The first iron-catalysed aluminium-variant Negishi coupling: Critical effect of co-existing salts on the dynamic equilibrium of arylaluminium species and their reactivity

Article abstract of DOI:10.1039/c0cc01216e

The first example of an iron-catalysed Negishi coupling between arylaluminium reagents and alkyl halides illustrates that the co-existing salts highly influence the dynamic equilibrium of the organoaluminium species, and have a critical effect on the reactivity and selectivity of the coupling reaction.

Full text of DOI:10.1039/c0cc01216e

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The first iron-catalysed aluminium-variant Negishi coupling: critical
effect of co-existing salts on the dynamic equilibrium of arylaluminium
species and their reactivityw
Shintaro Kawamura,ab Kentaro Ishizuka,ac Hikaru Takayaab and Masaharu Nakamura*abc
Received 2nd May 2010, Accepted 25th June 2010
DOI: 10.1039/c0cc01216e
The first example of an iron-catalysed Negishi coupling between
arylaluminium reagents and alkyl halides illustrates that the
co-existing salts highly influence the dynamic equilibrium of
the organoaluminium species, and have a critical effect on the
reactivity and selectivity of the coupling reaction.
Palladium- or nickel-catalysed cross-coupling reactions of
Scheme
1 Preparation of phenylaluminium reagents and the
organoaluminium reagents have shown their utility in organic
synthesis.1–3 On the other hand, only a few studies have reported
on coupling reactions of organoaluminium reagents under iron
catalysis,4 despite the significant progress in iron-catalysed cross-
coupling technology.5–8 This limitation is, in part, yet critically,
due to the complex and dynamic equilibrium of organo-
aluminium compounds in solution,9 which even dominate the
reactivity and selectivity of transition-metal catalysts. For
example, Gau et al. recently reported that salt-free triaryl-
aluminium compounds enable a high-yielding biaryl cross-coupling
under palladium catalysis to occur. In the course of our
studies, we have found that the salt-free system is ineffective
for iron catalysis, and adversely, co-existing metal salts
critically modify the catalytic activity of iron salts and
complexes.7b,10 Herein, we report on the first iron-catalysed
aluminium-variant Negishi coupling of arylaluminium
compounds with alkylhalides,11 where the organoaluminium
ate species is generated in situ through disproportionation and
a dynamic equilibrium, and is responsible for the coupling
reaction.
iron-catalysed cross-coupling reaction with bromocycloheptane.
Table 1 Difference in reactivity of phenylaluminium compounds
prepared from different Grignard reagents at various ratios
Yield (%)b,c
RSMd
Entrya Phenylaluminium
4
5
6
3 (%)b,c
1
2
3
4
5
Ph3AlÁ3MgBrCl (1a)
Ph3AlÁ3MgCl2 (1b)
31
72
3
8
23
20
1
3
16
4
4
3
59
0
0
0
93
[Ph4Al]ÀMgBr+Á3MgBrCl (2a) 75
[Ph4Al]ÀMgCl+Á3MgCl2 (2b)
70
0
Ph3Al–THF
a
b
Reactions were carried out on the 0.5 mmol scale. The reaction
c
time was 12 h for all entries. The yield was estimated from GLC
d
analysis using undecane as an internal standard. Recovery of
starting material.
yield (entries 1 and 2). On the other hand, anionic tetra-
phenylaluminium ate reagents prepared using a 1 : 4 ratio of
AlCl3 and PhMgBr (or PhMgCl) showed a similar reactivity,
regardless of the different composition of the co-existing salts
(entries 3 and 4). Note that salt-free triphenylaluminium,
which shows excellent reactivity in the Pd-catalysed cross-
coupling reaction, was not effective at all (entry 5). These
contrasting results suggest that the in situ generated magnesium
salts influence the formation of the reactive phenylaluminium
species.
First, we conducted the coupling reaction between a series
of phenylaluminium compounds (1, 2, and Ph3Al–THF) and
bromocycloheptane in the presence of a catalytic amount of
anhydrous FeCl3 (Scheme 1 and Table 1). A notable difference
was found among the reactivities of the phenylaluminium
compounds prepared using PhMgBr and PhMgCl with AlCl3.
Whereas the triphenylaluminium prepared from a 1 : 3 ratio
of AlCl3 and PhMgBr, denoted as ‘‘Ph3AlÁ3MgBrCl (1a)’’,
gave the desired cycloheptylbenzene in only 31% yield, the
triphenylaluminium derived from PhMgCl and AlCl3, denoted
as ‘‘Ph3AlÁ3MgCl2 (1b)’’, completely consumed 3 under the
same reaction conditions to give the coupling product in 72%
27Al NMR studies clearly distinguished between the
unreactive triphenylaluminium reagent (Ph3Al–THF) and the
reactive reagents (1a, 1b, and 2b). A broad peak (d = 148 ppm,
1
Dn = 3600 Hz) was observed for the unreactive salt-free
phenylaluminium as in Fig. 1(1). In contrast, a sharp peak
2
a International Research Center for Elements Science (IRCELS),
Institute for Chemical Research, Kyoto University, Uji, Kyoto,
611-0011, Japan. E-mail: masaharu@scl.kyoto-u.ac.jp;
Fax: +81 774-38-3186; Tel: +81 774-38-3180
1
2
(Dn = 19 Hz) appeared in the 132 ppm region in the spectra
of 1a, 1b, and 2b as in Fig. 1(2)–(4). The sharp peaks appeared
with almost the same chemical shift, regardless of the difference
in halide ion (BrÀ or ClÀ) as well as of the stoichiometry of the
Grignard reagent (1 : 3 or 1 : 4). The broad peak is characteristic
of neutral triorganoaluminium compounds,12 and the latter
sharp peaks are usually observed for highly symmetrical
tetraphenylaluminium ate complexes.13 Addition of MgCl2
b Department of Hydrocarbon Chemistry, Graduate School of
Engineering, Kyoto University, Japan
c Institute of Sustainability Science, Kyoto University, Japan
w Electronic
Experimental details and spectral data for the coupling products.
supplementary
information
(ESI)
available:
See DOI: 10.1039/c0cc01216e
c
6054 Chem. Commun., 2010, 46, 6054–6056
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Fig. 1 27Al NMR spectra of 1a, 1b, 2b and the salt-free triphenyl-
aluminium–THF complex (conditions: 0.28 M, THF-d8, 25 1C,
n0 = 78.2 MHz, Varian Mercury spectrometer).
Fig. 2 (a) GC traces of the cross-coupling reactions with 1a and 1b
shown in the red and blue lines, respectively. (b) 27Al NMR monitoring
of the consumption of the tetraphenylaluminium ate species.
0.014 mmol (5%). On the other hand, the amount of
aluminium ate species decreased from 0.073 mmol (24%) to
0.038 mmol (13%) during the initial stage of the reaction
(o40 min), and maintained this concentration during the later
stage, with the continuous formation of the product 4
(48% yield, after 180 min). These results suggest that the
equilibrium between the reactive aluminium ate species and
the unreactive neutral aluminium species depends strongly on
the nature of the co-existing in situ generated magnesium salts,
and that MgCl2 facilitates the generation of the reactive
aluminium species.15
to a THF-d8 solution of the salt-free phenylaluminium did not
change the 27Al NMR spectrum, showing a broad peak at 148
ppm region. It suggests that a one-sided equilibrium occurs to
give Ph3Al–THF once the magnesium salts are precipitated.3
The yield of the aluminium ate complexes was determined
to be ca. 25% for 1a and 1b, and ca. 45% for 2b from a
comparison with aluminium nitrate in a small sealed tube. A
notable amount of the tetraphenylaluminium ate complex was
formed, even when the 1 : 3 ratio of AlCl3 and PhMgX was
expected to produce neutral Ph3AlÁ3MgX2 (Fig. 1(2) and (3)).
The in situ generated MgX2, thus, facilitated the disproportionation
of triphenylaluminium to the aluminium ate complex and a
diphenylaluminium halide.13b When AlCl3 was treated with
4 equiv. of PhMgCl (Fig. 1(4)), the aluminium ate complex
formed, but not quantitatively (ca. 45% yield). The above-
mentioned equilibrium shifted more, but not completely, to
the aluminium ate complex side.
Table 2 Cross-coupling of arylaluminium reagents and alkyl halides
Whereas the 27Al NMR study on the phenylaluminium
species showed a distinct difference between the reactive and
unreactive aluminium reagents, it does not account for the
different reactivities of 1a and 1b prepared from PhMgBr and
PhMgCl, respectively. Hence, we conducted GC monitoring
and 27Al NMR of the cross-coupling reaction between the
phenylaluminium reagents 1a and 1b, and bromocycloheptane
3 in the presence of 3 mol% FeCl3 (Fig. 2).14
Product and
isolated yield (%)
Entrya RX
‘‘Ar3Al’’
1b
2
c-Heptyl-Br Ph3AlÁ3MgCl2
c-Heptyl-Cl Ph3AlÁ3MgCl2
4
4
94
85c
(4-MeOC6H4)3AlÁ
c-Heptyl-Br
3
72
3MgCl2
(4-MeC6H4)3AlÁ
c-Heptyl-Br
4
5
6
7
96
56
87
As expected from the results in Table 1, a notable contrast
was found by the GC-monitoring in the rates of formation of
the cross-coupling product 4 (Fig. 2a): the reaction with 1b
proceeded at 60 1C to give the product in 48% yield after
180 min. The formation of 4 consists of an early stage of rapid
coupling (o40 min) and a later stage of slow but steady-going
coupling (>40 min). On the other hand, the reaction of 1a was
considerably slower from the beginning, and, quickly stopped
only to provide 6% of the cross-coupling product under the
same reaction conditions.
The 27Al NMR monitoring shown in Fig. 2(b) shows that
changes over time in the concentration of the reactive aluminium
ate species are different for the reactions with 1a and 1b: despite
the slow formation of 4, the amount of reactive aluminium ate
species decreased constantly from 0.068 mmol (23%) to
3MgCl2
(4-FC6H4)3AlÁ
c-Heptyl-Br
3MgCl2
(4-MeC6H4)3AlÁ
c-Hexyl-Br
3MgCl2
Decyl-Br
Ph3AlÁ3MgCl2
Ph3AlÁ3MgCl2
82
55
8
a
b
Reactions were carried out on the 1.0 mmol scale. Conducted for a
c
period of 12 h. The yield was determined from quantitative GLC
analysis using undecane as an internal standard.
c
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Given the reactive organoaluminium reagent in hand, we
optimized the Negishi coupling conditions by intensive ligand
and additive screening,16 which led us to find that
FeCl2(dppbz)2 markedly improved the yield and selectivity
of the reaction.7c,d It should be noted that aluminium reagent
1a gave the cross-coupling product in at most 41% yield even
in the presence of the phosphine ligand. Table 2 demonstrates
the substrate scope of the present coupling reaction. In the
presence of 3 mol% of the iron–phosphine complex, secondary
and primary alkyl halides coupled with several arylaluminium
compounds, which were prepared from AlCl3 and 3 equiv. of
the corresponding arylmagnesium chloride. An alkyl chloride,
as well as a bromide, participated in the reaction with good
yields (entries 1 and 2). Electron-rich 4-anisyl and 4-tolyl
aluminium compounds gave the corresponding coupling
products in higher yields than the reaction of rather electron
poor 4-fluorophenyl aluminium compound (entries 3, 4 vs. 5).
Primary alkyl bromides also took part in the coupling reaction
(entries 7 and 8). As seen in entry 8, the functional group
compatibility was modest owing to the severe reaction conditions
(80 1C, 48 h), posing a future challenge on the elaboration of
the phosphine ligand in achieving a higher reactivity.
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In conclusion, we have found that arylaluminium
compounds exist in a dynamic equilibrium and the resulting
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is gratefully acknowledged.
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6056 Chem. Commun., 2010, 46, 6054–6056
This journal is The Royal Society of Chemistry 2010