Iron-catalyzed reductive radical cyclization of organic halides in the presence of NaBH4: Evidence of an active hydrido iron(I) catalyst

Article abstract of DOI:10.1002/anie.201200589

Iron made'em: Iron(II) complexes such as FeCl₂ and [FeCl ₂(dppe)₂] (dppe=1,2-bisdiphenylphosphinoethane) are efficient precatalysts for the radical cyclization of unsaturated iodides and bromides in the presence of NaBH₄ (see scheme). Cyclic voltammetry studies suggests that the reaction occurs through a radical mechanism via an anionic hydrido iron(I) species as the key intermediate for the activation of the substrates by electron transfer. Copyright

Full text of DOI:10.1002/anie.201200589

Angewandte
Chemie
DOI: 10.1002/anie.201200589
Iron Catalysis
Iron-Catalyzed Reductive Radical Cyclization of Organic Halides in
the Presence of NaBH4: Evidence of an Active Hydrido Iron(I)
Catalyst**
Audrey Ekomiꢀ, Guillaume Lefꢁvre, Louis Fensterbank,* Emmanuel Lacꢂte, Max Malacria,
Cyril Ollivier,* and Anny Jutand*
Radical chain reactions have become a very useful tool for
organic synthesis.[1] Organotin hydrides stand out as the
leading mediators for these processes. However, organotin
hydrides generate toxic by-products that are extremely
difficult to remove at trace level.[2] Currently, an actively
pursued goal in radical chemistry is the discovery of
alternatives to tin hydride mediators.[3–5] Hydrides of other
Scheme 1. Iron(II)-mediated reductive cyclization of 3-iodo-2-(allyloxy)-
tetrahydropyran in the presence of NaBH4.
main-group elements including silicon,[3a] boron,[3c,4e–h]
gallium,[4b] and indium[4a–d] as well as hydrides of transition
metals have been examined.[6]
In this context, we became interested in exploring the
reactivity of iron hydrides. Iron is abundant, cheap, and has
low toxicity. Although organoiron catalysis is a very active
field,[7] iron hydride radical chemistry is still in its infancy.[8]
Iron is known to accommodate low oxidation states,[9–12] and
thus we decided to investigate iron(II) catalysts in the
presence of NaBH4 for the direct reduction and cyclization
of organic halides. The mechanism of the reaction was
investigated by means of electrochemistry (Scheme 1).
In a typical experiment, a solution of iodoalkene 1a in
acetonitrile (0.5m) was treated with FeCl2 (10 mol%) and
NaBH4 (1.5 equivalents) at 508C under argon for 16 hours;
the bicyclic product 2a was isolated in 73% yield (Scheme 2).
Control experiments with 1a confirmed that both the iron salt
and NaBH4 were required for the transformation.
Scheme 2. Optimization of reaction conditions for the FeCl2-mediated
cyclization of iodoalkene 1a in the presence of NaBH4.
moderate yields, respectively (Table 1, entries 1 and 2). A
small amount of unsaturated acetal 2c’ was formed together
with the expected product 2c.[13] Primary iodoalkene 1d gave
the 5-exo product 2d (70%; Table 1, entry 3). The
O-homoallyl derivative 1e gave the 6-exo product 2e
(Table 1, entry 4), which was obtained in relatively low
yield, together with the directly reduced compound 2e’, thus
showing, as expected, that the 6-exo-trig cyclization is less
favored than the 5-exo-trig cyclization.[14] The iodoalkyne 1 f
gave 2 f through a 5-exo-dig cyclization (52%; Table 1,
entry 5). The method was successfully extended to the
reduction of tertiary iodide 1g (94%; Table 1, entry 6) and
aryl iodides 1h (96%; Table 1, entry 7). Similarly, the ethyl 4-
bromobutyrate 1i and 4-bromopiperidine derivative 1j gave
the reduced ethyl butyrate 2i and piperidine 2j in 85% and
84% yield, respectively, (Table 1, entries 8 and 9).[15] The
reaction of primary bromoalkene 1k and secondary bromoal-
kene 1l led to cyclopentane 2k (78%; Table 1, entry 10) and
hexahydrofuropyranyl derivative 2a (70%; Table 1, entry 11),
respectively.
