Fe-Cu cooperative catalysis in the isomerization of alkyl Grignard reagents

Article abstract of DOI:10.1039/b717717h

Alkyl Grignard reagents were found to be isomerized to more stable ones in high isomerization ratios (>99%) under cooperative catalysis by iron and copper, which promote isomerization of alkyl groups and transmetalation between Fe-Mg, respectively. The Ro

Full text of DOI:10.1039/b717717h

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Fe–Cu cooperative catalysis in the isomerization of alkyl Grignard
reagentsw
Eiji Shirakawa,* Daiji Ikeda, Shigeru Yamaguchi and Tamio Hayashi*
Received (in Cambridge, UK) 15th November 2007, Accepted 7th December 2007
First published as an Advance Article on the web 4th January 2008
DOI: 10.1039/b717717h
Alkyl Grignard reagents were found to be isomerized to more
stable ones in high isomerization ratios (499%) under coopera-
tive catalysis by iron and copper, which promote isomerization of
alkyl groups and transmetalation between Fe–Mg, respectively.
give alcohol 5 and carboxylic acid 6a (Scheme 1). Under the
cooperative catalysis, other 2-alkyl Grignard reagents 1b and
1c also underwent complete isomerization (Scheme 1).
Several results are available to discuss the reaction mechan-
ism. The Fe–Cu-catalyzed isomerization of 1,1,1-trideuterio-2-
hexylmagnesium reagent 1a-d3 followed by the reaction with
CO2 gave 2,2,3-trideuterioheptanoic acid (6a-d3) (Scheme 2).
The result that a deuterium atom migrated from the a-position
to b is consistent with the b-hydride elimination–hydrometala-
tion mechanism, as proposed in the titanium-catalyzed iso-
merization.2 Stoichiometric reactions of FeCl3 or CuBr with
2-octylmagnesium chloride (1b) gave us a clue toward solving
which catalyst is responsible for the isomerization of the alkyl
group. Thus, treatment of FeCl3–PBu3 with 1b (6 equiv.) at
À25 1C for 10 min followed by quenching with D2O gave
1-deuteriooctane (7) in 77% yield (based on Fe), whereas the
same treatment of CuBr–PBu3 gave only 2-deuteriooctane
(Scheme 3).9 The production of 7 in the reaction of FeCl3 is
Alkyl Grignard reagents, obtainable simply by mixing alkyl
halides with magnesium metal, are one of the most convenient
alkylmetals in organic synthesis. Ti(IV) and Ni(II) complexes
are known to catalyze isomerization of secondary alkyl
Grignard reagents to primary ones through a b-hydride
elimination–hydrometalation sequence but the conversion is
generally low.1–4 On the other hand, we have developed
arylmagnesiation of alkynes catalyzed by iron and copper
complexes, featuring a rare example of cooperative catalysis
of two different metals, where iron and copper deal with
addition to alkynes and transmetalation between Fe–Mg,
respectively.5,6 Here we report that Fe–Cu cooperative cata-
lysis works effectively in the isomerization of alkyl Grignard
reagents to more stable ones, where isomerization of the alkyl
groups and transmetalation between Fe–Mg are promoted by
Fe and Cu, respectively.7
Table 1 Isomerization of 2-hexylmagnesium bromidea
The efficiency of the catalyst system was evaluated for the
isomerization of 2-hexylmagnesium bromide (1a) to 1-hexyl
derivative 2a, which is more favored both electronically and
sterically. Thus, 1a was treated with a catalyst consisting of
FeCl3 (2.5 mol%) and/or CuBr (5 mol%) along with PBu3 (10
mol%), and the isomerization ratio was determined after
transformation to 2-hexyl(phenyl)silane (3) and 1-hexylsilane
4 upon treatment with chloro(phenyl)silane (2 equiv.) at 30 1C
for 2 h (Table 1). With both the iron and copper catalysts,
isomerization was completed within 10 min at À25 1C to give 4
in 83% yield and with 499% selectivity (entry 1).8 The
isomerization was slow at a lower temperature (entries 2 and
3), whereas the isomerization ratio decreased as the reaction
temperature was raised, probably because the catalyst is
unstable at higher temperatures (entries 4 and 5). In contrast,
with the iron catalyst alone, the isomerization proceeded only
to a small extent (p3%) even over a prolonged reaction
period or at a lower temperature (entries 6–8). CuBr did not
catalyze the isomerization at all in the absence of FeCl3 (entry
9). Thus obtained 2a reacted with benzaldehyde and CO2 to
Amount (mol%)
FeCl3 CuBr
Entry
T/1C Time
Yield (%)b 3 : 4b
1
2
3
4
5
6
7
8
9
a
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
0
5
5
5
5
5
0
0
0
5
À25 10 min 83 (81)c
À40 10 min 95
1 : 499
94 : 6
À40 24 h
77
1 : 499
15 : 85
95 : 5
À10 10 min 88
30 10 min 89
À25 10 min 84
97 : 3
97 : 3
98 : 2
499 : 1
À25 24 h
À40 24 h
74
83
À25 10 min 499
The reaction was carried out in THF (2.0 mL) under a nitrogen
atmosphere using 2-hexylmagnesium bromide (1a: 0.30 mmol) and
PBu3 (30 mmol) in the presence of FeCl3 (7.4 mmol) and/or CuBr
(15 mmol), which was followed by treatment with ClSiH2Ph (0.60 mmol)
at 30 1C for 2 h. Determined by GC. Isolated yield based on 1a
is given in the parentheses.
