Iron-catalyzed oxidative direct α-C-H bond functionalization of cyclic ethers: Selective C-O bond formation in the presence of a labile aldehyde group

Article abstract of DOI:10.1021/ol5004115

Iron catalyzed oxidative coupling of salicylaldehydes with cyclic ethers proceeded through the direct α-C-H functionalization of ethers, forming the corresponding acetals in moderate to excellent yields. This is the first example of iron catalyzed selective C-O bond formation in the presence of a sensitive aldehyde moiety.

Full text of DOI:10.1021/ol5004115

Letter
pubs.acs.org/OrgLett
Iron-Catalyzed Oxidative Direct α‑C−H Bond Functionalization of
Cyclic Ethers: Selective C−O Bond Formation in the Presence of a
Labile Aldehyde Group
Balaji D. Barve,†,‡ Yang-Chang Wu,†,§ Mohamed El-Shazly,†,∥ Michal Korinek,† Yuan-Bin Cheng,†
Jeh-Jeng Wang,*,‡ and Fang-Rong Chang*,†,⊥
†Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan
‡Department of Medicinal and Applied Chemistry, College of Life Sciences, Kaohsiung Medical University, Kaohsiung 807, Taiwan
§School of Pharmacy, College of Pharmacy, China Medical University, Taichung 404, Taiwan
∥Department of Pharmacognosy and Natural Products Chemistry, Faculty of Pharmacy, Ain-Shams University, Organization of
African Unity Street 11566, Abassia, Cairo, Egypt
⊥Translational Research Center and Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
S
* Supporting Information
ABSTRACT: Iron catalyzed oxidative coupling of salicylalde-
hydes with cyclic ethers proceeded through the direct α-C−H
functionalization of ethers, forming the corresponding acetals
in moderate to excellent yields. This is the first example of iron
catalyzed selective C−O bond formation in the presence of a
sensitive aldehyde moiety.
Scheme 1. Reported Method for C−O Bond Formation via
α-C−H Bond Functionalization of Ethers
etal catalyzed coupling reactions have become an
Mimportant tool in organic chemistry for carbon−carbon
and carbon−heteroatom bond formation.1 Pharmaceutical
drugs and complex natural products were successfully
synthesized utilizing these reactions.2 Due to the abundant
existence of C−H bonds in organic molecules, the function-
alization of these stable bonds is always a stimulating task.
Metal catalyzed direct C−H bond activation/functionalization
has emerged as a useful strategy to tackle this task.2a,b,3
Transition metal catalyzed direct α-C(sp3)−H bond function-
alization of ethers is one such reaction which has recently
attracted more attention.4
In the past few years, different Cross-Dehydrogenative-
Coupling (CDC) reactions were employed for the formation of
C−C bonds via α-C−H bond functionalization of heter-
oatoms.5 However, reports on the formation of the C−O bond
via α-C−H bond activation/functionalization of ethers are
scarce.6 In a recent successful attempt, Reddy et al. reported a
copper catalyzed construction of the C−O bond through
reacting β-ketoesters or 2-keto-substituted phenols with
ethers.6c The Phan group investigated the use of a
heterogeneous copper catalyst in promoting the reaction
between ethers and 2-carbonyl-substituted phenols.6a The 2-
keto-substituted phenols (ketone group) used in these
protocols are known to be more stable in the presence of an
oxidant and a transition metal (TM) compared with the labile
2-formyl-substituted phenols (aldehyde group). Therefore the
selective C−O bond formation in the presence of an ortho-
formyl group under oxidative conditions is still a challenging
goal (Scheme 1).
