Iron-catalyzed direct α-arylation of ethers with azoles

Article abstract of DOI:10.1039/c5cc05005g

The direct α-arylation of cyclic and acyclic ethers with azoles has been achieved, which features a novel iron-catalyzed cross-dehydrogenative coupling (CDC) process. This practical oxidative method allowed the efficient C2-alkylation of a variety of (ben

Full text of DOI:10.1039/c5cc05005g

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: A. Correa, B. Fiser
and E. Gomez, Chem. Commun., 2015, DOI: 10.1039/C5CC05005G.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/chemcomm

Please do not adjust margins
ChemComm
Page 1 of 4
View Article Online
DOI: 10.1039/C5CC05005G
ChemComm
COMMUNICATION
Iron‐Catalyzed Direct α‐Arylation of Ethers with Azoles
Arkaitz Correa,*a Béla Fiserb and Enrique Gómez‐Bengoab
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
The direct α‐arylation of cyclic and acyclic ethers with azoles has been
achieved featuring a novel iron‐catalyzed cross‐dehydrogenative coupling
(CDC) process. This practical oxidative method allowed the efficient C2‐
alkylation of a variety of (benzo)azoles constituting a straightforward
access to heterocycles of utmost medicinal significance and highlighting
the convenient use of feedstock substrates and iron catalysis. Preliminary
mechanism supported by DFT calculations is discussed as well.
A) Previous work
Cu cat.
K2S2O8
route a
H
HetAr
OR1
R2
TBHP
HetAr
+
H
route b
Ir cat.
Na2S2O8
R2
OR1
route c
B) This work (route d)
Since the end of the last century sustainable development
constitutes a matter of genuine concern for our society and
scientific community. As a result, “Green Chemistry” represents one
of the key factors for scientists when designing new chemical
processes.1 In this respect, the use of ethers such as
tetrahydrofuran (THF) and related derivatives as important raw
chemicals for the construction of more complex molecules of
pharmaceutical interest has recently received a great deal of
attention.2 Indeed, direct functionalization of molecules containing
C(sp3)–H bonds stands out today as one of the most challenging and
relevant areas in modern organic chemistry offering numerous
attractive advantages such as reducing the reliance on existing
functional groups while improving atom economy and energy
efficiency.3 The last years have witnessed a blooming of the Cross‐
Dehydrogenative Couplings (CDCs) involving the use of catalytic
amounts of first‐row transition metals.4 Based on their low‐price,
readily availability, and environmentally friendly character iron
salts5 constitute potentially ideal catalysts which offer attractive
advantages in this particular area of expertise. Despite the
impressive achievements, the assembly of new C–C linkages based
upon iron‐catalyzed C(sp3)–H functionalization events are still rare
in the literature.6
OR2
OR2
R3
N
N
X
Iron cat.
R1
R1
H
H
+
R3
X
tBuOOR
X = S, O, NCO2Et
Cheap chemicals
User-friendly protocol
Scheme 1 Direct α‐arylation of cyclic and acyclic ethers with
azoles.
liquid crystals and fluorescent dyes.7 Accordingly, C–H
functionalization of azoles is an active area of research which
provides simple and rapid access to a plethora of valuable
functionalized heterocyclic cores. Whereas arylation, alkenylation,
alkynylation and amination processes of azole derivatives have
been widely explored,8 the direct alkylation stills represents a
challenge.9 N‐Tosylhydrazones10 and carboxylic acids11 are among
the most common coupling partners to perform C2‐alkylation
reactions of azoles. Nevertheless, the most straightforward and
convenient approach involves the use of non‐functionalized ethers
via the addition of in situ generated α‐oxyalkyl radical species to
heteroarenes generally referred as the Minisci reaction.12 Such
processes are of prime importance within medicinal chemistry and
have been accomplished with both copper13a and photoredox
iridium catalyst13b and even under metal‐free conditions.13c While
efficient and elegant procedures, they still suffer from certain
limitations such as the restricted use of (benzo)thiazoles (route a),
isoquinolines and pyridines (route c) or harsh reaction conditions
like using 4.0 equiv. of oxidant at high temperatures (route b). In
this context, we envisioned whether the use of iron salts would
facilitate the development of a complementary and advantageous
strategy for the C2‐alkylation of azoles with a relatively broader
scope and operational simplicity. In fact, iron complexes are known
to react with alkyl peroxides to generate organic radical species
Azoles are prevalent key motifs in a myriad of biologically active
compounds, agrochemicals and organic functional materials such as
a. Department of Organic Chemistry I, University of the Basque Country (UPV/EHU),
Joxe Mari Korta R&D Center, Avda. Tolosa 72, 20018 Donostia‐San Sebastián
(Spain). E‐mail: arkaitz.correa@ehu.es.
