Fe-catalysed Kumada-type alkyl-alkyl cross-coupling. Evidence for the intermediacy of Fe(i) complexes

Article abstract of DOI:10.1039/c2sc21754f

A novel Fe-NHC catalytic system allows the alkyl-alkyl cross-coupling reaction of alkyl halides and alkylmagnesium reagents has been developed. To our knowledge, this is the first Fe-catalysed Kumada-type coupling for the formation of C(sp³)-C(sp³) bonds in the presence of functional groups. The process takes place under mild conditions, avoiding the formation of β-elimination products. Mechanistic studies suggest the intermediacy of Fe(i) complexes, formed by reduction with the Grignard reagent, as the active species.

Full text of DOI:10.1039/c2sc21754f

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ARTICLE TYPE
Fe-Catalysed Kumada-type Alkyl-Alkyl Cross-Coupling. Evidence for
the intermediacy of Fe(I) complexes
Manuel Guisán-Ceinos, a Francisco Tato, a Elena Buñuel, a Paloma Calle b and Diego J. Cárdenas,*a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
coupling reaction was published in 2007,15 and very recently, a
A novel Fe-NHC catalytic system allows the alkyl-alkyl cross-
Suzukiꢀtype reaction involving heteroleptic tetraalkylborates has
50 been reported.16
coupling reaction of alkyl halides and alkylmagnesium
reagents has been developed. To our knowledge, this is the
first Fe-catalysed Kumada-type coupling for the formation of
10 C(sp3)-C(sp3) bonds in the presence of functional groups. The
process takes place under mild conditions, avoiding the
formation of β–elimination products. Mechanistic studies
suggest the intermediacy of Fe(I) complexes, formed by
reduction with the Grignard reagent, as the active species.
Acquiring knowledge on metalꢀcatalyzed reaction mechanisms is
especially important in order to improve their scope and
performance. In this respect, getting insight into the nature of the
actual species involved in Feꢀcatalyzed crossꢀcoupling reactions
55 is essential for the development of new useful synthetic methods.
Herein, we report a novel Feꢀbased catalytic system for the
formation of alkylꢀalkyl bonds from alkyl electrophiles and
Grignard reagents, and propose Fe(I)ꢀNHC complexes as the
catalytically active species. Bis(phosphine)ꢀFe complexes have
60 been recently recognized as intermediates in Feꢀcatalysed arylꢀ
alkyl coupling of alkyl halides.12
The catalytic system used in the above mentioned Kumadaꢀtype
alkylꢀalkyl coupling employed Fe(OAc)2 and phosphine ligands,
and afforded reasonable results for the crossꢀcoupling reaction of
65 unactivated primary alkyl bromides and alkyl Grignard
reagents.15 However, the functional group tolerance of this
transformation was not reported, and the reaction seems to be
limited to unsubstituted long chain alkyl bromides as starting
materials. In this work, we report a novel Feꢀbased catalytic
70 system which is able to promote Kumadaꢀtype alkyl–alkyl crossꢀ
coupling in the presence of a variety of functional groups,
involving both primary and secondary alkyl iodides. Since this
type of heterocoupling has not been developed yet, our work
significantly widens the Feꢀcatalyzed reactions scope, and
75 provides a new tool for the development of novel synthetic
approaches to complex molecules.
We started our search for appropriate ligands for the iron
catalyzed crossꢀcoupling reaction of 1ꢀiodoꢀ3ꢀphenylpropane 1
and (1,3ꢀdioxanꢀ2ꢀylethyl)magnesium bromide. Fe(OAc)2 was
80 initially selected as the iron source. In the absence of added
ligands, we could not observe the formation of the desired crossꢀ
coupling product 2a (Table 1, entry 1).
Chai et al. had previously reported the use of phosphine ligands,
and had obtained the best results with Xantphos.15 In our model
85 reaction, the use of this ligand afforded 2a in low yield (27%,
Table 1, entry 2), even when the reaction was performed by slow
addition of the Grignard reagent to a THF solution of Fe(OAc)2,
ligand, and alkyl iodide. It seems that the presence of a large
excess of Grignard reagent in the reaction medium inactivates the
90 catalytic system. This fact has been previously observed by other
authors.13g,k,n,p,14,18d
15 New methodologies involving the single step formation of
C(sp3)ꢀC(sp3) bonds by crossꢀcoupling reactions have
a
significant impact on synthetic organic chemistry and continue to
represent a challenging topic.1 Considerable advances in the
development of these strategies have been achieved by means of
20 the use of the Ni and Pd catalysis,2 overcoming the difficulties
associated to alkylꢀalkyl crossꢀcoupling reactions, especially
oxidative addition of alkyl halides and βꢀelimination of hydrogen.
