IBX/LiBr-promoted one-pot oxidative anti-Markownikov bromohydroxylation/bromoalkoxylation of Baylis-Hillman olefins

Article abstract of DOI:10.1016/j.tetlet.2008.11.119

The first example of one-pot oxidative anti-Markownikov bromohydroxylation and bromoalkoxylation of Baylis-Hillman (BH) adducts (olefins) is reported. The reaction is performed at rt using LiBr as the bromine source and 2-iodoxybenzoic acid (IBX) as the o

Full text of DOI:10.1016/j.tetlet.2008.11.119

Tetrahedron Letters 50 (2009) 715–718
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IBX/LiBr-promoted one-pot oxidative anti-Markownikov
bromohydroxylation/bromoalkoxylation of Baylis–Hillman olefins
*
Lal Dhar S. Yadav , Chhama Awasthi
Green Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad 211 002, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The first example of one-pot oxidative anti-Markownikov bromohydroxylation and bromoalkoxylation of
Baylis–Hillman (BH) adducts (olefins) is reported. The reaction is performed at rt using LiBr as the bro-
mine source and 2-iodoxybenzoic acid (IBX) as the oxidant. The process involves oxidation of BH adducts
with IBX to give b-ketomethylene compounds in situ, which undergo highly regioselective vicinal func-
Received 25 September 2008
Revised 18 November 2008
Accepted 28 November 2008
Available online 3 December 2008
tionalization with LiBr/H2O or LiBr/ROH in the same vessel to afford a-bromo-b-hydroxy or a-bromo-b-
alkoxy compounds, respectively, in excellent yields. The
transformed into epoxides in aq NaOH.
a
-bromo-b-hydroxy compounds are readily
Keywords:
Baylis–Hillman adducts
Hypervalent iodine
Oxidation
Ó 2008 Elsevier Ltd. All rights reserved.
Bromohydrins
Bromoethers
LiBr
The development of new, one-pot and selective synthetic meth-
odologies has been an important area of current research in organ-
ic chemistry. These sequential multistep reactions are of increasing
academic, economic and ecological interests because they address
fundamental principles of synthetic efficiency and reaction design.
The vicinal functionalization of an olefin is a powerful synthetic
tool for organic chemists, especially when the reaction is carried
out in regioselective fashion. A great deal of attention has been
paid to the selective introduction of two different functional
groups such as hydroxy or alkoxy and halogen, in organic synthe-
sis.1 The resulting halohydrins and alkoxy halides are important
building blocks in organic, medicinal as well as industrial chemis-
mations.7 BH adducts have been employed as Michael acceptors
to produce functionalized aldol products with oxygen, sulfur,
nitrogen and carbon-centred nucleophiles.8 However, there has
been no report on vicinal functionalization of BH olefins 1 via oxi-
dative bromohydroxylation and bromoalkoxylation (Scheme 1).
Usual methods available for the synthesis of halohydrins in-
clude ring opening of epoxides9 or cyclic sulfates10 by hydrogen
halides or metal halides. The general approach for heterolytic addi-
tions of halogen and water to an olefinic bond involves the use of
molecular halogen or N-halosuccinimide.11
a,b-Unsaturated car-
bonyl compounds and carboxylic acids have also been reported
to undergo halohydrin reactions with N-halosuccinimide.12
However, the halohydrin reactions suffer from several disad-
vantages such as the use of stoichiometric amounts of corrosive
Br2/N-halosuccinimide or the formation of large amounts of organ-
ic and inorganic wastes.12 Recently, halohydrin reactions have
been advantageously performed using LiBr as the halogen source
tries.2,3
precursors, which can be readily transformed into epoxides,
ketones and unusual b-hydroxy-
-amino acids,4 and thus enhance
a-Halo-b-hydroxy derivatives (halohydrins) are versatile
a
the versatility of molecules containing these structural fragments.
