Simple mixed Fe-Zn catalysts for the Suzuki couplings of tetraarylborates with benzyl halides and 2-halopyridines

Article abstract of DOI:10.1039/b915945b

Employing co-catalytic zinc reagents facilitates the iron-catalysed Suzuki cross-coupling of tetraarylborates with both benzyl and 2-heteroaryl halides.

Full text of DOI:10.1039/b915945b

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Simple mixed Fe–Zn catalysts for the Suzuki couplings
of tetraarylborates with benzyl halides and 2-halopyridinesw
Robin B. Bedford,*a Mark A. Hall,a George R. Hodges,b Michael Huwea and
Mark C. Wilkinsonc
Received (in Cambridge, UK) 4th August 2009, Accepted 10th September 2009
First published as an Advance Article on the web 28th September 2009
DOI: 10.1039/b915945b
Employing co-catalytic zinc reagents facilitates the iron-
catalysed Suzuki cross-coupling of tetraarylborates with both
benzyl and 2-heteroaryl halides.
Table 1 Fe-catalysed Negishi coupling of halopyridinesa
The use of iron catalysis in C–C bond-forming processes
(Scheme 1) is undergoing a renaissance due in no small part
to the low cost and toxicity of iron compared with palladium.1
In most cases the organometallic coupling partner employed is
a Grignard reagent and whilst these can be used in a wide
range of reactions, the application of softer, more substrate
tolerant aryl metal nucleophiles remains underdeveloped.2,3
We recently found that the preformed catalyst 1 or similar
catalysts formed in situ show good to excellent activity in the
Negishi coupling of arylzinc reagents with benzyl halides
and phosphates.4 Similarly, Nakamura and co-workers
demonstrated that 1 can be used in the Negishi coupling of
electron-deficient fluoroaryl zinc reagents with alkyl halides.5
Heteroaryl
halide
Spec. yieldb
(%) (isolated)
Entry
1
Product
65c
2
3
4
5
6
75 (53)
15d
2e
35
55
X = Cl
X = I
7
8
58 (58)
None
0
9
None
None
0
The iron-catalysed Negishi coupling can be extended to
2-halopyridine and pyrimidine substrates, as summarised
briefly in Table 1.6w Good activity was observed in toluene–
THF mixtures; pure THF led to poorer results. Increasing the
amount of ditolylzinc beyond 1.2 equiv. gave higher yields
of product but also led to substantial quantities of bitolyl
impurity. The presence of the catalyst proved to be essential
for activity (entry 4). Only 2-halopyridines reacted, in contrast
with the previously reported iron-catalysed cross-coupling
with aryl Grignard reagents.6 This allowed for selective
2-arylation, as illustrated in entry 11.
10
0
11
56 (50)
a
Conditions: heteroarylhalide (1.0 mmol), Zn(4-tolyl)2 (0.25 M in
b
THF, 4.8 ml), 1 (0.05 mmol), toluene (6 ml), 100 1C, 4 h. Spectro-
scopic yield determined by 1H NMR (1,3,5-C6H3(OMe)3 internal
c
d
standard). 1 equiv. Zn(4-tolyl). THF only. No catalyst.
e
Having established the iron-catalysed Negishi coupling of
both benzylhalides4 and 2-halopyridines with diarylzinc
reagents, we were keen to see whether this could be extended
to analogous Suzuki cross-couplings,7 however preliminary
experiments using arylboronic acids and esters as substrates
proved unsuccessful.
Scheme 1 Iron-catalysed cross-coupling reactions.