Thus, the use of bulky trialkylphosphines or NHC ligands
hampers β−elimination in alkylꢀPd(II) intermediates, which has
25 broadened the scope of alkylꢀalkyl crossꢀcouplings.2 A different
approach to general and effective alkylꢀalkyl crossꢀcoupling
reactions is to use first row transition metal complexes, whose
success is based on the occurrence of novel mechanisms. Niꢀ
catalysed reactions have been proposed to take place through
30 Ni(I)ꢀNi(III) catalytic cycles, in which transmetalation precedes
oxidative addition, involving radical species both carbon and
metalꢀcentered.3 More recently, Cuꢀbased catalytic systems have
been also developed.4 However, due to economic issues, toxicity
and environmental reasons,5 Fe constitutes a more convenient
35 alternative for the development of new catalysts. Since the
pioneering work published by Kochi four decades ago,6 several
authors have recently contributed to the renaissance of iron
catalysts for the development of crossꢀcouplings.7ꢀ16 Thus, aryl
and alkenyl electrophiles have been reported to couple with a
40 variety of Grignard reagents, including aryl, alkenyl, alkynyl and
alkyl derivatives.8ꢀ11 Noticeably, although alkyl halides and other
alkyl electrophiles have been extensively used as coupling
partners with different nucleophiles in Feꢀcatalyzed Negishiꢀtype
and, especially, Kumadaꢀtype reactions,12ꢀ14 the formation of
45 C(sp3)ꢀC(sp3) bonds is still in the preliminary stages. In fact, just
a couple of articles regarding this topic can be found in the
literature. The first Feꢀcatalyzed Kumada alkylꢀalkyl crossꢀ
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suggest that the active FeꢀNHC catalyst is efficiently formed at
40 50ºC and that it is able to catalyse the crossꢀcoupling reaction at
room temperature.
Table 1. Ligand survey for the alkylꢀalkyl crossꢀcoupling reaction
Table 2. Temperature survey for alkylꢀalkyl crossꢀcoupling reaction.
Entry[a]
1
2
Ligand (mol%)
SIMesꢁHCl (12)
SIMesꢁHCl (12)
SIMesꢁHCl (12)
IMesꢁHCl (12)
IMesꢁHCl (24)
IMesꢁHCl (6)
T (º C) [b]
ꢀ20
50
RT
RT
RT
RT
T (º C) [c]
ꢀ20
50
Yield [%][d]
21
58
67
70
66
70
3
50
50
50
50
4
5[e]
6[f]
[a] Unless otherwise noted, reaction was carried out with 5 mol %
Fe(OAc)2 in THF, with slow addition of the Grignard reagent over 7.5 h
45 at the stated temperature. [b] Reaction temperature. [c] Activation
temperature: active Fe complex was formed by addition of 30 mol% of
Grignard reagent to a mixture of Fe(OAc)2 and ligand and stirred for 20
min at 50 ºC. [d] Yield of the isolated product. [e] Reaction was carried
out with 10 mol% of Fe(OAc)2. [f] Reaction was carried out with 2.5
50 mol% of Fe(OAc)2.
Entry[a]
Ligand
(mol%)
Yield
[%][b]
NR
27
8
13
Entry[a]
Ligand
(mol%)
L6 (10)
L7 (12)
L8 (12)
L9 (12)
L10 (12)
L11 (12)
Yield
[%][b]
19
42
16
16
12
11
Regarding the catalytic loading of the crossꢀcoupling reaction, the
use of 10 mol% of Fe(OAc)2 decreased slightly the yield (Table
2, entry 5). However a lower catalyst loading (2.5 mol%) could
55 be employed maintaining the yields (Table 2, entry 6). The use of
IMesꢁHCl in 1:1 ratio in relation to the Fe salt improved slightly
the yield affording a 70% (Table 2, entry 4). Regarding the metal
source, Fe(II) and Fe(III) fluorides, chlorides, bromides, and
iodides were tested. Surprisingly, several salts gave the same
60 results, showing little influence of the counterion on the reaction
yield. Other parameters such as the amount of Grignard reagent
or the addition flow rate were also checked (more details of these
experiments are described in the ESI). Since yields could not be
further increased, experiments were performed in order to
65 determine the nature of the byꢀproducts. GC analysis of the
reaction mixture after reaction completion is shown in Scheme 1.
