Catalytic double C-Cl bond activation in CHlby iron(III) salts with grignard reagents

Article abstract of DOI:10.1055/s-0030-1259922

Cross-coupling of Grignard reagents with dichloromethane is achieved using iron(III) catalysts. Aryl- and benzylmagnesium bromides show a range of activity toward double C-Cl bond activation resulting in the insertion of methylene fragments between two equivalents of the nucleophilic partner. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1259922

852
LETTER
Catalytic Double C–Cl Bond Activation in CH2Cl2 by Iron(III) Salts with
Grignard Reagents
D
ouble C–Cl Bond
i
A
ctiv
n
I
ron(III
)
Qian, Christopher M. Kozak*
Department of Chemistry, Memorial University of Newfoundland, St. John’s, NL, A1B 3X7, Canada
Fax +1(709)8643702; E-mail: ckozak@mun.ca
Received 22 December 2010
We have recently found that the amine–bis(phenolate)
Abstract: Cross-coupling of Grignard reagents with dichlo-
romethane is achieved using iron(III) catalysts. Aryl- and benzyl-
magnesium bromides show a range of activity toward double C–Cl
bond activation resulting in the insertion of methylene fragments
between two equivalents of the nucleophilic partner.
iron complex (m-dichloro)bis[(n-propylamino-N,N-bis(2-
methylene-4-tert-butyl-6-methylphenoxo)iron], abbrevi-
ated {(m-Cl)[O2N]Fe}2, (1; Scheme 1) is an effective cat-
alyst for the cross-coupling of aryl and benzyl Grignard
reagents with primary and secondary alkyl halides, in-
cluding chlorides. However, when dihalogenated sub-
strates, such as 1,4-dichlorobutane, were used, only
arylation at one chloride position was observed.14 We
were therefore surprised to find over the course of that in-
vestigation that addition of aryl Grignards to dichlo-
romethane solutions of complex 1 resulted in the
formation of diarylmethane and diarylethane compounds
(Scheme 1). A study of catalyst loading, ratio of Grignard
to dichloromethane, addition rate and temperature effects
was performed using o-tolylmagnesium bromide (1.0 M
in THF; Table 1). Yield of diarylmethane (Product A)
based on the Grignard reagent increased upon increasing
catalyst loading from 1.0 mol% to 2.5 mol% Fe versus
Grignard at 25 °C, with a Grignard reagent-to-dichlo-
romethane ratio of 1:12.5 (entries 1 and 2). Increasing the
loading of 1 to 5.0% and 10.0% versus the aryl Grignard
reagent actually decreased the yields of diarylmethane
formed (entries 3 and 4). It has been proposed that iron-
catalyzed cross-coupling of Grignard reagents with elec-
trophiles proceeds by the formation of reduced Fe as the
active species, which is generated by excess Grignard.11
Higher catalyst loading consumes more Grignard reagent,
which is the limiting reagent since the alkyl halide
(dichloromethane) is present in large excess. Therefore,
the optimum loading of 1 was found to be 2.5 mol% Fe
versus Grignard (entry 2) giving 83% yield of cross-cou-
pled product. The absence of 1 gave no cross-coupled
products (entry 5).15
Key words: cross-coupling, iron, catalysis, arylation, Grignard re-
agent
Transition-metal-catalyzed C–C cross-coupling is a pow-
erful tool in organic synthesis and significant advances
have been made using aryl and alkenyl halides and
pseudohalides as electrophiles.1 Unactivated alkyl ha-
lides, however, continue to pose a challenge,2 and only a
few examples of C–C catalysis using alkyl chlorides in
particular have been reported.3–5 Even fewer reports exist
of catalytic coupling of di- or polychloroalkanes with or-
ganometallic nucleophiles. Particularly noteworthy is the
amidobis(amine) [NN2]Ni-catalyzed activation of CH2Cl2
and CHCl3 leading to selective C–C bond formation with
alkyl Grignard reagents.6 Related amidobis(phosphine)
[NP2]Ni(II) alkyl complexes can react slowly with CH2Cl2
(765 equiv) at 110 °C, but no organic product was identi-
fied.7 Furthermore, [tpb]Ag-catalyzed insertion of a car-
bene into one C–Cl bond of CH2Cl2, CHCl3 and CCl4
forming a new C–C bond has also been reported ([tbp] =
tris(pyrazolyl)borate).8 Stoichiometric double C–Cl oxi-
dative addition reactions have been reported for basic
Rh(I) complexes. A recent report involving Rh(I) with P-
functionalized aminopyridine ligands describes both sin-
gle and double C–Cl activation to give terminal CH2Cl
and CH2 groups simultaneously.9
The use of iron for catalytic C–C cross-coupling is under-
going a renaissance and various iron-based processes
have been described.3,10–12 Iron is cheap, non-toxic and en-
vironmentally benign; therefore, the use of readily pre-
pared iron catalysts that are easily handled is extremely
desirable. Particularly tantalizing is the use of iron for C–
C bond formation using dichloroalkane electrophiles.13
Herein we report the first example of double C–Cl bond
cleavage in dichloromethane with aryl and benzyl Grig-
nard reagents by Fe(III) under mild conditions.
