An intriguing effect of Yb(OTf)3-TMSCl in the halogenation of 1,1-disubstituted alkenes by NXS: Selective synthesis of allyl halides

Article abstract of DOI:10.1016/S0040-4039(02)00260-5

A novel protocol to effect the efficient selective halogenation of 1,1-disubstituted alkenes with NXS catalyzed by Yb(OTf)₃-TMSCl, which affords the corresponding allyl halides in high yield, including allyl bromide, chloride, iodide and fluori

Full text of DOI:10.1016/S0040-4039(02)00260-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2403–2406
An intriguing effect of Yb(OTf)3–TMSCl in the halogenation
of 1,1-disubstituted alkenes by NXS: selective synthesis
of allyl halides
Masamichi Yamanaka, Mitsuhiro Arisawa, Atsushi Nishida and Masako Nakagawa*
Graduate School of Pharmaceutical Sciences, Chiba University, Yayoi-cho 1-33, Inage-ku, Chiba 263-8522, Japan
Received 16 January 2002; accepted 1 February 2002
Abstract—A novel protocol to effect the efficient selective halogenation of 1,1-disubstituted alkenes with NXS catalyzed by
Yb(OTf)3–TMSCl, which affords the corresponding allyl halides in high yield, including allyl bromide, chloride, iodide and
fluoride, is described. A remarkable feature of Yb(OTf)3–TMSCl-catalyzed halogenation is that, unlike conventional radical
halogenation with N-halosuccinimides, the reaction discriminates between the allylic and benzylic positions. The reaction occurs
selectively at the allylic position to give allylic halides, but not at the benzylic position. © 2002 Elsevier Science Ltd. All rights
reserved.
Allyl halides are a fundamental and important class of
compounds which undergo a variety of transformations
as excellent electrophiles. They also serve as precursors
for allylic organometallic reagents which are powerful
tools in modern organic synthesis.1 Given their signifi-
cance, it is important to develop efficient methods for
their synthesis.
amines (Scheme 1).3 In studying the mechanism of this
reaction, we discovered that Yb(OTf)3–TMSCl also
catalyzed the allylic bromination of 1,1-disubstituted
alkenes using NBS. In this letter, we report the first
selective allylic halogenation and the utility of this
novel reaction.
We first investigated the bromination of a-methyl-
styrene (1) with NBS without initiator, which produced
only a trace amount of the allyl bromide 2a, whereas
the same reaction in the presence of a catalytic amount
of (PhCO)2O2 under a typical protocol for radical
bromination gave 2a in 24% yield after 8 h (Table 1,
entries 1, 2).4 In contrast, treatment of 1 with NBS in
the presence of 5 mol% of Yb(OTf)3 increased the yield
of 2a up to 48% (entry 3). The bromination of 1 was
dramatically enhanced by the combination of Yb(OTf)3
and TMSCl in CH2Cl2–THF (4: 1) at room tempera-
ture. The reaction was completed within 30 min and
gave 2a in 84% yield (entry 5), whereas the use of
TMSCl itself gave 2a in only 11% yield (entry 4). These
conditions were found to be quite general for effecting
not only allylic bromination but also allylic
chlorination4b,5 and iodination of 1 (entries 6, 7). To the
One of the most common approaches for the synthesis
of allyl halides is the direct halogenation of alkenes.
N-Bromosuccinimide (NBS) has been used extensively
in allylic bromination, while N-chloro (NCS) and N-
iodosuccinimide (NIS) have been used to a much lesser
extent.2 Allylic chlorides are important in industry.
They are made commercially by the gaseous chlorina-
tion of alkenes with Cl2 at high temperature (ꢀ400°C).
Generally, these halogenations proceed by a radical
mechanism in the presence of radical initiators such as
AIBN or benzoylperoxide which is promoted either by
light or heat. Consequently, these reactions sometimes
become complicated and give a mixture of products.
Under these reaction conditions, benzylic halogenation
also takes place. No selectivity between allylic and
benzylic halogenation has been observed. Therefore,
there has been continuing interest in the development
Yb(OTf)3 (5 mol%)
of
a
new method for highly selective allylic
Ts
H
Ts
N
NH
TMSCl (5 mol%)
CH2Cl2-THF
(4 : 1)
+
halogenation.
Ph
Ph
Ph
Ph
94%
We recently found a facile imino ene reaction that was
catalyzed by Yb(OTf)3–TMSCl to give homoallyl
rt, 0.25 h
Scheme 1. Imino ene reaction.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00260-5

