Bromination of 4-dichloromethyl-4-methylcyclohexa-2,5-dien-1-ones

Article abstract of DOI:10.1080/00397910701465958

Bromination of 4-dichloromethyl-4-methylcyclohexa-2,5-dien-1-one and 4-dichloromethyl-3,4-dimethylcyclohexa-2,5-dien-1-one has been studied. The reaction conditions required for the formation of mono-, di-, and tribrominated products have been optimized.

Full text of DOI:10.1080/00397910701465958

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Bromination of
4‐Dichloromethyl‐4‐methylcyclohexa‐2,5‐dien‐1‐o
G. V. Gavrilova a , I. N. Rusetskaya a , A. A. Gavrilov a , I. V. Trushkov a & D.
P. Krut'ko a
a Department of Chemistry , M. V. Lomonosov Moscow State University ,
Moscow, Russia
Published online: 14 Aug 2007.
To cite this article: G. V. Gavrilova , I. N. Rusetskaya , A. A. Gavrilov , I. V. Trushkov & D. P. Krut'ko (2007)
Bromination of 4‐Dichloromethyl‐4‐methylcyclohexa‐2,5‐dien‐1‐ones , Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:16, 2729-2736, DOI:
10.1080/00397910701465958
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Synthetic Communicationsw, 37: 2729–2736, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701465958
Bromination of 4-Dichloromethyl-4-
methylcyclohexa-2,5-dien-1-ones
G. V. Gavrilova, I. N. Rusetskaya, A. A. Gavrilov,
I. V. Trushkov, and D. P. Krut’ko
Department of Chemistry, M. V. Lomonosov Moscow State University,
Moscow, Russia
Abstract: Bromination of 4-dichloromethyl-4-methylcyclohexa-2,5-dien-1-one and
4-dichloromethyl-3,4-dimethylcyclohexa-2,5-dien-1-one has been studied. The reaction
conditions required for the formation of mono-, di-, and tribrominated products have
been optimized.
Keywords: bromination, 4-dichloromethyl-4-methylcyclohexa-2,5-dien-1-ones
INTRODUCTION
Geminal (di)halogenomethyl-substituted cyclohexadienones are attracting
attention both as model compounds for investigation of different reactions
such as the Michael addition and the Diels–Alder reaction [1]and as precursors
in synthesis of drugs and pesticides.[2,3] The important examples of halogen-
omethyl-substituted cyclohexadienones are 9-fluoropregna-1,4-dien-3-one
and its derivatives.[4–7] 9-Chloro and 9-bromo-substituted pregna-1,4-dien-
3-ones are also known.[8,9] Cyclohexadienones with halogen-substituted
rings are especially interesting because these compounds, on the one hand,
can be used in cross-coupling reactions and, on the other hand, are attractive
1,2-dielectrophiles. Moreover, brominated cyclohexa-2,5-dienones isolated
from sponges of Latrunculia[10–12] and Aplisina[13,14] families show potent
Received in the U.K. April 24, 2006
Dedicated to the memory of Professor K. P. Butin, friend and teacher.
Address correspondence to I. V. Trushkov, Department of Chemistry, M. V.
Lomonosov Moscow State University, Leninskie Gory, 1/3, 119992 Moscow,
Russia. E-mail: trush@org.chem.msu.ru
2729

2730
G. V. Gavrilova et al.
cytotoxicity and antibacterial activity. Although cyclohexa-2,5-dienones with
halogens both at ring atom(s) and the one(s) attached to geminal center are
attractive substrates for further modifications and can show different kinds
of bioactivity, these compounds have received little attention. The main
reason is the absence of good preparative approaches to these compounds
because complex mixtures are usually obtained during their syntheses.
Therefore, the development of simple and effective methods for the
synthesis of halogenated cyclohexadienones and optimization of reaction con-
ditions for selective preparation of the required derivatives remain important
problems.
Here, we describe the optimized reaction conditions for bromination of
4-dichloromethyl-4-methylcyclohexa-2,5-dien-1-one (1) and 4-dichloro-
methyl-3,4-dimethylcyclohexa-2,5-dien-1-one (2) with the goal of selective
preparation of the corresponding mono-, di-, and tribrominated adducts with
good to excellent yields.
RESULTS AND DISCUSSION
Scheme 1 illustrates the synthetic route to the goal compounds. Bromination
of substrates 1 and 2 have been performed in CCl4 at room temperature in the
dark. Reaction products were isolated by column chromatography. Their
1
structures have been proven by IR, UV-vis, H NMR, and 13C NMR spec-
troscopy data using the spectra of the corresponding 4-dibromomethyl-substi-
tuted cyclohexadienones[15] as references.
For both cyclohexadienones, the first step of bromination is substitution
of the hydrogen atom in the a-position to the carbonyl group. In the case of
unsymmetrical cyclohexadienone 2, unsubstituted double bond was reacted.
Cyclohexadienones 1 and 2 show the similar behavior. In contrast, the mono-
brominated derivatives react differently. When 1 was brominated by excess
of bromine, the increase of reaction time leads to formation of tribromide
Scheme 1.

4-Dichloromethyl-4-methylcyclohexa-2,5-dien-1-ones
2731
5 by addition of bromine to the unreacted double bond. The following dehy-
drobromination of 5 yields a,a0-dibromocyclohexadienone 6. In the case of
the methyl-substituted analogue 2, methyl group at C(3) atom was brominated
by excess of bromine with formation of 3-bromomethyl- and 3-dibromo-
methyl-substituted products 8 and 9. This route of bromination is a result of
acid-catalyzed enolization of 7.
For the development of optimal procedures for preparation of mono-, di-,
and tribrominated products, we have studied the effects of bromine/substrate
ratio, reaction time, temperature, different additives, and other factors on the
composition of the reaction mixture. It was found that bromination of cyclo-
hexadienones 1 and 2 is accelerated by hydrogen bromide. Indeed, addition of
potassium carbonate inhibited the bromination of 1 and 2: only traces of bro-
minated products have been found in reaction mixture after treatment for 1
week. Hydrogen bromide is evolved during the first step of bromination;
that is, this reaction is autocatalytic. These data as well as the order of reactiv-
ity of two C55C double bonds in 2 support our previous assumption that the
reaction mechanism can be described as nucleophilic attack by bromide
anion on protonated cyclohexadienone followed by electrophilic bromination
of the formed dienol (Scheme 2).
Thus, the formation of polybrominated compounds is stimulated by 1) use
of bromine excess, 2) increase of reaction time, and 3) presence of acids.
Oppositely, synthesis of monobrominated adducts is possible if the reaction
is performed with an equimolar ratio of reagents at autocatalytic conditions.
At these conditions, the formed acid concentration is not enough for
effective acceleration of polybromination. With these conclusions in mind,
we have found that the yield of 4 has maximum value when ratio of
substrate to bromine is 1:1.25 and reaction is quenched immediately after
reaction mixture decoloration. At these conditions, yield of 2-bromo-4-
dichloromethyl-4-methylcyclohexa-2,5-dien-1-one (4) was 82%. The
corresponding dibromination product 6 has been formed with 91% yield at
the substrate-to-bromine ratio of 1:2.5 and reaction mixture stirring for 1
day. According to 1H and 13C NMR data, 6 was contaminated by its
unstable precursor 5 (product ratio was estimated to be ca. 14:1). Treatment
of reaction mixture with alkaline alumina quantitatively converted enone 5
to the final product 6.
Bromination of cyclohexadienone 2 is a more complex process. After
some attempts, we have optimized the reaction conditions for the preparation
of monobromide 7, dibromide 8, and tribromide 9 with good to excellent
Scheme 2.

2732
G. V. Gavrilova et al.
yields. The synthesis of tribromide 9 has the simplest procedure: dienone 2 was
treated with large excess of bromine for 1 day; yield of 9 was 92% when 25
equiv of Br2 has been applied. Use of 1 equiv of bromine renders preparation
of monobrominated cyclohexadienone 7 in 74% yield if the reaction mixture
was quenched immediately after color disappearance. The most complex
problem in this case is the effective synthesis of dibrominated compound 8.
The procedure applied for introduction of two bromine atoms into cyclohexa-
dienone 1 is not effective for this case: treatment of 2 with 2.5 equiv of Br2 leads
to the mixture of 8 and 9. Isolated yields of di- and tribrominated adducts were
32% and 43%, respectively. However, product 8 can be obtained in good yields
by the fractional addition of 2 equiv of bromine. In this method, substrate 2 and
bromine were stirred in the ratio of 1:1 until decoloration of reaction mixture
(the reaction progress was also monitored by thin-layer chromatography
TLC). When 2 was totally consumed, the reaction mixture was diluted by
the addition of the same volume of solvent and 1 more equiv of bromine was
added. Quenching reaction mixture immediately after the color disappeared
and usual treatment allows isolation of product 8, with yields from 60 to 80%.
CONCLUSION
In this investigation, we have optimized reaction conditions for selective bro-
mination of 4-dichloromethyl-4-methylcyclohexa-2,5-dien-1-one (1) and
4-dichloromethyl-3,4-dimethylcyclohexa-2,5-dien-1-one (2) into their mono-
bromides (4, 7), dibromides (6, 8), or tribromide 9.
EXPERIMENTAL
1H (400 MHz) and 13C NMR (100 MHz) spectra were recorded on a Bruker
Avance 400 spectrometer. All spectra were taken at 248C in CDCl3 solution
using tetramethylsilane as an internal standard. IR spectra were run on an
UR-20 spectrometer in Nujol. UV spectra were obtained on a Specord
M-40 in ethanol solution. Alkaline Al2O3 (LSL 5/40) was used as a dehydro-
brominating agent. The preparative column chromatography was performed
on silica gel L 40/100.
4-Dichloromethyl-4-methylcyclohexa-2,5-dien-1-one (1) and 4-dichloro-
methyl-3,4-dimethylcyclohexa-2,5-dien-1-one (8) were prepared according to
the published method.[15–17]
2-Bromo-4-(dichloromethyl)-4-methylcyclohexa-2,5-dien-1-one (4)
Bromine (0.251 g, 1.57 mmol) was added to the solution of dienone 1
(0.300 g, 1.57 mmol) in 10 ml of CCl4. The resulting mixture was kept in

4-Dichloromethyl-4-methylcyclohexa-2,5-dien-1-ones
2733
the dark at room temperature until disappearing of color (ca. 20 min).
Solvent and gaseous by-products were distilled off under reduced
pressure. The yellow residue was dissolved in diethyl ether, concentrated
in vacuo, and redissolved in ether. The solution was shaken with alkaline
Al2O3. Then ether was evaporated. The resulting residue was placed on
the top of the silica-gel column and eluted with a benzene/diethyl ether
mixture (5:0.3; Rf 0.66) to give 0.35 g (82%) of compound 4 as a clean
colorless oil. After keeping for 2 days, the oil crystallized to give a white
solid. It was recrystallized from chloroform/hexane mixture and then
from hexane; mp 59–608C (lit. 90–918C);[18] UV, lmax, nm (lg 1): 240
(4.30), 268 (3.67); IR: 1660, 1640, 1600 cm21 1H NMR: 7.41 (d, 1H,
;
J ¼ 2.9 Hz, H3), 6.99 (dd, 1H, J ¼ 10.1, J ¼ 2.9, H5), 6.51 (d, 1H,
J ¼ 10.1, H6), 5.76 (s, 1H, CHCl2), 1.54 (s, 3H, CH3); 13C NMR: 177.8
(CO), 148.8, 148.7 (C3, C5), 129.1 (C6), 126.7 (C2), 75.8 (CHCl2), 51.6
(C4), 22.5 (CH3). Anal. calcd. for C8H7BrCl2O: C, 35.55; H, 2.59. Found:
C, 35.48; H, 2.57.
2,6-Dibromo-4-(dichloromethyl)-4-methylcyclohexa-2,5-dien-1-one (6)
Bromine (0.627 g, 3.93 mmol) was added to the solution of dienone 1
(0.300 g, 1.57 mmol) in 10 ml of CCl4. The resulting mixture was stirred
for 1 day. NMR analysis of mixture showed the presence of two ketones
5 and 6 in a ratio of 1:14. Solvent and gaseous by-products were distilled
off in vacuo. The yellow residue was dissolved in diethyl ether, concen-
trated in vacuo, and redissolved in ether. After treatment with alkaline
Al2O3, ether was evaporated. The residue was purified by silica-gel chrom-
atography with benzene/diethyl ether mixture (5:0.3) as eluent, Rf 0.84. The
yield of dibromoketone 6 was 0.490 g (91%). The solid was dissolved in
chloroform and precipitated by hexane. Mp 109–1128C (lit. 120–
1218C[18], 172-1748C[19]). UV, lmax, nm (lg 1): 259 (4.30); IR: 1670
1
cm21; H NMR: 7.43 (s, 2H, H3, H5), 5.77 (s, 1H, CHCl2), 1.58 (s, 3H,
CH3); 13C NMR: 171.9 (CO), 148.9 (C3, C5), 124.2 (C2, C6), 75.1
(CHCl2), 53.8 (C4), 22.3 (CH3). Anal. calcd. for C8H6Br2Cl2O: C, 27.50;
H, 1.71. Found: C, 27.50; H, 1.65.
2,5,6-Tribromo-4-(dichloromethyl)-4-methylcyclohex-2-en-1-one (5)
1H NMR: 7.79 (s, 1H, H3), 6.11 (s, 1H, CHCl2), 4.94 (AB system,
2H, J ¼ 11.7 Hz, H5, H6), 1.56 (s, 3H, CH3); 13C NMR: 181.0 (CO),
149.4 (C3), 122.9 (C2), 77.6 (CHCl2), 57.4, 54.0 (C5, C6), 53.7 (C4),
20.5 (CH3).

2734
G. V. Gavrilova et al.
2-Bromo-4-(dichloromethyl)-4,5-dimethylcyclohexa-2,5-dien-1-one (7)
Bromine (0.080 g, 0.50 mmol) was added to the solution of dienone 2
(0.1025 g, 0.50 mmol) in 5 ml of CCl4. The resulting mixture was kept at
room temperature until disappearance of color. The solvent and gaseous by-
products were distilled off under reduced pressure. The yellow residue was
dissolved in diethyl ether, concentrated in vacuo, and redissolved in ether.
The mixture was treated with alkaline Al2O3. Ether was evaporated. The
resulting residue was placed on the top of the silica-gel column and eluted
with benzene/diethyl ether mixture (5:0.3; Rf 0.44). Product was crystallized
from CHCl3–hexane to afford 0.098 g (69%) of compound 7. Mp 99–1008C;
UV, lmax, nm (lg 1): 248 (4.158); IR: 1660, 1640 (sh), 1610 cm21; 1H NMR:
7.53 (s, 1H, H3), 6.23 (q, 1H, J ¼ 1.3, H6), 5.87 (s, 1H, CHCl2), 2.00 (d, 3H,
J ¼ 1.3, C5-CH3), 1.45 (s, 3H, C4-CH3); 13C NMR: 178.0 (CO), 158.2 (C5),
148.0 (C3), 128.1 (C6), 126.8 (C2), 75.4 (CHCl2), 53.9 (C4), 23.5 (C4-CH3),
18.6 (C5-CH3). Anal. calcd. for C9H9BrCl2O: C, 38.02; H, 3.16. Found:
C, 37.94; H, 3.12.
2-Bromo-5-(bromomethyl)-4-(dichloromethyl)-4-methylcyclohexa-
2,5-dien-1-one (8)
Bromine (40 mg, 0.25 mmol) was added to the solution of dienone 2 (54 mg,
0.25 mmol) in 0.25 ml of CCl4 and stirred until the color disappeared (ca.
25 min). The solution of 42 mg (0.26 mmol) of bromine in 2 ml of CCl4
was added to the resulting mixture. After 4 h, the reaction mixture was
poured into diethyl ether (10 ml), alkaline Al2O3 was added, and it was
kept, overnight. Solvent was evaporated. Residue was purified by silica-gel
chromatography with benzene/diethyl ether mixture (5:0.3) as eluent, Rf
0.61. The yield of dibromoketone 8 was 57 mg (63%). Mp 79–808C; UV,
1
l
max, nm (lg 1): 251 (3.74); IR: 1665, 1610 cm21; H NMR: 7.48 (s, 1H,
H3), 6.70 (s, 1H, H6), 5.99 (s, 1H, CHCl2), 4.12 (AB system, 2H, J ¼ 12.4,
CH2Br), 1.62 (s, 3H, CH3); 13C NMR: 178.0 (CO), 154.8 (C5), 148.1 (C3),
132.2 (C6), 126.7 (C2), 75.3 (CHCl2), 54.1 (C4), 26.8 (CH2Br), 23.7 (CH3).
Anal. calcd. for C9H8Br2Cl2O: C, 29.75; H, 2.20. Found: C, 29.85; H, 2.12.
2-Bromo-5-(dibromomethyl)-4-(dichloromethyl)-4-
methylcyclohexa-2,5-dien-1-one (9)
Bromine (4.0 g, 25 mmol) was added to the solution of dienone 2 (0.205 g,
1.0 mmol) in 20 ml of CCl4. The resulting mixture was kept at room tempera-
ture for 1 day. Solvent and gaseous by-products were distilled off in vacuo.
The residue was dissolved in diethyl ether, concentrated in vacuo, and redis-
solved in ether. The mixture was treated with alkaline Al2O3. Ether was

4-Dichloromethyl-4-methylcyclohexa-2,5-dien-1-ones
2735
evaporated. The product was purified by precipitation from chloroform
solution with hexane. Yield was 0.406 g (92%). Mp 187–1888C; UV, lmax
,
nm (lg 1): 257 (3.12); IR: 1650, 1630, 1605 cm21; H NMR: 7.35 (s, 1H,
H3), 7.25 (s, 1H, H6), 6.25 (s, 1H, CH2Br), 5.90 (s, 1H, CHCl2), 1.65
(s, 3H, CH3); 13C NMR: 178.1 (CO), 158.9 (C5), 147.1 (C3), 134.2 (C6),
126.6 (C2), 74.4 (CHCl2), 53.7 (C4), 31.1 (CHBr2), 22.6 (CH3). Anal.
calcd. for C9H7Br3Cl2O: C, 24.43; H, 1.58. Found: C, 24.32; H, 1.49.
1
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