Increasing the CH2Cl2-to-Grignard ratio also lowered the
yield of diarylmethane (entry 6). A 2:1 loading of Grig-
nard to CH2Cl2 resulted in much lower yields of diaryl-
methane and no diarylethane (entry 7). Slow addition of
Grignard reagent over a period of 20 minutes using a sy-
ringe pump (entries 8 and 9) decreased the yield of diaryl-
methane regardless of catalyst loading, as did conducting
the reaction at 0 °C (entry 10).
Simple iron salts, such as FeCl3 and Fe(acac)3, both with
and without the use of additives, have been shown to be
efficient catalysts for the cross-coupling of aryl Grignard
reagents with alkyl halides.12,16 However, trace impurities
of copper, palladium and other metals have also been
SYNLETT 2011, No. 6, pp 0852–0856
Advanced online publication: 16.03.2011
DOI: 10.1055/s-0030-1259922; Art ID: S09810ST
x
x.
x
x.
2
0
1
1
© Georg Thieme Verlag Stuttgart · New York

LETTER
Double C–Cl Bond Activation by Iron(III)
853
to considerably inferior yields compared to FeCl3 alone
(entries 4–7). Using FeCl2, however, was also less effec-
tive (entry 8), whereas CuCl and CuBr2 (entries 9 and 10)
gave no yield of either product A or B. Using Fe(acac)3
with and without TMEDA did not catalyze cross-coupling
of phenyl Grignard reagent with CH2Cl2 (entries 11 and
12), but these conditions were effective when o-tolyl
Grignard reagent reacted with CH2Cl2 (entries 13 and 14).
Using PdCl2 and Pd(OAc)2 gave moderate yields when o-
tolyl Grignard reagent reacted with CH2Cl2 (entries 15
and 16). It is worth noting that Pd catalysts produced
product B, diarylethane, as the major products.
RCH2R
+
product A
product B
[Fe]
RMgX + CH
2Cl2
R = aryl or benzyl
RCH2CH2R
[Fe] = 1 or FeCl3
t-Bu
t-Bu
O
Cl
O
N
Fe
O
Fe
O
N
Cl
t-Bu
t-Bu
With these results in hand, we screened a number of Grig-
nard reagents using 1 and anhydrous FeCl3 as the catalysts
(Table 3). When phenyl- and p-tolylmagnesium bromide
solutions were added to solutions of 1 in CH2Cl2 at room
temperature, only poor yields of diarylmethane were ob-
tained (entries 2 and 3). The presence of the ortho-methyl
group may be important to the stability of Fe-aryl interme-
diates. Use of secondary and primary alkyl Grignard nu-
cleophiles (entries 4 and 5) gave little or no cross-coupled
products, contrary to results obtained using [NN2]Ni(II)
complexes where good yields of cross-coupling products
were observed using alkyl nucleophiles but no conversion
was shown for aryl nucleophiles.6 Benzyl Grignard re-
agents reacted with CH2Cl2 and gave good yields of di-
arylpropane cross-coupling products (entries 5 and 6).
