Polybromoaromatic compounds: IX. Reactions of polybromobenzyl bromides with enolates derived from some dicarbonyl compounds

Article abstract of DOI:10.1023/A:1012474416163

The reaction of polybromobenzyl bromides RC₆Br₄CH₂Br (R = Br, OCH₃) with diethyl malonate sodium salt in ethanol and dimethylformamide leads to formation of diethyl 2-(polybromobenzyl)malonates, whereas in aqueous ethanol ethyl polybromobenzyl malonates are formed. The same polybromobenzyl bromides react with an equimolar amount of ethyl acetoacetate sodium salt or acetylacetone sodium salt to give C-alkylation products; with excess sodium enolates ethyl 3-(polybromophenyl)propionates and 4-(polybromophenyl)-2-butanones are formed, respectively.

Full text of DOI:10.1023/A:1012474416163

Russian Journal of Organic Chemistry, Vol. 37, No. 7, 2001, pp. 975 980. Translated from Zhurnal Organicheskoi Khimii, Vol. 37, No. 7, 2001,
pp. 1027 1032.
Original Russian Text Copyright
2001 by Shishkin, Vakaeva, Belozerov, Tanaseichuk, Butin.
Polybromoaromatic Compounds: IX.* Reactions
of Polybromobenzyl Bromides with Enolates Derived
from Some Dicarbonyl Compounds**
V. N. Shishkin1, S. S. Vakaeva1, A. I. Belozerov1,
B. S. Tanaseichuk1, and K. P. Butin2
1
Ogarev Mordovian State University, ul. Bol’shevistskaya 68, Saransk, 430000 Russia
2
Faculty of Chemistry, Moscow State University, Vorob’evy gory, Moscow, 119899 Russia
Received April 20, 2000
Abstract The reaction of polybromobenzyl bromides RC6Br4CH2Br (R = Br, OCH3) with diethyl malonate
sodium salt in ethanol and dimethylformamide leads to formation of diethyl 2-(polybromobenzyl)malonates,
whereas in aqueous ethanol ethyl polybromobenzyl malonates are formed. The same polybromobenzyl
bromides react with an equimolar amount of ethyl acetoacetate sodium salt or acetylacetone sodium salt to
give C-alkylation products; with excess sodium enolates ethyl 3-(polybromophenyl)propionates and 4-(poly-
bromophenyl)-2-butanones are formed, respectively.
Benzyl bromides are known to react with diethyl
malonate in the presence of bases to give exclusively
C-alkylation products [2]. However, we found [3] that
the reaction of pentabromobenzyl bromide (Ia) with
diethyl malonate sodium salt (II) in ethanol leads to
formation of ethyl pentabromobenzyl malonate (IIIa),
whereas the reaction between the same compounds in
toluene and dimethylformamide yields diethyl penta-
bromobenzylmalonate (IVa). The reasons for the dif-
ferent reaction pathways were unclear.
bromobenzyl bromide (Ia) and 2,3,5,6-tetrabromo-4-
methoxybenzyl bromide (Ib) with sodium enolates
derived from some -dicarbonyl compounds (diethyl
malonate, ethyl acetoacetate, and acetylacetone) in
ethanol and dimethylformamide. The reactions were
carried out with a 2 3-fold excess of the dicarbonyl
compound (Table 1). The progress of reactions was
monitored, and the final products were identified,
by GLC, TLC, and 1H NMR spectroscopy using
authentic samples (Table 2).
The present communication reports on the results
of a more detailed study of the reactions of penta-
The reaction of pentabromobenzyl bromide (Ia)
with diethyl malonate sodium salt (II) in ethanol at
Scheme 1.
R = Br (a), OMe (b).
____________
*
For communication VIII, see [1].
**
This study was financially supported by the Ministry of
Education of the Russian Federation (project no. 03.03.01.07).
1070-4280/01/3707-0975$25.00 2001 MAIK Nauka/Interperiodica

976
SHISHKIN et al.
