A photoirradiative phase-vanishing method: Efficient generation of HBr from alkanes and molecular bromine and its use for subsequent radical addition to terminal alkenes

Article abstract of DOI:10.1055/s-0030-1258482

A triphasic phase-vanishing (PV) system comprised of an alkane, perfluorohexanes, and bromine was successfully combined by photoirradiation to efficiently generate hydrogen bromide, which underwent radical addition with 1-alkenes in the hydrocarbon layer to afford terminal bromides in high yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258482

2014
CLUSTER
A Photoirradiative Phase-Vanishing Method: Efficient Generation of HBr
from Alkanes and Molecular Bromine and Its Use for Subsequent Radical
Addition to Terminal Alkenes
Efficient
G
eneratio
i
n of
H
r
Br
a
nd It
o
s
Radical
A
d
s
dition to T
h
erminal Alk
i
enes Matsubara,* Masaaki Tsukida, Daisuke Ishihara, Kenji Kuniyoshi, Ilhyong Ryu*
Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan
Fax +81(72)2549695; E-mail: matsu@c.s.osakafu-u.ac.jp; E-mail: ryu@c.s.osakafu-u.ac.jp
Received 16 May 2010
"PV"
Br2
Abstract: A triphasic phase-vanishing (PV) system comprised of
an alkane, perfluorohexanes, and bromine was successfully com-
bined by photoirradiation to efficiently generate hydrogen bromide,
which underwent radical addition with 1-alkenes in the hydrocar-
bon layer to afford terminal bromides in high yields.
Br
H
Br
+
Br
R
R
hexane
R
1
2
3
major product
by-product
Key words: fluorous solvent, phase-vanishing, photoirradiation,
bromination, hydrogen bromide
Equation 1
Looking back to the original procedure of PV bromination
of alkenes with bromine, shielding the test tube from sun-
light with aluminum foil is important for the prevention of
the formation of 1-bromoalkane 3 as a by-product
(Equation 1).6 The formation of 3 was puzzling; however,
we hypothesized that hydrogen bromide would form in
this system by sunlight-irradiative reaction of the hydro-
carbon solvent with molecular bromine. This led us to ex-
amine the ‘photoirradiative’ phase-vanishing reaction as a
means for the generation of anhydrous HBr. In this Letter,
we report on the efficient in situ generation of HBr and its
use for the synthesis of terminal alkyl bromides via anti-
Markovnikov addition to terminal alkenes.
Reduction or elimination of the use of hazardous organic
solvents is one of the major issues of the green chemistry,
and in this regard fluorous solvents represent workable al-
ternatives to the organic solvents.1,2 Fluorous solvents are
generally immiscible with common organic solvents,
while exhibiting thermomorphic nature to give homoge-
neous solution upon heating. Thus far we have developed
recyclable organic/fluorous amphiphilic solvents, such as
F-6263 and fluorous DMF.4 In our recent work, we also re-
ported that fluorous chiral amines can be used repeatedly
for enantioselective desymmetrization of ketones.5
In a different direction of utilizing fluorous media for or-
ganic synthesis, multiphasic reactions appear promising.
The Curran group and we have jointly developed phase-
vanishing (PV) methods, which utilize triphasic reactions
based on the phenomenon that fluorous media act as liq-
uid membranes to transport reagents to organic layers
containing substrates.6 Since the first demonstration of the
PV method,7 which is used for room temperature bromi-
nation of alkenes with molecular bromine to give vic-di-
bromoalkanes, a number of applications to various
reagents other than bromine have been developed by us8
and the others.9 Recent advances in phase-vanishing bro-
mination include a quadraphasic PV bromination of ke-
tones and aromatic compounds,8c in which an aqueous
‘scavenger’ phase was added to the original triphasic PV
method to remove HBr. In a related study using a triphasic
system, Iskra and co-workers reported benzylic bromina-
tion under irradiation conditions,9d and Dragojlovic and
co-workers employed Teflon tape as the fluorous phase
screen.9h,i Weiss and co-workers carried out stereoselec-
tive bromination of alkenes using an ionic liquid as the
phase screen of the PV method.9g
With 1-dodecene (1b) as the substrate and hexane as the
solvent, PV bromination was carried out under a variety of
conditions using a Xenon lamp as the light source
(Table 1). When FC-72 (perfluorohexanes, 3 mL) was
placed in a test tube (Pyrex, ∆ = 13 mm ) to which bro-
mine (1.05 equiv) was slowly introduced, the heavier bro-
mine sank to the bottom, forming two layers. A hexane
(1.5 mL) solution containing 1-dodecene (2 mmol) was
then added; this floated on top of the FC-72 layer, forming
a triphasic system (Figure 1, Picture A). The test tube was
Figure 1 Pictures of the photoirradiative phase-vanishing bromina-
tion of 1-dodecene with bromine. A: Before irradiation. B: With irra-
diation, the FC-72 layer turned milky. C: After ca. 1.5 h, the bromine
layer disappeared and the FC-72 layer recovered transparency.