1
Scheme 1 General dichloromethane activation cross-coupling reac-
tions
Table 1 Effect of Catalyst Loading of 1, Ratio of Nucleophile to
Electrophile, and Grignard Addition Rate
Entry Loading RMgBr
(mol%)
Ratioa
Yield (%) of Yield (%) of
product A product B
1
1.0
2.5
5.0
10.0
0
o-tolyl
o-tolyl
o-tolyl
o-tolyl
o-tolyl
o-tolyl
o-tolyl
o-tolyl
o-tolyl
o-tolyl
1:12.5
1:12.5
1:12.5
1:12.5
1:12.5
1:25
56
83
72
69
0
7
13
7
2b
3b
4b
5
Anhydrous FeCl3 (3.0 mol%) showed poor yields and se-
lectivity for cross-coupling of p-tolylMgBr, but o-tolyl
Grignard gave excellent results (entries 8 and 9). 2,6-Di-
methylphenyl gave negligible yields of diarylmethane, in-
stead producing diarylethane, the yield of which improved
slightly upon microwave heating to 100 °C (entry 11).
Other nucleophiles such as anisyl and 4-fluorophenyl
Grignards all gave modest yields and selectivity (entries
12–15). It is worth noting that reaction of 4-methoxyphe-
nylmagnesium bromide with CH2Cl2 produced 1,3-diaryl-
propane and 1,4-diarylbutane in addition to diarylmethane
and diarylethane. Also, heating of entry 13 to 100 °C led
to lower yields of cross-coupled products. 1-Naphthyl
Grignard reagent only gave product A in modest yield
(entry 16) whereas 2-methyl-1-naphthylmagnesium bro-
mide (entry 17) gave no detectable products. For 4-meth-
oxybenzyl Grignard reagent (entry 18), 1 is a more
effective catalyst than FeCl3 and allyl Grignard showed no
cross-coupling products (entry 19).
7
0
6
2.5
2.5
2.5
5.0
2.5
51
27
56
58
48
10
0
7
2:1
8b,c
9b,c
1:12.5
1:12.5
1:12.5
10
14
9
10d
a Ratio of Grignard reagent to CH2Cl2.
b Average of two runs.
c Grignard reagent (3.8 mmol) was added dropwise by syringe pump
over 20 min.
d Reaction temperature was 0 °C.
shown to strongly influence the yields of cross-coupling
reactions where iron salts were used as catalysts.17 There-
fore, we studied a variety of other simple metal salts and
additives for their ability to perform this reaction
(Table 2). Anhydrous FeCl3 (2.5 mol% vs. Grignard) was
extremely effective at coupling o-tolylmagnesium bro-
mide with CH2Cl2 at room temperature (entry 1). Surpris-
ingly, phenylmagnesium bromide led to much lower
yields of diphenylmethane and approximately equal quan-
tities of 1,2-diphenylethane. Microwave heating of the re-
action to 100 °C led to a slightly improved yield of
diphenylmethane (entry 2). Interestingly, using FeBr3
gave lower yields of diarylmethane (entry 3) than the
chloride salt, and no diarylethane was observed. Using ad-
ditives such as TMEDA, DMF and olefins with FeCl3 led
It is worth noting that 1,2-dichloroethane has been shown
to be an effective oxidant for FeCl3-catalyzed homocou-
pling of arylmagnesium bromides.18 Indeed, homocou-
pling is the main side reaction of iron-catalyzed cross-
coupling between aryl Grignards and alkyl halides pos-
sessing b-hydrogens.3,10–12,14 For the reaction of dichlo-
romethane with Grignard reagents, we propose a possible
mechanism (Scheme 2) based on the mechanism pro-
posed by Hayashi.18 Hayashi suggests dichloroethane ox-
idatively adds to a low valent iron complex, generated by
the reaction of FeCl3 with Grignard reagent (producing bi-
aryls in the process). The same can occur with dichlo-
Synlett 2011, No. 6, 852–856 © Thieme Stuttgart · New York

854
X. Qian, C. M. Kozak
LETTER
Table 2 Different Metal Salts and Use of Additives
Entry
Catalyst
FeCl3
Loading (mol%)
RMgBr
o-tolyl
Ph
Yield (%) of product A Yield (%) of product B
1
2
2.5
2.5
90
<1
FeCl3
21
25
43a
27a
3
4b
5b
6b
7
FeBr3
2.5
2.5
2.5
2.5
2.5
2.5
2.5
5.0
5.0
5.0
5.0
5.0
5.0
5.0
o-tolyl
o-tolyl
o-tolyl
o-tolyl
o-tolyl
o-tolyl
o-tolyl
o-tolyl
Ph
56
17
16
33
25
12
0
0
25
5
FeCl3 + TMEDA
FeCl3 + DMF
FeCl3 + 1-octene
FeCl3 + cod
FeCl2
17
21
10
0
8
9
CuCl
10
11
12c
13
14c
15
16
CuBr2
0
0
Fe(acac)3
<1
<1
90
81
23
13
<1
<1
<1
7
Fe(acac)3 + TMEDA
Fe(acac)3
Ph
o-tolyl
o-tolyl
o-tolyl
o-tolyl
Fe(acac)3 + TMEDA
Pd(OAc)2
51
31
PdCl2
a Microwave-assisted, 100 °C, 10 min.
