A synthetic approach towards novel alkyl 4,5-dibromo-2-methylbenzoate derivatives

Article abstract of DOI:10.1016/j.tet.2008.05.086

Alkyl 4,5-dibromo-2-methylbenzoate derivatives 16-18 were synthesized from 1,2-dibromo-4-alkoxymethyl-5-methylbenzene 2-4 in the presence of catalytic amounts of NBS as a radical initiator. Only primary ether derivatives rendered the corresponding esters.

Full text of DOI:10.1016/j.tet.2008.05.086

Tetrahedron 64 (2008) 7242–7246
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A synthetic approach towards novel alkyl 4,5-dibromo-2-methylbenzoate
derivatives
,
Gabriela Alejandra Gauna a, Diego Cobice b, Josefina Awruch a
*
a
´
´
´
Departamento de Qu´ımica Organica, Facultad de Farmacia y Bioquımica, Universidad de Buenos Aires, Junın 956, 1113 Buenos Aires, Argentina
b Boehringer Ingelheim S.A., R&DdDevelopment Center, Av. del Libertador 7208, 1429 Buenos Aires, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
Alkyl 4,5-dibromo-2-methylbenzoate derivatives 16–18 were synthesized from 1,2-dibromo-4-alkoxy-
methyl-5-methylbenzene 2–4 in the presence of catalytic amounts of NBS as a radical initiator. Only
primary ether derivatives rendered the corresponding esters.
Received 31 March 2008
Received in revised form 8 May 2008
Accepted 16 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Available online 21 May 2008
Keywords:
Arenes
Ethers
Esters
Oxidation
N-Bromosuccinimide
1. Introduction
2. Results and discussion
Benzyl ethers react with NBS in carbon tetrachloride under free
radical conditions to give favorable yields of the corresponding
benzaldehydes.1,2 When benzylic trimethylsilyl ethers are allowed
to react with NBS in the presence of a catalytic amount of 2,20-
azobisisobutyronitrile in boiling carbon tetrachloride, the corre-
sponding aldehydes are obtained in good yields.3 However, ali-
phatic primary trimethylsilyl ethers give esters directly formed
from two molecular equivalents of the starting trimethylsilyl ethers
rather than the expected aliphatic aldehydes.4 In addition, alcohols
were found to be oxidized to the corresponding carboxylic acid in
the presence of catalytic NBS in an oxygen atmosphere at room
temperature and irradiation with a 400 W high-pressure mercury
lamp. Among the solvents examined, ethyl acetate and acetonitrile
were found to be the most effective to afford the corresponding
carboxylic acid. Additionally, 4-substituted electron-donating or
electron-withdrawing benzyl alcohols afforded the corresponding
benzoic acids in good yields.5,6
2.1. Synthesis and characterization
Attempts to obtain compounds 9–15 by reaction of 2–8 (1 equiv)
and NBS (1 equiv) under reflux in carbon tetrachloride failed. As
shown in Scheme 1, the starting material was 1,2-dibromo-4-bro-
momethyl-5-methylbenzene (1) synthesized from 1,2-dibromo-
4,5-dimethylbenzene (1 equiv) and NBS (1 equiv) in boiling carbon
tetrachloride. This reaction was achieved without a radical initiator
since there was no difference whatever with or without benzoyl
peroxide, used as an initiator; results were practically the same.7
The reaction of 1 with sodium alkoxide gave 1,2-dibromo-4-
alkoxymethyl-5-methylbenzenes 2–8.
When a mixture of 2–4 (1 equiv) and NBS (1 equiv) was heated
overnight under reflux in carbon tetrachloride esters 16–18 were
Br
Br
CH2Br
CH3
Br
Br
CH2OR
CH3
Br
Br
CH2OR
CH2Br
NBS, CCl4
X
ROH
Methyl bromination of 1,2-dibromo-4-alkoxymethyl-5-methyl-
benzene (2–8) could be a possible route to prepare precursors for
different degrees of liphophilic derivatives by replacing the bro-
mine atom. However, the reaction of 2–8 (1 equiv) with NBS
(1 equiv) to obtain desired compounds 9–15 gave unexpected
results.
reflux
9-15
1
2-8
2, 9; R = C2H5
3, 10; R = CH2(CH2)3CH3
4, 11; R = CH2(CH2)6CH3
5, 12; R =CH2C6H5
6, 13; R = C6H5
7, 14; R = CH(CH3)2
8, 15; R = (CH3)CH(CH2)5CH3
* Corresponding author. Tel.: þ54 11 4964 8252; fax: þ54 11 4508 3645.
