Cationic palladium-catalyzed [5+2] annulation: Synthesis of 1-benzoxepines from 2-aroylmethoxyarylboronic acids

Article abstract of DOI:10.1002/adsc.200700369

The synthesis of 1-benzoxepines from 2aroylmethoxyarylboronic acids and alkynes in the presence of a catalytic amount of [Pd(dppp)(H₂O) ₂J²⁺(TfC^-)₂ was developed. This [5+2] annulation involves the in

Full text of DOI:10.1002/adsc.200700369

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DOI: 10.1002/adsc.200700369
Cationic Palladium-Catalyzed [5+2]Annulation: Synthesis of
1-Benzoxepines from 2-Aroylmethoxyarylboronic Acids
Guixia Liua and Xiyan Lua,*
a
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Lu, Shanghai 200032, Peopleꢀs Republic of China
Fax : (+86)-21-64166128; e-mail: xylu@mail.sioc.ac.cn
Received: June 29, 2007; Revised: July 27, 2007
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: The synthesis of 1-benzoxepines from 2-
aroylmethoxyarylboronic acids and alkynes in the
ketones [Eq (1)].[7] Bearing both a nucleophilic
carbon-boron bond and an electrophilic carbonyl
bond, the substrate 2-aroylmethoxyarylboronic acids
1 are in fact ambiphilic bifunctional arylboron com-
pounds. In contrast to the seminal studies on the Rh-
catalyzed cascade reaction of bifunctional organobor-
ons and alkynes,[8,9] the corresponding palladium-cata-
lyzed reaction has not been seen, perhaps owing to
the lower nucleophilicity of the vinylpalladium spe-
cies.[10]
presence of a catalytic amount of [Pd
A
ACHTREUNG
lation involves the intramolecular nucleophilic addi-
tion of a vinylpalladium species to ketones.
Keywords: alkynes; arylboronic acids; benzoxe-
pines; cationic palladium; ketones
Inspired by the examples of the addition of vinyl-
palladium species to ketones,[6,10] we next attempted
to extend the application of substrate 1 from simple
The 1-benzoxepine moiety is an important structural intramolecular addition reaction to the tandem cycli-
unit in many natural products,[1] biologically active zation with alkynes [Eq (1)]. Unlike most Pd(0)-cata-
molecules,[1b] and natural herbicides.[2] The simple and lyzed nucleophilic addition reaction in which a Pd(0)/
efficient synthesis of 1-benzoxepine derivatives is at- Pd(II) redox system must be involved,[5] using Pd(II)
tractive in synthetic organic chemistry and medicinal as the catalyst for this type of reaction may be advan-
chemistry.[3] We reported herein a new, efficient syn- tageous regarding the maintenance of Pd(II) through-
thesis of 1-benzoxepines by cationic palladium-cata- out the catalytic cycle.
lyzed tandem cyclization of 2-aroylmethoxyarylboron-
ic acids (1) and alkynes (2) [Eq (1)] involving the ad- in combination with alkyne 2a (2 equivs.) to test the
dition of vinylpalladium species to ketones. possibility of the tandem reaction (Table 1). This cas-
Initially, we chose 1a (1 equiv.) as a model substrate
In general, vinylpalladium species have a relatively cade reaction would be obviously unfavorable due to
low nucleophilicity.[4] There are only a limited number the facility of intramolecular cyclization[7] and the
of examples concerning the direct addition of vinyl- generation of a seven-membered ring which occurred
palladium species to electrophilic carbon-heteroatom uncommonly. In spite of these obstacles, the cascade
multiple bonds, such as ketones.[5] Our group previ- cyclization of 1a and 2a did take place with a catalytic
[11]
ously reported the Pd(II)-catalyzed cyclization of al- amount of [Pd
G
(H2O)2]2+(TfOÀ)2
in dioxane
kynes containing ketones initiated by the acetoxypal- at 608C. Although only a trace of the desired product
ladation[6a] or carbopalladation[6b] of alkynes.