b Ligand (1 equiv) to Grignard reagent.
c Additives (10 mol%) were added to Grignard reagent.
romethane (cycle A). These first two steps are generally Grignard reagent gives high yield of double cross-cou-
believed to be key to cross-coupling as they lead to alkyl pling products. For the remaining Grignard reagents at-
iron halides, which can undergo transmetallation with the tempted, biaryl homocoupling products were observed.
Grignard to give alkylaryliron complexes. Reductive The formation of diarylethane in the cross-coupling of
elimination gives the desired cross-coupled product, but CH2Cl2 suggests the formation of arylmethyl radical,
side reactions may ensue from the alkyliron halide. For which subsequently undergoes radical coupling. Since
example, in Hayashi’s system b-hydride elimination yields of the diarylmethane products are favored under
would lead to the formation of chloroethene, whereas b- optimized conditions, the reaction of arylmethyl radicals
chloride elimination would lead to a dichloroiron species with aryl nucleophiles proceeds faster than homocou-
and ethane. The dichloroiron can now be again reduced by pling, particularly if the concentration of Grignard versus
the aryl Grignard, and thus produce another equivalent of Fe (and alkyl radical) is high. Further studies to extend the
biaryl. In the case of dichloromethane, neither b-hydro- scope of this method and to gain detailed mechanistic in-
gens nor b-chlorides are present; therefore transmetalla-
tion with aryl Grignard to form an alkylaryliron complex
FeCl3
becomes favored. Cross-coupling at this stage leads to the
ArMgX
product A
formation of benzylhalide, which is capable of oxidative
ArCH2Ar
Ar–Ar
CH2Cl2
addition (OA) at a reduced iron centre (cycle B), which
leads to product A, as well as single electron transfer
(SET). The occurrence of the latter is reasonable taking
into account the formation of product B with many of the
aryl Grignards in Table 3.
Cl
Cl
Ar
[Fe]
[Fe]
[Fe]
Ar
ArMgX
MgX2
cycle A
cycle B
[Fe]
ArMgX
Cl
MgX2
Ar
Cl
[Fe]
In summary, iron complex 1 and simple iron salts can cat-
alyze multiple C–Cl activation in CH2Cl2.19 Under similar
conditions, simple Pd and Cu salts were less selective and
productive, respectively. The effect of Grignard reagent
on cross-coupling was screened; however, only o-tolyl
Ar
OA or
SET
ArCH2Cl
product B
⋅
0.5 ArCH2CH2Ar
[Fe]Cl + ArCH2
Scheme 2 Mechanism leading to the formation of products A and B
Synlett 2011, No. 6, 852–856 © Thieme Stuttgart · New York

LETTER
Double C–Cl Bond Activation by Iron(III)
855
a
Table 3 Effect of Grignard Reagent on Cross-Coupling Catalyzed by 1 and FeCl3
Entry
Catalyst
RMgBr
o-tolyl
Yield (%) of product A
Yield (%) of product B
1b
2
1
83
11
21
1.3
0
13
22
10
1
Ph
3
1
p-tolyl
4
1
cyclohexyl
n-Bu
0.8
5
1
0
9
6
1
4-methoxybenzyl
4-fluorobenzyl
p-tolyl
71
60
14
90
7
1
0
8
FeCl3
FeCl3
FeCl3
10
<1
9c
10c
o-tolyl
Ph
21
25
43d
27d
11
FeCl3
2,6-dimethylphenyl
<1
16
40d
12
13
14
15
FeCl3
FeCl3
FeCl3
FeCl3
2-methoxyphenyl
3-methoxyphenyl
4-methoxyphenyl
4-fluorophenyl
36
18
23
19
18
13
33
10
7d
18d
16
17
18
19
FeCl3
FeCl3
FeCl3
FeCl3
1-naphthyl
35
0
0
0
9
0
2-methyl-1-naphthyl
4-methoxybenzyl
allyl
38
0
a Ratio of Grignard reagent to CH2Cl2 = 1:12.5, [Fe] loading = 2.5 mol%.
b Taken from Table 1.
c Taken from Table 2.
d Microwave-assisted, 100 °C, 10 min.