b. Department of Organic Chemistry I, University of the Basque Country (UPV/EHU),
P.O. Box 1072, 20080 Donostia‐San Sebastián (Spain)
† Electronic Supplementary Information (ESI) available. See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
Chem. Commun.,2015 | 1
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 2 of 4
COMMUNICATION
Journal Name
Table 2 Iron‐catalyzed CDC of azoles 1a‐l with THF.a,b
DOI: 10.1039/C5CC05005G
View Article Online
Table 1 Optimization of reaction conditions for the iron‐catalyzed
CDC of 1a with THF.a,b
a
Reaction conditions:
1
(0.5 mmol), FeF2 (10 mol%), TBHP (1.0
equiv, 5.0‐6.0 M in decane) in a mixture 2a:DCE (1:1, 1.0 mL) at
b
90 ºC for 24 h under argon. Yield of isolated product after
column chromatography, average of at least two independent
runs. c TBHP (2.0 equiv) using 2a (1.0 mL). d tBuOOBz (2.0 equiv)
using 2a (1.0 mL).
a Reaction conditions: 1a (0.5 mmol), 2a (1.0 mL), metal salt (10
evidenced that both iron catalyst and peroxide were critical for
success (Table 1, entries 15‐16).
mol%), oxidant (2.0 equiv) at 90 ºC for 24 h under argon. b Yield
c
of isolated product after column chromatography. TBHP (1.0
equiv) using 2a (0.5 mL) in 1,2‐dichloroethane (0.5 mL). d under
e
air. 80 ºC. TBHP = tert‐butyl hydroperoxide (5.0‐6.0 M in
Having identified the optimal reaction conditions, we next focused
on examining the preparative scope and generality of our iron‐
catalyzed direct arylation event. As shown for 3a‐f, moderate to
good yields were obtained when differently substituted
benzothiazoles were utilized. Noteworthy, electron‐deficient
derivatives provided lower yields since full conversion was not
achieved. Importantly, several functional groups were
accommodated such as ester (3c), amide (3d), halides (3b, 3e), and
ethers (3f). Strikingly, strongly coordinating nitrogen motif in 3d did
not interfere in the coupling, which reveals a low Lewis acidity, if
any, of our catalyst system. Of particular importance is the
compatibility with the presence of halides which provides additional
functionalization opportunities via cross‐coupling techniques.
Notably, the method was found applicable to the use of non‐
benzofused thiazoles (3g‐h) and benzimidazoles (3i), albeit the
products were obtained in moderate yields. When benzoxazole
derivatives were submitted to the optimized conditions, the desired
products were not detected. Gratifyingly, minor modifications on
the reaction conditions such as replacing the use of TBHP by tert‐
butyl peroxybenzoate allowed for the efficient coupling of several
benzoxazoles (3j‐l).17 In these cases, less basic benzoate species are
generated by homolytic cleavage of the oxidant and hence the
decane); TBHP aq = 70 wt% tBuOOH in H2O.
which can further act as powerful oxidizing agents.14 Herein we
describe a novel CDC of (benzo)azoles and ethers featuring the
efficient use of a combination of FeF2 and organic peroxides as
oxidant.