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M. Yamanaka et al. / Tetrahedron Letters 43 (2002) 2403–2406
Table 1. Allylic halogenation of a-methylstyrene
group accelerated the reaction to induce polymeriza-
tion, and the corresponding allyl halides were not iso-
lated (entries 3, 4). Bromination of 2,4,4-trimethyl-
1-pentene (9) in the presence of AIBN under reflux
conditions in CCl4 has been reported to give a mixture
of bromides due to two allylic positions.7 However, the
reactions catalyzed by Yb(OTf)3–TMSCl provided 2-
(halomethyl)-4,4-dimethyl-1-pentene (10) in high yield
as a single product (entries 7, 8). Optically active iso-
pregol derivative (11) also gave 12 without epimeriza-
tion (entry 9), accompanied by a small amount of a
dibromide.
O
catalyst
+
X
N X
Ph
CH2Cl2-THF
Ph
1
2
(4 : 1)
rt
O
Entry
X
Catalyst (mol%)
Time (h)
Yield (%)a
1
Br None
72
8
0.5
0.5
0.5
2a (6)
2b
3
Br (PhCO)2O2 (10)
Br Yb(OTf)3 (5)
Br TMSCl (5)
Br Yb(OTf)3 (5)
TMSCl (5)
2a (24)
2a (48)
2a (11)
2a (84)
4
5
A remarkable feature of Yb(OTf)3–TMSCl-mediated
halogenation is that, unlike conventional radical halo-
genation with N-halosuccinimides, the reaction discrim-
inates between the allylic and benzylic positions.2 The
reaction occurs selectively at the allylic position to give
allylic halides, but not at the benzylic position. To
evaluate the halogenation promoted by Yb(OTf)3–
TMSCl, a competitive reaction was carried out with 1
and 4-substituted toluenes (13), the most commonly
used reactive substrates in radical bromination. To our
surprise, the only product detected in the reaction
mixture was 2a (71–78% yield) and toluenes were recov-
ered essentially unchanged, showing high selectivity
between the allylic and benzylic positions toward
Yb(OTf)3–TMSCl-catalyzed bromination. We were also
surprised to ascertain that 14, which has both allylic
and benzylic protons, reacted selectively with NXS at
the allylic position to give the corresponding halides 15
in high yields. No other isomer was detected by 1H
NMR spectroscopy (Scheme 2). These result suggested
the halogenation with NXS mediated by Yb(OTf)3–
TMSCl probably proceeded via a non-free-radical
mechanism.
6
7
Cl
Yb(OTf)3 (5)
TMSCl (5)
Yb(OTf)3 (5)
TMSCl (5)
0.5
0.5
2b (76)
2c (61)
I
a Isolated yield.
b Reaction was carried out under reflux in CCl4.
best of our knowledge, a similar direct allylic iodination
of alkenes has not been realized by another method.
To explore the generality of this halogenation, we
investigated the similar reaction of other substrates. As
shown in Table 2, both allylic chlorides and bromides
were formed in good yields, although the bromination
of a-methylstyrenes proceeded more cleanly and gave a
better yield than the corresponding chlorination. 4-
Chloro4c,6 and 2-toluenesulfonylamino substituents on
the aromatic ring had little effect on the yield of
halogenation (entries 1, 2 and 5, 6), whereas a methoxy
Table 2. Allylic halogenation catalyzed by Yb(OTf)3–
TMSCl
Interestingly, 1,2-disubstituted alkene such as trans-b-
methylstyrene or monosubstituted alkene such as 3-
phenyl-1-propene was completely inert under the same
conditions, and no reaction was observed, indicating
that the current method is useful for selective halogena-
tion of 1,1-disubstituted alkenes.
yield (%)a
entry
product
substrate
X
X
R
R
1
2
3
4
5
6
7
8
3
3
5
5
7
7
R = 4-Cl
R = 4-Cl
4a (44)
4b (82)
6a (0)
Cl
Br
Cl
Br
Cl
Br
Cl
Br
R = 4-OMe
R = 4-OMe
R = 2-NHTs
R = 2-NHTs
6b (0)
8a (46)
8b (52)
10a (78)
10b (76)
X
9
Br 12 (64)b
9
OR'
11
OR'
X
R' = TBDPS (t-butyldiphenylsilyl).
a Isolated yield.
b 27% of allylic and vinylic di-brominated product
was also isolated.
Scheme 2. Competitive halogenations.

