Construction of aromatic [5,5] spiroketals via hypoiodite-catalyzed etherification combined in relay cascades

Article abstract of DOI:10.1021/ol300107v

An approach is developed for the synthesis of bisbenzannelated spiro[5,5]ketals via a catalytic relay reaction cascade involving a new cyclo-etherification, which is prompted by fluoride and catalyzed by the hypoiodite species generated in situ from irrad

Full text of DOI:10.1021/ol300107v

ORGANIC
LETTERS
2012
Vol. 14, No. 4
1158–1161
Construction of Aromatic [5,5] Spiroketals
via Hypoiodite-Catalyzed Etherification
Combined in Relay Cascades
Wei Wei, Yao Wang, Jianpeng Yin, Jijun Xue,* and Ying Li*
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and
Chemical Engineering, Lanzhou University, Lanzhou 730000, P.R. China
xuejj@lzu.edu.cn; liying@lzu.edu.cn
Received January 16, 2012
ABSTRACT
An approach is developed for the synthesis of bisbenzannelated spiro[5,5]ketals via a catalytic relay reaction cascade involving a new cyclo-
etherification, which is prompted by fluoride and catalyzed by the hypoiodite species generated in situ from irradiative aerobic oxidation of an
iodide ion formed in the former step of the reaction cascade.
Intramolecular R-oxyphenylation of carbonyl com-
pounds has proven to be highly useful for the formation
of oxa-benzocycles.1 Generally, oxidative conditions are
used in R-oxyphenylation. There are relatively few reports
of the R-oxyphenylation of carbonyl compounds, mak-
ing investigations on new conditions and their adapt-
ability necessary and worthwhile. Organohypervalent
iodine reagents have attracted significant recent interest
as versatile and environmentally benign oxidants with
many applications in organic synthesis.2,3 Most recent
research found organohypervalent iodine reagents
useful for the R-cyclo-etherification of carbonyl com-
pounds, which may be applicable for the construction
of bisbenzannulated spiroketals.
skeleton-defined molecular complexity and diversity is still
valuable and challenging work.4 To achieve this goal,
cascade reactions have been considered as one of the most
effective approaches, in which multiple transformations
have occurred in a single vessel and increase resource
efficiency for the overall process.5 Furthermore, the com-
bination of two catalysts has been elegantly employed in
one-pot and in cascade reactions.6,7 In particular, catalysts
with orthogonal, but mutually compatible, reactant acti-
vation modes have proven to be ideal catalysts for the relay
catalysis.8 This development is very interesting in that the
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r
10.1021/ol300107v
Published on Web 02/03/2012
2012 American Chemical Society

byproduct from the first cycle takes part in the subsequent
reaction as a catalyst.
catalyst in the R-oxyphenylation, which was the last step
of the reaction cascade.
Our investigation was initiated by reacting HDA with 1a
and 2a. In the presence of tetrabutylammonium fluoride
Scheme 1. Silica Gel-Mediated and Irradiative Reaction
Figure 1. Natural products within spiro[5,5]ketal cores.
The reports on the synthesis of bisbenzannelated spir-
oketals especially spiro[5,5]ketal skeletons (Figure 1) have
not fully elucidated them, despite the importance of these
skeletons in the larger spirocycle family. Therefore, as a
continuation of our previous work on the synthesis of
spiroketal cores9 and to relay the significance and novelty
of the reaction cascade, we proposed to integrate the
Hetero-DielsÀAlder (HDA) reaction for a new, more
combined relay catalysis, new transformation conditions,
and a synthesis of the bioactive spiroketals. Through this
investigation, three reactionswere foundtobe combinedin
a reaction cascade, including a silica gel-mediated10 hydro-
lyzation of amino acetal, silica gel-mediated decarbonyla-
tion of acetal, and in situ generated hypoiodite-catalyzed
cyclo-etherification of carbonyl compounds. The cyclo-
etherification in this case is a new catalytic application of
hypoiodite reagents, in which two novelties are very im-
portant: (1) the hypoiodite in this transformation is gen-
erated from irradiative aerobic oxidation of iodide ion; (2)
this is also a new oxidative nucleophile substitution of
hydrogen prompted by fluoride. In this cascade, silica gel
and TBAI acted as catalysts in succession, forming a
catalytic relay. This is a new type of catalytic relay where
TBAI, the byproduct of HDA reaction,11 acted as a
(TBAF), 2a was deprotected and converted to a reactive
species, o-quinone methide (o-QM), which was captured
immediately and formed 3a. However, when the crude
HDA solution was eluted onto silica gel, 5a along with a
small amount of 4a and 6a was found, indicating that 3a
can be converted to 4a or 5a by silica gel. To investigate
further, a successive experiment was performed. After the
HDA reaction was completed, silica gel was added to the
resultant solution in a clear round bottle flask in the
daytime under natural light and stirred for several hours
in petroleum ether (PE) in the air. Surprisingly, the yield of
6a increased and 5a formed subsequently decreasing with
increasing reaction time. We postulated that the cascade
reaction developed through the steps shown in Scheme 1.
The HDA reaction formed the amino acetal 3a, which
then was hydrolyzed by H2O under a silica gel reaction
to yield the acetal 4a. The subsequent degradation of 4a
under a silica gel reaction formed 5a, which was con-
verted to 6a through the R-oxyphenylation of a carbonyl
compound.
To demonstrate our postulation, purified 3a12 was
treated with silica gel in petroleum ether, resulting in 5a
with a 93% yield and a small amount of 4a being found in
the residue in the initial stage of the process. This result
clearly showed that 3a converted to 5a using 4a as an
intermediate.
Further optimization and substrate screening were con-
ducted at each stage of the reaction. First, experiments
were performed to optimize the HDA reaction.13 Solvents
at varying ratios of 1a/2a/TBAF were screened. Dichlor-
omethane (DCM) was found to be the best solvent, and the
best result was obtained when the ratio of 1a, 2a, and
TBAF of 1:2:2.8 was used. Subsequently, the sequence of
adding substrates and reagents was also studied.
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(12) Compound 3 was purified by chromatography in a silica gel
support doped with NEt3.
(13) See Supporting Information.
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Org. Lett., Vol. 14, No. 4, 2012
1159

