An efficient method for the preparation of benzylic bromides

Article abstract of DOI:10.1055/s-2001-18060

Substituted benzylic compounds are brominated with an excess of N-bromosuccinimide (NBS) in CCl₄ to the corresponding polybrominated mixtures which are then debrominated with diethyl phosphite and N,N-diisopropylethylamine to afford the desired monobromides in satisfactory yields and high purity.

Full text of DOI:10.1055/s-2001-18060

2
078
SHORT PAPER
An Efficient Method for the Preparation of Benzylic Bromides
a
b
b
a
Preparation of
e
B
enzylic
B
i
romide
n
s
ian Liu, Yingchun Chen, Jingen Deng,* Yongqiang Tu
a
Department of Chemistry & National Laboratory of Organic Chemistry, Lanzhou University, Lanzhou 730000, China
b
Union Laboratory of Asymmetric Synthesis, Chengdu Institute of Organic Chemistry, the Chinese Academy of Sciences, Chengdu
610041, China
Fax +86(28)5223978; E-mail: jgdeng@cioc.ac.cn
Received 19 April 2001; revised 6 August 2001
work we report a convenient two-step procedure for the
preparation of benzylic bromides from methyl benzenes
which are brominated first with an excess of NBS in CCl4
Abstract: Substituted benzylic compounds are brominated with an
excess of N-bromosuccinimide (NBS) in CCl to the corresponding
4
polybrominated mixtures which are then debrominated with diethyl
phosphite and N,N-diisopropylethylamine to afford the desired and then debrominated selectively to the monobromides
monobromides in satisfactory yields and high purity.
with diethyl phosphite and N,N-diisopropylethylamine (i-
Pr NEt) in satisfactory yields and high purity.
Key words: debromination, benzylic bromides, diethyl phosphite,
N,N-diisopropylethylamine
2
Initially, compound 1a was reacted with 2 equivalents of
1
3
NBS in CCl at reflux temperature in the presence of a
4
catalytic amount of benzoyl peroxide, but the subsequent
The benzylic bromides, especially the poly(monobro- debromination of the mixture of the bromides with diethyl
momethyl)arenes are very useful intermediates in organic phosphite and triethylamine gave the corresponding qua-
synthesis. They are used widely in the synthesis of the ternary ammonium halide. The debromination of dibromo
1
2
dendrimers, caged compounds, cappedophanes and product in the reaction mixture to the monobromide 2a
3
cuppedophanes, etc. Generally, the preparation of such could be successfully achieved by treating with 2 equiva-
compounds is carried out by converting benzylic alcohols lents diethyl phosphite and a non-nucleophilic base, such
to benzylic bromides, however, the alcohols are common- as i-Pr NEt in THF at room temperature in 75% yield
2
ly very expensive or have to be synthesized following a (Table 1). Under these reaction conditions, polymethylat-
1
,3–5
cumbersome route.
Although the benzylic bromina- ed benzenes 1b–d, 2,6-lutidine (1e) and 4-methylbenzoni-
6
tion with N-bromosuccinimide (NBS) is an important trile (1f) were also brominated with 2 equivalents of NBS
method and the reaction gives 67% yield of benzyl bro- and then debrominated with diethyl phosphite and i-
mide from toluene, it is not satisfactory for three reasons. Pr NEt to give the monobromides 2b–f in satisfactory
2
First, in multiple brominations, e.g., of xylenes or mesity- yields and high purity (Scheme, Tables 1 and 2). Further
lene, yields are reduced significantly because of the inev- debromination of the monobromide was not observed by
1
itable dibromination or even polybromination. Secondly, TLC or H NMR analysis, except for 2e.
the byproducts, polybromides and monobromides have
In contrast to the reaction with the substrates carrying an
electron-withdrawing group (1a,b), the debromination of
polybrominated m-xylene could not be carried out com-
the same R values in TLC, which causes the purification
f
very difficult. Finally, the electron-withdrawing substitu-
ents and heteroatoms make the yields worse. For example,
pletely with 4 equivalents of reagents even in 5 days with
2
,6-lutidine was brominated in only 2% yield to 2,6-
portionwise addition of the reagents . When the reaction
temperature was increased to 60 °C, the conversion of po-
7
,8
bis(bromomethyl)pyridine in CCl4.
Many reports have demonstrated that diethyl phosphite– lybromide to monobromide took place completely in 40
triethylamine system is a good choice for debromination hours, but the yield (7%) fell greatly. Finally, we in-
of a,a-dibromomethyl arylketones, gem-dibromoalkenes creased the quantities of reagents to 8 equivalents and the
9
–12
and gem-dibromocyclopropanes
to the corresponding reaction progressed smoothly at room temperature. For
monobromo compounds in good yields. In the present mesitylene (1d), 4 equivalents of reagents were needed
OAc
OAc
OAc
2
NBS/Bz O2
HPO(OEt) /i-Pr NEt
2
2
CCl4
(Br)m
(Br)n
THF
Br
Br
1a
m, n=1,2,3
2a
Scheme
Synthesis 2001, No. 14, 26 10 2001. Article Identifier:
437-210X,E;2001,0,14,2078,2080,ftx,en;F03401SS.pdf.
Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881
1
©

SHORT PAPER
Preparation of Benzylic Bromides
Yield (%)
2079
Table 1 Preparation of Benzylic Bromides 2a–fa
Entry
Substrate
Time (h)
HPO(OEt)2/
Productb
i-Pr NEt (equiv)
2
found
75
reported
OAc
OAc
1
24
2:2
–
Br
Br
1
a
2a
2
24
2:2
79
2814
CO2Me
CO2Me
Br
Br
Br
1
1
b
c
2b
3
4
72
29
8:8
4:4
54
52
3115
Br
2c
2316
Br
Br
Br
Br
1
1
d
e
2
d
5c
6
a
5
4.4
4:4
76
82
27
Br
N
N
2e
15
3815
Br
NC
NC
1
f
2f
All reactions were carried out in THF at 25 °C under argon with 3 mmol of the substrate.
All compounds prepared showed physical and spectral data in accordance with their expected structures (see Table 2).
The debromination of this substrate could be monitored by TLC.
b
c
for complete debromination. However, the debromination morpholine formed the corresponding quaternary ammo-
of polybromides of o- and p-dimethylarenes was unsuc- nium halides with the monobromides. Tetrahydrofuran
cessful. For example, o-xylene and 3,4-dimethylphenyl was found to be the best solvent for the debromination as
acetate gave complicated mixtures and an undetectable compared to dichloromethane and no product was detect-
gum was obtained from the debromination of p-xylene ed in DMSO as solvent. The debromination could also be
and 1,2,4,5-tetramethylbenzene, respectively.
carried out neat without solvent.
Although the polybromides of 2,6-lutidine (1e) were com- In conclusion, we have developed a practical and efficient
pletely debrominated with 2 equivalents of reagents at 60 method to prepare monobromomethyl and meta bis- or
°
C, higher yield (76% vs. 50%) was obtained when 4 tris-bromomethyl benzenes, having various substituents
equivalents of reagents were used (Table 1). Because the or heteroatom, in satisfactory yields and high purity. This
polybromides are separable on TLC (silica gel), 1e was method overcomes the shortcomings of classical benzylic
subjected to further investigations to study the influence bromination with NBS.15
of reaction conditions. The results showed that the inor-
ganic base K CO also accelerated the debromination re-
action, but the debromination could not be carried out
when pyridine, 2,6-lutidine, 2,4,6-trimethylpyridine, N- sured using Bruker 300 MHz and 400 MHz spectrometers. IR
2
3
Melting points were determined on an electrothermal digital melt-
ing point apparatus and are uncorrected. H NMR spectra were mea-
1
methylmorpholine or proton sponge was used as the base spectra were recorded on a Nicolet Mx-1 spectrometer. Mass spec-
tra were recorded on a VG7070E, GC/MS/DS instrument. Elemen-
tal analyses were carried out on a Carlo Erba-1160 instrument. All
with diethyl phosphite. Moreover, pyridine and N-methyl-
Synthesis 2001, No. 14, 2078–2080 ISSN 0039-7881 © Thieme Stuttgart · New York

2
080
P. Liu et al.
SHORT PAPER
Table 2 Melting Points and Spectral Data of Benzylic Bromides 2a–f
Product
Mp (°C)
84–85
1H NMR (CDCl3)
d, J (Hz)
MS (70 eV, EI)
M/z (%)
IR (KBr)
cm
–
1
2
aa
b
2.26 (s, 3 H), 4.40 (s, 4 H),
322 (M + 2, 5), 280 (37), 241 (16), 1764 (C=O), 1614, 1589, 1451, 1369,
7
1
.04 (d, 2 H, J = 1.6), 7.23 (t, 199 (56), 120 (32), 91 (29), 43 (100) 1296, 1203, 1141, 1022, 982, 913, 693
H, J = 1.6)
2
95–97
3.93 (s, 3 H), 4.49 (s, 4 H),
322 (M + 2, 6), 291 (8), 241 (100), 1728 (C=O), 1604, 1436, 1318, 1231,
7
.61 (br s, 1 H), 7.99 (d, 2 H, 162 (43), 103 (24)
1108, 996, 902, 771, 698, 600
J = 1.6)
2c
2d
2e
2f
75–77
94–95b
87–88c
116–118
4.50 (s, 4 H), 7.32 (m, 3 H),
264 (M + 2, 10), 185 (89), 104 (100) 1485, 1439, 1263, 1209, 1163, 897, 798,
698, 583, 532
7
.44 (m, 1 H)
4.45 (s, 6 H), 7.35 (s, 3 H)
355 (M + 1, 17), 275 (100), 233
10), 196 (54), 115 (54), 91 (28)
1824, 1800, 1610, 1460, 1440, 1218,
1171, 1128, 986, 900, 862, 708
(
4.55 (s, 4 H), 7.39 (d, 2 H,
J = 7.8), 7.72 (t, 1 H, J = 7.8) (35), 78 (20)
265 (M + 2, 16), 184 (100), 105
1595, 1578, 1460, 1220, 1210, 1169,
1090, 1000, 962, 872, 820, 749
4.49 (s, 2 H), 7.53 (m, 2 H), 197 (M + 2, 4), 116 (100), 89 (18)
2225 (C∫N), 1605, 1504, 1411, 1289,
1230, 1097, 847, 743, 604
7
.66 (dd, 2 H, J = 2.1, 6.6)
a
b
c
Anal. Calcd for C H Br O : C, 37.31; H, 3.11; Br, 49.64. Found: C, 37.53; H, 3.23; Br, 50.00.
1
0
10
2
2
16
Lit. mp 94 °C.
4
Lit. mp 85–89 °C.
substrates and reagents were obtained commercially except 1a and
b, which were prepared by standard procedures. THF was distilled
(2) Otsuka, H.; Araki, K.; Matsumoto, H.; Harada, T.; Shinkai,
S. J. Org. Chem. 1995, 60, 4862.
1
from sodium/benzophenone. CCl was distilled and NBS was re-
crystallized before use.
(3) Vinod, T. K.; Hart, H. J. Org. Chem. 1991, 56, 5630.
(4) Newcomb, M.; Timko, J. M.; Walba, D. M.; Cram, D. J. J.
Am. Chem. Soc. 1977, 99, 6392.
4
Benzylic Bromides 2a–f; Genearl Procedure
NBS (10.8 g, 60 mmol) was added in three equal portions during 9
(5) Cochrane, W. P.; Pauson, P. L.; Stevens, T. S. J. Chem. Soc.
(C) 1968, 630.
h to a solution of 1 (10 mmol) in refluxing CCl (60 mL), each ad-
dition being followed by a few milligrams of benzoyl peroxide. The
mixture was cooled and filtered to remove the succinimide. The fil-
(6) Ziegler, K.; Spath, A.; Schaaf, E.; Schumann, W.;
Winkelmann, E. Liebigs Ann. Chem. 1942, 551, 80.
(7) Barnes, R. A.; Fale, H. M. J. Am. Chem. Soc. 1953, 75, 3830.
(8) The yields were somewhat improved by selective choice of
solvents and addition of Lewis acid, see: (a) Offermann,
W.; Vögtle, F. Synthesis 1977, 272. (b) Xue, G.-P.; He, Y.-
B.; Wu, C.-T. Chinese Chem. Lett. 1994, 5, 23. (c) Chem.
Abstr. 1994, 121, 9378.
4
trate was washed with aq NaHCO solution (30 mL) and brine (30
3
mL). After drying (Na SO ), the solvent was evaporated under re-
2
4
duced pressure and the residue was dissolved in anhyd THF (20
mL). To the resulting solution were added diethyl phosphite (15.4
mL, 120 mmol) and i-Pr NEt (20.8 mL, 120 mmol) at 0 °C under Ar
2
with stirring. The mixture was gradually warmed to r.t. and stirred
for 29 h (the reaction was monitored by H NMR). The mixture was
(9) Diwu, Z.; Beachdel, C.; Klaubert, D. H. Tetrahedron Lett.
1998, 39, 4987.
1
poured into ice/water and extracted with Et O (3 ¥ 40 mL). The or-
(10) Hirao, T.; Masunaga, T.; Ohshiro, Y.; Agawa, T. J. Org.
Chem. 1981, 46, 3745.
2
ganic layer was washed with 1 M HCl (except for 2e) and brine,
dried (Na SO ), filtered and evaporated to give the crude product.
The pure product was obtained by silica gel column chromatogra-
phy with petroleum ether (bp 60–90 °C) as eluent (Tables 1 and 2).
(11) (a) Hirao, T.; Masunaga, T.; Hayashi, K.; Ohshiro, Y.
Nippon Kagaku Kaishi 1987, 1277. (b) Chem. Abstr. 1988,
108, 94084.
2
4
(
(
(
12) Hirao, T.; Kohno, S.; Ohshiro, Y.; Agawa, T. Bull. Chem.
Soc. Jpn. 1983, 56, 1881.
Acknowledgement
13) Two equivalents of NBS were necessary for the complete
3
,14,15
bromination of the methyl groups; see also Ref.
We are grateful to the National Science Fund for Distinguished
Young Scholars of China (No. 20025205).
14) Löwik, D. W. P. M.; Weingarten, M. D.; Broekema, M.;
Brouwer, A. J.; Still, W. C.; Liskamp, R. M. J. Angew.
Chem. Int. Ed. 1998, 37, 1846.
(
15) Offermann, W.; Vögtle, F. J. Org. Chem. 1979, 44, 710; and
references cited therein.
References
(
1) (a) Chessa, G.; Scrivanti, A. J. Chem. Soc., Perkin Trans. 1
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001, 1488.
(16) Vögttle, F.; Zuber, M.; Lichtenthaler, R. G. Chem. Ber.
1973, 106, 712.
1
2
Synthesis 2001, No. 14, 2078–2080 ISSN 0039-7881 © Thieme Stuttgart · New York