A New Regioselective Synthesis of Vicinal Bromohydrins via Free Radical Decarboxylative Bromination of β-Hydroxycarboxylic Acids

Article abstract of DOI:10.1055/s-2003-43379

Diisopropylcarbodiimide-mediated condensations between N-hydroxypyridine- 2(1H)-thione and β-hydroxycarboxylic acids afforded mixed anhydrides which were regioselectively converted into vicinal bromohydrins under neutral conditions.

Full text of DOI:10.1055/s-2003-43379

LETTER
69
A New Regioselective Synthesis of Vicinal Bromohydrins via Free Radical
Decarboxylative Bromination of b-Hydroxycarboxylic Acids
V
a
icinal Bromohydrins
a
from
b
-Hy
r
c
boxylic
A
c
o
ids Greb,a Jens Hartung*b
b
Received 24 October 2003
2-Ethyl-3-methyl-3-hydroxybutyric acid (3a) was select-
ed as starting material in order to establish a synthetically
useful radical-based route to 3-bromo-2-methyl-2-pen-
tanol (1a) (trapping of a secondary radical in vicinity of a
tertiary hydroxyl group, Table 1). For this purpose, a so-
lution of N-hydroxypyridine-2(1H)-thione13 (not shown
in Table 1) and b-hydroxycarboxylic acid 3a in anhydrous
CH2Cl2 was treated for 20 hours at 20 °C with diisopro-
pylcarbodiimide (DIC) to furnish N-acyloxy-substituted
pyridinethione 4a in approximately 70% yield. No trans-
formation was seen if N-hydroxypyridine-2(1H)-thione
was stirred in the presence DIC in a solution of CH2Cl2
alone. In the absence of N-hydroxypyridine-2(1H)-thione,
substrate 3a was almost quantitatively converted by DIC
into 2-ethyl-3,3-dimethyl-b-propiolactone14 (81%, if puri-
fied by column chromatography) – a product that was not
observed in the original reaction mixture, from which
target product 4a had been obtained. Treatment of this
b-lactone for 20 hours in CH2Cl2 with N-hydroxypyri-
dine-2(1H)-thione furnished 10% of thione 4a (NMR).
Approximately 60% of b-lactone was recovered from this
experiment.
Abstract: Diisopropylcarbodiimide-mediated condensations be-
tween N-hydroxypyridine-2(1H)-thione and b-hydroxycarboxylic
acids afforded mixed anhydrides which were regioselectively con-
verted into vicinal bromohydrins under neutral conditions.
Key words: 1,2-bromohydrin, bromination, carbon radical, pyridi-
nethione, stereoselective synthesis
Terpene- or acetogenine-derived 1,2-bromohydrins have
been purified from several marine organisms.1,2 The bio-
logical role of such secondary metabolites is subject of
ongoing research.3,4 From a synthetic point of view, it is
known that vicinal bromohydrins serve as alkylating
reagents5 and are synthetically useful intermediates in a
variety of selective transformations.6 In view of this
background, efficient and reliable syntheses of b-
bromohydrins7 have been developed which predominant-
ly start from olefins,8 epoxides,9 or diols.10 Surprisingly,
nothing has been reported so far on the synthesis of 2-bro-
moalcohols using free radical-based methods.11 The latter
type of transformations may be performed under mild and
neutral conditions thus offering advantages for regiose-
lectively preparing unsaturated b-bromohydrines without
competing electrophile-induced side reactions. In order to
pursue a project which requires the availability of pure 2-
bromoalkenols in sufficient quantities, we have addressed
the synthetic problem of converting 2-hydroxycarboxylic
acids 3 via intermediate alkyl radicals 2 into 2-bromoalco-
hols 1 (Figure 1). We disclose our results in the present
communication.11,12
Radical precursor 4a was identified by its characteristic
13C NMR signals, especially those originating from the
pyridinethione entity [e.g. d = 175.4 (C=S) and 113.1
(C4)].15 This compound was stable, if stirred for 20 hours
at 20 °C in the dark (1H NMR) but it decomposed to a
considerable degree when subjected to column chroma-
tography. Therefore, crude 4a, as obtained after work up
using extractions only, was dissolved in C6H6 and photo-
lyzed in the presence of BrCCl3 to furnish target com-
pound 1a in ca 75% yield (50% from 3a).16,17 No attempts
were made to apply alternative bromine atom donors
for this purpose since this issue had been addressed previ-
ously.18 Addition of DMAP in order to facilitate the anhy-
dride forming step did not improve the overall yield of
bromohydrin 1a from hydroxyacid 3a (Table 1, entries 1
and 2). It should be added that this modification was in
other instances useful in order to raise the yields of alkyl
radical precursors by ca 5–10% thus improving the overall
efficiency of the new bromohydrin synthesis (see
Schemes 1 and 3). A change to dicyclohexylcarbodiimide
(DCC) as dehydrating reagent provided comparable
results to DIC (Table 1, entry 3).19 In view of the fact
that N,N¢-diisopropyl urea was frequently easier to re-
move on a quantitative scale from the reaction mixtures,
we adhered to the use of DIC as standard reagent. An
Figure 1 Starting material 3 and reactive intermediates 2 in a new
synthesis of b-bromohydrins 1 under neutral conditions. R1, R2 = H,
alkyl, phenyl.
SYNLETT 2004, No. 1, pp 0069–0072
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Advanced online publication: 4.12.2003
DOI: 10.1055/s-2003-43379; Art ID: G21503ST
© Georg Thieme Verlag Stuttgart · New York

