chapter 4 oxybromination -...

Chapter 4 Oxybromination

71

Chapter 4 Oxybrominations using

oxone


72

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-3-

methylpyridinium tribromide [3], 2,4,4,6-tetrabromo-2,5-cyclohexadienone [4], Br2/SO2Cl2 [5],

hexamethylenetetramine-bromine [6], (Bmim)Br3 [7], NBS-ammonium acetate [8], NBS-

photochemical [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).


73

R

NH4Br, Oxone

MeOH or H2O, r.t.

R

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


74

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.


75

Table 4.1. Optimization of the oxybromination of resorcinola

OH

OH

Br source, Oxidant

Solvent, r.t.

OH

OH

Br

OH

OH

Br

Br

+

1 2 3 Entry Br source

(mmol)

Oxidant

(mmol)

Solvent Time

(min)

Conversion

(%)b

Selectivity (Yield, %)c

2 3

1

2

3

4

5

6

7

8

9

10

11

12

NH4Br

(2)

NH4Br

(2.2)

NH4Br

(2)

NH4Br

(2.2)

NH4Br

(2)

NH4Br

(2.2)

NH4Br

(2)

NH4Br

(2.2)

KBr

(2)

KBr

(2.2)

KBr

(2)

KBr

(2.2)

Oxone

(2.2)

Oxone

(2.2)

Oxone

(2.2)

Oxone

(2.2)

Oxone

(2.2)

Oxone

(2.2)

H2O2

(2.2)

H2O2

(2.2)

Oxone

(2.2)

Oxone

(2.2)

Oxone

(2.2)

Oxone

(2.2)

CH3CN

CH3CN

MeOH

MeOH

H2O

H2O

AcOH

AcOH

CH3CN

CH3CN

MeOH

MeOH

120

120

30

30

10

10

120

120

90

90

60

60

99

99

99

98

99

99

99

94

99

97

99

98

85 (84) 15 (15)

98 (97) 2 (2)

88 (87) 12 (12)

97 (95) 3 (3)

53 (52) 47 (47)

86 (85) 14 (14)

67 (66) 33 (33)

92 (87) 8 (7)

83 (82) 17 (17)

95 (92) 5 (5)

77 (76) 23 (23)

93 (91) 7 (7)


76

13

14

15

KBr

(2.2)

KBr

(2)

KBr

(2.2)

Oxone

(2.2)

H2O2

(2.2)

H2O2

(2.2)

H2O

AcOH

AcOH

10

420

270

91

99

95

75 (68) 25 (23)

71 (70) 29 (29)

88 (84) 12 (11)

aReaction conditions: resorcinol (2 mmol), Br source, oxidant, solvent (10 mL), room temperature.

bConversions determined by GC.

cThe products were characterized by

1H NMR spectroscopy, mass spectrometry and quantified by GC.

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). 1,3,5-

Trihydroxybenzene 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). 2-

Methylnaphthalene 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-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.

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


77

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

NH4Br, Oxone

H2O, r.t.

R

Br

Entry Substrate Time Product (Yield, %)b

1

2

3

4

5

OH

OH

OH

OH

OH

OHOH

OH

OMe

OH

10 min

25 min

5 min

45 min

3 h

OH

OH

Br

OH

OH

Br

Br

(85) (14)

OH

OH

Br

OH

OH

Br

Br

(66) (29)

OH

OH

Br

OH

OH

OH

Br

Br

OH

(75) (24)

OH

Br

OMe

OH

Br

OMe

(40) (56)

OH

Br

(66)


78

6

7

8

9

10

11

12

13

CH

3

Br

NO2

24 h

4 h

2 h

4 h

40 min

24 h

24 h

24 h

Br

(75)

Br

(66)

Br

(53)

Br

(72)

Br

(61)

-

-

-

aSubstrate (2 mmol), NH4Br (2.2 mmol), Oxone (2.2 mmol), H2O (10 ml), Room temperature.

bGC yield.


79

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 2-

methoxyphenol in methanol afforded the para isomer (4-bromo-2-methoxyphenol) and 5-bromo-

2-methoxyphenol in the ratio 77:22 (Table 4.3, entry 4). 2-Hydroxynaphthalene provided 1-

bromo-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-2-

methylnaphthalene 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


80

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

NH4Br, Oxone

MeOH, r.t.

R

Br

Entry Substrate Time Product (Yield, %)b

1

2

3

4

5

OH

OH

OH

OH

OH

OHOH

OH

OMe

OH

30 min

30 min

30 min

3 h

45 min

OH

OH

Br

OH

OH

Br

Br

(95) (3)

OH

OH

Br

OH

OH

Br

Br

(90) (9)

OH

OH

Br

OH

OH

OH

Br

Br

OH

(90) (9)

OH

Br

OMe

OH

Br

OMe

(77) (22)

OH

Br

(99)


81

6

7

8

9

10

11

12

13

14

CH

3

O

OH

O Br

NO

2

24 h

18 h

3 h

3 h

3 h

45 min

24 h

24 h

24 h

Br

(80)

Br

(99)

Br

(92)

Br

(99)

Br

(85)

O

OH

O

Br

(98)

-

-

-

aSubstrate (2 mmol), NH4Br (2.2 mmol), Oxone (2.2 mmol), MeOH (10 ml), Room temperature.

bGC yield.