Secondary iodides 1b and 1c were converted into the
corresponding bicyclic compounds 2b and 2c in good and
[*] A. Ekomiꢀ, Prof. L. Fensterbank, Dr. E. Lacꢁte,[+] Prof. M. Malacria,
Dr. C. Ollivier
Institut Parisien de Chimie Molꢀculaire (UMR CNRS 7201), UPMC
Univ-Paris 06, Sorbonne Universitꢀs
4 Place Jussieu, C. 229, 75005 Paris (France)
E-mail: louis.fensterbank@upmc.fr
cyril.ollivier@upmc.fr
G. Lefꢂvre, Dr. A. Jutand
Dꢀpartement de Chimie, Ecole Normale Supꢀrieure
UMR CNRS-ENS-UPMC 8640, 24 Rue Lhomond
75231 Paris Cedex 5 (France)
E-mail: anny.jutand@ens.fr
The generation of bicycle 2a (R’H) from 1a (RI) probably
proceeds through a mechanism involving the generation of
a radical 3 (RC) by reduction of 1a (Scheme 3), followed by
[+] Institut de Chimie des Substances Naturelles CNRS
Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex (France)
[**] We thank UPMC, ENS, CNRS, IUF (M.M. and L.F.), the Rꢀgion
Martinique (A. E.), and the Ministꢂre de la Recherche (G.L.) for
financial support. Technical assistance was generously offered by FR
2769.
=
a 5-exo-trig intramolecular attack of the radical onto the C C
bond; the resulting radical 4 (R’C) is then converted into the
reduction product R’H.
When NaBD4 was used as the stoichiometric reductant,
[D]-2a was isolated with greater than 95% incorporation of
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201200589.
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Table 1: Investigation of the reaction scope.
Entry
1
Substrate RX
Product[a]
d.r.[b]
Yield [%]
75
Scheme 4. Deuterium-labelling experiment.
80:20
À
deuterium at one of primary C H bonds (Scheme 4). In
contrast, no deuterated product was detected when the
reaction was carried out with NaBH4 in CD3CN. This rules
out any hydrogen atom transfer from the solvent and suggests
that the hydrogen atom in 2a might come from BH4À directly,
from an in situ formed derivative of BH4À, or from an iron
hydride generated by hydride transfer from BH4À (see below).
The iron species that was responsible for the reaction was
unknown. It could be either the FeII species that is added to
the reaction or a reduced derivative that is generated in the
presence of NaBH4. FeI,[9,10] Fe0,[10,11] and FeÀII[12] species have
been reported. Electrochemical techniques appeared well
suited for obtaining insight into the mechanism of the
reaction.[10,16] Indeed, iron complexes can be characterized
by their reduction/oxidation potential. Moreover, their con-
centration in solution can be quantified by their oxidation/
reduction current.[16]
60:40
60:40
2
51[c]
3
4
70:30
70
79
68:32
–
The cyclic voltammetry (CV) of FeCl2 in acetonitrile did
not give a clean voltammogram because of the lack of
stabilizing ligands. [FeCl2(dppe)2] (dppe = 1,2-bisdiphenyl-
phosphinoethane)[17] was thus tested. The reaction of 1a
(1 mmol) with [FeCl2(dppe)2] (10 mol%) and NaBH4
(1.5 equivalent) in acetonitrile was allowed to proceed for
4 hours at 508C and led to the expected product 2a in 77%
yield (Scheme 5). This result suggests that [FeCl2(dppe)2] is
a valid model catalyst for mechanistic investigation.
5
6
7
60:40
52
94
96
–
–
8
9
–
–
85[d]
84
Scheme 5. [FeCl2(dppe)2]-mediated reductive cyclization of iodoalkene
1a in the presence of NaBH4.
10
11
–
78
70
The CV of [FeCl2(dppe)2] in acetonitrile (4 mm) exhibited
an irreversible reduction peak at EpR1 = À1.47 V versus the
standard calomel electrode (SCE; Figure 1a). A broad
oxidation peak characteristic of an iron(0) species that is
adsorbed at the electrode surface was observed at O1 on the
reverse scan (Figure 1a). The reduction peak of [FeCl2-
(dppe)2] (EpR1 = À1.47 V) disappeared upon addition of
NaBH4 (1 equivalent) and a new reduction peak was
observed at EpR2 = À1.99 V. The new peak was assigned to
the reduction peak of the 18 electron complex [HFeCl-
(dppe)2] by comparison to an authentic sample (Figure 1b).[17]
The latter was irreversible at the scan rate of 0.5 VsÀ1 but
became partly reversible at a higher scan rate (5 VsÀ1, see O2
at EpO2 = À1.90 V in Figure 1b). Therefore, [HFeCl(dppe)2]
undergoes a one-electron reduction to the anionic 19 electron
85:15
[a] The major diastereoisomer (as depicted) was assigned by analogy
with literature data. [b] The diastereomeric ratio was determined by
1H NMR analysis. [c] A 36:64 mixture of the product derived from the
direct reduction of 1c and a product derived from isomerization of 2c’
(8% yield overall) was also isolated. [d] Yield based on 1H NMR analysis
with sulfolene as an internal standard.
Scheme 3. Radical pathway in the reductive cyclization of 1a.