Free intact formyl functionality can be easily converted to
various functional groups and holds enormous potential
applications in organic synthesis.7 Just recently the Patel
group reported an efficient protocol for copper catalyzed O-
aroylation of phenols under oxidative conditions without
affecting the formyl moiety.8
Inspired by the unique approaches of Reddy, Phan, and Patel
along with our continuing efforts to explore new avenues in
metal catalyzed reactions,9 we report here a novel iron catalyzed
direct α-C−H bond functionalization of ethers for the
formation of C−O bonds under oxidative conditions while
selectively saving the labile formyl functionality.10 According to
our knowledge this is the first report on iron catalyzed
formation of a C−O bond via α-C−H bond functionalization of
cyclic ethers.10
Iron catalysts play an important role in organic synthesis
because they are relatively safe, inexpensive, stable, and less
Received: February 9, 2014
Published: March 17, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
a
hazardous to the environment when compared to other
transition metal catalysts.4a,c,d,5e,10 Recently, pioneering work
by Zhiping Li successfully demonstrated the applications of
iron catalysts in several cross dehydrogenative coupling
reactions including phenolic substrates.10a,d We started our
investigation through checking the reaction between salicylal-
dehyde (1a), tert-butyl hydroperoxide (TBHP, 70 wt % in
water, 6.0 equiv), and 1,4-dioxane (2a) in the presence of iron
oxide (10 mol %). Based on previous reports we assumed that
the formyl moiety in 1a will be oxidized or may undergo
subsequent reactions.11,12 However, the reaction did not
proceed (Table 1, entry 1). Fortunately, we tested another
Table 2. Oxidant Optimization
b
entry
oxidant
yield (%)
c
1
−
NR
2
DDQ
PIFA
NaIO4
H2O2
NR
de
,
3
ND
NR
4
6
trace
trace
a
Table 1. Catalyst Optimization
7
benzoquinone
Mg(ClO4)2
Oxone
e
8
NR
e
9
NR
10
11
12
13
14
15
16
MnO2
NR
NR
20%
69%
86%
NR
NR
MCPBA
di-tert-butyl peroxide
TBHP (H2O)
TBHP (decane)
m-CPBA
b
entry
catalyst
Fe2O3
yield (%)
c
1
2
3
4
5
6
7
8
9
10
NR
d
sodium chlorite
FeBr2
42
a
Reaction conditions: 1a (1.0 equiv), 1,4-dioxane (2.0 mL), Fe2(CO)9
(10 mol %), oxidant (6.0 equiv), 110 °C, 15 min. Isolated yields. No
reaction. Not detected. 3.0 equiv of oxidant were used.
Fe2(SO4)3
FeCl3
NR
b
c
de
,
ND
NR
ND
69
d
e
Fe(powder)
FeCl3·6H20
Fe2(CO)9
FeSO4·7H2O
Fe(acac)3
−
d
catalyst or an oxidant suggesting their crucial importance for
this type of transformation (Table 1, entry 10; Table 2, entry
1).
NR
d
40
The aforementioned optimization results suggested that the
highest yield of the target acetal (3a) (85%) can be obtained by
reacting 1a with 1,4-dioxane (2a) using Fe2(CO)9 (10 mol %)
as the catalyst and TBHP (6.0 equiv. 5−6 M in decane) as the
oxidant at 110 °C for 15 min. With the optimized conditions in
hand, we next explored the substrate scope of this reaction
using several ethers and different substituted salicylaldehydes
(Scheme 2). The reaction of salicylaldehydes carrying electron-
donating groups with 1,4-dioxane offered the desired acetals in
good yields (Scheme 2, 3b−3d). However, 4-methoxy
substituted salicylaldehyde yielded the corresponding acetal in
a lower yield (Scheme 2, 3e). Salicylaldehydes with electron-
withdrawing groups such as −OCF3 reacted smoothly forming
the target product in an excellent yield (Scheme 2, 3f). But this
protocol failed to deliver the corresponding acetal when the 5-
nitro-salicylaldehyde was used as the starting material (Scheme
2, 3g). Interestingly, the reaction of tetrahydrofuran (THF)
with different salicylaldehydes carrying electron-donating and
-withdrawing as well as bromo groups provided the
corresponding acetals in good to excellent yields (Scheme 2,
3h−3n). However, salicylaldehydes with 3-chloro or 5-nitro
substituents did not react with THF (Scheme 2, 3o and 3p).
This result may be due to the presence of electron-withdrawing
groups (NO2 and Cl) at meta position to the formyl group
reducing its ability to form a complex with Fe. Moreover, the
six-membered cyclic ether, tetrahydropyran, reacted smoothly
rendering the target acetals in good yields (Scheme 2, 3q and
3r). The developed methodology proved useful with other
aromatic aldehydes such as naphthaldehydes which furnished
the corresponding products in moderate to good yields
(Scheme 2, 3s and 3t). Unfortunately, the protocol was not
applicable to aliphatic ethers forming a complex mixture (3u),
which may be attributed to the competitive reaction between
NR
a
Reaction conditions: 1a (1.0 equiv), 1,4-dioxane (2 mL), catalyst (10
mol %), TBHP (70 wt % in water, 6.0 equiv), 110 °C, 15 min.
b
c
d
Isolated yields. No reaction. Trace amount of salicylic acid was
e
formed. Not detected.
iron salt and the target acetal was formed in the presence of
FeBr2 in a moderate yield along with traces of salicylic acid
(Table 1, entry 2).
Encouraged by these results, we screened different iron
catalysts aiming to improve the reaction yield (Table 1). In the
presence of FeCl3 or FeCl3·6H2O, traces of salicylic acid were
detected (Table 1, entries 4, 6). Gratifyingly, the use of
Fe2(CO)9 as a catalyst offered the target acetal in 69% yield
(Table 1, entry 7), making it the most optimum catalyst which
was utilized for further investigation. Due to the reported
sensitivity of the aldehyde group toward different oxidants, we
also screened several oxidants to check the reaction outcome
(Table 2).11 The use of aqueous TBHP (70 wt % in water, 6.0
equiv) as an oxidant resulted in the formation of 69% of the
target product (Table 2, entry 13). Replacing the aqueous
TBHP with TBHP in decane (5−6 M) resulted in a significant
increase in the product yield (85%) (Table 2, entry 14). We
also evaluated the effect of temperature, catalyst loading,
oxidant equivalent, and solvent type on the reaction yield.
Running the reaction at lower temperature, lowering the
catalyst loading, or decreasing the oxidant equivalent resulted in
a lower reaction yield (<65%). Different solvents such as
water11b,12a and 1,1,2-trichloroethane11c in 1:1 ratio (with 1,4-
dioxane) did not provide the product, while in the presence of
acetonitrile11e−g and methanol11j (with 1,4-dioxane) the target
product was formed in lower yields (<40%) along with traces of
salicylic acid. The reaction did not proceed without a metal
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Organic Letters
Letter
TEMPO to the reaction medium prevented any product
formation suggesting a radical pathway. It is proposed that the
salicylaldehyde may form a coordination complex with
iron.10,15b This complex can react with the dioxane radical
(formed following H-abstraction by a tert-butoxyl radical of
TBHP)4a,5b,6d,15a furnishing the corresponding acetal.
Scheme 2. Substrate Scope for the α-C−H Bond
a
Functionalization of Ethers
In summary, we developed a simple, efficient, and novel iron
catalyzed protocol for selective C−O bond formation without
affecting the sensitive aldehyde group in the presence of a
transition metal and an oxidant. This approach can be used for
the selective protection of hydroxyl groups by ethers.
Importantly, the products with intact aldehyde groups can be
utilized in several organic transformations. Further studies to
reveal the reaction mechanism and extend the applications of
this methodology are currently underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedure, characterization data of new products,
1H and 13C NMR copies of all the compounds are available in
Supporting Information. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: aaronfrc@kmu.edu.tw.
*E-mail: jjwang@kmu.edu.tw.
Notes
a
Reaction conditions: 1 (1.0 equiv), ether (2.0 mL), Fe2(CO)9 (10
mol %), TBHP (6.0 equiv 5−6 M, in decane), 110 °C, 15−90 min.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
the terminal methyl and the internal methylene groups. Also
heterocyclic aldehydes such as 3-hydroxy-2-pyridinecarbalde-
hyde provided traces of the target product (3v).
■
This project received generous support from the National
Science Council of Taiwan (NSC 99-2628-B-037-003-MY3)
and the Ministry of Health and Welfare of the Republic of
China (MOHW103-TD-B-111-05). The authors would like to
thank the Centre for Research Resources and Development
(CRRD), Kaohsiung Medical University for technical support
and services in LC-MS and NMR analysis.
Notably in all successful substrates, the use of an oxidant and
a transition metal led to the selective formation of a C−O bond
without affecting the sensitive formyl moiety. Moreover, no
further extraction (workup) was required for product
purification. This protocol also offers an efficient and alternative
route for the protection of the phenolic hydroxyl group as an
acetal by overcoming several drawbacks of known protection
methods.13
Using this methodology we successfully synthesized an
important pharmaceutical intermediate (3r) in a single step by
avoiding the tedious protocols which utilize resorcinol as the
starting material.14 This compound is the intermediate in the
preparation of the immunomodulatory drug, tucaresol, and its
related analogues.14 Thus, the developed protocol represents an
attractive and alternative route for the preparation of an
important intermediate in tucaresol synthesis (Scheme 3).
The reaction mechanism was investigated by running
different control experiments. Simple phenol did not react
with 1,4-dioxane suggesting the crucial importance of the ortho-
formyl group. The addition of a radical scavenger such as
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