Trihaloisocyanuric Acid/Triphenylphosphine: An Efficient System for Regioselective Conversion of Epoxides into Vicinal Halohydrins and Vicinal Dihalides under Mild Conditions

Article abstract of DOI:10.1055/s-0035-1560408

A new synthetic method has been developed for the regioselective conversion of epoxides to vicinal chloro-/bromohydrins and vicinal dihalides by reaction with the system trihaloisocyanuric acid/tri?phenylphosphine in acetonitrile under mild and neutral conditions. The reactions proceed smoothly in high yield at room temperature and at reflux, respectively, over a short time.

Full text of DOI:10.1055/s-0035-1560408

SYNTHESIS
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©
Georg Thieme Verlag Stuttgart · New York
2016, 48, A–H
A
paper
Synthesis
V. S. C. de Andrade, M. C. S. de Mattos
Paper
Trihaloisocyanuric Acid/Triphenylphosphine: An Efficient System
for Regioselective Conversion of Epoxides into Vicinal Halohydrins
and Vicinal Dihalides under Mild Conditions
Vitor S. C. de Andrade
Marcio C. S. de Mattos*
OH
MeCN
H2O
O
1
6 examples
84–95% yield)
regioselective
C
C
(
X
X
O
N
N
r.t.
X
+
+ PPh3
Departamento de Química Orgânica, Instituto de Química,
Universidade Federal do Rio de Janeiro, CP 68545, Rio de Ja-
neiro CEP 21945-970, Brazil
C
C
mild conditions
high yield
O
N
O
MeCN
X
8
examples
X
C
C
(
74–87% yield)
mmattos@iq.ufrj.br
X
X = Cl, Br
Received: 04.12.2015
OH
Accepted after revision: 18.01.2016
Published online: 19.02.2016
DOI: 10.1055/s-0035-1560408; Art ID: ss-2015-m0699-op
O
H
Br
Cl
H
O
H
HO
Abstract A new synthetic method has been developed for the regiose-
lective conversion of epoxides to vicinal chloro-/bromohydrins and vici-
nal dihalides by reaction with the system trihaloisocyanuric acid/tri-
phenylphosphine in acetonitrile under mild and neutral conditions. The
reactions proceed smoothly in high yield at room temperature and at
reflux, respectively, over a short time.
HO
O
H
chlorochrymorin
15-bromoparguer-7-en-16-ol
HO
OH
Br
Br
Key words dihalide, epoxide, halohydrin, halogenation, N-halo re-
agent
H
OH
rogioldiol B
deschloroelatol
OH
HO
Epoxides occupy a privileged position in organic syn-
O
1
thesis as important synthetic intermediates. Their strained
H
Cl
three-membered ring facilitates the attack of various spe-
cies (e.g., nucleophiles, acids, bases, etc.); consequently the
ring-opening reaction is a versatile transformation for the
H
Figure 1 Examples of naturally occurring halohydrins
2
preparation of diverse moieties. The most representative
class of epoxide derivatives are vicinal halohydrins. In addi-
3
tion to being useful synthetic building blocks, these com-
7
8
9
10
pounds have been used for the preparation of a wide range
boranes, LiX, LiCl/TiCl , and pyridine hydrochloride. An-
4
4
of other functionalities. Furthermore, vicinal haloalcohols
other interesting approach involves the use of triphenyl-
phosphine combined with an electrophilic source of halogen
are constituents of a variety of naturally occurring organo-
5
11
12
halogens in marine organisms and, therefore, a potential
(PPh /X , PPh /N-halosuccinimides, and PPh /N-halo-
3
2
3
3
12
source of medicinal drugs. A few examples of naturally oc-
curring halohydrins are shown in Figure 1.
saccharins ).
On the other hand, there are only a few methodologies
to achieve the direct conversion of epoxides to vicinal diha-
lides. These include the reactions of epoxides with chloro-
benzoxazolium salts,13 triphenylphosphine dihalides, or
with in situ formed organophosphonium halides from
The ring-opening of epoxides to produce vicinal halohy-
drins is a well-known reaction and it is generally achieved
by using hydrogen halides, molecular halogens, or metal
14
6
halides. However, these approaches face some disadvan-
15
tages due to the use of expensive and toxic reagents. In ad-
dition, acid-sensitive substrates may not tolerate such
harsh conditions. Therefore, a large number of alternative
methods to accomplish these transformations are reported
in the literature and a few examples include the use of halo-
phosphines in combination with carbon tetrahalides,
DDQ,16 and N-halo compounds.