Using the modified conditions, the combination reac-
tion of HDA/hydrolyzation of amino acetal/degradation
of acetal was investigated with varied 1 and 2. The main
products of the reaction, 5aÀ5j, are formed, and the yields
were good to excellent. Similar to the HDA reactions, the
yield of 5 changed with the change of the electronic effect
of R3.
Table 1. Synthetic Conditions of Cyclization of Compound 6a
This mechanism of the cyclo-etherification still does not
specify the reagent and conditions that prompted the
cyclization of 5a to 6a. To gain a better understanding of
this process, a series of controlled experiments were con-
ducted with the purified substrate 5a. Initially, irradiation
was screened. It was found that 6a did not form in the dark
(Table 1, entry 1). Furthermore, purified 5a was treated
under irradiative conditions, without any additives
(Table 1, entry 2). However, neither natural light nor
ultraviolet light produced a diagnosable reaction. Another
controlled experiment was designed, and the reaction was
carried out in the absolute absence of oxygen. Purified 5a
was treated with TBAI (20 mol %) and TBAF (30 mol %)
under irradiation of UV light and an argon atmosphere.
Dramatically, no reaction happened at all (Table 1, entry
3). This result showed that oxygen is obligatory for the
transformation. So air and oxygen were introduced re-
spectively into the reaction mixture of 5a, TBAI, and
TBAF in THF. Compound 6a was obtained smoothly in
moderate yield. This work describes a new method for the
R-oxyphenylation of a carbonyl compound. All of these
experiments showed that irradiation, TBAI, and oxygen
are obligatory (Table 1, entry 4), TBAF is a good auxiliary
reagent for this transformation (Table 1, entry 5), and
oxygen gave better results than air (Table 1, entry 5, 6). At
the same time, a hypothesis was proposed for the cyclo-
etherification. The iodide may be oxidized to iodine by
oxygen, and the iodine generated in situ catalyzed the
cyclization. In order to prove this process, iodine was used
to catalyze the reaction instead of TBAI. However, iodine
gives an obviously lower yield than TBAI (Table 1, entry
7). Furthermore, increasing the amount of TBAF to 40
mol % increased the yield to 76% (Table 1, entry 8).
In this transformation, iodide was shown to be the main
catalyst, with TBAF possibly acting as a cocatalyst. To the
best of our knowledge, there is no precedent for the aerobic
irradiative reactions catalyzed by iodide and prompted by
fluoride for the R-oxyphenylation of carbonyl compounds,
but our protocol described here provides a new synthetic
mode.
additive
(mol %)
light
time yielda,b
entry solvent
source
atm
(h)
(%)
1
2
THFc
TBAI (20)
none
none
O2/
air
O2/
air
12
0
THF
natural
light or
UVd
12
3
0
0
3
THF
TBAI (20)
TBAF (30)
TBAI (20)
TBAI (20)
TBAF (30)
TBAI (20)
TBAF (30)
I2 (20)
UV
Ar
4
5
THF
THF
UV
UV
air
air
3
3
17
44
6
7
8
THF
THF
THF
UV
UV
UV
O2
air
O2
3
3
3
56
26
76
TBAF (30)
TBAI (20)
TBAF (40)
a Yields were calculated after column chromatography by silica gel.
b Unless otherwise noted, all reactions were carried out with 5a (0.1
mmol) in 3 mL of THF. c THF was dried by distillation over LiAlH4.
d Unless otherwise noted, photolysis was performed in a flask under
irradiation at λ = 200À700 nm.
Scheme 2. Hypothesized Mechanism of Hypoiodite-Catalyzed
Cyclo-etherification
According to the above results and the literature14 on
hypoiodite and oxidative cyclo-etherification, a mechnism
was hypothesized as follows (Scheme 2): iodide was oxidized
by oxygen to hypoiodite and fluoride promoted the en-
olization of ketone 5a to 7a. Then an eletrophilic substitu-
tion of 7a and hypoiodite gave the iodo or hypoiodo 8a.
The subsequent intramolecular SN1 displacement of an
iodo or a hypoiodo group in 8a by a phenolic hydroxyl
group activated by a hydrogen bond with fluoride affords
spiroketal 6a.
Using the modified cyclo-etherification conditions (Table 1,
entry 8), varied substrates were investigated in this trans-
formation. Under irradiation of a UV lamp, the mixture of
5, TBAI, and TBAF in THF formed 6 in moderate to good
yields. Obviously, R1, R2, and R3 have different effects on
(14) Ochiai, M.; Takeuchi, Y.; Katayama, T.; Sueda, T.; Miyamoto,
K. J. Am. Chem. Soc. 2005, 127, 12244–12245.
1160
Org. Lett., Vol. 14, No. 4, 2012

