A novel synthesis of 2-trichloromethylchromones and 7-trichloromethylnorkhellin

Article abstract of DOI:10.1055/s-2002-31966

The reaction of 2-hydroxyacetophenones with trichloroacetyl chloride in the presence of pyridine at -30°C followed by treatment of the reaction mixture with potassium tert-butylate affords 2-hydroxy-2-trichloromethylchroman-4-ones. Dehydration then provides the 2-trichloromethyl-chromones.

Full text of DOI:10.1055/s-2002-31966

SHORT PAPER
1007
A Novel Synthesis of 2-Trichloromethylchromones and
7-Trichloromethylnorkhellin
A
N
ovel Synthesis
y
of 2-Trichlo
a
romethylch
c
r
omones
a
n
h
d 7-Trichlor
e
omethylno
srkhellin lav Ya. Sosnovskikh,* Boris I. Usachev
Department of Chemistry, Ural State University, 620083 Ekaterinburg, Russia
Fax +7(3432)615978; E-mail: Vyacheslav.Sosnovskikh@usu.ru
Received 4 February 2002
ortho-trichloroacetoacetylphenols and are dehydrated
when boiling in acetic acid with concentrated HCl for 5
minutes to give 2-trichloromethylchromones 3a c in high
yields. We have earlier11 used the intramolecular cycliza-
tion of esters of aliphatic -hydroxyketones under the ac-
tion of lithium hydride to prepare 3,3-dialkyl-2,3-
dihydro-6-trifluoromethyl(trichloromethyl)pyran-4-ones.
Abstract: The reaction of 2-hydroxyacetophenones with trichloro-
acetyl chloride in the presence of pyridine at –30 °C followed by
treatment of the reaction mixture with potassium tert-butylate af-
fords 2-hydroxy-2-trichloromethylchroman-4-ones. Dehydration
then provides the 2-trichloromethyl-chromones.
Key words: condensation, 2-hydroxyacetophenones, 2-hydroxy-2-
trichloromethylchroman-4-ones, 2-trichloromethylchromones
R'
O
R'
O
2-Trichloromethylchromones were first synthesized in
1972 by boiling of 2-methylchromones with thionyl
chloride in benzene, but the procedure lacked details.1 We
showed that these compounds can be obtained by the con-
densation of 2-hydroxyacetophenones with trichloroace-
tonitrile in the presence of N-methylanilinomagnesium
bromide followed by acid hydrolysis of the ami-
noenones.2 5In several cases, formation of aminoenones
was accompanied by considerable polymerization of the
reaction mixture, impeding the isolation of target prod-
ucts. Till date, this reaction was the only method for ob-
taining 2-trichloromethylchromones in moderate yields
because the Claisen condensation usually used for synthe-
sis of chromones gives unsatisfactory results in the case of
trichloroacetic acid esters due to side reactions associated
with haloformic splitting6 and formation of dichlorocar-
bene.7,8Since 2-trichloromethylchromones contain the la-
bile CCl3 group and are of interest in the synthesis of
hydrogenated nitrogen-containing heterocycles, such as
(2-acylmethylene)-imidazolidines9 and hexahydropyrim-
idines,10 we attempted to make these compounds more ac-
cessible from the preparative point of view.
Me
Me
OH
CCl3COCl
Py
R
OCOCCl3
R
1
ButOK
R'
O
R'
O
AcOH
HCl
OH
CCl3
R
O
CCl3
R
O
2a-c
3a-c
R = R' = H (a); R = MeO, R' = H (b);
R = R' = Me (c)
Scheme 1
The condensation of khellinone with tricholoroacetoni-
trile recently12 allowed us to obtain 7-trichloromethyl-
norkhellin (4) with an overall yield of 32%. Compound 4
is the chlorinated analog of natural furochromone khellin,
an efficient medicinal agent,13 which is present in the
Ammi visnaga L plant known for its curative properties
since the ancient Egyptians.14 We applied the reaction de-
scribed above to khellinone and synthesized the new
khellin derivative, namely furochromanone 5, whose de-
hydration affords furochromone 4 in 64% yield after two
stages (Scheme 2). The improvement of the overall yield
from tricholoroacetonitrile with this approach rose to
about 30%. Note that ring-chain and ketoenol tautomer-
ism (5A:5B:5C = 3:10:87) is observed in a solution of
compound 5 in CDCl3. Under similar conditions, com-
pounds 2a,b contain about 3 9% diketo and ketoenol
forms, and 2c exists exclusively in the chromanone form.