E-mail address: jawruch@ffyb.uba.ar (J. Awruch).
Scheme 1. Obtention of ethers 2–8 from compound 1.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.05.086

G.A. Gauna et al. / Tetrahedron 64 (2008) 7242–7246
7243
obtained in good yields (Scheme 2),8 while benzylic (5) and phenol
(6) ethers, as well as secondary alcohol ethers (7, 8) yielded 4,5-
dibromo-2-methylbenzoic acid (19), in fair to good yields.
On the other hand, an attempt to purify 1,2-dibromo-4-tert-
butoxymethyl-5-methylbenzene by filtering through a silica gel
column failed to afford it. 1,2-Dibromo-4-hydroxymethyl-5-
methylbenzene was obtained in good yields due to hydrolysis.
Formation of the esters can be rationalized as outlined in
Scheme 3. A radical species 20 is generated by the abstraction of
a hydrogen radical with a bromo radical. The radical species traps
molecular oxygen to afford peroxy radical 21, which subsequently
turns into ester 23 via hydroperoxide 22. This mechanism is similar
to that reported by Kuwabara and Itoh5 who described the oxida-
tion of benzyl alcohols to acids by means of N-bromosuccinimide,
oxygen and light at room temperature. Traces of 4,5-dibromo-2-
methylbenzoic acid (19) were obtained as an additional evidence of
the proposed mechanism. Besides, the obtention of esters 16–18 in
the presence of catalytic amount of NBS is a further evidence of the
proposed path.
Br
Br
CO2R
CH3
NBS, CCl4
2-4
2, 16; R = C2H5
3, 17; R = CH2(CH2)3CH3
4, 18; R = CH2(CH2)6CH3
Scheme 2. Conversion of ethers 2–4 to esters 16–18.
Based on these results, further studies have been initiated to
investigate the reaction of 2–8 with catalytic amounts of NBS.
Therefore, 2–4 (1 equiv) and NBS (0.02 equiv) were reacted in
boiling carbon tetrachloride. Different reaction times were ana-
lyzed, showing 40% yield during the first 2 h of the reaction and
reaching 71, 63 and 87% yield after 4 h reaction for compounds 16,
17 and 18, respectively. The reaction of 5–8 with NBS (0.02 equiv)
carried out in boiling carbon tetrachloride afforded 19 after a 2 h
reaction, Figure 1. The reaction of 2–8 with NBS (0.02 equiv) in the
presence of benzoyl peroxide (0.02 equiv) as initiator in carbon
tetrachloride at reflux temperature, under the above conditions,
rendered the same products and yields obtained without any rad-
ical initiator. These results are consistent with those obtained by
our group some years ago.7
The formation of acid 19 can be understood taking into account
that secondary alcohol derivatives, as well as benzylic alcohol and
phenol esters, are capable of giving a stable carbonium ion in the
acidic medium after protonation and SN1 hydrolysis thus allowing
us to obtain 4,5-dibromo-2-methylbenzoic acid (19). On account of
the instability of the corresponding carbocation, ester derivatives of
the primary alcohols are unable to follow the proposed mechanism,
hence esters 16–18 are obtained as the main product.
O
O
CH2OR
Br
Br
Br
Br
Br
Br
CH-OR
CH-OR
Br
HBr
O2
CH3
CH3
CH3
21
20
OH
O
Br
Br
CH-OR
Br
Br
C-OR
CH3
HBr
21
CH3
H2O
22
23
Scheme 3. Mechanism of ether oxidation.
Substrate
Product
Yield (%)
Br
Br
CH2OCH2CH3
CH3
Br
Br
CO2CH2CH3
CH3
71
2
16
Br
Br
Br
Br
CO2CH2(CH2)3CH3
CH3
CH2OCH2(CH2)3CH3
63
CH3
17
3
Br
Br
CO2CH2(CH2)6CH3
CH3
Br
Br
CH2OCH2(CH2)6CH3
CH3
87
4
18
Br
Br
CH2OCH2C6H5
CH3
Br
Br
CO2H
CH3
50
41
19
19
5
Br
Br
CH2OC6H5
CH3
6
Br
Br
Br
Br
CH2OCHCH3
CH3
CH3
71
68
19
7
CH2OCH(CH2)5CH3
CH3
CH3
19
8
Figure 1. Reaction products of 1,2-dibromo-4-alkoxymethyl-5-methylbenzene with catalytic amounts of NBS.