70
M. Greb, J. Hartung
LETTER
application of trispropanephosphonic acid anhydride for competing ring closure reactions were observed in both
this purpose completely failed.20 Likewise, attempts to instances (1H NMR).
convert N-hydroxy-4-methyl-5-(p-anisyl)thiazole-2(3H)-
thione21 (not shown) into the corresponding N-acyloxy
derivative, according to the conditions which are outlined
in Table 1, were not successful for reasons which have yet
to be explored.
Table 1 The Synthesis of 3-Bromo-2-methyl-2-pentanol (1a) from
2-Ethyl-3-methyl-3-hydroxybutyric Acid (3a)
Scheme 2 Formation of unsaturated 2,3-halohydrins 1d and 5.
Reagents and conditions: (a) N-hydroxypyridine-2(1H)-thione, DIC,
CH2Cl2, 20 °C; (b) BrCCl3, C6H6, 20 °C, hn; (c) CCl4, C6H6, 20 °C, hn.
The conversion of 2-hydroxy-1-methylcyclohexylcarbox-
ylic acid 3e into cyclic b-bromohydrin rac-1e
(cis:trans = 20:80, trapping of a tertiary radical in vicinity
of a secondary hydroxyl group) was feasible although the
yields remained moderate. The relative trans-configura-
tion of the major diastereomer of 1e was verified by an
independent synthesis of this compound. Treatment of
1-methylcyclohexene oxide under stereocontrolled condi-
tions using MgBr2·Et2O in Et2O (T = 20 °C)25 and subse-
quent hydrolysis of the reaction mixture using an aqueous
phosphate buffer provided 83% of a 56:44 mixture of
trans-1e and trans-2-bromo-1-methylcyclohexanol (not
shown), i.e. the product of HOBr-addition to 1-methylcy-
clohexene.26 The observed stereoselectivity in the radical-
based bromohydrin synthesis is explicable via selective
bromine atom delivery that occurs for steric reason pre-
ferentially from the opposite side of the hydroxyl substit-
uent, which affords trans-1e as major bromoalcohol
(Scheme 3).27
Entry
Conditionsa
DIC
1a Yield (%)
1
2
3
50
48
51
DIC/DMAP
DCC/DMAP
The new method was applied for the synthesis of enantio-
merically pure (R)-2-bromo-1-phenyl-1-ethanol (1b)
20
{[a]D = –40.8 (c 1.01, CH2Cl2)}22 from (S)-configured
acid 3b (> 98% ee; trapping of a primary radical in vicin-
ity of a benzylic hydroxyl group, Scheme 1). Although the
yield of this two step sequence could not compete with the
synthesis of bromohydrin 1b from styrene via HOBr addi-
tion,23 it represents one of the rare examples that proceeds
with complete regioselectivity and a full conservation of
stereointegrity at C1.24 The synthesis of 2-bromo-2-phe-
nylethanol (1c) was unfortunately associated with a poor
yield (trapping of a benzylic radical in vicinity of a prima-
ry hydroxyl group). Complications in the latter reaction
arose especially in the initial step (not shown in
Scheme 1) which provided significant amounts of yet un-
identified products besides the desired N-acyloxypyri-
dine-2(1H)-thione.
Scheme 3 Stereoselective synthesis of trans-2-bromo-2-methyl-
cyclohexanol (trans-3e) from hydroxycarboxylic acid 1e. Reagents
and conditions: (a) N-hydroxypyridine-2(1H)-thione, DIC, DMAP,
CH2Cl2, 20 °C; (b) BrCCl3, C6H6, 20 °C, hn.
Scheme 1 Regioselective synthesis of styrene-derived b-bromohy-
drins 1b and 1c. Reagents and conditions: (a) N-hydroxypyridine-
2(1H)-thione, DIC, DMAP, CH2Cl2, 20 °C; (b) BrCCl3, C6H6, 20 °C, hn.
In conclusion, we have demonstrated the feasibility,
scope, and limitation of b-bromohydrin formation under
neutral, i.e. non-oxidative conditions, starting from b-hy-
droxycarboxylic acids. The reaction is considered to offer
advantages for syntheses of unsaturated b-bromo- or b-
chlorohydrins, where polar methods lead to complications
such as a partial racemization or rearrangements.
d-Unsaturated b-bromohydrin 1d (42%, BrCCl3 as trap-
ping reagent) and the corresponding chlorohydrin 5 (36%,
CCl4 as chlorine atom donor) were prepared on a synthetic
scale starting from 2-(1-methyl-1-hydroxyethyl-5-meth-
ylhexenoic acid (3d) (Scheme 2). No spectroscopic evi-
dence for the formation of side products originating from
Synlett 2004, No. 1, 69–72 © Thieme Stuttgart · New York

