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Cite this: Chem. Commun., 2011, 47, 5852–5854

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Iron oxide mediated direct C–H arylation/alkylation at a-position

of cyclic aliphatic ethersw
Parvinder Pal Singh, Satish Gudup, Srinivas Ambala, Umed Singh, Sumit Dadhwal,
Baldev Singh, Sanghapal D. Sawant and Ram A. Vishwakarma*
Received 24th February 2011, Accepted 29th March 2011
DOI: 10.1039/c1cc11094b

We report a new and efficient iron oxide catalyzed cross- FeCl3 used by us contained a substantial quantity of iron
coupling reaction between organometallic species such as hydroxide.
alkyl/arylmagnesium halides or organolithium species and With this knowledge, we were encouraged to explore a new
a-hydrogen bearing cyclic aliphatic ethers via activation of C–C bond formation to synthesize 2-substituted furans using
C(sp3)–H. This is the first example of iron oxide mediated direct iron oxide catalysis. Since many biologically active natural
C–C bond formation without expensive or toxic ligands. products are comprised of tetrahydrofuran or tetrahydro-
pyran units with substituents a to the oxygen atom,6,7 this
Metal catalyzed cross-coupling reaction for C–C bond formation reaction offers tremendous potential for introducing groups
via the activation of C(sp2)–H or C(sp3)–H is a hot topic in into the a-position of cyclic ethers that are strategically
catalysis research,1,2 attracting many research groups all over important for synthesis.
the world. Traditionally, a cross-coupling reaction involves In the last two decades, iron based catalysts5b,c,8 have drawn
two starting materials: organometallic species (RMgX or RLi) attention as cheap, nontoxic and environmentally-friendly
and organic halide (C–Y). Replacing organic halides (C–Y) materials for generation of radicals5b,c,9 as well as activation
with a C–H species would be a more efficient coupling strategy of electrophilic substrates.10 Keeping in mind the radical
receiving greater attention.3 In the last two decades, various chemistry literature of iron and recent findings regarding the
transition metals catalyzed cross-coupling reactions via the role of aluminium–vanadium oxides in C–H activation via
activation of C(sp2)–H have been developed,4 but examples of hydrogen abstraction,11–13 we envisioned that iron oxides
such cross-coupling through the activation of C(sp3)–H are could be utilized for the cross-coupling reaction of organo-
limited.5 metallic species with unactivated ethers via activation of the
In this direction, we now report a novel iron oxide catalyzed C(sp3)–H bond. Accordingly, we selected various iron salts
cross-coupling reaction between organometallic halides and viz. Fe(OH)3, FeCl3 and Fe2O3 to test the idea. We started
a-hydrogen bearing cyclic ethers such as tetrahydrofuran via this study by reaction of phenylmagnesium bromide with
direct activation of a C(sp3)–H centre. This work was guided unactivated cyclic ethers such as THF (results summarized
by an unprecedented observation in our lab on the formation in Table 1). During our study, THF was used also as a solvent.
of 2-phenyltetrahydrofuran instead of 2-phenylbutane during When we examined the reaction of phenylmagnesium bromide
a reaction of phenylmagnesium bromide with 2-bromobutane 1a with THF in the presence of 10 mol% of Fe(OH)3 at room
in the presence of TMEDA and a catalytic amount of FeCl3. temperature, the desired 2-phenyltetrahydrofuran 2a was
Recently, Yoshikai et al.5b developed an efficient iron catalyzed obtained in 40% yield together with biphenyl 3, phenol 4
C–C bond formation at the a-position of aliphatic amines via
C(sp3)–H bond activation as an unexpected finding during the Table 1 Screening of different iron based catalysts for cross-coupling
reaction of Ph2Zn and 4-iodotoluene in THF in the presence of reaction of phenylmagnesium bromide with cyclic ether THF via
activation of a-C(sp3)–H
an iron-bispyridine catalyst, yielding 2-phenyltetrahydrofuran
instead of the expected biaryl product. These findings Yields (%)a
provoked interest in us to further explore this reaction. Careful
Entry Catalyst Catalyst Qty Temp. Time (h) 2a 3 4 5
examination of catalyst used suggested that the old bottle of
a Fe(OH)3 10 mol (%) rt 8 40 10 20 5
b FeCl3 10 mol (%) rt 8 o5 8 — —
Medicinal Chemistry Division, Indian Institute of Integrative Medicine c Fe2O3 10 mol (%) rt 8 77 4 7 1
(Council of Scientific & Industrial Research), Jammu 180 001, India. d Fe2O3 10 mol (%) 0 1C 8 85 3 1 —
E-mail: ram@iiim.res.in; Fax: +91-191-2569333; e Fe2O3 10 mol (%) 10 1C 12 92 2 1 —
Tel: +91-191-2569111 f Fe2O3 10 mol (%) 70 1C 12 90 2 1 —
w Electronic supplementary information (ESI) available: 1H/13C g Fe2O3 10 mol (%) 10 1C 8 85 5 8 —
NMR, GCMS, etc. of all compounds. Tables with details of C–C h Fe2O3 1 mol (%) 0 1C 8 95 — 0.5 —
formation of alkyl Grignard reagents and aryl lithiates with aliphatic a
HPLC yield.
ethers. See DOI: 10.1039/c1cc11094b