We initially selected the direct coupling of benzothiazole (1a) and
tetrahydrofuran (THF, 2a) as the model system to evaluate the
feasibility of our approach. We anticipated that the nature of the
metal source and oxidant would have a profound impact on
reactivity and accordingly the effect of such variables was
systematically examined.15 To our delight, the target CDC event
took place in a remarkable 51% yield when utilizing a combination
of FeF2 and tert‐butyl peroxybenzoate at 90 ºC (Table 1, entry 6).
Further screening of the oxidants clearly revealed that TBHP was
the best choice while other common oxidants were much less
effective (Table 1, entries 1‐8). It is worth noting that the process
was found compatible with the use of an aqueous solution of TBHP,
albeit the product was obtained in comparatively lower yield (entry
8). Importantly, the catalytic activity was highly dependent of the
counteranion and the use of other fluoride salts seemed to have a
crucial effect on the reaction outcome. FeF3 was found as efficient
as FeF2 (entry 12), but other iron sources (entries 9‐11) as well as
other fluoride metal salts (entries 13‐14) provided lower yields.15
Remarkably, the yield was dramatically improved when reducing
the amount of THF and adding 1,2‐dichloroethane as co‐solvent.
Under those conditions the amount of oxidant could be importantly
reduced to 1.0 equivalent and 3a was obtained in 80 % yield (entry
17). The performance of the process under air atmosphere was
detrimental for the reaction, although 3a was obtained in 62%
yield. The addition of other additives or variation of the
temperature was found ineffective to improve the catalyst
performance.15‐16 Additionally, several control experiments
corresponding coupling product can be satisfactorily obtained,18
a
significant improvement comparing to the parent Cu‐catalyzed
process.13a
Aside from THF, other related cyclic and acyclic ethers are
commonly used as solvents in chemical processes as well as
prevalent key structures in a wide range of valuable compounds. Of
particular interest is 1,3‐dioxolane given that its coupling would
provide a masked formyl derivative through a practical and
aldehyde‐free synthetic protocol. Accordingly, we next explored the
scope of our iron‐catalyzed heteroarylation process regarding the
ether coupling partner. As shown in Table 3, a wide variety of
2 | J. Name., 2012, 00, 1‐3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 4
ChemComm
Please do not adjust margins
Journal Name
COMMUNICATION
View Article Online
Table 3 Iron‐catalyzed CDC of azoles with other ethers.a,b
DOI: 10.1039/C5CC05005G
GR = -82.9
tBuOOH
tBuO
R3
N
R3
N
FeF2 (10 mol%)
O
R1
H
H
R1
+
H
OR2
X
OR2
TBHP (1.0 equiv)
DCE, 90 ºC
24 h
X
FeF2
FeF2(OH)
1
2
3m-x
tBuOH
1a
OH
O
R
N
S
O
N
O
N
3a
O
O
O
O
O
O
O
R
GR = -11.5
82% (9:1)c (R = H, 3m)
72% (R = NHBz, 3n)
64% (R = CO2tBu 3o)
76% (9:1)c,d (R = F, 3p)
72% (85:15)c,e (R = H, 3q)
63% (85:15)c,e (R = Me, 3r)
3s
77%e (3t)
GR = -82.1
OH
H2O
II
GR = -4.8
I
62% (6:4)c,e (R = Cl,
)
Scheme 3 Proposed mechanism
OMe
O
N
Ar
Ar
O
+
OMe
OMe
conversion of the azole and just traces of the product were
detected. These experimental evidences tentatively support a
radical pathway. Notably, subsequent competition experiments
with benzoxazole 1j utilizing an equimolecular mixture of THF/THF‐
d8 showed a significant kinetic isotopic effect (kH/kD = 3.18) thus
suggesting that the C(sp3)–H bond cleavage with concomitant
formation of an α‐oxyalkyl radical is likely the rate‐determining
step. In order to clarify the role of the iron catalyst, Sc(OTf)3,
Bi(OTf)3 and AlCl3 were used instead and the coupling product 3a
was obtained in much lower yields; hence FeF2 is unlikely acting as a
simple Lewis acid.15,21 Based on the above results, a plausible
mechanism supported by DFT studies is outlined in scheme 3.
