Highly efficient synthesis of benzodioxins with a 2-site quaternary carbon structure by secondary amine-catalyzed dual Michael cascade reactions

Article abstract of DOI:10.1039/c8ob01029c

Salicylic acids and substituted ynones were employed as substrates to afford a class of valuable 4H-benzo[d][1,3]dioxin-4-ones with a 2-site quaternary carbon structure in up to 92% yield by secondary amine-catalyzed dual Michael cascade reactions under mild reaction conditions. The α,β-unsaturated ketone as the key intermediate in the cascade process was successfully separated and characterized. As a result, a new reaction route for ynone species is demonstrated, which is totally different from the existing allenamine activation model.

Full text of DOI:10.1039/c8ob01029c

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Takeharu Haino et al.
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DOI: 10.1039/C8OB01029C
Journal Name
ARTICLE
Highly Efficient Synthesis of Benzodioxins with a 2-Site
Quaternary Carbon Structure by Secondary Amine-Catalyzed Dual
Michael Cascade Reactions
Received 00th January 20xx,
Accepted 00th January 20xx
Xuefeng He,a Yongsu Li,a Meng Wang,a Hui-Xuan Chen,a Bin Chen,a Hao Liang,a Yaqi Zhang,a Jiyan
Panga and Liqin Qiua,*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Salicylic acids and substituted ynones were employed as the substrates to afford a class of valuable 4H-
benzo[d][1,3]dioxin-4-ones with a 2-site quaternary carbon structure in up to 92% yield by secondary amine-
catalyzed dual Michael cascade reactions under mild reaction conditions. The α,β-unsaturated ketone as the
key intermediate was successfully separated and characterized in the cascade process. As the result, a new
reaction route for ynone species was demonstrated, which was totally different from the existing allenamine
activation model.
[d][1,3]dioxin-4-one with acetone under the promotion of 4-
dimethylamino pyridine (DMAP) and SOCl2 (Fig. 2, a),21 or with
Introduction
As part of Polycyclic heterocycles, benzo[d][1,3]dioxin-4-one
and its derivatives play important roles in natural products,1,2
drug research (Fig.1
),3-5 as well as some building blocks in
Fig. 1 Bioactive molecules based on the benzodioxin skeleton
organic process,6-18 for their unique chemical properties and
various product spectra under selective manipulation.19,20
Different methods for synthesis of these heterocyclic skeletons
have been developed for many years. For instance, salicylic
acids were used to construct the core structure benzo-
a
School of Chemistry, The Key Laboratory of Low-Carbon Chemistry & Energy
Conservation of Guangdong Province, South China Sea Bio-Resource Exploitation
and Utilization Collaborative Innovation Center, Sun Yat-sen University, No. 135
Xingangxi Road, Guangzhou 510275, People’s Republic of China
Fig. 2 Previous and this work
† Liqin Qiu, Tel: +(86)-20-8411-0996; e-mail: qiuliqin@mail.sysu.edu.cn.
Electronic Supplementary Information (ESI) available: Copies of 1 H, 13C and 19F NMR
spectra of products. See DOI: 10.1039/x0xx00000x
ketones in mixed trifluoroacetic acid (TFA) and trifluoroacetic
anhydride (TFAA) (Fig. 2, b).10,16 K3PO4 was also found to be a
suitable base to activate the reaction of salicylic acids well in
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Table 1, Entry 15) and ethyl acetate (EtOAc) (TablVeie1w,AErtnictleryOn1li4ne
dichloromethane (DCM)22
(
Fig.
