Chapter 4
Oxybromination
Chapter 4
Oxybrominations using
oxone
71
Chapter 4
Oxybromination
Section A
Oxybromination of aromatic compounds
4.1. State of art
The classical direct bromination involves the use of potentially hazardous and difficult to
handle molecular bromine [1], sometimes with expensive transition metal-based catalysts [2].
These reactions involve several environmental drawbacks because of the toxic nature of the
reagents and the formation of hydrogen bromide as a byproduct which is corrosive, toxic and
pollutant to the environment. Moreover, while using bromine, only half of the Br atoms are
utilized and the other turns into hydrobromic acid, reducing the atom efficiency by 50%.
Recently, bromination of aromatic compounds has been reported using 1-butyl-3methylpyridinium tribromide [3], 2,4,4,6-tetrabromo-2,5-cyclohexadienone [4], Br2/SO2Cl2 [5],
hexamethylenetetramine-bromine [6], (Bmim)Br3 [7], NBS-ammonium acetate [8], NBSphotochemical [9], KBr-H2O2-titania-pillared zirconium phosphate and titanium phosphates [10],
iso-amyl
nitrate/HBr
[11],
N,N,N’,N’-tetrabromobenzene-1,3-disulfonylamide
[12],
N-
bromophthalimide [13], alkylbromide-NaH-DMSO [14]. However, many existing bromination
processes do not advance the goal of non-toxic, waste-free chemistry. Therefore, the
development of an efficient, ecofriendly, 100% utilization of bromine and selective reaction for
monobromination of aromatic compounds is still a major challenge in organic synthesis.
In this section of the chapter, bromination of various aromatic compounds in H2O and
MeOH at room temperature has been discussed (Scheme 4.1).
72
Chapter 4
Oxybromination
R
R
NH4Br, Oxone
MeOH or H2O, r.t.
Br
Scheme 4.1. Bromination of aromatic compounds
4.2. General experimental procedure
4.2.1. General information
All chemicals were reagent grade and were used without further purification. 1H NMR
spectra were recorded on a Gemini-200 MHz spectrometer in CDCl3 or DMSO-d6 with TMS as
the internal standard. Mass spectra were recorded on a Finnigan MAT 1020 mass spectrometer
operating at 70 eV. GC was carried out using Shimadzu (GC-14B) instrumentation. Column
chromatography was accomplished using silica gel (Acme, <200 mesh). Spectral data (1H NMR
and MS) of representative products are provided.
4.2.2. General procedure for the bromination of aromatic compounds
To a solution of aromatic compound (2 mmol) in MeOH or H2O (10 mL) were added
NH4Br (2.2 mmol) and oxone (2.2 mmol) and the mixture was stirred at room temperature for
the time shown in Table 4.2 and Table 4.3. After completion (as indicated by TLC), the reaction
mixture was filtered and the solvent evaporated under reduced pressure. The products were
purified by column chromatography over silica gel.
4.3. Results and discussion
4.3.1. Optimization of reaction conditions
Initially, we investigated the oxybromination of resorcinol with ammonium bromide as
the bromine source and oxone as the oxidant, in various solvents. The best results were obtained
with methanol, water or acetonitrile as solvent (Table 4.1). The reaction was complete within 10
73
Chapter 4
Oxybromination
minutes in water, but was less selective toward the para isomer compared to methanol and
acetonitrile. Using methanol, the reaction was complete in 30 minutes and the selectivity for the
para isomer was 97%, whilst the selectivity for the same isomer was 98%, after two hours, when
using acetonitrile as the solvent. Hydrogen peroxide (H2O2) as the oxidant (with acetic acid as
the solvent) gave inferior results to those obtained with oxone (Table 4.1). Furthermore,
ammonium bromide proved to be a superior bromine source compared to potassium bromide
(KBr) with both oxone and hydrogen peroxide as oxidants (Table 4.1).
To establish the general applicability of the NH4Br–oxone system, the bromination of a
number of aromatic compounds was investigated and the results are summarized in Table 4.2
and Table 4.3. The brominated products were identified on the basis of 1H NMR and mass
spectral data and by comparison with literature data [8,15].
This study included activated and inactivated aromatics as well as compounds of
moderate activity. All the reactions were performed at room temperature using equimolar
amounts (1.1 equivalents) of ammonium bromide and oxone and methanol or water as the
solvent. The reactions typically proceeded via selective monobromination, preferentially at the
para position.
74
Chapter 4
Oxybromination
Table 4.1. Optimization of the oxybromination of resorcinol
OH
OH
OH
Br
Br source, Oxidant
OH
a
+
Solvent, r.t.
OH
OH
Br
Br
2
Time Conversion
(min)
(%)b
3
Selectivity (Yield, %)c
2
3
1
Br source
(mmol)
Oxidant
(mmol)
Solvent
1
NH4Br
(2)
Oxone
(2.2)
CH3CN
120
99
85 (84)
15 (15)
2
NH4Br
(2.2)
Oxone
(2.2)
CH3CN
120
99
98 (97)
2 (2)
3
NH4Br
(2)
Oxone
(2.2)
MeOH
30
99
88 (87)
12 (12)
4
NH4Br
(2.2)
Oxone
(2.2)
MeOH
30
98
97 (95)
3 (3)
5
NH4Br
(2)
Oxone
(2.2)
H2O
10
99
53 (52)
47 (47)
6
NH4Br
(2.2)
Oxone
(2.2)
H2 O
10
99
86 (85)
14 (14)
7
NH4Br
(2)
H2O2
(2.2)
AcOH
120
99
67 (66)
33 (33)
8
NH4Br
(2.2)
H2O2
(2.2)
AcOH
120
94
92 (87)
8 (7)
9
KBr
(2)
Oxone
(2.2)
CH3CN
90
99
83 (82)
17 (17)
10
KBr
(2.2)
Oxone
(2.2)
CH3CN
90
97
95 (92)
5 (5)
11
KBr
(2)
Oxone
(2.2)
MeOH
60
99
77 (76)
23 (23)
12
KBr
(2.2)
Oxone
(2.2)
MeOH
60
98
93 (91)
7 (7)
Entry
75
Chapter 4
Oxybromination
13
KBr
(2.2)
Oxone
(2.2)
H2O
10
91
75 (68)
25 (23)
14
KBr
(2)
H2O2
(2.2)
AcOH
420
99
71 (70)
29 (29)
15
KBr
(2.2)
H2O2
(2.2)
AcOH
270
95
88 (84)
12 (11)
a
Reaction conditions: resorcinol (2 mmol), Br source, oxidant, solvent (10 mL), room temperature.
Conversions determined by GC.
1
c
The products were characterized by H NMR spectroscopy, mass spectrometry and quantified by GC.
b
4.3.2. Bromination of aromatic compounds using H2O as a solvent
Bromination of 2-methylresorcinol gave the para isomer, with respect to the hydroxy
groups, as the major product along with the dibrominated product (Table 4.2, entry 2). 1,3,5Trihydroxybenzene also provided the monobrominated derivative as the major product, along
with the dibrominated product (Table 4.2, entry 3). Reaction of 2-methoxyphenol gave the para
isomer (4-bromo-2-methoxyphenol) and 5-bromo-2-methoxyphenol in the ratio 40:56 (Table 4.2,
entry 4). 2-Hydroxynaphthalene furnished 1-bromo-2-hydroxynaphthalene after three hours with
66% yield (Table 4.2, entry 5). Interesting results were obtained with alkyl substituted aromatic
compounds which afforded ring-brominated products in water (Table 4.2, entries 6–10). 2Methylnaphthalene rendered 1-bromo-2-methylnaphthalene as the only product in water (Table
4.2, entry 6). In the case of isobutylbenzene α-brominated derivative, (1-bromo-2methylpropyl)benzene, was formed in water (Table 4.2, entry 8). Bromination of alkyl benzenes
required longer reaction times compared to those of the hydroxy benzene derivatives.
Bromobenzene, nitrobenzene and naphthalene proved unreactive even after prolonged
reaction times (Table 4.2, entries 11–13). Thus, less reactive aromatic substrates did not undergo
nuclear bromination under these conditions. The ability of the substrate to undergo the
76
Chapter 4
Oxybromination
bromination reaction would appear to depend on the electron density of the aromatic ring. The
results indicate that bromination favors formation of para-substituted products over the
corresponding ortho derivatives.
Table 4.2. Bromination of aromatic compounds using NH4Br and oxone in H2Oa
R
R
NH4Br, Oxone
H2O, r.t.
Br
Entry
Substrate
Product (Yield, %)b
Time
OH
OH
OH
Br
1
10 min
(85)
OH
(14)
OH
OH
Br
Br
OH
OH
OH
2
Br
25 min
(29)
(66)
OH
OH
OH
Br
Br
OH
OH
OH
Br
3
HO
HO
OH
HO
OH
Br
OH
OH
OMe
OH
Br
OH
4
(24)
(75)
5 min
OMe
(56)
OMe
(40)
45 min
Br
Br
Br
OH
5
OH
3h
(66)
77
Chapter 4
Oxybromination
CH 3
Br
6
24 h
7
4h
(75)
(66)
Br
Br
8
2h
9
4h
(53)
(72)
Br
10
(61)
40 min
Br
Br
11
-
24 h
NO2
a
12
24 h
13
24 h
-
-
Substrate (2 mmol), NH4Br (2.2 mmol), Oxone (2.2 mmol), H2O (10 ml), Room temperature.
GC yield.
b
78
Chapter 4
Oxybromination
4.3.3. Bromination of aromatic compounds using MeOH as a solvent
Bromination of 2-methylresorcinol gave the para isomer, with respect to the hydroxy
groups, as the major product in methanol along with a small amount of the corresponding
dibrominated product (Table 4.3, entry 2). 1,3,5-Trihydroxybenzene also furnished the
monobrominated derivative as the major product, along with a small amount of the
corresponding dibrominated product, in methanol (Table 4.3, entry 3). Reaction of 2methoxyphenol in methanol afforded the para isomer (4-bromo-2-methoxyphenol) and 5-bromo2-methoxyphenol in the ratio 77:22 (Table 4.3, entry 4). 2-Hydroxynaphthalene provided 1bromo-2-hydroxynaphthalene in methanol, the reaction was completed in 45 minutes and the
yield was 99% (Table 4.3, entry 5). Interesting results were obtained with alkyl substituted
aromatic compounds which gave ring-brominated products in methanol (Table 4.3, entries 6–10).
Monobromination occurred exclusively at the para-position relative to the alkyl group in
methanol as solvent (Table 4.3, entries 7–10). 2-Methylnaphthalene yielded 1-bromo-2methylnaphthalene as the only product (Table 4.3, entry 6). Different results were obtained in the
case of isobutylbenzene depending on the solvent. The ring-brominated product was obtained in
methanol
(Table
4.3,
entry
8),
whilst
the
α-brominated
derivative
(1-bromo-2-
methylpropyl)benzene, was formed in water (Table 4.2, entry 8). Bromination of alkyl benzenes
required longer reaction times compared to those of the hydroxy benzene derivatives. This
method was also suitable for the bromination of 4-hydroxycoumarin (Table 4.3, entry 11). In this
case, bromination took place at C-3 to give the corresponding product in very high yield.
Bromobenzene, nitrobenzene and naphthalene proved unreactive even after prolonged reaction
times (Table 4.3, entries 12–14). Thus, less reactive aromatic substrates did not undergo nuclear
bromination under these conditions. The ability of the substrate to undergo the bromination
79
Chapter 4
Oxybromination
reaction would appear to depend on the electron density of the aromatic ring. The results indicate
that bromination favors formation of para-substituted products over the corresponding ortho
derivatives.
Table 4.3. Bromination of aromatic compounds using NH4Br and oxone in MeOHa
R
R
NH4Br, Oxone
MeOH, r.t.
Br
Entry
Substrate
Product (Yield, %)b
Time
OH
OH
OH
Br
1
30 min
(95)
OH
(3)
OH
OH
Br
Br
OH
OH
OH
2
Br
30 min
(9)
(90)
OH
OH
OH
Br
Br
OH
OH
OH
Br
3
HO
HO
HO
OH
OH
Br
OH
OH
OMe
OH
Br
OH
4
(9)
(90)
30 min
OMe
(22)
OMe
(77)
3h
Br
Br
Br
5
OH
OH
45 min
(99)
80
Chapter 4
Oxybromination
CH 3
Br
6
24 h
7
18 h
(80)
(99)
Br
(92)
8
3h
Br
9
(99)
3h
Br
10
(85)
3h
Br
OH
OH
Br
11
(98)
45 min
O
O
O
O
Br
12
24 h
-
13
24 h
-
14
24 h
NO2
a
Substrate (2 mmol), NH4Br (2.2 mmol), Oxone (2.2 mmol), MeOH (10 ml), Room temperature.
GC yield.
b
81
Chapter 4
Oxybromination
Methyl (-CH3) and methylene (-CH2-) group attached aromatic compounds gave good
yields of ring brominated products in MeOH (Table 5.3, entries 6-10). An unexpected result was
observed when iso-propyl group attached aromatic compounds (cumene and p-cymeme)
subjected to bromination using the same reagent system. Instead of ring bromination, ether
formation was observed with cumene and p-cymene (Scheme 4.2).
OMe
68%
NH4Br (1.1 equiv)
Oxone (1.1 equiv)
OMe
MeOH (10 ml)
6 h, r.t.
47%
Scheme 4.2. Reaction of iso-propyl substituted aromatics with NH4Br and oxone in MeOH
4.3.4. Mechanism
The bromination of aromatic compounds with ammonium bromide in the presence of
oxone proceeds according to the stoichiometry shown in Scheme 4.3. It is believed that the
reaction proceeds via the formation of hypobromous acid (HOBr) which is very unstable due to
its pronounced ionic nature and is thus more reactive toward aromatic nuclei.
ArH+NH4Br+2KHSO5.KHSO4.K2SO4
ArBr+NH4OH+K2S2O8.KHSO4.K2SO4+H2O
Scheme 4.3. Reaction stoichiometry
82
Chapter 4
Oxybromination
4.4. Spectral data
4-Bromo-1,3-dihydroxybenzene [16]
OH
OH
Br
1
H NMR (200 MHz, CDCl3): δ 4.81 (bs, 1 H, OH), 5.49 (bs, 1 H, OH), 6.37 (dd, 1 H, J = 8.5, 2.7
Hz, ArH), 6.50 (d, 1 H, J = 2.7 Hz, ArH), 7.25 (d, 1 H, J = 8.5 Hz, ArH).
13
C NMR (50 MHz, CDCl3): δ 98.4, 103.5, 110.1, 132.4, 154.1, 156.9.
2,4-Dibromo-5-hydroxyphenol [16]
OH
Br
OH
Br
1
H NMR (200 MHz, CDCl3): δ 5.42 (s, 2 H, OH), 6.76 (s, 1 H, ArH), 7.61 (s, 1 H, ArH).
13
C NMR (50 MHz, CDCl3): δ 100.1, 103.6, 133.1, 153.9.
2-Methoxy-4-bromophenol [17]
OH
OMe
Br
1
H NMR (200 MHz, CDCl3): δ 3.83 (s, 3 H), 6.70 (d, 1 H, J = 7.92 Hz), 6.83-6.90 (m, 2 H), 8.3
(bs, 1 H).
13
C NMR (50 MHz, CDCl3): δ 56.2, 111.7, 114.3, 116.0, 124.2, 144.9, 147.4.
5-Bromo-2-methoxyphenol [18]
83
Chapter 4
Oxybromination
OH
OMe
Br
1
H NMR (200 MHz, CDCl3): δ 3.87 (s, 3 H), 6.71 (d, 1 H, J = 8.6 Hz), 6.97 (dd, 1 H, J = 8.6,
2.41 Hz), 7.07 (d, 1 H, J = 2.4 Hz).
13
C NMR (50 MHz, CDCl3): δ 56.6, 112.4, 113.8, 118.3, 123.3, 146.4, 147.0.