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Acknowledgment
We thank Memorial University, the Natural Sciences and Engineer-
ing Research Council of Canada, the Canada Foundation for Inno-
vation and the Government of Newfoundland and Labrador for
funding. We are grateful to Prof. F. M. Kerton for use of the GC–
MS instrument.
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Synlett 2011, No. 6, 852–856 © Thieme Stuttgart · New York

856
X. Qian, C. M. Kozak
LETTER
(19) General Experimental Conditions: Unless otherwise
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stated, all manipulations were performed under an
atmosphere of anhyd oxygen-free nitrogen by means of
standard Schlenk or glove box techniques. Dichloromethane
was purified using an MBraun Solvent Purification System.
Reagents were purchased from Aldrich, Alfa Aesar or Strem
and used without further purification. Grignard reagents
were titrated prior to use and analyzed by GC–MS after
being quenched with dilute HCl (aq) to quantify biaryl
complexes or other impurities present prior to their use in
catalyst runs. Complex 1 was prepared according to the
previously published procedure.14 Anhydrous FeCl3 (97%)
from Aldrich was used for the synthesis of 1 and for cross-
coupling catalysis experiments.
General Conditions for Room-Temperature Reactions;
For 2.5 mol% [Fe] Loading with a 12.5-Fold Excess of
CH2Cl2 to ArMgBr (Table 1, Entry 2): Complex 1 (50.1
mg; 0.1 mmol of Fe) was added to a flask and dissolved in
CH2Cl2 (4.24 g, 3.2 mL, 50 mmol). To this stirred solution
was added o-tolylmagnesium bromide (4.0 mL, 1.0 M in
THF, 4.0 mmol). The reaction mixture was stirred for 30
min, after which time it was quenched by adding HCl (2.0
M, 5.0 mL) and filtered through a 10 cm silica column. The
products were detected and quantified using GC–MS
(relative to standard curves) with dodecane as the internal
standard. Reported yields were confirmed by 1H NMR on
isolated product mixtures. Complete separation of products
A and B was not possible given their structural similarity,
hence the NMR spectra consistently showed contamination
with minor products. Yields are reported with respect to
Grignard reagent. Since the Grignard reagents are obtained
in THF or Et2O solutions, the addition of Grignard is
concomitant with the addition of solvent, e.g. 4.0 mmol of a
1.0 M o-tolylmagnesium bromide solution results in the
addition of 4.0 mL THF to the reaction.
Catalytic Method for Microwave Heating: In a glove box,
1 (25.0 mg, 0.05 mmol) or FeCl3 (8.1 mg, 0.05 mmol) and a
magnetic stir bar were added to a BiotageTM microwave vial,
which was sealed with a septum cap. To this vial was
injected CH2Cl2 (2.13 g, 25.0 mmol), followed by slow
injection of the Grignard reagent (2.0 mmol). The mixture
was heated in a Biotage InitiatorTM Microwave Synthesizer
using the following parameters: time = 10 min; temperature
= 100 °C; prestirring = off; absorption level = high; fixed
hold time = on. Upon completion, dodecane (1.9 mmol) was
added to the mixture followed by 1 M HCl (aq; 5 mL). The
product yields were quantified by GC–MS and for high-
yielding reactions by 1H NMR as described for the general
method.
(13) Nishii, Y.; Wakasugi, K.; Tanabe, Y. Synlett 1998, 67.
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(15) It is proposed that the Grignard serves to form reduced iron
species that act as catalyst, therefore yields based on
Grignard used do not take into consideration the quantity of
Grignard consumed by reduction of Fe(III). The presence of
biaryls resulting from homocoupling of the Grignard
reagents are commonly observed in the GC–MS chromato-
grams of the reactions, however, the quantity of homo-
coupled product varies considerably with the nature of the
nucleophile.
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Synlett 2011, No. 6, 852–856 © Thieme Stuttgart · New York

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