CBr4 promoted intramolecular aerobic oxidative dehydrogenative arylation of aldehydes: application in the synthesis of xanthones and fluorenones

Article abstract of DOI:10.1039/c7ob00080d

A simple and practical carbon tetrabromide promoted intramolecular aerobic oxidative dehydrogenative coupling reaction has been developed to provide a straightforward ring closure protocol for 2-aryloxybenzaldehydes to furnish xanthones. The reaction was performed under metal-, additive- and solvent-free conditions with good tolerance of functional groups. The present method is also applicable to the synthesis of fluorenones by using 2-arylbenzaldehydes as substrates. Preliminary studies of the reaction mechanism indicated that the reaction may proceed through a radical pathway.

Full text of DOI:10.1039/c7ob00080d

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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DOI: 10.1039/C7OB00080D
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CBr4 Promoted Intramolecular Aerobic Oxidative Dehydrogenative
Arylation of Aldehydes: Applied in the Synthesis of Xanthones and
Fluorenones
Received 00th January 20xx,
Accepted 00th January 20xx
Jing Tang,a Shijun Zhao,b Yuanyuan Wei,a Zhengjun Quan,a Congde Huo,a,*
DOI: 10.1039/x0xx00000x
A simple and practical carbon tetrabromide promoted intramolecular aerobic oxidative dehydrogenative coupling reaction
has been developed to provide a straightforward ring closure protocol of 2-aryloxybenzaldehydes to furnish xanthones.
The reaction was performed under metal-, additive- and solvent-free conditions with good tolerance of functional groups.
The present method is also applicable to the synthesis of fluorenones by using 2-arylbenzaldehydes as substrates.
Preliminary Studies of the reaction mechanism indicated that the reaction may proceed through a radical pathway.
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Scheme 1. Xanthones formation from 2-aryloxybenzaldehydes
Introduction
Xanthones, an important type of oxygen-containing
heterocyclic compounds, are the core structures of many
natural products and pharmaceuticals; they are also versatile
synthetic blocks in organic synthesis.1 Therefore, the
construction of xanthone skeletons is of great importance and
synthetically attractive.2 Traditionally and most frequently, the
Friedel-Crafts acylation of arenes is a prevailing reaction for
accessing aryl ketones. However, the Friedel-Crafts ring
closures of 2-aryloxybenzoic acids or derivatives to construct
xanthone derivatives are usually limited to electron-rich
arenes or require multiple steps.3
O
H
H
O
O
∆
Ar1
Ar1
Ar2
Ar2
O
non-metal
metal
oxidant
solvent
ref 5:
ref 6:
ref 7:
PPh3
-
RhCl3
TBHP
TBHP
TBHP
O2
PhCl
MeCN
H2O
-
FeCp2
TBAB
CBr4
-
this work:
-
Since 2004, the cross-dehydrogenative coupling (CDC)
reaction, which means the direct coupling of two different C–H
bonds, has become a growing and attractive field in organic
synthesis.4 Recently, Li et al developed a straightforward
strategy to the preparation of xanthones via an intramolecular
oxidative CDC reaction of 2-aryloxybenzaldehydes using RhCl3
as the catalyst and tert-Butyl hydroperoxide (TBHP) as the
oxidant.5 Later on, two more catalytic systems, FeCp2/TBHP6
and TBAB/TBHP7 have been achieved in this transformation. In
general, theses catalytic systems were complicated and
stoichiometric amounts of chemical oxidant TBHP which is
potentially explosive were required. On the contrary, O2 is one
of the most environmentally benign and sustainable oxidants.8
Therefore, the development of new oxidative dehydrogenative
ring closure reaction of 2-aryloxybenzaldehydes to form
xanthones under simpler aerobic conditions is highly desired.
Since 2015, we have for the first time discovered that carbon
tetrabromide (CBr4) showed good reactivity for CDC reactions.9
We found that CBr4 could efficiently promote the oxidative
coupling of isochromans with aromatic ketones, the
dehydrogenative
tetrahydroisoquinolines with nucleophiles such as indoles,
ketones and phosphites, the dehydrogenative
C-H
functionalization
of
N-aryl
Povarov/aromatization tandem reaction of glycine derivatives
with alkenes, the double-oxidative dehydrogenative
cyclization/acidic ring opening/aromatization tandem reaction
of glycine derivatives with dioxane, and the oxidative C−N
bond formation of 2-aminopyridines or 2-aminopyrimidines
with β-keto esters or 1,3-diones.