82

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

OMe

NH4Br (1.1 equiv)

Oxone (1.1 equiv)

MeOH (10 ml) 6 h, r.t.

68%

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


83

4.4. Spectral data

4-Bromo-1,3-dihydroxybenzene [16]

OH

OH

Br

1H 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).

13C NMR (50 MHz, CDCl3): δ 98.4, 103.5, 110.1, 132.4, 154.1, 156.9.

2,4-Dibromo-5-hydroxyphenol [16]

OH

OH

Br

Br

1H NMR (200 MHz, CDCl3): δ 5.42 (s, 2 H, OH), 6.76 (s, 1 H, ArH), 7.61 (s, 1 H, ArH).

13C NMR (50 MHz, CDCl3): δ 100.1, 103.6, 133.1, 153.9.

2-Methoxy-4-bromophenol [17]

OH

Br

OMe

1H 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).

13C NMR (50 MHz, CDCl3): δ 56.2, 111.7, 114.3, 116.0, 124.2, 144.9, 147.4.

5-Bromo-2-methoxyphenol [18]


84

OH

OMe

Br

1H 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).

13C NMR (50 MHz, CDCl3): δ 56.6, 112.4, 113.8, 118.3, 123.3, 146.4, 147.0.

1-Bromo-2-naphthol [19]

OH

Br

1H 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).

13C 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

1H 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).

MS (EI): m/z (%) = 222 [M+,81

Br] (19), 220 [M+,79

Br] (19), 141 (100).

1-Bromo-2,4-dimethylbenzene [20]


85

Br

1H 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)

13C 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

1H 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).

MS (EI): m/z (%) = 214 [M+,81

Br] (12), 212 [M+,79

Br] (12), 133 [M+ – Br] (67), 91 [PhCH2+]

(100).

1-Bromo-4-isobutylbenzene [15e]

Br

1H 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).

MS (EI): m/z (%) = 214 [M+,81

Br] (32), 212 [M+,79

Br] (32), 169 [M+ – 43] (100), 91 [M

+ – 121]

(27).

Bromomesitylene [21]


86

Br

1H NMR (200 MHz, CDCl3): δ 2.22 (s, 3 H), 2.35 (s, 6 H), 6.83 (s, 2 H).

13C NMR (50 MHz, CDCl3): δ 20.6, 23.6, 124.2, 129, 136.2, 137.8.

MS (EI): m/z (%) = 200 [M+,

81Br] (21), 198 [M

+,

79Br] (21), 119 [M

+ – 79] (100), 91 [M

+ – 107]

(96),

1-bromo-2,4,5-trimethylbenzene [22]

Br

1H 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]

O

OH

Br

O

1H 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).

MS (EI): m/z (%) = 242 [M+,

81Br] (23), 240 [M

+,

79Br] (23), 211 (100).

2-Methoxy-2-phenylpropane [23]


87

O

1H 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).

13C 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

1H 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).


88

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.


89

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.


90

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], NBS-

silica 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-methylpyrrolidin-

2-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.


91

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).

NH4Br,Oxone®

MeOH

O

R

O

O

R Br

O

Br

O O O O

Br

R ArAr

R

R = Alkyl/ ArylRI = Alkyl/ Aryl/ OR

R RI R RI

Scheme 4.4. Bromination of carbonyl compounds



All chemicals used were reagent grade and used as received without further purification.

1H 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)


92

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


NH4Br (4.4 mmol) in methanol (10 ml) and the reaction mixture was allowed to stir at room


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


NH4Br (4.4 mmol) in DCM (10 ml) and the reaction mixture was allowed to stir at room


reaction mixture was quenched with aqueous sodium thiosulfate and extracted with DCM (3×25


93

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.


4.8.1. 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.


94

Table 4.4. α-Bromination of acetophenone: Effect of solventa

O O

BrNH4Br, Oxone

Solvent

1a

Entry Solvent NH4Br Oxone Yield (%)b

1

2

3

4

5

6

7

8

9

10

11

MeOH

CH3CN

H2O

DCM

CHCl3

CCl4

Hexane

EtOH

Ether

THF

MeOH

2.2

,,

,,

,,

,,

,,

,,

,,

,,

,,

,,

2.2

,,

,,

,,

,,

,,

,,

,,

,,

,,

1.1

81

12

13

-

-

-

-

-

-

-

33

a Acetophenone (2 mmol), Solvent (10 ml), Room temperature, 7 h.

b 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).


95

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).