Table 1. Reactions of polybromobenzyl bromides with sodium enolates derived from -dicarbonyl compounds
Run Substrate
Reagent
no.
Bromide reagent
ratio
Time,
h
Tempera-
ture,
Product (fraction, %),
yield, %
Solvent
EtOH
no.
no.
C
1
2
Ia
Ia
II
II
1: 1.4
1: 1.63
4
4.4
78
78
IVa (>98), 72; Va (traces)
IIIa (>97), 92; Va (traces),
VIa (traces)
96% EtOH
3
4
5
6
7
Ia
Ib
Ib
Ib
Ia
II
II
II
II
DMF
EtOH
96% EtOH
DMF
EtOH
1: 1.07
1: 1.4
1: 1.05
1: 1.05
1: 1.04
0.5
3.5
8
0.25
4
100
78
78
100
78
IVa, 82
IVb, 75
IIIb (>98), 85; Vb (traces)
IVb, 75
Ia (traces); Va (traces),
VIIIa (>97), 82
VIIIa (65); IXa (35)
IXa (>98), 93; IXc (traces)
Va; VIIIa; IXa; IXc
VIIIa (>98), 86;
IXc (traces)
VIIa
8
9
10
11
Ia
Ia
Ia
Ia
VIIa
VIIa
VIIa
VIIa
EtOH
EtOH
96% EtOH
DMF
1: 1.23
1: 2.5
1: 1.22
1: 1.05
3.5
5.5
4
78
78
78
1
100
12
13
14
Ib
Ib
Ia
VIIa
VIIa
VIIb
EtOH
EtOH
EtOH
1: 1.05
1: 2.5
3.3
1.5
4
78
78
78
VIIIb (>98), 70;
IXb (traces)
IXb (>98), 74;
VIIIb (traces)
Ia (4); Va (2); VIIIc (46);
IXc (48)
1: 1.05
15
16
Ia
Ia
VIIb
VIIb
EtOH
96% EtOH
1: 2.5
1: 1.2
3
4.5
78
78
IXc, 93.2
Ia (5); Va (12); VIa (14);
VIIIc (52); IXc (17)
Ia (54); VIIIc (46), 20
Ib (traces); Vb (traces),
VIIId (>96), 74;
IXd (traces)
17
18
Ia
Ib
VIIb
VIIb
Toluene
EtOH
1: 1.1
1: 1.05
31
4.5
110
78
19
20
Ib
Ib
VIIb
VIIb
EtOH
EtOH
1: 2.5
1: 2.5
2
6
78
78
VIIId (40); IXd (60)
IXd (>98), 85;
VIIId (traces)
78 C was not selective, and the product composition
strongly depended on the concentration of water in
the solvent (Scheme 1). C-Alkylation product IVa
was formed as the major one when the reaction was
carried out in anhydrous ethanol. In addition, traces
of ethyl pentabromobenzyl ether (Va) were detected.
Even such a small concentration of water as 0.1 0.2%
in ethanol gives rise to formation of compound IIIa
which becomes the major product in 96% ethanol. In
this case, traces of pentabromobenzyl alcohol (VIa)
were also detected.
2,3,5,6-Tetrabromo-4-metoxybenzyl bromide (Ib)
behaves similarly in the reaction with sodium salt
II in ethanol (Table 1, run nos. 4 and 5). It should
be noted that bromides Ia and Ib react with diethyl
malonate sodium salt (II) in anhydrous dimethyl-
formamide to give exclusively C-alkylation products
IVa and IVb. The reaction in dimethylformamide is
much faster than in ethanol (it is complete in 0.25 to
0.5 h at 100 C.
It could be presumed that in aqueous ethanol
sodium hydroxide formed via exhange reaction
promotes hydrolysis of benzyl bromides Ia and Ib to
the corresponding benzyl alcohols VIa and VIb which
then react with excess NaOH (or EtONa) to give
alkoxides. The latter can be involved in transesterifica-
tion of diethyl malonate according to Scheme 2.