We previously postulated that formation of mixed Fe–Zn
bimetallic intermediates of the type 2 is important for the
success of 1 in the Negishi reaction; the arylzinc reagent helps
to stabilise the putative active catalyst 3, preventing premature
catalyst decomposition.4
a School of Chemistry, University of Bristol, Cantock’s Close, Bristol,
UK BS8 1TS. E-mail: r.bedford@bristol.ac.uk
b Syngenta, Jealotts Hill International, Research Centre, Bracknell,
Berkshire, UK RG42 6EY
c Chemical Development, GlaxoSmithKline, Gunnels Wood Road,
Stevenage, UK SG1 2NY
We reasoned that if intermediates of the type 2 are indeed
significant then appropriate Fe–Zn mixtures might act as
catalysts in other cross-coupling reactions provided the
w Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/b915945b
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Table 2 Optimisation of Suzuki coupling of benzyl halidesa
THF as solvent switched off activity (entry 9), whilst changing
the diarylzinc reagent had little impact (entry 10). No
difference in yield was obtained on reducing the Zn : Fe ratio
from 2 : 1 to 1 : 1 (entry 11), but in the absence of zinc reagents
no activity was observed (entry 12). Interestingly, zinc chloride
could be used in place of the diarylzinc (entry 13) although the
activity was somewhat lower. Diethylzinc also showed some
activity (entry 14). When diarylzinc reagents were used as
the co-catalysts, essentially no incorporation of their aryl
functions into cross-coupled products was observed—
presumably the original aryl groups on the zinc were
consumed during the reductive activation of the pre-catalyst.
Lowering the iron loading to 2.5 mol% did not have a
Spec. yieldb
(%)
Entry ZnR2
ArBYn
Base
1
2
Zn(C6H4-4-OMe)2 PhB(OH)2
None
K2CO3
0
0
3
4
None
0
0
K2CO3
substantial impact, whilst
1 mol% could be exploited
effectively under more forcing conditions (entries 15 and 16).
The presence of an iron catalyst proved essential (entry 17).
Poorer activities were obtained with [Fe(acac)3], [FeCl2(dppp)2]
and [FeCl2(py)4] (entries 18–20).
5
None
0
6
7
8
9
Et2Zn
17
0
Replacing the tetraarylborate with either an aryltrifluoroborate
or the activated aryl triolborate 411 proved unsuccessful (entries 21
and 22). The use of Li[PhBBu3] formed in situ from PhLi and
BBu3 (entry 24) showed promise, but the reaction was accom-
panied by substantial homocoupling (39%) of the benzyl halide.
Having established that sodium tetraphenylborate gave
excellent results, we next examined the coupling of tetraaryl-
borates with a range of benzyl and 2-heteropyridyl halides
and these results are summarised in Table 3. In general the
reactions with the 2-halopyridines needed to be performed at
higher temperature for a longer time in order to maximise
conversion, although the conditions for individual reactions
were not optimised. Apart from the nitro-function all other
functional groups tested on the benzyl halide substrates—
cyano, ester and bromide—were tolerated well. Slightly lower
activity was observed with a benzyl chloride substrate (entry 2)
and contrary to previous findings in the analogous iron-
catalysed Negishi reaction,4 benzyl phosphates proved to be
poor substrates (entry 4). As observed in the Negishi coupling,
the ability to selectively couple a benzyl bromide decorated
with a second bromide on the aromatic ring (entries 8 and 16)
is particularly noteworthy as this selectivity would be difficult
if not impossible to achieve with palladium catalysis and opens
the possibility for further catalytic functionalisation.
K2CO3
None
Zn(C6H4-4-OMe)2 Na[BPh4]
96
0c
10
11
12
13
14
15
16
17
18
19
20
21
Zn(C6H4-4-Me)2
Zn(C6H4-4-OMe)2
None
ZnCl2
ZnEt2
Zn(C6H4-4-OMe)2
95
96d
0
48
29
93e
71f
0g
24h
44i
59j
0
K[4-tolylBF3]
Li[PhBBu3]
22
0
23
49k
a
Conditions: ZnR2 (0.1 mmol in THF, 0.14–0.34 ml), ArBYn
(1.25 mmol), 3-MeOC6H4CH2Br (1.0 mmol), 1 (0.05 mmol), toluene
(8 ml), 85 1C, 4 h. Spectroscopic yield, determined by 1H NMR
(1,3,5-C6H3(OMe)3 internal standard). Solvent = THF. 5 mol%
b
c
d
e
Ar2Zn. 2.5 mol% Fe. 1 mol% Fe, reflux, 16 h. No catalyst.
f
g
h
i
j
cat = [Fe(acac)3], 16 h. cat = [FeCl2(dppp)2], 16 h. cat =
k
[FeCl2(py)4], 16 h. 39% homocoupled bibenzyl product observed.
Good results were observed when Na[BPh4] was replaced
with K[B(4-tolyl)4] (entry 12), unfortunately the less nucleophilic
substrate Na[B(C6H4–Cl)4] displayed very low reactivity.
At present, mechanistic detail is limited, but we note the
following observations. The lack of activity in the absence of a
zinc co-catalyst supports the supposition that transmetallation
occurs from the aryl boron reagent to the iron centre via an
arylzinc intermediate.12 Effectively the zinc reagent functions
in much the same manner as the copper co-catalyst in
Sonogashira coupling reactions.13 As for the oxidation state
of the iron complex when the aryl group is transferred, this has
yet to be fully determined but we favour an iron(I)14,15 species
in agreement with the results obtained recently by Norrby and
co-workers in the iron-catalysed coupling of aryl halides with
alkyl Grignard reagents.16 Whilst there may be commonality
in the transmetallation steps between the reactions reported
here and Grignard cross-coupling reactions, there are stark
nucleophilic coupling partners employed are capable of
arylating the zinc centre. Given that aryl boron reagents have
been used as stoichiometric arylating species for zinc
reagents,8 we wondered could co-catalytic amounts of zinc
reagents be exploited to initiate Suzuki cross-coupling?9
We focussed initially on the coupling of 3-methoxybenzyl
bromide with various aryl boron reagents and these results are
summarised in Table 2. Where diarylzinc reagents were employed,
these were prepared in situ from the appropriate Grignard reagent.
Again, no activity was seen with phenylboronic acid or its pinacol
ester in either the presence or absence of base (entries 1–4),
however some, albeit poor, activity was observed when triphenyl-
boroxine was employed with diethylzinc (entry 6).10
The key to success proved to be in the use of tetraarylborate
salts as the arylating reagents, with excellent activity observed
with sodium tetraphenylborate (entry 8). Changing to pure
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Table 3 Fe-catalysed Suzuki coupling of RX with M[BAr4]a
In summary, simple mixed iron–zinc catalysts formed in situ
give good activity in the cross-coupling of arylborate salts with
both benzyl and heteroaryl halides. We are currently exploring
the full scope of these reactions, particularly with regard to
increasing the range of aryl boron nucleophiles that can be
employed, as well as their mechanisms.
Entry RX
1
M[BAr4]
Na[BPh4]
Spec. yieldb (%)
X = Br, 88 (96)
2
3
X = Cl (75)
63 (91)
We thank GlaxoSmithKline, Syngenta and EPSRC for funding.
Notes and references
4
5
(14)c
1 Reviews: (a) W. M. Czaplik, M. Mayer, J. Cvengros and A. J. von
Wangelin, ChemSusChem, 2009, 2, 396; (b) B. D. Sherry and
A. Furstner, Acc. Chem. Res., 2008, 41, 1500; (c) Iron Catalysis in
Organic Chemistry, ed. B. Plietker, Wiley-VCH, Weinheim, 2008;
(d) E. B. Bauer, Curr. Org. Chem., 2008, 12, 1341; (e) A. Furstner and
R. Martin, Chem. Lett., 2005, 34, 624; (f) C. Bolm, J. Legros, J. Le
Paih and L. Zani, Chem. Rev., 2004, 104, 6217.
2 For examples of iron-catalysed organocopper couplings see:
(a) C. C. Kofink, B. Blank, S. Pagano, N. Gotz and
Paul Knochel, Chem. Commun., 2007, 1954; (b) G. Dunet and
P. Knochel, Synlett, 2006, 407; (c) I. Sapountzis, W. Lin,
C. C. Kofink, C. Despotopoulou and P. Knochel, Angew. Chem.,
Int. Ed., 2005, 44, 1654.
3 For examples of iron-catalysed arylzinc coupling reactions see:
(a) M. Nakamura, S. Ito, K. Matsuo and E. Nakamura, Synlett,
2005, 1794; (b) C. K. Reddy and P. Knochel, Angew. Chem., Int.
Ed. Engl., 1996, 35, 1700.
4 R. B. Bedford, M. Huwe and M. C. Wilkinson, Chem. Commun.,
2009, 600.
61 (90)
6
7
(499)
80 (98)
8
9
79d (95)
0
5 T. Hatakeyama, Y. Kondo, Y. Fujiwara, H. Takaya, S. Ito,
E. Nakamura and M. Nakamura, Chem. Commun., 2009, 1216.
6 For examples of iron-catalysed cross-coupling of aryl Grignards with
halopyridines see: (a) L. Vandromme, H.-U. Reißig, S. Groper and
J. P. Rabe, Eur. J. Org. Chem., 2008, 2049; (b) A. Furstner,
A. Leitner, M. Mendez and H. Krause, J. Am. Chem. Soc., 2002,
124, 13856; (c) A. Furstner and A. Leitner, Angew. Chem., Int. Ed.,
2002, 41, 609; (d) J. Quintin, X. Franck, R. Hocquemiller and
B. Figadere, Tetrahedron Lett., 2002, 43, 3547.
7 To the best of our knowledge, the only successful examples of
iron-catalysed Suzuki couplings reported previously required very
high pressures (15 kbar), see: Y. Guo, D. J. Young and T. S. A.
Hor, Tetrahedron Lett., 2008, 49, 5620.
10
11
(499)
73 (85)
(96)e
12
13
14
K[B(4-tolyl)4]
Na[B(4-C6H4Cl)4] Tracee
Na[BPh4]
64 (76)
8 For recent catalytic applications see: (a) S. W. Smith and G. C. Fu,
J. Am. Chem. Soc., 2008, 130, 12645; (b) C. Jimeno, S. Sayalero,
T. Fjermestad, G. Colet, F. Maseras and M. A. Pericas, Angew.
Chem., Int. Ed., 2008, 47, 1098; (c) F. Schmidt, R. T. Stemmler,
J. Rudolph and C. Bolm, Chem. Soc. Rev., 2006, 35, 454.
9 For co-catalytic copper in Fe-catalysed couplings see: (a) J. Mao,
G. Xie, M. Wu, J. Guo and S. Ji, Adv. Synth. Catal., 2008, 350,
2477; (b) C. M. Rao Volla and P. Vogel, Tetrahedron Lett., 2008,
49, 5961.
10 For the mechanism and exploitation of arylation of dialkylzinc
reagents with triphenylboroxine, see ref. 9b.
11 Y. Yamamoto, M. Takizawa, X.-Q. Yu and N. Miyaura, Angew.
Chem., Int. Ed., 2008, 47, 928.
15
16
17
51 (69)
38 (49)f
53 (77)
52 (94)
12 For transmetallation from a fourcoordinate boronate to zinc, see
ref. 9b.
18
13 For recent reviews of the Sonogashira reaction see: (a) R. Chinchilla
and C. Najera, Chem. Rev., 2007, 107, 874; (b) H. Doucet and
J.-C. Hierso, Angew. Chem., Int. Ed., 2007, 46, 834.
14 Reaction (1) with Ar2Zn generates a complex corresponding to the
formulation ‘‘FeAr(dpbz)2’’ as determined by ESI-MS (see ref. 4).
We assumed an oxidation state of Fe(II), but subsequent investi-
gations suggest instead that an uncharged Fe(I) complex is formed.
We are currently exploring the reactivity of this complex and the
results will be published shortly.
a
Conditions: Zn(C6H4-4-OMe)2 (0.1 mmol in THF, 0.34 ml),
M[BAr4] (1.25 mmol), RX (1.0 mmol), 1 (0.05 mmol), toluene
(8 ml), 85 1C, 4 h, (benzyl halides) or reflux, 16 h (halopyridines).
b
Spectroscopic yield, determined by 1H NMR (1,3,5-C6H3(OMe)3
c
d
e
f
internal standard). 24 h. B90% purity. 0.5 mmol scale. Only
2-arylated product observed.
15 For recent examples of Fe(I) aryl complexes see: (a) C. Ni,
B. D. Ellis, T. A. Stich, J. C. Fettinger, G. J. Long, R. D. Britta
and P. P. Power, Dalton Trans., 2009, 5401; (b) C. Ni, B. D. Ellis,
J. C. Fettinger, G. J. Long and P. P. Power, Chem. Commun., 2008,
1014, and references therein.
contrasts between the oxidative addition steps. Thus whilst
only 2-heteroaryl halides are coupled in the reactions reported
here, this is not the case in Grignard cross-coupling reactions.6
Obviously this dichotomy will need to be explored further.
16 J. Kleimark, A. Hedstrom, P.-F. Larsson, C. Johansson and
P.-O. Norrby, ChemCatChem, 2009, 1, 152.
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6432 | Chem. Commun., 2009, 6430–6432