12,17
Recently, Denton et al.
reported a convenient conversion of epoxides into corre-
sponding vicinal dihalides promoted by the triphenylphos-
phine oxide (catalytic)/oxalyl chloride system.18
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

B
Synthesis
V. S. C. de Andrade, M. C. S. de Mattos
Paper
Trihaloisocyanuric acids [1,3,5-trihalo-1,3,5-triazine-
,4,6-(1H,3H,5H)-triones, Figure 2], which are safe and sta-
Based on these results, the optimized conditions were
extended to different epoxides 1 using TCCA and TBCA as
electrophilic halogen sources to produce the corresponding
vicinal halohydrins 2 in high yields (Table 2). Although tri-
haloisocyanuric acids are effective reagents for oxidation of
alcohols and halogenation of arenes, none of these prod-
ucts were detected by the analytical techniques employed
in the crude reaction.
2
ble electrophilic halogenating reagents, belong to the large
group of N-haloimides. Trichloroisocyanuric acid (TCCA) is
an inexpensive commercially available solid mainly used
19
26
27
for cleaning and disinfection purposes. Tribromoisocy-
anuric acid (TBCA)2 is an analogue that can be easily pre-
0
21
pared from inexpensive materials (i.e., cyanuric acid, KBr,
TM
and Oxone ). From the green chemistry point of view,
Despite numerous reports on the chemistry of halo-
+
these reagents can transfer three electrophilic halogens at-
oms to a substrate, corresponding to up to 46% (TCCA) and
phosphonium salts [Ph PX] (i.e., the reactive species
3
formed from triphenylphosphine and
source ), the mechanism of the conversion of epoxides to
a
halenium
25a
6
6% (TBCA) of their mass.22 In addition, at the end of the ha-
logenations process, cyanuric acid, which is obtained as a
by-product, precipitates and can be recovered to produce
more of the corresponding trihaloisocyanuric acid.
Table 2 Conversion of Epoxides into Halohydrins with TXCA/PPh3a
23
OH
O
TXCA, PPh3
O
C
C
C C
X
X
MeCN, H2O (2%)
r.t., 5–10 min
Cl (TCCA)
Br (TBCA)
X
N
N
X =
O
N
X
O
Entry
a
Epoxide 1
Halohydrin 2
Yield (%)
X = Cl X = Br
b
Figure 2 Trihaloisocyanuric acids (TXCA)
O
Cl
X
a
Cl
89
88
91
93
OH
OH
Recently, we reported an effective conversion of alco-
hols into alkyl bromides using the system PPh /TBCA as
an alternative to the Appel reaction. Herein, we wish to
report our results on the regioselective conversion of epox-
ides to vicinal halohydrins and dihalides using the system
24
3
b
O
25
X
OH
c
O
88
87
85
84
X
trihaloisocyanuric acid/PPh under mild and neutral condi-
3
tions.
OH
5
X
+
5
Optimization studies were performed by using epichlo-
rohydrin as a model substrate in a molar ratio 1.0:0.5:1.5 of
d
5
X
OH
O
3:1)c
(
epoxide/TCCA/PPh at room temperature and the results are
3
OH
O
shown in Table 1. When dichloromethane and acetonitrile
were used as solvents, a mixture of the trichloride and the
chlorohydrin was obtained. However, when the reaction
was performed in 2% aqueous acetonitrile, a highly chemo-
selective conversion of the epoxide to 1,3-dichloro-2-pro-
panol was achieved.
O
O
X
X
e
f
90
93
92
95
O
OH
Table 1 Optimization Studies for the Conversion of Epoxides to Vicinal
Halohydrins
X
O
g
89
87
93
90
OH
OH
Cl
TCCA, PPh3
O
(3:1)c,d
OH
Cl
Cl
Cl
+
Cl
Cl
solvent, r.t., 5 min
chlorohydrin
trichloride
X
+
Solvent
Chlorohydrin/trichloridea,b
h
O
X
OH
1:1 (X = Cl)c
:1 (X = Br)c
CH
2
Cl
2
83:17
26:74
100:0
2
MeCN
a
Reactions were performed using a molar ratio 1.0:0.5:1.5 of epoxide/
MeCN/H
2
O (2%)
3
TXCA/PPh .
a
b
Reactions were performed using a molar ratio 1.0:0.5:1.5 of epichlorohy-
Isolated yield.
Determined by GC-MS.
Ratio of anti/syn.
c
drin/TCCA/PPh
3
.
b
d
Conversion determined by GC-MS.
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Synthesis
V. S. C. de Andrade, M. C. S. de Mattos
Paper
halohydrins is still complex and controversial as the con-
junction of steric and electronic effects seems to be a key
factor that controls the regioselectivity of the reaction.