However, by special experiments we showed that such
reaction pathway does not occur. In the reaction of
alcohol VIa with excess diethyl malonate in ethanol
in the presence of sodium hydroxide or ethoxide,
other conditions being the same, we did not detect
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POLYBROMOAROMATIC COMPOUNDS: IX.
977
Scheme 2.
Scheme 3.
even trace amount of malonate IIIa over a period of
4 h; only unreacted pentabromobenzyl alcohol (VIa)
was isolated. Moreover, we found that bromide Ia
in 96% ethanol in the presence of NaOH is converted
exclusively into ether Va; only traces of alcohol VIa
were detected in the reaction mixture.
nate (IXa) (Table 1, run no. 8). The latter becomes
the major product when the reaction is carried out
with more than twofold excess of VIIa (Table 1, run
no. 9). Analogous products are formed in the reaction
of sodium salt VIIa with bromide Ib (Table 1,
runs nos. 12 and 13). Under the same conditions, the
reaction of Ia with an equimolar amount of acetyl-
acetone sodium salt (VIIb) leads to formation of
a mixture of the C-alkylation product and 4-(penta-
bromophenyl)-2-butanone (IXc) (Table 1, run no. 14);
some amount of unchanged bromide Ia is also present
in the reaction mixture. The reaction with excess
sodium salt VIIb yields ketone IXc as the major
product (Table 1, run no. 15). Pure 3-(pentabromoben-
zyl)-2,5-pentanedione (VIIIc) was obtained in 20%
yield by slow reaction of bromide Ia with compound
VIIb in toluene at 110 C (the conversion of Ia was
50%; Table 1, run no. 17). Bromide Ib reacted with
an equimolar amount of VIIb to give mainly dione
VIIId, whereas butanone IXc was the major product
in the reaction of Ib with more than twofold excess
of sodium salt VIIb.
Presumably, ketones IXc and IXd and esters IXa
and IXb are formed by cleavage of the primary
C-alkylation products VIIIa VIIId in the presence of
excess sodium ethoxide (Scheme 5). This assumption
was proved by special experiments. It should be noted
that dione VIIId is more stable than VIIIc. The latter
undergoes cleavage immediately following its forma-
tion, while complete transformation of compound
VIIId into IXd requires high concentration of EtONa
Obviously, the reactions in anhydrous ethanol and
dimethylformamide follow SN2 mechanism, resulting
in C-alkylation of diethyl malonate, whereas in
aqueous ethanol ionization of benzyl bromides Ia and
Ib is possible. The subsequent attack by ambident
nucleophile II in which the greatest negative charge
is localized on the oxygen atom leads to formation of
unstable intermediate O-alkylation product (SN1-like
process, Scheme 3). An analogous scheme for forma-
tion of transesterification products via O-alkylation
of sodium salt derived from methyl O-(tetrahydro-
pyran-2-yl)amygdalic acid in DMSO at 80 C was
proposed in [4]. It should be noted that products of
intramolecular O-alkylation of cyanoacetic, malonic,
and acetoacetic acid -bromoethyl esters by the action
of sodium hydride in THF were isolated for the first
time by Parker [5] and were identified as substituted
ketene acetals.
The reactions of bromides Ia and Ib with ethyl
acetoacetate sodium salt (VIIa) at a ratio of 1:1 gave
exclusively the corresponding C-alkylation products,
ethyl 3-oxo-2-(polybromobenzyl)butanoates VIIIa and
VIIIb (Scheme 4). By reaction of Ia with a slight
excess (1:1.2) of enolate VIIa we obtained a mixture
of ester VIIIa and ethyl 3-(pentabromophenyl)propio-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 7 2001

978
SHISHKIN et al.
Scheme 4.
VII, R2 = Me, R3 = OEt (a); R2 = R3 = Me (b); VIII, IX, R1 = Br, R2 = Me, R3 = OEt (a); R1 = OMe, R2 = Me, R3 = OEt (b);
R1 = Br, R2 = R3 = Me (c); R1 = OMe, R2 = R3 = Me (d).
