The first synthesis of 3-hydroxy-2-(polyfluoroalkyl)chromones and their ammonium salts. 3-Hydroxychromone in the Mannich reaction

Article abstract of DOI:10.1002/jhet.386

(Chemical Equation Presented) 3-Hydroxy-2-(polyfluoroalkyl)chromones were obtained in good yields via the nitrozation reaction of 2-(polyfluoroalkyl) chroman-4-ones with isopropyl nitrite in the presence of hydrochloric acid. Treatment of 3-acetoxy-2-(tri

Full text of DOI:10.1002/jhet.386

944
The First Synthesis of 3-Hydroxy-2-(polyfluoroalkyl)chromones
and Their Ammonium Salts. 3-Hydroxychromone in the Mannich
Reaction
Vol 47
Roman A. Irgashev,a Vyacheslav Ya. Sosnovskikh,a* Anna A. Sokovnina,a and
b
¨
Gerd-Volker Roschenthaler
aDepartment of Chemistry, Ural State University, Ekaterinburg 620083, Russian Federation
bInstitute of Inorganic and Physical Chemistry, University of Bremen, Bremen 28334, Germany
*E-mail: Vyacheslav.Sosnovskikh@usu.ru
Received September 1, 2009
DOI 10.1002/jhet.386
Published online 21 June 2010 in Wiley InterScience (www.interscience.wiley.com).
3-Hydroxy-2-(polyfluoroalkyl)chromones were obtained in good yields via the nitrozation reaction of
2-(polyfluoroalkyl)chroman-4-ones with isopropyl nitrite in the presence of hydrochloric acid. Treatment
of 3-acetoxy-2-(trifluoromethyl)chromone with primary amines and hydrazine gave the corresponding
ammonium salts. Reaction of 3-hydroxychromone, prepared by this method, with formaldehyde and a-
aminoacids has been studied.
J. Heterocyclic Chem., 47, 944 (2010).
INTRODUCTION
kyl)chromones with respect to nucleophilic reagents [4].
The variety of the reactions of 2-RF-chromones makes this
class of compounds very useful for synthesis of RF-con-
taining heterocycles with potential biological activity [2].
However, to the best of our knowledge, very little is
known about the synthesis and properties of 3-substi-
tuted 2-RF-chromones. There have been only some
papers on the preparation of 3-chloro- [5], 3-bromo- [6],
3-cyano- [7], 3-carbamoyl- [7], and 3-carbethoxychro-
mones [8] with a RF group at the 2-position. 2-(Poly-
fluoroalkyl)chromones containing electron-donating sub-
stituents at the 3-position had not been described yet. In
view of the unique biological properties displayed by
chromones [1,2] on one hand and by many fluorine-con-
taining heterocycles [9] on the other hand, it was of in-
terest to obtain 2-RF-chromones with an electron-donat-
ing hydroxy group at the C-3 atom and their derivatives.
It is worth to note that 3-hydroxyflavone is the most
simple model of aglucones of polyhydroxyflavones
The chromone ring is an integral part of many natural
and biologically active substances. The biological po-
tency of chromone derivatives and, in particular, halo-
gen-containing chromones, has been widely documented
[1,2]. Therefore, considerable efforts have been paid to
explore new synthetic route to halogenated derivatives
of chromone and to study their chemical properties. Pol-
yfluoroalkyl groups, especially the CF3 group, are highly
important substituents in the field of organic chemistry.
The introduction of these groups into organic molecules
can bring about some remarkable changes in the physi-
cal properties, chemical reactivity, and biological activ-
ity of the derived fluorinated compounds [3]. Thus, it is
well known that the insertion of polyfluoroalkyl sub-
stituents into the 2-position of chromones activates mol-
ecules of these compounds and reveals significant differ-
ences in the reactivity of 2-alkyl- and 2-(polyfluoroal-
C
V
2010 HeteroCorporation

July 2010 The First Synthesis of 3-Hydroxy-2-(polyfluoroalkyl)chromones and Their Ammonium Salts. 3-
Hydroxychromone in the Mannich Reaction
945
Scheme 1
as a representative example was allowed to react with
MeI and Ac2O. Our results showed that 4a smoothly
reacts with an excess of MeI (refluxing acetone, K2CO3,
8 h) and Ac2O (pyridine, ꢁ20ꢀC, 2 days) to produce the
expected 3-methoxy- and 3-acetoxy-2-(trifluoromethyl)-
chromones 5 and 6 in 87% and 77% yields, respectively
1
(Scheme 2). The most notable feature in the H NMR
spectra of 5 and 6 is the absence of a signal of the
hydroxy group and the appearance of singlets at d 4.04
and 2.41 ppm due to the MeO and MeCO groups. Previ-
ously, their non-fluorinated analogs, 3-methoxy-, 3-ace-
toxy-, and 3-hydroxy-2-methylchromones, were obtained
by reaction of x-bromo-2-hydroxyacetophenone with
acetic acid anhydride and sodium acetate [11]. The syn-
thesis of 3-hydroxy-2-methylchromone has been also
achieved by oxidation of 2-methylchroman-4-one with
isoamyl nitrite [12].