M. Yamanaka et al. / Tetrahedron Letters 43 (2002) 2403–2406
2405
F3C
Yb(OTf)3
(25 mol%)
SO3 CH2Cl2-THF
rt, 9 h
As a logical extension of our Yb(OTf)3–TMSCl-cata-
lyzed halogenation by NXS regarding allylic halide
formation, the bromination of 2H-labeled a-
methylstyrene[C6H5CCH2(CD3)] 16 was investigated to
determine the mechanistic aspects of these reactions.
The bromination of 16 was carried out using 2.5 mol%
Yb(OTf)3–TMSCl under the same conditions as were
used for 1 (Table 1, entry 5), and a large degree of
positional randomization of the deuterium label was
observed, as shown in Scheme 3. As control experi-
ments, 16 was treated similarly but without NBS, and
again deuterium scrambling was observed. Thus, when
16 was treated with 2.5 mol% Yb(OTf)3–TMSCl (1:1)
without NBS for 1 h, 76% of 16 was recovered with
71% of the deuterium atoms in allylic position and 10%
incorporated at the terminal position of the alkene.
However, treating 16 with either Yb(OTf)3 (2.5 mol%)
or TMSCl (2.5 mol%) showed no scrambling of deu-
terium and 16 was recovered unchanged, showing that
the disproportionation of deuterium in 16 by
Yb(OTf)3–TMSCl appears to occur partially before
bromination.
+
F
N
F
Ph
Ph
21
1
22
63%
Scheme 5. Allylic fluorination.
developed imino ene reaction catalyzed by Yb(OTf)3–
TMSCl (Scheme 4).3
Finally, we also investigated allylic fluorination, which
has not been reported previously.10 Our initial attempts
to apply our present methodology to fluorination using
N - fluoro - 5 - (trifluoromethyl)pyridinium - 2 - sulfonate
(21)11 as a fluorinating reagent failed and produced
polymerization. However, a modified procedure which
uses Yb(OTf)3 without TMSCl gave the corresponding
fluoride 22 in 63% yield from 1 (Scheme 5).
In summary, we have for the first time developed a
selective method for the synthesis of allyl halides using
Yb(OTf)3–TMSCl or Yb(OTf)3 as a catalyst. The reac-
tion conditions are mild enough to be applicable to
large-scale conversions. Further investigations of the
scope and limitations of these reactions are underway
in our laboratories.
Although the mechanism still remains to be resolved,
bromide 8 is a suitable compound for further function-
alization. For example, treating 8b with K2CO3 in
DMF at room temperature gave indolidene 19, which is
a novel method for the synthesis of indole derivatives.8
Interestingly, 19 could be readily converted to the tryp-
tophan derivative 209 in high yield using our recently
Acknowledgements
This research was supported by a Grant-in-Aid for
Scientific Research on Priority Areas (A) ‘Exploitation
of Multi-Element Cyclic Molecules’ from the Ministry
of Education, Culture, Sports, Science and Technology,
Japan and Uehara Memorial. We also thank Ms. R.
Hara at the Analytical Center, Chiba University, for
performing mass spectroscopy.
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Scheme 3. Reaction of 16 catalyzed Yb(OTf)3–TMSCl with
NBS or without NBS.
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