5852 Chem. Commun., 2011, 47, 5852–5854 This journal is c The Royal Society of Chemistry 2011
 View Article Online

Table 2 Iron oxide catalyzed cross-coupling reaction of arylmagnesium

halide with THF via activation of a-C(sp3)–H
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Entry ArMgX 2 Time (h) Yield (%)a

a 5 95.08

b 5 91.70
Scheme 1 Iron oxide catalyzed cross-coupling reaction of organo-
metallic species with cyclic ether THF via activation of a-C(sp3)–H.

and bis-phenol 5 (Table 1, entry a) as byproducts (Scheme 1). c 6 89.10

The use of fresh anhydrous FeCl3 decreased the chemical yield
of 2a to less than 5% along with the formation of biphenyl 3 in
less than 8% yield (Table 1, entry b). Interestingly, the use
of 10 mol% of Fe2O3 at room temperature increased the d 6 93.20
chemical yield of 2a from 40% to 77% (Table 1, entry c).
Furthermore, we found that lowering the amount of Fe2O3
catalyst (from 10 mol% to 1 mol%) and temperature (from rt
to 0 1C) greatly affected the chemical yield of 2a (Table 1, e 5 92.32
entries d–h). For example, 1 mol% of Fe2O3 at 0 1C increased
the yield of 2a from 77% to 95% and suppressed the forma-
tion of undesired byproduct (Table 1, entry h). However,
f 6 90.92
further lowering of temperature, i.e. to 10 1C and 70 1C
did not show much improvement in the yield of 2a and a
longer reaction time was required for completion (Table 1,
entries e and f). When this reaction was attempted in the g 6 94.20
absence of Fe2O3, no product formation was observed even
after prolonged reaction. As can be seen from Table 1, the
cheap and non-hygroscopic iron oxide (Fe2O3) is the most
appropriate catalyst from the practical viewpoint. Further- h 6 91.32
more, our investigation suggested that cross-coupling reaction
of organometallic species with a-hydrogen bearing ethers via
activation of C(sp3)–H did not require expensive or toxic
ligands. i 6 95.88
Next, the reactivity of various Grignard reagents was
investigated (Table 2). Aryl Grignard reagents bearing
different substituents provided the desired products 2a–l in
moderate to excellent yields with 1 mol% of Fe2O3. Substrates j 5 95.60
possessing electron-donating (Table 2, entries c–h) and
electron-withdrawing groups (Table 2, entries i, j and k) at
the arylmagnesium halide moiety smoothly underwent cross-
coupling reaction to afford corresponding 2-phenyltetrahydro- k 5 92.84
furan in high yields. Moreover, hindered 1-naphthylmagnesium
bromide underwent cross-coupling to afford 2-naphthyltetra-
hydrofuran in good yield (Table 2, entry l). The present
approach is also applicable to both primary (Table S3, entries a, l 6 91.30
b and c, as given in Electronic Supplementary Information
(ESI)) as well as secondary aliphatic (Table S3, entry d in ESI)
organometallic species; although the yields of aliphatic
organometallic species are comparatively less as compared to All reactions carried out in THF in the presence of Fe2O3 (1 mol%).
a
Isolated yield.
aromatic organometallic species.

This journal is c The Royal Society of Chemistry 2011 Chem. Commun., 2011, 47, 5852–5854 5853

The scope of the present methodologies was also explored
with organolithium species and results are summarized in
Table S4 (in ESI). Aryl lithium species underwent cross-
coupling reaction with cyclic ether THF and gave desired
products in good to excellent yields.
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The exact mechanism of this remarkable C–C bond forma-
tion is ambiguous, but previous reports proposed a radical
process for iron mediated C–C cross-coupling reactions.14 We
speculate that there is involvement of radical intermediates
and a plausible mechanism can be visualized via the addition
of organometallic species on iron oxide, leading to generation
of organoiron species followed by abstraction of proton from
the 2-position of tetrahydrofuran to produce 2-tetrahydro-
furanyl radical. This radical and organometallic species could
then be coupled directly to generate 2-phenyltetrahydrofuran
2a. The formation of phenol 4 and bis-phenol 5 byproducts
may suggest intervention of unstable radicals or organoiron
intermediates. However, the reaction of allyl substrate was
sluggish (entry e in Table S3 of ESI) and the desired product
was obtained in very low yield along with a mixture of
unidentified products, suggesting a radical mechanism. The
results of the present methodology suggest that Fe2O3 based
intermediates help in generation of carbon radicals and
provide d-block organometallic surfaces for cross-coupling.
In summary, we have discovered a new method for cross-
coupling of organometallic species with cyclic ether THF via
activation of the C(sp3)–H bond using Fe2O3. No toxic or/and
expensive ligand is required for this metallic catalysis. Further
studies on the mechanism of this new method and its extension
to related alkyl ether substrates are in progress and will be
reported in due course.
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This journal is c The Royal Society of Chemistry 2011