It is known that reactions of 2-RF-chromones 1 with
amines and hydrazines proceed at the C-2 atom with py-
rone ring opening to form b-aminovinylketones [13] and
pyrazoles [14]. However, the acetylated derivative 6 did
not show any analogous behavior to 1 and reacted with
isoamyl-, benzyl-, and p-fluorobenzylamines in ethanol
at room temperature immediately to give the corre-
sponding salts 7a–c as the sole isolated products in 47–
85% yields. Similarly, reaction with hydrazine hydrate
leads to hydrazinium 4-oxo-2-(trifluoromethyl)-4H-chro-
men-3-olate 7d in 69% yield (Scheme 2). These salts
are stable compounds and can be stored at room
which, linked by glucoside bond at the C-3 atom, are
very widely spread heterocycles in the nature.
Recently [10], we have reported that reduction of
readily available 2-(polyfluoroalkyl)chromones 1 with
sodium borohydride provides a simple preparative pro-
cedure to cis-2-(polyfluoroalkyl)chroman-4-ols 2, the ox-
idation of which to 2-(polyfluoroalkyl)chroman-4-ones 3
was performed with chromic acid in ethyl ether. We
regarded these compounds as desirable targets because
of their relationship to naturally occurring benzopyran
derivatives and usefulness as RF-containing building
blocks for the preparation of more complex partially flu-
orinated heterocycles and other highly functionalized
biologically and medicinally important products.
Scheme 2
RESULTS AND DISCUSSION
Now we wish to report the successful nitrozation
reaction of 2-RF-chroman-4-ones 3 for the synthesis of
previously unknown 3-hydroxy-2-(polyfluoroalkyl)chro-
mones 4. We found that treatment of an alcoholic solu-
tion of 3a–c with an excess of isopropyl nitrite (3.0
equiv) and concentrated hydrochloric acid at 0–80ꢀC for
3 h gave chromones 4a–c in 42–68% yields as colorless
crystals (Scheme 1). In the 1H NMR spectra of these
products in DMSO-d6, a singlet at d 10.4–10.7 ppm for
the OH proton appeared in place of the disappearance of
signals at d 2.9–3.0 and 4.8–4.9 ppm associated with the
C-3 methylene and C-2 methine protons of the starting
2-RF-chroman-4-ones 3. It was also observed that all
protons of the benzene ring shifted to lower field and,
hence, formation of the pyrone ring took place under
the action of isopropyl nitrite.
To demonstrate the ability of compounds 4 to
undergo alkylation and acylation reactions, chromone 4a
Journal of Heterocyclic Chemistry
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¨
R. A. Irgashev, V. Y. Sosnovskikh, A. A. Sokovnina, and G.-V. Roschenthaler
946
Vol 47
Table 1
Selected 13C NMR data of chromones 1a [16], 6, 4a, 7a, and 8 [17a].
sented in Table 1 to demonstrate the deshielding and
shielding effects of the oxygen substituent at the 3-posi-
tion on the C-3 and C-2 atoms compared with H-3 of
chromone 1a. As can been seen from Table 1, the
appearance of the 3-OH group leads to considerable
shielding of the C-2 atom, which is related to the lack
of usual chromone reactivity.
Chemical shifts, d (ppm)
Chromone
C-2
C-3
C-4
1aa
6a
152.2
144.8
133.7
131.8
139.9
110.4
135.2
141.3
152.3
142.1
176.8
171.7
173.6
180.4
174.0
4ab
7ab
8a
Next, taking into account the above results and that
the 3-hydroxychromone ring is an important structural
fragment of many natural and biologically active sub-
stances [18], we decided to investigate the possibility of
preparing 3-hydroxychromone 8 through nitrozation
reaction of chroman-4-one under our reaction condi-
tions. Previously, this compound was prepared by oxida-
tion of chromone and 3-formylchromone using different
reagents in two steps [17]. We found that the reaction
between commercially available chroman-4-one and iso-
propyl nitrite is a useful method for the preparation of 8
because it requires only one step, cheap common
reagents, and short reaction times (2–3 h in this case),
albeit in only 35% yield (Scheme 3).
a In CDCl3.
b In DMSO-d6.
temperature within several months. Thus, the salts for-
mation was achieved without destruction of the chro-
mone ring system. However, when an ethanolic solution
of 4a or 6 with benzylamine or hydrazine was heated,
the reaction did not occur and only resinification was
observed. Also, we were unable to obtain the corre-
sponding salts from 6 and tert-butylamine, cyclohexyla-
mine, and ethylenediamine. It should be noted that 3-
hydroxychromone reacts with hydrazine hydrate in
methanol to give 4-hydroxy-3-(2-hydroxyphenyl)-1H-
pyrazole [15].
The replacement of a H-3 atom in 2- and 3-unsubsti-
tuted chromones by an alkyl- or dialkylaminomethyl
group in the Mannich reaction is well known [19]. Very
recently [20], it has been shown that 3-formylchromones
react with a-aminoacids in the presence of excess form-
aldehyde to produce N-(chromone-3-ylmethyl)-a-amino-
acids by a deformylative Mannich type reaction. It was
also observed that a-aminoacids can be used as the
amine component in a Mannich reaction with kojic acid
[21]. However, the use of 3-hydroxychromones in this
reaction has not been reported in the literature. Our pre-
liminary results showed that 3-hydroxychromone 8
smoothly reacted with such a-aminoacids as sarcosine
Reaction of the chromone derivative 6 with amines
and hydrazine under mild conditions represents an easy
access to the ammonium salts of 3-hydroxy-2-(trifluoro-
methyl)chromone 7a–d, which could not be directly pre-
pared from chromone 4a and amines. The salts produced
by this addition-elimination sequence gave the starting
compound 4a when treated by an ethanolic solution of
hydrochloric acid at ꢂ30ꢀC. The lack of chromone reac-
tivity towards amines and hydrazine can be caused by
the conjugation effect of the electron releasing OH and
OAc groups, which decrease the electrophilic character
of the C-2 atom, which is usually attacked first in the
reaction of a chromone system with nucleophiles [2].
The IR spectra of 7a–d display two distinct absorp-
tion bands at approximately 1630 and 1610 cm–1
assigned to the C¼¼O and C¼¼C functions, respectively,
as in the case of the protonated form 4a. In the 1H
NMR spectra of these compounds, the ammonium pro-
tons appeared as broad singlets within the range d 3.0–
7.2 ppm (CDCl3). The 13C spectra of compounds 7a,d
are much more informative and display low field signals
at ca. d 180.3, 154.2, and 152.1 ppm, which are
assigned to C-4, C-8a, and C-3, respectively. The aro-
matic carbons fall within the range d 118–133 ppm; the
C-2 atom, adjacent to the CF3 group, appeared as a
quartet at d 131.8–132.0 ppm (2JC,F ¼ 32.0 Hz), shifted
upfield compared with C-2 of chromones 1, 4, and 6.
Scheme 3
1
The H-coupled 13C NMR spectrum of 7a was used to
assign signals for the quaternary carbon atoms. The
chemical shifts of the pyrone carbon atoms are pre-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2010 The First Synthesis of 3-Hydroxy-2-(polyfluoroalkyl)chromones and Their Ammonium Salts. 3-
Hydroxychromone in the Mannich Reaction
947
3-Hydroxy-2-(1,1,2,2-tetrafluoroethyl)chromone (4c). Yield
470 mg (66%), mp 134–135ꢀC; IR (KBr) 3238, 1628, 1611,
1575 cm–1; 1H NMR (400 MHz, DMSO-d6) d 6.96 (tt, 1H,
and valine in the presence of 37% formalin in refluxing
ethanol for 5 h to give the corresponding chromone
derivatives 9a,b in high yields (70–80%). The resulting
products represent an important class of chromone
derivatives, in which two different fragments with
remarkably interesting biological and pharmaceutical
activities are linked at the same carbon atom.
