One-pot halogenation-Heck coupling reactions in ionic liquids

Article abstract of DOI:10.1055/s-2006-948192

Traditional cross-coupling approaches rely upon two steps - halogenation and coupling - each of which is viewed and conducted independently. In an effort to develop a one-pot approach, we have noted that the halogenation and Heck coupling reactions can both be conducted in a room-temperature ionic liquid without the need to isolate the halogenated intermediate. Application to several systems shows that this approach works well for moderately to highly electron-rich aromatics. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-948192

3176
LETTER
One-Pot Halogenation–Heck Coupling Reactions in Ionic Liquids
One-Pot
H
alog
c
enation–H
o
t
React
t
Tiquids . Handy*
Department of Chemistry, Middle Tennessee State University, Murfreesboro, TN 37132, USA
Fax +1(615)8985182; E-mail: shandy@mtsu.edu
Received 27 March 2006
This paper is dedicated to Professor Richard Heck, whose efforts opened a vast new area of fundamental importance to the synthesis of
organic products.
More recently, there have been efforts to use RTILs in the
Abstract: Traditional cross-coupling approaches rely upon two
halogenation of aromatic substrates. Yadav and co-work-
ers have reported that halogenations using N-halosuccin-
imides are remarkably accelerated using RTILs such as 1-
steps – halogenation and coupling – each of which is viewed and
conducted independently. In an effort to develop a one-pot
approach, we have noted that the halogenation and Heck coupling
reactions can both be conducted in a room-temperature ionic liquid butyl-3-methylimidazolium hexafluorophosphate or tet-
rafluoroborate ([BMIM]PF6 or [BMIM]BF4).6 Thus, even
without the need to isolate the halogenated intermediate. Applica-
tion to several systems shows that this approach works well for
moderately to highly electron-rich aromatics.
the less reactive N-iodosuccinimide (NIS) will rapidly
iodinate a wide range of moderately to highly electron-
Key words: cross-coupling, Heck coupling, room-temperature
ionic liquids
rich aromatics, providing reliable access to these com-
pounds quickly and in high yield.7
Since it is clear that both reactions will work independent-
ly in a RTIL, the next question was if such reactions could
Certainly, transition-metal-mediated cross-coupling reac-
be carried out sequentially in one pot (Scheme 1). The pri-
tions, including the Heck coupling, the Stille coupling,
mary advantage of such an approach would be in avoiding
and the Suzuki coupling, have revolutionized the way that
the necessity of working up the reaction and isolating the
the organic chemist approaches synthesis.1 The ready
intermediate product. This could be of particular value in
availability of halogenated aromatics and various cou-
automated and/or parallel synthesis.
pling partners (alkenes, organotins, organoborons, etc.)
has made these reactions one of the basic methods for
forming carbon–carbon bonds.
At the same time, it is somewhat surprising to note that the
two critical parts of these couplings – the preparation of
the halogenated aromatic and the coupling itself – remain
viewed as completely independent entities. As a result,
Scheme 1
assuming that the haloaromatic is not commercially
As an initial test, the iodination of anisole was conducted
available, the common approach is always to halogenate
in [BMIM]BF4 (Table 1, entry 1). After 2 hours, a Heck
the aromatic ring, work up and purify this product, and
coupling with methyl acrylate was performed under con-
then perform the cross-coupling reaction. But, is it really
ditions used previously in these labs and the reaction was
necessary to isolate the halogenated intermediate or can
allowed to proceed overnight.8 Extraction with diethyl
these two steps be performed in a sequential, but one-pot,
ether then afforded the clean Heck coupling product in
method?
99% yield.9
Part of the driving force behind this question is our long-
Table 1 Halogenation–Heck Coupling of Anisolea
standing interest in the use of room-temperature ionic
liquids (RTILs) in organic synthesis.2 Numerous groups,
including our own, have studied many cross-coupling
reactions in RTILs,3 especially the Heck coupling.4 RTILs
based on imidazole have been demonstrated to be excel-
lent reaction solvents for these reactions, with the solvent
often times playing an active role in maintaining, and even
enhancing, the reactivity of the palladium catalyst.5 As a
result, the concept of using a RTIL for a cross-coupling
reaction is well established.
Entry
Alkene
Isolated yield (%)
1
Methyl acrylate
Styrene
99
78
10b
98
2
3
1-Decene
4c
Methyl acrylate
a Reaction conditions: 0.5 mmol of anisole, 0.5 mmol of NIS, 2 mL of
[BMIM]BF4. After 2–3 h, 0.75 mmol of alkene, 0.05 mmol of
Pd(OAc)2, and 1 mmol of Et3N at 140 °C for 20 h.
b 80% Recovery of p-iodoanisole.
c 1-Butyl-3-methyl-4-hydroxymethylimidazolium triflimide was used
as the solvent.
SYNLETT 2006, No. 18, pp 3176–3178
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Advanced online publication: 04.08.2006
DOI: 10.1055/s-2006-948192; Art ID: S04806ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
One-Pot Halogenation–Heck Coupling Reactions in Ionic Liquids
3177
Anisole was also employed as the starting point for Heck Although aryl iodides are the most reactive of the aryl
couplings with two other, less-activated alkenes (Table 1, halides in the Heck coupling, they are also the most diffi-
entries 2 and 3). With styrene, the reaction proceeded well cult and expensive to prepare (particularly on less elec-
to afford the anticipated stilbene in 78% yield. On the oth- tron-rich aromatic rings). As a result, there is clear interest
er hand, the reaction with less reactive 1-decene afforded in examining the potential for using a similar bromina-
only a small amount of the Heck coupling product and tion–Heck coupling sequence. Much to our delight, bro-
mostly recovered p-iodoanisole. While the low reactivity mination proceeded well in the ionic liquid solvent. The
of the alkene is clearly part of the problem, another factor Heck coupling, however, did not proceed as well under
could be the relatively limited solubility of 1-decene in the simple palladium acetate conditions. Still, the Heck
[BMIM]BF4.
coupling product with anisole could be isolated in 58%
yield over this two-step, one-pot sequence (Table 3, entry
1). The bulk of the remainder of the material was p-bro-
moanisole. Presumably, the lower yield is due to the lower
reactivity of aryl bromides in the Heck coupling. As a re-
sult, one possible solution to this incomplete conversion
would be to employ a more reactive catalyst for the Heck
coupling, of which many are available.
Although it was anticipated that these conditions should
be applicable to a wide range of RTILs, it was encourag-
ing to note that this was actually the case (Table 1, entry
4). Thus, the use of our fructose-derived RTIL again
afforded the Heck coupling product over these two steps
in excellent overall yield.10 There is a potential additional
advantage to the use of a much more hydrophobic RTIL
in that the succinimide by-product can be removed at the
end of the reaction by extraction with water. As a result, it
should be possible to recycle the solvent through several
couplings, thereby reducing the cost associated with the
use of RTIL solvents in this one-pot approach.
Table 3 Halogenation–Heck Coupling Using NBS and Methyl
Acrylatea
Entry
Aromatic
Anisole
Isolated yield (%)b
1
58 (30)
21 (78)
75
In examining other aromatic substrates, the one-pot se-
quence again worked well (Table 2). Thus, highly elec-
tron-rich aromatics such as dimethylaniline, thiophene,
and mesitylene all afforded the desired Heck products in
good yield (Table 2, entries 1–3). A problem was encoun-
tered when attempting this sequence on less electron-rich
aromatics, though. Application of the conditions reported
by Yadav for the iodination of naphthalene and m-xylene
failed completely. Fortunately, this limitation could be
overcome by either heating the solution to 80 °C for 6–12
hours or by employing an acid catalyst, as has been report-
ed by Castanet and co-workers in the iodination of aro-
matics in acetonitrile using N-iodosuccinimide.11 With
this modification, the moderately electron-rich aromatic
m-xylene afforded good yields of the anticipated Heck
product (Table 2, entry 5). Unfortunately, an even less
electron-rich aromatic – naphthalene – failed to undergo
iodination even with this activation.