SYNLETT 2010, No. 13, pp 2014–2018
Advanced online publication: 09.07.2010
DOI: 10.1055/s-0030-1258482; Art ID: Y01610ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
0

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Efficient Generation of HBr and Its Radical Addition to Terminal Alkenes
2015
hν
Br
1b
3b
HBr
hexane
hν
hν
FC-72
d = 1.67
Br2
hexane
+
bromohexanes
Br2
d = 3.12
Scheme 1 Photoirradiative phase-vanishing bromination of 1-dodecene (1b) leading to 1-bromododecane (3b)
then irradiated with a 500 W Xenon lamp. The FC-72 lay- anism, bromohexanes were detected by GC–MS analysis
er gradually turned milky and small bubbles of hydrogen of the crude reaction mixture. As we expected, the use of
bromide gas began to evolve (Figure 1, Picture B). As the isooctane and 2,4-dimethylpentane, having tertiary C–H
bromine layer disappeared after 45 minutes, the evolution bonds, as the solvent raised the yield to 61% and 77%, re-
of small bubbles ceased gradually and after 1.5 hours the spectively (entries 3 and 6).10 The use of perfluorinated
FC-72 layer recovered transparency (Figure 1, Picture C). polyether Galden HT135 also worked well to give a better
The hexane layer was then taken, washed with aqueous yield of 3b (entry 5). Since HBr is supposed to be gener-
Na2S2O3, and dried over Na2SO4. After aqueous workup, ated by the reaction of alkanes partially dissolved in the
purification by short column chromatography on silica gel fluorous phase with diffusing bromine, we hypothesized
with hexane gave a mixture of 1,2-dibromododecane (2b) that simply increasing the length of the fluorous phase
and 1-bromododecane (3b) in 68% and 32% yields, re- would give the bromine a greater chance for reaction with
spectively (Table 1, entry 1).
isooctane. Indeed, the simple manipulation to double the
fluorous phase (22 mm to 44 mm by length, 3 mL to 6 mL
by volume) in volume, yielded 1-bromodecane (3b) as the
sole product (96%; entry 4).
The formation of 1-bromododecane (3b) was the result of
two consecutive radical reactions: (i) generation of HBr
via a photoinduced radical reaction of molecular bromine
with the hydrocarbon solvent, hexane, and (ii) the photo- Under these optimal conditions obtained for entry 4, we
induced free-radical addition of the resulting HBr to 1b to examined the generality of the hydrobromination of alk-
give 3b (Scheme 1). Consistent with this proposed mech- enes under irradiative PV bromination conditions. As
Table 1 Control Experiments for Photoirradiative Phase-Vanishing Bromination of 1b
13 mm
C10H21
1b (2 mmol)
solvent
(1.5 mL)
Br
Br
Xe lamp (500 W)
r.t., 2 h
Br
or
C10H21
6 mL
fluorous
phase
+
C10H21
3 mL
3b
2b
Br2
(2.1 mmol)
Entry
Solvent
Fluorous phase
Light
+
Yield (%)a
2b
3b
1
2
3
4
5
6
hexane
FC-72, 3 mL
FC-72, 3 mL
FC-72, 3 mL
FC-72, 6 mL
68
32
b
c
hexane
–
90
–
isooctane
isooctane
isooctane
+
+
+
+
39
61
96
90
77
Trace
10
GALDEN HT-135, 3 mL
FC-72, 3 mL
2,4-dimethylpentane
22
a Isolated yield from organic layer after silica gel column chromatography.
b With aluminum foil and gentle stirring.
c Not detected.