2
3
CF2CF2H, JH,F ¼ 51.9 Hz, JH,F ¼ 5.5 Hz), 7.54 (ddd, 1H,
H-6, J ¼ 8.0, 7.1, 1.0 Hz), 7.71 (dd, 1H, H-8, J ¼ 8.6, 1.0
Hz), 7.88 (ddd, 1H, H-7, J ¼ 8.6, 7.1, 1.7 Hz), 8.14 (dd, 1H,
H-5, J ¼ 8.0, 1.7 Hz), 10.70 (s, 1H, OH). Anal. Calcd. for
C11H6F4O3: C, 50.40; H, 2.31. Found: C, 50.66; H, 2.46.
3-Methoxy-2-(trifluoromethyl)chromone (5). To a solution
of chromone 4a (400 mg, 1.74 mmol) and MeI (740 mg, 5.22
mmol) in acetone (10 mL) was added K2CO3 (600 mg, 4.35
mmol) and the mixture was reflux for 8 h. After cooling, the
inorganic salts were filtered off and washed with acetone (10
mL). Evaporation of the filtrate at heating gave a solid, which
was recrystallized from hexane to give colorless crystals. Yield
In conclusion, we have shown that the reaction of 2-
(polyfluoroalkyl)chroman-4-ones with isopropyl nitrite is a
simple and practical method for the preparation of 3-
hydroxy-2-(polyfluoroalkyl)chromones and 3-hydroxychro-
mone. Treatment of 3-acetoxy-2-(trifluoromethyl)chromone
with primary amines and hydrazine gave the corresponding
ammonium salts. 3-Hydroxychromone reacts with formal-
dehyde and a-aminoacids to form previously unknown N-
(3-hydroxychromone-2-ylmethyl)-a-aminoacids.
1
370 mg (87%), mp 57ꢀC; IR (ATR) 1614 cm–1; H NMR (400
MHz, CDCl3) d 4.04 (s, 3H, MeO), 7.46 (ddd, 1H, H-6, J ¼
8.1, 7.1, 1.0 Hz), 7.55 (dd, 1H, H-8, J ¼ 8.6, 1.0 Hz), 7.75
(ddd, 1H, H-7, J ¼ 8.6, 7.1, 1.7 Hz), 8.24 (dd, 1H, H-5, J ¼
8.1, 1.7 Hz). Anal. Calcd. for C11H7F3O3: C, 54.11; H, 2.89.
Found: C, 54.03; H, 3.14.
EXPERIMENTAL
1H (400 MHz), 19F (376 MHz), and 13C (100 MHz) NMR
spectra were recorded on a Bruker DRX-400 spectrometer in
DMSO-d6 and CDCl3 with TMS and CFCl3 as the internal
standards. IR spectra were recorded on Perkin-Elmer Spectrum
BX-II and Bruker Alpha instruments as KBr discs and ATR
(ZnSe), respectively. Elemental analyses were performed at the
Microanalysis Services of the Institute of Organic Synthesis,
Ural Branch, Russian Academy of Sciences. Melting points are
uncorrected. All solvents used were dried and distilled per stand-
ard procedures. The starting 2-(polyfluoroalkyl)chroman-4-ones
3a–c were prepared according to described procedure [10].
General procedure for the synthesis of 3-hydroxy-2-(poly-
fluoroalkyl)chromones (4a–c). Concentrated hydrochloric acid
(3.4 mL) was added dropwise over 1 h to a cold stirred solu-
tion of chroman-4-one 3 (2.0 mmol) and isopropyl nitrite (6.0
mmol) in ethanol (5 mL) and methanol (2 mL). On completion
of the addition, the reaction mixture was allowed to warm to
room temperature (1 h) and was then heated to 80ꢀC for 2–3
h. After cooling, the precipitated product was isolated by filtra-
tion and washed with water to give colorless crystals.
3-Acetoxy-2-(trifluoromethyl)chromone (6). A solution of
6 (330 mg, 1.43 mmol) and acetic anhydride (300 mg, 2.87
mmol) in pyridine (5 mL) was kept at room temperature for 2
days. Then the reaction mixture was poured into diluted hydro-
chloric acid (1:10) and allowed to stand for 1 day at room
temperature. The resulting colorless solid was filtered and
washed with water. Yield 300 mg (77%), mp 110ꢀC; IR
(ATR) 1790, 1664, 1611 cm–1; 1H NMR (400 MHz, DMSO-
d6) d 2.41 (s, 3H, Me), 7.64 (ddd, 1H, H-6, J ¼ 8.0, 7.1, 1.0
Hz), 7.85 (ddd, 1H, H-8, J ¼ 8.6, 1.0, 0.4 Hz), 7.98 (ddd, 1H,
H-7, J ¼ 8.6, 7.1, 1.7 Hz), 8.13 (ddd, 1H, H-5, J ¼ 8.0, 1.7,
0.4 Hz); 19F NMR (376 MHz, CDCl3) d ꢂ67.87 (s, CF3); 13C
NMR (100 MHz, CDCl3) d 20.00 (Me), 118.44 (C8), 118.75
1
(q, CF3, JC,F ¼ 275.8 Hz), 123.56 (C4a), 126.27 (C5/6),
126.29 (C6/5), 135.18 (C7/3), 135.26 (C3/7), 144.80 (q, C2,
2JC,F ¼ 37.7 Hz), 154.73 (C8a), 167.17 (OC¼¼O), 171.73
(C¼¼O). Anal. Calcd. for C12H7F3O4: C, 52.95; H, 2.59.