1-Bromo-2-naphthol [19]
Br
OH
1
H NMR (200 MHz, CDCl3): δ 7.23 (d, 1 H, J = 9.4 Hz), 7.29 (t, 1 H, J = 7.05 Hz), 7.48 (t, 1 H,
J = 8.62 Hz), 7.64 (d, 1 H, J = 8.62), 7.71 (d, 1 H, J = 7.83 Hz), 8.06 (d, 1 H, J = 8.6 Hz), 9.83
(bs, 1 H).
13
C NMR (50 MHz, CDCl3): δ 106.1, 117.1, 124.1, 125.3, 127.8, 128.2, 129.3, 129.7, 132.3,
150.6.
1-Bromo-2-methylnaphthalene [15d]
Br
1
H NMR (200 MHz, CDCl3): δ 2.61 (s, 3 H), 7.29 (d, 1 H, J = 8.3 Hz), 7.4 (ddd, 1 H, J = 7.9,
7.1, 0.9 Hz), 7.52 (ddd, 1 H, J = 8.5, 6.8, 1.1 Hz), 7.64 (d, 1 H, J = 8.3 Hz,), 7.72 (d, 1 H, J = 8.5
Hz), 8.25 (d, 1 H, J = 8.5 Hz).
+ 81
+ 79
MS (EI): m/z (%) = 222 [M , Br] (19), 220 [M , Br] (19), 141 (100).
1-Bromo-2,4-dimethylbenzene [20]
84
Chapter 4
Oxybromination
Br
1
H NMR (200 MHz, CDCl3): δ 2.26 (s, 3 H), 2.34 (s, 3 H), 6.80 (d, 1 H, J = 8.05 Hz), 6.99 (s, 1
H), 7.34 (d, 1 H, J = 8.05 Hz)
13
C NMR (50 MHz, CDCl3): δ 20.8, 22.7, 121.5, 128.2, 131.7, 132.0, 137.0, 137.4.
(1-Bromo-2-methylpropyl)benzene [15f]
Br
1
H NMR (200 MHz, CDCl3): δ 0.82 (d, 3 H, J = 6.6 Hz), 1.08 (d, 3 H, J = 6.6 Hz), 2.20-2.36 (m,
1 H), 4.65 (d, 1 H, J = 8.3 Hz), 7.15-7.35 (m, 5 H).
+ 81
+ 79
+
MS (EI): m/z (%) = 214 [M , Br] (12), 212 [M , Br] (12), 133 [M – Br] (67), 91 [PhCH2+]
(100).
1-Bromo-4-isobutylbenzene [15e]
Br
1
H NMR (200 MHz, CDCl3): δ 0.90 (d, 6 H, J = 6.6 Hz), 1.80-1.91 (m, 1 H), 2.45 (d, 2 H, J =
7.3 Hz), 7.09 (d, 2 H, J = 7.3 Hz), 7.20 (d, 2 H, J = 7.3 Hz).
+ 81
+ 79
+
+
MS (EI): m/z (%) = 214 [M , Br] (32), 212 [M , Br] (32), 169 [M – 43] (100), 91 [M – 121]
(27).
Bromomesitylene [21]
85
Chapter 4
Oxybromination
Br
1
H NMR (200 MHz, CDCl3): δ 2.22 (s, 3 H), 2.35 (s, 6 H), 6.83 (s, 2 H).
13
C NMR (50 MHz, CDCl3): δ 20.6, 23.6, 124.2, 129, 136.2, 137.8.
+ 79
+
+
MS (EI): m/z (%) = 200 [M+, 81Br] (21), 198 [M , Br] (21), 119 [M – 79] (100), 91 [M – 107]
(96),
1-bromo-2,4,5-trimethylbenzene [22]
Br
1
H NMR (200 MHz, CDCl3): δ 2.16 (s, 3 H), 2.18 (s, 3 H), 2.30 (s, 3 H), 6.93 (s, 1 H), 7.23 (s, 1
H).
3-Bromo-4-hydroxycoumarin [15g]
OH
Br
O
1
O
H NMR (200 MHz, DMSO-d6): δ 7.24–7.32 (m, 2 H), 7.54 (t, 1 H, J = 6.3 Hz), 7.96 (d, 1 H, J =
8.4 Hz).
+ 81
+ 79
MS (EI): m/z (%) = 242 [M , Br] (23), 240 [M , Br] (23), 211 (100).
2-Methoxy-2-phenylpropane [23]
86
Chapter 4
Oxybromination
O
1
H NMR (200 MHz, CDCl3): δ 1.51 (s, 6 H), 3.05 (s, 3 H), 7.18-7.23 (m, 1 H), 7.27-7.32 (m, 2
H), 7.35-7.39 (m, 2 H).
13
C NMR (50 MHz, CDCl3): δ 28.4, 51.1, 77.5, 126.2, 126.9, 128.9, 146.1.
P-(l-Methoxy)-isopropyltolue [24]
O
1
H NMR (200 MHz, CDCl3): δ 1.50 (s, 6 H), 2.34 (s, 3 H), 3.02 (s, 3 H), 7.08 (d, 2 H, J = 7.1
Hz), 7.25 (d, 2 H, J = 7.1 Hz).
87
Chapter 4
Oxybromination
4.5. References
1.
R. Taylor, Electrophilic Aromatic Substitution; Wiley: Chichester (1990).
2.
R. C. Larock, Comprehensive Organic Transformations: a Guide To Functional Group
Preparations; Wiley-VCH: New York (1989) 315.
3.
S. P. Borikar, T. Daniel, V. Paul, Tetrahedron Lett., 50 (2009) 1007.
4.
N. Gupta, G. L. Kad, Synth. Commun., 37 (2007) 3421.
5.
J. M. Gnaim, R. A. Sheldon, Tetrahedron Lett., 46 (2005) 4465.
6.
M. M. Heravi, N. Abdolhosseini, H. A. Oskooie, Tetrahedron Lett., 46 (2005) 8959.
7.
Z. G. Le, Z. C. Chen, Y. Hu, Q. G. Zheng, Chin. Chem. Lett., 16 (2005) 1007.
8.
B. Das, K. Venkateswarlu, A. Majhi, V. Siddaiah, K. R. Reddy, J. Mol. Catal. A: Chem.,
267 (2007) 30.
9.
P. K. Chhattise, A. V. Ramaswamy, S. B. Waghmode, Tetrahedron Lett., 49 (2008) 189.
10.
D. P. Das, K. Parida, Catal. Commun., 7 (2006) 68.
11.
L. Gavara, T. Boisse, B. Rigo, J. P. Henichart, Tetrahedron Lett., 64 (2008) 4999.
12.
R. G. Vaghei, H. Jalili, Synthesis, (2005) 1099.
13.
A. Khazaei, A. A. Mahesh, V. R. Safi, J. Chin. Chem. Soc., 52 (2005) 559.
14.
M. J. Guo, L. Varady, D. Fokas, C. Baldino, L. Yu, Tetrahedron Lett., 47 (2006) 3889.
15.
(a) Z.-G. Le, Z.-C. Chen, Y. Hu, Chin. J. Chem., 23 (2005) 1537. (b) P. Bovicelli, E.
Mincione, R. Antonioletti, R. Bernini, M. Colombari, Synth. Commun., 31 (2001) 2955.
(c) C. Venkatachalapathy, K. Pitchumani, Tetrahedron, 53 (1997) 2581. (d) A.
Podgorsek, S. Stavber, J. Iskra, M. Zupan, Tetrahedron, 65 (2009) 4429. (e) L. Jin, Y.
Zhao, L. Zhu, H. Zhang, A. Lei, Adv. Synth. Catal., 351 (2009) 630. (f) B. Meynhardt, U.
Luening, C. Wolff, C. Naether, Eur. J. Org. Chem., 9 (1999) 2327. (g) B. Talapatra, S. K.
88
Chapter 4
Oxybromination
Mandal, K. Biswas, R. Chakrabarti, S. K. Talapatra, J. Ind. Chem. Soc., 78 (2001) 765.
16.
K. Kotaro, M. Toshiyuki, H. Toshikazu, Tetrahedron Lett., 51 (2010) 340.
17.
L. Menini, L. A. Parreira, E. V. Gusevskaya, Tetrahedron Lett., 48 (2007) 6401.
18.
A. S. Paraskar, A. Sudalai, Tetrahedron, 62 (2006) 4907.
19.
K. Raju, K. Kulangiappar, M. A. Kulandainathan, U. Uma, R. Malini, A. Muthukumaran,
Tetrahedron Lett., 47 (2006) 4581.
20.
F. Habib, I. Nasser, K. Somayeh, G. Arash, G. Atefeh, Adv. Synth. Catal., 351 (2009)
1925.
21.
S. Fergus, S. J. Eustace, A. F. Hegarty, J. Org. Chem., 69 (2004) 4663.
22.
R. Wasylishen, T. Schaefer, R. Schwenk, Can. J. Chem., 48 (1970) 2885.
23.
J. A. Murphy, T. A. Khan, S. Zhou, D. W. Thomson, M. Mahesh, Angew. Chem. Int. Ed.,
44 (2005) 1356.
24.
B. Isidoro, T. Marcial, Tetrahedron, 48 (1992) 9967.
89
Chapter 4
Oxybromination
Section B
Oxybromination of carbonyl compounds
4.6. State of art
The most commonly used reagents for α-bromination of ketones include molecular
bromine [1], N-bromosuccinimide (NBS) [2] and cupric bromide [3]. Recently, various methods
have been reported using NBS-NH4OAc [4], NBS-photochemical [5], NBS-PTSA [6], NBSsilica supported sodium hydrogen sulfate [7], NBS-Amberlyst-15 [8], NBS-Lewis acids [9],
NBS-ionic liquids [10], MgBr2-(hydroxy(tosyloxy)iodo)benzene-MW [11], N-methylpyrrolidin2-one hydrotribromide (MPHT) [12], (CH3)3SiBr-KNO3 [13], BDMS [14] and NaBr [15].
Reagents used for the bromination of unsymmetrical acyclic ketones are NBS-NH4OAc [4],
NBS-photochemical [5] and NBS-PTSA [6] and all these methods provide a mixture of 1-bromo
(terminal) and 3-bromo ketones with predominant formation of 3-bromo product. Gaudry and
Marquet reported the selective terminal bromination of unsymmetrical acyclic ketone using
elemental bromine [16].
From the green chemistry point of view the use of elemental bromine has several
environmental drawbacks. The handling of liquid bromine, due to its hazardous nature, is
troublesome and special equipment and care is needed for the transfer of these materials in large
scale. Though all these methods provide good yields, most of them suffer from one or more
disadvantages such as long reaction times, harsh reaction conditions, use of hazardous chemicals
and cumbersome work-up procedures. The use of NBS is a better alternative for molecular
bromine, which does not produce HBr in this reaction; but it is expensive and generates organic
waste. Furthermore, most of these methods generally employ strongly acidic or basic conditions
and accompany undesirable formation of α,α-dibrominated products in significant amount.
90
Chapter 4
Oxybromination
Hence, the development of an efficient, eco-friendly, atom-economic (100% with respect to
bromine) and selective procedure for the α-monobromination of ketones remains a major
challenge for synthetic organic chemists.
In this section of the chapter, a highly efficient, environmentally safe and economic
method for selective α-monobromination of aralkyl, cyclic, acyclic, 1,3-diketones and β-keto
esters and α,α-dibromination of 1,3-diketones and β-keto esters without catalyst using
ammonium bromide as a bromine source and oxone as an oxidant has been discussed (Scheme
4.4).
O
O
R
R
Ar
Ar
O
R
MeOH
O
R
Br
O
NH 4Br,Oxone®
R
Br
O
O
RI
R = Alkyl/ Aryl
RI = Alkyl/ Aryl/ OR
O
RI
R
Br
Scheme 4.4. Bromination of carbonyl compounds
4.7. General experimental procedure
4.7.1. General information
All chemicals used were reagent grade and used as received without further purification.
1
H NMR spectra were recorded at 300, 400 and 500 MHz in CDCl3. The chemical shifts () are
reported in ppm units relative to TMS as an internal standard for 1H NMR. Coupling constants
(J) are reported in hertz (Hz) and multiplicities are indicated as follows: s (singlet), bs (broad
singlet), d (doublet), dd (doublet of doublet), t (triplet), m (multiplet). Mass spectra were
recorded under impact (EI) conditions at 70 eV. Column chromatography was carried out using
silica gel (finer than 200 mesh)
91
Chapter 4
Oxybromination
4.7.2. General procedure for monobromination of carbonyl compounds
Oxone (2.2 mmol) was added to the well stirred solution of substrate (2 mmol) and
NH4Br (2.2 mmol) in methanol (10 ml) and the reaction mixture was allowed to stir at room
temperature (or reflux temperature). After completion of the reaction, as monitored by TLC, the
reaction mixture was quenched with aqueous sodium thiosulfate and extracted with ethyl acetate
(3×25 ml). Finally, the combined organic layer was washed with water, dried over anhydrous
sodium sulfate, filtered and removal of solvent in vacuo yielded a crude residue, which was
further purified by column chromatography over silica gel (finer than 200 mesh) to afford pure
products. All the products were identified on the basis of 1H NMR and mass spectral data.
4.7.3. General procedure for dibromination of carbonyl compounds
Oxone (4.4 mmol) was added to the well stirred solution of substrate (2 mmol) and
NH4Br (4.4 mmol) in methanol (10 ml) and the reaction mixture was allowed to stir at room
temperature (or reflux temperature). After completion of the reaction, as monitored by TLC, the
reaction mixture was quenched with aqueous sodium thiosulfate and extracted with ethyl acetate
(3×25 ml). Finally, the combined organic layer was washed with water, dried over anhydrous
sodium sulfate, filtered and removal of solvent in vacuo yielded a crude residue, which was
further purified by column chromatography over silica gel (finer than 200 mesh) to afford pure
products. All the products were identified on the basis of 1H NMR and mass spectral data.
4.7.4. General procedure for dehydrogenation of tetralone and substituted tetralones
Oxone (2.2 mmol) was added to the well stirred solution of substrate (2 mmol) and
NH4Br (4.4 mmol) in DCM (10 ml) and the reaction mixture was allowed to stir at room
temperature (or reflux temperature). After completion of the reaction, as monitored by TLC, the
reaction mixture was quenched with aqueous sodium thiosulfate and extracted with DCM (3×25
92
Chapter 4
Oxybromination
ml). Finally, the combined organic layer was washed with water, dried over anhydrous sodium
sulfate, filtered and removal of solvent in vacuo yielded a crude residue, which was further
purified by column chromatography over silica gel (finer than 200 mesh) to afford pure products.
All the products were identified on the basis of 1H NMR and mass spectral data.
4.8. Results and discussion
4.8.1. Optimization of reaction conditions
Initially, the effect of different solvents on the -bromination of acetophenone was
studied using NH4Br/oxone system (Table 4.4). In methanol at room temperature, the reaction
completed within 7 h to give the -brominated product in 81% yield together with recovery of
starting material. The reaction in CH3CN, H2O gave less than 15% yield after 7 h and in case of
other solvents (DCM, CHCl3, CCl4, hexane, EtOH, ether and THF) the yields were negligible.
Among the solvents used, methanol appeared to be the most suitable in terms of maximum yield.
93
Chapter 4
Oxybromination
Table 4.4. α-Bromination of acetophenone: Effect of solventa
O
O
NH4Br, Oxone
Br
Solvent
1a
a
b
Entry
Solvent
NH4Br
Oxone
Yield (%)b
1
MeOH
2.2
2.2
81
2
CH3CN
,,
,,
12
3
H2O
,,
,,
13
4
DCM
,,
,,
-
5
CHCl3
,,
,,
-
6
CCl4
,,
,,
-
7
Hexane
,,
,,
-
8
EtOH
,,
,,
-
9
Ether
,,
,,
-
10
THF
,,
,,
-
11
MeOH
,,
1.1
33
Acetophenone (2 mmol), Solvent (10 ml), Room temperature, 7 h.
GC yield.
4.8.2. Bromination of aralkyl ketone
With the optimized conditions in hand, a variety of aralkyl ketones (acetophenone,
substituted acetophenones, acetonaphthone and substituted acetonaphthones) were subjected to
the bromination reaction to test the generality of this method and the results are summarized in
Table 4.5. All the reactions were performed using 2 mmol of substrate with 2.2 mmol of NH4Br
and 2.2 mmol of oxone in 10 ml methanol at room temperature (or reflux temperature).
94
Chapter 4
Oxybromination
It is interesting to mention the effect of reaction temperature on course of bromination,
high yields are obtained at reflux temperature in short reaction time compared to room
temperature. In order to determine the influence of the substitution on aromatic ring on the
reaction path with this reagent system, we studied the reaction with different substitutions on
phenyl ring of acetophenone and acetonaphthones. Presence of highly activating groups (Table
4.5, entries 17, 18 and 22) on phenyl ring favours nuclear bromination, whilst moderately
activating and deactivating groups favours the -bromination (Table 4.5, entries 2-13). Strong
electron-withdrawing groups (Table 4.5, entries 14 and 15) present on phenyl ring gave brominated product, along with substantial amount of -bromo dimethyl ketals. Propiophenone
provided the -brominated product with this reagent system, but yield was less even after longer
reaction time (Table 4.5, entry 19). 2-Hydroxy-1,4-naphthoquinone showed good reactivity with
this reagent system and furnished 3-bromo-2-hydroxy-1,4-naphthoquinone (1x) in high yield
within short reaction time (Table 4.5, entry 23).
95
Chapter 4
Oxybromination
Table 4.5. Bromination of aralkyl ketones using NH4Br and oxonea
Entry
Substrate
Time
Yield (%)b
Product
O
O
c
7h
15 mind
1
Br
81
97
Br
92
91
Br
84
96
1a
O
O
c
26 h
2.5 hd
2
1b
O
O
24 hc
40 mind
3
1c
O
O
Br
6 hc
2.5 hd
4
63
94
1d
O
O
5
Br
7 hc
1.5 hd
Et
Et
54
86
1e
O
O
Br
48 hc
4 hd
6
Br
1f
O
Br
O
Br
48 hc
2 hd
7
42
56
37 (28)e
73
Br
Br
1g
O
O
Br
48 hc
1.5 hd
8
37
98
Br
Br
1h
96
Chapter 4
Oxybromination
O
O
Br
48 hc
3 hd
9
Cl
50
73
Cl
1i
O
O
Br
c
10
47 h
2 hd
49
87
Cl
Cl
1j
O
O
Br
24 hc
2 hd
11
F
81
85
F
1k
O
O
Br
24 hc
2 hd
12
F
39 (34)e
83
F
1l
O
13
O
Br
44 hc
1.3 hd
F
F
89
97
1m
O
O
Br
48 hc
3 hd
14
NO2
14 (16)e
46 (14)e
NO2
1n
O
O
Br
c
15
24 h
1.5 hd
O2 N
8 (12)e
21 (34)e
O2N
1o
O
O
Br
c
16
NC
48 h
16 hd
38
35 (6)e
NC
1p
97
Chapter 4
Oxybromination
O
O
4.5 hc
1.5 hd
17
61 (26)f
48 (28)f
Br
OH
OH
1q
O
O
c
18
1h
5 mind
93
83
Br
NH2
NH2
1s
O
19
O
26 hc
7.5 hd
10
58
Br
1t
O
O
Br
c
20
24 h
1.25 hd
39
87
1u
O
O
Br
24 hc
20 mind
21
60
97
1v
O
O
40 minc
10 mind
22
O
97
94
O
Br
1w
O
OH
O
OH
23
3 hc
15 mind
Br
O
98
98
1x
O
a
Reaction conditions : Substrate (2 mmol), NH4Br (2.2 mmol), Oxone (2.2 mmol), Methanol (10 ml), Room or
Reflux temperature.
b
The products were characterized by 1H NMR, Mass spectra and quantified by GC.
c
Room temperature.
d
Reflux temperature.
e
-bromo dimethyl ketal. f 3-bromo-2-hydroxyacetophenone (1r).
98
Chapter 4
Oxybromination
4.8.3. Bromination of cyclic and acyclic ketones
Further, we studied the bromination of cyclic and acyclic ketones under similar reaction
conditions and results are summarized in Table 4.6. Cyclic ketones are reacted well under the
present reaction condition to furnish the corresponding -bromo ketone in good to excellent
yields, except 5-methoxy and 7-methoxytetralone. 5-Methoxytetralone afforded the respective
ring brominated product (2e) selectively and 7-methoxy-1-tetralone at room temperature forms
the corresponding -brominated (2f) and ring brominated (2g) products in the ratio of 17: 42 in
2.5 h and the same reaction at reflux temperature afforded a 42: 18 ratio within 1 h.
Interesting results were observed when unsymmetrical acyclic ketones subjected to the
bromination with this reagent system. On contrary to the earlier reports [8-10], bromination took
place at less substituted α-position predominantly (Table 4.6, entries 7-11).
99
Chapter 4
Oxybromination
Table 4.6. Bromination of various cyclic and acyclic ketones using NH4Br and oxonea
Entry
Substrate
Products (Yield (%))b
Time
O
O
c
Br
2h
30 mind
1
(65)
(80)
2a
O
O
6 hc
20 mind
2
Br
(92)
(98)
2b
O
O
Br
28 hc
2 hd
3
(77)
(77)
2c
O
O
Br
6 hc
20 mind
4
(79)
(95)
2d
O
Br
O
(90)
(87)
2 hc
20 mind
5
OMe
OMe
2e
O
MeO
MeO
2.5 hc
1 hd
6
Br
O
Br
(42)
(18)
(17)
(42)
2f
2g
O
O
O
Br
c
7
(80)
8h
(09)
Br
2h
O
8
O
MeO
2i
O
7 hc
50 mind
Br
O
(90)
(85)
Br
2j
100
2k
(06)
Chapter 4
Oxybromination
O
9
Ph
5 hc
30 mind
O
O
(10)
(21)
Br (65)
(71) Ph
Ph
Br
2l
10
2m
O
O
c
9h
1 hd
C4H9
O
C4H9
Br
(62) C4H9
(55)
(37)
(44)
Br
2n
11
O
C6H13
c
7h
20 mind
O
C6H13
2o
O
(71)
Br (76) C6H13
(28)
(23)
Br
2p
2q
Substrate (2 mmol), NH4Br (2.2 mmol), Oxone (2.2 mmol), Methanol (10 ml).
b
The products were characterized by 1H NMR, Mass spectra and quantified by GC.
c
Room temperature.
d
Reflux temperature.
a
4.8.4. Bromination of 1,3-diketones and -keto esters
Finally, we investigated the bromination of 1,3-dicarbonyl compounds under similar
reaction conditions. A variety of -unsubstituted 1,3-diketones and -keto esters were -mono
brominated and ,-dibrominated using NH4Br and oxone with excellent yields (Table 4.7,
entries 1-5). Similarly, -substituted--keto esters underwent -bromination smoothly under
similar conditions and afforded the corresponding -brominated product in high yields (Table
4.7, entries 6-8).
101
Chapter 4
Entry
Oxybromination
Table 4.7. Bromination of 1,3-dicarbonyl compounds using NH4Br and oxone
Substrate
Time
Products (Yield (%))a
O
1
O
Ph
O
Ph
40 minb
3 hc
O
Ph
O
Ph
Br
(94)
- Ph
Ph
O
-
Br
O
O
3c
O
3h
30 mind
O
O
3d
O
O
(75)
-
O
Br
3e
O
O
4
O
Ph
35 min
30 mind
Ph
Br
Br
O
(81)
-
O
Br
O
O
Ph
O
30 minb
Ph
3 hc
O
(90)
Ph
O
Br
O
O
O
Br
O
9 hb
(09)
(94)
Br
3j
O
O
(18)
(96)
3h
O
3i
O
Ph
Br
3g
.
5
O
O
(24)
(94)
3f
O
b
O
O
Br
O
(10)
(95)
O
b
3
Br
Br (80)
1 hb
40 mind
O
3b
O
2
(90)
Br Br
3a
O
O
O
O
(70)
Br
6
3k
O
O
O
O
7
5 hb
(87)
Ph
3l
O
O
O
8
O
Br
Ph
O
O
30 min
O
Br
b
O
(95)
3m
a
The products were characterized by 1H NMR, Mass spectra and quantified by GC. b Substrate (2 mmol), NH4Br (2.2 mmol), Oxone (2.2
mmol), Methanol (10 ml), Room temperature. c Substrate (2 mmol), NH4Br (4.4 mmol), Oxone (4.4 mmol), Methanol (10 ml), Reflux
temperature. d Room temperature.
102
Chapter 4
Oxybromination
4.8.5. Dehydrogenation of tetralone and substituted tetralones
Different results were observed in case of tetralone depending on the solvent. Reaction of
tetralone with NH4Br and oxone was tested in different chlorinated and non-chlorinated solvents
(Table 4.8). In non-chlorinated solvents like methanol, water, acetone, ethanol, iso-propanol and
ether selectively -brominated product (4a) was observed (Table 4.8, entries 1-6). In case of
chlorinated solvents like DCM, CHCl3, CCl4 and DCE along with -brominated product (4a),
dehydrogenated product i.e. 1-naphthol (4b) was also formed (Table 4.8, entries 7-10). The
highest yield of -brominated product (4a) was obtained in MeOH, whilst the corresponding
dehydrogenated product i.e. 1-naphthol (4b), was formed in DCM, 1 equivalent of tetralone with
1.1equivalent of NH4Br and 1.1equivalent of oxone in DCM yielded 65% of 4b, with 2.2
equivalents of NH4Br yielded 90% of 4b (Table 4.8, entry 20).
With the optimized conditions in hand, a variety of substituted tetralones were subjected
to the dehydrogenation reaction to test the generality of this method and the results are
summarized in Scheme 4.5. In case of 5,7-dimethyltetralone and 2-methyltetralone the
dehydrogenated product was formed in 31% and 27% respectively.
103
Chapter 4
Oxybromination
Table 4.8. Reaction of tetralone with NH4Br and oxone: Variation of solventsa
O
O
OH
Br
NH4Br, Oxone
+
Solvent
4a
Entry
Solvent
4b
NH4Br
(mmol)
Oxone
(mmol)
Time (h)
Yield (%)b
4a
4b
1
MeOH
2.2
2.2
6
93
-
2
H2O
2.2
2.2
6
37
-
3
Acetone
2.2
2.2
24
13
-
4
EtOH
2.2
2.2
24
53
-
5
i-PrOH
2.2
2.2
24
34
-
6
Ether
2.2
2.2
24
20
-
7
DCM
2.2
2.2
24
-
65
8
CHCl3
2.2
2.2
24
35
18
9
CCl4
2.2
2.2
48
11
-
10
DCE
2.2
2.2
24
-
40
11
MeOH
2.2
-
6
-
-
12
,,
,,
0.2
,,
10
-
13
,,
4.4
4.4
20c
71 (28)e
-
14
DCM
-
2.2
24
-
-
15
,,
0.2
2.2
,,
09
-
16
,,
0.55
,,
,,
-
-
17
,,
1.1
2.2
,,
-
17
18
,,
1.65
,,
,,
17
43
104
Chapter 4
a
e
Oxybromination
19
,,
2.2
4.4
,,
06
65
20
,,
4.4
2.2
,,
-
90
21
,,
,,
,,
,,d
-
-
Tetralone (2 mmol), Solvent (10 ml), Room temperature. b GC yield. c At reflux temperature. d At 0oC.
α,α-Dibromotetralone
OH
OH
O
RII
R
NH4Br,Oxone®
R
RII
RII
RI
4 R = H, RI = H, RII = H
5 R = H, RI = Me, RII = Me
6 R = Me, RI = H, RII = H
R
+
+
DCM
O
RII
Br
Br
RI
RI
RI
7
8
9
90
31
27
8
-
17
8
Scheme 4.5. Aromatization of tetralones
4.8.6. Mechanism
We propose a plausible reaction mechanism for the -bromination of ketones as shown in
Scheme 4.6. It is assumed that oxidation of bromide ion by peroxymonosulfate ion could give
the hypobromite ion, which in turn reacts with ketones to afford -brominated ketones.
HSO5- + Br-
HO-Br+
OH
O
+
SO42-
+
H
HO
Br
R
R
HO-Br+
- H2O
O
O
Br
R
R
Scheme 4.6. Plausible reaction mechanism
105
Chapter 4
Oxybromination
4.9. Spectral data
2-Bromo-1-phenylethanone (1a) [17]
m.p. 49-51 °C
1
H NMR (300 MHz, CDCl3): δ 4.40 (s, 2 H), 7.42-7.49 (m, 2 H), 7.54-7.6 (m, 1 H), 7.91-8.00
(m, 2 H).
MS (EI): m/z (%) = 200 [M+, 81Br] (13), 198 [M+, 79Br] (13), 105 (100), 91 (67), 77 (90).
2-Bromo-1-(2-methylphenyl)ethanone (1b) [31]
1
H NMR (300 MHz, CDCl3): δ 2.52 (s, 3 H), 4.34 (s, 2 H), 7.20-7.30 (m, 2 H), 7.40 (t, 1 H, J =
8.3 Hz), 7.66 (d, 1 H, J = 7.36 Hz).
2-Bromo-1-(3-methylphenyl)ethanone (1c) [38]
1
H NMR (300 MHz, CDCl3): δ 2.44 (s, 3 H), 4.36 (s, 2 H), 7.32-7.40 (m, 2 H), 7.72-7.78 (m, 2
H).
2-Bromo-1-(4-methylphenyl)ethanone (1d) [17]
m.p. 51-53 °C
1
H NMR (300 MHz, CDCl3): δ 2.42 (s, 3 H), 4.34 (s, 2 H), 7.26 (d, 2 H, J = 8.3 Hz), 7.86 (d, 2
H, J = 8.3 Hz).
MS (EI): m/z (%) = 214 [M+,
81
Br] (12), 212 [M+,
79
Br] (12), 119 (100), 105 (32), 91 (79), 77
(27), 65 (71).
2-Bromo-1-(4-ethylphenyl)ethanone (1e) [18]
1
H NMR (300 MHz, CDCl3): δ 1.25 (t, 3 H, J = 7.55 Hz), 2.72 (q, 2 H, J = 7.55 Hz), 4.35 (s, 2
H), 7.28 (d, 2 H, J = 8.3 Hz), 7.88 (d, 2 H, J = 8.3 Hz).
2-Bromo-1-(4-bromophenyl)ethanone (1h) [17]
m.p. 109-111 °C
106
Chapter 4
1
Oxybromination
H NMR (300 MHz, CDCl3): δ 4.34 (s, 2 H), 7.62 (d, 2 H, J = 8.4 Hz), 7.85 (d, 2 H, J = 8.4 Hz).
2-Bromo-1-(3-chlorophenyl)ethanone (1j) [19]
m.p. 39-42 °C
1
H NMR (300 MHz, CDCl3): δ 4.35 (s, 2 H), 7.42 (t, 1 H, J = 7.93 Hz), 7.56 (d, 1 H, J = 8.30
Hz), 7.84 (d, 1 H, J = 7.74 Hz), 7.94 (s, 1 H).
2-Bromo-1-(2-fluorophenyl)ethanone (1k) [20]
1
H NMR (300 MHz, CDCl3): δ 4.40 (s, 2 H), 7.17 (m, 1 H), 7.3-7.5 (m, 2 H), 7.81 (m, 1 H).
2-Bromo-1-(3-fluorophenyl)ethanone (1l) [39]
1
H NMR (300 MHz, CDCl3): δ 4.35 (s, 2 H), 7.30 (m, 1 H), 7.46 (m, 1 H), 7.66 (m, 1 H), 7.76
(m, 1 H).
2-Bromo-1-(4-fluorophenyl)ethanone (1m) [19]
m.p. 45-47 °C
1
H NMR (300 MHz, CDCl3): δ 4.33 (s, 2 H), 7.10-7.20 (m, 2 H), 7.95-8.05 (m, 2 H).
2-Bromo-1-(4-cyanophenyl)ethanone (1p) [21]
m.p. 90-93 °C
1
H NMR (300 MHz, CDCl3): δ 3.95 (s, 2 H), 7.74 (d, 2 H, J = 8.49 Hz), 8.12 (d, 2 H, J = 8.49
Hz).
1-(5-Bromo-2-hydroxyphenyl)ethanone (1q) [22]
m.p. 60-61 °C
1
H NMR (300 MHz, CDCl3): δ 2.62 (s, 3 H), 6.87 (d, 1 H, J = 8.87 Hz), 7.52 (dd, 1 H, J = 2.26,
8.87 Hz), 7.78 (d, 1 H, J = 2.26 Hz), 12.06 (s, 1 H).
1-(3-Bromo-2-hydroxyphenyl)ethanone (1r) [23]
107
Chapter 4
1
Oxybromination
H NMR (300 MHz, CDCl3): δ 2.65 (s, 3 H), 6.77 (t, 1 H, J = 8.3 Hz), 7.65-7.73 (m, 2 H), 12.84
(s, 1 H).
1-(2-Amino-5-Bromophenyl)ethanone (1s) [24]
m.p. 84-85 °C
1
H NMR (300 MHz, CDCl3): δ 2.55 (s, 3 H), 6.28 (bs, 2 H), 6.51 (d, 1 H, J = 9.06 Hz), 7.28 (dd,
1 H, J = 2.26, 9.06 Hz), 7.74 (d, 1 H, J = 2.26 Hz).
2-Bromo-1-phenylpropan-1-one (1t) [25]
1
H NMR (300 MHz, CDCl3): δ 1.90 (d, 3 H, J = 6.04 Hz), 5.24 (q, 1 H, J = 6.04 Hz), 7.46 (t, 2
H, J = 7.55 Hz), 7.56 (t, 1 H, J = 6.79 Hz), 8.00 (d, 2 H, J = 8.3 Hz).
MS (EI): m/z (%) = 214 [M+, 81Br] (46), 212 [M+, 79Br] (46), 105 (100), 77 (38), 51 (16).
2-Bromo-1-(1-naphthyl)ethanone (1u) [32]
1
H NMR (300 MHz, CDCl3): δ 4.48 (s, 2 H), 7.40-7.63 (m, 3 H), 7.80-7.90 (m, 2 H), 7.96 (d, 1
H, J = 8.12 Hz), 8.64 (d, 1 H, J = 8.49 Hz).
2-Bromo-1-(2-naphthyl)ethanone (1v) [26]
m.p. 82-84 °C
1
H NMR (300 MHz, CDCl3): δ 4.49 (s, 2 H), 7.50-7.63 (m, 2 H), 7.82-8.03 (m, 4 H), 8.47 (s, 1
H).
5-Bromo-6-methoxy-2-acetonaphthone (1w) [37]
m.p. 126-128 °C
1
H NMR (300 MHz, CDCl3): δ 2.68 (s, 3 H), 4.06 (s, 3 H), 7.33 (d, 1 H, J = 9.06 Hz), 7.92 (d, 1
H, J = 9.06 Hz), 8.02 (dd, 1 H, J = 1.7, 9.06 Hz), 8.19 (d, 1 H, J = 8.87 Hz), 8.36 (s, 1 H).
2-Bromocycloheptanone (2a) [17]
108
Chapter 4
1
Oxybromination
H NMR (300 MHz, CDCl3): δ 1.3-1.84 (m, 5 H), 1.86-2.12 (m, 3 H), 2.28-2.52 (m, 2 H), 2.8-
2.94 (m, 1 H), 4.30 (dd, 1 H, J = 5.28, 9.44 Hz).
2-Bromo-3,4-dihydro-2H-naphthalen-1-one (2b) [27]
m.p. 40-43 °C
1
H NMR (300 MHz, CDCl3) : δ 2.39-2.58 (m, 2 H), 2.89 (dt, 1 H, J = 4.15, 16.99 Hz), 3.25-3.40
(m, 1 H), 4.66 (t, 1 H, J = 4.15 Hz), 7.24 (d, 1 H, J = 7.74 Hz), 7.33 (t, 1 H, J = 7.74 Hz), 7.48
(td, 1 H, J = 1.32, 7.74 Hz), 8.05 (dd, 1 H, J = 0.94, 7.74 Hz).
MS (EI): m/z (%) = 226 [M+, 81Br] (10), 224 [M+, 79Br] (10), 144 (20), 118 (100), 90 (50).
8-Bromo-5-methoxy-3,4-dihydro-2H-naphthalen-1-one (2e) [28]
m.p. 52-53 °C
1
H NMR (300 MHz, CDCl3): δ 2.01-2.15 (m, 2 H), 2.63 (t, 2 H, J = 6.23 Hz), 2.87 (t, 2 H, J =
6.23 Hz), 3.84 (s, 3 H), 6.78 (d, 1 H, J = 8.68 Hz), 7.44 (d, 1 H, J = 8.68 Hz).
MS (EI): m/z (%) = 256 [M+, 81Br] (100), 254 [M+, 79Br] (100), 226 (72), 198 (50), 76 (27).
2-Bromo-7-methoxy-3,4-dihydro-2H-naphthalen-1-one (2f) [30]
m.p. 80-82 °C
1
H NMR (300 MHz, CDCl3) : δ 2.37-2.57 (m, 2 H), 2.82 (dt, 1 H, J = 3.96, 16.8 Hz), 3.19-3.33
(m, 1 H), 3.85 (s, 3 H), 4.65 (t, 1 H, J = 3.96 Hz), 7.05 (dd, 1 H, J = 2.83, 8.49 Hz), 7.15 (d, 1 H,
J = 8.49 Hz), 7.49 (d, 1 H, J = 2.83 Hz).
8-Bromo-7-methoxy-3,4-dihydro-2H-naphthalen-1-one (2g) [29]
m.p. 92-93 °C
1
H NMR (300 MHz, CDCl3): δ 2.02-2.13 (m, 2 H), 2.66 (t, 2 H, J = 6.24 Hz), 2.90 (t, 2 H, J =
6.24 Hz), 3.89 (s, 3 H), 6.95 (d, 1 H, J = 8.32 Hz), 7.11 (d, 1 H, J = 8.32 Hz).
MS (EI): m/z (%) = 256 [M+, 81Br] (100), 254 [M+, 79Br] (100), 226 (60), 198 (72).
109
Chapter 4
Oxybromination
1-Bromobutan-2-one (2h) [33]
1
H NMR (500 MHz, CDCl3): δ 1.10 (t, 3 H, J = 6.92 Hz), 2.67 (q, 2 H, J = 6.92 Hz), 3.80 (s, 2
H).
3-Bromobutan-2-one (2i) [33]
1
H NMR (500 MHz, CDCl3): δ 1.71 (d, 3 H, J = 6.92 Hz), 2.34 (s, 3 H), 4.32 (q, 1 H, J = 6.92
Hz).
1-Bromo-4-methylpentan-2-one (2j) [7]
1
H NMR (500 MHz, CDCl3): δ 0.95 (d, 6 H, J = 6.92 Hz), 2.14-2.22 (m, 1 H), 2.53 (d, 2 H, J =
6.92 Hz), 3.78 (s, 2 H).
1-Bromo-2-nonanone (2p) [17]
1
H NMR (500 MHz, CDCl3): δ 0.85-0.92 (m, 4 H), 1.22-1.40 (m, 8 H), 1.56-1.64 (m, 2 H), 2.64
(t, 2 H, J = 6.92 Hz), 3.78 (s, 2 H).
2-Bromo-1,3-diphenylpropane-1,3-dione (3a) [14]
m.p. 89-92 °C
1
H NMR (300 MHz, CDCl3): δ 6.40 (s, 1 H), 7.44 (t, 4 H, J = 7.55 Hz), 7.56 (t, 2 H, J = 7.55
Hz), 7.98 (d, 4 H, J = 7.55 Hz).
Ethyl-2-bromo-3-oxobutanoate (3e) [14]
1
H NMR (300 MHz, CDCl3): δ 1.33 (t, 3 H, J = 7.17 Hz), 2.43 (s, 3 H), 4.28 (q, 2 H, J = 7.17
Hz), 4.66 (s, 1 H).
Ethyl-2,2-dibromo-3-oxobutanoate (3f) [34]
1
H NMR (300 MHz, CDCl3): δ 1.37 (t, 3 H, J = 7.17 Hz), 2.58 (s, 3 H), 4.36 (q, 2 H, J = 7.17
Hz).
Benzyl-2-bromo-3-oxobutanoate (3g) [14]
110
Chapter 4
1
Oxybromination
H NMR (300 MHz, CDCl3): δ 2.38 (s, 3 H), 4.70 (s, 1 H), 5.22 (s, 2 H), 7.30-7.38 (m, 5 H).
Benzyl-2,2-dibromo-3-oxobutanoate (3h) [35]
1
H NMR (500 MHz, CDCl3): δ 2.51 (s, 3 H), 5.29 (s, 2 H), 7.30-7.38 (m, 5 H).
Ethyl-2-bromo-3-oxo-3-phenylpropanoate (3i) [14]
1
H NMR (300 MHz, CDCl3): δ 1.27 (t, 3 H, J = 6.79 Hz), 4.28 (q, 2 H, J = 6.79 Hz), 5.56 (s,
1H), 7.48 (t, 2 H, J = 6.79 Hz), 7.60 (t, 1 H, J = 6.79 Hz), 7.98 (d, 2 H, J = 6.79 Hz).
Ethyl-2,2-dibromo-3-oxo-3-phenylpropanoate (3j) [36]
1
H NMR (300 MHz, CDCl3): δ 1.17 (t, 3 H, J = 7.17 Hz), 4.28 (q, 2 H, J = 7.17 Hz), 7.44 (t, 2 H,
J = 6.79 Hz), 7.56 (t, 1 H, J = 6.79 Hz), 8.01 (d, 2 H, J = 6.79 Hz).
Ethyl-2-bromo-2-ethyl-3-oxobutanoate (3k) [14]
1
H NMR (300 MHz, CDCl3): δ 1.00 (t, 3 H, J = 6.93 Hz), 1.32 (t, 3 H, J = 6.93 Hz), 2.15-2.29
(m, 2 H), 2.38 (s, 3 H), 4.27 (q, 2 H, J = 6.93 Hz),
1-Bromo-2-oxo-cyclohexanecarboxylic Acid Ethyl Ester (3m) [14]
1
H NMR (300 MHz, CDCl3): δ 1.33 (t, 3 H, J = 7.55 Hz), 1.70-2.00 (m, 4 H), 2.16-2.27 (m, 1
H), 2.37-2.48 (m, 1 H), 2.78-3.00 (m, 2 H), 4.29 (q, 2 H, J = 7.55 Hz).
111
Chapter 4
Oxybromination
4.10. References
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(a) L. A. Bigelow, R. S. Hanslick, In Organic Synthesis; Wiley: New York, (1943)
Collect. Vol. 2, p. 244. (b) K. Hakam, M. Thielmann, T. Thielmann, E. Winterfeldt,
Tetrahedron, 43 (1987) 2035.
2.
(a) R. E. Boyd, C. R. Rasmussen, J. B. Press, Synth. Commun., 25 (1995) 1045. (b) S.
Karimi, K. G. Grohmann, J. Org. Chem., 60 (1995) 554. (c) D. P. Curran, E. Bosch, J.
Kaplan, M. N. Comb, J. Org. Chem., 54 (1989) 1826.
3.
(a) S. J. Coats, H. H. Wasserman, Tetrahedron Lett., 36 (1995) 7735. (b) A. V. R. Rao,
A. K. Singh, K. M. Reddy, K. R. Kumar, J. Chem. Soc., Perkin Trans.1, (1993) 3171.
4.
K. Tanemura, T. Suzuki, Y. Nishida, K. Satsumabayashi, T. Horaguchi, Chem. Commun.,
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S. S. Arbuj, S. B. Waghmode, A. V. Ramaswamy, Tetrahedron Lett., 48 (2007) 1411.
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I. Pravst, M. Zupan, S. Stavber, Tetrahedron, 64 (2008) 5191.
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B. Das, K. Venkateswarlu, G. Mahender, I. Mahender, Tetrahedron Lett., 46 (2005)
3041.
8.
H. M. Meshram, P. N. Reddy, K. Sadashiv, J. S. Yadav, Tetrahedron Lett., 46 (2005)
623.
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D. Yang, Y. L. Yan, B. Lui, J. Org. Chem., 67 (2002) 7429.
10.
H. M. Meshram, P. N. Reddy, P. Vishnu, K. Sadashiv, J. S. Yadav, Tetrahedron Lett., 47
(2006) 991.
11.
J. C. Lee, J. Y. Park, S. Y. Yoon, Y. H. Bae, S. J. Lee, Tetrahedron Lett., 45 (2004) 191.
12.
A. Bekaert, O. Provot, O. Rasolojaona, M. Alami, J. D. Brion, Tetrahedron Lett., 46
(2005) 4187.
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Chapter 4
13.
Oxybromination
G. K. S. Prakash, R. Ismail, J. Garcia, C. Panja, G. Rasul, T. Mathew, G. A. Olah,
Tetrahedron Lett., 52 (2011) 1217.
14.
A. T. Khan, M. A. Ali, P. Goswami, L. H. Choudhury, J. Org. Chem., 71 (2006) 8961.
15.
E.-H. Kim, B.-S. Koo, C.-E. Song, K.-J. Lee, Synth. Commun., 31 (2001) 3627.
16.
M. Gaudry, A. Marquet, Tetrahedron, 26 (1970) 5611.
17.
R. D. Patil, G. Joshi, S. Adimurthy, B. C. Ranu, Tetrahedron Lett., 50 (2009) 2529.
18.
K. Masaru, K. Minoru, K. Yoshimaro, N. Yoshimitsu, Heterocycles, 34 (1992) 747.
19.
K. Masaru, K. Minoru, K. Yoshimaro, Tetrahedron, 48 (1992) 67.
20.
G. Campiani, V. Nacci, S. Bechelli, S. M. Ciani, A. Garofalo, I. Fiorini, H. Wikstrom, P.
D. Boer, Y. Liao, P. G. Tepper, A. Cagnotto, T. Mennini, J. Med. Chem., 41 (1998) 3763.
21.
A. Tsuruoka, Y. Kaku, H. Kakinuma, I. Tsukada, M. Yanagisawa, K. Nara, T. Naito,
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A. T. Johnson, L. Wang, A. M. Standeven, M. Escobar, R. A. S. Chandraratna, Bioorg.
Med. Chem., 7 (1999) 1321.
23.
E. Verner, B. A. Katz, J. R. Spencer, D. Allen, J. Hataye, W. Hruzewicz, H. C. Hui, A.
Kolesnikov, A. Martelli, K. Radika, R. Rai, M. She, W. Shrader, P. A. Sprengeler, S.
Trapp, J. Wang, W. B. Young, R. L. Mackman, J. Med. Chem., 44 (2001) 2753.
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T. Nittoli, K. Curran, S. Insaf, M. D. Grandi, M. Orlowski, R. Chopra, A. Agarwal,
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A. Podgorsek, S. Stavber, M. Zupan, J. Iskra, Tetrahedron, 65 (2009) 4429.
113
Chapter 4
Oxybromination
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A. Latorre, A. Urbano, M. C. Carreno, Chem. Commun., (2009) 6652.
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P. S. Poon, A. K. Banerjee, J. Chem. Res., (2009) 737.
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M. Voets, I. Antes, C. Scherer, U. M. Vieira, K. Biemel, S. M. Oberwinkler, R. W.
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T. Sakurai, A. Kageyama, H. Hayashi, H. Inoue, Bull. Chem. Soc. Jpn., 65 (1992) 2948.
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W. Peter, B. Joachim, Liebigs Ann. Chem., 7 (1992) 669.
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H. Y. Choi, D. Y. Chi, Org. Lett., 5 (2003) 411.
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K. Kikushima, T. Moriuchi, T. Hirao, Tetrahedron, 66 (2010) 6906.
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C. H. Jean, T. Eliane, M. Philippe, C. Henri, Phosphorus, Sulfur Silicon Relat.
Elem., 25 (1985) 357.
38.
G. Nv, N. Francois, J. Catherine, B. Roland, L. J. Michel, P. Christophe, D. Pierre, T.
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0014958, (2006).
114
Chapter 4
Oxybromination
Section C
Oxybromination of olefins
4.11. State of art
Regioselective functionalization of olefins is an important process in synthetic organic
chemistry. In particular, selective introduction of two functional groups, such as hydroxybromo,
alkoxybromo and dibromo in a highly regio- and stereoselective manner remains important and
challenging task [1]. Bromohydrins are usually prepared by the ring opening of epoxides [2]
using hydrogen bromide or metal bromides. These procedures are generally associated with the
formation of byproducts such as vicinal dibromides, 1,2-diols and these methods also require
prior synthesis of epoxides. Apart from this, there are two general approaches for heterolytic
addition of water (or alcohol) and bromine to an olefinic bond. One, involves the use of
molecular bromine or N-bromoimides [3,6] and the other uses metal bromide or HBr along with
an oxidizing agent [4,5].
Classical bromination involves the use of hazardous elemental bromine, which is a
pollutant and generates hazardous HBr as byproduct. The use of N-bromoimide is a better
alternative for molecular bromine, which does not produce HBr in the bromination of olefins, but
they are expensive and generate organic waste. Another drawbacks of these methods are low
yield and long reaction times.
At present, oxidative bromination continues to be of great interest because it precludes
the use of volatile, hazardous bromine. A number of protocols are available to achieve
bromination of alkenes using Br- instead of Br2. The oxidative bromination requires a metal salt
as bromine source, an oxidizing agent and a catalyst to carry out the transformation. However,
such oxidative brominations involve the use of heavier metals in stoichiometric amounts and
115
Chapter 4
Oxybromination
often resulting in poor yields and selectivity (poor stereo selectivity and unwanted side products).
Most of the reported methods for such transformation rely on modification of molecular
bromine, N-bromoimides or metal salts with an oxidizing agent, whilst the use of other reagents
have been less investigated [8,9]. In spite of the variety of methods available for the preparation
of vic-bromohydrins, bromo ethers and dibromides directly from olefins, many of them often
involve the use of expensive reagents and the formation of mixture of products resulting in low
yields of the desired products. The replacement of such reagents by non-toxic, mild, selective
and easy-to-handle reagents are very desirable and represents an important goal in the context of
clean synthesis.
In this section of the chapter, a very simple, mild and efficient method for direct synthesis
of bromohydrins, bromo ethers and dibromides from olefins using NH4Br as a bromine source
and oxone as an oxidant without catalyst in a highly regio- and stereo selective fashion in short
reaction time has been discussed (Scheme 4.7).
X
RI
RII
R I = Alkyl, Aryl
RII = H, CH 3, CH2OH,
COR, COOR, Ph
RII
RI
Br
NH4Br, Oxone
CH3CN:H2O (1:1)
or CH3CN
or ROH
X = OH, Br, OR
X
RII
RI
RI
RII
Br
Scheme 4.7. Cobromination and dibromination of olefins
116
Chapter 4
Oxybromination
4.12. General experimental procedure
4.12.1. General information
All chemicals used were reagent grade and used as received without further purification.
1
H NMR spectra were recorded at 300, 400 and 500 MHz and
13
C NMR spectra 75 MHz in
CDCl3 or DMSO-D6. The chemical shifts () are reported in ppm units relative to TMS as an
internal standard for 1H NMR and CDCl3 for
13
C NMR spectra. Coupling constants (J) are
reported in hertz (Hz) and multiplicities are indicated as follows: s (singlet), bs (broad singlet), d
(doublet), dd (doublet of doublet), t (triplet), m (multiplet). Mass spectra were recorded under
impact (EI) conditions at 70 eV. Column chromatography was carried out using silica gel (finer
than 200 mesh)
4.12.2. General procedure for the synthesis of bromohydrins:
To a solution of olefin (2 mmol) in CH3CN/H2O (1:1) (10 mL) were added NH4Br (2.2
mmol) and oxone (2.2 mmol) and the mixture was stirred at room temperature for the time
shown in Table 4.10. After completion (as indicated by TLC), the reaction mixture was filtered
and the solvent evaporated under reduced pressure. The products were purified by column
chromatography (Hexane/EtOAc, 90:10) over silica gel.
4.12.3. General procedure for the synthesis of dibromides:
To a solution of olefin (2 mmol) in CH3CN (10 mL) were added NH4Br (4.4 mmol) and
oxone (2.2 mmol) and the mixture was stirred at reflux temperature for the time shown in Table
4.12. After completion (as indicated by TLC), the reaction mixture was filtered and the solvent
evaporated under reduced pressure. The products were purified by column chromatography
(Hexane/EtOAc, 98:2) over silica gel.
117
Chapter 4
Oxybromination
4.12.4. General procedure for the synthesis of alkoxybromides:
To a solution of olefin (2 mmol) in alcohol (10 ml) were added NH4Br (2.2 mmol) and
oxone (2.2 mmol) and the mixture was stirred at room/reflux temperature for the time shown in
Table 4.14. After completion (as indicated by TLC), the reaction mixture was filtered and the
solvent evaporated under reduced pressure. The products were purified by column
chromatography over silica gel.
4.13. Results and discussion
4.13.1. Hydroxybromination of olefins
4.13.1.1. Optimization of reaction conditions
Initially, we investigated the bromohydroxylation of styrene with NH4Br and oxone in
various solvents such as CH3CN, DCM, CCl4, acetone and in combination with water (Table 4.9,
entries 1–17). The results obtained suggested that a mixture of acetonitrile and water in 1:1 ratio
was the best solvent system for bromohydrin formation (Table 4.9, entry 10).
118
Chapter 4
Oxybromination
Table 4.9. Optimization of the bromohydrins
OH
NH4Br, Oxone
Ph
Solvent
+
Ph
Ph
Br
1a
Entry
Br
3a
2a
Solvent
Br
Yield (%)a
Time
2a
3a
1
CH3CN
24 hb
-
60
2
Acetone
24 hb
2
48
3
DCM
24 hb
-
-
4
CHCl3
24 hb
9
11
5
CCl4
24 hb
-
-
6
H2O
2 minb
56
29
7
CH3CN:H2O
(9:1)
10 minb
65
30
8
CH3CN:H2O
(4:1)
10 minb
84
12
9
CH3CN:H2O
(3:2)
5 minb
85
10
10
CH3CN:H2O
(1:1)
2 minb
92
5
11
CH3CN:H2O
(2:3)
2 minb
83
12
12
CH3CN:H2O
(1:4)
2 minb
79
16
13
DCM:H2O
(1:1)
3 minb
10
48
14
DCM:H2O
(1:1)
30 minb
10
49
119
Chapter 4
a
b
Oxybromination
15
CHCl3:H2O
(1:1)
3 minb
8
55
16
CCl4:H2O
(1:1)
3 minb
12
40
17
Acetone:H2O
(1:1)
2 minb
85
10
Isolated yields.
Styrene (2 mmol), NH4Br (2.2 mmol), Oxone (2.2 mmol), Solvent (10 mL), rt.
4.13.1.2. Hydroxybromination of various olefins
Stimulated by these affirmative preliminary results, we decided to examine the NH4Broxone reagent system for hydroxybromination on a number of different activated, inactivated,
and moderately activated aromatic alkenes (Table 4.10, entries 2–7), asymmetric trans-alkenes
(Table 4.10, entries 10–14), symmetric trans/cis alkenes (Table 4.10, entries 15-16), cyclic and
linear
alkenes
(Table
4.10,
entries
17–22)
under
similar
reaction
conditions.
Hydroxybromination of all olefins took place quickly and completed in less than or equal to 5
minutes.
Olefin with highly activated arenes, that is, 4-methoxystyrene produced the
corresponding bromohydrin in excellent yield without the formation of ring or dibrominated
products (Table 4.10, entry 2). Olefins with moderately activated arenes (alkyl substituted), i.e.
4-methyl, 4-tert-butyl, and 2,4-dimethylstyrene yielded the corresponding bromohydrins in
moderate to high yields without forming any side-chain and ring brominated products (Table
4.10, entries 3–5). α-Methylstyrene gave the respective bromohydrin in a 97% yield, whereas 4chloro-α-methylstyrene afforded the corresponding bromohydrin in an 84% yield, along with a
substantial amount (10%) of dibrominated product (Table 4.10, entries 8 and 9).
120
Chapter 4
Oxybromination
Table 4.10. Synthesis of bromohydrins from various olefinsa
R
Entry
Olefin
OH
NH4Br, Oxone
RI
RI
R
CH3CN : H2O
(1:1)
Br
Time (min)
Yield (%)b
Product
OH
1
2
92 (2a)
Br
OH
2
1
O
Br
O
90 (2b)
OH
3
2
Br
79 (2c)
OH
4
1
Br
70 (2d)
OH
5
1
Br
66 (2e)
OH
6
2
Cl
Cl
Br
89 (2f)
OH
7
Br
3
Br
Br
89 (2g)
OH
8
2
Br
121
97 (2h)
Chapter 4
Oxybromination
OH
9
2
Br
84 (2i)
CH2OH
92c (2j)
COCH3
77c (2k)
COOH
80c (2l)
COOMe
63c (2m)
Cl
Cl
OH
10
CH2OH
Ph
3
Ph
Br
OH
11
COCH3
Ph
3
Ph
Br
OH
12
COOH
Ph
3
Ph
Br
OH
13
14
15
COOMe
Ph
4
Ph
Br
OH
Ph
Ph
COPh
COPh
Ph
3
62c (2n)
Br
Ph
OH
5
Ph
Ph
78c (2o)
Br
OH
16
Ph
Ph
Ph
2
Ph
15c (2o) 51d (2p)
Br
OH
17
Br
1
86 (2q)
OH
18
3
85 (2r)
Br
OH
19
1
89 (2s)
Br
122
Chapter 4
Oxybromination
OH
20
1
HO
84 (2t)
HO
Br
OH
21
CH3(CH2)9
CH3(CH2)9
2
Br
47 (2u)
Br
(14) (2uI)
CH3(CH2)9
OH
OH
CH3(CH2)4
22
1
CH3(CH2)4
Br
25c (2v)
OH
(36)c (2vI)
Br
CH3(CH2)4
O
O
OH
23
60
Br
O
-
O
OH
Br
24
O
O
60
O
O
a
Olefin (2 mmol), NH4Br (2.2 mmol), Oxone (2.2 mmol), CH3CN:H2O (1:1) (10 mL) at room
temperature.
b
Isolated yields.
c
Only erythro products.
d
threo product.
Regio- as well as stereoselective products were formed when asymmetric trans-alkenes
were subjected to bromohydroxylation and selectively corresponding erythro isomers were
obtained. trans-Cinnamyl alcohol provided the corresponding erythro bromohydrin in excellent
yield (Table 4.10, entry 10). When the conjugated ketones, acids and esters with a phenyl group
123
Chapter 4
Oxybromination
at the β-position were subjected to bromohydroxylation under similar reaction conditions,
furnished the corresponding erythro-β-hydroxy-α-bromo products (Table 4.10, entries 11–14).
The role of alkene geometry on the anti stereochemistry of the addition was tested by
conducting reactions with cis and trans-stilbene. Hydroxybromination of cis-stilbene were more
rapid than its trans-isomer and both gave anti addition products. trans-Stilbene produced erythro
hydroxybrominated (Table 4.10, entry 15) product. In case of cis-stilbene, significant amount of
corresponding erythro isomer was also obtained (Table 4.10, entry 16).
Not only aromatic olefins, cyclic and linear olefins also gave the corresponding
hydroxybrominated products in moderate to high yields (Table 4.10, entries 18-22). 1-Methyl-1cyclohexene and 3-methyl-3-butene-1-ol exclusively yielded the Markovnikov’s products (Table
4.10, entries 19 and 20), while with monosubstituted linear olefin, a limited anti-Markovnikov
product was also observed. For example, 1-dodecene resulted in the formation of Markovnikov
product (1-bromododecan-2-ol) as well as anti-Markovnikov product (2-bromododecan-1-ol) in
47% and 14% yields, respectively (Table 4.10, entry 21). Mixed regioselectivity is observed with
linear asymmetric trans-alkene, that is, trans-2-octene afforded the erythro-2-bromooctan-3-ol
and erythro-3-bromooctan-2-ol in the ratio of 25:36 (Table 4.10, entry 22).
Bromohydroxylation of electron-deficient double bond in 1,4-naphthoquinone and
coumarin failed to react (Table 4.10, entries 23 and 24). The attempted bromohydroxylation of
cholesterol and cholest-4-ene-3-one resulted in a complex mixture, which contained virtually no
bromohydrin.
124
Chapter 4
Oxybromination
4.13.2. Dibromination of olefins
4.13.2.1. Optimization of reaction conditions
From the investigated results of bromohydroxylation of styrene in different solvents, we
observed that acetonitrile turned out to be the best solvent for the formation of respective
dibrominated product in terms of yield and reaction rates (Table 4.9, entry 1). Thus, we
investigated the dibromination of styrene with NH4Br and oxone in CH3CN and in combination
with H2O at room temperature and reflux temperature (Table 4.11, entries 1-6). One equivalent
of styrene treated with 2.2 equiv of NH4Br and 1.1 equiv of oxone in CH3CN at room
temperature gave the corresponding dibrominated product with an 80% yield in 24 h (Table 4.11,
entry 2). Significant improvement in yield and decrease in reaction time were achieved by
conducting the reaction at reflux temperature and yielded the respective dibrominated product in
a 97% yield within 7 h (Table 4.11, entry 3).
125
Chapter 4
Oxybromination
Table 4.11. Optimization of the dibromides.
OH
NH4Br, Oxone
Ph
Solvent
+
Ph
Ph
Br
1a
a
Br
3a
2a
Br
Entry
Solvent
Time
Yield (%)a
2a
3a
1
CH3CN
5 hb
-
65
2
CH3CN
24 hc
-
80
3
CH3CN
7 hd
-
97
4
CH3CN:H2O
(10:0.25)
19hc
13
81
5
CH3CN:H2O
(10:0.5)
1.3hc
20
73
6
CH3CN:H2O
(10:1)
3 minc
33
60
Isolated yields.
b
Styrene (2 mmol), NH4Br (2.2 mmol), Oxone (2.2 mmol), Solvent (10 mL), Reflux temperature.
c
Styrene (2 mmol), NH4Br (4.4 mmol), Oxone (2.2 mmol), Solvent (10 mL), Room temperature.
d
Reflux temperature.
4.13.2.2. Dibromination of various olefins
After optimizing the reaction conditions, we have extended the process to a variety of
olefins, which are summarized in Table 4.12. They were conveniently converted into their
respective dibromides in excellent yields (in exception 4-methoxystyrene and α-methylstyrene
provided a mixture of unidentified products (Table 4.12, entries 2, 8 and 9)).
Dibromination of asymmetric trans-alkenes selectively formed the corresponding erythro
isomers (Table 4.12, entries 10–14). The role of alkene geometry on the anti stereochemistry of
the addition was tested by conducting reactions with cis and trans-stilbene. Dibromination of cis126
Chapter 4
Oxybromination
Table 4.12. Synthesis of dibromides from various olefinsa
R
Entry
Olefin
Br
NH4Br, Oxone
RI
RI
R
CH3CN
Br
Time (h)
Yield (%)b
Product
Br
1
7
97 (3a)
Br
Br
2
O
Br
O
-
Br
3
5
Br
95 (3c)
Br
4
4
Br
92 (3d)
Br
5
6
Br
90 (3e)
Br
6
13
Cl
Cl
Br
96 (3f)
Br
90 (3g)
Br
7
Br
13
Br
Br
8
10
Br
127
- (3h)
Chapter 4
Oxybromination
Br
9
10
Cl
Br
Cl
10
CH2OH
Ph
- (3i)
Br
12
CH2OH
98d (3j)
COCH3
90d (3k)
COOH
96d (3l)
COOMe
97d (3m)
COPh
97d (3n)
Ph
80d (3o)
Ph
95e (3p)
Ph
Br
11
Br
COCH3
Ph
15
Ph
Br
12
COOH
Ph
Br
13
Ph
Br
13
14
Br
COOMe
Ph
12
Ph
Ph
Br
Br
COPh
Ph
13
Br
Ph
Ph
Br
c
15
20
Ph
Br
Ph
16
Br
Ph
16c
Ph
Br
Br
17
8.3
18
c
Br
90 (3q)
Br
23
96 (3r)
Br
Br
19
20c
93 (3s)
Br
128
Chapter 4
Oxybromination
Br
20
4
HO
89 (3t)
HO
Br
Br
21
9
CH3(CH2)9
97 (3u)
CH3(CH2)9
Br
Br
22
96d (3v)
5
CH3(CH2)4
CH3(CH2)4
Br
O
O
Br
23
5
97 (3w)
O
Br
O
24
Br
10
O
23 (3x)
O
O
O
Olefin (2 mmol), NH4Br (4.4 mmol), Oxone (2.2 mmol), CH 3CN (10 mL) at reflux temperature.
b
Isolated yields.
c
Room temperature.
d
Only erythro products.
e
threo product.
a
stilbene were more rapid than its trans-isomer and both gave anti addition products. transStilbene produced meso dibrominated product (Table 4.12, entry 15), whereas cis-stilbene
afforded the corresponding threo dibrominated product (Table 4.12, entry 16). Cyclic and linear
alkenes furnished the corresponding dibrominated products in excellent yields (Table 4.12,
entries 18-22). In case of 1,4-naphthoquinone, instead of the expected dibrominated product, 2bromo-1,4-naphthoquinone was obtained in excellent yield (Table 4.12, entry 23).
129
Chapter 4
Oxybromination
4.13.3. Alkoxybromination of olefins
Initially methanolic solution of 1 equivalent of styrene was treated with 1.1 equivalents
of NH4Br and 1.1 equivalents of oxone at room temperature. After 50 minutes, complete
disappearance of styrene was observed (indicated by TLC) and 2-bromo-1-methoxystyrene was
formed in excellent yield (Table 4.13, entry 1). Here methanol served as the reaction medium
as well as the nucleophile source. Encouraged by this result, we decided to test the scope of
other alcohols in the alkoxybromination of styrene at room temperature and 80C and the data
obtained were presented in Table 4.13. Among the different alcohols, primary alcohols (such as
EtOH, n-PrOH and n-BuOH) gave the corresponding alkoxybromo products in good yields,
while secondary (2-PrOH, 2-BuOH) and tertiary alcohols (t-BuOH) provided poor yields due to
steric hindrance.
A number of different olefins were used as reactants in the methoxy and
ethoxybromination with NH4Br/oxone reagent system and results are summarized in Table 4.14.
Activated, inactivated and moderately activated aromatic olefins furnished the respective 2bromo-1-methoxy and 2-bromo-1-ethoxy products in high yields with-out forming any sidechain and ring brominated products (Table 4.14, entries 2-7).
Selectively erythro isomer was formed when asymmetric trans-alkenes were subjected
to alkoxybromination (Table 4.14, entries 10-14). In ethanol a distinct difference of products
were observed between room and reflux temperature with 4-phenyl-3-butene-2-one (5). At
reflux temperature, the corresponding -brominated product i.e. 1-bromo-4-phenyl-3-butene-2one (6) was obtained in 50% yield. On the contrary, reaction at room temperature resulted in
the formation of the respective double bond addition products i.e. ethoxybrominated (mixture
of erythro and threo (65:35)) and dibrominated product (Scheme 4.8).
130
Chapter 4
Oxybromination
Table 4.13. Alkoxybromination of styrene using various alcoholsa
OR
NH4Br, Oxone
Ph
Ph
ROH
Br
+
Ph
Br
1a
Entry
ROH
Br
4
3a
Yield (%)b
Time
4
3a
1
MeOH
50 minc
85
<5
2
EtOH
24 hc
64
14
3
,,
2.45 hd
84
<5
4
n-PrOH
24 hc
55
22
5
,,
11 hd
70
9
6
i-PrOH
24 hc
30
41
7
,,
10 hd
35
12
8
n-BuOH
24 hc
50
15
9
,,
10 hd
61
<5
10
2-BuOH
24 hc
6
12
11
,,
12 hd
8
<5
12
i-BuOH
24 hc
25
19
13
,,
12.3 hd
34
10
14
t-BuOH
42 hc
7
30
15
,,
10.3 hd
22
55
a
Styrene (2 mmol), NH4Br (2.2 mmol), Oxone (2.2 mmol), ROH (10 mL).
Isolated yields.
c
At room temperature.
d
At 80˚C.
b
131
Chapter 4
Oxybromination
Table 4.14. Methoxy and Ethoxybromination of various aromatic olefins
Entry
Olefin
R
Time
Yield (%)a
Me
Et
50 minb
2.45 hc
85 (4a)
84 (4A)
Me
Et
40 minb
2 hc
90 (4b)
92 (4B)
Me
Et
15 minb
45 minc
93 (4c)
84 (4C)
Me
Et
6 minb
1.15 hc
80 (4d)
75(4D)
Me
Et
15 minb
2.30 hc
76 (4e)
80 (4E)
Me
Et
30 minb
3 hc
91 (4f)
85 (4F)
Me
Et
1 hb
3 hc
84 (4g)
85 (4G)
Me
Et
13 minb
2.15 hc
92 (4h)
83 (4H)
Br
Me
Et
15 minb
2 hc
88 (4i)
72 (4I)
CH2OH
Me
Et
40 minb
3.30 hc
84e (4j)
89e (4J)
Product
OR
1
Br
OR
2
O
Br
O
OR
3
Br
OR
4
Br
OR
5
Br
OR
6
Br
Cl
Cl
OR
7
Br
Br
Br
OR
8
Br
OR
9
Cl
Cl
OR
10
Ph
CH2OH
Ph
Br
132
Chapter 4
Oxybromination
OR
11
COCH3
Ph
COOH
Ph
Br
OR
COOH
Ph
Br
12
13
COCH3
Ph
COOMe
Ph
76e (4k)
Me
Et
2.30 hb
24 hd
76e (4l)
31e (4L)
Me
Et
3 hb
24 hd
71e (4m)
20e (4M)
Me
Et
1 hb
3.3 hc
70e (4n)
75g (4N)
Me
Et
1.3 hb
3.3 hc
80e (4o)
76e (4O)
Me
Et
1 hb
1.3 hc
73f (4p)
40h (4P)
15 minb
4 hc
76 (4q)
81 (4Q)
COOMe
Ph
Br
OR
Ph
COPh
COPh
Ph
Br
OR
Ph
Ph
Ph
Ph
Br
OR
Ph
Ph
16
2.15 hb
OR
14
15
Me
Ph
Ph
Br
OR
Br
17
OR
Me
Et
18
Br
OR
Me
Et
5 minb
24 hd
64 (4r)
34(4R)
19
Br
OR
Me
Et
10 minb
24 hd
71 (4s)
66(4S)
Br
Me
Et
30 minb
2.3 hc
75 (4t)
63 (4T)
Br
Me
Et
45 minb
4 hc
60 (4u)
54 (4U)
OR
Me
Et
HO
20
HO
OR
CH3(CH2)9
21
CH3(CH2)9
Br
CH3(CH2)9
133
5 (4uI)
5 (4UI)
Chapter 4
Oxybromination
OR
CH3(CH2)4
22
CH3(CH2)4
Br
Br
CH3(CH2)4
Me
Et
45 minb
4 hc
24 (4v)
18 (4V)
39 (4vI)
33 (4VI)
Me
Et
OR
O
O
OR
23
Br
Me
Et
24 hb
5 hc
-
Me
Et
24 hb
10 hc
-
O
OR
O
Br
24
O
O
O
O
a
Isolated yields.
Olefin (2 mmol), NH4Br (2.2 mmol), Oxone (2.2 mmol), MeOH (10 mL) at room temperature.
c
Olefin (2 mmol), NH4Br (2.2 mmol), Oxone (2.2 mmol), EtOH (10 mL) at reflux temperature.
d
At room temperature.
e
erythro products.
f
threo products.
g
Molar ratio of erythro and threo 62:38, determined by 1H NMR.
h
Molar ratio of threo and erythro 33:67, determined by 1H NMR.
b
In case of symmetric olefins (Table 4.14, entries 15 and 16), trans-stilbene produced the
corresponding erythro-methoxybromo product (4o), whereas cis-stilbene gave the respective
threo-methoxybromo product (4p) in methanol. In ethanol trans-stilbene yielded selectively
erythro-ethoxybromo product (4O), whilst cis-stilbene furnished mixture of threo and erythro
isomers.
Cyclic and linear olefins also provided good results with this reagent system (Table 4.14,
entries 18-22). Exclusively Markovnikov’s product was formed with 1-methyl-1-cyclohexane
and 3-methyl-3-butene-1-ol (Table 4.14, entries 19-20). In case of linear olefins regioselectivity
was not observed, for example 1-dodecene gave the corresponding Markovnikov’s product
(4u/4U) and anti-Markovnikov product (4uI/4UI), while mixed regioselectivity was observed for
134
Chapter 4
Oxybromination
trans-2-octene (Table 4.14, entries 21-22). 1,4-Naphthoquinone furnished the 2-bromo-1,4naphthoquinone instead of the expected alkoxybrominated product in excellent yield (Table 4.14,
entry 23). The stereochemistry of the products is confirmed by comparing the 1H NMR coupling
constant data of protons attached to the carbons bearing -OR and -Br groups of the
alkoxybromides with previously reported data.
O
O
Ph
5
NH4Br, Oxone
Reflu
x
5h
Ph
EtOH
50%
6
OEt O
rt
24 h
Br
Br
+
Ph
Br
59%
7
O
Ph
Br
15%
3k
Scheme 4.8. Bromnination of 4-phenyl-3-butene-2-one in ethanol
4.13.4. Mechanism
The plausible reaction mechanism for cobromination and dibromination of olefins is
shown in Scheme 4.9. It is assumed that oxidation of bromide ion by peroxymonosulfate ion
could give the hypobromite ion, which further undergoes electrophilic addition onto the olefin to
give cyclic bromonium ion intermediate. The cyclic intermediate is attacked by the nucleophile
of corresponding solvent or bromide ion of ammonium bromide via the SN2 path way to yield
anti vicinal hydroxybromo / alkoxybromo / dibromo substituted product. In all aromatic olefins,
the incoming nucleophile entered at the benzylic position of cyclic intermediate exclusively. The
stereochemistry of the products are confirmed by comparing the 1H NMR coupling constant data
of protons attached to the carbons bearing –OH/-Br/-OR and –Br groups of the bromohydrins /
dibromides / alkoxybromides with previously reported data [5-12].
135
Chapter 4
Oxybromination
HSO5- + Br-
RII
HOBr +
HO- Br+
RI
RI
SO4-2
+ OH
Br
RII
RO- H+
R = H / Alkyl
NH4+ Br-
OR
Br
RII
RII
NH4OH + RI
RI
+ H2O
Br
Br
Scheme 4.9. The plausible reaction mechanism
4.14. Spectral data
2-Bromo-1-phenylethanol (2a) [5e]
1
H NMR (300 MHz, CDCl3):  2.61 (bs, 1 H), 3.45-3.63 (m, 2 H), 4.87 (dd, 1 H, J = 3.02, 9.06
Hz), 7.25-7.36 (m, 5 H).
C NMR (75 MHz, CDCl3):  40, 73.8, 125.9, 128.4, 128.6, 140.2.
13
MS (EI): m/z (%) = 202 [M + 2]+ (2), 200 [M+] (2), 121 (1), 107 (100), 91 (7), 79 (45), 65 (4), 51
(21).
2-Bromo-1-(4-methoxyphenyl)ethanol (2b) [5d]
1
H NMR (300 MHz, CDCl3):  2.50 (bs, 1 H), 3.43-3.59 (m, 2 H), 3.79 (s, 3 H), 4.79-4.86 (m, 1
H), 6.85 (d, 2 H, J = 8.3 Hz), 7.26 (d, 2 H, J = 8.3 Hz).
2-Bromo-1-(4-methylphenyl)ethanol (2c) [5d]
1
H NMR (400 MHz, CDCl3):  2.35 (s, 3 H), 2.54 (bs, 1 H), 3.42-3.60 (m, 2 H), 4.82 (dd, 1 H, J
= 3.75, 9.02 Hz), 7.12 (d, 2 H, J = 8.26 Hz), 7.22 (d, 2 H, J = 8.26 Hz).
C NMR (75 MHz, CDCl3):  21.1, 40.1, 73.6, 125.8, 129.3, 137.3, 138.2.
13
136
Chapter 4
Oxybromination
MS (EI): m/z (%) = 216 [M + 2]+ (4), 214 [M+] (4), 121 (100), 105 (15), 91 (70), 77 (51), 65
(26), 51 (13).
2-Bromo-1-(2,4-dimethylphenyl)ethanol (2d) [11]
1
H NMR (300 MHz, CDCl3):  2.30 (s, 6 H), 2.51 (bs, 1 H), 3.38-3.55 (m, 2 H), 5.04 (dd, 1 H, J
= 3.02, 9.06 Hz), 6.92 (s, 1 H), 7.00 (d, 1 H, J = 7.55 Hz), 7.35 (d, 1 H, J = 8.3 Hz).
MS (EI): m/z (%) = 230 [M + 2]+ (2), 228 [M+] (2), 135 (100), 119 (15), 107 (60), 91 (63), 77
(25), 65 (13), 51 (14).
2-Bromo-1-(4-chlorophenyl)ethanol (2f) [5e]
1
H NMR (300 MHz, CDCl3):  2.66 (bs, 1 H), 3.40-3.60 (m, 2 H), 4.85 (dd, 1 H, J = 3.21, 8.87
Hz), 7.25-7.35 (m, 4 H).
C NMR (75 MHz, CDCl3):  39.9, 72.8, 127.3, 129, 134.2, 138.8.
13
2-Bromo-1-(4-bromophenyl)ethanol (2g) [5e]
1
H NMR (500 MHz, CDCl3):  2.66 (bs, 1 H), 3.42-3.62 (m, 2 H), 4.85 (dd, 1 H, J = 3.12, 9.37
Hz), 7.25 (d, 2 H, J = 8.32 Hz), 7.49 (d, 2 H, J = 8.32 Hz)
1-Bromo-2-phenylpropan-2-ol (2h) [5d]
1
H NMR (300 MHz, CDCl3):  1.65 (s, 3 H), 2.47 (bs, 1 H), 3.66 (d, 1 H, J = 10.38 Hz), 3.72 (d,
1 H, J = 10.38 Hz), 7.24 (m, 1 H), 7.33 (m, 2 H), 7.42 (d, 2 H, J = 7.36 Hz).
C NMR (75 MHz, CDCl3):  28, 46.2, 73.1, 124.7, 127.5, 128.4, 144.1.
13
MS (EI): m/z (%) = 216 [M + 2]+ (0.5), 214 [M+] (0.5), 121 (100), 105 (22), 91 (39), 77 (44), 51
(43).
erythro-2-Bromo-3-hydroxy–3-phenylpropan-1-ol (2j) [5d]
1
H NMR (300 MHz, CDCl3):  3.82 (dd, 1 H, J = 5.28, 12.84 Hz), 3.96 (dd, 1 H, J = 5.28, 12.84
Hz), 4.20 (ddd, 1 H, J = 4.53, 5.2, 6.04 Hz), 4.95 (d, 1 H, J = 6.04 Hz), 7.22-7.38 (m, 5 H).
137
Chapter 4
Oxybromination
C NMR (75 MHz, CDCl3):  59.3, 64.1, 76.7, 126.5, 128.4, 128.5, 140.2.
13
erythro-3-Bromo-4-hydroxy–4-phenylbutan-2-one (2k) [1d]
1
H NMR (300 MHz, CDCl3):  2.37 (s, 3 H), 3.34 (bs, 1 H), 4.30 (d, 1 H, J = 8.68 Hz), 4.98 (d,
1 H, J = 8.68 Hz), 7.24-7.38 (m, 5 H).
erythro-2-Bromo-3-hydroxy-3-phenylpropanoic aicd (2l) [7]
1
H NMR (300 MHz, DMSO-D6):  4.16 (d, 1 H, J = 9.44 Hz), 4.88 (d, 1 H, J = 9.44 Hz), 7.23-
7.46 (m, 5 H).
erythro-Methyl-2-bromo-3-hydroxy-3-phenylpropionate (2m) [10a]
1
H NMR (300 MHz, CDCl3):  3.38 (bs, 1 H), 3.78 (s, 3 H), 4.27 (d, 1 H, J = 8.49 Hz), 4.99 (d, 1
H, J = 8.49 Hz), 7.24-7.38 (m, 5 H).
C NMR (75 MHz, CDCl3):  47.3, 53.1, 75.1, 126.9, 128.5, 128.7, 138.9, 169.8.
13
MS (EI): m/z (%) = 260 [M + 2]+ (0.5), 258 [M+] (0.5), 107 (100), 91 (28), 79 (70), 51 (28).
erythro-2-Bromo-3-hydroxy-1,3-diphenylpropan-1-one (2n) [7]
1
H NMR (300 MHz, CDCl3):  3.36 (bs, 1 H), 5.12 (d, 1 H, J = 8.3 Hz), 5.28 (d, 1 H, J = 8.3
Hz), 7.3-7.5 (m, 7 H), 7.58 (t, 1 H, J = 7.36, 14.73 Hz), 8.01 (d, 2 H, J = 7.36 Hz).
C NMR (75 MHz, CDCl3):  47.8, 74.7, 127.2, 128.2, 128.4, 128.6, 128.8, 128.9, 134.1, 134.5,
13
139.3, 194.5.
erythro-2-Bromo-1,2-diphenylethanol (2o) [10f]
1
H NMR (300 MHz, CDCl3):  2.30 (bs, 1 H), 5.03 (d, 1 H, J = 6.7 Hz), 5.15 (d, 1 H, J = 6.7
Hz), 7.2-7.35 (m, 10 H).
C NMR (75 MHz, CDCl3):  58.9, 78.1, 127, 128.2, 128.3, 128.4, 128.7, 128.9, 137.6, 139.7.
13
threo-2-Bromo-1,2-diphenylethanol (2p) [10f]
138
Chapter 4
1
Oxybromination
H NMR (300 MHz, CDCl3):  2.94 (bs, 1 H), 4.97 (d, 1 H, J = 9.06 Hz), 5.06 (d, 1 H, J = 9.06
Hz), 7.03-7.20 (m, 10 H).
C NMR (75 MHz, CDCl3):  64.3, 78.3, 126.8, 128.2, 128.3, 128.4, 128.5, 138.2, 138.6.
13
trans-2-Bromo-1-hydroxyindane (2q) [5d]
1
H NMR (500 MHz, CDCl3):  3.20 (dd, 1 H, J = 7.95, 15.91 Hz), 3.55 (dd, 1 H, J = 5.96, 15.91
Hz), 4.20-4.26 (m, 1 H), 5.27 (d, 1 H, J = 5.59 Hz), 7.16-7.42 (m, 5 H).
C NMR (75 MHz, CDCl3):  40.4, 54.5, 83.3, 124, 124.5, 127.6, 129, 139.7, 141.6
13
trans-2-Bromocyclohexan-1-ol (2r) [5d]
1
H NMR (300 MHz, CDCl3):  1.20-1.46 (m, 3 H), 1.64-1.92 (m, 3 H), 2.14 (m, 1 H), 2.35 (m, 1
H), 2.60 (bs, 1 H), 3.50-3.62 (m, 1 H), 3.80-3.92 (m, 1 H).
trans-2-Bromo-1-methylcyclohexan-1-ol (2s) [10b]
1
H NMR (300 MHz, CDCl3):  1.33 (s, 3 H), 1.35-2.29 (m, 9 H), 4.10 (dd, 1 H, J = 4.15, 11.14
Hz).
1-Bromododecan-2-ol (2u) [10c]
1
H NMR (300 MHz, CDCl3):  0.88 (t, 3 H, J = 6.79 Hz), 1.22-1.57 (m, 18 H), 2.05 (bs, 1 H),
3.3-3.38 (m, 1 H), 3.50 (dd, 1 H, J = 3.77, 10.57 Hz), 3.68-3.79 (m, 1 H).
C NMR (75 MHz, CDCl3):  14.1, 22.6, 25.6, 29.3, 29.5, 29.6, 29.6, 31.9, 35.1, 40.7, 71.1.
13
2-Bromododecan-1-ol (2uI) [10c]
1
H NMR (300 MHz, CDCl3):  0.88 (t, 3 H, J = 6.98 Hz), 1.22-1.60 (m, 16 H), 1.78-1.88 (m, 2
H), 1.97 (bs, 1 H), 3.65-3.82 (m, 2 H), 4.04-4.14 (m, 1 H).
C NMR (75 MHz, CDCl3):  14.1, 22.7, 27.4, 29, 29.3, 29.4, 29.5, 29.6, 31.9, 34.8, 60.2, 67.3.
13
erythro-2-Bromooctan-3-ol (2v) [5d]
139
Chapter 4
1
Oxybromination
H NMR (300 MHz, CDCl3):  0.91 (t, 3 H, J = 6.79 Hz), 1.22-1.60 (m, 8 H), 1.64 (d, 3 H, J =
6.79 Hz), 1.96 (bs, 1 H), 3.64-3.72 (m, 1 H), 4.17-4.26 (m, 1 H).
erythro-3-Bromooctan-2-ol (2vI) [5d]
1
H NMR (300 MHz, CDCl3):  0.91 (t, 3 H, J = 6.79 Hz), 1.24 (d, 3 H, J = 6.04 Hz), 1.27-1.82
(m, 8 H), 1.99 (bs, 1 H), 3.73-3.82 (m, 1 H), 4.08-4.16 (m, 1 H).
C NMR (75 MHz, CDCl3):  14, 19, 22.4, 27.5, 31.1, 33.9, 66.2, 70.3.
13
1,2-Dibromo-1-phenylethane (3a) [5e]
1
H NMR (300 MHz, CDCl3):  3.98-4.08 (m, 2 H), 5.06-5.12 (dd, 1 H, J = 5.28, 5.47 Hz), 7.28-
7.40 (m, 5 H).
1,2-Dibromo-1-(4-methylphenyl)ethane (3c) [5b]
1
H NMR (300 MHz, CDCl3):  2.36 (s, 3 H), 4.01-4.06 (m, 2 H), 5.08 (dd, 1 H, J = 5.28, 10.57
Hz), 7.15 (d, 2 H, J = 7.55 Hz), 7.26 (d, 2 H, J = 7.55 Hz)
1,2-Dibromo-1-(4-chlorophenyl)ethane (3f) [5b]
1
H NMR (300 MHz, CDCl3):  3.89-4.08 (m, 2 H), 5.06 (dd, 1 H, J = 5.09, 11.33 Hz), 7.28-7.40
(m, 4 H).
C NMR (75 MHz, CDCl3):  34.6, 49.5, 128.9, 129.1, 134.9, 137.1.
13
erythro-2,3-Dibromo-3-phenylpropan-1-ol (3j) [6]
1
H NMR (300 MHz, CDCl3):  4.16-4.36 (m, 2 H), 4.61-4.70 (m, 1 H), 5.22 (d, 1 H, J = 11.14
Hz), 7.25-7.40 (m, 5 H).
MS (EI): m/z (%) = 296 [M + 4]+ (0.5), 294 [M + 2]+ (1), 292 [M+] (0.5), 91 (100), 77 (81), 51
(62).
erythro-3,4-Dibromo-4-phenylbutan-2-one (3k) [5c]
140
Chapter 4
1
Oxybromination
H NMR (300 MHz, CDCl3):  2.45 (s, 3 H), 4.86 (d, 1 H, J = 11.52 Hz), 5.26 (d, 1 H, J = 11.52
Hz), 7.28-7.45 (m, 5 H).
erythro-2,3-Dibromo-3-phenylpropanoic aicd (3l) [10d]
1
H NMR (300 MHz, DMSO-D6):  4.84 (d, 1 H, J = 11.7 Hz), 5.32 (d, 1 H, J = 11.7 Hz), 7.30-
7.47 (m, 5 H).
erythro-Methyl-2,3-dibromo-3-phenylpropionate (3m) [5e]
1
H NMR (500 MHz, CDCl3):  3.89 (s, 3 H), 4.77 (d, 1 H, J = 11.7 Hz), 5.29 (d, 1 H, J = 11.7
Hz), 7.25-7.40 (m, 2 H).
C NMR (75 MHz, CDCl3):  46.7, 50.8, 53.4, 128, 128.9, 129.4, 137.5, 168.3.
13
MS (EI): m/z (%) = 324 [M + 4]+ (0.5), 322 [M + 2]+ (1), 320 [M+] (0.5), 103 (100), 91 (3), 77
(73), 51 (76).
erythro-2,3-Dibromo-1,3-diphenylpropan-1-one (3n) [5c]
1
H NMR (300 MHz, CDCl3):  5.54 (d, 1 H, J = 11.33 Hz), 5.77 (d, 1 H, J = 11.33 Hz), 7.34-
7.70 (m, 8 H), 8.08 (d, 2 H, J = 7.55 Hz).
C NMR (75 MHz, CDCl3):  46.8, 49.8, 128.3, 128.8, 128.9, 129, 129.3, 134.2, 134.4, 138.2,
13
191.2
meso-1,2-Dibromo-1,2-diphenylethane (3o) [5a]
1
H NMR (300 MHz, CDCl3):  5.40 (s, 2 H), 7.30-7.42 (m, 6 H), 7.45-7.50 (m, 4 H)
threo-1,2-Dibromo-1,2-diphenylethane (3p) [5a]
1
H NMR (300 MHz, CDCl3):  5.42 (s, 2 H), 7.14 (s, 10 H).
trans-1,2-Dibromoindane (3q) [5e]
1
H NMR (300 MHz, CDCl3):  3.24 (d, 1 H, J = 17.64 Hz), 3.80 (dd, 1 H, J = 5.88, 17.64 Hz),
4.83 (d, 1 H, J = 4.9 Hz), 5.58 (s, 1 H), 7.20-7.33 (m, 4 H).
141
Chapter 4
Oxybromination
trans-1,2-Dibromocyclohexane (3r) [5d]
1
H NMR (300 MHz, CDCl3):  1.48-1.61 (m, 2 H), 1.75-1.96 (m, 4 H), 2.39-2.53 (m, 2 H), 4.48
(s, 2 H).
1,2-Dibromododecane (3u) [12]
1
H NMR (300 MHz, CDCl3):  0.88 (t, 3 H, J = 6.98 Hz), 1.24-1.65 (m, 16 H), 1.69-1.86 (m, 1
H), 2.09-2.21 (m, 1 H), 3.59 (t, 1 H, J = 10.19 Hz), 3.84 (dd, 1 H, J = 4.34, 10.19 Hz), 4.08-4.19
(m, 1 H).
C NMR (75 MHz, CDCl3):  14.1, 22.7, 26.7, 28.8, 29.3, 29.4, 29.5 29.6, 31.9, 36, 36.3, 53.1.
13
erythro-2,3-Dibromooctane (3v) [4a]
1
H NMR (300 MHz, CDCl3):  0.92 (t, 3 H, J = 6.79 Hz), 1.24-1.70 (m, 6 H), 1.82-1.96 (m, 4
H), 2.08-2.20 (m, 1 H), 4.02-4.10 (m, 1 H), 4.12-4.23 (m, 1 H).
C NMR (75 MHz, CDCl3):  14, 22.4, 25, 26.6, 31, 37.1, 52.4, 61.8.
13
2-Bromo-1,4-naphthoquinone (3w) [10e]
1
H NMR (300 MHz, CDCl3):  7.51 (s, 1 H), 7.72-7.82 (m, 2 H), 8.05-8.12 (m, 1 H), 8.15-8.20
(m, 1 H).
2-Bromo-1-methoxy-1-phenylethane (4a) [5e]
1
H NMR (300 MHz, CDCl3):  3.28 (s, 3 H), 3.38 (dd, 1 H, J = 6.04, 10.5 Hz), 3.48 (dd, 1 H, J =
2.26, 10.57 Hz), 4.32 (dd, 1 H, J = 4.5, 4.53 Hz), 7.28-7.40 (m, 5 H).
C NMR (75 MHz, CDCl3):  36.8, 57.8, 83.3, 126.6, 128.5, 128.7, 138.9.
13
MS (EI, 70 eV): m/z (%) = 216 [M + 2]+ (6), 214 [M+] (6), 121 (100), 91 (15), 77 (30), 51 (7).
2-Bromo-1-methoxy-1-(4-methylphenyl)ethane (4c) [5e]
1
H NMR (300 MHz, CDCl3):  2.36 (s, 3 H), 3.27 (s, 3 H), 3.36-3.52 (m, 2 H), 4.28 (dd, 1 H, J =
4.53, 8.3 Hz), 7.10-7.20 (m, 4 H).
142
Chapter 4
Oxybromination
C NMR (75 MHz, CDCl3):  21.2, 36.4, 57.1, 83.3, 126.7, 129.3, 135.9, 138.3.
13
MS (EI, 70 eV): m/z (%) = 230 [M + 2]+ (18), 228 [M+] (17), 135 (100), 117 (30), 91 (45), 77
(5), 65 (8), 51 (10).
2-Bromo-1-methoxy-1-(2,4-dimethylphenyl)ethane (4d)
1
H NMR (300 MHz, CDCl3): δ 2.30 (s, 3 H), 2.32 (s, 3 H), 3.26 (s, 3 H), 3.30-3.45 (m, 2 H),
4.55 (dd, 1 H, J = 3.77, 8.30 Hz), 6.93 (s, 1 H), 7.00 (d, 1 H, J = 8.30 Hz), 7.21 (d, 1 H, J = 8.30
Hz).
13
C NMR (75 MHz, CDCl3): δ 19.0, 21.0, 35.5, 57.1, 80.1, 125.9, 127.1, 131.5, 133.9, 135.6,
137.8.
Anal. Calcd for C11H15BrO: C, 54.33; H, 6.21. Found: C, 54.21; H, 6.28.
2-Bromo-1-methoxy-1-(4-t-butylphenyl)ethane (4e) [5f]
1
H NMR (300 MHz, CDCl3):  1.32 (s, 9 H), 3.29 (s, 3 H), 3.34-3.52 (m, 2 H), 4.30 (dd, 1 H, J
= 4.15, 8.3 Hz), 7.20 (d, 2 H, J = 8.12 Hz), 7.34 (d, 2 H, J = 8.3 Hz).
C NMR (75 MHz, CDCl3):  31.3, 34.6, 36.4, 57.2, 83.2, 125.5, 126.4, 135.9, 151.4.
13
MS (EI, 70 eV): m/z (%) = 272 [M + 2]+ (0.5), 270 [M+] (0.5), 177 (100), 162 (55), 147 (26), 117
(11), 91 (15), 77 (7), 57 (10).
2-Bromo-1-methoxy-1-(4-chlorophenyl)ethane (4f) [5e]
1
H NMR (300 MHz, CDCl3):  3.29 (s, 3 H), 3.32-3.52 (m, 2 H), 4.30 (dd, 1 H, J = 4.91, 7.55
Hz), 7.25 (d, 2 H, J = 8.49 Hz), 7.34 (d, 2 H, J = 8.49 Hz).
C NMR (75 MHz, CDCl3):  35.9, 57.3, 82.6, 128.1, 128.8, 134.3, 137.5.
13
2-Bromo-1-methoxy-1-(4-bromophenyl)ethane (4g) [5e]
1
H NMR (300 MHz, CDCl3):  3.29 (s, 3 H), 3.32-3.50 (m, 2 H), 4.29 (dd, 1 H, J = 4.53, 7.55
Hz), 7.20 (d, 2 H, J = 9 Hz), 7.50 (d, 2 H, J = 9 Hz)
143
Chapter 4
Oxybromination
1-Bromo-2-methoxy-2-phenylpropane (4h) [5e]
1
H NMR (300 MHz, CDCl3):  1.69 (s, 3 H), 3.12 (s, 3 H), 3.45 (d, 1 H, J = 10.38 Hz), 3.57 (d, 1
H, J = 10.38 Hz), 7.23-7.41 (m, 5 H).
C NMR (75 MHz, CDCl3):  21.8, 43.1, 51, 77.8, 126.4, 127.8, 128.4, 141.7.
13
1-Bromo-2-methoxy-2-(4-chlorophenyl)propane (4i)
1
H NMR (300 MHz, CDCl3): δ 1.67 (s, 3 H), 3.12 (s, 3 H), 3.4-3.55 (m, 2 H), 7.28-7.32 (m, 4
H).
13
C NMR (75 MHz, CDCl3): δ 21.6, 42.5, 51, 77.6, 127.9, 128.6, 133.7, 140.3.
Anal. Calcd for C10H12BrClO: C, 45.57; H, 4.58. Found: C, 45.61; H, 4.78.
erythro-2-Bromo-3-methoxy–3-phenylpropan-1-ol (4j) [5e]
1
H NMR (300 MHz, CDCl3):  2.65 (bs, 1 H), 3.22 (s, 3 H), 3.60-3.90 (m, 2 H), 4.18-4.25 (m, 1
H), 4.50 (d, 1 H, J = 7.36 Hz), 7.24-7.42 (m, 5 H).
C NMR (75 MHz, CDCl3):  57.5, 57.8, 64.6, 86, 127.5, 128.4, 128.5, 138.
13
MS (EI, 70 eV): m/z (%) = 246 [M + 2]+ (0.5), 244 [M+] (0.5), 121 (100), 105 (41), 91 (70), 77
(87), 51 (38).
erythro-3-Bromo-4-methoxy-4-phenylbutan-2-one (4k) [17]
1
H NMR (300 MHz, CDCl3):  2.36 (s, 3 H), 3.19 (s, 3 H), 4.18 (d, 1 H, J = 9.44 Hz), 4.50 (d, 1
H, J = 9.44 Hz), 7.24-7.42 (m, 5 H).
erythro-2-Bromo-3-methoxy-3-phenylpropanoic acid (4l) [5f]
1
H NMR (300 MHz, DMSO-D6):  3.28 (s, 3 H), 4.18 (d, 1 H, J = 9.82 Hz), 4.52 (d, 1 H, J =
9.82 Hz), 7.32-7.40 (m, 5 H).
erythro-Methyl-2-bromo-3-methoxy-3-phenylpropionate (4m) [10a]
144
Chapter 4
1
Oxybromination
H NMR (300 MHz, CDCl3):  3.22 (s, 3 H), 3.84 (s, 3 H), 4.14 (d, 1 H, J = 9.82 Hz), 4.50 (d, 1
H, J = 9.82 Hz), 7.30-7.52 (m, 5 H).
C NMR (75 MHz, CDCl3):  47, 53, 57.5, 84, 128, 128.3, 128.9, 136.7, 169.4.
13
erythro-2-Bromo-3-methoxy-1,3-diphenylpropan-1-one (4n) [5f]
1
H NMR (400 MHz, CDCl3):  3.18 (s, 3 H), 4.80 (d, 1 H, J = 9.76 Hz), 5.02 (d, 1 H, J = 9.76
Hz), 7.30-7.50 (m, 7 H), 7.56 (t, 1 H, J = 7.32, 14.64 Hz), 8.01 (d, 2 H, J = 7.32 Hz).
C NMR (75 MHz, CDCl3):  47.2, 57.6, 83.3, 128.2, 128.3, 128.7, 133.7, 135.2, 137.8, 193.1.
13
erythro-1-Bromo-2-methoxy-1,2-diphenylethane (4o) [5c]
1
H NMR (400 MHz, CDCl3):  3.18 (s, 3 H), 4.60 (d, 1 H, J = 6.61 Hz), 4.98 (d, 1 H, J = 6.61
Hz), 7.14-7.32 (m, 10 H).
C NMR (75 MHz, CDCl3):  57, 57.6, 87, 127.9, 128.1, 128.1, 128.2, 128.3, 128.8, 138.3,
13
138.7.
threo-1-Bromo-2-methoxy-1,2-diphenylethane (4p) [14]
1
H NMR (300 MHz, CDCl3):  3.32 (s, 3 H), 4.45 (d, 1 H, J = 8.3 Hz), 4.94 (d, 1 H, J = 8.3 Hz),
6.98-7.40 (m, 10 H).
C NMR (75 MHz, CDCl3):  57.2, 58.8, 87.4, 127.6, 128.1, 128.2, 128.5, 137.8, 138.8.
13
trans-2-Bromo-1-methoxyindane (4q) [5e]
1
H NMR (300 MHz, CDCl3):  3.20 (m, 1 H), 3.56 (s, 3 H), 3.66 (m, 1 H), 4.38-4.46 (m, 1 H),
4.92 (d, 1 H, J = 3.58 Hz), 7.16-7.38 (m, 4 H).
C NMR (75 MHz, CDCl3):  41.6, 50.7, 57.7, 91.7, 124.7, 125.2, 127.2, 129.1, 139.9, 140.4.
13
4-Bromo-3-methoxy-3-methylbutane-1-ol (4t) [13]
145
Chapter 4
1
Oxybromination
H NMR (500 MHz, CDCl3):  1.35 (s, 3 H), 1.75-1.81 (m, 1 H), 1.97-2.04 (m, 1 H), 2.51 (bs, 1
H), 3.26 (s, 3 H), 3.39-3.45 (m, 2 H), 3.68-3.79 (m, 2 H).
2-Bromo-1-ethoxy-1-phenylethane (4A) [15]
1
H NMR (300 MHz, CDCl3):  1.20 (t, 3 H), 3.38-3.51 (m, 4 H), 4.39-4.45 (dd, 1 H, J = 4.53,
8.30 Hz), 7.25-7.49 (m, 5 H).
C NMR (75 MHz, CDCl3):  15.1, 36.5, 64.9, 81.6, 126.7, 128.3, 128.6, 139.8.
13
MS (EI, 70 eV): m/z (%) = 229 [M + 2]+ (10), 227 [M+] (10), 135 (100), 121 (20), 107 (83), 91
(17), 77 (66), 51 (34).
2-Bromo-1-ethoxy-1-(4-methylphenyl)ethane (4C)
1
H NMR (300 MHz, CDCl3): δ 1.20 (t, 3 H, J = 7.55, 14.35 Hz), 2.35 (s, 3 H), 3.32-3.52 (m, 2
H), 4.38 (dd, 1 H, J = 4.53, 7.55 Hz), 7.10-7.21 (m, 4 H).
13
C NMR (75 MHz, CDCl3): δ 15.1, 21.2, 36.6, 64.8, 81.4, 126.6, 129.2, 136.7, 138.1.
Anal.Calcd for C11H15BrO: C, 54.33; H, 6.21. Found: C, 53.95; H, 6.35.
2-Bromo-1-ethoxy-1-(2,4-dimethylphenyl)ethane (4D)
1
H NMR (300 MHz, CDCl3): δ 1.20 (t, 3 H, J = 7.16 Hz), 2.29 (s, 3 H), 2.31 (s, 3 H), 3.30-3.46
(m, 4 H), 4.64 (dd, 1 H, J = 4.15, 8.49 Hz), 6.92 (s, 1 H), 6.98 (d, 1 H, J = 7.74 Hz), 7.25 (d, 1 H,
J = 7.74 Hz).
13
C NMR (75 MHz, CDCl3): δ 15.1, 18.9, 20.9, 35.7, 64.7, 78.3, 125.9, 127, 131.3, 134.7, 135.3,
137.6.
MS (EI, 70 eV): m/z (%) = 258 [M + 2]+ (0.5), 256 [M+] (0.5), 163 (100), 135 (47), 117 (22), 107
(56), 91 (30), 77 (12), 65 (5), 51 (4).
Anal. Calcd for C12H17BrO: C, 56.04; H, 6.66. Found: C, 56.14; H, 6.79.
2-Bromo-1-ethoxy-1-(4-t-butylphenyl)ethane (4E)
146
Chapter 4
1
Oxybromination
H NMR (300 MHz, CDCl3): δ 1.20 (t, 3 H, J = 6.79 Hz), 1.32 (s, 9 H), 3.33-3.52 (m, 4 H), 4.4
(dd, 1 H, J = 4.53, 8.3 Hz), 7.20 (m, 2 H), 7.33 (m, 2 H).
13
C NMR (75 MHz, CDCl3): δ 15.1, 31.3, 34.6, 36.7, 64.9, 81.4, 125.5, 126.3, 136.7, 151.3.
Anal. Calcd for C14H21BrO: C, 58.95; H, 7.42. Found: C, 59.25; H, 7.28.
2-Bromo-1-ethoxy-1-(4-chlorophenyl)ethane (4F)
1
H NMR (300 MHz, CDCl3): δ 1.20 (t, 3 H), 3.30-3.50 (m, 4 H), 4.40 (dd, 1 H, J = 5.09, 7.55
Hz), 7.25 (d, 2 H, J = 8.49 Hz), 7.32 (d, 2 H, J = 8.49 Hz).
13
C NMR (75 MHz, CDCl3): δ 15.1, 36.1, 65.1, 80.9, 128.1, 128.8, 134.1, 138.3.
Anal. Calcd for C10H12BrClO: C, 45.57; H, 4.58. Found: C, 45.32; H, 4.50.
2-Bromo-1-ethoxy-1-(4-bromophenyl)ethane (4G)
1
H NMR (500 MHz, CDCl3): δ 1.20 (t, 3 H, J = 6.84, 13.69 Hz), 3.32-3.48 (m, 4 H), 4.38 (dd, 1
H, J = 4.89, 6.84 Hz), 7.20 (d, 2 H, J = 9 Hz), 7.48 (d, 2 H, J = 9 Hz).
13
C NMR (75 MHz, CDCl3): δ 15.1, 36, 65.1, 81, 122.3, 128.4, 131.8, 138.8.
Anal. Calcd for C10H12Br2O: C, 38.99; H, 3.92. Found: C, 39.22; H, 3.71.
1-Bromo-2-ethoxy-2-phenylpropane (4H)
1
H NMR (300 MHz, CDCl3): δ 1.19 (t, 3 H, J = 6.98 Hz), 1.69 (s, 3 H), 3.11-3.22 (m, 1 H), 3.29-
3.40 (m, 1 H), 3.45 (d, 1 H, J = 10.38 Hz), 3.57 (d, 1 H, J = 10.38 Hz), 7.20-7.40 (m, 5 H).
13
C NMR (75 MHz, CDCl3): δ 15.6, 22.6, 43.1, 58.6, 77.6, 126.2, 127.6, 128.3, 142.5.
Anal. Calcd for C11H15BrO: C, 54.33; H, 6.21. Found: C, 54.16; H, 6.39.
1-Bromo-2-ethoxy-2-(4-chlorophenyl)propane (4I)
1
H NMR (300 MHz, CDCl3): δ 1.18 (t, 3 H, J = 6.79, 13.59 Hz), 1.67 (s, 3 H), 3.08-3.54 (m, 4
H), 7.24-7.34 (m, 4 H).
13
C NMR (75 MHz, CDCl3): δ 15.6, 22.5, 42.6, 58.7, 77.4, 127.7, 128.5, 133.6, 141.2.
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Anal. Calcd for C11H14BrClO: C, 47.59; H, 5.08. Found: C, 47.87; H, 5.13.
erythro-2-Bromo-1-ethoxy-1-phenylpropanol (4J)
1
H NMR (300 MHz, CDCl3): δ 1.20 (t, 3 H, J = 6.98 Hz), 2.71 (bs, 1 H), 3.40 (m, 2 H), 3.85-
4.04 (m, 2 H), 4.08-4.15 (m, 1 H), 4.53 (d, 1 H, J = 7.55 Hz), 7.25-7.38 (m, 5 H).
13
C NMR (75 MHz, CDCl3): δ 15.1, 57.7, 64.9, 65.4, 84.7, 127.4, 128.4, 128.7, 138.9.
Anal. Calcd for C11H15BrO2: C, 50.98; H, 5.83. Found: C, 50.63; H, 5.71.
erythro-1-Bromo-2-ethoxy-1,2-diphenylethane (4O)
1
H NMR (300 MHz, CDCl3): δ 1.08 (t, 3 H, J = 6.79, 14.35 Hz), 3.24-3.44 (m, 2 H), 4.68 (d, 1
H, J = 6.79 Hz), 4.92 (d, 1 H, J = 6.79 Hz), 7.14-7.32 (m, 10 H).
13
C NMR (75 MHz, CDCl3): δ 15, 57.2, 65.3, 85.1, 127.7, 127.9, 128, 128.1, 128.1, 128.9, 138.7,
139.2.
Anal. Calcd for C16H17BrO: C, 62.96; H, 5.61. Found: C, 63.21; H, 5.76.
trans-2-Bromo-1-ethoxyindane (4Q) [15]
1
H NMR (300 MHz, CDCl3):  1.25 (t, 3 H, J = 6.98 Hz), 3.19 (dd, 1 H, J = 5.09, 16.61 Hz),
3.60-3.92 (m, 3 H), 4.34-4.45 (m, 1 H), 5.00 (d, 1 H, J = 3.77 Hz), 7.12-7.38 (m, 4 H).
trans-2-Bromo-1-ethoxy-1-methylcyclohexane (4S)
1
H NMR (300 MHz, CDCl3): δ 1.60 (t, 3 H, J = 6.79 Hz), 1.28 (s, 3 H), 1.35-1.85 (m, 7 H), 2.21-
2.32 (m, 1 H), 3.34-3.46 (m, 2 H), 4.15-4.20 (m, 1 H).
13
C NMR (75 MHz, CDCl3): δ 16, 21.8, 23.3, 32.9, 33, 56.2, 60, 75.8.
Anal. Calcd for C9H17BrO: C, 48.88; H, 7.74. Found: C, 49.26; H, 7.62.
4-Bromo-3-ethoxy-3-methylbutane-1-ol (4T)
1
H NMR (300 MHz, CDCl3): δ 1.19 (t, 3 H, J = 6.98 Hz), 1.37 (s, 3 H), 1.69-1.80 (m, 1 H), 1.98-
2.10 (m, 1 H), 3.36-3.54 (m, 4 H), 3.7-3.84 (m, 2 H).
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13
C NMR (75 MHz, CDCl3): δ 15.8, 21.5, 38.8, 38.9, 57.3, 59.2, 76.8.
Anal. Calcd for C7H15BrO2: C, 39.83; H, 7.16. Found: C, 39.91; H, 7.04.
1-Bromo-4-phenyl-3-butene-2-one (6) [16]
1
H NMR (300 MHz, CDCl3):  4.01 (s, 2 H), 6.94 (d, 1 H, J = 16.05 Hz), 7.35-7.45 (m, 3 H),
7.53-7.61 (m, 2 H), 7.67 (d, 1 H, J = 16.05 Hz).
3-Bromo-4-ethoxy-4-phenylbutan-2-one (mixture of erythro and threo) (7)
1
H NMR (300 MHz, CDCl3):  1.09 (t, 3 H, J = 6.98, 13.97 Hz, erythro), 1.20 (t, 3 H, J = 6.98,
13.97 Hz, threo), 2.17 (s, 3 H, threo), 2.40 (s, 3 H, erythro). 3.30-3.49 (m, 4 H, erythro+threo).
4.24 (d, 1 H, J = 9.63 Hz, erythro), 4.44 (d, 1 H, J = 7.55 Hz, threo), 4.61-4.69 (m, 2H,
erythro+threo), 7.30-7.45 (m, 10 H, erythro+threo).
13
C NMR (75 MHz, CDCl3): δ 14.1, 14.9, 26.6, 28.4, 54.3, 57.8, 64.8, 65.2, 80.6, 82.1, 127.5,
127.8, 128.3, 128.5, 128.6, 137.7, 199.4, 200.9.
MS (EI, 70 eV): m/z (%) = 272 [M + 2]+ (10), 270 [M+] (10), 191 (5), 135 (100), 91 (11), 77
(15), 51 (34).
Anal. Calcd for C12H15BrO2: C, 53.15; H, 5.58. Found: C, 53.24; H, 5.54.
2-Bromo-1-isopropoxy-1-phenylethane (Table 4.13, entry 6) [8c]
1
H NMR (300 MHz, CDCl3):  1.09 (d, 3 H, J = 6.04 Hz), 1.21 (d, 3 H, J = 6.04 Hz), 3.33-3.48
(m, 2 H), 3.50-3.61 (m, 1 H), 4.52 (dd, 1 H, J = 4.53, 8.3 Hz), 7.25-7.35 (m, 5 H).
149
Chapter 4
Oxybromination
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