7244
G.A. Gauna et al. / Tetrahedron 64 (2008) 7242–7246
All compounds were characterized by 1H NMR, IR and mass spec-
trometry. Traditionally, electron and chemical ionization were the
principal methods to produce ions for mass spectrometry. The
advent of atmospheric pressure ionization (API) provided a method
of ionizing labile and non-volatile substances so that they could be
examined by mass spectrometry. API has become strongly linked to
HPLC as a basis for ionizing the eluent on its way into the mass
spectrometry. As a consequence, compounds 4, 18 and 1,2-
dibromo-4-hydroxymethyl-5-methylbenzene, which cannot be
vaporized without thermal decomposition were effectively per-
formed by APCI(þ) TOF/TOF mass spectrometry in order to achieve
a better molecular cluster ion abundance leading to [Mþ] (100).
hexane (3:7) and filtered through a silica gel column packed and
pre-washed with the same solvent. After evaporation of the sol-
vent, an oil was obtained. Yield: 0.240 g (74%). IR (KBr): 2931, 2858,
1588, 1471, 1363, 1250, 1222, 1157, 1101, 1037, 881, 729, 655,
626 cmꢂ1. 1H NMR (300 MHz, CDCl3):
d
¼0.90 (t, 3H, CH3), 1.34 (m,
4H, CH2CH2), 1.61 (m, 2H, CH2), 2.24 (s, 3H, CH3), 3.48 (t, 2H,
J¼7.0 Hz, CH2), 4.38 (s, 2H, CH2), 7.41 (s, 1H, Ar), 7.57 (s, 1H, Ar). 13
C
NMR (75 MHz, CDCl3):
d
¼14.11 (CH3), 20.61 (ArCH3), 22.78
(CH2CH2CH3), 28.51 (OCH2CH2), 29.26 (CH2CH2CH2CH3), 71.67
(OCH2CH2), 72.83 (ArCH2O), 125.25 (CBr), 126.31 (CBr), 131.79 (CH),
133.32 (CH), 136.72 (CCH3), 141.44 (CCH2O). MS (EI, 70 eV): m/z
(%)¼352 [Mꢃþ, 2 81Br, 5], 350 [Mꢃþ
,
81Br and 79Br, 10], 348 [Mꢃþ, 2
79Br, 5], 265 [2 81Br, 24], 263 [81Br and 79Br, 48], 261 [2 79Br, 23]. Anal.
Calcd for C13H18Br2O: C, 44.60; H, 5.18. Found: C, 44.62; H, 5.20.
3. Conclusions
Taking into account that alkyl 4,5-dibromo-2-methylbenzoate
derivatives cannot be successfully obtained by using 1-alkoxy-
carbonyl-2-methylbenzene,9 NBS oxidation of the primary alcohol
derivatives of 1,2-dibromo-4-alkoxymethyl-5-methylbenzene is a
useful method to prepare the corresponding esters in good yields.
This reaction was achieved with catalytic amounts of NBS as radical
initiator.
4.4. 1,2-Dibromo-4-methyl-5-octyloxymethylbenzene (4)
Compound 1 (0.200 g, 0.58 mmol) was added to a solution of Na
(0.034 g, 1.48 mmol) in anhydrous octanol (15 mL). The mixture
was stirred and heated at 195 ꢀC for 20 h. CH2Cl2 (50 mL) was added
to the reaction mixture and then washed with H2O (3ꢁ50 mL). The
organic phase was dried with Na2SO4 and evaporated to dryness in
vacuo. The oily residue was dissolved in a small volume of CH2Cl2–
hexane (3:7) and filtered through a silica gel column packed and
pre-washed with the same solvent. After evaporation of the sol-
vent, an oil was obtained. Yield: 0.198 g (86%). IR (KBr): 2926, 2855,
4. Experimental
4.1. General
1728, 1635, 1468, 1378, 1261, 1101, 880, 799, 655 cmꢂ1
.
1H NMR
Melting points were determined on an Electrothermal 9100
capillary melting point apparatus. 1H NMR and 13C NMR spectra
were recorded on a Bruker MSL 300 spectrometer. Mass spectra
were obtained with a TRIO 2 (electronic ionization 70 eV) spec-
trometer and a Perkin Elmer Claruss 500 mass spectrometer
(electronic ionization 20 eV). Infrared spectra were performed with
a Perkin Elmer Spectrum One FT-IR spectrometer. Microanalyses
were carried out with a Carlo Erba EA 1108 elemental analyzer.
