Domino iron catalysis: Direct aryl-alkyl cross-coupling

Article abstract of DOI:10.1002/anie.200804434

(Chemical Equation Presented) Striking while the iron is hot: Cheap FeCl₃ serves as the precatalyst for the direct cross-coupling of aryl and alkyl halides that is based on the sequence of Grignard formation and subsequent cross-coupling. This

Full text of DOI:10.1002/anie.200804434

Angewandte
Chemie
DOI: 10.1002/anie.200804434
Iron Catalysis
Domino Iron Catalysis: Direct Aryl–Alkyl Cross-Coupling**
Waldemar Maximilian Czaplik, Matthias Mayer, and Axel Jacobi von Wangelin*
In memory of Jay K. Kochi
Over the past decade, transition-metal-catalyzed cross-cou-
pling reactions have matured into an indispensable class of
reactions for organic synthesis.[1] Palladium and nickel com-
plexes, in particular, boast high catalytic activity for a wide
range of substrates and high functional-group tolerance. In
view of potential industrial applications,[2] the drive towards
higher levels of efficiency and sustainability remains una-
bated. The high costs[3] associated with the use (and removal)
of palladium and nickel catalysts as well as toxicological
aspects[4] have limited the more general use of such protocols
in large-scale production. Based upon the pioneering work by
Kharasch[5a] and Kochi,[5] and recent developments of iron-
catalyzed cross-coupling procedures using cheap and non-
toxic iron catalysts by Fꢀrstner,[6] Knochel,[7] Nakamura,[8]
Cahiez,[9] Bolm,[10] and others[11] have addressed these sus-
tainability issues.[12] Despite the economic use of simple iron
salt/amine precatalysts, the employment of hazardous orga-
Bogdanovic et al. demonstrated earlier that formal [Fe-
(MgX)2] complexes catalyze the formation of Grignard
species from aryl halides and magnesium.[14] Electronically
analogous complexes have also been postulated by Fꢀrstner
and others to be catalytically competent in cross-coupling
reactions of organomagnesium halides with organohali-
des.[6,9c,15] The obvious involvement of low-valent iron–
magnesium complexes in both the formation of organo-
magnesium species and the cross-coupling with organohalides
raises the question whether domino catalysis for the direct
cross-coupling of two electrophilic organohalides is feasible.
We chose the reaction of p-tolyl bromide (1a) with cyclohexyl
bromide (2a) in the presence of magnesium as our model
system.[16a] Although the components are electronically
differentiated, potential (catalyzed) transmagnesiation from
the kinetic (alkyl–MgX) to the thermodynamic (aryl–MgX)
Grignard species, competitive reductive processes, and ther-
modynamically favored biaryl coupling could deplete the
selectivity for the cross-coupling product.
ꢀ
nomagnesium reactants inC C coupling reactions still
imposes stringent and elaborate safety precautions for the
overall process.[13] As part of our research program, we rose to
the challenge to develop a sustainable methodology for the
direct cross-coupling of aryl halides 1 with alkyl halides 2
which obviates the presence of large quantities of hard-to-
handle and sensitive Grignard reagents. We report herein on a
new, operationally simple, one-pot synthesis of substituted
arenes 3 by iron-catalyzed cross-coupling under mild con-
ditions (Scheme 1).
Initial experiments documented the feasibility of such
direct cross-coupling reactions with unexpectedly high selec-
tivities. In the presence of FeCl3 as the precatalyst and
stoichiometric amounts of magnesium turnings and
N,N,N’,N’-tetramethylethylendiamine (TMEDA) as an addi-
tive, the cross-coupling product was obtained in up to 73%
yield in a practical one-pot reaction (Table 1).[16a] The best
results were obtained in THF and 2-methyl-THF, while other
ether solvents inhibited the reaction. Primary amines and
pyridine as additives gave no conversion under the reaction
conditions. Interestingly, the THF/N-methylpyrrolidinone
(NMP) solvent mixture[6,9] favored by Fꢀrstner and Cahiez
resulted in low conversion. The best selectivities were
obtained in dilute solution (0.1–0.2m) which also reduces
competitive biaryl formation. Higher precatalyst loadings (>
5 mol%) enhanced the occurrence of side reactions. The
inherent formation of a low-valent iron–magnesium catalyst
by reduction of FeCl3 with in situ formed alkylmagnesium
halide accounts for the need for a slight excess of alkyl
halide.[6] When a larger excess of one component was
employed, yields were slightly increased albeit at the cost of
reduced selectivities.
We screened various commercial iron salts as precata-