Based on the results shown in Table 2, the regioselective
formation of halohydrins 2a–e suggested a nucleophilic
opening of the epoxide on the less-substituted carbon. A
plausible scheme for such a transformation (via a in
Scheme 1) proceeds via the formation of a halophosphoni-
um ion pair 3, which is in equilibrium with the inverted
species 4. Further attack of the halide counterion opens
the epoxide with subsequent formation of the alkoxyphos-
phonium 5. Water reacts with 5 to produce the correspond-
ing halohydrin along with triphenylphosphine oxide. After
two repetitions of the whole process, cyanuric acid is
formed and precipitates at the end of the reaction.
gests that a benzylic carbocation might be involved in these
cases. In order to support this hypothesis, we performed
the reaction using (R)-(+)-styrene oxide (97% ee) as sub-
strate and obtained (S)-(+)-2-chlorophenylethanol in 43%
ee by polarimetry28 (44% ee by chiral-GC ), a considerable
low ee value, implying a partial racemization during the re-
action. On the other hand, trans-1-phenylpropene oxide
(1g) gave a mixture of syn- and anti-1-halo-1-phenyl-2-
propanols, the relative configurations of which were con-
firmed by chemical correlation. The diasteromeric mixture
was converted into 1-phenylpropene oxide by alkaline
treatment and the cis- and trans-epoxides were determined
by co-injection in GC-MS with reference samples. The syn-
halohydrin gives the cis-epoxide while the anti-halohydrin
gives the trans-epoxide.30
29
25a
However, the regioselective formation of halohydrins
f,g demonstrates that the above mechanism is not always
valid, especially when phenyloxiranes are the substrates.
Using styrene oxide (1f), the reaction leads to a regioselec-
tive formation of 2-halo-2-phenylethanol 2f, which sug-
Therefore, via b in Scheme 1 depicts a plausible way for
these transformations via intermediacy of the pentavalent
phosphorane 6, formed from the attack of the epoxide to
the inverted phosphonium species 4. Epoxide ring-opening
appears to occur mainly from a direct attack of the halide
2
Ph
b
O
PPh3
O
O
O
O
X
X
X
X
PPh3
N
N
N
N
N
N
C
C
Ph3P
X
X
O
N
X
O
O
N
X
O
O
N
X
O
a
via a
via b
(
3)
(4)
Ph
PPh3
O
Ph
X
O
O
X
O
N
N
PPh3
PPh3
C C
O
O
X
O
N
X
O
X
N
X
N
N
N
(5)
O
N
X
O
O
N
X
O
(
7)
(6)
Ph3 P
O
C
C
X
Ph
OH2
X
OH2
O
PPh3
O
X
N
N
OH
HO
O
N
X
O
N
N
+
+
OPPh3
C
C
X
HO
N
OH
OH
X
N
N
+
+
OPPh3
OH
Ph
HO
N
OH
Scheme 1 Mechanistic scheme for the formation of halohydrins from epoxides and TXCA/PPh3
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

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Synthesis
V. S. C. de Andrade, M. C. S. de Mattos
Paper
counterion to the pentavalent phosphorane adduct, which
results in the inversion of stereochemistry at the benzylic
position. Alternatively, equilibrium between species 6 and
the benzylic cation 7, followed by halide attack and further
reaction with water yields the halohydrin along with tri-
phenylphosphine oxide. Once more, after two repetitions of
the whole process, cyanuric acid is formed.
As expected, regioselective formation of products 2f–h
is in agreement with the intermediacy of benzylic carbocat-
ions. Therefore, the reaction appears to proceed via two
major competitive pathways (Scheme 1), depending on the
nature of the substrate. The use of methylcyclohexene oxide
Table 3 Conversion of Epoxides into Dihaloalkanes with TXCA/PPh3
X
O
TXCA, PPh3
MeCN, reflux
X
20 min
Yield (%)a,b
Epoxide
Dihalide
X = Cl
X = Br
75
X
5
78
5
O
X
X
O
X
X
8
5
7
80
(
1h) as substrate evidenced the competitive nature of both
mechanisms. Anyway, clearly the driving force of these re-
actions is the formation of a thermodynamically favored
phosphine oxide by-product.
O
O
O
O
X
8
80
Another important consideration is based on the reac-
tion of cycloalkene oxides 1b,c with TXCA/PPh system to
3
form trans-halohydrins. In these cases, both mechanistic
pathways lead to the desired product. However, displace-
ment of triphenylphosphine oxide may occur via an anchi-
meric assistance of the halide. Further attack of water to the
halonium ion results in the vicinal halohydrin with anti-
stereochemistry (Scheme 2). The substrate scope of these
reactions highlights how steric and electronic effects gov-
ern their reactivity pattern.
X
X
74c,d
77c,d
a
Reactions were performed using a molar ratio 1.0:0.85:2.5 of epoxide/
3
TXCA/PPh .
b
Isolated yield.
Conversion (determined by GC-MS).