2
,
c) using 1,4-
(
)
DOI: 10.1039/C8OB01029C
diazabicyclo[2.2.2]octane (DABCO) as the catalyst instead. showed some tolerance to the reaction. However, N,N-
What’s more, reaction of phenyl salicylate with aldehydes could dimethylformamide (DMF) (Table 1, Entry 12) and toluene
yield the ring-closure products too,23 though it had
a
(
Table 1, Entry 13) resulted in sharp drop in the yield. In fact,
requirement on the substituents on the salicylate ring (Fig. 2, the reaction was found to provide a complicated mixture in
). While o-anisic acid protocol was proved feasible along with DMF due to the strong reactivity; while the poor solubility for
d
1,3-diiodo-5,5-dimethylhydantoin (DIH) by photocatalysis (Fig. the alicyclic acid in toluene might be the main reason of the low
2, e). 24 Besides, several metal-catalyzed ring-closure reactions yield. Some other conditions were further investigated. When
for salicylic acid derivatives had also been investigated (Fig. 2, the reaction temperature was raised to 50 °C (Table 1, Entry
f
).25,26 Despite of the progress acquired, some problems such as 16), the yield had a slight drop. The amount of catalyst exhibited
complicated procedures, limited substrate scope, harsh great effect on the yield and 20% catalyst loading is the best. In
conditions and the waste from metal catalysis still exist. contrast, the yield dropped to 42 % at 5% catalyst loading (Table
Following up our previous studies,27,28 organocatalyzed cascade
process was taken into our consideration to build this unique
skeleton for its green process, mild conditions and broad
application.
Table 1 Optimization of the reaction conditionsa
On the other hand, ynone is a useful synthon for the
construction of heterocyclic skeletons in many fields such as
total synthesis of natural products29-32 and drug discovery.33-35
T. K. Vijay and co-workers once used terminal ynone to prepare
the desired products having a 2-tertiary carbon structure under
the catalysis of triethylamine (Fig. 2, g),36 but the system didn’t
work for internal ynones. This leads to a limited substrate scope.
Inspired by Tong’s,34 Wang’s37,38 and Kwon’s39 recent work,
secondary amine catalyzed (all-)enamines/imines cascade
process40-45 may been considered as a potential pathway to
construct complicated benzodioxin skeletons. Herein we report
a successful application of this protocol in the synthesis of 4H-
Benzo[d][1,3]dioxin-4-one compounds with 2-site quaternary
carbon structure. A new reaction path is also revealed, which is
different from the existing allenamine activation model in this
cascade process.
Entry
1
Catalyst
Pyrrolidine
L-Proline
SnCl4
Solvent
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
Acetone
DMF
Yield
91 %
-
2
3
--
4
Quinine
-
5
DBU
-
6
TEA
-
7
DMAP
-
8
KOH
-
9
Piperidine
Morpholine
Morpholine
Morpholine
Morpholine
Morpholine
Morpholine
Morpholine
Morpholine
Morpholine
65 %
92 %
80 %
13 %
16 %
60 %
67 %
81 %
42 %
85 %
Results and discussion
On the basis of our previous work on the synthesis of polycyclic
heterocycles and the domino syntheses,27,28 a novel cascade
sequence starting from salicylic acid (1a) and commercially
10
11
12
13
14
15
16b
17c
18d
Toluene
EtOAc
CH3CN
DCM
DCM
DCM
available 4-phenyl-3-butyn-2-one
(
2a)
to afford 4H-
benzo[d][1,3]dioxin-4-one (3a) catalyzed by secondary amines
was firstly tried (Table 1). As showed in Table 1, pyrrolidine as
the reaction catalyst led to the desired product with a high yield
of 91% at room temperature (Table 1, Entry 1), but L-proline
just gave a very poor result (Table 1, Entry 2), this was also
consistent with that catalyzed with Lewis acid TiCl4 (Table 1,
Entry 3). Furthermore, some other organic bases such as
quinine,
1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU),
a
General conditions: 1a (0.3 mmol), 2a (0. 3 mmol), catalyst (20
triethylamine (TEA) and 4-dimethylaminopyridine (DMAP)
mol%), solvent (2 mL). stirred for 24 h under RT; b temp = 50 °C
mol% catalyst loaded; d 40 mol% catalyst loaded.
;
c 5
(
(
Table 1, Entries 4-7) were tested along with inorganic base KOH
Table 1, Entry 8), and no product was given. This suggest
special secondary amine might be necessary to initiate this
reaction. After realizing this, several secondary amines such as
piperidine and morpholine (Table 1, Entries 9-10) were
examined. To our delight, morpholine worked well with a yield
of 92 %. The feasibility of the reaction in other solvents was also
evaluated. Significant solvent effect on this reaction was
displayed. Acetone (Table 1, Entry 11), acetonitrile (CH3CN)
1, Entry 17). 40% catalyst loading also brought a negative
influence on the yield (Table 1, Entry 18).