1
2[c]
3
4
5
-
7
L1 (6)
L2 (10)
L3 (10)
L4 (10)
L5 (10)
8[d]
9[d]
10[d]
11[d]
12[d]
9
15
6
5
[a] Unless otherwise noted, the reaction was carried out by slow addition
of the Grignard reagent (2 equiv) to a THF solution of alkyl iodide (1
equiv), Fe(OAc)2 (5 mol%) and ligand, under Argon at 23°C. [b] Yield of
the isolated product. [c] Reaction was carried out with 3 mol% of
Fe(OAc)2. [d] Imidazolium and imidazolidinium salts were previously
10 deprotonated by the addition of 30 mol% Grignard reagent.
Various pyridineꢀbased ligands such as bipyridine, terpyridine,
and phenantroline gave also low yields (Table 1, entries 3ꢀ5)
suggesting that sp2ꢀnitrogen ligands are not suitable for the
15 formation of an active iron complex. The yield did not improve
either when the reaction was carried out in the presence of
bidentate N,P ligands such as iPrꢀphox or QUINAP, which
afforded 15% and 19% yield of the crossꢀcoupled product 2a,
respectively (Table 1, entries 6ꢀ7).
Ph
O
75 %
O
Ph
I
2a
Fe(OAc)2 (2.5 mol%)
IMes·HCl (12 mol%)
12 %
1 %
20 Finally, we decided to use the stronger σꢀdonor NHC ligands,17
generated in situ from the deprotonation of imidazolidinium salts
with the Grignard reagent. Among a variety of NHC ligands
employed in the crossꢀcoupling reaction, SIMesꢁHCl provided the
best result (42% yield, Table 1, entry 8).
Ph
Ph
Ph
CH3
CH3
O
MgBr
(1.5 equiv)
9 %
O
1
THF, 24 h
Ph
3 %
Ph
25 We observed that temperature strongly affected the reaction yield.
When reaction was carried out at ꢀ20 ºC (Table 2, entry 1) the
desired product 2a was obtained in lower yield (21%). However,
when the reaction was performed at 50 ºC, the yield raised to
58%. With these results in hand, we wondered whether heating
30 could be decisive for the appropriate formation of the active Feꢀ
NHC complex responsible for the crossꢀcoupling reaction, since
formation of the desired product at ꢀ20ºC, albeit in low yield,
suggests that the crossꢀcoupling is fast enough to proceed at low
temperature. Thus, a mixture of Fe(OAc)2, Grignard reagent (6
35 equiv), and SIMesꢁHCl (2.4 equiv) was heated at 50 ºC for 20
min, followed by cooling to room temperature and addition of the
alkyl halide. With this procedure, the crossꢀcoupled product 2a
was isolated in a 67% yield (Table 2, entry 3). These results
Scheme 1. Composition of the mixture after reaction completion obtained
by GC analysis using dodecane as internal standard.
70
In addition to the coupling product 2a, around 13% of elimination
compounds is observed. These may be formed by β–elimination
reaction in a putative alkylꢀFe complex, since in the absence of
Fe and ligand, elimination compounds that could result from a E2
75 reaction promoted by the Grignard reagent on the starting iodide
1, were not observed. On the other hand, formation of
propylbenzene (9%) could be the result of either radical reduction
by solvent or reductive elimination on an intermediate Fe alkyl
hydride. Homocoupling of the 1 is also observed although in very
80 low yield (3%). Finally, the bromide exerting from substitution of
2
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I in 1 is observed along the reaction (up to 3%), but it is
completely consumed at the end.