Formed along with 3-halocyclohexene (ca. 23%).
c
d
Although TXCA gives similar yields compared to other
N-halo reagents, they have advantages as being easily acces-
X
sible (or prepared) and possess a higher percentage of mass
O
X
Ph3P
X
Table 4 Preparation of 1-Halo-3-phenoxy-2-propanol Using Diverse
N-Halo Reagents
X
OH
OH
H2O
O
O
O
X
N-halo reagent
O
PPh3
O
PPh3
N-Halo reagent
Yield (%)
X = Cl
Mass transferred (%)a
Reference
N
NX
X = Br
93
X = Cl
X = Br
O
N
O
X
O
Scheme 2 Mechanistic scheme for the formation of trans-halohydrins
N
X
88
92
26.5
44.9
12
12
On the other hand, when the reaction was performed in
acetonitrile under reflux using a molar ratio 1.0:0.85:2.5 of
epoxide/TXCA/PPh , quantitative conversion of the epox-
O
O
3
ides to vicinal dihaloalkanes was achieved within 20 min-
utes (Table 3). These conditions avoid the use of strong
acidic conditions and metal salts, traditionally employed in
the synthesis of vicinal halohydrins and dihalides.6
Based on the mechanistic proposals shown above, the
transformation of the epoxide to its dihalide by the TXCA/
PPh3 system can be explained in an analogue form from
Scheme 1.
95
92
16.3
45.7
30.4
65.5
N
X
S
O2
,8–10,31
O
X
X
N
N
90
this work
O
N
X
O
a
3
Mass of the reagent (%) transferred to PPh .
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

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Synthesis
V. S. C. de Andrade, M. C. S. de Mattos
Paper
transferred to triphenylphosphine to generate the halo-
phosphonium salt (reactive species), which is consistent
with the green chemistry approach32 (Table 4).
In summary, we have developed an efficient route for
the preparation of vicinal halohydrins from epoxides using
2-Chloro-2-phenylethanol8
Colorless oil (145 mg, 93% yield).
IR (neat): 3372, 3085, 3064, 3031, 3008, 2948, 2927, 2871, 1492,
1454, 1386, 1253, 1195, 1066, 1025, 966, 914, 842, 798, 761, 698,
–1
615, 518 cm
.
1
TXCA/PPh system under mild and neutral conditions. The
H NMR (CDCl , 300 MHz): δ = 7.43–7.33 (m, 5 H), 5.00 (dd, J = 7.2, 5.9
3
3
chosen substrates allowed important mechanistic consider-
ations. The reactions are easily reproducible and the prod-
ucts are obtained over a short period of time and high yield.
We have also presented an alternative route to vicinal diha-
lides from epoxides and further examples are under investi-
gation in our laboratory.
Hz, 1 H), 3.99–3.89 (m, 2 H), 2.08 (br s, 1 H).
13
C NMR (CDCl , 75 MHz): δ = 138.0, 129.1, 129.0, 127.6, 68.1, 65.0.
3
+
+
MS (70 eV): m/z = 158 (M + 2), 156 (M ), 127, 126, 125 (100%), 91, 77,
65, 51.
2-Bromo-2-phenylethanol8
Light yellow oil (191 mg, 95% yield).
IR (neat): 3263, 3095, 6064, 3031, 2950, 2935, 2888, 1492, 1454,
1390, 1209, 1195, 1078, 1056, 1022, 1002, 984, 840, 761, 698, 682,
Epoxides were purchased from Aldrich or prepared by epoxidation of
the corresponding alkenes with mCPBA. All products are known com-
pounds and identified by their spectral data in comparison with the
–1
617, 592, 559, 509 cm
.
1
H NMR (CDCl , 300 MHz): δ = 7.43–7.30 (m, 5 H), 5.06 (dd, J = 7.7, 5.8
3
1
13
literature data. H and C NMR spectra were recorded on a Bruker AC
00 spectrometer at 300 MHz and 75 MHz, respectively. IR spectra
Hz, 1 H), 2.15 (br s, 1 H).
3
13
C NMR (CDCl , 75 MHz): δ = 138.4, 129.1, 129.0, 128.1, 67.7, 57.0.
3
were recorded on a Nicolet 6700FT-IR spectrophotometer as neat
films on KBr plates. MS (electron impact) were recorded on a GCMS-
QP2010S. Chiral-GC analysis were performed on a Shimadzu GC2010
+
+
MS (70 eV): m/z = 202 (M + 2), 200 (M ), 171, 169, 121 (100%), 103,
91, 77, 65, 51.
(
FID) using a Supelco β-Dex120 (30 m × 0.25 mm × 0.25 μm) column.