2
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transfer. A catalytic cycle is proposed for the cyclization of 1a
(Scheme 7). The passage of two electrons per mole of
substrate indicates that the cyclized radical R’C (4) is reduced
at the cathode to generate the anion R’À (5), which is then
protonated to give 2a. This mechanism is reminiscent of the
radical cyclization of unsaturated a-bromoesters by electro-
chemically generated nickel(I) complexes.[18,19]
Figure 1. Cyclic voltammetry performed at a gold disk electrode
(d=1 mm) at 228C in acetonitrile containing nBu4NBF4 (0.3m) as the
supporting electrolyte. a) Reduction of [FeCl2(dppe)2] (4 mm) at a scan
rate of 0.5 VsÀ1. b) Reduction of [HFeCl(dppe)2] (4 mm) at a scan rate
of 5 VsÀ1. c) Reduction of [HFeCl(dppe)2] (4 mm) at a scan rate of
5 VsÀ1 in the presence of increasing amounts of 1a (1 equiv, solid
line; 2, 3, and 4 equiv, dashed lines). d) Reduction of [HFeCl(dppe)2]
(4 mm), (solid line); reduction of [HFeCl(dppe)2] (4 mm) in the
presence of NaBH4 (2 mm) at a scan rate of 0.5 V.sÀ1 (dashed line).
Scheme 7. Mechanism of the electroreductive cyclization of 1a cata-
lyzed by electrogenerated [HFeICl(dppe)2]À in CH3CN.
The mechanism of the catalytic reductive cyclization
performed in the presence of the chemical reductant NaBH4
was then investigated (Scheme 5). In the presence of a stoi-
chiometric amount of [FeCl2(dppe)2] and in the absence of
NaBH4, 1a did not undergo cyclization to give 2a. In contrast,
the cyclization did occur in the presence of a catalytic amount
of [FeCl2(dppe)2] (10 mol%) and NaBH4 (1.5 equivalents;
Scheme 5). Thus, [FeCl2(dppe)2] is not the active catalyst.
Similarly, no reaction was observed between [HFeCl(dppe)2],
present in a stoichiometric amount, and 1a, thus also ruling
out [HFeCl(dppe)2] as being the active catalyst. As expected,
1a underwent cyclization in the presence of a catalytic
amount of [HFeCl(dppe)2] (10 mol%) and NaBH4 (1.5 equiv-
alents), thus delivering 2a in 63% yield (Scheme 8).
complex [HFeICl(dppe)2]À, which is oxidized at the voltage
corresponding to the O2 peak and is moderately stable within
the time scale of the CV.
Iodoalkene 1a, analyzed as a solution in acetonitrile, was
not reduced up until À2.5 V. The addition of 1a to [HFeCl-
(dppe)2] resulted in a lack of reversibility in reduction/
oxidation events at a scan rate of 5 VsÀ1 (Figure 1c). The
oxidation peak O2 of [HFeICl(dppe)2]À disappeared whereas
the reduction peak current of [HFeCl(dppe)2] at R2 increased
with increasing amounts of 1a (from one to four equivalents;
Figure 1c). From these experiments, one deduces that the
one-electron reduction of [HFeCl(dppe)2] gives the anionic
hydrido FeI complex [HFeICl(dppe)2]À which transfers one
electron to 1a to generate the radical anion 1aCÀ and
[HFeCl(dppe)2]. [HFeCl(dppe)2] again undergoes reduction
in the diffusion layer at the electrode, thus giving rise to
a catalytic-reduction current, which is observed at R2
(Figure 1c). A preparative-scale electrolysis of a solution of
1a (0.4 mmol) in the presence of [HFeCl(dppe)2] (10 mol%)
in acetonitrile (12 mL) was performed at the controlled
reduction potential of [HFeCl(dppe)2] (À2 V, Scheme 6).
After the passage of 85 Cb (2.2 F), the electrolysis gave the
expected product 2a in 50% yield.
Scheme 8. [HFeCl(dppe)2]-mediated cyclization of iodoalkene 1a in the
presence of NaBH4.
These experiments show that [HFeCl(dppe)2] only
becomes active upon its reduction by NaBH4. The addition
of NaBH4 (0.5 equivalents) to a solution of [HFeCl(dppe)2] in
acetonitrile (4 mm) resulted in an increase of the oxidation
peak of [HFeICl(dppe)2]À at O2 (Figure 1d), thus establishing
that NaBH4 transfers one electron to [HFeCl(dppe)2] to
generate the active species [HFeICl(dppe)2]À. This active
species then activates 1a by single electron transfer (SET) to
give 1aCÀ (Scheme 9), which eventually gives 2a.
Scheme 6. [HFeCl(dppe)2]-mediated electroreductive cyclization of 1a.
