0.6 [hexane-Et2O (9:1)];
νmax (KBr)/cm-1 3076, 1507, 1228, 1067; H NMR (300 MHz,
.
128.55, 129.88, 130.95, 131.47, 151.19, 151.79, 153.01, 153.07,
154.61, 161.42; HRMS-ESI (m/z): Calcd for C16H12N3O2 [M+H]+
278.0930, found 278.0918.
1
CDCl3) δ 7.27 (d, J = 17.2 Hz, 2H), 7.65 (t, J = 7.5 Hz, 1H), 7.78 (t,
J = 7.7 Hz, 1H), 8.19 (d, J = 8.1 Hz, 1H), 8.28 (d, J = 8.5 Hz, 2H),
8.80 – 8.71 (m, 2H);13C NMR (75 MHz, CDCl3) δ 115.47, 115.65,
115.76, 120.17, 127.13, 129.51, 129.97, 131.42, 131.54, 131.66,
132.93, 132.97, 145.72, 149.70, 151.44, 152.50, 162.50, 165.82;
HRMS-ESI (m/z): Calcd for C16H10FN2O [M+H]+, 265.0777 found
265.0781.
2-(Oxazolo[4,5-c][1,8]naphthyridin-4-yl)phenol (7c): Yield: 61%.
Yellow solid, m.p. 170 oC; Rf 0.5[hexane-EtOAc (4:6)]; νmax
1
(KBr)/cm-1 3092, 2931, 1502, 1263; H NMR (300 MHz, DMSO) δ
7.00 (t, J = 6.6 Hz, 2H), 7.43 (t, J = 7.5 Hz, 1H), 7.75 (dd, J = 7.8,
4.2 Hz, 1H), 8.69 (d, J = 8.1 Hz, 1H), 9.08 (d, J = 3.4 Hz, 1H), 9.24
(d, J = 9.2 Hz, 2H), 15.25 (s, 1H); 13C NMR (75 MHz, DMSO) δ
110.56, 117.71, 118.46, 119.17, 123.52, 130.53, 131.39, 131.57,
133.77, 150.69, 152.62, 153.46, 154.22, 155.46, 161.59; HRMS-ESI
(m/z): Calcd for C15H10N3O2 [M+H]+ 264.0773, found 264.0761.
4-(4-Bromophenyl)oxazolo[4,5-c]quinoline (4j): Yield: 61%. Light
o
yellow solid, m.p. 170-175 C; Rf 0.5[hexane-EtOAc(9:1)]; νmax
(KBr)/cm-1 2928, 1514,1064; 1H NMR (300 MHz, CDCl3) δ 7.66
(d, J = 7.2 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.79 (t, J = 7.7 Hz, 1H),
8.21 (d, J = 8.1 Hz, 1H), 8.29 (d, J = 9.3 Hz, 1H), 8.65 (d, J = 8.0
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 115.79, 120.20, 124.84,
127.31, 129.55, 130.11, 130.94, 131.75, 131.78, 135.70, 145.78,
149.56, 151.45, 152.54; HRMS-ESI (m/z): Calcd for C16H10BrN2O
[M+H]+ 324.9977, found 324.9973.
4-(Thiophen-2-yl)oxazolo[4,5-c][1,8]naphthyridine (7d):
Yield: 55%. Yellow solid, m.p. 154-158 oC; Rf 0.5[hexane-
EtOAc (6:4)]; νmax (KBr)/cm-1 2925, 1498, 1278, 1065; 1H
NMR (300 MHz, DMSO) δ 7.36 – 7.30 (m, 1H), 7.70 (dd,
8.0, 4.3 Hz, 1H), 7.92 (d,
J =
J
= 4.9 Hz, 1H), 8.72 – 8.59 (m, 3H),
9.10 – 9.06 (m, 1H), 9.20 (s, 1H); 13C NMR (75 MHz, DMSO)
δ 110.83, 122.76, 129.47, 130.51, 130.84, 132.18, 132.33,
141.47, 147.63, 152.10, 153.48, 153.72, 155.76; HRMS-ESI
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 5

Organic & Biomolecular Chemistry
Page 6 of 6
ARTICLE
VJieowuArrtnicalelONnlainme e
DOI: 10.1039/C4OB02224F
(m/z): Calcd for C13H8N3OS [M+H]+ 254.0388, found
254.0383.