Haloalkoxy compounds have been used as versatile intermediates
in the synthesis of various natural products.5,6 Hence, the develop-
ment of a convenient and efficient methodology for the synthesis
13
in the presence of an oxidant NaIO4 or ceric ammonium nitrate
(CAN).14
of
a
-halo-b-hydroxy and
a
-halo-b-alkoxy compounds (haloethers)
Amongst various hypervalent iodine reagents,15 2-iodoxyben-
zoic acid (IBX) has become the reagent of choice due to its easy
handling, ready availability, tolerance to moisture,16 mild reaction
conditions and zero toxic waste generation. IBX selectively oxi-
dizes alcohols in the presence of olefins, thioethers and amino
groups,17 and is also useful for other elegant oxidative transforma-
tions.18 It has been reported that IBX efficiently oxidizes BH
alcohols to the corresponding ketones.19 Because of IBX explosive-
ness and insolubility in most organic solvents, several research
groups have synthesized IBX derivatives that are stable and
is an interesting target of investigation. Herein, Baylis–Hillman
(BH) chemistry has been applied for this purpose.
Baylis–Hillman adducts contain a minimum of three chemo-
specific functional groups, that is, hydroxy (or amino), alkene and
electron-withdrawing groups, thereby providing handles for
further manipulation in a multitude of synthetic organic transfor-
* Corresponding author. Tel.: +91 5322500652; fax: +91 5322460533.
E-mail address: ldsyadav@hotmail.com (L. D. S. Yadav).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.119

716
L. D. S. Yadav, C. Awasthi / Tetrahedron Letters 50 (2009) 715–718
O
O
OH
Br
EWG
EWG
O
EWG
10% NaOH (aq)
IBX/LiBr
CH3CN/R2OH
rt, 8-10 h
rt, 5-10 min
R1
OR2
R1
R1
Only for R2 = H
2, R2 = H, Yield 81-89%
1
3
4, R2 = Me, Et, Yield 78-87%
EWG = CN, COOMe
84-94%
Scheme 1. IBX/LiBr-promoted oxidative bromohydroxylation and bromoalkoxylation of BH olefins 1.
Table 1
One-pot oxidative synthesis of bromohydrins 2 and epoxides 3 (Scheme 1)
O
O
R1
EWG
Reaction time (h)
Yielda,b (%)
CN
Br
Compound 2, 3
CN
IBX/LiBr
(Br2)
2
3
2
3
6
5
a
b
c
d
e
f
H
H
OMe
OMe
Cl
CN
COOMe
CN
COOMe
CN
COOMe
9
9
10
10
8
7
7
8
8
5
8
86
85
83
81
89
87
89
87
85
84
94
91
-HBr
ROH
O
OH
Cl
9
Br
CN
OR
CN
a
Yield of pure products 2 and 3 after column chromatography.
All compounds gave C, H and N (if present) analyses within 0.36% and satis-
b
factory spectral (IR, 1H NMR, 13C NMR and EIMS) data.
1
2
4
R = H
R = Me, Et
Table 2
Scheme 2. Plausible mechanism for the oxidative bromohydroxylation and
bromoalkoxylation of BH olefins 1.
One-pot oxidative synthesis of bromoethers 4 (Scheme 1)
Compound 4
R1
EWG
R2
Reaction time (h)
Yielda,b (%)
a
b
c
d
e
f
g
h
i
H
H
OMe
OMe
Cl
Cl
H
H
CN
COOMe
CN
COOMe
CN
COOMe
CN
COOMe
CN
COOMe
CN
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
9
9
10
10
8
8
9
9
84
82
83
80
87
85
81
80
81
78
84
82
soluble.20 Furthermore, some preparations of IBX scaled up to its
one mole have also been reported.21 During experimentation with
IBX, we have found that it smoothly liberates Br2 from LiBr under
ambient conditions.
Considering the above points and our ongoing efforts to develop
new one-pot synthetic processes,22 we report herein, the first
example of IBX/LiBr-promoted one-pot oxidative bromohydroxyla-
tion and bromoalkoxylation of BH adducts 1 (Scheme 1), which
opens up a new aspect of the synthetic utility of BH adducts. In or-
der to optimize reaction conditions, we carried out bromohydroxy-
lation23 of the representative BH adduct 1 (Scheme 1) using KBr,
NaBr, or LiBr as the bromine source and NaIO4, CAN, or IBX as
the oxidant. Among these, LiBr and IBX gave the best results in
terms of the yield of bromohydrin 2 (86%) under the reaction con-
ditions.23 Herein, Li+ ions appear to play a more efficient catalytic
role than K+ or Na+ ions in the addition of Br2 to the olefinic bond,
which leads to the formation of 2 or 4 (Scheme 2). This is in confor-
mity with earlier observations that LiBr is useful as an efficient Le-
wis acid in a variety of organic transformations including Biginelli,
Knoevenagel, Wadsworth–Emmons reactions, dithioacetalizations
and dihydrohalogenations.24 Similarly, the use of LiBr with the oxi-
dant NaIO4 or CAN under the same reaction conditions afforded 2
in 51% or 42% yields, respectively. This is presumably because
IBX oxidizes BH alcohols into the corresponding ketones more effi-
ciently as compared to NaIO4 or CAN under the same reaction con-
ditions.23 Thus, the overall yield of 2 (86%) is significantly higher in
the case of IBX than in the case of NaIO4 (51%) or CAN (42%).