96

Table 4.5. Bromination of aralkyl ketones using NH4Br and oxonea

Entry Substrate Time Product Yield (%)

b

1

2

3

4

5

6

7

8

O

O

O

O

O

Et

O

Br

O

Br

O

Br

7 hc

15 mind

26 hc

2.5 hd

24 hc

40 mind

6 hc

2.5 hd

7 hc

1.5 hd

48 hc

4 hd

48 hc

2 hd

48 hc

1.5 hd

O

Br

1a

O

Br

1b

O

Br

1c

O

Br

1d

O

Et

Br

1e

O

Br

Br

1f

O

Br

Br

1g

O

Br

Br

1h

81

97

92

91

84

96

63

94

54

86

42

56

37 (28)e

73

37

98


97

9

10

11

12

13

14

15

16

O

Cl

O

Cl

O

F

O

F

O

F

O

NO2

O

O2N

O

NC

48 hc

3 hd

47 hc

2 hd

24 hc

2 hd

24 hc

2 hd

44 hc

1.3 hd

48 hc

3 hd

24 hc

1.5 hd

48 hc

16 hd

O

Cl

Br

1i O

Cl

Br

1j O

Br

F 1k

O

Br

F 1l

O

Br

F 1m

O

NO2

Br

1n

O

Br

O2N

1o

O

NC

Br

1p

50

73

49

87

81

85

39 (34)e

83

89

97

14 (16)e

46 (14)e

8 (12)e

21 (34)e

38

35 (6)e


98

17

18

19

20

21

22

23

O

OH

O

NH2

O

O

O

O

O

O

OH

O

4.5 hc

1.5 hd

1 hc

5 mind

26 hc

7.5 hd

24 hc

1.25 hd

24 hc

20 mind

40 minc

10 mind

3 hc

15 mind

O

OH

Br

1q

O

NH2

Br

1s

O

Br

1t O

Br

1u

O

Br

1v

O

Br

O

1w

O

OH

O

Br

1x

61 (26)f

48 (28)f

93

83

10

58

39

87

60

97

97

94

98

98

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).


99

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).


100

Table 4.6. Bromination of various cyclic and acyclic ketones using NH4Br and oxonea

Entry Substrate Time Products (Yield (%))

b

1

2

3

4

5

6

7

8

O

O

O

O

O

OMe

O

MeO

O

O

2 hc

30 mind

6 hc

20 mind

28 hc

2 hd

6 hc

20 mind

2 hc

20 mind

2.5 hc

1 hd

8 hc

7 hc

50 mind

OBr

(65)(80)

2a

O

Br(92)(98)

2b

O

Br(77)(77)

2c O

Br(79)(95)

2d OBr

OMe

(90)(87)

2e

O

BrMeO(17)(42)

O

MeO

Br

(42)(18)

2f 2g

O

Br (80)

O

Br

(09)

2h 2i

O

Br(90)(85)

O

Br

-(06)

2j 2k


101

9

10

11

O

Ph

O

C4H9

O

C6H13

5 hc

30 mind

9 hc

1 hd

7 hc

20 mind

O

BrPh

(65)(71)

O

Br

Ph(10)(21)

2l 2m

(62)(55)

(37)(44)

O

Br

C4H9

O

Br

C4H9

2n 2o

(71)(76)

(28)(23)

O

BrC6H13

O

Br

C6H13

2p 2q

a 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.


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).


102

Table 4.7. Bromination of 1,3-dicarbonyl compounds using NH4Br and oxone

Entry Substrate Time Products (Yield (%))a

1

2

3

4

.

5

6

7

8

O O

Ph Ph

O

O

O

O

O

O

O

O

Ph

O

O

O

Ph

O

O

O

O

O

O

Ph

O

OO

40 minb

3 hc

1 hb

40 mind

3 hb

30 mind

35 minb

30 mind

30 minb

3 hc

9 hb

5 hb

30 minb

O O

Ph Ph

Br

O O

Ph Ph

Br Br

(94) -

-(90)

3a 3b O

O

Br

O

O

Br

Br

(80)

-

(10)(95)

3c 3d

O

O

O

Br

(75) -

O

O

O

BrBr

(24)(94)

3e 3f

O

O

O

Br

Ph(81) -

O

O

O

BrBr

Ph

(18)(96)

3g 3h O

O

O

Br

Ph(90) -

O

O

O

BrBr

Ph

(09)(94)

3i 3j

O

O

O

Br(70)

3k

O

O

O

Ph

Br(87)

3l

O

OO

Br (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.


103

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.


104

Table 4.8. Reaction of tetralone with NH4Br and oxone: Variation of solventsa

O O

Br

OH

+

4a 4b

NH4Br, Oxone

Solvent

Entry Solvent NH4Br

(mmol)

Oxone

(mmol)

Time (h) Yield (%)b

4a 4b

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

MeOH

H2O

Acetone

EtOH

i-PrOH

Ether

DCM

CHCl3

CCl4

DCE

MeOH

,,

,,

DCM

,,

,,

,,

,,

2.2

2.2

2.2

2.2

2.2

2.2

2.2

2.2

2.2

2.2

2.2

,,

4.4

-

0.2

0.55

1.1

1.65

2.2

2.2

2.2

2.2

2.2

2.2

2.2

2.2

2.2

2.2

-

0.2

4.4

2.2

2.2

,,

2.2

,,

6

6

24

24

24

24

24

24

48

24

6

,,

20c

24

,,

,,

,,

,,

93 -

37 -

13 -

53 -

34 -

20 -

- 65

35 18

11 -

- 40

- -

10 -

71 (28)e -

- -

09 -

- -

- 17

17 43


105

19

20

21

,,

,,

,,

2.2

4.4

,,

4.4

2.2

,,

,,

,,

,,d

06 65

- 90

- -

a Tetralone (2 mmol), Solvent (10 ml), Room temperature.