Scheme 5.
and considerable time (Table 1; runs. nos. 14, 15,
19, and 20).
pounds contained no less than 97.5 98.5% of the
main substance. Polybromobenzyl alcohols VIa and
VIb [1] and bromides Ia [6] and Ib [7] were syn-
thesized by known procedures.
The structure of the C-alkylation products of di-
carbonyl compounds was additionally proved by their
alkaline and acid hydrolysis to the corresponding
ketones and carboxylic acids. The reactions under
study can be used as the basis of convenient prepara-
tive procedures for synthesis of -polybromophenyl
derivatives of carboxylic acids, esters, and ketones,
which attract interest as starting compounds in the
synthesis of biologically active substances.
Reaction of polybromobenzyl bromides Ia and
Ib with sodium salts of -dicarbonyl compounds.
A mixture of ethanol, sodium ethoxide, and a 2 3-fold
excess of -dicarbonyl compound was heated for
10 min, bromide Ia or Ib was added, and the mixture
was heated under reflux until the latter disappeared
(TLC on Silufol plates, eluent toluene). Excess sol-
vent was distilled off, the residue was treated with
water, and the precipitate was filtered off, washed
with water, dried, and analyzed by GLC, TLC, and
1H NMR spectroscopy. Individual products were
isolated by recrystallization from ethanol. When the
reaction was performed in dimethylformamide and
toluene, diethyl malonate sodium salt was prepared
by dissolving metallic sodium in a 3-fold amount
of diethyl malonate.
EXPERIMENTAL
The 1H NMR spectra were recorded on Tesla
BS-467 (60 MHz), Bruker AM-200 (200 MHz), and
Varian VXR (300 MHz) instruments in CCl4 and
CDCl3 using HMDS as internal reference. The IR
spectra were obtained on a UR-20 spectrometer from
samples dispersed in mineral oil. Chromatographic
analysis was performed on a Chrom-42 instrument
using glass columns 3000 3.5 and 1500 3.5 mm;
stationary phases 5% of SE-30 on Chromaton
N-AW-HMDS (0.16 0.20 mm) and 3% of OV-17 on
Chromaton N-Super (0.16 0.20 mm); oven tempera-
ture 220 260 C; thermoionic detector; carrier gas
nitrogen. The purity of the initial compounds and final
products was checked by GLC. All individual com-
During GLC analysis (200 260 C) malonates IVa
and IVb and butanoates VIIIa and VIIIb partially
decomposed to give propionates IXa and IXb and
ketones IXc and IXd, respectively. Therefore, in some
cases quantitative analysis of the products was per-
1
formed by H NMR spectroscopy using CDCl3 or
CCl4 as solvent; the following signals were used as
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 7 2001

POLYBROMOAROMATIC COMPOUNDS: IX.
979
1
Table 2. Melting points, H NMR spectra, and elemental analyses of polybromoaromatic compounds IIIa, IIIb, IVa,
IVb, VIIIa VIIId, and IXa IVd
Found, %
Calculated, %
Comp.
no.