Akula, P. Z. El-Khoury, A. Nag and A. Bhattacharya, RSC.
Adv., 2014, 4, 25605.
8. (a) E. A. Voight, J. F. Daanen, and M. E. Kort. J. Org. Chem.
2010, 75, 8713. (b) S. Eswaran, A. V. Adhikari and R. Ajay
Kumar. Eur. J. Med. Chem. 2010, 45, 957.
Acknowledgements
M.A. thanks University Grants Commission (India) for SRF.
A.B. thanks Department of Science and Technology,
Government of India for the fast-track grant.
9. (a) J. C. Hodges, W.C.Patt and C. J. Connolly, J. Org. Chem.,
1991, 56, 449. (b) E. Crowe, F. Hossner and M. J. Hughes,
Tetrahedron, 1995, 51, 8889. (c) E. Vedejs and L. M. Luchetta,
J. Org. Chem., 1999, 64, 1011.
Notes and references
a
Department of Chemistry, Birla Institute of Technology and Science-
10. (a) H. H.Wasserman, R. W. DeSimone, W. B. Ho, K. E.
McCarthy, K. S. Prouse and A. P. Spada, Tetrahedron Lett.
1992, 33, 7207. (b) J. Saunders, M. Cassidy, S. B. Freedman, E.
A. Harley, L.L. Iversen, C. Kneen, A. M. Macleod, K. J.
Merchant, R. J. Snow and R. J. Baker, J. Med. Chem. 1990, 33,
1128.
Pilani(Hyderabad Campus), Hyderabad-500078, India. E-mail:
anupam@hyderabad.bits-pilani.ac.in; Fax: +91-40-66303998; Tel: +91-
40-66303522.
b Department of Biology and Chemistry, Nipissing University, North Bay,
ON, P1B 8L7, Canada.
11. (a) T. R. Kelly and F. Lang, J. Org. Chem., 1996, 61, 4623. (b)
B. Li, R. A. Buzon and Z. Zhang, Org. Process Res. Dev. 2007,
11, 951. (c) A. B. Smith III, P. R. Verhoest, K. P. Minbiole and
M. J. Schelhaas, J. Am. Chem. Soc. 2001, 123, 4834. (d) A. B.
Smith III, T. M. Razler, J. P. Ciavarri, T. Hirose and T.
Ishikawa, Org. Lett. 2005, 7, 4399. (e) B. Clapham and A.
Sutherland, J. Org. Chem., 2001, 66, 9033. (f) J. V. Schaus and
J. S. Panek, Org. Lett. 2000, 2, 469. (g) H. Araki, T. Katoh and
M. Inoue, Synlett. 2006, 555. (h) N. F. Langille, L. A. Dakin
and J. S. Panek, Org. Lett. 2002, 4, 2485. (i) E. F. Flegeau, M.
W. Popkin and M. F. Greaney, Org. Lett. 2006, 8, 2495.
12. S. Cui, L. Wojtas and J.C. Antilla, Org. Lett. 2011, 13, 5040.
13. (a) J. Sisko, A. J. Kassick, M. Mellinger, J. J. Filan, A. Allen
and M. A. Olsen, J. Org. Chem. 2000, 65, 1516. (b) P. Radha
Krishna, V. V. Ramana Reddy, G. V. M. Sharma,
Synlett. 2003, 1619. (c) T. G. Murali Dhar, Z. Shen, C. A.
Fleener, K. A. Rouleau, J. C. Barrish, D. L. Hollenbaug and E.
J. Iwanowicz, Bioorg. Med. Chem. Lett. 2002, 12, 3305.
14. (a) Z. H. Skraup, Berichte, 1880, 13, 2086. (b) R. H. F. Manske,
Chem. Rev. 1942, 30, 113.