b GC yield.

c At reflux temperature.

d At 0

oC.

e α,α-Dibromotetralone

RNH4Br,Oxone®

DCM+ +

4 R = H, RI = H, RII = H 90 - -5 R = H, RI = Me, RII = Me 31 8 176 R = Me, RI = H, RII = H 27 - 8

7 8 9

Br

OH

RI

RIIO

R

RI

RIIOH

R

RI

RIIO

Br

RI

RII

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-

OH

O

Br

O+

H

O

Br

- H2O

OH

HO-Br+

HO-Br+ + SO42-

R

R

R

R Scheme 4.6. Plausible reaction mechanism


106

4.9. Spectral data

2-Bromo-1-phenylethanone (1a) [17]

m.p. 49-51 °C

1H 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]

1H 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]


H).

2-Bromo-1-(4-methylphenyl)ethanone (1d) [17]

m.p. 51-53 °C

1H 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+,

81Br] (12), 212 [M

+,

79Br] (12), 119 (100), 105 (32), 91 (79), 77

(27), 65 (71).

2-Bromo-1-(4-ethylphenyl)ethanone (1e) [18]

1H 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


107

1H 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

1H 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]

1H 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]

1H 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

1H 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

1H 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

1H 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]


108

1H 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

1H 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]

1H 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]

1H 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

1H 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

1H 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]


109

1H 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

1H 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

1H 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

1H 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

1H 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).


110

1-Bromobutan-2-one (2h) [33]

1H 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]

1H 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]

1H 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]

1H 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

1H 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]

1H 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]

1H 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]


111

1H 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]

1H 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]

1H 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]

1H 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]

1H 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]

1H 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).


112

4.10. References

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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.,

(2004) 470.

5. S. S. Arbuj, S. B. Waghmode, A. V. Ramaswamy, Tetrahedron Lett., 48 (2007) 1411.

6. I. Pravst, M. Zupan, S. Stavber, Tetrahedron, 64 (2008) 5191.

7. 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.

9. 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.


113

13. 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,

Chem. Pharm. Bull., 46 (1998) 623.

22. 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.

24. T. Nittoli, K. Curran, S. Insaf, M. D. Grandi, M. Orlowski, R. Chopra, A. Agarwal,

A. Y. M. Howe, A. Prashad, M. B. Floyd, B. Johnson, A. Sutherland, K. Wheless,

B. Feld, J. O. Connell, T. S. Mansour, J. Bloom, J. Med. Chem., 50 (2007) 2108.

25. R. P. Perera, D. S. Wimalasena, K. Wimalasena, J. Med. Chem., 46 (2003) 2599.

26. G. Wang, Z. Li, C. Ha, K. Ding, Synth. Commun., 38 (2008) 1629.

27. A. Podgorsek, S. Stavber, M. Zupan, J. Iskra, Tetrahedron, 65 (2009) 4429.


114

28. A. Latorre, A. Urbano, M. C. Carreno, Chem. Commun., (2009) 6652.

29. P. S. Poon, A. K. Banerjee, J. Chem. Res., (2009) 737.

30. M. Voets, I. Antes, C. Scherer, U. M. Vieira, K. Biemel, S. M. Oberwinkler, R. W.

Hartmann, J. Med. Chem., 49 (2006) 2222.

31. E. Reimann, H. Renz, Arch. Pharm., 326 (1993) 253.

32. T. Sakurai, A. Kageyama, H. Hayashi, H. Inoue, Bull. Chem. Soc. Jpn., 65 (1992) 2948.

33. W. Peter, B. Joachim, Liebigs Ann. Chem., 7 (1992) 669.

34. H. Y. Choi, D. Y. Chi, Org. Lett., 5 (2003) 411.

35. R. V. Hoffman, W. S. Weiner, N. Maslouh, J. Org. Chem., 66 (2001) 5790.

36. K. Kikushima, T. Moriuchi, T. Hirao, Tetrahedron, 66 (2010) 6906.

37. 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.

Nicolas, W. P. T. B. Paul, N. F. Sylvie, Galapagos, Belgium, PCT Patent No. 029119,

(2010).

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0014958, (2006).


115

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


116

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).

NH4Br, OxoneCH3CN:H2O (1:1)

or CH3CNor ROH

RIRII

RIRII

X

Br

X

Br

RII = H, CH3, CH

2OH, X = OH, Br, OR

RI = Alkyl, Aryl

COR, COOR, Ph

RI

RII

RII

RI

Scheme 4.7. Cobromination and dibromination of olefins


117



All chemicals used were reagent grade and used as received without further purification.

1H NMR spectra were recorded at 300, 400 and 500 MHz and

13C 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

13C 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.


118

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.


4.13.1. 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).