Synlett 2010, No. 13, 2014–2018 © Thieme Stuttgart · New York

2016
H. Matsubara et al.
CLUSTER
shown in Table 2, a variety of terminal alkenes 1a–f, some to give a mixture of an anti-Markovnikov product 3k and
of which have a functional group, were converted to the a Markovnikov product 3k¢ (entry 12).
corresponding 1-bromoalkanes 3a–f in high yields (en-
tries 1–6). Dienes 1g–1i were also examined as substrates.
The reaction of 1,9-decadiene (1g) with bromine (2.5 mol
Somewhat tedious indirect methods exist for the synthesis
of 1-bromoalkanes from terminal alkenes, which employ
initial conversion of alkenes to organometallic species
equiv) yielded 92% yield of 1,10-dibromoalkane (3g; en-
try 7). Under similar conditions, 1,11-dodecadiene (1h)
and 1,13-tetradecadiene (1i) yielded the corresponding di-
bromoalkanes 3h (93%) and 3i (97%), respectively. On
the other hand, the reaction of these dienes with equimolar
amounts of bromine gave a mixture of 1:1 and 1:2 prod-
ucts. For example, the reaction of 1h gave a mixture of 12-
bromododec-1-ene (3h¢) (13%) and 3h (36%) together
with a large amount of unreacted 1h (41%; entry 9). It is
interesting to note that the major formation of dibromide
may suggest that after the first HBr addition, a bromine
radical forms in a reaction cage, which might undergo ad-
dition to another alkene terminus. The reactions were also
tested for endo- and exocyclic alkenes, 1j and 1k, (entries
11 and 12). While 1j gave monobromide 3j in good yield
(entry 11), in the case of 1k, ionic HBr addition competed
such as organoboron,11 organosilicon12 or organo groups
IV13 and XIII11i,14 compounds. Irradiative PV bromination
involving in situ generation of HBr provided a simple
method for the preparation of 1-bromoalkanes from termi-
nal alkenes using molecular bromine and appropriate hy-
drocarbons.15 It should also be noted that this
methodology provided a spontaneous ‘molecular-level’
flow reaction system in which two successive photoradi-
cal reactions occurred in just one test tube: formation of
hydrogen bromide from hydrocarbon solvent and molec-
ular bromine, and addition of hydrogen bromide to ole-
fins. Many useful synthetic methodologies, based on in
situ generation of fresh HBr and its use for additional
transformations may therefore be possible.16
Table 2 Photoirradiative Phase-Vanishing Reaction of Terminal Alkenes 1 Leading to Bromoalkanes 317
Br2 (1.05 equiv), isooctane (1.5 mL)
Br
R
R
FC-72 (6 mL), 500 W Xe lamp
test tube (∅ 13 mm), r.t., 2 h
1
3
Entry
Alkene 1
Product 3
Yield (%)a
R
1
2
3
3a
3b
3c
89
96
94
1a R = C9H19
1b R = C10H21
1c R = C12H25
R = C9H18OMe
3d
OMe
OMe
4
84
80
86
92
1d
R = C8H16CO2Me
3e
5
1e
O
R = C9H18Cl
3f
Cl
6
1f
Br
Br
Br
7b
8
3g
1g
Br
8b
93
10
3h
1h
1h
36
13
3h
9c
Br
9
3h′
Br
Br
10b
97
12
3i
1i
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Efficient Generation of HBr and Its Radical Addition to Terminal Alkenes
2017
Table 2 Photoirradiative Phase-Vanishing Reaction of Terminal Alkenes 1 Leading to Bromoalkanes 317 (continued)
Br2 (1.05 equiv), isooctane (1.5 mL)
Br
R
R
FC-72 (6 mL), 500 W Xe lamp
test tube (∅ 13 mm), r.t., 2 h
1
3
Entry
Alkene 1
Product 3
Yield (%)a
96
Br
11
1j
3j
Br
31
17
3k
12
Br
1k
3k¢
a Isolated yield from organic layer after silica gel column chromatography.
b Br2 (2.5 mol equiv).
c Br2 (1.05 mol equiv).
(8) (a) Nakamura, H.; Usui, T.; Kuroda, H.; Ryu, I.; Matsubara,
H.; Yasuda, S.; Curran, D. P. Org. Lett. 2003, 5, 1167.
(b) Matsubara, H.; Yasuda, S.; Ryu, I. Synlett 2003, 247.