Department of Chemistry, Graduate School of Science, Kyoto
University, Sakyo, Kyoto 606-8502, Japan. E-mail:
shirakawa@kuchem.kyoto-u.ac.jp. E-mail: thayashi@kuchem.
kyoto-u.ac.jp; Fax: +81 75 753 3988
w Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/b717717h
b
c
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Scheme 1
Scheme 5
Scheme 2
Scheme 6
Scheme 3
ascribed to a 1-octyliron species generated through isomeriza-
tion of the octyl group on iron. From these results, in addition
to the essential role of copper as a co-catalyst, we assumed that
a cooperative catalysis similar to that in the arylmagnesiation
of alkynes5 is operative as shown in Scheme 4. Here, FeCl3,
after being converted into 2-alkyliron complex 8 upon reaction
with 1, promotes isomerization of alkyl groups through a
b-hydride elimination–hydrometalation sequence to give 11
(cycle A),10 which goes into cycle B on transmetalation with
cuprate 13 to give 1-alkylcuprate 12 and to regenerate 8.
Further transmetalation of 12 with 1 gives 1-alkyl Grignard
reagent 2 and regenerates cuprate 13.
Scheme 7
internal alkenes dissociate from complexes 18, generated from
17 as shown in Scheme 6, to give free iron–hydride complex 19,
which decomposes with loss of the catalytic activities.11 The
reaction of 14 in the presence of 1-decene (1 equiv.) gave 60%
yield of 1-decylsilane 16, where most of the MgBr moiety was
transferred from the C6 component to C10.3,12 As shown in
Scheme 6, the added terminal alkene probably prevents free
iron–hydride complex 19 from decomposition by forming
complex 20, which is converted into 21 through hydroirona-
tion and then to 22 via cycle B.13
In contrast to 2-hexylmagnesium bromide (1a), 3-hexyl
derivative 14 did not undergo the efficient isomerization to
2a, even in the presence of twice the amount (Fe: 5 mol%) of
the Fe–Cu catalyst, giving 3-hexyl(phenyl)silane (15) and
1-hexylsilane 4 in 61% and 10% yields, respectively, upon
treatment with ClSiH2Ph (Scheme 5). Coproduction of a
considerable amount (18% yield) of hexenes, mainly consist-
ing of internal ones, implies that the sterically demanding
The Fe–Cu system also catalyzed isomerization of b-phe-
nethylmagnesium chloride (2d) to the a-phenethyl derivative,
presumably because the anion stabilizing ability of the phenyl
group surpasses the steric repulsion between the phenyl and
MgCl groups.14 Thus, treatment of 2d with the Fe–Cu catalyst
(5 mol% of Fe) at À25 1C for 1 h followed by the reaction with
ClSiH2Ph gave 23 in an isomeric purity over 99% (Scheme 7).
In conclusion, we have disclosed that an effective coopera-
tive catalysis is observed in the isomerization of alkyl Grignard
reagents to more stable ones with a system consisting of iron
and copper, which promote isomerization of alkyl groups and
transmetalation between iron and magnesium, respectively.
This work has been supported financially by Grants-in-Aid
for Creative Scientific Research (16GS0209) and for Scientific
Research on Priority Areas (No. 19028029, ‘‘Chemistry of
Concerto Catalysis’’) from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
Notes and references
1 Isomerization triggered by a double bond or a strained cycle, as in
allylic and cyclopropylmethyl Grignard reagents, is known. For a
review, see: E. A. Hill, J. Organomet. Chem., 1975, 91, 123–271.
Scheme 4
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2 For titanium-catalyzed isomerization to give n-alkyl Grignard
reagents, see: (a) H. L. Finkbeiner and G. D. Cooper, J. Org.
Chem., 1961, 26, 4779–4780; (b) G. D. Cooper and H. L. Finkbei-
ner, J. Org. Chem., 1962, 27, 1493–1497; (c) B. Fell, F. Asinger and
R. A. Sulzbach, Chem. Ber., 1970, 103, 3830–3841. For nickel-
catalyzed isomerization to give n-alkyl and a-arylalkyl Grignard
coupling of alkyl Grignard reagents with aryl electrophiles, com-
plexes of À2 valent iron were shown to be active species by
Furstner and co-workers: (b) A. Furstner and A. Leitner, Angew.
¨
Chem., Int. Ed., 2002, 41, 609–612; (c) A. Furstner, A. Leitner, M.
¨
¨
Mendez and H. Krause, J. Am. Chem. Soc., 2002, 124,
´
13856–13863.
9 The reaction mixture quenched by D2O was diluted with CHCl3
and subjected to 2H NMR analysis. The yield was determined
using Cl2CDCDCl2 as an internal standard.
10 Isomerization from tert-butylmetal to a more stable isobutylmetal
with iron is known: (a) J. Vela, J. M. Smith, R. J. Lachicotte and P.
L. Holland, Chem. Commun., 2002, 2886–2887; (b) J. Vela, S.
Vaddadi, T. R. Cundari, J. M. Smith, E. A. Gregory, R. J.
Lachicotte, C. J. Flaschenriem and P. L. Holland, Organometallics,
2004, 23, 5226–5239.
reagents in the presence of an alkene, see: (d) L. Fara
´
dy and L.
Marko, J. Organomet. Chem., 1971, 28, 159–165..
´
3 n-Alkyl and a-arylalkyl Grignard reagents are obtained by metal-
catalyzed exchange between terminal alkenes and alkyl Grignard
reagents. For Ti catalysts, see: (a) H. L. Finkbeiner and G. D.
Cooper, J. Org. Chem., 1962, 27, 3395–3400; (b) E. C. Ashby and
R. D. Ainslie, J. Organomet. Chem., 1983, 250, 1–12, see also ref.
2a and b. For Ni catalysts, see: (c) L. Fara
Marko, J. Organomet. Chem., 1967, 10, 505–510, see also ref. 2d..
´
dy, L. Bencze and L.
´
4 Isomerization of the alkyl group derived from alkyl Grignard
reagents during the transition metal-catalyzed cross-coupling reac-
tion with aryl halides is known. For an early example, see: K.
Tamao, Y. Kiso, K. Sumitani and M. Kumada, J. Am. Chem. Soc.,
1972, 94, 9268–9269.
5 E. Shirakawa, T. Yamagami, T. Kimura, S. Yamaguchi and T.
Hayashi, J. Am. Chem. Soc., 2005, 127, 17164–17165.
6 For a recent review on cooperative catalysis, see: J. M. Lee, Y. Na,
H. Han and S. Chang, Chem. Soc. Rev., 2004, 33, 302–312. See also
references cited in ref. 5.
11 Hexenes are produced in 6% yield also in the Fe–Cu-catalyzed
reaction of 1a in entry 1 of Table 1, probably during reduction of
the iron(III) complex to a catalytically active low valent complex.
12 The transfer ratio of the MgBr moiety from the C6 component
to C10 was much less using 1-hexylmagnesium bromide (2a)
instead of 14. Thus, the reaction of 2a in the presence of
1-decene under the same conditions as in Scheme 5 gave 4
(70% yield), hexenes (11% yield), 16 (7% yield) and decenes
(92% yield).
13 The addition of 1-decene after 30 min premixing of all the other
components did not affect the yields of 15, 4 and hexenes (59%,
7% and 23%, respectively), where most of 1-decene remained
unreacted (1-decene: 83%; 16: 3%).
7 FeCl3 is reported to catalyze the exchange between 1-propylmag-
nesium bromide and styrene to give a-phenethylmagnesium
bromide, albeit in a low yield (15%), see ref. 3a.
8 Some amount of Grignard reagents must be consumed for reduc-
tion of the iron(III) complex and formation of dialkylcuprates.
Kochi and Neumann reported that iron(III) complexes are reduced
to iron(I) complexes by an excess amount of alkyl Grignard
reagents: (a) S. M. Neumann and J. K. Kochi, J. Org. Chem.,
1975, 40, 599–606. On the other hand, in the iron-catalyzed cross-
14 Isomerization of b-phenethyltantalum to the a-phenethyl deriva-
tive is known: H. Guo, F. Kong, K. Kanno, J. He, K. Nakajima
and T. Takahashi, Organometallics, 2006, 25, 2045–2048. For
formation of a-arylethyl Grignard reagents by metal-catalyzed
exchange between vinylarenes and alkyl Grignard reagents, see
ref. 2a, d and 3a.
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