PdBr2-Catalyzed Acetal Formation of Carbonyl Compounds Using Diazophenanthrenequinone: Utility of 9,10-Phenanthrenedioxyacetal

Article abstract of DOI:10.1002/ejoc.202000315

We developed a new acetalization method of ketones and aldehydes under non-acidic conditions using diazophenanthrenequinone and PdBr₂. The formed acetals that have a phenanthrene skeleton withstand under mild acidic conditions. Removal of acetals was successfully proceeded under strong acidic or oxidation conditions using aqueous ceric ammonium nitrate (CAN) to afford corresponding ketones and aldehydes.

Full text of DOI:10.1002/ejoc.202000315

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: PdBr2-catalyzed acetal formation of carbonyl compounds using
diazophenanthrenequinone: utility of 9,10-phenanthrenedioxy
acetal
Authors: Mitsuru Kitamura, Ryo Fujimura, Tomoaki Nishimura, Shuhei
Takahashi, Hirokazu Shimooka, and Tatsuo Okauchi
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the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000315
Link to VoR: https://doi.org/10.1002/ejoc.202000315
01/2020

10.1002/ejoc.202000315
European Journal of Organic Chemistry
COMMUNICATION
PdBr2-catalyzed acetal formation of carbonyl compounds using
diazophenanthrenequinone: utility of 9,10-phenanthrenedioxy
acetal
Mitsuru Kitamura,[a]* Ryo Fujimura,[a] Tomoaki Nishimura,[a] Shuhei Takahashi,[a] Hirokazu Shimooka,[a]
Tatsuo Okauchi [a]
[a]
Prof. Dr. M. Kitamura, R. Fujimura, T. Nishimura, Dr. S. Takahashi, Dr. H. Shimooka, Prof. Dr. T. Okauchi.
Department Applied Chemistry
Kyushu Institute of Technology
1-1 Sensuicho, Tobata, Kitakyushu, 804-8550
E-mail: kita@che.kyutech.ac.jp
Homepage: http://www.che.kyutech.ac.jp/chem27/chem27.html
Supporting information for this article is given via a link at the end of the document.
Abstract: We developed a new acetalization method of ketones and
aldehydes under non-acidic conditions using
depicted and conducted using diazoquinone 1 and a metal
catalyst. Diazoquinone 1 reacts with metal catalysts to form metal
carbene I,[9] that is attacked with a carbonyl compound 2 to form
oxonium ylide II.[10] Internal cyclization proceeds to afford the
corresponding acetal 3. As the diazoquinone for the acetalization,
diazophenanthrenequinone 1 was chosen because two outside
benzene rings in phenanthrene are responsible for the cyclization
to force the reaction sites close, as shown in II (vs II'). Moreover,
the acetal carbon in acetal 3 is not a chiral center, which helps in
the multistep transformation so that it does not lead to the
formation of a diastereomer via the protection step (acetalization).
diazophenanthrenequinone and PdBr2. The formed acetals that have
a phenanthrene skeleton withstand under mild acidic conditions.
Removal of acetals was successfully proceeded under strong acidic
or oxidation conditions using aqueous ceric ammonium nitrate (CAN)
to afford corresponding ketones and aldehydes.
For the synthesis of complex and functional organic compounds,
the carbonyl group is one of the useful functional groups. They
are used as both nucleophiles and electrophiles, and various
carbon–carbon bond formation reactions using carbonyl
compounds are reported.[1] For example, carbonyl groups suffer
nucleophilic attacks at carbon atoms of carbonyl groups owing to
carbon nucleophiles such as organometallic reagents and
enolates. In contrast, enolates and enols formed by deprotonation
and tautomerization from corresponding carbonyl compounds are
used as carbon nucleophiles that react with carbon electrophiles
such as alkyl halides and carbonyl compounds. However, such
high reactivity of carbonyl compounds sometimes interrupts the
desired reaction in the multistep synthesis of organic compounds.
Side reaction of
a carbonyl group can be inhibited via
protection/deprotection processes in the group, and acetal is
usually used to protect the carbonyl group.[2]
Acetalization of carbonyl compounds is generally conducted via
dehydration reaction of alcohol under acidic conditions.[2]