Chromatography columns were prepared with TLC Kieselgel
(Merck). Reagents were purchased from Sigma–Aldrich.
(300 MHz, CDCl3):
d
¼0.88 (t, 3H, J¼7.0 Hz, CH3), 1.27 (br s, 10H,
(CH2)5CH3), 1.59 (m, 2H, J¼7.0 Hz, OCH2CH2), 2.26 (s, 3H, CH3), 3.48
(t, 2H, J¼7.0 Hz, OCH2CH2), 4.41 (s, 2H, ArCH2O), 7.45 (s, 1H, Ar), 7.57
(s, 1H, Ar). 13C NMR (75 MHz, CDCl3):
d¼14.05 (CH3), 20.61 (ArCH3),
22.68 (CH2CH2CH3), 27.06 (OCH2CH2CH2CH2), 29.24 (OCH2CH2CH2),
29.33 (OCH2CH2CH2CH2), 29.37 (CH2CH2CH2CH3), 71.36 (OCH2CH2),
71.77 (ArCH2O), 125.25 (CBr), 126.31 (CBr), 131.09 (CH), 133.32 (CH),
136.02 (CCH3), 140.71 (CCH2O). MS (EI, 20 eV): m/z (%)¼394 [Mꢃþ, 2
81Br, 2], 392 [Mꢃþ 81Br and 79Br, 4], 390 [Mꢃþ, 2 79Br, 2], 265 [2
,
81Br, 15], 263 [81Br and 79Br, 29], 261 [2 79Br, 15]. Anal. Calcd for
16H24Br2O: C, 49.00; H, 6.17. Found: C, 49.05; H, 6.19.
C
4.2. 1,2-Dibromo-4-ethoxymethyl-5-methylbenzene (2)
4.5. 1,2-Dibromo-4-benzyloxymethyl-5-methylbenzene (5)
Compound 1 (0.200 g, 0.58 mmol) was added to a solution of Na
(0.034 g, 1.48 mmol) in anhydrous EtOH (20 mL). The mixture was
stirred and heated at 80 ꢀC for 20 h. CH2Cl2 (30 mL) was added to
the reaction mixture and then washed with H2O (3ꢁ30 mL). The
organic phase was dried with Na2SO4 and evaporated to dryness in
vacuo and the solid residue was recrystallized from MeOH–H2O.
Yield: 0.166 g (93%); mp 32–34 ꢀC. IR (KBr): 2973, 2852, 1469, 1454,
1408, 1375, 1356, 1344, 1273, 1249, 1225, 1158, 1123, 1107, 1033, 891,
The reaction of 1 with anhydrous benzyl alcohol at 140 ꢀC using
the procedure described for 4 afforded 5 after purification by fil-
tering through a column, packed and pre-washed with CH2Cl2.
Yield: 0.121 g (96%). IR (KBr): 2926, 2855, 1718, 1691, 1583, 1544,
1496, 1467, 1452, 1380, 1363, 1264, 1092, 1028, 904, 880, 801, 738,
698, 640 cmꢂ1. 1H NMR (300 MHz, CDCl3):
(s, 2H, CH2), 4.58 (s, 2H, CH2), 7.35 (br s, 5H, Ar), 7.42 (s, 1H, Ar), 7.62
(s, 1H, Ar). 13C NMR (75 MHz, CDCl3):
d¼2.23 (s, 3H, CH3), 4.44
878, 864, 654 cmꢂ1
.
1H NMR (300 MHz, CDCl3):
d
¼1.26 (t, 3H,
d
¼20.61 (ArCH3), 71.78
J¼6.9 Hz, CH3), 2.24 (s, 3H, CH3), 3.54 (q, 2H, J¼7.1 Hz, CH2), 4.39 (s,
(ArCH2O), 72.50 (OCH2Ar),125.46 (CBr), 126.31 (CBr), 128ꢁ3, 129ꢁ2
2H, CH2), 7.41 (s, 1H, Ar), 7.58 (s, 1H, Ar). 13C NMR (75 MHz, CDCl3):
(Ar),131.91 (CH), 133.53 (CH), 136.85 (CCH3), 139.26 (OCH2C),141.39
d
¼15.70 (CH3), 20.61 (ArCH3), 65.70 (OCH2CH3), 71.63 (ArCH2O),
(CCH2O). MS (EI, 20 eV): m/z (%)¼372 [Mꢃþ, 2 81Br, 3], 370 [Mꢃþ
,
125.51 (CBr), 125.82 (CBr), 131.43 (CH), 133.59 (CH), 136.36 (CCH3),
81Br and 79Br, 5], 368 [Mꢃþ, 2 79Br, 3], 265 [2 81Br, 21], 263 [81Br
and 79Br, 38], 261 [2 79Br, 18]. Anal. Calcd for C15H14Br2O: C, 48.68;
H, 3.81. Found: C, 48.70; H, 3.79.