Table 2. Synthesis of Varied Bisbenzannelated Spiro[5,5]ketals
via Irradiative Aerobic Cyclization
Table 3. Synthesis of Varied Compound 6 via Cascade Reaction
yielda,b
yielda
entry
R1
R2
R3
products
(%)
entry
R1
R2
R3
products
(%)
1
2
3
4
5
6
7
8
9
H
H
H
6a
6b
6c
6d
6e
6f
59
60
47
42
40
37
48
46
39
1
2
3
4
5
6
7
8
9
10
H
H
H
6a
6b
6c
6d
6e
6f
76
83
69
60
59
55
64
60
62
59
H
H
Me
H
H
Me
H
H
Br
H
H
Br
H
H
COOEt
Br
H
H
COOEt
Br
H
MeO
MeO
H
H
MeO
MeO
H
H
COOEt
Br
H
COOEt
Br
MeO
MeO
Br
6g
6h
6i
MeO
MeO
Br
Br
6g
6h
6i
H
COOEt
Br
H
COOEt
Br
H
H
a Yields were calculated after 4 steps and column chromatography by
silica gel. b Unless otherwise noted, all reactions were carried out with
compound 5 (0.25 mmol).
H
COOEt
6j
a Unless otherwise noted, all reactions were carried out with com-
pound 5 (0.1 mmol) in 3 mL of THF.
of a hypoiodite catalyst based on the irradiative aerobic
oxidation of an iodide ion. This is a new catalytic applica-
tion of an organohypo iodite reagent and new fluoride-
prompted oxidative nucleophilic substitution of aliphatic
hydrogen. This approach also yielded an interesting new
relay catalysis reaction, where the byproduct of the first
transformation took part in the subsequent reaction cycle as
a catalyst. We hope that this work will arouse more atten-
tion on multistep cascade reactions and the synthesis of
spiroketal compounds.
the conversion. The electron-donating R1 group slightly
decreased the yield (Table 2, entries 3 and 7, entries 4 and 8).
The electron-donating R2 group, however, obviously de-
creased the efficiencies (Table 2, entries 3 and 5, entries 4
and 6). In contrast to R1 and R2, the electron-donating R3
group obviously increased the conversion (Table 2, entries
1, 2) and the substrate with an electron-withdrawing R3
group gave a low yield (Table 2, entries 3, 4).
Finally, the entire cascade reaction was investigated, and
the investigations showed that 6aÀ6j were formed in
moderate to good yields from 1aÀ1d and 2aÀ2d, which
issummarizedinTable3. Ofthetestedsubstituents, R3 had
the most obvious effect on the conversion. Electron-donating
R3 groups benefited the conversion. Hence, the reaction of
1a and 2b was more efficient than that of 1a and 2a. 6d gave
the lowest yield when R3 is an electron-withdrawing group.
In summary, a new approach toward the synthesis of the
bisbenzannelated spiro[5,5]ketal cores has been developed.
This approach involves a catalytic relay cascade of TBAF-
induced HDA, silica gel-mediated hydrolyzation/degrada-
tion, and cyclo-etherification catalyzed by in situ generation
Acknowledgment. This work was supported by the
NSFC (Nos. 20872053 and 21072084). We also thank
Dr. XianXingJiang and Dr. Wei Yu(Lanzhou University,
P. R. China) for helpful discussions.
Supporting Information Available. Experimental pro-
cedures, CIF files, and NMR spectral data for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 4, 2012
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