3aa was produced, the dehydrated product 4aa was
We recently reported the cationic palladium-cata- isolated in moderate yield (72%, Table 1, entry 1). To
lyzed intramolecular addition of arylboronic acids to prevent the dehydration of the normal product, the
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Guixia Liu and Xiyan Lu
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Table 1. Optimizing the tandem cyclization conditions.[a]
pines in moderate to good yields (57–94% yield,
Table 2). When the arylboronic acid 1c bearing an
ortho-substituted aryl ketone was subjected to the re-
action conditions, a good yield (89%) was still achiev-
ed (Table 2, entry 3). Alphatic ketone 1f was able
to react with 2a at 808C to produce 3fa in 41% yield
(Table 2, entry 7). We then investigated the effect of
substituents on the aromatic ring of the boronic acids.
The reaction of Cl- and CH3-substituted phenylboron-
ic acids 1g and 1h with methyl-2-butynoate (2b) led to
good yields of the desired products (90 and 81%, re-
spectively, Table 2, entries 10 and 11). Thus, the sub-
stitution on ketone or phenylboronic acid did not play
a pronounced role in this tandem cyclization. In spite
of the successful results above, the reaction of sub-
strates 1i–k with butynedioic acid dimethyl ester (2a)
under the optimized conditions resulted in the recov-
ery of the starting materials (Figure 1).
Entry Additive (equivs.)
Product Yield
[%][b]
1
2
3
4
none
4aa
-
3aa
3aa
72
-
90
86
K3PO4 (2), H2O (2)
Ba(OH)2 (1.5)
Amberlite IRA-400 (OH)
(1.5)
Amberlite IRA-400 (OH)
(1.5)
When substrate 1l, bearing a cylic ketone moiety,
was treated with 2b in the presence of 5mol% of
5[c]
3aa
3aa
94
88
[Pd
N
N
ature, a tricyclic product 3lb was formed in moderated
yield (Scheme 1). Encouraged by the good results ob-
tained for alkynes featuring an electron-withdrawing
ester group, alkoxymethyl-substituted alkyne 2d was
also examined for our [5+2]annulation. The reaction
of 2d and 1a under the optimized conditions gave a
complicated mixture of products. If the anion ex-
change resin was subtracted from the reaction, 2d re-
acted with 1a at 908C for two days to produce a 30%
yield of the dehydrated product 3ad (Scheme 1). The
relatively high temperature and low yield suggested
6[c,d]
Amberlite IRA-400 (OH)
(1.5)
[a]
Unless otherwise indicated, all reactions were performed
at 608C using 1a (0.1 mmol), 2a (0.2 mmol) and [Pd-
A
N
under N2.
Isolated yield.
DME was used as the solvent.
1.2 equivs. of 1a and 1 equiv. of 2a was used.
[b]
[c]
[d]
effect of base was examined. Adding K3PO4 that the alkoxymethyl-substituted alkyne is less active
(2 equivs.) and H2O (2 equivs.) resulted in the rapid than ester-substituted alkynes.
decomposition of 2a and none of the annulation prod-
Premilinary results on the asymmetric version of
uct was detected. However, the use of insoluble bases, this protocol are shown in Scheme 2. The annulation
such as Ba(OH)2 or Amberlite IRA-400 (OH), was of 1a and 2a proceeded very slowly catalyzed by
[12]
found to give high yield of the normal product 3aa [Pd((R)-binap)
(H2O)2]2+(TfOÀ)2 and after three to
A
(90% and 86%, respectively, Table 1, entries 3 and four days a moderate asymmetric induction was ob-
4). The yield of 3aa was also affected by the solvent. served. We then turned our efforts to the ligand (S,S)-
Reaction in DME led to the best result (94% yield, bdpp, which has a similar skeleton as dppp. The use
Table 1, entry 5), while in DCE and toluene large of in situ prepared [Pd
N
N
amounts of deboronated product of 1a was obtained. from Pd
AHCTREUNG
The use of 1.2 equivs. of 1a combined with 1 equiv. of reaction rate and the yield of product 3aa, whereas
2a still gave an 88% yield of desired product 3aa. the ee value was still 50%. Other chiral bisphosphine
Furthermore, the [5+2]annulation was not catalyzed ligands such as Segphos and DIOP turned out to be
by Pd
reaction conditions. This indicated that the cationic
palladium complex has great advantages over the could undergo intramolecular addition efficiently cat-
neutral one in this reaction. alyzed by [Pd(dppp)
(H2O)2]2+(TfOÀ)2. Interestingly,
A
ACHTREUNG
A
ACHTREUNG
As shown in Table 2, the cascade cyclization could the intramolecular reaction of 1 did not occur in the
be carried out with a variety of substrate combina- presence of alkynes implying that the stoichiometric
tions of 1 and 2 to furnish a series of 1-benzoxpines. amount of alkynes tuned the chemoselectivity of the
Arylboronic acids 1a–e containing either electron-do- substrates 1, which will be explained from the catalyt-
nating or electron-withdrawing aromatic ketones re- ic cycle.