In addition, radical clock experiments were carried out to confirm
whether radical pathways are actually involved in the reaction
mechanism.2k,13d,e,g,k,m Thus, 6ꢀiodohexꢀ1ꢀene was subjected to
Several alternatives have been proposed for the mechanism of the
Feꢀcatalyzed Kumadaꢀtype crossꢀcoupling,18,19 such as catalytic 50 the reaction conditions affording a 1.4:1 mixture of 3a and 3b
5
cycles involving Fe(I)/Fe(III), Fe(0)/Fe(II), or Fe(ꢀII)/Fe(0)
species. To elucidate the catalyst oxidation state and therefore the
catalytic cycle operating in this case, we studied the catalyst
activation process in the absence of electrophile. Formation of 2ꢀ
(cyclizationꢀcoupling and simple coupling products, respectively)
in 36% combined yield (Scheme 1, eq. 1). On the other hand, the
crossꢀcoupling of (iodomethyl)cyclopropane gave only the
formation of the ring opening coupled product 4a with a 63%
ethylꢀ1,3ꢀdioxolane (I), 2ꢀvinylꢀ1,3ꢀdioxolane (II), and Grignard 55 yield (Scheme 2, eq. 2). These results indicate that carbon
10 homocoupling (III) was monitored by GC (Figure 1).
radicals are actually formed, and suggest one electron oxidation
of Fe complexes involved in the activation of the alkyl iodide. In
addition, the partial cyclization for the hexene substrate and the
complete ring opening of the cyclopropylmethyl intermediate are
60 related to the lifetime of the alkyl radicals resulting by homolytic
cleavage of the CꢀI bond (the first order rate constants for the
MgBr
R
0.1
R-CH2-CH3 (I) R-CH=CH2 (II)
[Fen]
1.6 mmol
Fe(OAc)
2 +IMes·HCl
O
O
R-CH2-(CH2)2-CH2-R (III)
0.1 mmol
0.24 mmol
R =
cyclization
or ring opening of 5ꢀhexenꢀ1ꢀyl and
cyclopropylmethyl radicals are 2.3 ꢁ 105 and 6.7 ꢁ 107 sꢀ1,
respectively) and provide information about the relative rate of
65 the subsequent step compared to cyclization. After formation of
the radical, the rate of the subsequent step leading to the coupling
product competes with the unimolecular cyclization in the case of
the 5ꢀhexenyl derivative, whereas is much slower compared to
the ring opening of the cyclopropylmethyl radical.
Magnetic Field Strength (G)
Figure 1. Left: EPR experiment of the active iron species was carried out
in a THF solution at 100 K (modulation frequency 100 kHz; modulation
amplitude 5 G; power 6.32 kW. Values obtained from the spectrum:
15 g1=2.0434; g2= 2.0209; g3=1.9907; giso= 2.01833) . Right: Determination
of the iron oxidation state in the catalytic system by GC monitoring. The
experiments were carried out using dodecane as internal standard.
Compounds I and III were the only products detected, indicating
20 the lack of βꢀelimination processes, and therefore the absence of
Fe hydrides. Formation of II would have been observed if βꢀ
elimination had taken place. If Fe hydrides are not formed, the
whole 2ꢀethylꢀ1,3ꢀdioxolane (I) exerts from the hydrolytic
quenching of the remaining Grignard reagent prior to the GC
25 analysis. The change on oxidation state of the metal complex
formed by reduction of the starting Fe salt with the
alkylmagenium compound can be deduced by measuring the
amount of Grignard homocoupling product (III). In order to
obtain a reliable value of III, additional factors should be taken
30 into account as the Grignard homocoupling contaminant already
present in the reagent, or the stability of homocoupling product in
the presence of the organomagnesium compound. As it can be
observed in the graphic in Figure 1, the amount of Grignard
homocoupling product increases upon addition of the nucleophile
35 to the solution of the Fe precatalyst, and seems to stabilize at 0.5
mmol per 1 mmol of Fe salt. These data indicate that a half of the
starting Fe(II) is reduced to Fe(0), which formally corresponds to
reduction to Fe(I). Comproportion of Fe(0) and Fe(II) species
could afford true Fe(I) complexes, in a similar way to that
40 proposed for Ni complexes.3 The presence of Fe(I) species in the
reaction medium was confirmed by EPR spectroscopy of the
resulting solution, showing a value of g = 2.02, consistent with
the presence of low spin complex (S =1/2) with just one unpaired
electron (Figure 1). This result is in accord with the previous
45 observation by Bedford, that further reduction of Fe(I) complexes
is slow and cannot compete with the coupling process.12c
70
Scheme 2. Experimental evidences of radical pathway for the alkylꢀalkyl
crossꢀcoupling reaction
The participation of carbon radicals in the reaction pathway
suggests that activation of the electrophile takes place through
75 homolytic CꢀI cleavage, which formally leads to Fe(II)ꢀI
complexes.3e,g,13e,g,k,o The radicals released probably collapse with
this Fe(II) complexes to afford alkylꢀFe(III) as intermediates
(Scheme 3).