In this work, we wish to report a novel approach to the
synthesis of 2-trichloromethylchromones. The approach
(Scheme 1) is based on the modified Baker Venkatara-
man rearrangement of esters 1 and allows one to obtain
previously unknown 2-hydroxy-2-trichloromethylchro-
man-4-ones (2) without isolation of intermediate esters 1.
It was established that treatment of aryl trichloroacetates
1, formed in the reaction of 2-hydroxyacetophenones with
trichloroacetyl chloride in the presence of pyridine, with
potassium tert-butylate at –30 °C for 1.5 h leads to the
preparation of chromanones 2a c in good yields. These
compounds are the cyclic forms of the corresponding
Thus, we developed a simple and efficient method for the
synthesis of 2-hydroxy-2-trichloromethylchroman-4-ones
and 2-trichloromethylchromones, including 7-trichlorom-
ethylnorkhellin. This method made these compounds ac-
cessible for the preparation of heterocyclic systems with
pharmacophoric and natural fragments.
Synthesis 2002, No. 8, 04 06 2002. Article Identifier:
1437-210X,E;2002,0,08,1007,1009,ftx,en;Z02902SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1008
V. Ya. Sosnovskikh, B. I. Usachev
SHORT PAPER
OMe O
OH
CCl3
OMe O
O
OMe O
Me
CCl3
1. CCl3COCl, Py
2. ButOK
O
O
O
OH
OH
OH
OMe
OMe
OMe
5A (3%)
5B (10%)
OMe O
OMe O
AcOH
HCl
OH
CCl3
O
O
O
O
CCl3
OMe
OMe
4
5C (87%)
Scheme 2
(5), Jo = 8.8], the spectrum also contained signals from the diketo
and ketoenol forms (in total ~ 9%).
1H NMR spectra were recorded on a Bruker DRX-400 spectrometer
operating at 400.13 MHz in CDCl3 solutions with TMS as the inter-
nal standard. The IR spectra were measured on an IKS-29 instru-
ment as suspensions in vaseline oil. Melting points are uncorrected.
All solvents used were dried and distilled per standard procedures.
Anal. Calcd for C11H9Cl3O4: C, 42.41; H, 2.91. Found: C, 42.29; H,
3.03.
2-Hydroxy-5,7-dimethyl-2-trichloromethylchroman-4-one (2c)
Yield 67%, colorless substance; mp 172–173 °C.
IR: 3180 (OH), 1680 (C=O), 1620, 1570 (Ar) cm–1.
Chromanones 2a c and 5; General Procedure
Metallic potassium (2.9 g, 0.074 mol) was dissolved in boiling
tBuOH (50 mL, H2O content 0.1%) with stirring in a round-bottom
three-necked flask with a reflux condenser. A soln of aryl trichloro-
acetate 1 was added over 15 min to the obtained soln of tBuOK in
tBuOH, which initially was diluted with anhyd THF (25 mL) and
cooled to –30 °C. Aryl trichloroacetate 1 was prepared as follows:
Trichloroacetyl chloride (3.2 mL, 5.3 g, 0.029 mol) was added with
stirring to a soln of the corresponding 2-hydroxyacetophenone
(0.029 mol) and anhyd pyridine (2.6 mL, 2.7 g, 0.034 mol) in anhyd
THF (20 mL). Then the mixture was heated to boiling and left for 1
h at ~ 20 °C. The pyridinium hydrochloride precipitate was filtered
off and washed with a minor amount of anhyd THF, and the filtrate
containing aryl trichloroacetate 1 was used as described above.
Chromanone 2 was formed during stirring for 1.5 h at –30 °C, after
which HOAc (6 mL) diluted with THF (4 mL) was introduced into
the reaction mixture. The solvent was evaporated, H2O (100 mL)
was added to the residue, the precipitate of chromanone 2 was fil-
tered off, dried, and recrystallized from toluene. In the case of 2a,
crude product was as an oil and solidified after addition of hexane–
toluene, 2:1 (20 mL).
1H NMR (400 MHz, CDCl3): 2.33 [s, 3 H, Me (7)], 2.62 [s, 3 H,
(5)], 3.25 (d, 1 H, CHH, J = 16.7), 3.43 (d, 1 H, CHH, J = 16.7, both
peaks in the low-field part of the AB spectrum are broadened), 3.74
(s, 1 H, OH), 6.74 [s, 1 H, H (8)], 6.78 [s, 1 H, H (6)]. Protons H (6)
and H (8) were assigned on the basis of data in ref.15
Anal. Calcd for C12H11Cl3O3: C, 46.56; H, 3.58. Found: C, 46.81; H,
3.74.
7-Hydroxy-4,9-dimethoxy-7-trichloromethylfuro[3,2-g]chro-
man-5-one (5)
Yield 75%, yellow powder; mp 181–182 °C.
IR: 3360 (OH), 3150 (=CH), 1660 (C=O), 1610, 1550 (Ar) cm–1.
1H NMR (400 MHz, CDCl3):
5C (87%); 3.30 (d, 1 H, CHH, J = 16.7), 3.50 (d, 1 H, CHH,
J = 16.7), 4.00 (br s, 1 H, OH), 4.07 (s, 3 H, Me), 4.10 (s, 3 H, Me),
6.96 [d, 1 H, H (3), J = 2.3], 7.55 [d, 1 H, H (2), J = 2.3].
5B (10%); 4.05 (s, 3 H, Me), 4.17 (s, 3 H, Me), 4.78 (s, 2 H, CH2),
6.91 [d, 1 H, H (3), J = 2.3], 7.52 [d, 1 H, H (2), J = 2.3], 12.54 (s,
1 H, OH).
2-Hydroxy-2-trichloromethylchroman-4-one (2a)
5A (3%); 4.08 (s, 3 H, Me), 4.09 (s, 3 H, Me), 6.88 [d, 1 H, H (3),
J = 2.2], 7.41 (s, 1 H, =CH), 7.52 [d, 1 H, H (2), J = 2.2], 10.62 (s,
1 H, OH).
Yield 40%, colorless substance; mp 100 °C.
IR: 3430 (OH), 1690, 1680 (C=O), 1610, 1580 (Ar) cm–1.
1H NMR (400 MHz, CDCl3): 3.36 (d, 1 H, CHH, J = 16.7), 3.44 (d,
1 H, CHH, J = 16.7, both peaks in the low-field part of the AB spec-
trum are broadened doublets with 4JH,OH = 1.2), 3.85 (s, 1 H, OH),
7.10 [dd, 1 H, H (8), Jo = 8.3, Jm = 1.0], 7.14 [ddd, 1 H, H (6),
Jo = 7.8, 7.3, Jm = 1.0], 7.57 [ddd, 1 H, H (7), J = 8.3, 7.3, Jm = 1.7],
7.93 [dd, 1 H, H (5), J = 7.8, Jm = 1.7], the spectrum also contained
signals from the diketo and ketoenol forms (in total~ 3%).
Anal. Calcd for C14H11Cl3O6.: C, 44.07; H, 2.91. Found: C, 44.08;
H, 2.94.
Chromones 3a–c; General Procedure
A mixture of chromanone 2 (3.2 mmol), HOAc (8 mL), and concd
HCl (5 drops) was boiled for 5 min, then the mixture was cooled and
diluted by H2O (50 mL). The crystalline product was filtered off,
washed with EtOH, and dried. Yields of 3a–c were 83–87%, as col-
orless needle-like crystals.
Anal. Calcd for C10H7Cl3O3: C, 42.66; H, 2.51. Found: C, 42.86; H,
2.26.
2-Hydroxy-7-methoxy-2-trichloromethylchroman-4-one (2b)
Yield 39%, colorless substance; mp 160–161 °C.
3a
Mp 120 °C (Lit.5 118–119 °C).
IR: 3240 (OH), 1670 (C=O), 1620, 1580 (Ar) cm–1.
3b
1H NMR (400 MHz, CDCl3): 3.28 (d, 1 H, CHH, J = 16.7), 3.40 (d,
1 H, CHH, J = 16.7), 4.07 (s, 1 H, OH), 6.54 [d, 1 H, H (8),
Jm = 2.4], 6.67 [dd, 1 H, H (6), Jo = 8.8, Jm = 2.4], 7.85 [d, 1 H, H
Mp 159–160 °C (Lit.5 159–160 °C).
3c
Mp 173–174 °C (Lit.4 174–175 °C).
Synthesis 2002, No. 8, 1007–1009 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
A Novel Synthesis of 2-Trichloromethylchromones and 7-Trichloromethylnorkhellin
1009
7-Trichloromethylnorkhellin (4)
(4) Sosnovskikh, V. Y. Russ. Chem. Bull. 1998, 47, 354.
A mixture of chromanone 5 (1.5 g, 3.9 mmol), HOAc (5 mL), and
concd HCl (3 drops) were heated for 5 min, then mixed with EtOH
(7 mL), and cooled to 0 °C. The crystalline product was filtered off,
washed with EtOH, and dried. Yield 1.22 g (85%), yellow needles;
mp 169–170 °C (Lit.12 172–173 °C).
(5) Sosnovskikh, V. Y.; Kutsenko, V. A.; Ovsyannikov, I. S.
Russ. Chem. Bull. 2000, 49, 478.
(6) Meerwein, H.; Sönke, H. Berichte 1931, 64, 2375.
(7) Parham, W. E.; Schweizer, E. E. J. Org. Chem. 1959, 24,
1733.
(8) Moore, R. A.; Levine, R. J. Org. Chem. 1964, 29, 1883.
(9) Sosnovskikh, V. Y.; Kutsenko, V. A. Mendeleev Commun.
1999, 206.
Acknowledgement
(10) Sosnovskikh, V. Y.; Kutsenko, V. A. Russ. Chem. Bull.
1999, 48, 2117.
(11) Sosnovskikh, V. Y.; Mel’nikov, M. Yu. Zh. Org. Khim.
1998, 34, 203.
This work was financially supported by the Russian Foundation for
Basic Research (Project N 99-03-32960) and partially by the US Ci-
vilian Research and Development Foundation (Grant REC-005).
(12) Sosnovskikh, V. Y.; Kutsenko, V. A. Mendeleev Commun.
2000, 238.
(13) Mashkovskii, M. D. In Lekarstvennye sredstva (Drugs),
Vol. 1; Gamta: Vilnius, 1993, 396.
(14) Kandil, A.; Galal, E. E. J. Drug Res. 1975, 7, 109.
(15) Sosnovskikh, V. Ya.; Usachev, B. I.; Kodess, M. I. Izv.
Akad. Nauk, Ser. Khim. 2002, in press.
References
(1) Merchant, J. R.; Bhat, A. R.; Rege, D. V. Tetrahedron Lett.
1972, 2061.
(2) Sosnovskikh, V. Y.; Ovsyannikov, I. S. Russ. J. Org. Chem.
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(3) Sosnovskikh, V. Y. Mendeleev Commun. 1996, 189.
Synthesis 2002, No. 8, 1007–1009 ISSN 0039-7881 © Thieme Stuttgart · New York