Next, optimization of the solvent for the synthesis of 2 (Scheme
1) was investigated and it was found that, in general, a CH3CN–H2O
mixture was a better solvent system than the corresponding THF–
H2O mixture in terms of reaction time and the yield of 2 (Table 3).
This is because of a lower solubility of substrates in the THF–H2O
system than in the CH3CN–H2O mixture. Among the proportions
of CH3CN–H2O, (2:1) was found to be the best solvent system
affording the highest yield (86%) of 2 in the shortest (9 h) reaction
OMe
OMe
Cl
10
10
9
j
k
l
Cl
COOMe
Et
9
a
Yield of pure products 4 after column chromatography.
All compounds gave C, H and N (if present) analyses within 0.38% and satis-
b
factory spectral (IR, 1H NMR, 13C NMR and EIMS) data.
Table 3
Optimization of the solvent for the synthesis of 221 (Scheme 1)
Entry
Solvent-system
Reaction time (h)
Yielda (%)
1
2
3
4
5
6
THF/H2O (1:1)
THF/H2O (2:1)
THF/H2O (3:1)
CH3CN/H2O (1:1)
CH3CN/H2O (2:1)
CH3CN/H2O (3:1)
18
16
13
12
9
39
44
48
67
86
79
10
a
Isolated yields.
time (Table 3, entry 5). The present optimized synthesis of 223 in-
volves stirring a mixture of adduct 1 and IBX at rt for 2 h in CH3CN
followed by the addition of an aq LiBr solution and stirring for a
further 6–8 h at rt to afford bromohydrin 2 in consistently good
yields (81–89%) (Table 1). Bromohydrins 2 were transformed into
the corresponding epoxides 325 in (84–94%) yields on treatment
with 10% aq NaOH at rt for 5–10 min (Table 1). The requisite BH
adducts
1 and IBX were prepared employing the known
method.21a,26

L. D. S. Yadav, C. Awasthi / Tetrahedron Letters 50 (2009) 715–718
717
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After a successful attempt at the synthesis of bromohydrins 2,
we applied the same procedure for the synthesis of bromoethers
4 from BH adducts 1 using MeOH or EtOH instead of H2O to afford
4 in 78–87% yields27 (Table 2).
A plausible mechanistic pathway for the regioselective forma-
tion of bromohydrins 2 and bromoethers 4 is depicted in Scheme
2. Possibly a three-membered cyclic bromonium ion intermediate
6 is formed by the electrophilic addition of Br2 (generated in situ
from LiBr/IBX) to the double bond of the olefin 5, which is then at-
tacked by H2O, MeOH, or EtOH to form the product 2 or 4. With all
the substrates studied, the reaction proceeded with complete reg-
ioselectivity in favour of the anti-Markownikov product, that is, the
hydroxy or alkoxy group is added to the b-position, exclusively
(Scheme 2). No traces of dibromides were observed in the case of
any of the substrates 1 used in the present study.
19. Yadav, J. S.; Reddy, S.; Singh, A. P.; Basak, A. K. Tetrahedron Lett. 2007, 48, 7546–
7548.
20. (a) Jang, H. S.; Chung, W. J.; Lee, Y. S. Tetrahedron Lett. 2007, 48, 3731–3734; (b)
Mülbaier, M.; Giannis, A. Angew. Chem., Int. Ed. 2001, 40, 4393–4394; (c) Lei, Z.;
Denecker, C.; Jegasothy, S.; Sherrington, D. C.; Slater, N. K. H.; Sutherland, A. J.
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Tetrahedron Lett. 2003, 44, 9251–9254.
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22. (a) Yadav, L. D. S.; Yadav, S.; Rai, V. K. Green Chem. 2006, 8, 455–458; (b) Yadav,
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In summary, we have presented the first example of one-pot
oxidative bromohydroxylation and bromoalkoxylation of BH ad-
ducts to afford the corresponding
a-bromo-b-hydroxy and a-bro-
mo-b-alkoxy compounds by using LiBr as the bromine source
and IBX as the oxidant. The methodology avoids the use of heavy
metal halides or N-halosuccinimides as the halogen source, and
opens up a new aspect of the synthetic utility of BH adducts.