80
Scheme 3. Two step oxidative addition to Fe(I) complexes
Based on these experimental observations and related literature
proposals, we suggest a mechanism involving a Fe(I) complex as
the active species.20 This catalyst could evolve by either oxidative
85 addition with the alkyl iodide (Figure 2, cycle A), or by
transmetalation with the Grignard reagent (Figure 2, cycle B). At
this stage, we cannot ensure which of both alternatives is actually
operating in the crossꢀcoupling reaction. Nevertheless, activation
of the Fe salt to give the catalytically active complex requires
90 addition of an excess of Grignard reagent compared to the
amount necessary for the reduction to Fe(I). This fact suggests
that transmetalation to form an alkylꢀFe(I) complex may be
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chain lengths ranging from C2 to C12 afforded analogous results
should more likely follow cycle B. Whatever the sequence is, 35 (Scheme 4, products 2dꢀf) reaching a 60% yield. Regarding the
necessary prior to the oxidative addition, and then the reaction
reductive elimination would afford the crossꢀcoupled product Rꢀ
R’.
secondary alkyl halides, when iodocyclohexane was used as
starting material we could isolate the crossꢀcoupled product 2g in
excellent 88% yield (Scheme 4).
Fe(OAc)2 (2.5 mol%)
IMes·HCl (6 mol%)
BrMg
R
O
R
I
+
O
O
THF, RT
O
2
Me
O
O
MeO
O
O
n
O
Ph
O
n = 0; 2d (59%)
n = 2; 2e (60%)
n = 10; 2f (60%)
2
2c (66%)
2b (67%)
EtO2C
O
MeO2C
O
O
O
3
O
O
2h (57%)
2i (65%)
2g (88%)
O
O
O
Me
Me
O
O
O
O
O
O
5
O
2j (63%)
Figure 2. Proposed catalytic cycle for the alkylꢀalkyl crossꢀcoupling
reaction.
2k (83%)
2l (54%)
O
O
R
N
Other alternative pathway would involve formation an anionic
dialkyl Fe(I) species (Figure 2, bottom), which would give an
O
O
N
Ts
2o (36%)
2m (R = Boc; 67%)
2n (R = PhCH2; 78%)
3
10 easier oxidative addition. This route would involve a trialkyl
Fe(III) species which should give a mixture of crossꢀcoupling and
homocoupling compounds, including the homocoupling of the
electrophile. Nevertheless, the reaction between an aryl halide
and a nucleophile containing similar skeletons (Scheme 3) gave
15 just traces of the homocoupling product derived from the
electrophile, suggesting that trialkylꢀFe species are not formed
along the catalytic cycle and, therefore, cycle C can be
disregarded.
H
O
Me
Me
H
H
O
2q (52%)b
O
2p (75%)
40
Scheme 4. Scope of the alkylꢀalkyl crossꢀcoupling. [a] Reaction was
carried out under standard conditions as described in the Experimental
Section and yields refer to isolated product after column chromatography;
[b] Benzylmagnesium chloride was used as a Grignard reagent.
45
O
O
O
Interestingly, substrates containing an ester group also underwent
the crossꢀcoupling reaction; although in lower yields probably
due to the presence of the reactive ester group. Thus, primary and
secondary alkyl iodides having the ester functionality afforded
O
O
O
O
MgBr
O
Fe(OAc)2 (2.5%)
+
+
+
O
IMes·HCl (6%)
THF, 23 o
I
O
C
O
O
O
50 the crossꢀcoupled products 2h and 2i in 57% and 65% yields,
respectively (Scheme 4). Primary and secondary iodides
containing a tetrahydropyran ring are suitable substrates for the
crossꢀcoupling, providing fair to excellent yields. Thus, the
corresponding primary iodide afforded 63% of 2j, whereas a
55 secondary derivative coupled in excellent 83% yield (2k, Scheme
4). On the other hand, tetrahydropyranyl protected 3ꢀ
iodopropanol furnished the coupled product 2l in a lower yield
(54%) with respect to the other pyran derivatives (Scheme 4).
Piperidines are considered as highly valuable intermediates for
60 the pharmaceutical industry due to their presence in numerous
biologically active compounds. For that reason, we were also
interested in evaluating this process with 4ꢀiodopiperidine
derivatives as starting materials which would give a direct access
to an intermediate used in the synthesis of Elarofiban.21 Thus,
65 when NꢀBOC and Nꢀbenzylꢀ4ꢀiodopiperidines were subjected to
the reaction conditions, coupling products 2m and 2n were
obtained in good yields (67 and 78%, respectively).
0.41 mmol
0.73 mmol
O
O
O
0.021 mmol 0.16 mmol 0.004 mmol
20
Scheme 3. Experimental evidences disregarding the trialkylꢀFe species
pathway.
In order to investigate the scope of this reaction under the
optimized conditions, several alkyl iodides were employed as
25 starting materials. The substrates chosen include both primary
and secondary electrophiles, and bear a variety of functional
groups compatible with the reaction conditions in order to
illustrate the versatility of the reaction. The MeOꢀsubstituted
aromatic ring of our model substrate furnished 2b in 67% yield
30 (Scheme 4). A shortening of the alkyl chain as phenethyl also
gave similar results (2c, Scheme 4), in spite of the easier
elimination that could take place on this substrate to give a
conjugated alkene (styrene). Linear alkyl iodides with different
4
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2
Selected examples on the alkylꢀalkyl palladiumꢀ and nickelꢀcatalyzed
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P. Knochel, Angew. Chem. Int. Ed., 1998, 37, 2387; b) J. Zhou, G.C.
Fu, J. Am. Chem. Soc., 2003, 125, 12527; c) N. Hadei, E. A. B.
Kantchev, C. J. O’Brien, M. G. Organ, Org. Lett., 2005, 7, 3805; d) J.
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Int. Ed., 2004, 43, 6180; e) C. F. Malosh, J. M. Ready, J. Am. Chem.
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Chem. Soc., 2007, 129, 1908; g) S. W. Smith, G. C. Fu, Angew.
Chem. Int. Ed., 2008, 47, 9334; h) K. B. Urkalan, M. S. Sigman, J.
Am. Chem. Soc., 2009, 131, 18042; i) O. Vechorkin, X. Hu, Angew.
Chem. Int. Ed., 2009, 48, 2937; j) P. Ren, O. Vechorkin, K. von
Allmen, R. Scopelliti, X. Hu, J. Am. Chem. Soc., 2011, 133, 7084; k)
J. Breitenfeld, O. Vechorkin, C. Corminboeuf, R. Scopelliti, X. Hu,
Organometallics, 2010, 29, 3686; l) J. Choi, G. C. Fu, J. Am. Chem.
Soc., 2012, 134, 9102; m) P. M. P. García, T. Di Franco, A. Orsino,
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Haley, R. J. Brandon, T. Konovalova, P. J. Desrochers, P. Pulay, D.
A. Vicic, J. Am. Chem. Soc., 2006, 128, 13175; e) V. B. Phapale, E.
Buñuel, M. GarcíaꢀIglesias, D. J. Cárdenas, Angew. Chem. Int. Ed.,
2007, 46, 8790; f) V. B. Phapale, M. GuisánꢀCeinos, E. Buñuel, D. J.
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J. Org. Chem., 2008, 73, 3680.
Finally, the scope regarding the leaving group was studied. The
use of alkyl bromides and tosylates led to lower yields, and no
reaction was observed using alkyl chloride (see more details in
ESI). These results reinforce the proposal of the formation of
radicals by homolytic cleavage of the Cꢀhalogen bond by the
active Fe complex.
60
65
5
Experimental procedure for the cross-coupling reactions
Iron(II) acetate (2.5 mol%) and 1,3ꢀdimesitylꢀ1Hꢀimidazolꢀ3ꢀium
chloride (6 mol%) were placed in Schlenk flask and dried under
70
10 vacuum. Then, dry THF (2 mL) was added and the mixture was
heated at 50ꢀ60 ºC under Ar. A 0.5 M solution (in THF) of
alkylmagnesium bromide (30 mol%) was slowly added and the
reaction mixture was stirred at 50ꢀ60 ºC for 20 min. After cooling
at RT, alkyl iodide (0.407 mmol) was added followed by the slow
15 addition of 0.5 M solution of alkylmagnesium bromide (1.5
mmol) with syringe pump (flow rate = 0.16 mL/h). After the
addition of the Grignard reagent, the reaction was stirred for 8 h
and then, hydrolyzed with saturated aqueous NH4Cl solution. The
aqueous phase was extracted with DCM and the combined
20 organic phases were dried over MgSO4. The solvent was
evaporated under vacuum and the product was purified by
column chromatography.