141.18 (CCH2O). MS (EI, 70 eV): m/z (%)¼310 [Mꢃþ, 2 81Br, 7], 308
[Mꢃþ 81Br and 79Br, 14], 306 [Mꢃþ, 2 79Br, 7], 265 [2 81Br, 18], 263
,
[
81Br and 79Br, 34], 261 [2 79Br, 17]. Anal. Calcd for C10H12Br2O: C,
38.99; H, 3.93. Found: C, 38.97; H, 3.97.
4.6. 1,2-Dibromo-4-methyl-5-phenoxymethylbenzene (6)
4.3. 1,2-Dibromo-4-methyl-5-pentoxymethylbenzene (3)
Compound 1 (0.100 g, 0.29 mmol) was added to a solution of
phenol (0.027 g, 0.29 mmol) dissolved in anhydrous THF (6 mL)
containing Na (0.007 g, 0.29 mmol). The mixture was stirred and
heated at 65 ꢀC for 20 h. CH2Cl2 (30 mL) was added to the reaction
mixture and then washed with H2O (3ꢁ30 mL). The organic phase
was dried with Na2SO4 and evaporated to dryness in vacuo. The oily
residue was dissolved in a small volume of CH2Cl2–hexane (1:9)
and filtered through a silica gel column packed and pre-washed
Compound 1 (0.320 g, 0.93 mmol) was added to a solution of Na
(0.033 g, 1.43 mmol) in anhydrous pentanol (5 mL). The mixture
was stirred and heated at 140 ꢀC for 20 h. CH2Cl2 (30 mL) was added
to the reaction mixture and then washed with H2O (3ꢁ30 mL). The
organic phase was dried with Na2SO4 and evaporated to dryness in
vacuo. The oily residue was dissolved in a small volume of CH2Cl2–

G.A. Gauna et al. / Tetrahedron 64 (2008) 7242–7246
7245
with the same solvent. After evaporation of the solvent, an oil
was obtained. Yield: 0.069 g (66%). IR (KBr): 3062, 3040, 2925,
2854, 1736, 1599, 1587, 1496, 1474, 1457, 1383, 1347, 1301, 1239,
1172, 1152, 1121, 1078, 1933, 1014, 913, 883, 835, 788, 751, 690,
Yield: 0.080 g (71%); mp 46–48 ꢀC. IR (KBr): 2987, 2924, 2853, 1721
(CO2R), 1580, 1540, 1460, 1446, 1387, 1365, 1333, 1284, 1246, 1119,
1089, 1018, 904, 867, 823, 779, 642 cmꢂ1 1H NMR (300 MHz,
.
CDCl3):
d
¼1.41 (t, 3H, J¼7.0 Hz, CH3), 2.52 (s, 3H, CH3), 4.36 (q, 2H,
656, 630, 613, 509 cmꢂ1
.
1H NMR (300 MHz, CDCl3):
d
¼2.30 (s,
3H, CH3), 4.94 (s, 2H, CH2), 6.96 (m, 3H, Ar), 7.32 (m, 2H, Ar), 7.48
(s, 1H, Ar), 7.69 (s, 1H, Ar). 13C NMR (75 MHz, CDCl3):
J¼7.3 Hz, CH2), 7.52 (s, 1H, Ar), 8.13 (s, 1H, Ar). 13C NMR (75 MHz,
CDCl3):
d
¼14.65 (CH3), 23.60 (ArCH3), 61.53 (OCH2), 125.18 (CBr),
d¼20.61
128.50 (CBr), 132.38 (CCO2), 133.05 (CH), 133.19 (CH), 137.56 (CCH3),
(ArCH3), 71.09 (ArCH2O), 115.2ꢁ2 (CH), 120.84 (CH), 126.07 (CBr),
126.52 (CBr), 129.89ꢁ2 (CH), 131.77 (CH), 134.14 (CH), 136.71
(CCH3), 140.88 (CCH2O), 157.61 (COCH2). MS (EI, 70 eV): m/z
167.57 (CO). MS (EI, 70 eV): m/z (%)¼324 [Mꢃþ, 2 81Br, 10], 322 [Mꢃþ
,
81Br and 79Br, 21], 320 [Mꢃþ, 2 79Br, 11], 295 [2 81Br, 42], 293 [81Br
and 79Br, 100], 291 [2 79Br, 52]. Anal. Calcd for C10H10Br2O2: C, 37.30;
H, 3.13. Found: C, 37.32; H, 3.15.