However, when the carbonyl compounds have an acid-sensitive
functional group, acidic acetalization is difficult to apply to the
molecules. Therefore, various methods are being introduced in
developing non-acidic acetalization,[3-6] and several practical
methods have been developed, such as iodine promoted
reaction,[3] base-catalyzed reaction,[4] and metal-catalyzed
reaction.[5]
Scheme
diazophenanthrenequinone 1.
1.
Plan
of
metal-catalyzed
acetalization
using
Diazophenanthrenequinone 1 was prepared by diazo-transfer
reaction of 9-phenanthrol with 2-azido-1,3-
dimethylimidazolinium chloride (ADMC 5) in good yield (Scheme
2).[11]
4
We have studied the reaction of metal carbene formed from
diazoquinones.[7,8] We envisioned that a practical acetal formation
could be developed via the reaction between diazoquinones and
carbonyl compounds in the presence of a metal catalyst and
therefore experimented. In this letter, we describe the outcome of
the abovementioned investigation.
In Scheme 1, the outline of our strategy toward acetalization of
carbonyl compounds under non-acidic reaction conditions is
1
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10.1002/ejoc.202000315
European Journal of Organic Chemistry
COMMUNICATION
proceeded smoothly to afford acetal 3a in 68% yield. Other
palladium(II) halide and palladium(II) salts were ineffective for
acetalization compared with PdBr2 (Runs 1–5). In the reaction
with tris (dibenzylideneacetone)dipalladium, acetal 3a was
formed (Run 6), and the formation of 3a was well suppressed in
the presence PPh3 (Run 7). Although several Rh catalysts were
examined, remarkable increase in the yield of acetal 3a was not
observed (Runs 8–10). Cyclization of carbonyl compounds and 2-
diazo-1,3-dicarbonyl compounds using Cu(II) salt has been
reported5b]; however the Cu salt was not effective for the
cyclization using diazophenanthrenequinone
1
(Run 11).
Scheme 2. Preparation of diazophenanthrenequinone 1.
Additinally, trioxocin derivative 6a was formed as a by-product in
some cases.
The efficiency of PdBr2 may be attributed to the role of Br–. Since
5 endo-trig cyclization is highly disfavored commonly,[12] acetal 3a
is not formed directly from oxonium ylide IIa, but is formed by 5-
exo-tet cyclization of IIIa which was formed by the reaction of IIa
and Br– (Scheme 3).
Table 1. Optimization study of metal-catalyzed acetalization using
diazophenanthrenequinone 1.[a]
yield (%)[c]
Scheme 3. Efficiency of Br– for the cyclization.
Run
1
MLn (x mol%) [b]
PdBr2 (10)
3a
68
55
50
16
26
23
0
6a
10
5
Next, a variety of aldehydes and ketones were examined for the
PdBr2-catalyzed acetalization using diazophenanthrenequinone 1
(Table 2). Both the alkyl and aryl aldehydes were transformed to
corresponding acetals in good to high yields. In the series of
ketones, cyclic ketones were effective for the acetalization than
acyclic ketones in most cases. It is important to note that acid-
sensitive TBS group is tolerated under the reaction conditions as
shown in the formation of 3h.
Subsequently, experiment on stability under various conditions
and deprotection of acetal 3 was performed (Table 3). 3a was
stable under general conditions in which common acetal survive
[with piperidine (base), Bu4NF (F–), and LiAlH4 (hydride)].
Interestingly, 3a withstood mild acidic conditions (Table 3, Runs
1-4). Deprotection reaction of 3a was successfully proceeded
under stronger acidic conditions (2 M HCl aq.in 1,4-dioxane at
80 °C) or oxidation conditions with aqueous ceric ammonium
nitrate (CAN) to afford corresponding ketone 2a in high yields
(Runs 5 and 6).[13]
2
PdCl2 (10)
3
PdI2 (10)
12
trace
5
4
Pd(acac)2 (10)
Pd(OAc)2
5
6
Pd2(dba)3 (10)
Pd2(dba)3 (10), PPh3 (40)
Rh2(OAc)4 (3)
Rh2(oct)4 (3)
18
0
7
8
trace
6
0
9
0
10
11
Rh2(esp)2 (3)
Cu(CF3-acac)2•H2O
34
trace
trace
0
[a] Reaction conditions: 2a (0.3 mmol), 1 (0.45 mmol), MLn (3-10 mol%) in
benzene (1.5 mL) at reflux for 1.5 h. [b] dba = dibenzylideneacetone, acac =
acetoacetonato, oct
=
octanoate, esp
=