75
3
80
85
4
Recent examples on Cuꢀcatalysed alkylꢀalkyl crossꢀcouplings: a) P.
Ren, L.ꢀA. Stern, X. Hu, Angew. Chem. Int. Ed., 2012, 51, 9110; b)
C.ꢀT. Yang, Z.ꢀQ. Zhang, J. Liang, J.ꢀH. Liu, X.ꢀY. Lu, H.ꢀH. Chen,
L. Liu, J. Am. Chem. Soc., 2012, 134, 11124; c) J. Terao, H. Todo, S.
A. Begum, H. Kuniyasu, N. Kambe, Angew. Chem. Int. Ed., 2007,
46, 2086; d) J. Terao, A. Ikumi, H. Kuniyasu, N. Kambe, J. Am.
Chem. Soc., 2005, 123, 5646; e) R. Shen, T. Iwasaki, J. Terao, N.
Kambe, Chem. Commun., 2012, 48, 9313.
Conclusions.
In summary, we have developed a novel FeꢀNHC catalytic
25 system to perform the alkylꢀalkyl crossꢀcoupling reaction
between alkyl iodides and alkylmagnesium reagents in good to
excellent yields. Important features on the reaction mechanism
have been proposed on the basis of GC and EPR experiments,
which allow us to ensure that an Fe(I) species intervene in the
30 catalytic cycle, and that the activation of the halide takes place by
homolytic cleavage of the CꢀI bond leading to alkyl radicals.
Further studies will deal with investigation of the actual structure
of catalytic iron species responsible for the crossꢀcoupling
reaction, as well as the extension of the reaction scope to other
35 alkyl halides and Grignard reagents.
90
5
6
W. M. Czaplik, M. Mayer, J. Cvengroš, A. J. vonWangelin,
ChemSusChem, 2009, 2, 396.
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Tamura, J. K. Kochi, J. Organometal. Chem., 1971, 31, 289; c) S. M.
Neumann, J. K. Kochi, J. Org. Chem., 1975, 40, 599.
A. Leitner, in Iron Catalysis in Organic Chemitry: Reactions and
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147ꢀ176.
Arylꢀaryl crossꢀcoupling: a) I. Sapountzis, W. Lin, C. C. Kofink, C.
Despotopoulou, P. Knochel, Angew. Chem. Int. Ed., 2005, 44, 1654;
b) T. Hatakeyama, M. Nakamura, J. Am. Chem. Soc., 2007, 129,
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Am. Chem. Soc., 2009, 131, 11949; d) T. Hatakeyama, K. Ishizuka,
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14, 4818.
95
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8
100
105
110
115
Notes and references
a Departamento de Química Orgánica, Facultad de Ciencias,
Universidad Autónoma de Madrid. Fax: +34914973966; Tel:
+34914974358; E-mail: diego.cardenas@uam.es
40 b Departamento de Química Física Aplicada, Facultad de Ciencias,
Universidad Autónoma de Madrid.
9
Arylꢀalkenyl crossꢀcoupling: a) A. Furstner, A. Leitner, Angew.
Chem. Int. Ed., 2002, 41,609; b) A. L. Silberstein, S. D. Ramgren, N.
K. Garg, Org. Lett., 2012, 14, 3796.
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
10 Alkenylꢀalkyl crossꢀcoupling: a) G. Cahiez, Ho. Avedissian,
Synthesis 1998, 1199; b) B.ꢀJ. Li, L. Xu, Z.ꢀH. Wu, B.ꢀT. Guan, C.ꢀ
L.Sun, B.ꢀQ. Wang, Z.ꢀJ. Shi, J. Am. Chem. Soc., 2009, 131, 14657;
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45
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For comprehensive reviews in the alkylꢀalkyl metalꢀcatalyzed crossꢀ
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120 12 Alkylꢀaryl Negishiꢀtype coupling of alkyl electrophiles: a) R. B.
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125
M. Mansell, C. Mendoza, D. M. Murphy, E. C. Neeve, J. Nunn, J.
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14 Alkylꢀalkynyl coupling: T. Hatakeyama, Y. Okada, Y. Yoshimoto,
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40 21 J. H. Cohen, M. E. Bos, S. CescoꢀCancian, B. D. Harris, J. T.
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