mp,a
C
1H NMR spectrum, , ppm
Formula
C
H
C
H
IIIa
IIIb
IVa
149 150 (300 MHz, CDCl3): 1.26 t (3H, CH3), 3.42 s (2H, 23.25 1.61 C12H9Br5O4
23.37
1.47
CH2), 4.20 q (2H, CH2, J = 7.1 Hz), 5.67 s (2H,
CH2Ar)
104 105 (60 MHz, CCl4): 1.20 t (3H, CH3), 3.22 s (2H, 27.63 2.04 C13H12Br4O5 27.50
CH2), 3.82 s (3H, OCH3), 4.09 q (2H, CH2, J =
2.13
2.03
7 Hz), 5.50 s (2H, CH2Ar)
104 105 (200 MHz, CDCl3), 1.24 t (6H 2CH3), 3.71 25.92 2.01 C14H13Br5O4 26.08
3.91 m (3H, CHCH2), 4.21 q (4H, 2CH2, J =
7.2 Hz)
(300 MHz, CDCl3): 1.26 t (6H, 2CH3, J = 7.2 Hz),
3.75 t (1H, CH, J = 5.9 Hz), 3.88 d (2H, CH2,
J = 5.9 Hz), 4.19 q (4H, 2CH2, J = 7.2 Hz)
IVb
83
(60 MHz, CCl4): 1.15 t (6H, 2CH3), 3.48 3.72 m
(3H, CHCH2), 3.80 s (3H, OCH3), 4.08 q (4H, 30.41 2.73 C15H16Br4O5 30.23
2CH2, J = 7.2 Hz)
2.71
1.80
VIIIa
123 124 (200 MHz, CDCl3): 1.23 t (3H, CH3), 2.28 s (3H, 25.77 1.94 C13H11Br5O3 25.40
CH3CO), 3.73 3.90 m (3H, CHCH2), 4.19 q
(2H, CH2, J = 7.2 Hz)
VIIIb 100 101 (60 MHz, CCl4): 1.12 t (3H, CH3), 2.12 s (3H, 29.78 2.63 C14H14Br4O4 29.72
CH3CO), 3.53 3.72 m (3H, CHCH2), 3.78 s
2.49
(3H, OCH3), 4.06 q (4H, 2CH2, J = 7.5 Hz)
VIIIc
190
(300 MHz, CDCl3): 2.22 s (6H, 2CH3CO), 3.79 d 24.00 1.70 C12H9Br5O2
24.65
1.55
2.26
1.58
(2H, CH2Ar), 3.96 t (1H, CH, J = 6.7 Hz)
VIIId 143 144 (60 MHz, CCl4): 2.07 s (6H, 2CH3CO), 3.57 28.95 2.51 C13H12Br4O3 29.14
3.72 m (3H, CHCH2), 3.80 s (3H, OCH3)
IXa
IXb
121
127
(200 MHz, CDCl3): 1.30 t (3H, CH3), 2.54 2.62 m 23.55 1.64 C11H9Br5O2
(2H, CH2CO), 3.53 3.62 m (2H, CH2Ar),
4.19 q (2H, CH2, J= 7.2 Hz)
(300 MHz, CDCl3): 1.28 t (3H, CH3, J = 7.2 Hz),
2.57 t (2H, CH2CO, J = 8.5 Hz), 3.56 t (2H,
CH2Ar, J = 8.5 Hz), 4.19 q (2H, CH2, J =
7.2 Hz)
23.07
(60 MHz, CCl4): 1.22 t (3H, CH3), 2.18 2.63 m 27.48 2.13 C12H12Br4O3 27.51
(2H, CH2CO), 3.22 3.71 m (2H, CH2Ar),
3.80 s (3H, OCH3), 4.06 q (2H, CH2, J =
7.4 Hz)
2.31
IXc
IXd
152 153 (300 MHz, CDCl3): 2.21 s (3H, CH3SO), 2.69 t 22.40 1.23 C10H7Br5O
22.13
1.30
2.04
(2H, CH2CO), 3.47 t (2H, CH2Ar, J = 8.3 Hz)
148 149 (60 MHz, CCl4): 2.07 s (3H, CH3), 2.25 2.62 m 26.60 2.13 C11H10Br4O2 26.76
(2H, CH2CO), 3.12 3.51 m (2H, CH2Ar),
3.77 s (3H, OCH3)
a
From ethanol.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 7 2001

980
SHISHKIN et al.
reference: malonates IIIa, IIIb: ArCH2; IVa, IVb:
CHCH2; VIIIa, VIIIb: CH3CO; IXa, IXb: CH2CO;
the error in determination was 3 4%.