As part of our continuing interest in CBr4 assisted
transformations, herein, we developed a new and facile CBr4-
promoted intramolecular oxidative dehydrogenative protocol
to construct xanthones (and also fluorenones) from 2-
aryloxybenzaldehydes (and 2-arylbenzaldehydes) under
aerobic solvent-free conditions.
a.College of Chemistry and Chemical Engineering, Northwest Normal University,
Lanzhou, Gansu 730070, China.
b.College of Foreign Languages, Lanzhou University of Technology, Lanzhou, Gansu
730050, China.
Electronic Supplementary Information (ESI) available: [Experimental details,
compound characterization, and NMR spectra]. See DOI: 10.1039/x0xx00000x
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Scheme 3. CBr4 mediated synthesis of xanthones and fluorenones[a]
Results and Discussion
O
X
O
We started our study with the reaction of 2-
phenoxybenzaldehyde 1a in the presence of 1.2 equiv. of CBr4
in various solvents under oxygen atmosphere (O2 balloon)
(Scheme 2, entries 1–6). The best result for xanthone 2a
construction (60%) was obtained under solvent-free
conditions. The structure of 2a was identified by X-ray
crystallographic analysis.10 The use of solvents was found to be
less or no productive. Recently, there is an increasing attention
in solvent-free reactions because this strategy leads to an
economical technology with the increment of safety, the
simpleness of work-up, and the reduction of cost. The use of
other halogen reagents such as NBS, NCS, NIS, DBDMH instead
of CBr4, was found to be less effective (Scheme 2, entries 7–
10). BrCH2CH2Br, CHBr3 and CH2Br2 were inactive for this
transformation (Scheme 2, entries 11–13). On decreasing the
loading of promoter from 1.2 equiv. to 0.2 equiv., the yield
was decreased a little (from 60% to 52%) with much longer
reaction times (Scheme 2, entries 14–18). Then, temperature
effect was investigated too. Increasing or decreasing the
temperature of the reaction did not lead to any further
improvements in the yield (Scheme 2, entries 19, 20). The
control experiment showed that no reaction was observed in
absence of O2 (under an argon atmosphere) (Scheme 2, entry
22). Finally, only a trace amount of product was formed in the
absence of any promoter (Scheme 2, entry 23). Therefore, the
optimal reaction conditions were at 140oC, under oxygen
atmosphere using 1.2 equiv. of CBr4 without any solvent for 20
minutes (Scheme 2, entry 6).
CBr4 (120 mol %), O2
neat, 140oC
Ar1
Ar1
Ar2
Ar2
X
2
1
O
O
O
O
O
O
2a (60%)[b]
2c (43%)
2b (65%)
O
O
O
O
O
O
2f (53%)
2e (42%)
2d (48%)
O
O
O
O
O
O
O
2g (73%)
2h (80%)
2i (38%)
O
O
O
Cl
F
O
O
O
O
2l (67%)
2k (62%)
2j (35%)
O
O
O
O
Br
I
O
O
O
O
2o (39%)
2n (50%)
2m (52%)
O
O
O
O
O
Scheme 2. Screening of Reaction Conditions[a]
O
Cl
2p (50%)
2q (35%)
2r (82%)
O
F
O
O
Cl
S
O
O
2u (52%)
2t (70%)
2s (62%)
O
O
CBr4 (120 mol %), O2
neat, 140oC
Ar1
Ar1
Ar2
Ar2
1
2
O
O
O
2v (78%)
2w (56%)
O
O
O
F
Cl
Br
2x (51%)
2y (42%)
2z (48%)
[a] Reaction conditions:
[b] Yield of the isolated product.
1
(1 mmol), CBr4 (1.2 mmol), O2 balloon, 140oC, 0.33-8 h.
We then examined the substrate scope of this CBr4 promoted
intramolecular arylation reactions of aldehydes under the
optimized conditions. The structures of the obtained aromatic
[a] The amount of substrate 1a: 1 mmol. [b] Yield of the isolated product. NCS = N-
Chlorosuccinimide. NBS = N-Bromosuccinimide. NIS = N-Iodosuccinimide. DBDMH =
1,3-dibromo-5,5-dimethylhydantoin. DBE = dibromoethane.