Initially, FeF2 facilitates the homolytic cleavage of the starting
oxidant to form the hydroxyde and tert‐butoxy radical species
under heating conditions.6b,22 Computational data confirm that the
homolytic cleavage of tBuOOH is a highly endergonic process, with
an uphill Gibbs Free energy of 5.1 kcal/mol and Fe catalyst helps
stabilizing the arising radical species by formation of a very stable
Fe(III) complex, which lies ca. 80 kcal/mol lower in energy than the
starting reactants. Next, the C(sp3)–H adjacent to the oxygen atom
of THF can be abstracted by tert‐butoxy radical species to furnish I,
with an activation energy of only 12.5 kcal/mol,23 and further
oxidized through a SET event to the corresponding oxonium cation
II by FeF2(OH), lying ca. 5 kcal/mol lower in energy than the sum of
the starting Fe(III) complex and radical species.24 Finally, the
hydroxyde anion is basic enough to easily deprotonate the azole 1a,
with a low activation energy of only 2.6 kcal/mol, which eventually
reacts with oxonium ion II through an extremely favorable process
(ΔGR = ‐82.1 Kcal/mol).25 On balance then, we assume that FeF2
plays a key redox role to assist both the heterolytic cleavage of the
oxidant and the oxidation of the carbon radical I to oxonium ion II.
S
O
R
59%d (R = H, 3u)
74% (7:3)e (Ar = benzothiazole, 3w:3w')
51%d (R = OMe, 3v)
63% (8:2)e (Ar = 6-fluorobenzothiazole, 3x:3x')
a
Reaction conditions:
1 (0.5 mmol), FeF2 (10 mol%), TBHP (1.0
equiv, 5.0‐6.0 M in decane) in a mixture 2a:DCE (1:1,1.0 mL) at
90 ºC for 24 h under argon. Yield of isolated product after
b
column chromatography, average of at least two independent
runs. c Ratio of C2 vs C4 isomer. d TBHP (2.0 equiv) using
2 (1.0
mL). e tBuOOBz (2.0 equiv) using
2 (1.0 mL).
differently substituted benzothiazoles and benzoxazoles smoothly
underwent the coupling with 1,3‐dioxolane to afford the
corresponding acetal derivatives in good yields (3m‐s). Remarkably,
1,3‐dioxolane reacted selectively at C2 position versus the less
reactive C4 atom providing 3n and 3o as a single isomer. However,
in most cases both isomers were detected with high regioselectivity
(up to 9:1); whereas the products 3m and 3p bearing benzothiazole
core were easily separated by column chromatography,
benzoxazole derivatives 3q‐3s were isolated as inseparable
mixtures of both isomers (regioselectivity up to 85:15 determined
1
by H NMR spectroscopy). Interestingly, 1,4‐dioxane could also be
utilized to furnish the corresponding coupling products in moderate
to good yields (3t‐v). Noteworthy, the acyclic ether 1,2‐
dimethoxyethane also underwent the target reaction at both the
methylene and methyl sites with good combined yields and high
regioselectivities (up to 8:2; 3w:3w’ and 3x:3x’). Unfortunately,
other coupling partners such as dibutyl ether and ethanol or less
acidic heterocycles such as 1,2,3‐triazoles and indole were found
unreactive under our optimized conditions.
N
FeF2 (10 mol%)
H
H
+
O
Ph
TBHP (1.0 equiv)
1,1-diphenylethylene
(1.0 equiv)
S
O
In summary, we have developed a novel catalytic approach to the
direct α‐heteroarylation of cyclic and acyclic ethers with azoles. This
practical and environmentally friendly protocol highlights the
advantageous use of iron salts and cheap feedstock substrates
Ph
2a
1a
4 (10%)
DCE, 90 ºC
24 h
Me
N
while featuring
a dual C–H bond oxidative cross‐coupling.