lysts.[16a] The comparable activities of FeCl3 and FeCl2 are in
accordance with the literature.[6b] Interestingly, FeF2 and FeI2
were inactive. Diketone complexes [Fe(acac)3] and [Fe-
(bzac)3] (acac = acetylacetonate, bzac = benzoylacetonate)
gave only slightly lower yields than FeCl3. Iron(II) phthalo-
cyanine exhibited low activity, and iron powder was not a
competent catalyst.[6a] The preformed homobimetallic com-
plex [(FeCl3)2(tmeda)3] described by Cahiez et al.[9c] resulted
Scheme 1. Direct iron-catalyzed cross-coupling.
[*] W. M. Czaplik, M. Mayer, Dr. A. Jacobi von Wangelin
Department of Chemistry, University of Cologne
Greinstrasse 4, 50939 Kꢀln (Germany)
Fax: (+49)221-470-5057
E-mail: axel.jacobi@uni-koeln.de
Homepage: http://www.jacobi.uni-koeln.de
[**] This research was supported financially by Saltigo GmbH, the
Deutsche Forschungsgemeinschaft (DFG, Emmy-Noether pro-
gram), the Fonds der Chemischen Industrie (FCI), and the
Deutsche Bundesstiftung Umwelt (DBU). We thank Prof. H.-G.
Schmalz for generous support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200804434.
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Table 1: Selected optimization experiments.
Table 2 shows a series of 18 aryl–alkyl and 2 alkenyl–alkyl
cross-coupling products synthesized under one-pot conditions
from the corresponding organohalides.[16a] Aryl and hetero-
aryl bromides bearing alkyl, alkoxy, fluoro, and amine
substituents exhibited good reactivities with primary and
secondary alkyl bromides (3a–k, 3r–t). Tertiary alkyl bro-
mides gave only minimal conversion under the standard
conditions (< 10%). No isomerization of primary alkyl
bromides to the more stable secondary isomers was observed;
terminal olefins showed no double-bond migration (3l). The
resultant w-arylalkenes constitute versatile substrates for
additional transformations of the olefin moiety.
Vinyl bromide gave a complex mixture of products, but
higher homologues such as dimethylvinyl bromide and b-
bromostyrene afforded the corresponding internal olefins in
moderate yields (3n, 3o). Surprisingly, low conversion (<
15%) was observed with ester and cyano substituents in
either component. Here, consumption of the magnesium was
inhibited, probably as a result of surface deactivation.[17]
Employment of a larger excess of Mg turnings (> 1.5 equiv)
or powder (1.2 equiv) and catalytic TMEDA resulted in
moderate conversions at longer reaction times (3p, 3q).
Whereas chloroarenes and chloroalkanes (3g, 3j, 3m)
exhibited only low conversions under standard conditions
(3 h, 08C), a two-step protocol (preformation of the catalyst
at 08C, coupling at 208C) resulted in significantly increased
yields in reactions with alkyl chlorides (3a, 3j). The corre-
sponding alkanes and arenes (formed by hydrodehalogena-
tion,[18] each < 15%), alkenes (b-hydride elimination,
< 10%), and biaryls (mostly < 6%) are general by-products.
Notably, a major portion of these by-products stem from the
necessary in situ reduction of the FeCl3 to the postulated
cross-coupling catalyst [Fe(MgX)2].[19]
T [8C]
Solvent
Additive[a]
TMEDA
FeCl3
[mol%]
1a/2a
Yield
[%][b]
20
Et2O
5
1:1.2
0 (0)
0 (0)
<10 (0)
0 (0)
65 (9)
65 (6)
70 (9)
53 (10)
72 (14)
75 (14)
69 (14)
27 (8)
0 (0)
MTBE
dioxane
c-C6H12
THF
2-Me-THF
THF
0
45
0
TMEDA
TMEDA
5
1:1.2
1:1.2
THF
THF
7.5
10
15
5
0
–
1:1.3
py
phen
DMA
NEt3
DACH
Me4-DACH
NMP[c]
0 (0)
31 (9)
32 (15)
0 (0)
38 (12)
<5 (0)
[a] py=pyridine, phen=1,10-phenanthroline, DMA=N,N-dimethylani-
line, DACH=1,2-diaminocyclohexane, Me4-DACH=N,N,N’,N’-tetra-
methyl-DACH. [b] Yield of 3a (in brackets: 4,4’-bitolyl). [c] THF/NMP=
10:1.
in moderate yield of the cross-coupling product accompanied
by large amounts of unwanted 4,4’-bitolyl (4b) under the
reaction conditions.
The selectivity of the cross-coupling reactions was found
to depend significantly on the amount of TMEDA, which
potentially stabilizes the complexes of both metals (Fe, Mg)
(Figure 1).[16a] In the absence of TMEDA, reduction to
toluene (ArH) was dominant. The cross-coupling product
3b was favorably formed with increasing TMEDA concen-
trations, which can be explained by the slower formation of
the Grignard reagent. Reductive dehalogenation (to ArH)
and biaryl coupling (to 4b) were minimized upon addition of
1.2 equivalents of TMEDA.
Apart from the high practicality of the one-pot protocol
and the direct employment of simple organohalides as
starting materials, this novel cross-coupling methodology
also boasts high selectivity of the underlying domino reaction.
Despite the expected thermodynamic preference for homo-
coupling to give the biaryl, the reaction displays high
selectivity for the cross-coupling product. In all cases only
minimal amounts of the biaryl were formed (< 9%).[20]
Although the electronic differentiation of the two organo-
halides should favor magnesiation of the alkyl bromide
ꢀ
(weaker C(sp3) Br bond, reversible Mg!p*(ArBr) electron
transfer),[21] we postulate the intermediacy of both Grignard
species under the reaction conditions. Bogdanovic et al.
reported on the iron-catalyzed Grignard formation from
aryl halides catalyzed by an iron–magnesium complex under
similar conditions.[14] Our results support the operation of
iron-catalyzed Grignard-forming reactions for both model
substrates (1-bromonaphthalene (1 f) and cyclohexyl bromide
(2a), Figure 2). In the absence of FeCl3 the induction period
for the magnesiation of the alkyl– and aryl–Br bonds was
observed to be three times longer. Upon addition of 5 mol%
FeCl3 both organohalides were rapidly consumed.[16] Our one-
pot reaction is thus based upon a novel sequence of iron-
catalyzed Grignard formation and iron-catalyzed cross-cou-
pling. This constitutes the first example of a domino iron
catalysis for cross-coupling reactions.
Figure 1. TMEDA dependence of the model system p-tolyl bromide
(1a) and n-dodecyl bromide (2b). ArH=toluene.
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Chemie
Table 2: Synthesis of aryl–alkyl and vinyl–alkyl cross-coupling products.
Aryl/vinyl–X
Alkyl–Y
Product
Yield [%]
Aryl/vinyl–X
Alkyl–Y
Br
Product
Yield [%]
74[c]
Br
Br
Br
Cl
70
3a
3b
3c
Br
Br
3k
3l
75[a]
Br
Br
Br
Br
80
81
Br
50
Br
Cl
Br
Br
58
38
3m
Br
Br
Br
Br
3d
3e
67
75
Br
Br
Br
Br
3n
3o
52
54
Br
Br
3 f
67
Br
Br
3p
51[d]
Br
Cl
Br
Br
Br
Cl
77
3g
3h
20[b]
25
Br
Br
Br
Br
3q
3r
38[d]
48
Br
Br
Br
Br
62
65
3i
3j
Br
Br
Br
Br
3s
3t
68[e]
72
Br
Br
Br
Br
Cl
Cl
66
39
63[a]
[a] Aryl–Br/alkyl–Cl 1.2:1, 2 h at 08C, then 2 h at 208C. [b] 3 h at 208C. [c] Yield determined by GC methods. [d] 1.6 equiv Mg, 20 mol% TMEDA, 10 h.
[e] Yield determined by NMR spectroscopy.
Figure 2. Iron-catalyzed Grignard formation from 1-bromonaphthalene
Figure 3. Concentration–time plots for the model reaction of 4-tert-
(1 f) and cyclohexyl bromide (2a).
butylbromobenzene (1c) and dodecyl bromide (2b) with intermediate
2b–Mg.
Concentration–time plots (Figure 3) illustrate the faster
consumption of alkyl bromide 2b, possibly because of the
rapid reduction of FeCl3 by intermediate alkyl-MgBr. Fur-
thermore, quenching experiments[16a] documented the exis-
tence of minimal and rather constant (quasi-stationary)
concentrations of alkyl-MgBr over the course of the reaction
(< 4%). The Grignard-forming step thus appears to be rate-
determining and the subsequent coupling reaction relatively
fast. This impedes an induction period, which is known to
entail spontaneous heat release and rapid unselective reac-
tions in conventional Grignard-forming protocols (RX +
Mg).[13,16a] Unlike classical methodologies, our one-pot pro-
tocol obviates the need for stoichiometric amounts of
hazardous Grignard compounds, and hence, contributes to
the safer performance of such reactions.
We have demonstrated, for the first time, the concept of
domino iron catalysis in cross-coupling reactions. The reac-
tion uses a single cheap precatalyst (FeCl3). We postulate the
formation of both organomagnesium species under the
reaction conditions. Preliminary results showed that both
organohalides undergo rapid oxidative addition[22] to a [Fe-
Angew. Chem. Int. Ed. 2009, 48, 607 –610
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609

Communications
(MgBr)n] complex.[23] The reasons for the unexpectedly high
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cross-coupling selectivities under one-pot conditions as well
as mechanistic details are currently being investigated. We
regard the underlying general concept of domino iron
catalysis as a viable template for numerous related direct
coupling reactions between two electrophiles.[24] Extension of
this methodology to aryl–aryl coupling reactions is currently
in progress.
[12] Recent reviews: a) Iron Catalysis in Organic Synthesis (Ed.: B.
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Received: September 8, 2008
[13] Safety aspects of Grignard reagents: a) J. L. Leazer, R. Cveto-
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Published online: December 9, 2008
Keywords: cross-coupling · domino reactions ·
.
Grignard reactions · iron · sustainable chemistry
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610
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