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polycyclic ketones and the yields are depicted in Scheme 3. presence of radical scavengers such as TEMPO or BHT did not
The effect of substituents on the arene ring undergoing the occur (Scheme 5, entries 7–10), which signifies that the
cyclization was first examined. Both electron-donating groups reaction probably proceeds through a radical pathway.
such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl,
Scheme 5. Control experiments
phenyl, methoxy and phenoxy and electron-withdrawing
groups such as halogen atoms and carboxylate at the para-
position were well tolerated, and xanthones 2b-2o were
isolated in 35-80% yields. The introduction of halogen atoms
into this fused ring system makes this methodology more
useful for the further transformations. Moreover, the reaction
of substrates bearing a substituent at the ortho position of the
aryloxy group also proceeded well (Scheme 3, 2p-2r). We
further showed that the ortho-formyl biphenylether with both
arene rings carry substituents provided the corresponding
products in good yield (Scheme 3, 2s). The reaction of 2-
(naphthalen-2-yloxy) benzaldehyde yielded tetracyclic
compound 2t in high yield. In addition, this protocol can
facilitate the preparation of thioxanthones too (Scheme 3, 2u).
Encouraged by these promising results, to develop a more
general and useful method, we further applied the optimized
reaction conditions to construct fluorenones which are found
in a lot of naturally occurring molecules exhibiting promising
biological activities11 using 2-arylbenzaldehydes as the test
substrates. As shown in Scheme 3, to our delight, ortho-formyl
biphenyls with electron-donating substituents and with
electron-withdrawing substituents were all well tolerated
under the standard reaction conditions (Scheme 3, 2v-2z). The
Although the mechanism of this CBr4 initiated intramolecular
structure of fluorenone 2v was also identified by X-ray
CDC reaction is not fully clarified, on the basis of the
crystallographic analysis.12
preliminary results, a tentative mechanism was hypothesized
To demonstrate the practicability of the present methodology,
as shown in Scheme 6. Initially, a homolytic cleavage of the C-
as shown in Scheme 4, we carried out the reaction starting
Br bond of CBr4 occurs upon heating to produce CBr3 and Br
from 10 g of 2-phenoxybenzaldehyde 1a and the isolated yield
radicals. Then, after abstraction of a hydrogen atom of
of the corresponding product 2a was 58 %. That is to say, here
substrate
radical intermediate
Intermediate is generated by intramolecular radical addition
of intermediate . Finally, the previously formed OOH radical
would act as the hydrogen-abstractor to provide the desired
product
1
by the Br radical (or CBr3 radical), the carbonyl
we present a convenient and scalable synthetic route to
xanthone motifs.
A
is delivered. Subsequently,
B
A
Scheme 4. Scalability of the reaction to the multi-gram scale
2.
Scheme 6. Proposed mechanism
To get a better understanding on the mechanism of this CBr4
promoted oxidative coupling reaction,
a few control
experiments were conducted. First of all, on decreasing the
loading of CBr4 from 1.2 equiv. to 0.2 equiv., the comparable
yields of 2a were obtained with prolonging of reaction time
(Scheme 5, entries 1–4). Next, the reaction of 1a in the
absence of molecular oxygen (under argon atmosphere)
furnished no desired product (Scheme 5, entries 5, 6).
Moreover, 2,2,6,6-tetramethylpiperidin-1-yl hypobromite
formed from the reaction of TEMPO and bromine radical could
be detected by HRMS (Scheme 5, bottom). These results
suggest that CBr4 is the radical initiator and O2 is the terminal
oxidant for the reaction. In addition, the reactions in the
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In conclusion, we have for the first time demonstrated that
CBr4 is a highly effective promoter for the rapid synthesis of
xanthones and fluorenones through the intramolecular
oxidative dehydrogenative coupling of ortho-formyl
biphenylethers and ortho-formyl biphenyls under aerobic and
solvent-free conditions. The availability of the substrates, the
use of simple non-metal reagent as promoter and O2 as
terminal oxidant, as well as the atom economy and the
scalability make the process interesting for synthetic purposes
and industrial applications. Experimental results suggest that
the reaction proceeds through a radical pathway. Work to
uncover further capabilities of CBr4 is under way in our
laboratories and the results will be reported in due course.
Experimental Section
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Acknowledgements
We thank the National Natural Science Foundation of China
(21562037) and NWNU (NWNU-LKQN-15-1) for financially
supporting this work.
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