Potassium trinitromethanide as a 1,1-ambiphilic synthon equivalent: Access to 2-nitroarenofurans

Article abstract of DOI:10.1021/jo402543s

The first example of the use of potassium trinitromethanide as a 1,1-ambiphilic synthon equivalent for the construction of a benzofuran moiety mediated by triethylamine has been developed. The method tolerates a variety of functional groups on the starting quaternary ammonium salt and has been successfully extended to polysubstituted benzofurans. Formation of an o-quinone methide intermediate is postulated as a key to the mechanism of this cascade process.

Full text of DOI:10.1021/jo402543s

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Article
Potassium trinitromethanide as 1,1-ambiphilic
synthon equivalent: access to 2-nitroarenofurans
Vitaly Aleksandrovich Osyanin, Dmitry Vladimirovich Osipov,
Maxim Raulievich Demidov, and Yuri Nikolaevich Klimochkin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo402543s • Publication Date (Web): 13 Jan 2014
Downloaded from http://pubs.acs.org on January 14, 2014
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Potassium trinitromethanide as 1,1-ambiphilic synthon equivalent: access to 2-
nitroarenofurans
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Vitaly A. Osyanin*, Dmitry V. Osipov, Maxim R. Demidov and Yuri N. Klimochkin
Department of Organic Chemistry, Samara State Technical University, 244 Molodogvardeiskaya
St., 443100 Samara, Russian Federation.
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*Eꢀmail: vosyanin@mail.ru
Abstract: The first example of using of potassium trinitromethanide as a 1,1ꢀambiphilic synthon
equivalent for the construction of a benzofuran moiety mediated by triethylamine (TEA) has
been developed. The method tolerates a variety of functional groups on the starting quaternary
ammonium salt and has been successfully extended to polysubstituted benzofurans. Formation of
a oꢀquinone methide intermediate is postulated as a key to the mechanism of this cascade
process.
Keywords: oꢀQuinone methides, 2ꢀnitrobenzofurans, potassium trinitromethanide, C1 building
block, 1,1ꢀambiphile synthon.
Introduction
Ambiphilic synthons, which contain both electrophilic and nucleophilic centers in the same
molecule, are widely used in organic synthesis as useful building blocks.1 The development of
new synthetic methods using ambiphiles have a great potential in elaboration of new high step
economy reactions.2 Moreover, 1,1ꢀambiphiles with reaction centers on the same carbon atom
are promising for construction of cyclic molecules.3 However, this reaction type remains
undeveloped.
Use of polynitromethane derivatives in the synthesis of heterocycles are generally limited to
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isoxazole and isoxazolidine units.4 In these transformations polynitromethanes react as 1,3ꢀ
dipoles and C, N, O atoms are incorporated into the structure of heterocycles. Potassium
trinitromethanide (potassium nitroformate) is often used to introduce trinitromethyl group in
organic molecules. The reaction of potassium trinitromethanide as a 1,1ꢀambiphilic reagent,
wherein only the carbon atom was included into the formed heterocyclic structure, is
unprecedented.
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oꢀQuinone methides (oꢀQMs) are highly reactive and useful species which have been implicated
as intermediates in the synthesis of natural products, usually as heterodynes, to form chromane
systems.5 They also react with nucleophiles as 1,4ꢀMichael acceptors.6 Reactions of oꢀQM
precursors are exceptionally facile, compared with traditional Michael acceptors, because
aromatization energy provides additional product and transition state stabilization in the case of
the oꢀQM fragment. In addition, initial products of Michaelꢀtype reaction with oꢀQM may
undergo further intramolecular cyclization with phenolic hydroxyl groups to provide a pathway
to oxygenꢀcontaining heterocycles.7 However, alike cascade protocols are rare and require
further study.
In the process of an overall synthetic program aimed at the development of new cascade
transformations utilizing oꢀQM7b we put our efforts on the study of reaction of potassium
trinitromethanide with oꢀQM precursors. We have found that this reaction affords 2ꢀ
nitroarenofurans, which has drawn extensive attention because of their varied biological
activities. For example, many of these compounds exhibit antibacterial,8 antiparasitic,9
radiosensitizing,10 mutagenic properties11 and can be used as regulators of the nuclear receptor
HNF4α.12 Besides, 2ꢀnitrobenzofurans are useful intermediates for the preparation of 2ꢀ
halogenobenzofurans,13 dibenzofurans14 and benzofuro[2,3ꢀc]pyrroles.15
A number of methods have been reported for the syntheses of 2ꢀnitrobenzofurans. These
compounds are generally prepared by the condensation between oꢀhydroxybenzaldehydes and
bromonitromethane.12,16 Although this reaction has already been performed under miscellaneous
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conditions with a large variety of aldehydes, its applicability is not completely versatile and leads
to rather unsatisfactory yields in certain cases. The direct nitration of benzofurans in the 2ꢀ
position usually leads to low yields and unwanted nitration products.17
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3ꢀAlkylꢀ2ꢀnitrobenzofurans are also obtained by replacement of the acyl group in 2ꢀacylꢀ3ꢀ
alkylbenzofurans18 and by treating 3ꢀalkylbenzofurans successively with tꢀBuLi, then
trimethyltin chloride and finally tetranitromethane in DMSO.19 2ꢀNitrobenzofuran has been
prepared by ipsoꢀnitration of 2ꢀbenzofuranboronic acid using bismuth (III) nitrate20 and by
nitration of benzofuran using sodium nitrite in the presence of cerium (IV) ammonium nitrate.21
Recently, 3ꢀalkylꢀ2ꢀnitrobenzofurans were synthesized from 2ꢀ(2ꢀnitroethyl)phenols via a
hypervalent iodineꢀinduced oxidative cyclization.22
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Results and discussion
Potassium trinitromethanide reacts with oꢀQMs by carbon as a soft nuchleophilic center and acts
as synthetic equivalent of a 1,1ꢀdipole oneꢀcarbon synthon A or dinitrocarbene B (Scheme 1).
Scheme 1 Retrosynthetic approach to benzofuran moiety
We first investigated the reaction between the oꢀQM precursor 1a with potassium
trinitromethanide under various conditions. Potassium trinitromethanide was obtained from the
reaction of tetranitromethane with potassium hydroxide and ethanol in water solution.23
C(NO2)4 + KOH + C2H5OH → KC(NO2)3 + C2H5ONO2 + H2O
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When the reaction with potassium trinitromethanide was carried out in ethanol at room
temperature in the absence of any base, no desired product formation was observed (Table 1,
entry 1). The use of catalytic amount of TEA (0.1 equiv) at elevated temperature furnished only
a trace amount (<5%) of the expected 2ꢀnitrobenzofuran 2a in 40 min (entry 2). Attempts to
improve the yield by increasing the reaction time were unsuccessful. In order to achieve a high
yield, we did further investigation on other parameters, such as solvent, temperature and ratio of
components. If the ratio of 1a:KC(NO2)3:TEA was adjusted from 1:1:1 to 1:3:3, a good yield
(79%) was obtained (entry 8). A lower base loading caused a loss of reaction yield. No
significant improvement was gained in the yield of 2a when we employed more than 3 equiv of
potassium trinitromethanide. The reaction was also performed at various temperatures and the
best results were obtained at approximately 80 ºC. The reaction was not carried at higher
temperatures since the onset temperature of the decomposition of potassium trinitromethanide
was found to be 80 ºC.23a The influence of solvents was also examined. The results show that the
same reaction can also be performed in aqueous THF, ethanol, or acetonitrile, which afforded the
highest yield.