Analysis conditions: H2 pressure: 90 kPa, injector: 200 °C, detector:
00 °C, temperature program: 112–122 °C (0.4 °C/min)//122–170 °C
15 °C/min)//170 °C (15 min). Polarimetric analysis was done in a
trans-2-Chlorocyclohexanol33
2
(
Colorless oil (118 mg, 88% yield).
IR (neat): 3399, 2940, 2861, 1450, 1363, 1261, 1214, 1126, 1074,
Perkin Elmer 341LC polarimeter.
–1
1037, 960, 865, 798, 734, 705, 559, 476 cm .
1
H NMR (CDCl , 300 MHz): δ = 3.71 (ddd, J = 11.5, 9.3, 4.4 Hz, 1 H),
.50 (td, J = 11.8, 4.6, Hz, 1 H), 2.51 (br s, 1 H), 2.25–2.06 (m, 2 H),
.76–1.56 (m, 3 H), 1.41–1.21 (m, 3 H).
3
Vicinal Halohydrins; General Procedure
3
1
TXCA (0.5 mmol) was added to a stirred solution of PPh (393 mg, 1.5
3
mmol) in 2% aq MeCN (10 mL) at r.t. The appropriate epoxide (1
mmol) was added to the mixture and the reaction mixture was
stirred for 5–10 min. After completion of the reaction (TLC or GC), the
suspension was filtered and the solvent was removed under reduced
pressure. The crude residue was purified by column chromatography
13
C NMR (CDCl , 75 MHz): δ = 75.5, 67.6, 35.3, 33.2, 25.8, 24.1.
3
+
+
MS (70 eV): m/z = 136 (M + 2), 134 (M ), 118, 116, 80, 57 (100%), 44,
41.
on silica gel using pentane/Et O (1:1) to give the corresponding vici-
nal halohydrin (Table 2).
trans-2-Bromocyclohexanol21
2
Light yellow oil (166 mg, 93% yield).
IR (neat): 3394, 2939, 2859, 1448, 1361, 1186, 1072, 1035, 956, 862,
1
,3-Dichloro-2-propanol8
–1
690, 555 cm .
Colorless oil (114 mg, 89% yield).
1
H NMR (CDCl , 300 MHz): δ = 3.91 (ddd, J = 12.0, 9.4, 4.3 Hz, 1 H),
3
IR (neat): 3399, 2962, 2917, 1430, 1297, 1280, 1253, 1076, 1052, 964,
3.61 (td, J = 9.4, 4.3 Hz, 1 H), 2.41–2.32 (m, 2 H), 2.17–2.15 (m, 1 H),
8
85, 829, 759, 701, 572 cm–1
.
1.87–1.69 (m, 3 H), 1.46–1.21 (m, 3 H).
1
H NMR (CDCl , 300 MHz): δ = 4.06 (quint, J = 5.3 Hz, 1 H), 3.69 (d,
13
3
C NMR (CDCl , 75 MHz): δ = 75.5, 62.0, 36.4, 33.7, 26.8, 24.3.
3
J = 5.3 Hz, 4 H), 2.57 (br s, 1 H).
+
+
MS (70 eV): m/z = 180 (M + 2), 178 (M ), 134, 132, 99, 81 (100%), 57,
1.
13
C NMR (CDCl , 75 MHz): δ = 70.9, 45.8.
3
4
+
+
+
MS (70 eV): m/z = 131 (M + 4), 129 (M + 2), 127 (M ), 81, 79 (100%),
43.
trans-2-Chlorocyclooctanol34
Colorless oil (143 mg, 88% yield).
1
-Bromo-3-chloro-2-propanol8
IR (neat): 3423, 2928, 2857, 1464, 1446, 1239, 1078, 1050, 1002, 988,
Light yellow oil (157 mg, 91% yield).
–1
825, 743, 707, 571 cm
.
IR (neat): 3399, 2962, 2908, 1429, 1382, 1294, 1261, 1193, 1089,
1
1
H NMR (CDCl , 300 MHz): δ = 4.11 (ddd, J = 9.7, 7.5, 2.8 Hz, 1 H), 3.86
3
068, 1041, 995, 865, 821, 761, 711, 669, 642, 551, 522, 497 cm–1
.
(m, 1 H), 2.43 (s, 1 H), 2.26–2.16 (m, 1 H), 2.06–1.43 (m, 11 H).
1
H NMR (CDCl , 300 MHz): δ = 4.04 (m, 1 H), 3.76–3.67 (m, 2 H), 3.57
13
3
C NMR (CDCl , 75 MHz): δ = 76.4, 71.4, 32.5, 32.1, 25.9, 25.8, 24.9,
3
(d, J = 5.3 Hz, 2 H), 2.66 (br s, 1 H).
2
4.2.
13
C NMR (CDCl , 75 MHz): δ = 70.6, 46.6, 34.9.