α,α,α’,α’-tertramethyl-1,3-
benzenedipropionate, CF3-acac = hexafluoroacetylacetonato. [c] Isolated yield.
An initial trial of the metal-catalyzed acetalization using
diazophenanthrenequinone 1 was conducted with 4-phenyl-2-
butanone (2a) (Table 1). The desired acetalization proceeded
efficiently with PdBr2 (Run 1). When diazophenanthrenequinone
1 (1.5 equiv) in benzene was slowly added to a mixture of ketone
2a and 10 mol% of PdBr2 in benzene at reflux, acetalization
2
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10.1002/ejoc.202000315
European Journal of Organic Chemistry
COMMUNICATION
Table 2. PdBr2-acetalization of various aldehydes and ketiones with diazophenanthrenequinone 1.[a]
[a] Reaction conditions: 2/1/ PdBr2 = 1/1.5/0.1. Benzene (0.2 M for 2). Reflux for 1.5 h.
In Table 4, the results of the deprotection reaction of various 9,10-
phenanthrenedioxy acetals 3 are shown. Since several carbonyl
compounds 2 were over oxidized with the aqueous CAN solution,
the yields were low (Runs 3 and 6).
Table 3. Examination of the stability of acetal 3a under various conditions.[a]
Table 4. Deprotection of acetal 3.[a]
Run
Acetal 3
Product 2
Yield (%) [Time (h)]
Method A
Method B
84 [5]
Run
Conditions
Temp
Time
Yield (%)
1
2
3
4
5
6
3a
3c
3e
3i
2a
2c
2e
2i
82 [8]
2a
0
3a
88
90
90
92
6
80 [1]
80 [2.5]
40 [9][b]
100 [5]
1
p-TsOH (20 mol%), THF/H2O = 1:1
2 M HCl aq./1,4-dioxane = 1:1
10% H2SO4 aq./THF = 1:1
CH3CO2H
r.t.
5
5
5
5
8
5
82 [12]
90 [5][c]
24 [15][d]
80 [3]
2
r.t.
0
3
r.t.
0
3n
3q
2n
2q
78 [1.5][b]
38 [6][b]
4
r.t.
0
5
2 M HCl aq./1,4-dioxane =1/1
CAN (2.0 eq.), CH3CN/H2O=1/1
80 °C
0 °C
82
84
[a] Reaction conditions. Method A: In 1,4-dioxane/2 M HCl=1/1 at 80 °C. Method
B: CAN (2 equiv.) in CH3CN/H2O=1/2 at 0 °C. [b] In CHCl3/H2O=1/2. [c] In
CHCl3/2 M HCl=1/1. [d] 3n was recovered in 63% yield.
6[b]
0
[a] Reaction was carried out for 5 h. [b] CAN: (NH4)2[Ce(NO3)6].
3
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10.1002/ejoc.202000315
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phenanthrenedioxy acetal are shown. When 2 M HCl aqueous
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acetal 3d and ethylenglycol acetal 7 at room temperature in THF,
ethylenglycol acetal 7 was selectively deprotected and 9,10-
phenanthrenedioxy acetal was isolated in 84% yield. 3h
possesses two kinds of acid sensitive protective groups such as
tert-butyldimethylsilyl group and 9,10-phenanthrenedioxy acetal,
these protective groups are selectively removed by treatment
using tetrabutylammonium fluoride and CAN to afford phenol 8
and ketone 2h, respectively.
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Scheme 4. Demonstration of selective deprotection.
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In conclusion, we developed the PdBr2-catalyzed acetal formation
reaction with diazophenanthrenequinone under non-acidic
conditions. The acetal that has a phenanthrene skeleton has good
stability against mild acidic reaction conditions and was
transformed to the corresponding carbonyl compound under
strong acidic or oxidation conditions using aqueous CAN.
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Acknowledgements
[12] J. E. Baldwin, J. Chem. Soc. Chem. Commun. 1976, 734.
[13] 9,10-Phenanthrenequinone was formed as by-product in the
deprotection reaction.
This work was supported by a Grant in Aid for KAKENHI
(17K19125).
Keywords: acetal • diazo compounds • palladium • protective
group
4
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10.1002/ejoc.202000315
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
A new acetalization method of ketones and aldehydes under non-acidic conditions was developed using diazophenanthrenequinone and PdBr2.
The formed acetals that have a phenanthrene skeleton withstand under mild acidic conditions. Removal of acetals was successfully proceeded
under strong acidic or oxidation conditions using aqueous ceric ammonium nitrate (CAN).
Key topic
Acetal Formation
5
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