2
Mesitylene
Naphthalene
m-Xylene
3c
4
82
a Reaction conditions: 0.5 mmol of the arene, 0.5 mmol of NIS, 2 mL
of [BMIM]BF4. After 6–12 h, 0.75 mmol of methyl acrylate, 0.05
mmol of Pd(OAc)2, and 1 mmol of Et3N at 140 °C for 20 h.
b The yield in parenthesis is of recovered bromoarene.
c Initial bromination performed at 80 °C.
The potential advantage of the bromination conditions can
be more readily seen in the reaction with m-xylene
(Table 3, entry 4). In this case the bromination could be
performed at room temperature, instead of the elevated
temperature required with NIS. The Heck coupling
product was then isolated in 82% yield – a result nearly
equivalent to that obtained using the iodination sequence.
Even more impressive is the reaction with naphthalene
(Table 3, entry 3). The bromination reaction did have to
be heated to proceed to completion, but ultimately afford-
ed the Heck coupling product in reasonable yield.
Table 2 Halogenation–Heck Couplings of Aromatics with Methyl
Acrylatea
Entry
Aromatic
Isolated yield (%)
In conclusion, we have developed a one-pot method for
the halogenation and Heck coupling of a variety of aro-
matic substrates. Based upon the observations with the
less-polar triflimide RTIL, it should be possible to also
recycle the RTIL solvent, thereby rendering this method
of even greater use. Already it has promise in automated
or parallel synthesis. Further, the same approach should
be applicable to a wide range of coupling reactions and be
of very general utility.
1
Dimethylaniline
Thiophene
Mesitylene
m-Xylene
99
90
96
89
90
2
3
4b
5c
m-Xylene
a Reaction conditions: 0.5 mmol of the arene, 0.5 mmol of NIS, 2 mL
of [BMIM]BF4. After 6–12 h, 0.75 mmol of methyl acrylate, 0.05
mmol of Pd(OAc)2, and 1 mmol of Et3N at 140 °C for 20 h.
b Initial iodination performed at 80 °C.
c Iodination performed in the presence of 0.05 mmol of TFA.
Synlett 2006, No. 18, 3176–3178 © Thieme Stuttgart · New York

3178
S. T. Handy
LETTER
(4) (a) Howarth, J.; Dallas, A. Molecules 2000, 5, 851.
Representative Coupling Procedure
To 2.0 mL of 1-butyl-3-methylimidazolium tetrafluoroborate was
added 58 mL (0.50 mmol) of anisole and 112 mg (0.50 mmol) of N-
iodosuccinimide. The reaction was stirred for 2 h. Then, 140 mL (1.5
mmol) of Et3N and 12 mg (0.05 mmol) of Pd(OAc)2 was added and
the mixture stirred for 1–2 min before the addition of 68 mL (1
mmol) of methyl acrylate. The reaction was heated to 140 °C and
stirred overnight. The reaction was then cooled to r.t. and extracted
with Et2O (4 × 3 mL). The Et2O extracts were concentrated in vacuo
to afford 95 mg (99%) of the Heck coupling product as a pale
yellow solid.
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Acknowledgment
The author thanks Middle Tennessee State University for financial
support of this research.
References and Notes
(1) For an excellent monograph reviewing all aspects of cross-
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halogenations in RTILs is also quite high. In the
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(8) Handy, S. T.; Okello, M. Tetrahedron Lett. 2003, 44, 8395.
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Synlett 2006, No. 18, 3176–3178 © Thieme Stuttgart · New York