3
MS (70 eV): m/z = 146, 144, 116, 109, 95, 82, 67, 57 (100%), 41.
+
+
MS (70 eV): m/z = 175 (M + 2), 173 (M ), 125, 123, 81, 79, 43 (100%).
©
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Synthesis
V. S. C. de Andrade, M. C. S. de Mattos
Paper
trans-2-Bromocyclooctanol35
MS (70 eV): m/z = 188 (M + 2), 186 (M ), 169, 107, 94 (100%), 77, 65,
+
+
51.
Colorless oil (176 mg, 85% yield).
IR (neat): 3425, 2927, 2858, 1463, 1444, 1047, 823, 665 cm–1
.
1
-Bromo-3-phenoxy-2-propanol8
1
H NMR (CDCl , 300 MHz): δ = 4.29 (ddd, J = 9.8, 7.3, 2.8 Hz, 1 H), 3.98
3
Colorless oil (212 mg, 92% yield).
(m, 1 H), 2.36–2.25 (m, 2 H), 2.14–1.39 (m, 11 H).
1
3
IR (neat): 3409, 3093, 3062, 3039, 2931, 2877, 1598, 1588, 1496,
C NMR (CDCl , 75 MHz): δ = 76.8, 67.2, 33.1, 32.3, 25.9, 25.8, 25.2.
3
–1
1243, 1045, 754, 692, 509 cm .
MS (70 eV): m/z = 190, 188, 109, 81, 67, 57 (100%), 41.
-Chloro-1-phenyl-2-propanol36
1
H NMR (CDCl , 300 MHz): δ = 7.36–7.28 (m, 2 H), 7.04–6.93 (m, 3 H),
3
4.22 (quint, J = 5.2 Hz, 1 H), 4.16–4.05 (m, 2 H), 3.69 (dd, J = 10.4, 5.1
1
Hz, 1 H), 3.61 (dd, J = 10.5, 5.6 Hz, 1 H), 2.37 (br s, 1 H).
Mixture of diastereomers 3:1 (anti/syn); colorless oil (151 mg, 89%
yield).
13
C NMR (CDCl , 75 MHz): δ = 158.1, 129.5, 121.4, 114.5, 69.5, 69.1,
3
34.9.
+
+
MS (70 eV): m/z = 232 (M + 2), 230 (M ), 137, 133, 107, 94 (100%), 77,
anti-Isomer
51.
1
H NMR (CDCl , 300 MHz): δ = 7.43–7.28 (m, 5 H), 4.78 (d, J = 5.9 Hz, 1
3
H), 4.79–4.06 (m, 1 H), 2.10 (br s, 1 H), 1.26 (d, J = 6.2 Hz, 3 H).
1
-Chloro-2-octanol and 2-Chloro-1-octanol33
13
C NMR (CDCl , 75 MHz): δ = 138.0, 128.7, 128.2, 127.8, 71.9, 68.3,
3
Mixture of regioisomers (3:1); colorless oil (143 mg, 87% yield).
19.2.
1-Chloro-2-octanol
+
+
MS (70 eV): m/z = 172 (M + 2), 170 (M ), 126, 91 (100%), 77, 65, 45.
13
C NMR (CDCl , 75 MHz): δ = 71.6, 50.7, 34.4, 31.8, 29.3, 25.6, 22.7,
3
14.2.
syn-Isomer
1
MS (70 eV): m/z = 147, 115, 97, 79, 69, 55 (100%), 43.
H NMR (CDCl , 300 MHz): δ = 7.43–7.28 (m, 5 H), 4.70 (d, J = 7.8 Hz, 1
3
H), 4.79–4.06 (m, 1 H), 2.13 (br s, 1 H), 1.06 (d, J = 6.2 Hz, 3 H).
2-Chloro-1-octanol
13
13
C NMR (CDCl , 75 MHz): δ = 138.7, 128.9, 128.89, 128.81, 72.1, 71.1,
C NMR (CDCl , 75 MHz): δ = 67.2, 65.5, 34.4, 31.7, 28.9, 26.4, 22.7,
3
3
19.5.
14.2.
+
+
MS (70 eV): m/z = 172 (M + 2), 170 (M ), 126, 91 (100%), 77, 65, 45.
MS (70 eV): m/z = 123, 121, 93, 91, 82, 81, 70, 57, 55 (100%), 43, 41.
1
-Bromo-1-phenyl-2-propanol37
1-Bromo-2-octanol and 2-Bromo-1-octanol21
Mixture of diastereomers 3:1 (anti/syn); colorless oil (200 mg, 93%
Mixture of regioisomers (3:1); light yellow oil (175 mg, 84% yield).
yield).