Acknowledgement
23. General procedure for the synthesis of bromohydrins 2: A mixture of BH adduct 1
(1 mmol) and IBX (2.4 mmol) in acetonitrile (10 mL) was stirred at rt for 2 h
followed by the addition of a solution of LiBr (2 mmol) in H2O (5 mL) and
stirring for a further 6–8 h at rt (Table 1). After completion of the reaction
(monitored by TLC), the mixture was diluted with water and extracted with
diethyl ether (3 Â 20 mL). The combined organic layers were washed with
sodium thiosulfate followed by brine, dried over anhydrous Na2SO4 and
evaporated under reduced pressure to give the crude product, which was
purified by silica gel column chromatography using hexane/ethyl acetate
(9.4:0.6) as eluent to afford an analytically pure sample of 2. Physical data of
representative compounds. Compound 2a: Yellowish solid, yield 86%, mp
We sincerely thank SAIF, Punjab University, Chandigarh, for
providing microanalyses and spectra.
References and notes
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156 °C. IR (KBr)
mmax 3490, 3068, 2870, 2241, 1666, 1602, 1584, 1455, 760, 695,
534 cmÀ1
.
1H NMR (400 MHz; CDCl3/TMS): d 2.30 (br s, 1H, OH), 4.61 (d, 1H,
J = 12.2 Hz, b-Ha), 4.30 (d, 1H, J = 12.2 Hz, b-Hb), 7.34–7.95 (m, 5Harom). 13C
NMR (100 MHz; CDCl3/TMS): d 58.1, 63.3, 116.8, 127.0, 127.9, 133.5, 136.7,
198.3. EIMS (m/z): 253 (M+). Anal. Calcd for C10H8BrNO2: C, 47.43; H, 3.16; N,
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565 cmÀ1 1H NMR (400 MHz; CDCl3/TMS): d 2.10 (br s, 1H, OH), 3.60 (s, 3H,
.
COOMe), 3.80 (s, 3H, OMe), 4.56 (d, 1H, J = 12.2 Hz, b-Ha), 4.25 (d, 1H,
J = 12.2 Hz, b-Hb), 7.11 (d, 2H, J = 7.9 Hz, Harom), 7.69 (d, 2H, J = 7.9 Hz, Harom).
13C NMR (100 MHz; CDCl3/TMS): d 50.2, 55.0, 65.4, 71.6, 112.1, 130.1, 131.2,
167.7, 173.0, 196.8. EIMS (m/z): 316 (M+). Anal. Calcd for C12H13BrO5: C, 45.57;
H, 4.11. Found: C, 45.23; H, 4.43.
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25. General procedure for the synthesis of epoxides 3: Bromohydrin 2 (1 mmol) was
stirred in a 10% aq NaOH solution (5 mL) for 5–10 min (Table 1). Then, water
(5 mL) was added to the reaction mixture and it was extracted with EtOAc
(3 Â 10 mL). The combined organic layers were washed with brine and then
dried over anhydrous Na2SO4. The extract was filtered and the filtrate was
evaporated under reduced pressure to leave a residue, which was purified by
silica gel column chromatography (hexane/EtOAc 9.3:0.7) to afford the pure
product 3. Compound 3a: White solid, yield 89%, mp 110–111 °C. IR (KBr) mmax
3054, 2235, 1695, 1260, 870, 765, 698, cmÀ1 1H NMR (400 MHz; CDCl3/TMS): d
.
2.91 (d, 1H, J = 6.0 Hz, b-Ha), 3.20 (d, 1H, J = 6.0 Hz, b-Hb), 7.34–7.95 (m,
5Harom). 13C NMR (100 MHz; CDCl3/TMS): d 40.7, 63.4, 117.1, 127.8, 128.8,
131.2, 136.7, 198.2. EIMS (m/z): 173 (M+). Anal. Calcd for C10H7NO2: C, 69.34;
H, 4.04; N, 8.09. Found: C, 69.69; H, 4.40; N, 7.76. Compound 3d: White solid,
yield 84%, mp 147–149 °C. IR (KBr) mmax 2995, 2854, 1746, 1693, 1605, 1543,
1340, 1265, 875, 853 cmÀ1 1H NMR (400 MHz; CDCl3/TMS): d 2.81 (d, 1H,
.