FeF2 (10 mol%)
3j
+
[D]-3j
H
Furthermore, the method was found applicable to the assembly of
a wide variety of functionalized heterocycles of paramount
medicinal importance and represents an attractive, yet
complementary, strategy for the C–H alkylation of azoles. We
anticipate that our experimental and computational studies could
lead to new knowledge in catalyst design, thus opening up new
vistas in iron‐catalyzed C–H functionalization events.
tBuOOBz (2.0 equiv)
THF/THF-d8 (1:1)
90 ºC, 24 h
O
61%
KH/KD = 3.18
1j
Scheme 2 Control experiments.
Although a detailed mechanistic picture clearly requires further
studies, several control experiments as well as DFT studies15,19 were
performed to gain some insights into the reaction mechanism. The
CDC event was entirely suppressed upon addition of radical
scavengers such as BHT and 1,1‐diphenylethylene; interestingly, in
the latter case the coupling product 4 was isolated instead in 10%
yield.20 Besides, the addition of TEMPO results in very low
We thank MINECO for a Ramón y Cajal research contract (RYC‐
2012‐09873) and FP7 Marie Curie Actions of the European
Commission via the ITN ECHONET network (MCITN‐2012‐316379)
for financial support. We also thank SCAB from SGIker of UPV/EHU
for technical support and allocation of computational resources.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 3
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 4 of 4
COMMUNICATION
Journal Name
11 Selected references: (a) A. Voutchkova, A. Coplin, N. E.
Prof. J. M. Aizpurua is kindly acknowledged for providing equipment
and laboratory facilities.
View Article Online
Leadbeater and R. H. Crabtree, Chem.DCOoI:m10m.1u0n39.,/C250C0C80, 56030152G;
(b) F. Zhang and M. F. Greaney, Angew. Chem. Int. Ed., 2010,
49, 2768‐2771; (c) K. Yang, C. Zhang, P. Wang, Y. Zhang and
H. Ge, Chem. ‐ Eur. J., 2014, 20, 7241.
Notes and references
12 M. A. J. Duncton, Med. Chem. Commun., 2011, 2, 1135.
13 (a) Z. Xie, Y. Cai, H. Hu, C. Lin, J. Jiang, Z. Chen, L. Wang and Y.
Pan, Org. Lett., 2013, 15, 4600; (b) J. Jin, and D. W. C.
MacMillan, Angew. Chem. Int. Ed., 2015, 54, 1565; (c) T. He,
1
(a) P. Anastas and N. Eghbali, Chem. Soc. Rev., 2010, 39, 301;
(b) K. Sanderson, Nature News, 2011, 469, 18; (c) R. A.
Sheldon, Chem. Soc. Rev., 2012, 41, 1437.
L. Yu, L. Zhang, L. Wang and M. Wang, Org. Lett., 2011, 13
,
2
For selected examples, see: (a) Y. Zhang and C.‐J. Li, J. Am.
Chem. Soc., 2006, 128, 4242; (b) Z. Li, R. Yu and H. Li, Angew.
Chem. Int. Ed., 2008, 47, 7497; (c) D. Liu, C. Liu, H. Li and A.
Lei, Angew. Chem. Int. Ed., 2013, 52, 4453; (d) W.‐T, Wei, M.‐
B. Zhou, J.‐H. Fan, W. Liu, R.‐J. Song, Y. Liu, M. Hu, P. Xie and
J.‐H. Li, Angew. Chem. Int. Ed., 2013, 52, 3638; (e) M. Wan, Z.
5016.
14 (a) C. Sheu, S. A. Richert, P. Cofre, B. Ross, A. Sobkowiak, D.
T. Sawyer and J. R. Kanofsky, J. Am. Chem. Soc., 1990, 112
,
1936; (b) D. T. Sawyer, A. Sobkowiak and T. Matsushita, Acc.