1. (a) R. Jensen, H. Irschik, H. Reichenbach, G. Wray and G.
Hofle, Leibigs. Ann. Chem. 1994, 759. (b) M. J. Don, C. C.
Shen, Y. L. Lin, W. J. Syu, Y. H. Ding and C. M. Sun, J. Nat.
Prod. 2005, 68, 1066. (c) F. W. Lin, A. G. Damu and T. S. Wu,
J. Nat. Prod. 2006, 69, 93. (d) J. Ogino, R. E. Moore, G. M. L.
Patterson and C. D. Smith, J. Nat. Prod. 1996, 59, 581. (e) R.
H. Schelessinger and Y. –J. Li, J. Am. Chem. Soc. 1996, 118,
3301.
2. (a) G.C. Moraski, M. Chang, A. Villegas-Estrada, S. G.
Franzblau, U. Mollmann and M. J. Miller, Eur. J. Med. Chem.
2010, 45, 1703. (b) X. Lu, X. Liu, B. Wan, S. G. Franzblau, L.
Chen, C. Zhou and Q. You, Eur. J. Med. Chem. 2012, 49, 164.
(c) D. Sriram, P. Yogeeswari, R. Thirumurugan and R. K.
Pavana, J. Med. Chem. 2006, 49, 3448. (d) N. Rastogi, J.
Abdul, K. S. Goh, A. Devallois, E. Philogene and P. Bourgeois,
FEMS Immunol. Med. Microbiol. 1998, 20, 267.
3. (a) N. R. Stokes, N. Baker, J. M. Bennett, P. K. Chauhan, I.
Collins, D. T. Davies, M. Gavade, D. Kumar, P. Lancett, R.
Macdonald, L. Macleod, A. Mahajan, J. P. Mitchell, N. Nayal,
Y. N. Nayal, G. R. Pitt, M. Singh, A. Yadav, A. Srivastava, L.
G. Czaplewski and D. J. Haydon, Bioorg. Med. Chem. Lett.
2014, 24, 353. (b) E. A. Bakhite, T. A. Mohamed and A. E.
Abdel-Rahman, J. Chem. Tech. Biotech. 1992, 55, 157. (c) C.
W. Ford, G. E. Zurenko and M. R. Barbachyn, Curr. Drug.
Targets. Infect. Disord. 2001, 1, 181.
15. (a) T. M. U. Ton, F. Himawan, J. W. W. Chang and P. W. H.
Chan, Chem. Eur. J. 2012, 18, 12020. (b) T. M. U. Ton, C.
Tejo, D. L. Y. Tiong and P. W. H. Chan, J. Am. Chem. Soc.
2012, 134, 7344.
4. R. J. Perner, J. R. Koenig, S. Didomenico, A. Gomtsyan, R. G.
Schmidt, C. H. Lee, M. C. Hsu, H. A. McDonald, D. M.
Gauvin, S. Joshi, T. M. Turner, R. M. Reilly, P. R. Kym and M.
E. Kort, Bioorg. Med. Chem. 2010, 18, 4821.
5. (a) C. U. Murade, V. Subramaniam, C. Otto and M. L. Bennink,
Biophys. J. 2009, 97, 835. (b) F. Johansen and J. P. Jacobsen, J.
Biomol. Str. Dyn. 1998, 16, 205.
6. (a) Z. Fang, S. Wang, L. Zhao, B. Dong, Z. Xu, J. Ren and Q.
Yang, Mater. Lett. 2008, 62, 1514. (b) H. Takechi, Y. Oda, N.
Nishizono, K. Oda and M. Machida, Chem. Pharm. Bull. 2000,
48, 1702. (c) A. Mishra and G. Krishnamoorthy, Photochem.
Photobiol. Sci. 2012, 11, 1356. (d) F. Mahuteau-Betzer and S.
Piguel, Tetrahedron Lett. 2013, 54, 3188.
7. (a) M. Akula, J. Padma Sridevi, P. Yogeeswari, D. Sriram and
A. Bhattacharya, Monatsh. Chem. 2014, 145, 811. (b) M.
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