J = 6.0 Hz, b-Ha), 3.20 (d, 1H, J = 6.0 Hz, b-Hb) 3.53 (s, 3H, COOMe), 3.64 (s, 3H,
OMe), 7.11 (d, 2H, J = 7.9 Hz, Harom), 7.69 (d, 2H, J = 7.9 Hz, Harom). 13C NMR
(100 MHz; CDCl3/TMS): d 40.7, 55.8, 61.5, 76.8, 113.6, 128.0, 128.9, 130.3,
173.6, 196.8. EIMS (m/z): 236 (M+). Anal. Calcd for C12H12O5: C, 60.99; H, 5.08.
Found: C, 61.34; H, 5.36.
26. Cai, J.; Zhou, Z.; Zhao, G.; Tang, C. Org. Lett. 2002, 4, 4723–4725.
27. General procedure for the synthesis of bromoethers 4: The procedure followed
was the same as described above for the synthesis of 221 except that MeOH or
EtOH (5 mL) was used instead of H2O (5 mL). The crude product was purified
by column chromatography on silica gel with hexane/EtOAc (9.5:0.5) as eluent
to afford the pure product 4. Compound 4a: Yellowish solid, yield 84%, mp
10. Nandanan, E.; Phukan, P.; Sudalai, A. Ind. J. Chem. 1999, 38B, 283–286.
11. (a) Comprehensive Organic Transformation:
A Guide to Functional Group
Preparation; Larock, R. C., Ed., 2nd ed.; Wiley-VCH: New York, 1999; pp 629–
640; (b) Das, B.; Venkateswarlu, K.; Damodar, K.; Suneel, K. J. Mol. Catal. A:
Chem. 2007, 269, 17–21; (c) Barluenga, J.; Marco-Arias, M.; Gonzalez-Bobes, F.;
Ballesteros, A.; Gonzalez, J. M. Chem. Eur. J. 2004, 10, 1677–1682; (d) Masuda,
H.; Takase, K.; Nishio, M.; Hasegawa, A.; Nishiyam, Y.; Ishii, Y. J. Org. Chem.
1994, 59, 5050–5055; (e) Yadav, J. S.; Reddy, B. V. S.; Baishya, G.;
125 °C. IR (KBr) mmax 3052, 2996, 2856, 2239, 1697, 760, 697, 557 cmÀ1 1H
.
NMR (400 MHz; CDCl3/TMS): d 3.31 (s, 3H, OMe), 4.25 (d, 1H, J = 12.2 Hz, b-Ha),
4.56 (d, 1H, J = 12.2 Hz, b-Hb), 7.34–7.95 (m, 5Harom). 13C NMR (100 MHz;

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L. D. S. Yadav, C. Awasthi / Tetrahedron Letters 50 (2009) 715–718
CDCl3/TMS): d 51.0, 55.1, 72.8, 116.4, 117.1, 127.8, 128.9, 131.2, 198.2. EIMS
(s, 3H, COOMe), 3.64 (s, 3H, OMe), 4.21 (d, 1H, J = 12.2 Hz, b-Ha), 4.52 (d, 1H,
J = 12.2 Hz, b-Hb), 7.11 (d, 2H, J = 7.9 Hz, Harom), 7.69 (d, 2H, J = 7.9 Hz, Harom).
13C NMR (100 MHz; CDCl3/TMS): d 15.5, 47.9, 56.9, 64.4, 69.2, 72.6, 113.7,
128.1, 128.9, 167.2, 171.1, 198.3. EIMS (m/z): 344 (M+). Anal. Calcd for
C14H17BrO5: C, 48.83; H, 4.94. Found: C, 48.45; H, 4.67.
(m/z): 267 (M+). Anal. Calcd for C11H10BrNO2: C, 49.44; H, 3.74; N, 5.24. Found:
C, 49.78; H, 3.38; N, 4.91. Compound 4j: Yellowish solid, yield 78%, mp 160 °C.
IR (KBr) mmax 2995, 2854, 1742, 1695, 1605, 1543, 1340, 853, 560 cmÀ1 1H
.
NMR (400 MHz; CDCl3/TMS): d 1.23 (t, 3H, CH2CH3), 3.56 (q, 2H, CH2CH3), 3.53