A concise synthetic strategy to functionalized chromenones via [5+1] heteroannulation and facile C-N/C-S/C-O bond formation with various nucleophiles

Article abstract of DOI:10.1016/j.tetlet.2010.11.020

A highly efficient strategy to 2,3-substituted chromen-4H-ones has been developed. The methodology involves unexpected intramolecular heteroannulation of readily accessible substituted 2-hydroxy-ω-nitroacetophenone with carbon disulfide in the presence K<

Full text of DOI:10.1016/j.tetlet.2010.11.020

Tetrahedron Letters 52 (2011) 254–257
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A concise synthetic strategy to functionalized chromenones via [5+1]
heteroannulation and facile C–N/C–S/C–O bond formation with various
nucleophiles
Mahesh M. Savant a, Neetha S. Gowda b, Akshay M. Pansuriya a, Chirag V. Bhuva a, Naval Kapuriya a,
Sridhar M. Anandalwar b, Shashidhara J. Prasad b, Anamik Shah a, Yogesh T. Naliapara a,
⇑
a Department of Chemistry, Saurashtra University, Rajkot 360 005, Gujarat, India
b Department of Studies in Physics, Manasagangotri, Mysore 570 006, Mysore, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient strategy to 2,3-substituted chromen-4H-ones has been developed. The methodology
involves unexpected intramolecular heteroannulation of readily accessible substituted 2-hydroxy-
nitroacetophenone with carbon disulfide in the presence K2CO3 followed by methylation with methyl
iodide. These chromenones were further reacted with various nucleophiles such as amines, thiols, and
alkoxide resulting in the facile C–N, C–S, and C–O bond formation. The scope and generality have been
discussed.
Received 25 August 2010
Revised 1 November 2010
Accepted 4 November 2010
Available online 11 November 2010
x-
Ó 2010 Elsevier Ltd. All rights reserved.
In recent decades, chromenone and its derivatives have at-
tracted considerable attention of medicinal and synthetic organic
chemists because of a wide range of biological activities, like,
antitumor,1 anti-inflammatory,2 antiallergic,3 and inhibitors of
DNA-dependent protein kinase.4 The corresponding 2-substi-
tuted-3-nitro chromenones are molecules of current interest as
they have significant biological activity.5–7 Moreover, chromenon-
es bearing NO2 group at C3, afford the possibility of further modi-
fications through which, one can generate, a large number of
pharmacologically important compounds.8,9 Given the biological
significance of 2,3-substituted chromen-4H-ones, several routes
are reported in the literature for the synthesis of substituted
chromenone via [4+2] annulation,10 [5+1] addition,11 [4+1+1] addi-
tion reaction,12 or electrophilic substitution reactions over the pre-
constructed chromone motifs.13 However, these potentially useful
methods have not been thoroughly explored. Moreover, the few
existing examples are rather limited in scope and suffer from sev-
eral practical disadvantages such as extreme conditions or low
yields.14 Therefore, developing a simple and effective method to
synthesize 2-substituted-3-nitro chromenones via readily avail-
able starting material is essential.
recent progresses in the wide applications of nitroketene S,S-acetal
for the construction of a diverse array of polysubstituted carbon
and heterocyclic compounds,9c,17 we have focused our efforts on
design and synthesis of 2-substituted-3-nitro chromenone using
nitroketene S,S-acetal based synthons prepared from substi-
tuted
chromenone can be efficiently prepared through [5+1] heteroann-
ulation of substituted 2-hydroxy- -nitro acetophenone followed
x-nitro acetophenone. We found that 2-substituted-3-nitro
x
by direct C–N, C–S, and C–O bond formation with various nucleo-
philes (–NHR, –SR, –OR) in excellent yields and high chemical pur-
ity. We report herein a novel and facile reaction for the synthesis of
highly substituted chromenones.
We have recently reported an efficient general process for the
synthesis of nitro group containing dihydropyrimidines using 2-
hydroxy-x
-nitro acetophenone (1a),18b various arylaldehydes,
urea, and etidronic acid as catalysts.18c These studies motivated
us to utilize 1a as a versatile synthon to make new nitroketene
dithioacetals and study its utility for the synthesis of novel func-
tionalized chromenones. When 1a was reacted with carbon disul-
fide in the presence of a base and methyl iodide, the product
isolated was not the expected 2a but was characterized as
2-methylthio-3-nitro-4H-chromen-4-one 3a (Scheme 1). In addition
Many research groups13–17 exploring the chemistry of function-
alized ketene dithioacetals. Of particular interest are ketene dithio-
acetals and nitroketene dithioacetals for the construction of
heterocyclic compounds.16,17 Recently we have developed a library
of trisubstituted pyrazoles and isoxazoles derivatives using ketene
S,S-acetals as building block in aqueous medium.18a With the
OH
O
S
O
O
NO2
CS2/base,
rt, 1h
MeI,
rt, 6-7 h
NO2
NO2
0 oC
S
OH
S
O
0 oC
1a
2a
3a
⇑
Corresponding author. Tel.: +91 9428036310; fax: +91 281 2576802.
E-mail address: naliaparachem@yahoo.co.in (Y.T. Naliapara).
Scheme 1. Synthesis of novel chromenone 3a.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.020

M. M. Savant et al. / Tetrahedron Letters 52 (2011) 254–257
255
Table 1
Optimization of the reaction conditions for the synthesis of 3a
O
O
R -NH
4a-e,
R
2
2
NO2
Entry
Base (2 equiv)
Solvent
Timea (h)
Yieldb (%)
Δ , iPrOH
R1
NH
R2
40-45 min
6a-o
1
2
3
4
5
6
7
8
NaOi-Pr
NaOi-Pr
NaOMe
NaOMe
K2CO3
K2CO3
KF
THF
DMF
THF
DMF
THF
DMF
THF
DMF
1.5
1.7
2.0
2.3
1.5
1.5
3.0
3.2
52
48
64
60
88
80
68
66
3a-c
O
HN
X
R
NO2
N
5a-d,
Δ , Dioxane
40-45 min
R1
O
7a-l
X
KF
Scheme 3. Reaction of chromenone 3a–c with primary alkyl/aryl and secondary
amines.
a
For the reaction of substituted 1a, CS2 and base.
Isolated yields after purification.
b
Table 2
Reaction of chromenone 3a–c with various amines
the structure of 3a was confirmed by the analysis of single crystal
X-ray data.
Entry
Chromenones 6a–o and 7a–l
Yielda (%)
1
2
3
4
5
6a, R, R1 = H, R2 = Ph
96
95
94
94
95
95
92
91
97
93
95
96
94
92
94
89
93
93
91
92
92
94
90
92
96
89
90
Having developed a facile synthesis of chromenone 3a, we next
planned to optimize the reaction conditions using various bases
and solvents (Table 1). The yield of desired product 3a was poor
when strong bases such as, NaOi-Pr and NaOMe were used in
THF and DMF (Table 1, entries 1–4). The reaction of 1a with KF
in THF and DMF did not improve the yield and the reaction needed
longer time (Table 1, entries 7 and 8). It was found that the reaction
proceeded smoothly in the presence of K2CO3 and THF to furnish
the product 3a in excellent yield (Table 1, entry 5). To examine
the scope, we next synthesized substituted 1b and 1c.18b Using
our optimized reaction condition, compounds 1b and 1c were
reacted with CS2 in the presence of K2CO3. The chromenones
3b and 3c were obtained in excellent yields (84% and 82%)
(Scheme 2).20
6b, R, R1 = H, R2 = 4-MePh
6c, R, R1 = H, R2 = 4-OMePh;
6d, R, R1 = H, R2 = 4-ClPh
6e, R, R1 = H, R2 = Me
6
7
8
9
6f, R = H, R1 = Cl, R2 = Ph
6g, R = H, R1 = Cl, R2 = 4-MePh
6h, R = H, R1 = Cl, R2 = 4-OMePh
6i, R = H, R1 = Cl, R2 = 4-ClPh
6j, R = H, R1 = Cl, R2 = Me
6k, R = Me, R1 = H, R2 = Ph
6l, R = Me, R1 = H, R2 = 4-MePh
6m, R = Me, R1 = H, R2 = 4-OMePh
6n, R = Me, R1 = H, R2 = 4-ClPh
6o, R = Me, R1 = H, R2 = Me
7a, R, R1 = H, X = CH2
7b, R, R1 = H, X = O
7c, R, R1 = H, X = NMe
7d, R, R1 = H, X = NEt
7e, R = H, R1 = Cl, X = CH2
7f, R = H, R1 = Cl, X = O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
With novel functionalized chromenones in hand, we decided to
develop
a facile route to 2-substituted-3-nitro chromenones
through nucleophilic substitution of 2-methylthio group by vari-
ous nucleophiles such as amines, thiols, and phenol. It was found
that the elimination of methylthio group from aromatic or hetero-
cyclic moieties required more drastic conditions.15–17,19 It is impor-
tant to note that nucleophilic displacement at C2 possessing
methylthio group for C–N, C–S, or C–O bond formation required
either oxidation of sulfide to sulfone followed by the reaction with
nucleophiles or use of transition metal catalysts.9c,15a However, our
studies revealed that the elimination of methylthio group by vari-
ous nucleophilic species in the chromenones 3a–c was simple and
required neither oxidation nor transition metal catalysts. This can
be explained by the fact that the adjacent electron-withdrawing ef-
fect of nitro and carbonyl groups makes the methylthio moiety a
better leaving group.
7g, R = H, R1 = Cl, X = NMe
7h, R = H, R1 = Cl, X = NEt
7i, R = Me, R1 = H, X = CH2
7j, R = Me, R1 = H, X = O
7k, R = Me, R1 = H, X = NMe
7l, R = Me, R1 = H, X = NEt
a
Isolated yields after purification.
O
SH
R
NO2
S
i-PrOH
Δ,55-60 min
3a-c
O
R1
R3
9a-i
8a-c
R3
Thus, under the optimized conditions, the reaction of primary
alkyl/aryl amines 4a–e with chromenones 3a–c in iPrOH afforded
substituted 2-aryl/alkylamine-3-nitro-4H-chromenones 6a–o in
good yields (Scheme 3).21 However, the reaction of various second-
ary amines 5a–d with chromenones 3a–c was conducted using
dioxane as solvent which afforded chromenones 7a–l with good
to excellent yields (Table 2).22 Similarly, the reaction of thiols
8a–c with chromenones 3a–c in iPrOH furnished substituted
Scheme 4. Reaction of 3a–c with arylthiols 8a–c.
Table 3
Synthesis of substituted chromenones 9a–i
Entry
Chromenones 9a–i
Yielda (%)
1
2
3
4
5
6
7
8
9
9a, R, R1, R3 = H
86
88
90
85
91
86
87
89
87
9b, R, R1 = H; R3 = 4-Me
9c, R, R1 = H; R3 = 4-Cl
9d, R, R3 = H; R1 = Cl
9e, R = H; R1 = Cl; R3 = 4-Me
9f, R = H; R1, R3 = 4-Cl
9g, R = Me; R1, R2 = H
9h, R, R3 = 4-Me; R1 = H
9i, R = Me; R1 = H; R3 = 4-Cl
O
O
K2CO3/CS2,
0 oC rt, 1 h
MeI,
R
NO2
NO2
R
OH
1a-c
R1
O
3a-c
S
R1
0 oC rt, 5-6 h
a
3a, R, R1 = H (88%)
Isolated yields after purification.
b, R = Me, R1 = H (84%)
c, R = H, R1 = Cl (82%)
2-arylthio-3-nitro-4H-chromenones 9a–i in good yields (Scheme 4).21
The alkyl/aryl amines reacted faster with chromenones compared
to thiols under the optimized conditions (Tables 2 and 3).
Scheme 2. Synthesis of substituted chromenones 3a–c through intramolecular
heteroannulation.

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M. M. Savant et al. / Tetrahedron Letters 52 (2011) 254–257
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R
Phenol /iPrOH
O
10
O
Δ
R1
3a-c
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O
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NO2
R4
Alkoxide/alcohol
30-35 min
O
R1
11a-c
Scheme 5. Reaction of 3a–c with sodium methoxide in methanol.
Table 4
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Synthesis of chromenones 11a–c
Entry
Chromenones 11a–c
Yielda (%)
1
2
3
11a, R, R1 = H; R4 = Me
11b, R = H; R1 = Cl; R4 = Me
11c, R, R4 = Me; R1 = H
78
72
75
a
Isolated yields after purification.
13. (a) Dieter, R. K. Tetrahedron 1986, 42, 3029; (b) Junjappa, H.; Ila, H.; Asokan, C.
V. Tetrahedron 1990, 46, 5423; (c) Elgemeie, G. H.; Sayed, S. H. Synthesis 2001,
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Minami, T. J. Org. Chem. 2003, 68, 4947.
Subsequently, we found that the reaction of phenol with
chromenones in identical condition was unable to afford the corre-
sponding chromenone 10 in same fashion (Scheme 5). On the other
hand, using alkoxide as nucleophile reacted well, giving rise to the
novel 2-methoxy-3-nitro-4H-chromenones 11a–c in good yield
with short reaction time (Table 4).22
15. (a) Yuan, H. J.; Wang, M.; Liu, Y. J.; Liu, Q. Adv. Synth. Catal. 2009, 351, 112; (b)
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Wang, M.; Li, B.; Liu, Q.; Zhao, Y. J. Org. Chem. 2007, 72, 4401.
In summary, we have developed a novel synthetic strategy for
the synthesis of highly substituted 3-nitro chromenones through
[5+1] heteroannulation of readily accessible 2-hydroxy-x-nitro
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18. (a) Savant, M. M.; Pansuriya, A. M.; Bhuva, C. V.; Kapuriya, N.; Patel, A. S.;
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Butler, A. R.; Brown, E. H. Arkivoc 2002, 3, 166; (c) Savant, M. M.; Pansuriya, A.
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acetophenone with carbon disulfide followed by nucleophilic addi-
tion through elimination of methylthio with various amines, thiols,
and alkoxide. The direct C–N, C–S, and C–O bond formation reac-
tion at C2 was achieved by the presence of nitro functionality at
C3 position of chromenone. The newly developed methodology al-
lows direct access to 2-substituted-3-nitro chromenone in excel-
lent yield and high chemical purity. The presence of nitro
functionality further makes them useful substrates for various
transformations for biological interest.
Acknowledgments
20. Typical procedure for the synthesis of 3a–c. To a well-stirred suspension of
potassium carbonate (7.62 g, 55 mmol) in dry THF (15 mL) at 0 °C was added
CS2 (1.65 mL, 27.5 mmol) diluted with 10 mL THF along with substituted 2-
The authors are thankful to FIST-DST, SAP-UGC and DST New
Delhi, for their financial support. Special thanks are due to NFDD,
SU, Rajkot. M.M.S. thanks to Professor H. Junjappa for helpful
discussion. We appreciate SAIF, CIL, Chandigarh, and NRC, IISc,
Bangalore for providing spectroscopic analysis.
hydroxy-x-nitroacetophenone (27.5 mmol) over a period of 30 min. After
completion of the addition, the reaction mixture was stirred at 0 °C for 30 min
and rt for 30 min. Appearance of orange yellow solid in the reaction medium
indicated the formation of disodium salt. To this reaction, a solution of methyl
iodide (3.41 mL, 55 mmol) in THF (7 mL) was added dropwise over a period of
15 min at 0 °C. The mixture was allowed to warm to room temperature and
stirred for 5–6 h, and then poured onto crushed ice (100 g) under stirring. The
separated solid was collected by filtration, washed with water (2 Â 100 mL)
then hexane, dried in vacuo and crystallized from chloroform to furnish the
analytically pure products in excellent yield which were used for next step
without further purification. 2-(Methylthio)-3-nitro-4H-chromen-4-one (3a).
Yellow solid; Rf 0.41 (6:4 hexane–EtOAc); purity 98.91%; mp 185–187 °C; MS
m/z: 237(M+); 1H NMR (400 MHz): d 3.13(s, 3H), 7.56–7.61(t, 1H, Ar-H), 7.79(d,
J = 8.8 Hz, 1H, Ar-H), 7.85–7.91(t, 1H, Ar-H), 8.11(d, J = 8.6 Hz, 1H, Ar-H); 13C
NMR (100 MHz): 18.00, 118.54, 124.08, 124.65, 125.24, 125.81, 128.31, 134.88,
151.38, 158.99, 167.73. Anal. Calcd for C10H7NO4S: C, 50.63; H, 2.97; N, 5.90.
Found: C, 50.57; H, 2.90; N, 5.84.
Supplementary data
Supplementary data contains characterization data along with
spectral copies and ORTEP diagram of compound 3a. This material
is available via the Internet at www.elsevier.com. Crystallographic
data for the structure 3a in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publi-
cation nos. CCDC 760004. 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). Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.2010.11.020.
21. General procedure for the reaction of chromenones (3a–c) with various amines
(4a–e) or arylthiols (8a–c). A mixture of various chromenones (3a–c, 1 mmol)
and appropriate amines (4a–c, 1.1 mmol) or arylthiols (8a–c, 1.1 mmol) in i-
propyl alcohol (5 mL) was heated to reflux for 30–60 min. After completion of
the reaction, the separated solid was filtered, washed with water, dried under
vacuo and recrystallized from MeOH to give the desired product 6a–o or 9a–i.
3-nitro-2-(phenylamino)-4H-chromen-4-one (6a) cream colour solid; Rf 0.51
(6:4 hexane–EtOAc); purity 97.89%; mp 220–222 °C; MS m/z: 282(M+); 1H
NMR (400 MHz): d 7.24(d, J = 0.76 Hz, 1H, Ar-H), 7.40–7.55(m, 6H, Ar-H), 7.61–
7.66 (t, 1H, Ar-H), 8.29(dd, J = 7.92 Hz, 1H, Ar-H), 11.65(s, 1H, NH); 13C NMR
(100 MHz): 88.17, 116.84, 118.21, 122.19, 125.00, 125.76, 125.87, 126.93,
References and notes
1. Vasselin, A. D.; Westwell, A. D.; Matthews, C. S.; Bradshaw, T. D.; Stevens, M. F.
G. J. Med. Chem. 2006, 49, 3973.

M. M. Savant et al. / Tetrahedron Letters 52 (2011) 254–257
257
128.96, 134.18, 134.88, 151.01, 158.83, 167.32, Anal. Calcd for C15H10N2O4: C,
63.83; H, 3.57; N, 9.93. Found: C, 63.77; H, 3.50; N, 9.86%. 3-Nitro-2-
(phenylthio)-4H-chromen-4-one (9a) yellow solid; Rf 0.57 (6:4 hexane–
EtOAc); purity 98.49%; mp 195–197 °C; MS m/z: 300(M+); 1H NMR
(400 MHz): d 7.04–7.09(t, 1H, Ar-H), 7.38–7.43(t, 2H, Ar-H), 7.64–7.71(m, 3H,
Ar-H), 7.78–7.82(t, 1H, Ar-H), 8.04–8.09(t, 1H, Ar-H), 8.24(dd, J = 8.1 Hz, 1H, Ar-
H); 13C NMR (100 MHz): 118.21, 122.19, 123.64, 125.43, 126.76, 126.93,
128.32, 134.08, 135.77, 151.11, 158.79, 168.13. Anal. Calcd for C15H9NO4S: C,
60.19; H, 3.03; N, 4.68. Found: C, 60.14; H, 2.99; N, 4.64.
22. Reaction procedures for synthesis of 7a–l and 11a–c are provided with
Supplementary data. 2-(4-Ethylpiperazin-1-yl)-3-nitro-4H-chromen-4-one (7d).
Reddish solid; Rf 0.25 (4:6 hexane–EtOAc); purity 96.17%; mp 128–130 °C; MS
m/z: 303(M+); 1H NMR (400 MHz): d 1.11–1.14(t, 3H, Me), 2.48–2.52(q, 2H,
CH2), 2.62–2.64(t, 4H, CH2), 3.60–3.63(t, 4H, CH2), 7.31(d, J = 8.28 Hz, 1H,
Ar-H), 7.38–7.42(t, 1H, Ar-H), 7.61–7.66(t, 1H, Ar-H), 8.23(dd, J = 7.84 Hz,
1H, Ar-H); 13C NMR (100 MHz): 10.02, 45.98, 50.37, 52.61, 88.71, 120.22,
124.08, 124.98, 126.37, 151.38, 158.42, 168.73. Anal. Calcd for C15H17N3O4: C,
59.40; H, 5.65; N, 13.85. Found: C, 59.37; H, 5.59; N, 13.81.