LETTER
Vicinal Bromohydrins from b-Hydroxycarboxylic Acids
71
Experimental Section
References
A solution of 2-ethyl-3-hydroxy-3-methylbutyric acid (3a) (439
mg, 3.0 mmol) and N-hydroxypyridine-2(1H)-thione (401 mg, 3.15
mmol) in anhyd CH2Cl2 (8 mL) was treated at 0 °C dropwise (within
20 min) with a solution of DIC (416 mg, 3.30 mmol) in anhyd
CH2Cl2 (7 mL) in the dark. Stirring was continued for 2 h at 0 °C
and for 20 h at 20 °C in the dark. Afterwards the volatiles were re-
moved under reduced pressure to provide a crude product that was
taken up in Et2O. The precipitate was removed by filtration. The
solids were washed with Et2O. Combined filtrate and washings
were concentrated under reduced pressure to furnish pyridinethione
4a as brown oil: 856 mg (4a: 70% yield, 1H NMR). 1H NMR (400
MHz, CDCl3): d = 1.06 (t, J = 7.3 Hz), 1.36 (s, 3 H), 1.40 (s, 3 H),
1.65–1.95 (m, 2 H), 2.77 (dd, J = 11.8, 3.3 Hz, 1 H), 6.68 (dt, J =
7.0, 1.8 Hz, 1 H), 7.23 (ddd, J = 8.8, 7.0, 1.3 Hz, 1 H), 7.52 (dd, J =
7.0, 1.3 Hz, 1 H), 7.71 (dd, J = 8.8, 1.8 Hz, 1 H). 13C NMR (101
MHz, CDCl3): d = 12.9, 21.7, 25.3, 29.3, 58.2, 72.0, 113.1, 133.8,
137.2, 137.9, 169.8, 175.4. A flask was charged with crude 4a,
BrCCl3 (2.38 g, 12.0 mmol) and C6H6 (20 mL). The solution was
deaerated in 3 freeze-pump-thaw-cycles (Ar as flushing gas) and
was photolyzed at 20 °C for 30 min using incandescent light (250
W). The volatiles were removed under reduced pressure to furnish
an oil which was purified by Kugelrohr distillation (120–140 °C, 50
mbar) to provide 271 mg (50%) of 3-bromo-2-methyl-2-pentanol
(1a) as colorless oil. 1H NMR (250 MHz, CDCl3): d = 1.11 (t, J =
7.3 Hz, 3 H), 1.32 (s, 3 H), 1.36 (s, 3 H), 1.73 (ddq, J = 14.2, 11.3,
7.3 Hz, 1 H), 1.94 (ddq, J = 14.2, 2.1, 7.3 Hz, 1 H), 2.23 (s, 1 H,
OH), 3.98 (dd, J = 11.3, 2.1 Hz, 1 H). 13C NMR (63 MHz, CDCl3):
d = 13.7, 25.7, 26.8, 27.3, 72.5, 74.2. IR (neat): 3405 (s), 2974 (s),
2878 (s), 1704 (s), 1462 (m), 1380 (s), 1165 (s), 1132 (s), 806 (s),
624 (s) cm–1. MS (70 eV, EI): m/z = 165 (2) [M+ – CH3], 100 (4) [M+
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+