(%)¼358 [Mꢃþ, 2 81Br, 4], 356 [Mꢃþ
,
81Br and 79Br, 7], 354 [Mꢃþ, 2
79Br, 4], 265 [2 81Br, 45], 263 [81Br and 79Br, 100], 261 [2 79Br, 49].
Anal. Calcd for C14H12Br2O: C, 47.23; H, 3.40. Found: C, 47.20;
H, 3.37.
4.10. Pentyl 4,5-dibromo-2-methylbenzoate (17)
Compound 3 (0.110 g, 0.31 mmol) in CCl4 (5 mL) and NBS
(0.0011 g, 0.006 mmol) were reacted applying the procedure
described for 16. An oil was obtained. Yield: 0.072 g (63%) after
purification by filtering through a silica gel column, packed and
pre-washed with CH2Cl2–hexane (4:6). IR (KBr): 2957, 1725 (CO2R),
1465, 1383, 1280, 1243, 1088, 780 cmꢂ1. 1H NMR (300 MHz, CDCl3):
4.7. 1,2-Dibromo-4-isopropyloxymethyl-5-methylbenzene (7)
Compound 1 (0.200 g, 0.58 mmol) was added to a solution of Na
(0.034 g, 1.48 mmol) in anhydrous isopropyl alcohol (15 mL). The
mixture was stirred and heated at 90 ꢀC for 20 h. The work-up and
purification were performed using the procedure described for 3.
An oil was obtained that decomposed by standing at room tem-
perature. Yield: 0.0915 g (49%). IR (KBr): 2965, 1689, 1579, 1455,
1382, 1261, 1211, 1086, 892, 802 cmꢂ1. 1H NMR (300 MHz, CDCl3):
d
¼0.92 (t, 3H, CH3), 1.39 (m, 4H, (CH2)2CH3), 1.75 (m, 2H, OCH2CH2),
2.52 (s, 3H, CH3), 4.28 (t, 2H, OCH2CH2), 7.52 (s, 1H, Ar), 8.12 (s, 1H,
Ar). 13C NMR (75 MHz, CDCl3):
d
¼14.20 (CH3), 23.10 (CH2CH2CH3),
23.60 (ArCH3), 29.33 (OCH2CH2), 30.68 (CH2CH2CH2CH3), 65.70
(OCH2CH2), 125.18 (CBr), 128.50 (CBr), 132.50 (CCO2), 133.05 (CH),
133.60 (CH),138.18 (CCH3),169.56 (CO). MS (EI, 70 eV): m/z (%)¼366
d
¼1.22 (s, 3H, CH3), 1.24 (s, 3H, CH3), 2.24 (s, 3H, CH3), 3.68 (m, 1H,
CH), 4.38 (s, 2H, CH2), 7.41 (s, 1H, Ar), 7.59 (s, 1H, Ar). 13C NMR
(75 MHz, CDCl3):
d
¼20.61 (ArCH3), 22.24ꢁ2 (CH3), 69.82 (ArCH2O),
[Mꢃþ, 2 81Br, 2], 364 [Mꢃþ 81Br and 79Br, 5], 362 [Mꢃþ, 2 79Br,
,
70.73 (OCH), 125.61 (CBr), 125.77 (CBr), 130.57 (CH), 133.68 (CH),
2], 296 [2 81Br, 15], 294 [81Br and 79Br, 29], 292 [2 79Br, 16].
Anal. Calcd for C13H16Br2O2: C, 42.89; H, 4.43. Found: C, 42.87;
H, 4.40.
135.50 (CCH3), 141.40 (CCH2O). MS (EI, 20 eV): m/z (%)¼324 [Mꢃþ, 2
81Br, 6], 322 [Mꢃþ 81Br and 79Br, 10], 320 [Mꢃþ, 2 79Br, 6], 265 [2
,
81Br, 25], 263 [81Br and 79Br, 48], 261 [2 79Br, 25]. Anal. Calcd for
11H14Br2O: C, 41.03; H, 4.38. Found: C, 41.05; H, 4.39.
C
4.11. Octyl 4,5-dibromo-2-methylbenzoate (18)
4.8. 1,2-Dibromo-4(1-methylheptyloxy)methyl-5-
methylbenzene (8)
Compound 4 (0.137 g, 0.30 mmol) in CCl4 (25 mL) and NBS
(0.0012 g, 0.007 mmol) were reacted applying the procedure
described for 16. An oil was obtained. Yield: 0.123 g (87%) after
purification by filtering through a silica gel column, packed and
pre-washed with CH2Cl2–hexane (4:6). IR (KBr): 2956, 2927, 2855,
1728 (CO2R), 1634, 1466, 1378, 1279, 1243, 1112, 871, 801, 722,
Compound 1 (0.200 g, 0.58 mmol) was added to a solution of Na
(0.034 g, 1.48 mmol) in anhydrous 2-octanol (15 mL). The mixture
was stirred and heated at 180 ꢀC for 20 h. The work-up and puri-
fication were performed using the procedure described for 3. After
filtering through a silica gel column, packed and pre-washed with
CH2Cl2–hexane (4:6) an oil was obtained. Yield: 0.177 g (77%). IR
(KBr): 2927, 2856, 1627, 1465, 1378, 1263, 1121, 1088, 882, 745,
639 cmꢂ1. 1H NMR (300 MHz, CDCl3):
d
¼0.88 (t, 3H, CH3), 1.30 (br
s, 10H, (CH2)5CH3), 1.56 (m, 2H, J¼7.1 Hz, OCH2CH2), 2.53 (s, 3H,
CH3), 4.30 (t, 2H, J¼6.8 Hz, OCH2CH2), 7.53 (s, 1H, Ar), 8.13 (s, 1H,
Ar). 13C NMR (75 MHz, CDCl3):
d
¼14.05 (CH3), 22.68 (CH2CH2CH3),
593 cmꢂ1. 1H NMR (300 MHz, CDCl3):
d
¼0.89 (t, 3H, J¼7.0 Hz, CH3),
23.60 (ArCH3), 27.52 (OCH2CH2CH2CH2), 29.33 (OCH2CH2CH2CH2),
29.37 (CH2CH2CH2CH3), 29.58 (OCH2CH2CH2), 31.90 (CH2CH2CH3),
65.39 (OCH2CH2), 125.18 (CBr), 128.50 (CBr), 131.77 (CCO2), 133.05
(CH), 133.10 (CH), 137.47 (CCH3), 167.76 (CO). MS (EI, 20 eV): m/z
1.20 (d, 3H, CHCH3), 1.31 (m, 8H, (CH2)4CH3), 1.42 (m, 2H, J¼7.0 Hz,
OCHCH2), 2.25 (s, 3H, CH3), 3.39 (m, 1H, CH), 4.46 (s, 2H, ArCH2O),
7.39 (s, 1H, Ar), 7.60 (s, 1H, Ar). 13C NMR (75 MHz, CDCl3):
d¼14.00
(CH3), 20.61 (ArCH3), 21.60 (CHCH3), 22.80 (CH2CH3), 25.30
(CHCH2CH2), 30.40 (CHCH2CH2CH2), 32.20 (CH2CH2CH3), 34.88
(CHCH2CH2), 69.96 (ArCH2O), 72.39 (OCHCH2), 125.15 (CBr), 126.31
(CBr), 130.57 (CH), 133.23 (CH), 135.50 (CCH3), 141.06 (CCH2O). MS
(%)¼408 [Mꢃþ, 2 81Br, 3], 406 [Mꢃþ
,
81Br and 79Br, 6], 404 [Mꢃþ, 2
79Br, 3], 296 [2 81Br, 50], 294 [81Br and 79Br, 100], 292 [2 79Br,
51]. Anal. Calcd for C16H22Br2O2: C, 47.32; H, 5.46. Found: C, 47.30;
H, 5.44.
(EI, 20 eV): m/z (%)¼394 [Mꢃþ, 2 81Br, 2], 392 [Mꢃþ
,
81Br and 79Br,
3], 390 [Mꢃþ, 2 79Br, 2], 265 [2 81Br, 51], 263 [81Br and 79Br, 100],
261 [2 79Br, 52]. Anal. Calcd for C16H24Br2O: C, 49.00; H, 6.17. Found:
C, 49.03; H, 6.19.
4.12. 4,5-Dibromo-2-methylbenzoic acid (19)
Ethers 5–8 (1 equiv) and 0.02 equiv of NBS in carbon tetra-
chloride were refluxed for 2 h. The mixture was cooled, the succi-
nimide formed was removed by filtration and the solution checked
by TLC (Rf¼0.5; CH2Cl2–hexane, 4:6). Evaporation of the solvent
afforded a solid in good yields, which was recrystallized from EtOH;
mp 98–99 ꢀC, TLC (Rf¼0.5; CH2Cl2–hexane, 4:6). IR (KBr): 2958,
1702 (CO2H), 1582, 1542, 1465, 1413, 1385, 1345, 1282, 1244, 1125,
4.9. Ethyl 4,5-dibromo-2-methylbenzoate (16)
NBS (0.0012 g, 0.007 mmol) was added to a solution of 2
(0.107 g, 0.35 mmol) in CCl4 (20 mL). The mixture was stirred under
reflux for 4 h. After cooling, the precipitate was filtered, washed
with CCl4 and the filtrate evaporated in vacuo to eliminate the
solvent. The residue was then dissolved in a small volume of
CH2Cl2–hexane (4:6) and filtered through a silica gel column
packed and pre-washed with the same solvent. After evaporation of
the solvent, the solid residue was recrystallized from MeOH–H2O.
1090, 888, 781, 691, 641, 578 cmꢂ1 1H NMR (300 MHz, CDCl3):
.
d
¼2.60 (s, 3H, CH3), 7.57 (s, 1H, Ar), 7.99 (s, 1H, Ar), 10.16 (s, 1H,
CO2H). 13C NMR (75 MHz, CDCl3):
d
¼22.75 (ArCH3), 126.33 (CBr),
129.53 (CBr), 131.55 (CCO2), 133.75 (CH), 134.19 (CH), 138.32 (CCH3),
169.58 (CO). MS (EI, 70 eV): m/z (%)¼296 [Mꢃþ, 2 81Br, 38], 294 [Mꢃþ
,

7246
G.A. Gauna et al. / Tetrahedron 64 (2008) 7242–7246
81Br and 79Br, 87], 292 [Mꢃþ, 2 79Br, 44]. Anal. Calcd for C8H6Br2O2:
C, 32.69; H, 2.06. Found: C, 32.72; H, 2.04.
References and notes
1. (a) Okawara, M.; Sato, H.; Imoto, E. J. Chem. Soc. Japan, Ind. Chem. Sect. 1955, 68,
924; (b) Chem. Abstr. 1956, 50, 12878.
2. Filler, R. Chem. Rev. 1963, 63, 21.
3. Marko´, I. E.; Mekhalfia, A.; Ollis, W. D. Synlett 1990, 345.
4. Pinnick, H. W.; Lajin, N. H. J. Org. Chem. 1978, 43, 371.
5. Kuwabara, K.; Itoh, A. Synthesis 2006, 1949 and references cited therein.
6. Sugai, T.; Itoh, A. Tetrahedron Lett. 2007, 48, 2931.
7. Rodriguez, M. E.; Strassert, C. A.; Dicelio, L. E.; Awruch, J. J. Heterocycl. Chem.
2001, 38, 387.
Acknowledgements
This work was supported by grants from the University of
Buenos Aires, the Consejo Nacional de Investigaciones Cientıficas y
´
8. Gauna, G. A.; Monsalvo, A. C.; Garcı´a Vior, M. C.; Awruch, J. XXV Congreso
Argentino de Quı´mica, Olavarrı´a, Buenos Aires, Argentina, September 22–24,
2004; pp. 293–295.
9. Literatur bis 1. Januar 1910 umfassend; Beilsteins Handbuch der Organischen
Chemie, Vierte Auflage; von Julius Springer: Berlin, 1926; Band IX; p 463.
Te´cnicas (CONICET) and the Agencia Nacional de Promocio´n Cien-
´
´
tıfica y Tecnologica. We wish to thank the technical assistance as
regards chromatography of Ms. Juana Alcira Valdez. Language su-
pervision by Prof. Rex Davis is also appreciated.