119

Table 4.9. Optimization of the bromohydrins

PhSolvent

OH

Br

Ph +Br

Br

Ph

1a 2a 3a

NH4Br, Oxone

Entry Solvent

Time Yield (%)a

2a 3a

1

2

3

4

5

6

7

8

9

10

11

12

13

14

CH3CN

Acetone

DCM

CHCl3

CCl4

H2O

CH3CN:H2O

(9:1)

CH3CN:H2O

(4:1)

CH3CN:H2O

(3:2)

CH3CN:H2O

(1:1)

CH3CN:H2O

(2:3)

CH3CN:H2O

(1:4)

DCM:H2O

(1:1)

DCM:H2O

(1:1)

24 hb

24 hb

24 hb

24 hb

24 hb

2 minb

10 minb

10 minb

5 minb

2 minb

2 minb

2 minb

3 minb

30 minb

- 60

2 48

- -

9 11

- -

56 29

65 30

84 12

85 10

92 5

83 12

79 16

10 48

10 49


120

15

16

17

CHCl3:H2O

(1:1)

CCl4:H2O

(1:1)

Acetone:H2O

(1:1)

3 minb

3 minb

2 minb

8 55

12 40

85 10

a Isolated yields.

b 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 NH4Br-

oxone 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 4-

chloro-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).


121

Table 4.10. Synthesis of bromohydrins from various olefinsa

R

RI NH4Br, Oxone

CH3CN : H2O

(1:1)

OH

BrR

RI

Entry Olefin Time (min) Product Yield (%)b

1

2

3

4

5

6

7

8

O

Cl

Br

2

1

2

1

1

2

3

2

OH

Br

OH

BrO

Br

OH

Br

OH

Br

OH

Br

OH

Cl

Br

OH

Br

Br

OH

92 (2a)

90 (2b)

79 (2c)

70 (2d)

66 (2e)

89 (2f)

89 (2g)

97 (2h)


122

9

10

11

12

13

14

15

16

17

18

19

Cl CH

2OH

Ph

PhCOCH

3

PhCOOH

PhCOOMe

PhCOPh

PhPh

Ph Ph

2

3

3

3

4

3

5

2

1

3

1

Br

OH

Cl

PhCH

2OH

Br

OH

Ph

Br

OH

COCH3

Ph

Br

OH

COOH

Ph

Br

OH

COOMe

Ph

Br

OH

COPh

Ph

Br

OH

Ph

PhPh

Br

OH

Br

OH

Br

OH

Br

OH

84 (2i)

92c (2j)

77c (2k)

80c (2l)

63c (2m)

62c (2n)

78c (2o)

15c (2o) 51

d (2p)

86 (2q)

85 (2r)

89 (2s)


123

20

21

22

23

24

OH

CH3(CH2)9

CH3(CH2)4

O

O

O O

1

2

1

60

60

OH

Br

OH

CH3(CH2)9

Br

OH

CH3(CH2)9Br

OH

CH3(CH2)4Br

OH

CH3(CH2)4

Br

OH

O

O

OH

Br

O O

Br

OH

84 (2t)

47 (2u)

(14) (2uI)

25c (2v)

(36)c (2v

I)

-

-

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


124

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-1-

cyclohexene 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.


125

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).


126

Table 4.11. Optimization of the dibromides.

PhSolvent

OH

Br

Ph +Br

Br

Ph

1a 2a 3a

NH4Br, Oxone

Entry Solvent

Time Yield (%)a

2a 3a

1

2

3

4

5

6

CH3CN

CH3CN

CH3CN

CH3CN:H2O

(10:0.25)

CH3CN:H2O

(10:0.5)

CH3CN:H2O

(10:1)

5 hb

24 hc

7 hd

19hc

1.3hc

3 minc

- 65

- 80

- 97

13 81

20 73

33 60

a 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.


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 cis-


127

Table 4.12. Synthesis of dibromides from various olefinsa

R

RI NH4Br, Oxone

CH3CN

Br

BrR

RI

Entry Olefin Time (h) Product Yield (%)b

1

2

3

4

5

6

7

8

O

Cl

Br

7

-

5

4

6

13

13

10

Br

Br

Br

BrO

Br

Br

Br

Br

Br

Br

Br

Br

Cl

Br

Br

Br

Br

Br

97 (3a)

-

95 (3c)

92 (3d)

90 (3e)

96 (3f)

90 (3g)

- (3h)


128

9

10

11

12

13

14

15

16

17

18

19

Cl CH

2OH

Ph

PhCOCH

3

PhCOOH

PhCOOMe

PhCOPh

PhPh

Ph Ph

10

12

15

13

12

13

20c

16c

8.3

23c

20c

Br

Br

Cl

PhCH

2OH

Br

Br

Ph

Br

Br

COCH3

Ph

Br

Br

COOH

Ph

Br

Br

COOMe

Ph

Br

Br

COPh

Ph

Br

Br

Ph

PhPh

Br

Br

Br

Br

Br

Br

Br

Br

- (3i)

98d (3j)

90d (3k)

96d (3l)

97d

(3m)

97d (3n)

80d

(3o)

95e (3p)

90 (3q)

96 (3r)

93 (3s)


129

20

21

22

23

24

OH

CH3(CH2)9

CH3(CH2)4

O

O

O O

4

9

5

5

10

OH

Br

Br

CH3(CH2)9Br

Br

CH3(CH2)4Br

Br

O

O

Br

O O

Br

Br

89 (3t)

97 (3u)

96d (3v)

97 (3w)

23 (3x)

a Olefin (2 mmol), NH4Br (4.4 mmol), Oxone (2.2 mmol), CH3CN (10 mL) at reflux temperature.

b Isolated yields.

c Room temperature.

d Only erythro products.

e threo product.

stilbene were more rapid than its trans-isomer and both gave anti addition products. trans-

Stilbene 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, 2-

bromo-1,4-naphthoquinone was obtained in excellent yield (Table 4.12, entry 23).