– HBr], 83 (4) [M+ – HOBr], 59 (100) [C4H11+], 43 (28) [C3H7 ].
Anal. Calcd for C6H13BrO (181.1): C, 39.80; H, 7.24. Found: C,
40.65; H, 7.21.
3-Bromo-2,6-dimethyl-5-hepten-2-ol (1d): Purified by column
chromatography (SiO2, petroleum ether–tert-butyl methyl ether,
5:1, Rf = 0.42). 1H NMR (250 MHz, CDCl3): d = 1.35 (s, 3 H), 1.38
(s, 3 H), 1.63 (s, 3 H), 1.74 (d, J = 1.2 Hz, 3 H), 2.01 (s, 1 H, OH),
2.40–2.54 (m, 1 H, 4-H), 2.60–2.71 (m, 1 H), 4.02 (dd, J = 10.7, 2.9
Hz, 1 H), 5.22 (mc, 1 H). 13C NMR (63 MHz, CDCl3): d = 18.1, 25.7,
25.8, 26.8, 32.9, 71.2, 72.5, 121.6, 134.1. IR (neat): 3423 (s), 2974
(s), 2925 (m), 1450 (w), 1378 (m), 1258 (w), 1114 (w), 833 (w), 785
(w) cm–1. MS (70 eV, EI): m/z (%) = 123 (63) [M+ – HOBr], 69 (96)
+
+
[C5H9 ], 59 (96) [C3H6O+], 41 (100) [C3H5 ]. Anal. Calcd for
C9H17BrO (221.1): C, 48.88; H, 7.75. Found: C, 48.74; H, 7.88.
3-Chloro-2,6-dimethyl-5-hepten-2-ol (5): Purified by column
chromatography (SiO2, petroleum ether–tert-butyl methyl ether,
5:1, Rf = 0.44). 1H NMR (250 MHz CDCl3): d = 1.31 (s, 3 H), 1.33
(s, 3 H), 1.63 (s, 3 H), 1.74 (d, J = 0.9 Hz, 3 H), 2.06 (s, 1 H, OH),
2.26–2.39 (m, 1 H), 2.51–2.63 (m, 1 H), 4.02 (dd, J = 10.7, 2.8 Hz,
1 H), 5.23 (m, 1 H). 13C NMR (63 MHz, CDCl3): = 18.0, 25.2, 25.8,
26.5, 32.0, 72.8, 74.3, 120.8, 134.2. IR (neat): 3409 (s), 2979 (s),
2912 (m), 2871 (w), 1447 (m), 1381 (s), 1259 (m), 937 (m), 682 (m)
cm–1. MS (70 eV, EI): m/z (%) = 140 (6) [M+ – HCl], 123 (33)
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+
+
[C5H10OCl+], 69 (47) [C5H9 ], 59 (100) [C3H7O+], 41 (40) [C3H6 ].
HRMS: m/z [M+ – HCl] calcd for C9H16O: 140.1201; found:
140.1202.
Acknowledgment
Generous financial support was provided by the Deutsche For-
schungsgemeinschaft (grant Ha 1705/8–1) and the Fonds der Che-
mischen Industrie. Also, we express our gratitude to Mr. Alexander
Heckmann and Mr. Thomas Pfeuffer for technical assistance.
Synlett 2004, No. 1, 69–72 © Thieme Stuttgart · New York

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M. Greb, J. Hartung
LETTER
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Synlett 2004, No. 1, 69–72 © Thieme Stuttgart · New York