1-Bromo-2-octanol
anti-Isomer
13
C NMR (CDCl , 75 MHz): δ = 71.0, 40.4, 35.0, 31.6, 29.0, 25.4, 22.4,
3
1
H NMR (CDCl , 300 MHz): δ = 7.49–7.42 (m, 2 H), 7.38–7.31 (m, 3 H),
13.9.
3
4
.89 (d, J = 6.3 Hz, 1 H), 4.28–4.17 (m, 1 H), 2.15 (br s, 1 H), 1.36 (d,
MS (70 eV): m/z = 193, 191, 125, 123, 115, 97, 69, 55 (100%), 43.
J = 6.3 Hz, 3 H).
1
3
C NMR (CDCl , 75 MHz): δ = 138.2, 128.7, 128.7, 128.6, 71.5, 60.7,
3
2-Bromo-1-octanol
2
0.0.
13
C NMR (CDCl , 75 MHz): δ = 67.1, 59.9, 34.8, 31.5, 28.5, 27.3, 22.4,
3
+
+
MS (70 eV): m/z = 172 (M + 2), 170 (M ), 126, 91 (100%), 77, 65, 45.
13.9.
MS (70 eV): m/z = 167, 165, 137, 135, 111, 69 (100%), 55, 43, 41.
syn-Isomer
1
H NMR (CDCl , 300 MHz): δ = 7.49–7.42 (m, 2 H), 7.38–7.31 (m, 3 H),
.88 (d, J = 8.1 Hz, 1 H), 4.28–4.17 (m, 1 H), 2.15 (br s, 1 H), 1.12 (d,
3
2-Chloro-1-methylcyclohexanol and 2-Chloro-2-methylcyclohex-
anol
4
38
J = 6.2 Hz, 3 H).
Mixture of regioisomers (1:1); colorless oil (129 mg, 87% yield).
13
C NMR (CDCl , 75 MHz): δ = 139.1, 128.7, 128, 128,0, 71.5, 65.0,
3
1
9.6.
2
13
-Chloro-1-methylcyclohexanol
+
+
MS (70 eV): m/z = 172 (M + 2), 170 (M ), 126, 91 (100%), 77, 65, 45.
C NMR (CDCl , 75 MHz): δ = 72.8, 70.2, 38.0, 33.5, 24.9, 22.6, 21.9.
3
+
+
MS (70 eV): m/z = 150 (M + 2), 148 (M ), 114, 112, 71 (100%), 58, 43.
1
-Chloro-3-phenoxy-2-propanol8
Colorless oil (167 mg, 90% yield).
2-Chloro-2-methylcyclohexanol
IR (neat): 3399, 3095, 3062, 3041, 2950, 2931, 2879, 1598, 1588,
1
13
C NMR (CDCl , 75 MHz): δ = 77.2, 77.1, 40.7, 30.0, 23.3, 23.1, 22.6.
3
496, 1243, 1045, 754, 692, 509 cm–1
.
+
+
MS (70 eV): m/z = 150 (M + 2), 148 (M ), 132, 130, 104, 102, 95, 94,
68, 57 (100%), 41.
1
H NMR (CDCl , 300 MHz): δ = 7.35–7.26 (m, 2 H), 7.04–6.85 (m, 3 H),
3
4.24 (quint, J = 5.2 Hz, 1 H), 4.15–4.06 (m, 2 H), 3.81 (dd, J = 11.3, 5.4
Hz, 1 H), 3.76 (dd, 11.3, 5.4 Hz, 1 H), 2.63 (br s, 1 H).
2
anol
-Bromo-1-methylcyclohexanol and 2-Bromo-2-methylcyclohex-
13
39
C NMR (CDCl , 75 MHz): δ = 158.2, 129.5, 121.2, 114.5, 69.8, 68.4,
3
45.9.
Mixture of regioisomers (2:1); colorless oil (173 mg, 90% yield).
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

G
Synthesis
V. S. C. de Andrade, M. C. S. de Mattos
Paper
1
2-Bromo-1-methylcyclohexanol
H NMR (CDCl , 300 MHz): δ = 7.36–7.28 (m, 2 H), 7.05–6.95 (m, 3 H),
3
1
3
4.50–4.35 (m, 3 H), 4.00–3.86 (m, 2 H).
C NMR (CDCl , 75 MHz): δ = 72.5, 66.0, 38.2, 34.7, 26.2, 23.1, 22.8.
3
13
+
+
C NMR (CDCl , 75 MHz): δ = 157.9, 129.5, 121.6, 114.8, 69.1, 47.7,
MS (70 eV): m/z = 194 (M + 2), 192 (M ), 113, 95, 71 (100%), 43.
3
32.7.
+
+
+
2-Bromo-2-methylcyclohexanol
MS (70 eV): m/z = 296 (M + 4), 294 (M + 2), 292 (M ), 94 (100%), 77,
13
65, 51.