130

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 80C 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 2-

bromo-1-methoxy and 2-bromo-1-ethoxy products in high yields with-out forming any side-

chain 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-2-

one (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).


131

Table 4.13. Alkoxybromination of styrene using various alcoholsa

PhNH4Br, Oxone

ROH

OR

Br

Ph+

Br

Br

Ph

1a 4 3a

Entry ROH Time Yield (%)b

4 3a

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

MeOH

EtOH

,,

n-PrOH

,,

i-PrOH

,,

n-BuOH

,,

2-BuOH

,,

i-BuOH

,,

t-BuOH

,,

50 minc

24 hc

2.45 hd

24 hc

11 hd

24 hc

10 hd

24 hc

10 hd

24 hc

12 hd

24 hc

12.3 hd

42 hc

10.3 hd

85 <5

64 14

84 <5

55 22

70 9

30 41

35 12

50 15

61 <5

6 12

8 <5

25 19

34 10

7 30

22 55

aStyrene (2 mmol), NH4Br (2.2 mmol), Oxone (2.2 mmol), ROH (10 mL).

bIsolated yields.

cAt room temperature.

dAt 80˚C.


132

Table 4.14. Methoxy and Ethoxybromination of various aromatic olefins

Entry Olefin Product R Time Yield (%)a

1

2

3

4

5

6

7

8

9

10

O

Cl

Br

Cl

CH

2OH

Ph

OR

Br

OR

BrO

Br

OR

Br

OR

Br

OR

Br

OR

Cl

Br

OR

Br

Br

OR

Br

OR

Cl

PhCH

2OH

Br

OR

Me

Et

Me

Et

Me

Et

Me

Et

Me

Et

Me

Et

Me

Et

Me

Et

Me

Et

Me

Et

50 minb

2.45 hc

40 minb

2 hc

15 minb

45 minc

6 minb

1.15 hc

15 minb

2.30 hc

30 minb

3 hc

1 hb

3 hc

13 minb

2.15 hc

15 minb

2 hc

40 minb

3.30 hc

85 (4a)

84 (4A)

90 (4b)

92 (4B)

93 (4c)

84 (4C)

80 (4d)

75(4D)

76 (4e)

80 (4E)

91 (4f)

85 (4F)

84 (4g)

85 (4G)

92 (4h)

83 (4H)

88 (4i)

72 (4I)

84e (4j)

89e (4J)


133

11

12

13

14

15

16

17

18

19

20

21

PhCOCH

3

PhCOOH

PhCOOMe

PhCOPh

PhPh

Ph Ph

OH

CH3(CH2)9

Ph

Br

OR

COCH3

Ph

Br

OR

COOH

Ph

Br

OR

COOMe

Ph

Br

OR

COPh

Ph

Br

OR

Ph

PhPh

Br

OR

Br

OR

Br

OR

Br

OR

OH

Br

OR

CH3(CH2)9Br

OR

CH3(CH2)9

Br

OR

Me

Me

Et

Me

Et

Me

Et

Me

Et

Me

Et

Me

Et

Me

Et

Me

Et

Me

Et

Me

Et

Me

Et

2.15 hb

2.30 hb

24 hd

3 hb

24 hd

1 hb

3.3 hc

1.3 hb

3.3 hc

1 hb

1.3 hc

15 minb

4 hc

5 minb

24 hd

10 minb

24 hd

30 minb

2.3 hc

45 minb

4 hc

76e (4k)

76e (4l)

31e (4L)

71e (4m)

20e (4M)

70e (4n)

75g (4N)

80e (4o)

76e (4O)

73f (4p)

40h

(4P)

76 (4q)

81 (4Q)

64 (4r)

34(4R)

71 (4s)

66(4S)

75 (4t)

63 (4T)

60 (4u)

54 (4U)

5 (4uI)

5 (4UI)


134

22

23

24

CH3(CH2)4

O

O

O O

CH3(CH2)4

Br

OR

CH3(CH2)4

Br

OR

O

O

Br

OR

O O

Br

OR

Me

Et

Me

Et

Me

Et

Me

Et

45 minb

4 hc

24 hb

5 hc

24 hb

10 hc

24 (4v)

18 (4V)

39 (4vI)

33 (4VI)

-

-

-

-

aIsolated yields.

bOlefin (2 mmol), NH4Br (2.2 mmol), Oxone (2.2 mmol), MeOH (10 mL) at room temperature.

cOlefin (2 mmol), NH4Br (2.2 mmol), Oxone (2.2 mmol), EtOH (10 mL) at reflux temperature.

dAt room temperature.

eerythro products.

fthreo products.

gMolar ratio of erythro and threo 62:38, determined by

1H NMR.

hMolar ratio of threo and erythro 33:67, determined by

1H NMR.

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/4U

I), while mixed regioselectivity was observed for


135

trans-2-octene (Table 4.14, entries 21-22). 1,4-Naphthoquinone furnished the 2-bromo-1,4-

naphthoquinone 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

Ph

NH4Br, Oxone

EtOHO

Ph

Br

OEt O

Ph

Br

Br

Reflux5 h

rt

24 h

5

+

O

PhBr

50% 6

7 3k

59% 15%

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].


136

RI

RIIHO- Br+

Br

RIRII

+-OH

RO- H+

OR

Br

RII

RI + H2O

Br

Br

RIRII

NH4+ Br-

+NH4OH

R = H / Alkyl

HSO5- + Br- HOBr + SO4

-2

Scheme 4.9. The plausible reaction mechanism

4.14. Spectral data

2-Bromo-1-phenylethanol (2a) [5e]

1H 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).

13C NMR (75 MHz, CDCl3): 40, 73.8, 125.9, 128.4, 128.6, 140.2.

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]

1H 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]

1H 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).

13C NMR (75 MHz, CDCl3): 21.1, 40.1, 73.6, 125.8, 129.3, 137.3, 138.2.


137

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]

1H 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]


Hz), 7.25-7.35 (m, 4 H).

13C NMR (75 MHz, CDCl3): 39.9, 72.8, 127.3, 129, 134.2, 138.8.

2-Bromo-1-(4-bromophenyl)ethanol (2g) [5e]


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]

1H 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).

13C NMR (75 MHz, CDCl3): 28, 46.2, 73.1, 124.7, 127.5, 128.4, 144.1.

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]

1H 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).


138

13C NMR (75 MHz, CDCl3): 59.3, 64.1, 76.7, 126.5, 128.4, 128.5, 140.2.

erythro-3-Bromo-4-hydroxy–4-phenylbutan-2-one (2k) [1d]

1H 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]

1H 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]

1H 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).

13C NMR (75 MHz, CDCl3): 47.3, 53.1, 75.1, 126.9, 128.5, 128.7, 138.9, 169.8.

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]

1H 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).

13C NMR (75 MHz, CDCl3): 47.8, 74.7, 127.2, 128.2, 128.4, 128.6, 128.8, 128.9, 134.1, 134.5,

139.3, 194.5.

erythro-2-Bromo-1,2-diphenylethanol (2o) [10f]


Hz), 7.2-7.35 (m, 10 H).

13C NMR (75 MHz, CDCl3): 58.9, 78.1, 127, 128.2, 128.3, 128.4, 128.7, 128.9, 137.6, 139.7.

threo-2-Bromo-1,2-diphenylethanol (2p) [10f]


139


Hz), 7.03-7.20 (m, 10 H).

13C NMR (75 MHz, CDCl3): 64.3, 78.3, 126.8, 128.2, 128.3, 128.4, 128.5, 138.2, 138.6.

trans-2-Bromo-1-hydroxyindane (2q) [5d]

1H 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).

13C NMR (75 MHz, CDCl3): 40.4, 54.5, 83.3, 124, 124.5, 127.6, 129, 139.7, 141.6

trans-2-Bromocyclohexan-1-ol (2r) [5d]

1H 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]

1H 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]

1H 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).

13C 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.

2-Bromododecan-1-ol (2uI) [10c]

1H 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).

13C 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.

erythro-2-Bromooctan-3-ol (2v) [5d]


140

1H 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]

1H 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).

13C NMR (75 MHz, CDCl3): 14, 19, 22.4, 27.5, 31.1, 33.9, 66.2, 70.3.

1,2-Dibromo-1-phenylethane (3a) [5e]

1H 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]


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]

1H 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).

13C NMR (75 MHz, CDCl3): 34.6, 49.5, 128.9, 129.1, 134.9, 137.1.

erythro-2,3-Dibromo-3-phenylpropan-1-ol (3j) [6]

1H 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]


141

1H 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]

1H 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]


Hz), 7.25-7.40 (m, 2 H).

13C NMR (75 MHz, CDCl3): 46.7, 50.8, 53.4, 128, 128.9, 129.4, 137.5, 168.3.

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]

1H 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).

13C NMR (75 MHz, CDCl3): 46.8, 49.8, 128.3, 128.8, 128.9, 129, 129.3, 134.2, 134.4, 138.2,

191.2

meso-1,2-Dibromo-1,2-diphenylethane (3o) [5a]

1H 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]

1H NMR (300 MHz, CDCl3): 5.42 (s, 2 H), 7.14 (s, 10 H).

trans-1,2-Dibromoindane (3q) [5e]

1H 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).


142

trans-1,2-Dibromocyclohexane (3r) [5d]

1H 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]


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).

13C 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.

erythro-2,3-Dibromooctane (3v) [4a]


H), 2.08-2.20 (m, 1 H), 4.02-4.10 (m, 1 H), 4.12-4.23 (m, 1 H).

13C NMR (75 MHz, CDCl3): 14, 22.4, 25, 26.6, 31, 37.1, 52.4, 61.8.

2-Bromo-1,4-naphthoquinone (3w) [10e]

1H 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]

1H 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).

13C NMR (75 MHz, CDCl3): 36.8, 57.8, 83.3, 126.6, 128.5, 128.7, 138.9.

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]

1H 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).


143

13C NMR (75 MHz, CDCl3): 21.2, 36.4, 57.1, 83.3, 126.7, 129.3, 135.9, 138.3.

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)

1H 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).

13C 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]

1H 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).

13C NMR (75 MHz, CDCl3): 31.3, 34.6, 36.4, 57.2, 83.2, 125.5, 126.4, 135.9, 151.4.

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]


Hz), 7.25 (d, 2 H, J = 8.49 Hz), 7.34 (d, 2 H, J = 8.49 Hz).

13C NMR (75 MHz, CDCl3): 35.9, 57.3, 82.6, 128.1, 128.8, 134.3, 137.5.

2-Bromo-1-methoxy-1-(4-bromophenyl)ethane (4g) [5e]


Hz), 7.20 (d, 2 H, J = 9 Hz), 7.50 (d, 2 H, J = 9 Hz)


144

1-Bromo-2-methoxy-2-phenylpropane (4h) [5e]

1H 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).

13C NMR (75 MHz, CDCl3): 21.8, 43.1, 51, 77.8, 126.4, 127.8, 128.4, 141.7.

1-Bromo-2-methoxy-2-(4-chlorophenyl)propane (4i)


H).

13C 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]

1H 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).

13C NMR (75 MHz, CDCl3): 57.5, 57.8, 64.6, 86, 127.5, 128.4, 128.5, 138.

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]


H, J = 9.44 Hz), 7.24-7.42 (m, 5 H).

erythro-2-Bromo-3-methoxy-3-phenylpropanoic acid (4l) [5f]

1H 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]


145


H, J = 9.82 Hz), 7.30-7.52 (m, 5 H).

13C NMR (75 MHz, CDCl3): 47, 53, 57.5, 84, 128, 128.3, 128.9, 136.7, 169.4.

erythro-2-Bromo-3-methoxy-1,3-diphenylpropan-1-one (4n) [5f]


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).

13C NMR (75 MHz, CDCl3): 47.2, 57.6, 83.3, 128.2, 128.3, 128.7, 133.7, 135.2, 137.8, 193.1.

erythro-1-Bromo-2-methoxy-1,2-diphenylethane (4o) [5c]


Hz), 7.14-7.32 (m, 10 H).

13C NMR (75 MHz, CDCl3): 57, 57.6, 87, 127.9, 128.1, 128.1, 128.2, 128.3, 128.8, 138.3,

138.7.

threo-1-Bromo-2-methoxy-1,2-diphenylethane (4p) [14]

1H 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).

13C NMR (75 MHz, CDCl3): 57.2, 58.8, 87.4, 127.6, 128.1, 128.2, 128.5, 137.8, 138.8.

trans-2-Bromo-1-methoxyindane (4q) [5e]

1H 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).

13C NMR (75 MHz, CDCl3): 41.6, 50.7, 57.7, 91.7, 124.7, 125.2, 127.2, 129.1, 139.9, 140.4.

4-Bromo-3-methoxy-3-methylbutane-1-ol (4t) [13]


146

1H 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]

1H 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).

13C NMR (75 MHz, CDCl3): 15.1, 36.5, 64.9, 81.6, 126.7, 128.3, 128.6, 139.8.

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)

1H 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)

1H 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).

13C 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).


2-Bromo-1-ethoxy-1-(4-t-butylphenyl)ethane (4E)


147

1H 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).

13C 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.


2-Bromo-1-ethoxy-1-(4-chlorophenyl)ethane (4F)

1H 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).

13C NMR (75 MHz, CDCl3): δ 15.1, 36.1, 65.1, 80.9, 128.1, 128.8, 134.1, 138.3.


2-Bromo-1-ethoxy-1-(4-bromophenyl)ethane (4G)

1H 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).

13C 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)

1H 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).

13C NMR (75 MHz, CDCl3): δ 15.6, 22.6, 43.1, 58.6, 77.6, 126.2, 127.6, 128.3, 142.5.


1-Bromo-2-ethoxy-2-(4-chlorophenyl)propane (4I)

1H 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).

13C NMR (75 MHz, CDCl3): δ 15.6, 22.5, 42.6, 58.7, 77.4, 127.7, 128.5, 133.6, 141.2.


148


erythro-2-Bromo-1-ethoxy-1-phenylpropanol (4J)

1H 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).

13C 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)

1H 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).

13C 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.


trans-2-Bromo-1-ethoxyindane (4Q) [15]

1H 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)


2.32 (m, 1 H), 3.34-3.46 (m, 2 H), 4.15-4.20 (m, 1 H).

13C NMR (75 MHz, CDCl3): δ 16, 21.8, 23.3, 32.9, 33, 56.2, 60, 75.8.


4-Bromo-3-ethoxy-3-methylbutane-1-ol (4T)


2.10 (m, 1 H), 3.36-3.54 (m, 4 H), 3.7-3.84 (m, 2 H).


149

13C NMR (75 MHz, CDCl3): δ 15.8, 21.5, 38.8, 38.9, 57.3, 59.2, 76.8.


1-Bromo-4-phenyl-3-butene-2-one (6) [16]

1H 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)

1H 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).

13C 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).


2-Bromo-1-isopropoxy-1-phenylethane (Table 4.13, entry 6) [8c]

1H 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).


150

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chapter 4 oxybromination -...

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