(c) Rahman, M. T.; Kamata, N.; Matsubara, H.; Ryu, I.
Synlett 2005, 2664. (d) Matsubara, H.; Tsukida, M.; Yasuda,
S.; Ryu, I. J. Fluorine Chem. 2008, 129, 951.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We thank the JSPS and the MEXT for financial support of this
work.
(9) (a) Jana, N. K.; Verkade, J. G. Org. Lett. 2003, 5, 3787.
(b) Iskra, J.; Stavber, S.; Zupan, M. Chem. Commun. 2003,
2496. (c) Curran, D. P.; Werner, S. Org. Lett. 2004, 6, 1021.
(d) Podgoršek, A.; Stavber, S.; Zupan, M.; Iskra, J. Eur. J.
Org. Chem. 2006, 483. (e) Windmon, N.; Dragojlovic, V.
Tetrahedron Lett. 2008, 49, 6543. (f) Windmon, N.;
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References and Notes
(1) For a general review on fluorous chemistry, see: Handbook
of Fluorous Chemistry; Gladysz, J. A.; Curran, D. P.;
Horváth, I. T., Eds.; Wiley-VCH: Weinheim, 2004.
(2) For reviews on fluorous solvents, see: (a) Ryu, I.;
Matsubara, H.; Emnet, C.; Gladysz, J. A.; Takeuchi, S.;
Nakamura, Y.; Curran, D. P. In Green Reaction Media in
Organic Synthesis; Mikami, K., Ed.; Blackwell Publishing:
Oxford, 2005, 59. (b) Matsubara, H.; Ryu, I. In Green
Separation Processes: Fundamentals and Applications;
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Weinheim, 2005, 219.
(10) 1H NMR of the concentrated reaction mixture in entry 6 of
Table 1 shows peaks assigned to 2-bromo-2,4,4-trimethyl-
pentane as the product, suggesting that hydrogen abstraction
from isooctane would occur selectively at the tertiary
position of isooctane.
(11) (a) Brown, H. C.; Lane, C. F. J. Am. Chem. Soc. 1970, 92,
7212. (b) Brown, H. C.; Lane, C. F. Tetrahedron 1988, 44,
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Chem. Soc. 1970, 92, 6660. (e) Brown, H. C.; Lane, C. F.
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(g) Tufariello, J. J.; Hovey, M. M. J. Chem. Soc. D: Chem.
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(i) Maruoka, K.; Sano, H.; Shinoda, K.; Nakai, S.;
Yamamoto, H. J. Am. Chem. Soc. 1986, 108, 6036.
(j) Tufariello, J. J.; Hovey, M. M. J. Am. Chem. Soc. 1970,
92, 3221.
(3) Matsubara, H.; Yasuda, S.; Sugiyama, H.; Ryu, I.; Fujii, Y.;
Kita, K. Tetrahedron 2002, 58, 4071.
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(6) For reviews on the ‘Phase-Vanishing’ method, see: (a)Ryu,
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Synlett 2010, No. 13, 2014–2018 © Thieme Stuttgart · New York

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some HBr generated would outgas during the reaction.
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(15) The reaction without fluorous phase gave an inferior result.
For example, irradiation of a mixture of bromine (1.16
mmol) and isooctane (6 mL) with a 500 W Xe lamp for 30
min, followed by addition of 1-dodecene (1 mmol) at r.t.,
gave 1-bromododecane in 79% yield together with
(17) Typical Procedure for Photoirradiative Phase-Vanishing
Hydrogen Bromide Addition to Alkenes (Table 2, entry
2): FC-72 (6 mL) was placed in a Pyrex test tube (13 mm
∆ × 105 mm) to which bromine (2.1 mmol, 340 mg) was
added slowly using a glass pipette. Isooctane (1.5 mL)
solution of 1-dodecene (2.0 mmol, 340 mg) was then added
slowly, forming three layers. The test tube was irradiated
with a 500 W Xenon lamp for 2 h. The isooctane layer was
taken up with a pipette. Then, additional hexane (4 × 4 mL)
was placed on the residual FC-72 layer, followed by
decanting off. The combined organic layer was washed with
aq 10% Na2S2O3 (30 mL) and sat. brine (30 mL), dried over
Na2SO4, and concentrated. Purification by a short column
chromatography on silica gel with hexane gave 1-bromo-
dodecane (480 mg, 96%).
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