Chem. Res. 1996, 29, 409; (c) P. Stavropoulos, R. Celenligil‐
Cetin and A. E. Taper, Acc. Chem. Res., 2001, 34, 745 and
references cited therein.
Meng, H. Lou and L. Liu, Angew. Chem. Int. Ed., 2014, 53
,
13845; (f) L. Zhou, S.Tang, X. Qi, C. Lin, K. Liu, C. Liu, Y. Lan
and A. Lei, Org. Lett., 2014, 16, 3404.
15 For more details see the supporting information.
16 All attempts to use iodide sources such as
tetrabutylammonium iodide, sodium iodide or potassium
iodide were unsuccessful. Besides, the addition of supporting
ligands such as DMEDA, TMEDA or phen was detrimental for
the catalyst performance.
17 This distinct reactivity profile of benzothiazole vs
benzoxazole could be attributed to the higher acidity of the
latter and its tendency to open up under basic conditions.
18 When using tBuOOBz as oxidant, benzoic acid was observed
as side‐product, which was easily eliminated upon basic
workup of the reaction crude prior to chromatographic
purification.
3
4
(a) K. Godula and D. Sames, Science, 2006, 312, 67; (b) C‐H
Activation (Ed.: J.‐Q. Yu and Z. Shi) Topics in Current
Chemistry, Vol. 292; Springer‐Verlag: Berlin 2010; (c) C. Liu,
H. Zhang, W. Shi and A. Lei, Chem. Rev., 2011, 111, 1780.
For reviews, see: (a) C.‐J. Li, Acc. Chem. Res., 2009, 42, 335;
(b) C. J. Scheuermann, Chem. ‐ Asian J., 2010, 5, 436; (c) C. S.
Yeung and V. M. Dong, Chem. Rev., 2011, 111, 1215; (d) S. A.
Girard, T. Knauber and C.‐J. Li, Angew. Chem. Int. Ed., 2014,
53, 74. For recent achievements in metal‐free CDC events,
see: (e) X.‐F. Wu, J.‐L. Gong and X. Qi, Org. Biomol. Chem.,
2014, 12, 5807.
5
For general reviews, see: (a) C. Bolm, C.; J. Legros, J. Le Paih
and L. Zani, Chem. Rev., 2004, 104, 6217; (b) A. Fürstner and
R. Martin, Chem. Lett., 2005, 34, 624; (c) A. Correa, O.
19 DFT studies were carried out using the M06 functional as
implemented in Gaussian 09 and the 6‐311++G** basis sets
(SDD for Fe).
García‐Mancheño and C. Bolm, Chem. Soc. Rev., 2008, 37
,
20 Compound
4 has been previously isolated in other processes
1108; (d) Iron Catalysis: Fundamentals and Applications (Ed.:
B. Plietker) Topics in Organometallic Chemistry, Vol. 33;
Springer Verlag: Berlin, 2011; (e) I. Bauer and H.‐J. Knölker,
Chem. Rev., 2015, 115, 3170. For early reports on the use of
iron salts in the cross‐coupling arena, see for example: (f) M.
Tamura and J. K. Kochi, J. Am. Chem. Soc., 1971, 93, 1487; (g)
involving the formation of radical species, see: (a) R. P.
Pandit and Y. R. Lee, Adv. Synth. Catal., 2014, 356, 3171; (b)
Ref. 2c. For selected CDC events between olefins and C(sp3)–
H bonds, see: (c) K. Cheng, L. Huang and Y. Zhang, Org. Lett.,
2009, 11, 2908; (d) G. Majji, S. Guin, S. K. Rout, A. Behera and
B. K. Patel, Chem. Commun., 2014, 50, 12193; (e) D. Liu, C.
Liu, H. Li and A. Lei, Chem. Commun., 2014, 50, 3623; (f) Y.
M. Tamura and J. K. Kochi, J. Organomet. Chem. 1971, 31
,
289.
Zhu and Y. Wei, Chem. Sci., 2014, 5, 2379.