Found: C, 52.99; H, 2.79.
General procedure for the synthesis of ammonium salts
of 3-hydroxy-2-(trifluoromethyl)chromone (7a–d). To a so-
lution of 6 (270 mg, 1.0 mmol) in absolute ethanol (5 mL)
was added the corresponding amine (4.0 mmol). The resulting
colorless solid was filtered, washed with cooled ethanol, and
dried at 60–70ꢀC.
3-Hydroxy-2-(trifluoromethyl)chromone (4a). Yield 290 mg
(68%), mp 166–167ꢀC; IR (ATR) 3275, 1634, 1612, 1576 cm–1;
1H NMR (400 MHz, DMSO-d6) d 7.53 (ddd, 1H, H-6, J ¼ 8.0,
7.1, 1.0 Hz), 7.73 (dd, 1H, H-8, J ¼ 8.6, 1.0 Hz), 7.88 (ddd, 1H,
H-7, J ¼ 8.6, 7.1, 1.7 Hz), 8.14 (dd, 1H, H-5, J ¼ 8.0, 1.7 Hz),
10.71 (s, 1H, OH); 19F NMR (376 MHz, DMSO-d6) d ꢂ64.90
(s, CF3); 13C NMR (100 MHz, DMSO-d6) d 118.48 (C8),
Isoamylammonium 2-(trifluoromethyl)chromone-3-olate (7a). Yield
150 mg (47%), mp 132–133ꢀC; IR (ATR) 3035, 2958, 2874,
1633, 1609, 1584, 1557 cm–1; 1H NMR (CDCl3) d 0.70 (d,
6H, 2Me, J ¼ 6.6 Hz), 1.29–1.36 (m, 2H, CH2), 1.48 (sept,
1H, CH, J ¼ 6.6 Hz), 2.85–2.90 (m, 2H, NCH2), 6.70 (br s,
3H, NH3þ), 7.31 (ddd, 1H, H-6, J ¼ 8.1, 7.0, 1.0 Hz), 7.46 (d,
1H, H-8, J ¼ 8.6 Hz), 7.63 (ddd, 1H, H-7, J ¼ 8.6, 7.0, 1.7
Hz), 8.17 (dd, 1H, H-5, J ¼ 8.1, 1.7 Hz); 13C NMR (100
MHz, DMSO-d6) d 22.60 (qm, 2 Me, JC,H ¼ 125.0 Hz), 25.50
(dm, CH, JC,H ¼ 127.0 Hz), 36.70 (tm, CH2, JC,H ¼ 127.0
Hz), 37.77 (tm, CH2, JC,H ¼ 140.0 Hz), 118.60 (dd, C8, JC,H
¼ 165.4, 7.0 Hz), 121.99 (dd, C4a, JC,H ¼ 7.7, 4.0 Hz),
1
120.33 (q, CF3, JC,F ¼ 273.4 Hz), 121.48 (C4a), 125.16 (C5/6),
2
125.39 (C6/5), 133.71 (q, C2, JC,F ¼ 36.5 Hz), 135.04 (C7),
141.29 (C3), 154.07 (C8a), 173.59 (C¼¼O). Anal. Calcd. for
C10H5F3O3: C, 52.19; H, 2.19. Found: C, 52.15; H, 2.39.
3-Hydroxy-2-(difluoromethyl)chromone (4b). Yield 180 mg
(42%), mp 184–185ꢀC; IR (KBr) 3265, 1633, 1609 cm–1; 1H
2
NMR (400 MHz, DMSO-d6) d 7.33 (t, 1H, CF2H, JH,F
¼
51.8 Hz), 7.51 (ddd, 1H, H-6, J ¼ 8.0, 7.1, 1.0 Hz), 7.73 (dd,
1H, H-8, J ¼ 8.6, 1.0 Hz), 7.86 (ddd, 1H, H-7, J ¼ 8.6, 7.1,
1.7 Hz), 8.13 (dd, 1H, H-5, J ¼ 8.0, 1.7 Hz), 10.38 (s, 1H,
OH); 19F NMR (376 MHz, DMSO-d6) d ꢂ122.80 (d, CF2H,
2JF,H ¼ 51.8 Hz). Anal. Calcd. for C10H6F2O3: C, 56.61; H,
2.85. Found: C, 56.72; H, 2.86.
1
123.40 (dd, C5/6, JC,H ¼ 163.6, 7.3 Hz), 123.84 (q, CF3, JC,F
¼ 270.7 Hz), 125.75 (dd, C6/5, JC,H ¼ 164.3, 8.0 Hz), 131.75
2
(q, C2, JC,F ¼ 31.5 Hz), 133.10 (dd, C7, JC,H ¼ 164.3, 8.8
Hz), 152.27 (br s, C3), 154.20 (t, C8a, JC,H ¼ 8.8 Hz), 180.38
Journal of Heterocyclic Chemistry
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R. A. Irgashev, V. Y. Sosnovskikh, A. A. Sokovnina, and G.-V. Roschenthaler
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(s, C¼¼O). Anal. Calcd. for C15H18F3NO3: C, 56.78; H, 5.72;
7.60 (d, 1H, H-8, J ¼ 8.5 Hz), 7.75 (ddd, 1H, H-7, J ¼ 8.5,
7.1, 1.7 Hz), 8.08 (dd, 1H, H-5, J ¼ 8.0, 1.7 Hz), OH non
observed. Anal. Calcd. for C15H17NO5: C, 61.85; H, 5.88; N,
4.81. Found: C, 62.05; H, 5.74; N, 4.92.
N, 4.41. Found: C, 56.34; H, 5.38; N, 4.18.
Benzylammonium
2-(trifluoromethyl)chromone-3-olate
(7b). Yield 250 mg (74%), mp 167–168ꢀC; IR (ATR) 3167,
1
1597, 1547 cm–1; H NMR (CDCl3) d 3.93 (s, 2H, CH2), 4.72
(br s, 3H, NH3þ), 7.11 (tt, 1H, H-4’, J ¼ 7.3, 1.3 Hz), 7.18–
7.22 (m, 2H, H-3’, H-5’), 7.25–7.29 (m, 2H, H-2’, H-6’), 7.40
(ddd, 1H, H-6, J ¼ 8.1, 7.1, 1.0 Hz), 7.51 (ddd, 1H, H-8, J ¼
8.6, 1.0, 0.4 Hz), 7.72 (ddd, 1H, H-7, J ¼ 8.6, 7.1, 1.7 Hz),
8.18 (ddd, 1H, H-5, J ¼ 8.1, 1.7, 0.4 Hz). Anal. Calcd. for
C17H14F3NO3: C, 60.54; H, 4.18; N, 4.15. Found: C, 60.47; H,
4.21; N, 4.23.
(4-Fluorobenzyl)ammonium 2-(trifluoromethyl)chromone-
3-olate (7c). Yield 300 mg (85%), mp 156–157ꢀC; IR (ATR)
2895, 1633, 1608, 1585, 1546, 1512 cm–1; 1H NMR (CDCl3)
d 2.96 (br s, 3H, NH3þ), 3.87 (s, 2H, CH2), 6.96–7.02 (m, 2H,
arom.), 7.26–7.30 (m, 2H, arom.), 7.47 (ddd, 1H, H-6, J ¼
8.1, 7.1, 1.0 Hz), 7.57 (dd, 1H, H-8, J ¼ 8.6, 1.0 Hz), 7.78
(ddd, 1H, H-7, J ¼ 8.6, 7.1, 1.7 Hz), 8.23 (dd, 1H, H-5, J ¼
8.1, 1.7 Hz); 19F NMR (376 MHz, CDCl3) d ꢂ65.14 (s, CF3),
ꢂ115.23 (br s, F). Anal. Calcd. for C17H13F4NO3: C, 57.47;
H, 3.69; N, 3.94. Found: C, 57.85; H, 3.49; N, 3.92.
REFERENCES AND NOTES
[1] Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem Rev
2003, 103, 893.
[2] Sosnovskikh, V. Ya. Russ Chem Rev 2003, 72, 489.
[3] (a) Filler, R.; Kobayashi, Y.; Yagupolskii, L. M., Eds.
Organofluorine Compounds in Medicinal Chemistry and Biomedical
Applications; Elsevier: Amsterdam, 1993; (b) Welch, J. T.; Eswarak-
rishnan, S. Fluorine in Bioorganic Chemistry; Wiley: New York, NY,
1991; (c) Hiyama, T. Organofluorine Compounds. Chemistry and
Application; Springer: Berlin, 2000.
[4] (a) Sosnovskikh, V. Ya.; Usachev, B. I.; Sizov, A. Yu.;
Barabanov, M. A. Synthesis 2004, 942; (b) Sosnovskikh, V. Ya.; Usa-
chev, B. I.; Sizov, A. Yu. Synlett 2004, 1765; (c) Sosnovskikh, V.
¨
Ya.; Usachev, B. I.; Sevenard, D. V.; Roschenthaler, G.-V. Tetrahe-
dron 2003, 59, 2625; (d) Sosnovskikh, V. Ya.; Barabanov, M. A.; Usa-
chev, B. I. Org Lett 2003, 5, 2501; (e) Sosnovskikh, V. Ya.; Usachev,
B. I.; Sizov, A. Yu.; Vorontsov, I. I.; Shklyaev, Yu. V. Org Lett 2003,
5, 3123.
Hydrazinium 2-(trifluoromethyl)chromone-3-olate (7d). Yield
180 mg (69%), mp 118–119ꢀC; IR (ATR) 3320, 3243, 1630,
1610, 1594, 1550 cm–1; 1H NMR (DMSO-d6) d 7.20 (br s,
5H, NH2NH3þ), 7.34 (ddd, 1H, H-6, J ¼ 8.0, 7.0, 1.0 Hz),
7.54 (d, 1H, H-8, J ¼ 8.6 Hz), 7.69 (ddd, 1H, H-7, J ¼ 8.6,
7.0, 1.7 Hz), 8.04 (dd, 1H, H-5, J ¼ 8.0, 1.7 Hz); 13C NMR
(100 MHz, DMSO-d6) d 118.63 (C8), 121.94 (C4a), 123.58
[5] (a) Sosnovskikh, V. Ya.; Usachev, B. I.; Sizov, A. Yu.
Russ Chem Bull Int Ed 2003, 52, 508; (b) Sosnovskikh, V. Ya.; Usa-
chev, B. I.; Sizov, A. Yu. Russ Chem Bull Int Ed 2003, 52, 984.
[6] Usachev, B. I.; Shafeev, M. A.; Sosnovskikh, V. Ya. Russ
Chem Bull Int Ed 2004, 53, 2285.
1
(C5/6), 123.64 (q, CF3, JC,F ¼ 270.7 Hz), 125.74 (C6/5),
[7] Sosnovskikh, V. Ya.; Moshkin, V. S.; Kodess, M. I. Tetra-
hedron 2008, 64, 7877.
2
131.98 (q, C2, JC,F ¼ 32.3 Hz), 133.28 (C7), 151.90 (br s,
C3), 154.19 (C8a), 180.29 (C¼¼O). Anal. Calcd. for
C10H9F3N2O3ꢃ0.5H2O: C, 44.29; H, 3.72; N, 10.33. Found: C,
44.63; H, 3.50; N, 10.20.
[8] (a) Coppola, G. M.; Dodsworth, R. W. Synthesis 1981, 523;
(b) Coppola, G. M.; Dodsworth, R. W. U.S. Pat. 6,077,850 (2000);
Chem Abstr 2000, 133, 43440a.
3-Hydroxychromone (8). This compound was prepared
from chroman-4-one analogously to 4. Yield 290 mg (35%),
mp 178–180ꢀC (lit. [17a] mp 179–180ꢀC); 1H NMR (400
MHz, DMSO-d6) d 7.46 (ddd, 1H, H-6, J ¼ 8.0, 7.0, 1.0 Hz),
7.63 (dd, 1H, H-8, J ¼ 8.5, 1.0 Hz), 7.77 (ddd, 1H, H-7, J ¼
8.5, 7.0, 1.7 Hz), 8.12 (dd, 1H, H-5, J ¼ 8.0, 1.7 Hz), 8.24 (s,
1H, H-2), 9.15 (s, 1H, OH).
N-(3-hydroxychromone-2-ylmethyl)-N-methylglycine (9a). A
solution of 8 (200 mg, 1.23 mmol), sarcosine (110 mg, 1.23
mmol) and formaldehyde as 37% formalin (500 mg, 6.15
mmol) in ethanol (5 mL) was refluxed for 5 h. The reaction
[9] (a) Dolbier, W. R., Jr. J Fluor Chem 2005, 126, 157; (b)
´
´
Begue, J.-P.; Bonnet-Delpon, D. J Fluor Chem 2006, 127, 992.
[10] Sosnovskikh, V. Ya.; Irgashev, R. A.; Levchenko, A. A.
ARKIVOC 2009, iv, 125.
´
[11] Jerzmanowska, Z.; Zielinska, L. Pol J Chem 1983, 57, 49.
[12] Geissman, T. A.; Armen, A. J Am Chem Soc 1955, 77,
1623.
[13] Sosnovskikh, V. Ya.; Kutsenko, V. A.; Yachevskii, D. S.
Mendeleev Commun 1999, 204.
[14] Sosnovskikh, V. Ya.; Barabanov, M. A.; Sizov, A. Yu.
Russ Chem Bull Int Ed 2002, 51, 1280.
¨
[15] Eiden, F.; Dolcher, D. Arch Pharm 1975, 308, 385.
mixture was refrigerated until
a crystalline precipitate
[16] Sosnovskikh, V. Ya.; Usachev, B. I.; Kodess, M. I. Russ
Chem Bull Int Ed 2002, 51, 1817.
´
[17] (a) Constantino, M. G.; Junior, V. L.; da Silva, G. V. J. J
appeared. The colorless solid was filtered off and washed with
ethanol. Yield 260 mg (80%), mp 274–275ꢀC; IR (ATR):
1
3018, 1630, 1608, 1574 cm–1; H NMR (400 MHz, DMSO-d6)
Heterocycl Chem 2003, 40, 369; (b) Pace, P.; Nizi, E.; Pacini, B.;
Pesci, S.; Matassa, V.; De Francesco, R.; Altamura, S.; Summa, V.
Bioorg Med Chem Lett 2004, 14, 3257.
d 2.39 (s, 3H, Me), 3.34 (s, 2H, CH2), 3.89 (s, 2H, CH2), 7.44
(br t, 1H, H-6, J ¼ 7.5 Hz), 7.61 (d, 1H, H-8, J ¼ 8.5 Hz),
7.76 (ddd, 1H, H-7, J ¼ 8.5, 7.2, 1.5 Hz), 8.09 (br d, 1H, H-5,
J ¼ 8.0 Hz), 8.5–12.0 (br s, 2H, 2OH). Anal. Calcd. for
C13H13NO5: C, 59.31; H, 4.98; N, 5.32. Found: C, 59.41; H,
4.93; N, 5.02.
[18] (a) Ahmad-Junan, S. A.; Whiting, D. A. J Chem Soc Perkin
Trans 1 1990, 418; (b) Ahmad-Junan, S. A.; Whiting, D. A. J Chem
Soc Perkin Trans 1 1992, 675; (c) Nath, A.; Mal, J.; Venkateswaran,
R. V. J Org Chem 1996, 61, 4391.
N-(3-hydroxychromone-2-ylmethyl)valine (9b). This com-
pound was prepared from 8 and valine analogously to 9a.
Yield 200 mg (70%), mp 126–127ꢀC; IR (ATR): 3295, 1613
[19] (a) Wiley, P. F. J Am Chem Soc 1952, 74, 4326; (b) Sac-
quet, M.-C.; Fargeau-Bellassoued, M.-C.; Graffe, B. J Heterocycl
Chem 1991, 28, 667.
1
cm–1; H NMR (400 MHz, DMSO-d6) d 0.85 (d, 3H, Me, J ¼
[20] Panja, S. K.; Maiti, S.; Drew, M. G. B.; Bandyopadhyay, C.
Tetrahedron 2009, 65, 1276.
6.8 Hz), 0.89 (d, 3H, Me, J ¼ 6.8 Hz), 1.85–1.95 (m, 1H,
CH), 3.00 (d, 1H, NCH, J ¼ 5.1 Hz), 3.85 (AB-system, 2H,
CH2, J ¼ 14.6 Hz), 7.44 (ddd, 1H, H-6, J ¼ 8.0, 7.1, 1.0 Hz),
[21] O’Brien, G.; Patterson, J. M.; Meadow, J. R. J Org Chem
1962, 27, 1711.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet