Bromination of 9-dimedonyltetrahydroxanthenone as a route to a new type of substituted hydrochromeno[2,3,4-kl]xanthenones

Article abstract of DOI:10.1007/s11172-007-0357-9

Bromination of 9-dimedonyl-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-one was carried out to provide a route to a new series of substituted hydrochromeno[2,3,4-kl]xanthenones, which may find application for the synthesis of poorly accessible compounds i

Full text of DOI:10.1007/s11172-007-0357-9

Russian Chemical Bulletin, International Edition, Vol. 56, No. 11, pp. 2268—2271, November, 2007
2268
Bromination of 9ꢀdimedonyltetrahydroxanthenone as a route
to a new type of substituted hydrochromeno[2,3,4ꢀkl]xanthenones

A. Yu. Nikishin and O. V. Fedotova
Department of Chemistry, N. G. Chernyshevsky Saratov State University,
83 ul. Astrakhanskaya, 410012 Saratov, Russian Federation.
Fax: +7 (845 2) 24 0446. Еꢀmail: alehandron@mail.ru
Bromination of 9ꢀdimedonylꢀ3,3ꢀdimethylꢀ2,3,4,9ꢀtetrahydroꢀ1Hꢀxanthenꢀ1ꢀone was carꢀ
ried out to provide a route to a new series of substituted hydrochromeno[2,3,4ꢀkl]xanthenones,
which may find application for the synthesis of poorly accessible compounds including the
heteroanalogs. A dependence of transformations of dimedonyltetrahydroxanthenone on the
nature of the solvent was elucidated: bromination at the αꢀmethylene groups of the dimedonyl
substituent is accompanied by heterocyclization involving 1ꢀ and 5ꢀoxo groups. Quantum
chemical HF/6ꢀ311(d,p) ab initio calculations for the proposed mechanism of hemiacetalization
and halogenation were carried out.
Key words: oxo compounds, bromination, heterocyclization, enolization, hydrochromenoꢀ
xanthenones, quantum chemical calculations, HF/6ꢀ311(d, p) method.
Table 1. Total energies of the enol forms of oxo compound 1
according to RHF/6ꢀ311G(d,p) calculations
The continuous interest in the chemistry of diketones
is caused by the set of unique properties they possess
owing to the presence of oxo groups with different posiꢀ
tions and types (conjugated or nonconjugated), the methꢀ
ylene unit, and the ability to undergo heterocyclization,
which make them valuable substrates for investigations
and for practical purposes.
Form
Etot
∆Etot
kcal mol–1
As a continuation of the systematic research of the
properties of oxo compounds,1,2 we studied for the first
time electrophilic reactions with acids and bromination
of 3,3ꢀdimethylꢀ9ꢀ(4,4ꢀdimethylꢀ2,6ꢀdioxocyclohexanꢀ1ꢀ
yl)ꢀ1,2,3,4ꢀtetrahydroꢀ9Hꢀxanthenꢀ1ꢀone (1) and eluciꢀ
dated the dependence of its transformations on the nature
of the solvent. Triketone 1 occupies a special place among
oxoꢀ1,5ꢀdiketones. Apart from the presence of conjugated
and nonconjugated 1,3ꢀ and 1,5ꢀcarbonyl groups, it is
distinguished by the presence of a tetrahydroxanthene
fragment, which affects the reactivity, for example, toꢀ
ward nucleophilic reactions with amines.3
Since the molecule of triketone 1 has several reaction
centers, we carried out quantum chemical prediction of
the most likely site of electrophilic addition of bromine
taking into account the first step of bromination, i.e.,
enolization of one of the carbonyl functions.4,5
–99184.76
–99186.43
–99183.08
4.30
2.63
5.98
According to quantum chemical calculations, the forꢀ
mation of enol 1B is thermodynamically most favorable
(Table 1). For enol 1A, the energy barrier to the reaction
is much higher. Indeed, enolization of triketone 1 with
participation of carbonyl groups of the dimedonyl subꢀ
stituent was confirmed by 1H NMR data in particular, by
Note. ∆Etot was calculated as the difference between the total
energies of the enol and ketone forms of triketone 1 on the basis
of Etot of the ketone form (–99189.06 kcal mol–1).
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2191—2194, November, 2007.
1066ꢀ5285/07/5611ꢀ2268 © 2007 Springer Science+Business Media, Inc.

New type of substituted hydrochromenoxanthenones Russ.Chem.Bull., Int.Ed., Vol. 56, No. 11, November, 2007 2269
a broad lowꢀfield signal for the OH proton (δ 10.42) and a
signal for the tertiary proton at δ 5.06.
The alternative addition of the bromine atom at the
multiple bond of the xanthene fragment of substrate 1
also cannot be ruled out.
In acetic acid medium, the predominant route is enoꢀ
lization of the dimedonyl carbonyl (enol 1B), giving rise
to 9ꢀ(2ꢀbromoꢀ4,4ꢀdimethylꢀ2,6ꢀdioxocyclohexanꢀ1ꢀyl)ꢀ
3,3ꢀdimethylꢀ1,2,3,4ꢀtetrahydroꢀ9Hꢀxanthenꢀ1ꢀone (2),
involving the tertiary hydrogen atom as the most mobile
in oxo compound 1 (Scheme 1). Preferred bromination
along this route in acetic acid was also noted for related
bisdimedonylmethane.6
which promotes heterocyclization involving 1,5ꢀdioxo
groups and bromination of the hemiacetal thus formed.
Propanꢀ2ꢀol acts simultaneously as a reagent, resulting in
the formation of 2,4ꢀdibromoꢀ5аꢀisopropoxyꢀ3,3,7,7ꢀ
tetramethylꢀ2,3,4,5а,6,7,8,13bꢀoctahydroꢀ1Hꢀchromeꢀ
no[2,3,4ꢀkl]xanthenꢀ1ꢀone (4). According to TLC data,
brominated triketone 2 is also present among the reaction
products.
Bromination of triketone 1 implies two transformaꢀ
tion routes for the substrate under these conditions.
The first route includes the initial hemiacetalization
and bromination at the α´ꢀposition of the aliphatic
ring fused to the hemiacetalized heterofragment. The
subsequent transformations can take place after opening
of the heterocycle in monobrominated hemiacetal 6 folꢀ
lowed by probable rotation of the dimedonyl fragment
Compound 2 is the only product that can be isolated
1
from the reaction mixture. In the H NMR spectrum of
this compound, the signal for the tertiary proton shifts
downfield (δ 6.41). No signals are present for the hydroxyl
group protons of the enol form of 1. The spectral pattern
of the heterocyclic fragment is generally retained. The
signals for the methylene protons of the dimedonyl subꢀ
stituent change positions. The presence of bromine in the
βꢀposition removes the degeneracy of the signals of axial
and equatorial protons and gives rise to one more signal
at δ 2.12.
at C(9) around the single bond7 (7A
7B), heteroꢀ
cyclization, and repeated bromination of the resulting
compound 8 at the unsubstituted methylene unit of
the dimedonyl aliphatic ring capable of enolization
(Scheme 2).
The calculation of the total energies of tautomers 6,
7А and 7B, and 8 showed that the thermodynamic effect
of the ringꢀchain tautomerism of monobrominated subꢀ
strate does not exceed 8.4 kcal mol–1 (Fig. 1). This energy
barrier is most often lower when the reaction is carried
In chloroform or in a propanꢀ2ꢀol and carbon tetraꢀ
chloride mixture, the solubility of triketone 1 increases,
Scheme 1

2270
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 11, November, 2007
Nikishin and Fedotova
Scheme 2
out in a solvent;8 thus, the proposed bromination mechaꢀ
nism is feasible under the chosen conditions.
The alternative route includes the initial enolization
and, as shown above, bromination of the dimedonyl fragꢀ
ment of triketone 1 at the tertiary carbon atom, which
precludes hemiacetalization.
The possibility of hemiacetalization of triketone 1 was
confirmed by a special experiment, namely, on refluxing
in acetic acid in the presence of acetic anhydride, it
was converted into 5aꢀhydroxyꢀ3,3,7,7ꢀtetramethylꢀ
2,3,4,5a,6,7,8,13bꢀoctahydroꢀ1Hꢀchromeno[2,3,4ꢀkl]ꢀ
xanthenꢀ1ꢀone (5) (see Scheme 1).
The signals of the methylene protons of the xanthene
fragments in the 1H NMR spectra of compounds 3—5
retain their positions, while the signals of the dimedonyl
fragment in products 3, 4 disappear. The downfield shift
of the tertiary proton is insignificant. The appearance of
two new signals in the spectra of dibrominated products
3, 4 at δ 5.02, 5.03 and 5.37, 5.39, respectively, indicates
that bromination involves the methylene units of the
dimedonyl substituent.
Reaction coordinate
10
0
–10
5
1
–7760
–7770
–7780
–7790
8
7B
6
7A
Experimental and calculation procedure
–15570
–15580
The structures of all molecules participating in the brominaꢀ
tion reactions were determined by ab initio RHF/6ꢀ311G(d,p)
calculations9,10 with full geometry optimization in the gas phase
using the PC GAMESS program package.11
The melting points were determined on a Koefler hot stage.
IR spectra were measured on Specord Mꢀ80 spectrometer in
mineral oil and hexachlorobutadiene (thin film). The 1H and
∆Etot/kcal mol–1
Fig. 1. Relative total energy (∆Etot) vs. the reaction coordinate
for bromination of triketone 1 in chloroform (∆Etot calculated as
the difference between the total energy of the molecule and the
energy equal to –99190 kcal mol–1).

New type of substituted hydrochromenoxanthenones Russ.Chem.Bull., Int.Ed., Vol. 56, No. 11, November, 2007 2271
13C NMR spectra were measured on a Varian Unity Inova inꢀ
strument (600 (1H) and 150 MHz (13C)) in CDCl3 and
DMSOꢀd6 using Me4Si as the internal standard. The reactions
were monitored and the purity of compounds was checked by
TLC on Silufol UVꢀ254 plates using a hexane—ether—acetone
mixture (3 : 1 : 1) as the eluent and iodine vapor and
UV irradiation for visualization.
The initial 9ꢀdimedonylꢀ3,3ꢀdimethylꢀ1,2,3,4ꢀtetrahydroꢀ
9Hꢀxanthenꢀ1ꢀone (1) was prepared by condensation of
dimedone with salicylic aldehyde by a known procedure.3
1H NMR, δ: 0.89, 0.98, 1.05 (all s, 12 H, Me); 2.00, 2.21, 2.37
(all m, 8 H, CH2); 5.06 (s, 1 H, CH); 6.96, 7.10 (both m, 4 H,
H arom.).
(both m, 4 H, CH2); 4.82 (s, 1 H, CH(CH3)2); 5.02, 5.39 (both s,
2 H, CH—Br); 5.11 (s, 1 H, CH); 7.06—7.19 (m, 4 H, H arom.).
13C NMR, δ: 20.4, 27.6, 28.6, 28.8, 31.7 (Me); 38.6; 40.6; 41.1;
56.4 (C(4)); 64.4 (C(2)); 70.2 (CH(CH3)2); 115.5; 115.6; 115.7;
115.8; 124.5; 125.3; 127.4; 127.7; 128.0; 128.3; 149.5; 159.6;
159.7; 186.8 (C(1)).
5aꢀHydroxyꢀ3,3,7,7ꢀtetramethylꢀ2,3,4,5a,6,7,8,13bꢀoctaꢀ
hydroꢀ1Hꢀchromeno[2,3,4ꢀkl]xanthenꢀ1ꢀone (5). Triketone 1
(2 g, 5.5 mmol) was dissolved in a mixture of acetic anhydride
(50 mL) and glacial acetic acid (10 mL) and refluxed for 5 h.
The crystals that precipitated after cooling were washed with
diisopropyl ether and recrystallized from diethyl ether. Yield
1.09 g (54.5%), colorless crystals, m.p. 193—194 °C. Found (%):
C, 75.22; H, 7.23. C23H26O4. Calculated (%): C, 75.38; H, 7.15.
IR, ν/cm–1: 3650 (OH); 2885—2975 (C—H aliph.); 1650 (C=O,
C=C); 1560 (Ar); 1250 (=C—O—C); 1150 (C—O—C).
1H NMR, δ: 0.99—1.08 (m, 12 H, Me); 2.07—2.44 (m, 8 H,
CH2); 5.18 (s, 1 H, CH); 6.92—7.10 (m, 4 H, H arom.); 9.60
(s, 1 H, OH). MS, m/z (Irel (%)): 366 [M]+ (28), 364
[M – (CH3)2CH2CO]+ (100), 364 [M – C8H10O2]+ (52).
Bromination of 9ꢀ(4,4ꢀdimethylꢀ2,6ꢀdioxocyclohexanꢀ1ꢀyl)ꢀ
3,3ꢀdimethylꢀ1,2,3,4ꢀtetrahydroꢀ9Hꢀxanthenꢀ1ꢀone (1) (general
procedure). Triketone 1 (3 g, 8 mmol) was dissolved in 50 mL of
a solvent. Bromine (1.4 g, 8.8 mmol) was added dropwise with
continuous stirring.
9ꢀ(2ꢀBromoꢀ4,4ꢀdimethylꢀ2,6ꢀdioxocyclohexanꢀ1ꢀyl)ꢀ3,3ꢀ
dimethylꢀ1,2,3,4ꢀtetrahydroꢀ9Hꢀxanthenꢀ1ꢀone (2). Acetic acid
was used as the solvent. The reaction mixture was heated with
stirring for 12 h at 70 °C and treated with water (100 mL).
The product was isolated by column chromatography (silica
gel 100/400, elution with hexane—AcOEt, 20 : 1). Yield 1.53 g
(42%), redꢀcolored crystals, m.p. 129—130 °C. Found (%):
C, 61.97; H, 5.45; Br, 17.80. C23H25BrO4. Calculated (%):
C, 62.03; H, 5.66; Br, 17.94. IR, ν/cm–1: 3065 (C—H arom.);
2968—2872 (C—H aliphatic); 1763 (C=O); 1676 (C=O, C=C);
This work was supported by the Russian Foundation
for Basic Research (Project No. 06ꢀ03ꢀ32667ꢀа).
References
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1
1583, 750 (Ar); 716, 675 (C—Br). H NMR, δ: 1.21, 1.28, 1.39
(all s, 12 H, Me); 2.02, 2.12, 2.29, 2.41 (all m, 8 H, CH2); 6.41
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2 , 4 ꢀ D i b r o m o ꢀ 5 а ꢀ h y d r o x y ꢀ 3 , 3 , 7 , 7 ꢀ t e t r a m e t h y l ꢀ
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4 H, CH2); 5.03, 5.37 (s, 2 H, CH—Br); 5.12 (s, 1 H, CH);
7.01—7.24 (m, 4 H, H arom.); 9.29 (s, 1 H, OH).
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2,3,4,5а,6,7,8,13bꢀoctahydroꢀ1Hꢀchromeno[2,3,4ꢀkl]xanthenꢀ
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tography. The yield of compound 4 was 1.85 g (40%), colorless
crystals, m.p. 174—175 °C. Found (%): C, 55.05; H, 5.06;
Br, 27.91. C26H30Br2O4. Calculated (%): C, 55.14; H, 5.34;
Br, 28.22. IR, ν/cm–1: 1666 (C=C—CO); 1583, 750 (Ar); 1255,
1030 (=C—O—C); 1074 (C—O—C); 716, 675 (C—Br).
1H NMR, δ: 0.89, 1.03, 1.17, 1.32 (all s, 18 H, Me); 1.92, 2.40
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Received March 6, 2007;
in revised form September 20, 2007