The formation of [D]-2a in the presence of NaBD4
(Scheme 4) suggests that the radical R’C (4), which is formed
through intramolecular cyclization, abstracts a hydrogen
atom from [HFeIICl(dppe)2] (Scheme 9, step A) to generate
2a and [FeICl(dppe)2], which then presumably reacts with
These results suggest that [HFeCl(dppe)2] is a precatalyst,
the reduction of which at the very beginning of the electrolysis
to [HFeICl(dppe)2]À allows the activation of 1a by electron
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lization of 1a (RI) to 2a (R’H) in the presence of NaBH4 in CH3CN.
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BH4 to regenerate [HFeICl(dppe)2]À (Scheme 9, step A’).
À
À
However, a direct hydrogen-atom transfer from BH4 to the
radical 4 cannot be excluded (Scheme 9, step B).[6a,20]
Overall, the results suggest that NaBH4 is involved in
a number of steps in the catalytic cycle, namely it can i) donate
hydride to [FeCl2(dppe)2] in the very first step of the catalytic
reaction, ii) donate hydride to [FeICl(dppe)2] in a catalyst-
turnover step of the catalytic cycle (step A’) if step A takes
place, iii) transfer one electron[21] to [HFeIICl(dppe)2] to
generate the key complex [HFeICl(dppe)2]À, or iv) transfer
a hydrogen atom to substrate-derived radical 4 (step B;
Scheme 9).
In conclusion, we have shown that unsaturated organic
halides undergo a radical-based cyclization in the presence of
an iron catalyst and NaBH4 as the stoichiometric reductant.
Data from electrochemical investigations suggest that the
reaction proceeds though activation of the halide substrate by
electron transfer. This electron transfer is mediated by an
anionic hydrido iron(I) species, which is generated by
reduction of the iron(II) precatalyst by NaBH4. Future work
will focus on the use of other radical precursors and the
incorporation of this inexpensive and environmentally
friendly reaction into cascade and asymmetric reactions.
Received: January 20, 2012
Revised: May 3, 2012
Published online: && &&, &&&&
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Keywords: catalysis · electrochemistry · hydrides · iron ·
radical reactions
.
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recombination mechanism involving the tertiary radical RC and
the iron(I) complex [FeICl(dppe)] for the generation of the
intermediate [RFeIICl(dppe)], which could undergo a b-elimi-
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[19] The fact that the reduction peak R2 of [HFeIICl(dppe)2] increases
upon the addition of increasing amounts of RI establishes that
[HFeIICl(dppe)2] is generated at each catalytic cycle. This rules
out an alternative mechanism involving an oxidative addition of
RI to the 15-electron complex [HFeICl(dppe)]À, which can be
formed upon dissociation of one dppe ligand from the 19-
electron complex [HFeICl(dppe)2]À. This oxidative addition
would generate [HFeIIIR(I)(Cl)(dppe)]À, which would be in
equilibrium with [HFeIIIR(Cl)(dppe)]. An intramolecular car-
=
boferration reaction of the latter involving the C C bond would
À
generate, after C H reductive elimination, the product R’H and
[FeICl(dppe)]; the latter species could then be transformed into
[HFeICl(dppe)n]À (n = 1 or 2) after reaction with NaBH4;
[FeICl(dppe)] would not be transformed into [HFeIICl(dppe)2]
because of the reducing conditions. This sequence of chemical
steps involving FeI, FeIII, and FeI species would not be consistent
with the observed behavior of the reduction peak R2 of
[HFeIICl(dppe)2].
[15] The reaction conditions were tested on 4-iodo-acetophenone
(with 1.5 equiv of NaBH4) and
a
mixture of (4-
[20] a) A. N. Abeywickrema, A. L. J. Beckwith, Tetrahedron Lett.
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IC6H4)CH(OH)Me and PhCH(OH)Me (55:45) with an overall
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Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Iron Catalysis
A. Ekomiꢁ, G. Lefꢂvre, L. Fensterbank,*
E. Lacꢃte, M. Malacria, C. Ollivier,*
A. Jutand*
&&&& — &&&&
Iron made‘em: Iron(II) complexes such
as FeCl2 and [FeCl2(dppe)2] (dppe=1,2-
bisdiphenylphosphinoethane) are effi-
cient precatalysts for the radical cycliza-
tion of unsaturated iodides and bromides
in the presence of NaBH4 (see scheme).
Cyclic voltammetry studies suggests that
the reaction occurs through a radical
mechanism via an anionic hydrido iron(I)
species as the key intermediate for the
activation of the substrates by electron
transfer.
Iron-Catalyzed Reductive Radical
Cyclization of Organic Halides in the
Presence of NaBH4: Evidence of an Active
Hydrido Iron(I) Catalyst
6
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!