Rhodium-catalysed 1,4-addition-halogenation: the crucial role of lithium halide

Article abstract of DOI:10.1016/j.tetlet.2008.08.047

The rhodium-catalysed 1,4-addition-iodination or 1,4-addition-bromination of dimethylitaconate has been accomplished in high yield using arylzinc reagents and electrophilic halogenating agents. The product distribution is influenced by the presence of spe

Full text of DOI:10.1016/j.tetlet.2008.08.047

Tetrahedron Letters 49 (2008) 6217–6219
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Tetrahedron Letters
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Rhodium-catalysed 1,4-addition–halogenation:
the crucial role of lithium halide
*
Jérôme Le Nôtre, Christopher G. Frost
Department of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The rhodium-catalysed 1,4-addition–iodination or 1,4-addition–bromination of dimethylitaconate
has been accomplished in high yield using arylzinc reagents and electrophilic halogenating agents. The
product distribution is influenced by the presence of specific lithium halide salts.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 22 July 2008
Revised 5 August 2008
Accepted 11 August 2008
Available online 15 August 2008
The development of multistep syntheses involving two or more
transformations in a one-pot reaction is of great utility in organic
synthesis.1 Tandem reactions including catalytic processes have
emerged as significant methodology for the formation of new
chemical bonds in an efficient manner.2 In recent years, consider-
able efforts have been made to use conjugate addition as the initial
step of tandem processes,3 and in particular metal-catalysed 1,4-
additions have been combined with a range of different transfor-
mations including bromination,4 aldol reactions,5 cyclopropana-
tion,6 cyclisation reactions7 and enantioselective protonations.8
Ar
Y
O
[Rh]
O
Ar
M
MeO
[Rh]
R
OMe
Carbometallation
O
1
[ROH]
[F]
Protonation
Fluorination
Ar
Ar
O
O
MeO
MeO
Within this context, the
a-halogenation of carbonyl compounds
OMe
OMe
represents an area of great interest in organic chemistry.9 Interest-
ingly, an increasing number of isolated natural products contain
halogen atoms in their composition.10 In recent years, enantio-
selective halogenation processes have emerged as viable routes
to useful building blocks.11 In medicinal chemistry, the incorpora-
tion of halogens (particularly fluorine) can lead to beneficial prop-
erties.12 A number of electrophilic N–F fluorinating agents have
been developed to facilitate the synthesis of complex fluorine-con-
taining molecules.13
H
F
O
2
O
3
Figure 1. A strategy for the incorporation of fluorine using rhodium-catalysed
1,4-addition of organometallics.
Despite considerable efforts, this approach did not yield the
desired product (a wide range of solvents, temperatures, rhodium
complexes, other electrophilic fluorinating agents such as Select-
fluorÒ and other important reaction parameters were investi-
gated). In the majority of cases, we observed complex reaction
mixtures with only the 1,4-addition–protonation product 2 being
isolated cleanly (from trace amounts to modest yields depending
on exact conditions). It appeared that the electrophilic fluorinating
agents were not effective in this challenging transformation. This
could be attributed to a number of possible factors including a slow
rate of transmetallation in the absence of water; a slow rate of fluo-
rination (compared to transmetallation or protonation) on what
On the basis of reported studies describing a rhodium-catalysed
carbometallation–protonation of 1,10-alkenes,8 the development of
a new protocol for incorporating fluorine was proposed. The tan-
dem approach shown in Figure 1 depicts the quenching of an
oxa-p-allylrhodium intermediate with an electrophilic fluorinating
agent to install an aryl group and fluorine atom sequentially across
an activated alkene. At the outset of the project, it was decided to
examine a range of organometallics that could be utilised in the
selective fluorination of 1,10-alkenes triggered by rhodium-cata-
lysed 1,4-addition.14 We attempted the addition of both organo-
boron and organosilicon reagents to dimethylitaconate 1 with
N-fluorobenzenesulfonimide (NFSI) present at the time of addition
or introduced afterwards in a separate step.
would be a hindered oxa-p-allylrhodium intermediate; deleterious
side-reactions of the electrophilic fluorinating agents (preferential
reactions with other nucleophilic species in the reaction mixture)
and an accelerated catalyst decomposition pathway promoted by
the electrophilic fluorinating agent.
It is useful to note that water is not required for catalyst turn-
over when arylzinc reagents are employed in rhodium-catalysed
1,4-addition reactions.15 In a recent study, we noted that in
the addition of phenylzinc chloride to dimethylitaconate 1, the
* Corresponding author. Tel.: +44 0 1225 386142; fax: +44 0 1225 386231.
E-mail address: c.g.frost@bath.ac.uk (C. G. Frost).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.047

6218
J. L. Nôtre, C. G. Frost / Tetrahedron Letters 49 (2008) 6217–6219
intermediate silylketene acetal could be trapped and observed by
NMR.16 Following this protocol, the addition of phenylzinc chloride
to dimethylitaconate followed by treatment with NFSI (after 2 h)
furnished a single new product (100% conversion, 61% isolated
yield) that was fully characterised as the 1,4-addition–iodination
product rather than the desired 1,4-addition–fluorination product
(Scheme 1). This result was intriguing, and we sought an explana-
tion for the generation and activation of an iodine source.
ingly, the NFSI could be replaced by iodine or N-iodosuccinimide
to obtain the same product but with lower isolated yields along-
side some 1,4-addition–protonation product.
When the phenylzinc reagent was prepared from bromoben-
zene, the reaction afforded a mixture of products with NFSI: 1,4-
addition–protonation (2 50%), 1,4-addition–bromination (6a 30%)
and 1,4-addition–fluorination (3a 20%). This suggests that the reac-
tion of bromide at the fluorine site of N-fluorobenzenesulfonimide
The mechanism by which NFSI (and other electrophilic fluorine
sources) transfers fluorine is not fully understood. Both single elec-
tron transfer (SET) pathways and direct attack of the nucleophile at
fluorine (SN2) have been postulated.13 It has been established that
reagents such as SelectfluorÒ, NFSI or N-fluoropyridinium salts
possess good oxidative properties and can be used to activate other
halogen sources.17 An elegant study on the specific reactivity of
NFSI towards a wide range of nucleophiles by Crugeiras and co-
workers has demonstrated that this molecule has two different
electrophilic sites.18 Oxygen and nitrogen nucleophiles react at
the sulfonyl group, whereas halide ions attack the fluorine atom
of NFSI. This reactivity pattern can be rationalised in terms of Pear-
son’s principle of hard and soft acids and bases.19 This observation
is significant as the arylzinc reagents used in our study are pre-
pared from the corresponding aryl halides by lithium–halogen
exchange (followed by treatment with zinc(II) chloride) resulting
in an excess of lithium halide being present in the reaction mix-
ture. A mechanism consistent with the generation of a reactive
electrophilic iodine source (when the phenylzinc reagent is pre-
pared from iodobenzene) by attack of iodide ion at the fluorine site
of N-fluorobenzenesulfonimide is shown in Scheme 2.20 Interest-
is slower than iodide allowing the oxa-p-allylrhodium intermedi-
ate (or enolate) to react with N-fluorobenzenesulfonimide. Given
the relative ratio of products in the two reactions, it was clear that
the order of reactivity of the different electrophilic halogen sources
present in the reaction mixture was [I] > [Br] > [F].
1. PhZnCl 4a
(from PhBr),
[Rh(cod)Cl]2,
TMSCl, THF
MeO
2. NFSI
O
OMe
Br
O
O
6a 30% (22%)
MeO
1. PhZnCl 4a
OMe
(from PhBr),
O
1
[Rh(cod)Cl]2,
TMSCl, THF
O
MeO
OMe
2. NBS
Br
6a 100% (86%)
O
Scheme 3. Rhodium-catalysed 1,4-addition–bromination.
1. ArZnCl 4
(from PhI),
[Rh(cod)Cl]2,
TMSCl, THF
Ar
O
O
O
MeO
MeO
MeO
OMe
F
OMe
OMe
2. NFSI
I
5
6
O
O
1. PhZnCl 4a
(from PhI)
[Rh(cod)Cl]2,
TMSCl, THF
O
O
O
3a
MeO
1. ArZnCl 4
(from PhBr),
[Rh(cod)Cl]2,
TMSCl, THF
MeO
OMe
OMe
O
1
Ar
O
1
2. NFSI
O
2. NBS
MeO
Br
OMe
O
I
5a 100% (61%)
Scheme 1. Rhodium-catalysed 1,4-addition–iodination with NFSI.
O
O
O
[Rh(cod)Cl]2,
TMSCl, THF
Ph
MeO
MeO
O
MeO
OMe
OMe
OMe
-BuLi
I
Br
MeO
O
O
1
PhZnCl
OMe
O
5b 89%
6b 88%
n
OTMS
PhI
F
ZnCl2
PhO2S
SO2Ph
N
+
LiI
IF
I2
O
O
Ph
O
F
+ IŠ
O
MeO
MeO
MeO
MeO
OMe
OMe
OMe
OMe
MeO
+ IŠ
I
Br
OMe
Š
+ FŠ
I3
O
O
O
O
F
3a
5c 48%
6c 89%
Ph
Ph
O
O
O
O
MeO
OMe
I
I
Br
5a (100%)
5d 61%
6d 91%
Scheme 2. A plausible mechanism for rhodium-catalysed 1,4-addition–iodination
with NFSI.
Scheme 4. Examples of rhodium-catalysed 1,4-addition–halogenation.

J. L. Nôtre, C. G. Frost / Tetrahedron Letters 49 (2008) 6217–6219
6219
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be realised by switching from NFSI to N-bromosuccinimide (NBS)
as shown in Scheme 3. The 1,4-addition–bromination product 6a
was isolated as the sole product of the reaction (100% conversion,
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high yield. Interestingly, it was possible to use this process to
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Acknowledgements
We are grateful to the EPSRC for funding. Dr. Anneke Lubben
(Mass Spectrometry Service at the University of Bath) and the
EPSRC Mass Spectrometry Service at the University of Wales Swan-
sea are thanked for valuable assistance.
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Supplementary data
Experimental procedures and compound characterisation data
are available. Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.2008.08.047.
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