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Table 1 The results of the optimizationa
Entry
Solvent
T, ºC
Ratio of
1a:KC(NO2)3:TEA
1:1:0
Yielda (%)
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2
3
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5
EtOH
EtOH
25
78
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25
81
–
1:1:0.1
<5
20
25
55
CH3CN
CH3CN
CH3CN
1:1:1
1:3:3
1:1:1
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CH3CN
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81
78
65
80
80
1:2:2
1:2:3
1:3:3
1:3:3
1:3:3
1:3:3
1:3:3
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79
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69
31
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CH3CN
CH3CN
EtOH
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THF–H2O, 3:1
DMF
H2O
a Reaction conditions: compound 1a (1 mmol), KC(NO2)3, TEA, 20 mL of solvent, 40 min.
In order to evaluate the effect of the base on the reaction, a range of organic bases were
examined (Table 2). Triethylamine proved to be a more efficient base. Thus, in optimal
conditions, 3 equiv of the potassium trinitromethanide and 3 equiv of TEA in acetonitrile at 81
ºC provided the desired product in 79% yield in 40 min.
Table 2 Optimization of basesa
Entry
Base
TEA
pKa
10.75
11.4
7.38
7.4
Yieldb (%)
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8
79
54
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17
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10
DIPEA
NMM
Nꢀmethylimidazole
DMAP
9.2
DABCO
DBU
8.82
12.0
13.6
c
TMG
–
a 1 equiv of 1a, 3 equiv of potassium trinitromethanide, 3 equiv of base in CH3CN under reflux
are used. In all cases, the reaction times were 40 min.
b Isolated yields after silica gel chromatography.
c Only 1,3ꢀbenzoxazine 3 was isolated.
Scheme 2
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It is interesting to note that in the case of 1,1,3,3ꢀtetramethylguanidine (TMG) only 2ꢀ
dimethylaminoꢀ4Hꢀ1,3ꢀbenzoxazine 3 was isolated in 54% yield (Table 2, entry 8, Scheme 2).24
Under the optimized reaction conditions, the scope and generality of this cascade process were
then explored. A variety of electronically divergent oꢀbenzoquinone methide precursors were
examined, and the results are summarized in Table 3. The method turned out to be tolerant
toward a broad range of functional groups. The reaction proceeded without any problems for a
wide range of substrates bearing electronꢀdonating (CH3O, Alk) or electronꢀwithdrawing (NO2,
Hal, CO2CH3, CHO) substituents on the aryl ring, providing 2ꢀnitrobenzofurans in moderate to
good yields. The sterically hindered adamantylꢀsubstituted nitrobenzofuran 1f was obtained in
good yield, indicating that steric hindrance had no obvious influence on the efficiency of our
method.
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Table 3. Synthesis of 2ꢀnitrobenzofurans 2a-n.a,b,c
a
Optimal conditions: 1 equiv of 1, 3 equiv of potassium trinitromethanide, 3 equiv of TEA in
CH3CN under reflux.
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b Isolated yields after silica gel chromatography.
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c All reactions, except the first one, were carried out without additional optimization.
Scheme 3 outlines a proposed mechanism of the formation of 2ꢀnitrobenzofurans. The
mechanism involves initial elimination of trimethylamine from anion of quaternary ammonium
salt by an E1cB mechanism to afford an electrophilic oꢀQM. Subsequent a Michaelꢀtype addition
of trinitromethanide anion, intramolecular nucleophilic substitution and elimination of nitro
groups affords the 2ꢀnitrobenzofuran. TEA promotes generation of oꢀQMs and further
aromatization of intermediate dihydrobenzofurans. It also keeps the media basic which is
necessary for avoidance of formation of side waxy products.
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Scheme 3 Proposed mechanism for the synthesis of 2
In support of the proposed mechanistic pathway, in some cases intermediate trinitroethyl
derivatives and 2,2ꢀdinitroꢀ2,3ꢀdihydrobenzofurans can be isolated. From 2ꢀchloromethylphenols
1v,w and potassium trinitromethanide the phenols 4a,b were prepared in acetonitrile at room
temperature. In DMSO solution the trinitroethyl derivatives 4a,b undergo cyclization and form
2,2ꢀdinitroꢀ2,3ꢀdihydrobenzofurans 5a,b (Scheme 4). We have also found different reaction rates
of these transformations depending on nature of the substituent in the aromatic core. Thuswise,
full conversion of acetylꢀsubstituted phenol 4b to dihydrobenzofuran 5b was accomplished in 5
days at room temperature. On the other hand, nitrophenol 4a converted to 5a in 5 hours
(according to NMR monitoring). It should also be noted that compounds 5a,b in DMSO or
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acetonitrile solution slowly transform in 2ꢀnitrobenzofurans 2j and 2i, respectively. At the same
time, in nonꢀpolar solvents compounds 4a,b and 5a,b are more stable.
Scheme 4 Synthesis of dihydrobenzofurans 5a,b
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Attempts to extend this reaction to the Mannich bases of simple phenols failed to furnish the
expected products. The reason for failure may be due to the relatively greater thermal stability of
Mannich bases compared to that of the quaternary ammonium salts. However, instead of
quaternary salts 2ꢀacetoxybenzyl acetates 1o,p as well as ammoniophenolate 6 can be used
(Scheme 5).
Scheme 5 Extention of developed methodology to another oꢀQM precursors
In order to broaden the scope of the present method, we attempted the present protocol for the
naphthalene 1q and heterocyclic 1r,s,t, precursors of oꢀQMs. From Mannich bases 1r,s,t
heterocyclic systems benzo[1,2ꢀb:4,3ꢀb’]difuran 2r, furo[3,2ꢀe]indole 2s and furo[3,2ꢀ
e]pyrido[3,4ꢀb]indole 2t were prepared in moderate yields (Scheme 6).
Scheme 6 Synthesis of condensed nitrobenzofurans
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In summary, we have developed a simple and efficient method for the synthesis of 2ꢀ
nitroarenofurans from quaternary ammonium salts, some phenolic Mannich bases or 2ꢀ
acetoxybenzyl acetates and potassium trinitromethanide in moderate to good yields. This is the
first example of using of potassium trinitromethanide as a 1,1ꢀambiphilic reagent. The tolerance
of various substituents on the aromatic rings makes this protocol highly practical for diversityꢀ
oriented synthesis.
Experimental section
FTIRꢀspectra were taken in KBr pellets. 1H, 13C, and DEPT NMR spectra were recorded using a
400 MHz NMR spectrometer in CD3CN, CDCl3 or DMSOꢀd6 solutions with TMS as internal
standard. Chemical shifts and coupling constants were recorded in units of ppm and Hz,
respectively. The melting points were uncorrected. Elemental analysis was carried out on an
automatic CHNSꢀanalyzer. Mass spectra were recorded with 70 eV electron ionization energy.
Thinꢀlayer chromatography was carried out on aluminiumꢀbacked silica gel plates with
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visualisation of components by UV light (254 nm) or exposure to I2. Known oꢀQM precursors
3
4
5
were prepared according to the literature procedures.25ꢀ29
6
7
8
[2-Hydroxy-3-nitro-5-tert-butylbenzyl]trimethylammonium iodide (1k).
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Dimethylamine (6 mL of 33% aqueous solution, 0.04 mol) and formaldehyde (3 mL of 37%
aqueous solution, 0.04 mol) were added to a solution of 4ꢀtertꢀbutylꢀ2ꢀnitrophenol (7 g, 0.036
mol) in ethanol (50 mL). The reaction mixture was stored at room temperature for 2 days. The
solvent was evaporated in vacuo, the residue was dissolved in acetonitrile (20 mL) and treated
with CH3I (7 mL, 16 g, 0.11 mol). The resulting solution was stirred at room temperature for 2
days, the solvent was evaporated in vacuo, the residue was recrystallized from mixture ethanol–
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1
diethyl ether. Yield 62%; 8.77 g; orange crystals; mp 169–171 ºC (decomp.); H NMR (400
4
MHz, DMSOꢀd6) δ: 8.01 and 7.99 (d, J = 2.3 Hz, 2H), 4.63 (s, 2H), 3.08 (s, 9H), 1.27 (s, 9H)
ppm; 13C NMR (100 MHz, DMSOꢀd6) δ: 151.2 (C), 142.6 (C), 140.2 (CH), 136.7 (C), 124.0
(CH), 120.2 (C), 62.7 (CH2), 55.5 (C), 52.9 (3CH3), 34.7 (C), 31.2 (3CH3); IR νmax (KBr): 648,
887, 980, 1161, 1265, 1312, 1346, 1377, 1416, 1477, 1535 (NO2), 1597, 1620, 2870, 2951, 3001,
3400–3100 (OH) cmꢀ1. Anal. Calcd (%) for C14H23IN2O3: C, 42.65; H, 5.88; N, 7.11. Found: C
(%), 42.72; H, 5.90; N, 7.02.
Potassium trinitromethanide
Caution: Although we have encountered no difficulties in working with potassium
trinitromethanide and tetranitromethane, full safety precautions (goggles, shields, fume
hoods) should be taken whenever it possible due to explosive nature and toxicity of these
compounds.
Potassium hydroxide (18.6 g, 0.332 mol) was dissolved in 22 mL of water and 84 mL of ethanol
and stirred at ice bath temperature. To this solution, tetranitromethane (28 mL, 45.4 g, 0.232
mol) was added portionꢀwise over a period of ten minutes. The temperature of the reaction
mixture was kept below 20 ºC. The ice bath was removed and the reaction mixture was allowed
to warm to room temperature (20–25 ºC) and stirred for 20 min. After completion of the reaction,
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the mixture was cooled to 0 ºC and the solid was filtered off and washed with 20 mL of iceꢀcold
EtOH. Yield 91 %; 39.9 g; bright yellow crystals; mp 83 ºC (decomp.).
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6
7
General Experimental Procedure for the Synthesis of 2-nitroarenofurans
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Potassium trinitromethanide (1.14 g, 6 mmol) was added in three equal portions over a period of
20 minutes to a stirred solution of oꢀQM precursor (2 mmol) and triethylamine (0.84 mL, 6
mmol) in acetonitrile (20 mL) at reflux temperature under an Ar atmosphere. Afterwards, the
mixture was refluxed for another 20 minutes and poured into 50 mL of saturated water solution
of sodium chloride to yield a solid product, which was filtered, washed with water and dried. The
crude product was purified by column chromatography over silica gel using dichloromethane as
eluent, followed by recrystallization from ethanol.
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1
5,6-Dimethyl-2-nitrobenzofuran (2a): yield 79%; 302 mg; yellow solid; mp 135–136 ºC; H
NMR (400 MHz, CDCl3) δ: 7.58 (s, 1H), 7.48 (s, 1H), 7.37 (s, 1H), 2.41 (s, 3H), 2.36 (s, 3H);
13С NMR (100 MHz, CDCl3) δ: 152.7 (C), 152.7 (C), 140.9 (C), 134.9 (C), 123.8 (C), 123.6
(CH), 112.8 (CH), 107.5 (CH), 21.2 (CH3), 20.1 (CH3); IR, νmax (KBr): 729, 802, 864, 953,
1080, 1198, 1267, 1323, 1364 (NO2), 1452, 1503 (NO2), 1555, 1620, 2924, 3140 (CH Fu) cmꢀ1;
MS (EI) m/z: 191 [M]+ (51), 161 [M – NO]+ (93), 133 [M – CNO2]+ (36), 117 (41), 115 (74),
105 [C8H9]+ (22), 91 [C7H7]+ (44), 46 [NO2]+ (100). Anal. Calcd (%) for C10H9NO3: C, 62.82; H,
4.74; N, 7.33. Found (%): C, 62.90; H, 4.72; N, 7.27.
Methyl 2-nitrobenzofuran-6-carboxylate (2b): yield 51%; 225 mg; light yellow solid; mp
144–145 ºC; 1H NMR (400 MHz, CDCl3) δ: 8.30 (d, 4J = 1.3 Hz, 1H), 8.10 (dd, 3J = 8.4, 4J = 1.3
Hz, 1H), 7.83 (d, 3J = 8.4 Hz, 1H), 7.69 (d, 5J = 0.8 Hz, 1H), 3.98 (s, 3H); 13С NMR (100 MHz,
CDCl3) δ: 166.0 (C=O), 154.6 (C), 152.4 (C), 131.7 (C), 129.7 (C), 126.3 (CH), 124.0 (CH),
114.5 (CH), 106.7 (CH), 52.8 (CH3); IR, νmax (KBr): 729, 766, 814, 974, 1072, 1225, 1260,
1281, 1312, 1341 (NO2), 1373, 1422, 1435, 1526 (NO2), 1566, 1714 (C=O), 2854, 2924, 2959,
3138 (CH Fu) cmꢀ1. Anal. Calcd (%) for C10H7NO5: C, 54.31; H, 3.19; N, 6.33. Found (%): C,
54.40; H, 3.24; N, 6.26.
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5-Methoxy-2-nitrobenzofuran (2c): yield 59%; 228 mg; yellow solid; mp 127–128 ºC; H
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Hz, 1H), 7.11 (d, J = 1.8 Hz, 1H), 3.86 (s, 3H); 13С NMR (100 MHz, CDCl3) δ: 157.6 (C),
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153.5 (C), 148.5 (C), 126.5 (C), 120.6 (CH), 113.7 (CH), 107.4 (CH), 104.3 (CH), 56.0 (CH3);
IR, νmax (KBr): 748, 818, 878, 1026, 1169, 1202, 1265, 1327 (NO2), 1369, 1510 (NO2), 1562,
2924, 3102 (CH Fu), 3126 cmꢀ1; MS (EI) m/z: 193 [M]+ (84), 163 [M – NO]+ (100), 135 [M –
CNO2]+ (27), 119 (58), 107 [C7H7O]+ (7). Anal. Calcd (%) for C9H7NO4: C, 55.96; H, 3.65; N,
7.25. Found (%): C, 56.06; H, 3.60; N, 7.31.
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5-tert-Butyl-2-nitrobenzofuran (2d): yield 36%; 158 mg; light yellow solid; mp 80–81 ºC; H
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NMR (400 MHz, CDCl3) δ: 7.71 (d, J = 2.1 Hz, 1H), 7.66 (dd, 3J = 8.9, J = 2.1 Hz, 1H), 7.63
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(d, J = 0.7 Hz, 1H), 7.54 (d, J = 8.9 Hz, 1H), 1.38 (s, 9H); 13С NMR (100 MHz, CDCl3) δ:
153.3 (C), 151.8 (C), 148.8 (C), 128.6 (CH), 125.7 (C), 119.9 (CH), 112.2 (CH), 107.7 (CH),
35.1 (C), 31.6 (3CH3); IR, νmax (KBr): 731, 816, 841, 955, 1101, 1126, 1192, 1236, 1267, 1304,
1319, 1358 (NO2), 1466, 1520 (NO2), 1562, 2870 (CH3), 2961, 3138 (CH Fu) cmꢀ1. Anal. Calcd
(%) for C12H13NO3: C, 65.74; H, 5.98; N, 6.39. Found (%): C, 65.82; H, 6.04; N, 6.36.
5-(1-Adamantyl)-2-nitrobenzofuran (2e): yield 61%; 362 mg; light yellow solid; mp 165–167
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ºC; 1H NMR (400 MHz, DMSOꢀd6) δ: 7.64–7.67 (m, 3H), 7.53 (d, J = 8.7 Hz, 1H), 2.13 (br s,
3H), 1.92–1.97 (m, 6H), 1.75–1.84 (m, 6H); 13С NMR (400 MHz, DMSOꢀd6) δ: 153.3 (C), 151.9
(C), 149.1 (C), 128.2 (CH), 125.7 (C), 119.8 (CH), 112.2 (CH), 107.8 (CH), 43.5 (3CH2), 36.7
(3CH2), 36.6 (C), 29.0 (3CH); IR, νmax (KBr): 729, 800, 831, 849, 876, 955, 1092, 1242, 1317,
1331, 1344, 1362 (NO2), 1371, 1470, 1524 (NO2), 1568, 2851, 2901, 3142 (CH Fu) cmꢀ1. Anal.
Calcd (%) for C18H19NO3: C, 72.71; H, 6.44; N, 4.71. Found (%): C, 72.80; H, 6.39; N, 4.66.
5-Benzyl-2-nitrobenzofuran (2f): yield 68%; 344 mg; yellow solid; mp 130–131 ºC; 1H NMR
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(400 MHz, CDCl3) δ: 7.59 (d, J = 0.9 Hz, 1H), 7.51–7.53 (m, 2H), 7.43 (dd, J = 8.7, J = 1.8
Hz, 1H), 7.29–7.33 (m, 2H), 7.21–7.25 (m, 1H), 7.18–7.20 (m, 2H), 4.10 (s, 2H); 13С NMR (100
MHz, CDCl3) δ: 153.3 (C), 152.2 (C), 140.4 (C), 138.8 (C), 131.5 (CH), 129.0 (CH), 128.8
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(CH), 126.6 (CH), 126.1 (C), 123.6 (CH), 112.7 (CH), 107.3 (CH), 41.7 (CH2); IR, νmax (KBr):
700, 737, 835, 957, 1099, 1250, 1335 (NO2), 1373, 1433, 1468, 1506 (NO2), 1560, 3136 (CH
Fu) cmꢀ1. Anal. Calcd (%) for C15H11NO3: C, 71.14; H, 4.38; N, 5.53. Found (%): C, 71.20; H,
4.31; N, 5.61.
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5-Chloro-2-nitrobenzofuran (2g): yield 57%; 226 mg; light yellow solid; mp 118–120 ºC; H
NMR (400 MHz, CDCl3) δ: 7.75 (br s, 1H), 7.61 (s, 1H), 7.55–7.57 (m, 2H); 13С NMR (100
MHz, CDCl3) δ: 154.0 (C), 151.6 (C), 131.3 (C), 130.5 (CH), 127.1 (C), 123.4 (CH), 114.1
(CH), 106.5 (CH); IR, νmax (KBr): 692, 729, 814, 835, 880, 957, 1101, 1190, 1244, 1314, 1360
(NO2), 1435, 1449, 1506, 1524 (NO2), 1562, 3136 (CH Fu) cmꢀ1; MS (EI) m/z: 197 [M]+ (35),
167 [M – NO]+ (51), 139 [M – CNO2]+ (30), 123 (57), 111 [C6H4Cl]+ (22), 46 [NO2]+ (100).
Anal. Calcd (%) for C8H4ClNO3: C, 48.63; H, 2.04; N, 7.09. Found (%): C, 48.66; H, 1.97; N,
7.15.
Methyl 2-nitro-1-benzofuran-5-carboxylate (2h): yield 62%; 274 mg; light yellow solid; mp
145–147 ºC; 1H NMR (400 MHz, CDCl3) δ: 8.51 (d, 4J = 1.6 Hz, 1H), 8.28 (dd, 3J = 8.7 Hz, 4J =
1.6 Hz, 1H), 7.72 (s, 1H), 7.67 (d, 3J = 8.7 Hz, 1H), 3.97 (s, 3H); 13С NMR (100 MHz, CDCl3) δ:
166.1 (C=O), 155.5 (C), 153.9 (C), 131.2 (CH), 127.9 (C), 126.6 (CH), 125.9 (C), 112.9 (CH),
107.4 (CH), 52.7 (CH3); IR, νmax (KBr): 746, 770, 839, 912, 1101, 1128, 1194, 1234, 1273,
1298, 1335 (NO2), 1366, 1429, 1439, 1470, 1524 (NO2), 1566, 1618, 1715 (C=O), 3109 (CH
Fu), 3142 cmꢀ1. Anal. Calcd (%) for C10H7NO5: C, 54.31; H, 3.19; N, 6.33. Found (%): C, 54.26;
H, 3.24; N, 6.40.
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5-Acetyl-2-nitrobenzofuran (2i): yield 68%; 279 mg; light yellow solid; mp 161–163 ºC; H
NMR (400 MHz, CDCl3) δ: 8.40 (d, J = 1.6 Hz, 1H), 8.22 (dd, 3J = 8.7, J = 1.6 Hz, 1H), 7.74
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(s, 1H), 7.69 (d, J = 8.7 Hz, 1H), 2.68 (s, 3H); 13С NMR (100 MHz, CDCl3) δ: 196.4 (C=O),
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155.5 (C), 153.9 (C), 134.9 (C), 130.0 (C), 125.9 (CH), 125.3 (CH), 113.0 (CH), 107.5 (CH),
26.8 (CH3); IR, νmax (KBr): 581, 621, 733, 827, 916, 953, 1055, 1099, 1130, 1184, 1223, 1263,
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1335 (NO2), 1364, 1435, 1470, 1522 (NO2), 1568, 1612, 1676 (C=O), 3142 (CH Fu) cmꢀ1. Anal.
Calcd (%) for C10H7NO4: C, 58.54; H, 3.44; N, 6.83. Found (%): C, 58.62; H, 3.49; N, 6.77.
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2,5-Dinitrobenzofuran (2j): yield 50%; 208 mg; yellow solid; mp 172–173 ºC; H NMR (400
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MHz, CDCl3) δ: 8.75 (d, 4J = 2.3 Hz, 1H), 8.51 (dd, 3J = 9.2, 4J = 2.3 Hz, 1H), 7.81 (d, 5J = 0.9
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Hz, 1H), 7.79 (d, J = 9.2 Hz, 1H); С NMR (100 MHz, CDCl3) δ: 155.4 (C), 154.8 (C), 145.8
(C), 126.2 (C), 125.1 (CH), 120.7 (CH), 113.8 (CH), 107.3 (CH); IR, νmax (KBr): 683, 739, 831,
905, 955, 1069, 1194, 1296, 1342 (NO2), 1377, 1539 (NO2), 1570, 1626, 3115 (CH Fu), 3144
cmꢀ1; MS (EI) m/z: 208 [M]+ (42), 207 [M – H]+ (27), 178 [M – NO]+ (100), 162 [M – NO2]+ (8),
132 [M – NO2 – NO]+ (17), 120 [M – CNO2 – NO]+ (26), 104 (15), 88 (66), 76 (39), 62 (47).
Anal. Calcd (%) for C8H4N2O5: C, 46.17; H, 1.94; N, 13.46. Found (%): C, 46.22; H, 2.01; N,
13.43.
5-tert-Butyl-2,7-dinitrobenzofuran (2k): yield 39%; 206 mg; light yellow solid; mp 152–153
ºC; 1H NMR (400 MHz, CDCl3) δ: 8.09 and 8.48 (d, 4J = 1.8 Hz, 2H), 7.74 (s, 1H), 1.44 (s, 9H);
13C NMR (100 MHz, CDCl3) δ: 154.4 (C) 149.9 (C), 143.3 (C), 134.0 (C), 129.1 (C), 127.0
(CH), 124.0 (CH), 106.8 (CH), 35.5 (C), 31.4 (3CH3); IR, νmax (KBr): 725, 791, 845, 899, 926,
949, 1111, 1192, 1242, 1323, 1358 (NO2), 1481, 1531 (NO2), 1574, 2878, 2936, 2974, 3121 (CH
Fu) cmꢀ1. Anal. Calcd (%) for C12H12N2O5: C, 54.55; H, 4.58; N, 10.60. Found (%): C, 54.61; H,
4.56; N, 10.70.
7-(1-Adamantyl)-5-methyl-2-nitrobenzofuran (2l): yield 73%; 454 mg; colorless solid; mp
229–231 ºC; 1H NMR (400 MHz, CDCl3) δ: 7.55 (s, 1H), 7.34 (s, 1H), 7.23 (s, 1H), 2.45 (s, 3H),
2.14–2.19 (m, 9H), 1.81–1.88 (m, 6H); 13С NMR (100 MHz, CDCl3) δ: 152.7 (C), 150.5 (C),
136.4 (C), 135.1 (C), 128.2 (CH), 126.8 (C), 120.9 (CH), 107.0 (CH), 41.3 (CH2), 36.9 (CH2),
36.5 (С), 28.8 (CH), 21.7 (CH3); IR, νmax (KBr): 731, 853, 962, 1252, 1275, 1331, 1344, 1358
(NO2), 1402, 1454, 1524 (NO2), 1570, 2851, 2905, 3152 (CH Fu) cmꢀ1. Anal. Calcd (%) for
C19H21NO3: C, 73.29; H, 6.80; N, 4.50. Found (%): C, 73.33; H, 6.77; N, 4.59.
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7-Methoxy-2-nitrobenzofuran-5-carbaldehyde (2m): yield 59%; 261 mg; light yellow solid;
mp 163–164 ºC; 1H NMR (400 MHz, CDCl3) δ: 10.04 (s, 1H), 7.86 (d, 4J = 1.1 Hz, 1H), 7.75 (s,
1H), 7.58 (d, 4J = 1.1 Hz, 1H), 4.10 (s, 3H); 13С NMR (100 MHz, CDCl3) δ: 190.6 (CHO), 153.9
(C), 146.9 (C), 146.2 (C), 135.4 (C), 127.4 (C), 121.0 (CH), 108.5 (CH), 107.6 (CH), 56.6
(CH3); IR, νmax (KBr): 795, 988, 1098, 1144, 1215, 1277, 1325, 1356 (NO2), 1479, 1537 (NO2),
1570, 1599, 1616, 1697 (CO), 3115 (CH Fu), 3140 cmꢀ1. Anal. Calcd (%) for C10H7NO5: C,
54.31; H, 3.19; N, 6.33. Found (%): C, 54.38; H, 3.25; N, 6.26.
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Methyl 7-methoxy-2-nitro-1-benzofuran-5-carboxylate (2n): yield 60%; 301 mg; light yellow
solid; mp 185–187 ºC; 1H NMR (400 MHz, CDCl3) δ: 8.08 (d, 4J = 1.4 Hz, 1H), 7.72 (d, 4J = 1.4
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Hz, 1H), 7.69 (s, 1H), 4.08 (s, 3H), 3.96 (s, 3H); C NMR (100 MHz, CDCl3) δ: 166.2 (C=O),
153.8 (C), 145.8 (C), 145.3 (C), 128.7 (C), 127.0 (C), 118.2 (CH), 111.6 (CH), 107.7 (CH), 56.5
(CH3), 52.7 (CH3); IR, νmax (KBr): 772, 841, 976, 1103, 1180, 1207, 1231, 1246, 1285, 1358
(NO2), 1481, 1524 (NO2), 1570, 1605, 1620, 1713 (C=O), 2955, 3117, 3144 (CH Fu) cmꢀ1. Anal.
Calcd (%) for C11H9NO6: C, 52.60; H, 3.61; N, 5.58. Found (%): C, 52.70; H, 3.55; N, 5.64.
2-Nitronaphtho[2,1-b]furan (2q): yield 56%; 239 mg; greenish yellow solid; mp 143–144 ºC;
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1H NMR (400 MHz, CDCl3) δ: 8.17 (d, J = 8.2 Hz, 1H), 8.14 (d, J = 0.7 Hz, 1H), 7.99–8.03
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(m, 2H), 7.72 (td, J = 7.1, 4J = 1.2 Hz, 1H), 7.68 (d, J = 8.9 Hz, 1H), 7.62 (ddd, J = 8.2, 3J =
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7.1, J =1.2 Hz, 1H); 13С NMR (100 MHz, CDCl3) δ: 152.6 (C), 152.0 (C), 132.1 (CH), 130.9
(C), 129.5 (CH), 128.4 (CH), 128.0 (C), 126.6 (CH), 123.4 (CH), 122.3 (C), 112.4 (CH), 106.8
(CH); IR, νmax (KBr): 733, 758, 779, 806, 959, 1076, 1123, 1186, 1209, 1261, 1298, 1350 (NO2),
1512 (NO2), 1549, 1584, 3140 (CH Fu) cmꢀ1. Anal. Calcd (%) for C12H7NO3: C, 67.61; H, 3.31;
N, 6.57. Found (%): C, 67.62; H, 3.27; N, 6.64.
1-Acetyl-2-methyl-7-nitrobenzo[1,2-b:4,3-b’]difuran (2r): yield 52%; 269 mg; yellow solid;
mp 191–192 ºC; 1H NMR (400 MHz, CDCl3) δ: 8.55 (s, 1H), 7.49 and 7.63 (d, 3J = 9.0 Hz, 2H),
2.89 (s, 3H), 2.66 (s, 3H); 13С NMR (100 MHz, CDCl3) δ: 192.8 (C=O), 162.8 (C), 152.5 (C),
151.3 (C), 150.4 (C), 121.2 (C), 120.2 (C), 120.1 (C), 113.3 (CH), 110.8 (CH), 109.2 (CH), 30.6
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(CH3), 16.3 (CH3); IR, νmax (KBr): 844, 955, 1113, 1144, 1256, 1300, 1344 (NO2), 1408, 1516,
1551 (NO2), 1655 (C=O), 3169 (CH Fu) cmꢀ1. Anal. Calcd (%) for C13H9NO5: C, 60.24; H, 3.50;
N, 5.40. Found (%): C, 60.21; H, 3.41; N, 5.44.
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bright yellow solid; mp 211–213 ºC; H NMR (400 MHz, DMSOꢀd6) δ: 8.39 (s, 1H), 7.55 and
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7.86 (d, J = 9.2 Hz, 2H), 4.34 (q, J = 7.1 Hz, 2H), 3.79 (s, 3H), 2.71 (s, 3H), 1.38 (t, J = 7.1
Hz, 3H); 13С NMR (100 MHz, DMSOꢀd6) δ: 164.9 (C=O), 151.8 (C), 151.1 (C), 146.4 (C),
133.1 (C), 120.0 (C), 118.1 (C), 115.0 (CH), 110.9 (CH), 106.6 (CH), 104.7 (C), 60.2 (CH2),
31.0 (CH3N), 14.9 (CH3), 12.8 (CH3); IR, νmax (KBr): 860, 932, 1026, 1094, 1111, 1155, 1186,
1236, 1290, 1337 (NO2), 1402, 1499, 1545 (NO2), 1686 (C=O), 2924, 2988, 3090, 3175 (CH Fu)
cmꢀ1. Anal. Calcd (%) for C15H14N2O5: C, 59.60; H, 4.67; N, 9.27. Found (%): C, 59.69; H, 4.61;
N, 9.30.
2-Nitro-6,8,9,10-tetrahydro-7H-furo[3,2-e]pyrido[3,4-b]indol-7-one (2t): yield 39%; 211 mg;
red solid; mp > 300 ºC (decomp.); 1H NMR (400 MHz, DMSOꢀd6) δ: 12.28 (s, 1H), 8.44 (d, 5J =
0.7 Hz, 1H), 7.71 (s, 1H), 7.68 (d, 3J = 9.2 Hz, 1H), 7.59 (dd, 3J = 9.2, 5J = 0.7 Hz, 1H), 3.53 (td,
3J = 6.9, J = 2.3 Hz, 2H), 3.16 (t, J = 6.9 Hz, 2H); 13С NMR (100 MHz, DMSOꢀd6) δ: 161.7
(C=O), 152.7 (C), 150.1 (C), 134.1 (C), 129.1 (C), 119.0 (C), 118.9 (C), 118.1 (C), 117.5 (CH),
109.1 (CH), 108.7 (CH), 41.6 (CH2), 21.5 (CH2); IR, νmax (KBr): 820, 920, 1088, 1128, 1209,
1240, 1271, 1302, 1319, 1352 (NO2), 1400, 1445, 1499, 1543 (NO2), 1676 (C=O), 2926, 3123
(CH Fu), 3231 (NH), 3375 (NH) cmꢀ1. Anal. Calcd (%) for C13H9N3O4: C, 57.57; H, 3.34; N,
15.49. Found (%): C, 57.62; H, 3.28; N, 15.56.
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2-Nitrobenzofuran (2o)
Potassium trinitromethanide (1.14 g, 6 mmol) was added in three equal portions over a period of
20 minutes to a stirred solution of 2ꢀ(acetyloxy)benzyl acetate (0.42 g, 2 mmol) and
triethylamine (0.84 mL, 6 mmol) in 60% aqueous ethanol (20 mL) at reflux temperature under an
Ar atmosphere. Afterwards, the mixture was refluxed for another 20 minutes, poured into 50 mL
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of saturated aqueous sodium chloride and extracted with dichloromethane (2x20 mL), dried
(Na2SO4) and concentrated under reduced pressure. The crude product was purified by column
chromatography over silica gel using dichloromethane as eluent, followed by recrystallization
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from EtOH. Yield 150 mg (46%); light yellow solid; mp 134–135 ºC; H NMR (400 MHz,
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CDCl3) δ: 7.76 (d, J = 8.0 Hz, 1H), 7.68 (s, 1H), 7.57–7.63 (m, 2H), 7.39–7.44 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ: 153.4 (C), 153.2 (br s, C), 130.1 (CH), 125.9 (C), 125.4 (CH), 124.1
(CH), 112.8 (CH), 107.4 (CH); IR, νmax (KBr): 729, 756, 833, 955, 1090, 1244, 1265, 1304,
1315, 1333, 1368 (NO2), 1443, 1479, 1516, 1562 (NO2), 1612, 2926, 3154 (CH Fu) cmꢀ1. Anal.
Calcd (%) for C8H5NO3: C, 58.90; H, 3.09; N, 8.59. Found (%): C, 59.01; H, 3.02; N, 8.64.
5-Bromo-2-nitrobenzofuran (2p) was prepared similarly to compound 2o from 2ꢀ(acetyloxy)ꢀ
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5ꢀbromobenzyl acetate 1p. Yield 51%; 247 mg; light yellow solid; mp 168–169 ºC; H NMR
(400 MHz, CDCl3) δ: 7.92 (d, 4J = 1.8 Hz, 1H), 7.69 (dd, 3J = 9.2, 4J = 1.8 Hz, 1H), 7.61 (s, 1H),
7.52 (d, J = 9.2 Hz); 13C NMR (CDCl3) δ: 153.6 (C), 152.0 (C), 133.2 (CH), 127.6 (C), 126.6
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(CH), 118.6 (C), 114.4 (CH), 106.3 (CH); IR, νmax (KBr): 810, 837, 876, 957, 1099, 1188, 1238,
1312, 1373 (NO2), 1439, 1528 (NO2), 1562, 3140 (CH Fu) cmꢀ1. Anal. Calcd (%) for
C8H4BrNO3: C, 39.70; H, 1.67; N, 5.79. Found (%): C, 39.77; H, 1.59; N, 5.86.
6,7-Dimethyl-2-dimethylamino-4H-1,3-benzoxazine (3).
When using TMG instead of TEA only benzoxazine 3 was isolated under the conditions
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previously indicated. Yield 54%; 220 mg; white solid; mp 82–83 °С (from hexane); H NMR
(400 MHz, CDCl3) δ: 6.77 (s, 1H), 6.68 (s, 1H), 4.43 (s, 2H), 2.93 (s, 6H), 2.20 (s, 3H), 2.18 (s,
3H); 13C NMR (100 MHz, CDCl3) δ: 151.2 (C), 148.1 (C), 135.8 (C), 132.0 (C), 126.6 (CH),
118.5 (C), 116.0 (CH), 44.7 (CH2), 37.2 (2CH3), 19.6 (CH3), 19.1 (CH3); IR υmax (KBr): 866,
880, 959, 1099, 1175, 1202, 1254, 1269, 1373, 1389, 1450, 1462, 1487, 1504, 1674 (C=N), 2851
cmꢀ1; Anal. Calcd (%) for C12H16N2O: С, 70.56; Н, 7.90; N, 13.71. Found (%): С, 70.60; Н, 7.92;
N, 13.80.
4-Nitro-2-(2,2,2-trinitroethyl)phenol (4a)
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A mixture of 2ꢀ(chloromethyl)ꢀ4ꢀnitrophenol 1v (1 g, 5.3 mmol) and potassium trinitromethanide
(1.06 g, 5.6 mmol) in CH3CN (20 mL) under an Ar atmosphere was stirred at room temperature
for 4 h. Afterwards, the mixture was poured into 50 mL of saturated aqueous sodium chloride
and extracted with dichloromethane (2x20 mL), dried (Na2SO4) and concentrated under reduced
pressure. The crude product was purified by recrystallization from ethanol. Yield 50%; 800 mg;
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light orange solid; mp 139–140 ºC (decomp.); H NMR (DMSOꢀd6) δ: 11.86 (1H, br s), 8.12ꢀ
8.15 (2H, m), 6.99 (1H, d, J = 9.1 Hz), 4.79 (s, 2H); 13C NMR (DMSOꢀd6): 163.6 (C), 140.1
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(C), 129.1 (C), 128.5 (CH), 127.5 (CH), 116.1 (C), 116.0 (CH), 33.6 (CH2); IR, νmax (KBr): 638,
756, 812, 825, 839, 864, 920, 937, 1090, 1221, 1288, 1335 (NO2), 1495, 1516 (NO2), 1591
(C(NO2)3), 1609, 3500–3300 (OH) cmꢀ1. Anal. Calcd (%) for C8H6N4O9: C, 31.80; H, 2.00; N,
18.54. Found (%): C, 31.90; H, 1.96; N, 18.57.
1-[4-Hydroxy-3-(2,2,2-trinitroethyl)phenyl]ethanone (4b)
A mixture of 3ꢀchloromethylꢀ4ꢀhydroxyacetophenone 1w (1 g, 5.4 mmol) and potassium
trinitromethanide (1.06 g, 5.6 mmol) in CH3CN (20 mL) under an Ar atmosphere was stirred at
room temperature for 4 h. Afterwards, the mixture was poured into 50 mL of saturated aqueous
sodium chloride to yield a solid product, which was filtered, washed with water and purified by
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recrystallization from ethanol. Yield 71%; 1.15 g; pink solid; mp 160–161 ºC (decomp.); H
NMR (400 MHz, DMSOꢀd6) δ: 11.12 (1H, br s), 7.86 (dd, 3J = 8.5, 4J = 2.1 Hz, 1H), 7.79 (d, 4J
= 2.1 Hz, 1H), 6.91(d, J = 8.5 Hz, 1H), 4.72 (s, 2H), 2.44 (s, 3H); 13C NMR (100 MHz,
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CD3CN): 196.0 (C=O), 160.3 (C), 132.1 (CH), 131.9 (CH), 130.4 (C), 128.7 (br s, C), 115.1
(CH), 114.6 (C), 33.8 (CH2), 25.7 (CH3); IR, νmax (KBr): 814, 833, 864, 964, 1080, 1119, 1285,
1304, 1362, 1431, 1585, 1597 (C(NO2)3), 1667 (C=O), 3400–3100 (OH) cmꢀ1. Anal. Calcd (%)
for C10H9N3O8: C, 40.14; H, 3.03; N, 14.04. Found (%): C, 40.22; H, 2.96; N, 14.13.
2,2,5-Trinitro-2,3-dihydrobenzofuran (5a)
4ꢀNitroꢀ2ꢀ(2,2,2ꢀtrinitroethyl)phenol 4a (0.3 g, 1 mmol) was dissolved in DMSO (2 mL) and the
solution obtained was stored at room temperature for 5 h. The solution was poured into 15 mL of
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saturated aqueous sodium chloride to yield a solid product, which was filtered, washed with
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water and dried. Yield 43%; 110 mg; light yellow solid; mp 92–94 ºC; H NMR (400 MHz,
DMSOꢀd6) δ: 8.32ꢀ8.33 (m, 1H), 8.29 (dd, 3J = 8.9, J = 2.3 Hz, 1H), 7.58 (d, J = 8.9 Hz, 1H),
4.70 (s, 2H); 13С NMR (100 MHz, DMSOꢀd6): 160.7 (C), 145.1 (C), 130.1 (C), 126.7 (CH),
125.8 (C), 121.8 (CH), 111.8 (CH), 38.7 (CH2); IR, νmax (KBr): 745, 829, 903, 926, 1070, 1152,
1240, 1290, 1319, 1348 (NO2), 1474, 1524 (NO2), 1584 (C(NO2)2), 1603 cmꢀ1. Anal. Calcd (%)
for C8H5N3O7: C, 37.66; H, 1.98; N, 16.47. Found (%): C, 37.71; H, 1.98; N, 16.58.
5-Acetyl-2,2-dinitro-2,3-dihydrobenzofuran (5b)
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1ꢀ[4ꢀHydroxyꢀ3ꢀ(2,2,2ꢀtrinitroethyl)phenyl]ethanone 4b (0.3 g, 1 mmol) was dissolved in DMSO
(2 mL) and the solution obtained was stored at room temperature for 5 days. The solution was
poured into 15 mL of saturated aqueous sodium chloride, product extracted with CH2Cl2 and
solvent was evaporated in vacuo at room temperature. The residue was crystallized from
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chloroform. Yield 40%; 101 mg; light yellow solid; mp 108–110 ºC (decomp.); H NMR
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(DMSOꢀd6) δ: 7.98ꢀ8.02 (m, 2H), 7.43 (d, 1H, J = 9.2 Hz), 4.66 (s, 2H), 2.54 (s, 3H); С NMR
(DMSOꢀd6) δ: 196.9 (C=O), 159.6 (C), 134.6 (C), 131.2 (CH), 130.2 (C), 125.9 (CH), 124.2 (C),
111.0 (CH), 38.6 (CH2), 27.2 (CH3); IR, νmax (KBr): 621, 1119, 1146, 1254, 1296, 1362, 1485,
1605(C(NO2)2), 1670 (C=O) cmꢀ1. Anal. Calcd (%) for C10H8N2O6: C, 47.63; H, 3.20; N, 11.11.
Found (%): C, 47.73; H, 3.27; N, 11.04.
Acknowlegement
This work was financially supported by the Russian Ministry of Education and Science within
basic part of government assignment for scientific research with use of equipment of Multipleꢀ
Access Center “Investigation of the physicochemical properties of substances and materials” of
Samara State Technical University.
ASSOCIATED CONTENT
Supporting Information
Copies of 1H and 13C NMR spectra for all new synthesized compounds.
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This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
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Corresponding author
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*Eꢀmail: vosyanin@mail.ru.
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Present adress
Department of Organic Chemistry, Samara State Technical University, 244 Molodogvardeiskaya
St., 443100 Samara, Russian Federation.
Notes
The authors declare no competing financial interest.
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References
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(1) (a) Tietze, L. F; Brasche, G.; Gericke, K. M., Eds. Domino reactions in Organic Synthesis WileyꢀVCH:
Weinheim, Gemany, 2006, (b) Babaev, E. V. Chem. Heterocycl. Comp. 1993, 29, 796ꢀ817.
(2) For selected examples of the synthesis using ambiphilic building blocks, see: (a) Rofle, A.; Samarakoon, T. B.;
Hanson, P. R. Org. Lett. 2010, 12, 1216ꢀ1219; (b) Dudnik, A. S.; Chernyak, N.; Huang, C.; Gevorgyan, V.
Angew. Chem., Int. Ed. 2012, 49, 8729ꢀ8732; (c) Hili, R.; Rai, V.; Yudin, A. K. J. Am. Chem. Soc. 2010, 132,
2889ꢀ2891.
(3) For early reports on 1,1ꢀambiphiles, see: (a) Nakamura, Y.; Ukita, T. Org. Lett. 2002, 4, 2317ꢀ2320; (b) De
Fusco, C.; Fuoco, T.; Croce, G.; Lattanzi, A. Org. Lett. 2012, 14, 4078ꢀ4081; (c) Katritzky, A. R.; Wang, X.;
Xie, L.; Toader, D. J. Org. Chem. 1998, 63, 3445ꢀ3449; (d) Wasserman, H. H.; De Simone, R. W.; Ho, W.ꢀB.;
McCarthy, K. E. Tetrahedron Lett. 1992, 33, 7207ꢀ7210; (e) Trost, B. M.; Ghadiri, M. R. J. Am. Chem. Soc.
1984, 106, 7260ꢀ7261; (f) Wasserman, H. H.; Ho, W.ꢀB. J. Org. Chem. 1994, 59, 4364ꢀ4366; (g) Trost, B. M.;
Quayle, P. J. Am. Chem. Soc. 1984, 106, 2469ꢀ2471; (h) Katritzky, A. R.; Luo, Z.; Fang, Y.; Steel, P. J. J. Org.
Chem. 2001, 66, 2858ꢀ2861; (i) Sato, T.; Okura, S.; Otera, J.; Nozaki, H. Tetrahedron Lett. 1987, 28, 6299ꢀ3602;
(j) Trost, B. M.; Granja, J. R. J. Am. Chem. Soc. 1991, 113, 1044ꢀ1046.
(4) (a) Averina, E. A.; Kuznetsova, T. S.; Zefirov, N. S. Synlett 2009, 10, 1543ꢀ1557 (account); (b) Volkova, Yu.
A.; Averina, E. B.; Grishin, Yu. K.; Bruheim, P.; Kuznetsova, T. S.; Zefirov, N. S. J. Org. Chem. 2010, 75,
3047ꢀ3052; (c) Averina, E. B.; Samoilichenko, Yu. V.; Volkova, Yu. A.; Grishin, Yu. K.; Rybakov, V. B.;
Kutateladze, A. G.; Elyashberg, M. E.; Kuznetsova, T. S.; Zefirov, N. S. Tetrahedron Lett. 2012, 53, 1472ꢀ1475.
(5) Willis, N. J.; Bray, C. D. Chem. Eur. J. 2012, 18, 9160ꢀ9173.
(6) (a) De Water, R. W.; Pettus, T. R. R. Tetrahedron 2002, 58, 5367ꢀ5405. (b) Rokita, S. E., Ed. Quinone methides;
Wiley: Hoboken, 2009.
(7) (a) Samarakoon, T. B.; Hur, M. Y.; Kurtz, R. D.; Hanson, P. R. Org. Lett. 2010, 12, 2182ꢀ2185; (b) Osyanin, V.
A.; Osipov, D. V.; Klimochkin, Yu. N. J. Org. Chem. 2013, 78, 5505ꢀ5520 and references therein.
(8) Bilger, C.; Demerseman, P.; Buisson, J.ꢀP.; Royer, R.; Gayral, P.; Fourniat, J. Eur. J. Med. Chem., 1987, 22,
213ꢀ219.
(9) Cavier, R.; Buisson, J. P.; Royer, R. Eur. J. Med. Chem. 1982, 17, 91ꢀ92.
(10) Averbeck, D.; Bensasson, R. V.; Buisson, J. P.; Land, E. J.; Rene, L.; Royer, R.; Santus, R. Int. J. Radiat. Biol.
1982, 42, 457ꢀ468.
(11) Quillardet, P.; Touati, E.; Hofnung, M. Mutation Research 1996, 358, 113ꢀ122 and references therein.
(12) Guével, R.; Oger, F.; Lecorgne, A.; Dudasova, Z.; Chevance, S.; Bondon, A.; Barath, P.; Simonneaux, G.;
Salbert, G. Bioorg. Med. Chem. 2009, 17, 7021ꢀ7030.
(13) Lin, S.ꢀY.; Chen, C.ꢀL.; Lee, Y.ꢀJ. J. Org. Chem. 2003, 68, 2968ꢀ2971.
(14) Rosa, C. D. D.; Sanchez, J. P.; Kneeteman, M. N.; Mancini, P. M. E. Tetrahedron Lett. 2011, 52, 2316ꢀ2319.
(15) Gribble, G. W.; Pelkey, E. T.; Switzer, F. L. Synlett 1998, 1061ꢀ1062.
(16) (a) Tromelin, A.; Demerseman, P.; Royer, R. Synthesis 1985, 1074ꢀ1076 and references therein. (b) Yoshitaka,
O.; Doi, Y.; Nakanishi, T. Chem. Pharm. Bull. 1988, 36, 1336ꢀ1342.
(17) (a) Bastian, G.; Royer, R.; Cavier, R. Eur. J. Med. Chem. 1983, 18, 365ꢀ367. (b) Kaluza, F.; Perold, G. Chem.
Ber. 1955, 88, 597ꢀ601.
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(18) Royer, R. Ann. Pharm. Fr. 1983, 41, 299ꢀ311.
(19) Einhorn, J.; Demerseman, P.; Royer, R. Synthesis 1984, 978ꢀ980.
(20) Yadav, R. R.; Vishwakarma, R. A.; Bharate, S. B. Tetrahedron Lett. 2012, 53, 5958ꢀ5960.
(21) Hwu, J. R.; Chen, K.ꢀL.; Ananthan, S. J. Chem. Soc., Chem. Commun. 1994, 1425ꢀ1426.
(22) Lu, S.ꢀC.; Zheng, P.ꢀR.; Liu, G. J. Org. Chem. 2012, 77, 7711ꢀ7717.
(23) (a) Göbel, M.; Klapötke, T. M.; Mayer, P. Z. Anorg. Allg. Chem. 2006, 632, 1043ꢀ1050. (b) Altukhov, K. V.;
Perekalin, V. V. Russ. Chem. Rev. 1976, 45, 1052.
(24) Further studies of this reaction are in progress.
(25) BladéꢀFont, A.; Rocabayera, T. J. Chem. Soc., Perkin Trans. 1 1982, 841ꢀ848.
(26) Weinert, E. E.; Dondi, R.; ColloredoꢀMelz, S.; Frankenfield, K. N.; Mitchel, C. H.; Freccero, M.; Rokita, S. E.
J. Am. Chem. Soc. 2006, 128, 11940ꢀ11947.
(27) Tramontini, M. Synthesis 1973, 703ꢀ775.
(28) Brode, W. R.; Littman, J. B. J. Am. Chem. Soc. 1931, 53, 1531ꢀ1532.
(29) Fanghänel, E.; Böckelmann, J.; Grossman, N.; Pfeifer, D. J. Prakt. Chem. 1986, 328, 724ꢀ728.
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