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3c VS 3f
With the optimal reaction conditions in hand, substrate scope acids were better than 5-substituted ones (3b VSV3ieew Article Online
of the transformation was evaluated respectively. As shown in 3d VS 3g). 3) Substrates with a strong wDitOhId: r1a0w.10in39g/Cg8roOuBp010su29cCh
Scheme 1, different substituted salicylic acids were at first as -NO2 3i) and –CF3 group (3j) both afforded good yields.
,
,
(
Similarly, substitution on 4-site performed better than that on
5-site. These clearly reflect the effect of substituent site on
charge distribution of the aromatic ring and the product yield.
Salicylic acid bearing a 4-site electron withdrawing group (EWG)
might have greater acidity than those with 5-site counterpart
for comprehensive influence on both the carboxyl group and
the phenolic hydroxyl part. 4) While 4-methoxyl, 4-methyl and
5-methyl salicylic acids with an electron donating group were
used instead, in contrast, corresponding products 3k, 3l and 3m
were afforded in lower yields. 5) Furthermore, the reaction also
acquired a good yield when 3-hydroxy-2-naphthoic acid with a
Scheme 1. Scope of Substrates (I)a
a Reaction conditions:
(0.3 mmol), 2 (0. 3 mmol), Morpholine
1
(20 mol%), DCM (2 mL). Stirred for 24 h under RT; Isolated yield
Scheme 2. Scope of Substrates (II)a
tested, and several results can be found as below: 1) Overall,
whether electron-withdrawing group or electron donating one
were introduced to the phenyl ring, they all led to drop of the
product yield. However, the former was still superior to the
latter (3b-3j vs 3k-3m). 2) Halogenated salicylic acids as the
substrates provided the corresponding products 3b-3g in 70 %
a Reaction conditions:
1 (0.3 mmol), 2 (0. 3 mmol), Morpholine
(20 mol%), DCM (2 mL). Stirred for 24 h under RT; Isolated yield
larger electron-deficient aromatic ring was employed (3n). We
also tested other substrates in place of salicylic acid (see SI,
Table S3), however, only pyrocatechol afforded dioxoles
to 89 % yields, more specifically, 4-halogen substituted salicylic
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products (4a). This indicates that the hydroxyl group may play a catalysis of secondary amines, which demonstrates its key role
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key role to trigger this process, and the further addition is also in the process. Several literatures haDdOIa:l1s0o.10p3r9o/Cp8oOsBe0d10t2h9iCs
of the same importance that leads to the stable target molecule, activation mode, especially the possibility of alkyne activating
in which the mono added products couldn’t been found.
Subsequently, different kinds of ynones were investigated,
too (Scheme 2). First tested 3-butyn-2-one had low reactivity
instead of carbonyl.47-49
(
3o), and 3 equiv. of additive potassium acetate was necessary
for fluent reaction with a 75% yield, which was similar to
previous research on the terminal ynone.35 On the contrary,
substituted 3-butyn-2-ones could react with high efficacy under
no addition of the additive and afford corresponding desired
benzodioxin products in good yields, whether they have a
substituted phenyl (3p, 3q, 3s-3v) or aliphatic group (3r).
Furthermore, we also try 4-(trimethylsilyl)but-3-yn-2-one to
synthesize 3w, but at last only 3o was collected in 82% yield, it
seems TMS group was broken in the acidic environment. Some
other observation should be addressed. Several substrates did
not work at all in this reaction, for 3x, maybe this was caused by
the bulky steric hindrance from the naphthyl group. While for
3y and 3z, excessive electron withdrawing ability might hinder
the trigger process.
After completing the substrate screening, we further
explored the mechanism by means of 1H NMR analysis. In
comparison with the obtained spectra for the model reaction
with or without catalyst added, the difference distinctly
appeared in Fig. 3. At the starting point, no catalyst was added
into the reaction system. A clear methyl group signal (δ = 2.49)
from substrate 2a was appeared in the 1H-NMR spectrum
(Upper part in Fig. 3). With the addition of morpholine and
Fig. 4 Proposed Mechanism for the cascade process.
Therefore, it is proposed that the reaction follow a
mechanism of dual Michael addition process (Fig. 4). At first
substrates 3-butyn-2-ones (
morpholine ( ) to afford a α,β-unsaturated ketone (
than an allenamine. Our analysis of intermediate can surely
characterize this structure. Then, this α,β-unsaturated ketone
) would went through a transitional state ( ) under the
assistance of hydrogen bond. Subsequent dual Michael cascade
process proceeded to bear 6, 7 and in the end. We proposed
2) underwent a direct addition with
1
3) rather
3
(
3
5
8
the mechanism like this: The phenolic hydroxyl group first
attacked the conjugated system and triggered the 1st Michael
addition to form compounds 6. This step was followed with an
elimination of the morpholine moiety to give 7. Target
molecules
8 were finally yielded via 2nd Michael addition
Fig. 3 Proton signal shift on NMR spectrum analysis
including intramolecular carboxyl group attack and cyclization.
Looking through the process, we can find that the secondary
several minutes later, in contrast, the proton signal of the
methyl group moved to a high-field (δ = 1.63, bottom part in Fig.
amine moiety had escaped from the intermediate molecules
7
3) and it was kept until the reaction end. Similarly, we also
before the last Michael step occurring. Maybe that’s the reason
why previous work including ours didn’t exhibit any
stereoselection.28, 37, 39
observed this same shifting when pyrrolidine was employed
instead of morpholine. This means it is a general process in the
reaction system. Luckily enough, this unknown species was
successfully separated and surely characterized as an
intermediate having α,β-unsaturated ketone structure via LC-
MS and NMR analyses.46 This molecule can continuously react
with salicylic acid to afford the final product without the
Now that intermediate species
3 had been prepared and
characterized, it was supposed that this system can also goes
well on other chemicals similar to salicylic acid. Indeed, the
corresponding benzodioxin was given when salicylic acid was
used. As expected, the reaction didn’t need any catalyst.
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7
J. S. S. Rountree and P. V. Murphy, Org. Lett., 2009, 11
DOI: 10.1039/C8OB01029C
G. A. Holloway, H. M. Hügel, M. A. Rizzacasa, C. Herb, A. Bayer,
View Articl,e 8O7nl1in–e
However, the reactions didn’t happen when other substrates
with single nucleophile arm were employed in the control
experiments (SI, Table S3 on page S15). This indicates that the
first addition of hydroxyl moiety is important to trigger the
reaction, but the further addition is also of the same importance
that leads to the stable target molecule. That’s why we call this
reaction as a cascade process. As a proof, pyrocatechol can
afford the corresponding product benzo[1,3]dioxole in 72%
yield (4a), while phthalic acid and malonic acid cannot work.
This shows the great importance of the nucleophilicity of those
two arms.
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Conclusions
highly efficient and environment-friendly method for
A
constructing the useful skeleton 4H-benzo[d][1,3]dioxin-4-one
with a 2-site quaternary carbon structure was successfully
developed through an organocatalyzed Michael addition
cascade process. Reaction of salicylic acids with the
commercially available 3-butyn-2-ones afforded the target
molecules in up to 92% yield under mild reaction conditions.
Secondary amines such as morpholine were found to be
efficient catalysts for the initiation of the enamine activation
procedure, and the α,β-unsaturated ketone was confirmed as
the key intermediate instead of allenamine, which was strongly
supported by NMR spectra analysis of the reaction system as
well as the characterization of the separated species.
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Conflicts of interest
There are no conflicts to declare.
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Acknowledgements
We would like to thank Science and Technology Program of
Guangzhou (201510010080), Special Financial Fund of
Innovative Development of Marine Economic Demonstration
Project (GD2012-D01-001) for financial support. Besides, we
also need to appreciate Dr. Yuwei He, Ms. Chuyu Cheng for their
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46 Preparation and characterization of intermediate 3: 0.5 mmol
4-phenylbut-3-yn-2-one (2a) was added in a reaction tube,
diluted with DCM, and added with 1 eq. morpholine, stirred at RT
for 12 h. After the reaction finished, the solvent was moved in
vacuo and crude product was purified by column
chromatography. Light yellow oil. 78% yield. For more spectral
information, see supplementary Information: Table S2 on S14
and spectrums on page S45 47
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