Ethyl pentabromobenzyl ether (Va). a. Metallic
sodium, 2.6 mmol, was dissolved in 40 ml of anhy-
drous ethanol, 1.9 mmol of bromide Ia was added,
%: C 19.85; H 0.93. C9H5Br5O2. Calculated, %:
C 19.42; H 0.92.
b. A mixture of 16.3 mmol of ester VIIIa and
0.7 l of 0.5 N aqueous potassium hydroxide was
heated for 6 h under reflux. The undissolved material
was separated, washed with water, and recrystallized
and the mixture was heated for 2 h. It was then treated from dioxane to obtain 4-pentabromophenyl-2-buta-
with water, and the precipitate was filtered off,
washed with water, dried, and recrystallized from
ethanol. Yield 95%. Colorless crystals, mp 124
none (IXc) in 84% yield. The alkaline filtrate was
acidified with dilute hydrochloric acid to isolate 0.4 g
(4.4%) of 3-(pentabromophenyl)propionic acid.
c. A mixture of 12.5 mmol of compound VIIIa
and 200 ml of 40% H2SO4 was heated for 9 h under
reflux. The precipitate was filtered off, washed with
water, dried, and recrystallized from ethanol. The
product was ketone IXc. Yield 70%.
Hydrolysis of ethyl (pentabromophenyl)propio-
nate (IXa). A mixture of 60 ml of ethanol, 50 ml
of 10% aqueous sodium hydroxide, and 2.1 mmol
of ester IXa was heated for 0.5 h under reflux. The
mixture was treated with water and acidified with
dilute hydrochloric acid, and the precipitate was fil-
tered off, washed with water, and dried. Recrystalliza-
tion from ethanol gave 74% of 3-(pentabromophenyl)-
propionic acid.
1
125 C. H NMR spectrum (60 MHz, CCl4), , ppm:
1.17 t (3H, CH3), 3.37 q (2H, CH2, J = 7.2 Hz),
4.83 s (2H, CH2C6Br5). Found, %: C 20.35; H 1.14.
C9H7Br5O. Calculated, %: C 20.58; H 1.33.
b. A mixture of 100 ml of 96% ethanol, 5.78 mmol
of NaOH, and 3.54 mmol of bromide Ia was heated
for 4.5 h under reflux. The mixture was treated as
described above in a. Yield 92%.
Ethyl 2,3,5,6-tetrabromo-4-methoxybenzyl ether
(Vb) was synthesized from bromide Ib by the proce-
dure described above for ether Va (method a). Yield
1
65%. Colorless crystals, mp 75 76 C. H NMR spec-
trum (60 MHz, CCl4), , ppm: 1.13 t (3H, CH3),
3.36 q (2H, CH2, J = 7 Hz), 3.78 s (3H, OCH3),
4.83 s (2H, CH2C6Br4OCH3). Found, %: C 24.81;
H 2.38. C10H10Br4O2. Calculated, %: C 24.93; H 2.09.
REFERENCES
Reaction of ethyl 3-oxo-2-(pentabromobenzyl)-
butanoate (VIIIa) with sodium ethoxide. A mixture
of 30 ml of anhydrous ethanol, 0.81 mmol of ester
VIIIa, and 1.03 mmol of sodium ethoxide was heated
for 1 h under reflux. It was then treated with water,
and the precipitate was filtered off, washed with
water, dried, and recrystallized from ethanol. We thus
obtained 74% of ester IXa.
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butanoate (VIIIa). a. A mixture of 6.5 mmol of ester
VIIIa and 60 ml of an alcoholic solution of sodium
hydroxide (50 ml of 96% ethanol and 10 ml of 30%
aqueous NaOH) was heated for 1 h under reflux and
evaporated. The residue was treated with dilute hydro-
chloric acid, and the precipitate was washed with
water and recrystallized from ethanol to obtain
3-(pentabromophenyl)propionic acid as a colorless
crystalline substance. Yield 71%, mp 219 220 C. IR
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1
spectrum, , cm : 3200 (OH), 1700 s (CO). Found,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 7 2001