6
For a general review, see: (a) C.‐L. Sun, B.‐J. Li and Z.‐J. Shi,
Chem. Rev., 2011, 111, 1293. For selected papers, see: (b) Z.
Li, L. Cao and C.‐J. Li, Angew. Chem. Int. Ed., 2007, 46, 6505;
(c) Y.‐Z. Li, B.‐J. Li, X.‐Y. Lu, S. Lin and Z.‐J. Shi, Angew. Chem.
Int. Ed., 2009, 48, 3817; (d) H. Li, W. Li, W. Liu, Z. He and Z. Li,
Angew. Chem. Int. Ed., 2011, 50, 2975; (e) X.‐H. Yang, W.‐T.
Wei, H.‐B. Li, R.‐J. Song and J. H. Li, Chem. Commun., 2014,
50, 12867; (f) S. Murru, C. S. Lott, F. R. Fronczek and R. S.
Srivastava, Org. Lett., 2015, 17, 2122.
21 J. I. Padrón and V. S. Martín, Top. Organomet. Chem., 2011,
33, 1.
22 (a) H. B. Dunford and J. S. Stillman, Coord. Chem. Rev., 1976,
19, 187; (b) L. Regine and L. Marnett, J. Am. Chem. Soc.,
1989, 111, 6621; (c) Y. Zhang and C.‐J. Li, Eur. J. Org. Chem.
2007, 4654; (d) S. Pan, J. Liu, H. Li, Z. Wang, X. Guo and Z. Li,
Org. Lett., 2010, 12, 1932.
23 Radical I will be probably involved in an equilibrium between
its free form and a Fe(III)‐OtBu complex by combination with
the Fe(II) catalyst, thus compromising the availability of the
free radical. See Ref. 15.
7
8
(a) R. E. Martin, L. G. Green, W. Guba, N. Kratochwil and A.
Christ, J. Med. Chem., 2007, 50, 6291; (b) J. Easmon, G.
Pürstinger, K.‐S. Thies, G. Heinisch and J. Hofmann, J. Med.
Chem. 2006, 49, 6343; (c) I. K. Mangion, B. D. Sherry, J. Yin
and F. J. Fleitz, Org. Lett., 2012, 14, 3458.
24 Computational data confirm the experimentally observed
distinct reactivity profile of FeCl2 and FeF2. Whereas FeCl2
could also facilitate the homolytic cleavage of tBuOOH
through a favourable process (ΔGR = ‐111.1 Kcal/mol), the
(a) I. V. Seregin and V. Gevorgyan, Chem. Soc. Rev., 2007, 36
,
1173; (b) L. Ackermann, R. Vicente and A. R. Kapdi, Angew.
Chem. Int. Ed., 2009, 48, 9792; (c) T. W. Lyons and M. S.
Sandford, Chem. Rev. 2010, 110, 1147; (d) K. Hirano and M.
Miura, Synlett, 2011, 294; (e) T. Brückl, R. D. Baxter, Y.
Ishihara and P. S. Baran, Acc. Chem. Res., 2011, 45, 826.
For selected examples, see: (a) X. Zhao, G. Wu. Y. Zhang and
J. Wang, J. Am. Chem. Soc., 2011, 133, 3296; (b) T. Yao, K.
Hirano, T. Satoh and M. Miura, Angew. Chem. Int. Ed., 2012,
51, 775.
subsequent oxidation of intermediate
I to oxonium ion II
remains a rather unfavourable pathway when using FeCl2
(ΔGR = 47.0 Kcal/mol).
25 At this stage the intermediacy of a radical into the azole
derivative and subsequent C–C bond formation through
9
termination of such species and intermediate
I cannot be
entirely ruled out. However, it remains unlikely given the fact
that bisheteroaryl compound resulting from the
corresponding homocoupling was never detected.
10 (a) J. Barluenga and C. Valdés, Angew. Chem. Int. Ed., 2011,
50, 7486; (b) Z. Shao and H. Zhang, Chem. Soc. Rev., 2012,
41, 560.
4 | J. Name., 2012, 00, 1‐3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins