Iron-catalysed sp3-sp3 cross-coupling reactions of unactivated alkyl halides with alkyl grignard reagents

Article abstract of DOI:10.1002/adsc.200600383

Iron-catalysed sp³-sp³ Kumada coupling with primary and secondary alkyl halides (RX) and alkyl Grignard reagents has been achieved in low to good yields depending on the nature of the R group.

Full text of DOI:10.1002/adsc.200600383

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DOI: 10.1002/adsc.200600383
Iron-Catalysed sp3–sp3 Cross-Coupling Reactions ofUnactivated
Alkyl Halides with Alkyl Grignard Reagents
Krishna G. Dongol,a Huishi Koh,a Manisankar Sau,a and Christina L. L. Chaia,*
a
Institute of Chemical and Engineering Sciences, 1 Pesek Road, Jurong Island, Singapore 627833
Fax : (+65)-6316-6184; e-mail: Christina_chai@ices.a-star.edu.sg
Received: July 27, 2006; Revised: March 9, 2007
Abstract: Iron-catalysed sp3–sp3 Kumada coupling
with primary and secondary alkyl halides (RX) and
alkyl Grignard reagents has been achieved in low to
good yields depending on the nature of the R
group.
formation of undesired by-products such as that re-
sulting from homocoupling, disproportionation and
beta-elimination reactions. Thus for a reaction as out-
lined in Scheme 1, the desired cross-coupling reaction
to form product D suffers from competition with the
formation of decene A, decane B and eicosane C, the
by-products that arise from the limiting reagent, the
alkyl halide. By-products arising from the Grignard
reagents are also likely but due to their volatility,
these were not analysed.
Keywords: alkyl halides; cross-coupling; Grignard
reactions; iron
Our initial studies focused on the use of iron(II)
acetate as the catalyst in diethyl ether. A large
The direct carbon-carbon cross-coupling reaction of number of ligands (Figure 1) were screened – these
organometallic components with alkyl halides is one included the use of phosphines, phosphites, amines,
of the key chemical transformations in synthetic butadiene. Of these, the use of Xantphos (1) gave
chemistry. The field is dominated by the use of cata- moderate to good yields of the cross-coupling prod-
lysts such as nickel, palladium and copper with alkyl uct. It is interesting to note that the use of 2, a confor-
metals such as alkyl Grignards (Kumada coupling), mationally flexible diphosphine related to Xantphos
alkyl borons (Suzuki–Miyaura coupling) and alkyl gave much lower yields of the cross coupling product
zincs (Negishi coupling).[1] Recently, there has been (5% versus 51% yield). Similarly the diphosphine 3
intensive interest in the development of iron catalysts also gave poor yields of the desired cross-coupling
[2]
À
for C C bond formation. This is in part due to the product, indicating that the nature of the substitution
push towards the development of ꢀgreenerꢁ and on the phosphorus atom of the ligand is also crucial
cheaper catalysts. The use of cheap, non-toxic and en-
vironmentally benign iron compounds as catalysts in
Kumada coupling has been reported by Kochi[3] in
1971 but exploitation of this to synthesis was not real-
ised until the work Cahiez,[4] Furstner,[5] Nakamura,[6]
Hayashi[7] and Bedford.[8] To date, sp2–sp3 and sp2–sp2
couplings of Grignard reagents with alkyl or aryl hal-
ides have been achieved in synthetically viable yields.
However the efficient cross-coupling of sp3–sp3
carbon centres, using iron catalysts, remains an excit-
Scheme 1. Iron-catalysed sp3–sp3 Kumada coupling.
ing challenge. To our knowledge, there is only the
report of Kochiꢁs pioneering observations with cou-
pling of activated alkyl halides,[3] while sp3–sp3 cou-
pling of Grignard reagent with unactivated alkyl hal-
ides has not been reported. Our studies, reported
herein, provide an important precedence for extend-
ing the scope of iron catalysed sp3–sp3 reactions with
unactivated alkyl halides.
The obstacles to successful sp3–sp3 carbon-carbon
cross coupling using Grignard reagents include the Figure 1. Structures of selected phosphine ligands.
Adv. Synth. Catal. 2007, 349, 1015 – 1018
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Krishna G. Dongol et al.
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Table 1. Screening of ligands with Fe
(OAc)2 as catalyst.[a]
A
Ligands
A (%)
B (%)
C (%)
D (%)
No ligand
15
7
58
50
57
62
51
64
58
43
31
62
44
38
56
16
7
0
12
16
6
3
15
2
4
8
Triphenylphosphine, PPh3
Tricyclohexylphosphine
2-(Di-tert-butylphosphino)biphenyl
2-(Dicyclohexylphosphino)-2’,6’-dimethoxybiphenyl
1,2-Bis(dipentafluorophenylphosphino)ethane
1,2-Bis(diphenylphosphino)ethane
2,2-Bis(diphenylphosphino)-1,1-binaphthyl
9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (1)
Bis(2-diphenylphosphinophenyl) ether (2)
9,9-Dimethyl-4,5-bis(di-tert-butylphosphino)xanthene (3)
Tri-n-butyl phosphite
18
11
15
10
14
10
2
10
9
12
11
5
5
7
11
10
13
6
9
11
18
51
5
11
14
2
Tris(2,2,2-trifluoroethyl) phosphite
[a]
The reaction was carried out under standard conditions as described in the Experimental Section with 1 mol% iron(II)
acetate in the presence of 1 mol% ligand. The yields of the cross-coupling products were quantified using GC (relative to
response curves with appropriate standards). In the control experiment without the iron catalyst, only the alkyl halide
was recovered after work-up.
Table 2. Screening of Fe catalyst using Xantphos (1).[a]
Fe catalysts
Fe(acac)3
FeCl2
FeCl3
FeF3
A (%)
B (%)
C (%)
D (%)
G
18
9
32
9
2
15
36
51
54
31
31
27
11
15
9
5
10
6
9
3
2
15
51
3
Fe
A
Fe(CF3COCH=COCH3)3
[a]
The reaction was carried out under standard conditions as described in the Experimental Section, with 1 mol% iron(II)
catalyst in the presence of 1 mol% ligand. The yields of the cross-coupling products were quantified using GC (relative
to response curves with appropriate standards).
in promoting the desired cross-coupling reactions.
Some of the results are summarised in Table 1 below. mol% Fe
Using Xantphos as the ligand, the use of other iron at room temperature for 15 min], the reactions of the
complexes [Fe(II) and Fe(III)] as catalysts was also RꢁMgBr with some primary and secondary alkyl hal-
examined (Table 2). From these studies, Fe(OAc)2 ides were attempted (Scheme 2, Table 3). From these
Under the best conditions ascertained so far [3
AHCTREUNG
AHCTREUNG
AHCTREUNG
gave the best yields of the cross coupling product. At- studies, for the primary alkyl halides utilised, the
tempts to optimise the reaction conditions for the yields ranged from 46–64% of the desired cross cou-
cross coupling reaction included the choice of solvents pled product. The yields of the desired cross-coupled
and temperature. The use of THF, DCM and 1,4-diox- product with secondary alkyl halides were low (ca. 8–
ane as solvents reduced the yield of the cross-coupled 43%) under these conditions.
product. When the reaction was attempted under the
Our preliminary investigation of the possible mech-
reflux temperature of diethyl ether, no improvement anism of cross-coupling of primary systems suggests
in the yield of the desired cross coupled product D the intermediacy of radical intermediates (Scheme 3).
was obtained. The progress of reaction was also moni- In particular, the reaction of 4-phenoxybutylmagnesi-
tored over time and our studies showed that the reac- um bromide with 6-bromohexene gave cross-coupling
tion was completed in 15 min and that prolonged re- adducts 4 and 5 in a ratio of 95:5 with isolated yields
action times did not negatively or positively impact
on the yields of the desired product. When the load-
ing of the iron catalyst and ligand was increased to 3
mol% and 6 mol% respectively, the yields of the
cross-coupled products showed marked improvements
in some cases.
Scheme 2. ꢀBestꢁ conditions to date for cross-coupling.
1016
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Iron-Catalysed sp3–sp3 Cross-Coupling Reactions of Unactivated Alkyl Halides
Table 3. Cross-coupling yields[a] under standard reaction conditions.
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R-Br
R’
Yield [%] of R’-R
1-Bromodecane
n-butyl
n-butyl
n-butyl
n-butyl
n-butyl
n-butyl
n-hexyl
n-hexyl
64%
63%
63%
64%
8%
34%
46%
62%
43%
1-Bromododecane
1-Bromotetradecane
1-Bromohexadecane
exo-2-Bromonorbornane
1-Bromocyclohexane
4-Bromo-1-butene
1-Bromodecane
1-Bromocyclohexane
1-propylbenzene
[a]
The reaction was carried out under the best conditions, using 3 mol% Fe(OAc)2 as catalyst and 6 mol% Xantphos as
A
ligand. The yields of the cross-coupling products were quantified using GC (relative to response curves with appropriate
standards).
Scheme 3. Probing the mechanism of sp3–sp3 iron-catalysed cross-coupling reactions.
of 51%. Thus the cyclopentyl adduct 4 was formed as is tremendous and this report should provide the im-
the near exclusive cross-coupling adduct. When bro- petus for further development. The challenge is to un-
momethylcyclopropane replaced 6-bromohexene, the derstand the chemistry of these iron-catalysed cross-
cross-coupling adduct 6 was isolated in 48% yield. coupling reactions in order to enable further explora-
The cyclopropyl cross-coupled product 7 could not be tion of the scope and limitations of the reagents and
1
readily detected by H NMR spectroscopy or GC/MS substrates (structural and functional group tolerance).
techniques. Thus the near exclusive formation of both
4 and 6 suggest that alkyl radicals from the corre-
sponding alkyl halides are formed during the reaction.
The present study remains, to our knowledge, the
first exploitation of an sp3–sp3 cross-coupling reaction
between primary alkylmagnesium bromides and unac-
tivated primary alkyl bromides. Although further im-
provements should be realised for the secondary sys-
tems, the significance of this report should not be un-
Experimental Section
General Procedure for the Preparation of the
Grignard Reagent
All apparatus must be thoroughly dried in a hot oven before
use. A 2-necked round-bottomed flask equipped with a mag-
dermined. The potential scope for this transformation netic stirrer bar and a reflux condenser was evacuated and
Adv. Synth. Catal. 2007, 349, 1015 – 1018
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Krishna G. Dongol et al.
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backfilled with argon repeatedly. This was followed by the
addition of magnesium turnings (1.89 mmol). The magnesi-
um turnings were covered with 2 mL of anhydrous diethyl
ether which was removed via gentle vacuum, following
which the Mg turnings were further dried under high
vacuum with gentle heating. The flask was then backfilled
with argon and anhydrous diethyl ether (2 mL) followed by
a catalytic amount of iodine, and alkyl halide (1.35 mmol)
were added. After approximately 2 min, the colour of the
reaction mixture changed from brown to colourless. The re-
action mixture was refluxed at 608C for 1 h following which
the Grignard reagent was cooled to room temperature, after
which the solution can either be filtered or cannulated
under anhydrous conditions. The concentration of the
Grignard reagent was determined by titration following the
literature procedure.[9]
Acknowledgements
The authors thank the Agency for Science, Technology and
Research (ASTAR), Singapore for their support of this proj-
ect.
References
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To a round-bottomed flask in a glove-box was added 3
mol% Fe(OAc)2 and 6 mol% of ligand. The flask was evac-
A
uated and filled with argon (3 times) followed by the addi-
tion of anhydrous diethyl ether (1 mL). This was followed
by the addition of 1.5 equivalents (0.68 mmol) of the
Grignard reagent in diethyl ether (0.34M)[9] and 0.45 mmol
of the alkyl halide at room temperature. The reaction mix-
ture was stirred for 15 min following which an internal stan-
dard was added to the reaction mixture and the reaction
was quenched with 1 N HCl. The reaction mixture was dilut-
ed with pentane and analysed by gas chromatography (GC
column: HP-5). The quantities of the products of the reac-
tion were quantified using GC (relative to response curves
with appropriate standards). In some cases, the products of
the reaction were purified via column chromatography.
[9] The concentration of the Grignard reagent was deter-
mined following the procedure of A. Krasovskiy, P. Kno-
chel, Synthesis 2006, 5, 890–891.
1018
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Adv. Synth. Catal. 2007, 349, 1015 – 1018