C NMR (CDCl , 75 MHz): δ = 77.8, 75.9, 42.4, 34.7, 29.9, 23.8, 23.6.
3
MS (70 eV): m/z = 148, 146, 113, 95 (100%), 67, 57.
1
,2-Dichloro-1-phenylethane18
Colorless oil (148 mg, 85%).
IR (neat): 3065, 3033, 2952, 1493, 1455, 1426, 771, 733, 697, 592 cm–1
Vicinal Dihalides; General Procedure
.
TXCA (0.85 mmol) was added to a stirred solution of PPh3 (655 mg,
1
2.5 mmol) in MeCN (15 mL). The appropriate epoxide (1 mmol) was
H NMR (CDCl , 300 MHz): δ = 7.38–7.32 (m, 5 H), 4.97 (dd, J = 7.9, 6.6
3
added to the mixture and the system was refluxed for 20 min. After
the completion of the reaction (GC), the suspension was filtered and
Hz, 1 H), 3.97 (dd, J = 11.3, 6.6 Hz, 1 H), 3.89 (dd, J = 11.3, 7.8 Hz, 1 H).
13
C NMR (CDCl , 75 MHz): δ = 137.9, 129.1, 128.7, 127.3, 61.7, 48.3.
3
H O (5 mL) was added to the solution. The mixture was extracted
2
+
+
+
MS (70 eV): m/z = 178 (M + 4), 176 (M + 2), 174 (M ), 141, 139, 127,
with pentane (3 × 7 mL). The combined organic phase were dried over
Na SO and concentrated under vacuum. The crude product was puri-
125 (100%), 103, 77, 51.
2
4
fied by column chromatography on silica gel using pentane/Et O (8:2)
to give the corresponding vicinal dihalide (Table 3).
2
1
,2-Dibromo-1-phenylethane44
White solid (211 mg, 80%); mp 72–73 °C (Lit.45 mp 73–74 °C).
1
,2-Dichlorooctane40
IR (neat): 3064, 3029, 2980, 2922, 1496, 1455, 1431, 769, 691, 589,
–1
Colorless oil (142 mg, 78% yield).
IR (neat): 2956, 2927, 2858, 1465, 1444, 1432, 1378, 727, 663 cm–1
553 cm
1H NMR (CDCl
5.5 Hz, 1 H), 4.14–4.01 (m, 2 H).
13C NMR (CDCl
, 75 MHz): δ = 138.6, 129.1, 128.8, 127.6, 50.8, 34.9.
.
.
, 300 MHz): δ = 7.45–7.35 (m, 5 H), 5.17 (dd, J = 10.4,
3
1
H NMR (CDCl , 300 MHz): δ = 4.08–4.00 (m, 1 H), 3.76 (dd, J = 11.2,
3
5.0 Hz, 1 H), 3.65 (dd, J = 11.3, 7.4 Hz, 1 H), 2.04 (m, 1 H), 1.76–1.65
3
(
1
m, 1 H), 1.56–1.30 (m, 8 H), 0.90 (t, J = 6.7 Hz, 3 H).
+
+
+
MS (70 eV): m/z = 266 (M + 4), 264 (M + 2), 262 (M ), 185, 183, 104
(100%), 77, 51.
3
C NMR (CDCl , 75 MHz): δ = 61.4, 48.4, 35.2, 31.7, 28.8, 25.9, 22.7,
3
14.2.
MS (70 eV): m/z = 155, 153, 141, 139, 104, 97, 81, 70, 55, 43 (100%).
Acknowledgment
1
,2-Dibromooctane41
We thank CNPq and FAPERJ for the financial support.
Colorless oil (204 mg, 75% yield).
IR (neat): 2956, 2929, 2858, 1465, 1432, 1145, 725, 646, 570 cm–1
.
Supporting Information
1
H NMR (CDCl , 300 MHz): δ = 4.23–4.10 (m, 1 H), 3.87 (dd, J = 10.2,
3
4
.4 Hz, 1 H), 3.65 (t, J = 10.0 Hz, 1 H), 2.21–2.10 (m, 1 H), 1.90–1.74
Supporting information for this article is available online at
(m, 1 H), 1.63–1.32 (m, 8 H), 0.91 (t, J = 6.4 Hz, 3 H).
http://dx.doi.org/10.1055/s-0035-1560408.
S
u
p
p
ortioIgnfmr oaitn
S
u
p
p
o
nrtogI
i
f
rm oaitn
13
C NMR (CDCl , 75 MHz): δ = 53.3, 36.5, 36.2, 31.7, 28.6, 26.9, 22.7,
3
14.2.
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H
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1
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3
20
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R
(
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©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H