acted smoothly with substitued propynoic acid methyl
A plausible mechanism of this [5+2]annulation re-
esters 2a–c to afford the corresponding 1-benzoxe- action is shown in Scheme 3. The mono-hydroxo cat-
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Synthesis of 1-Benzoxepines from 2-Aroylmethoxyarylboronic Acids
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Table 2. [Pd
N
N
Entry
1
Substrate
t [h]
Product
Yield [%][b]
1
2
1a
2a
33
94
2[c]
1b
1c
1d
2a
2a
2a
16
18
4
57
89
82
3
4
5
6
1e
1a
2b
2b
4
87
59
12
7[c]
1f
2a
36
41
8
1b
1d
2b
2b
72
12
75
87
9[d]
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Guixia Liu and Xiyan Lu
Yield [%][b]
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Table 2. (Continued)
Entry
Substrate
t [h]
Product
1
2
10
1g
2b
5
90
81
68
11
1h
1b
2b
2c
4
12
12
[a]
Unless otherwise indicated, all reactions were performed using 1 (0.1 mmol), 2 (0.2 mmol), Amberlite IRA-400 (OH)
(1.5equivs.) and [Pddppp
A
[b]
[c]
[d]
Isolated yield.
The reaction temperature was 808C.
The reaction temperature was 408C.
cationic palladium center in species C may activate
the carbonyl group by coordination resulting in facile
1,2-addition of vinylpalladium to ketone to furnish
the seven-membered ring intermediate D which, upon
hydrolysis, forms product 3 and regenerates the cata-
lytically active species A. Thus, the presence of a
vacant coodination site and high Lewis acidity of cat-
Figure 1. The limitation of substrates.
ionic palladium species A[12c,14] is believed to be the ionic palladium[16] are cricial for the the addition of vi-
active catalyst, which enables smooth transmetalation nylpalldium to ketones.
with the substrate 1 without any assistance of additive
It is supposed that the tuneable role of alkynes may
bases.[7,15] Meanwhile, the alkyne will coordinate to arise from the stronger affinity of the late transition
the palladium center followed by regioselective carbo- metal palladium with the carbon-carbon triple bond
palladation giving intermediate C, in which the palla- rather than with the intramolecular carbonyl group in
dium is proposed to coordinate with the oxygen atom intermediate B, facilitating the insertion of alkynes
of the internal ketone. The high Lewis acidity of the into the carbon-palladium bond to form intermediate
Scheme 1.
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Synthesis of 1-Benzoxepines from 2-Aroylmethoxyarylboronic Acids
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Scheme 2. Preliminary results of the asymmetric version of the reaction.
Scheme 3. Plausible mechanism of the [5+2]annulation.
was stirred at 608C for 33 h. After the reaction was complet-
ed as monitored by TLC, the reaction mixture was cooled to
room tempretrue, filtered and concentrated. The residue
was purified by flash column chromatography to afford the
3aa; yield: 36 mg (94%).
C. Otherwise, intermediate B’ will be formed favoring
the intramolecular reaction.[7]
In summary, we have achieved the synthesis of 1-
benzoxepines from 2-aroylmethoxyarylboronic acids
(1) and alkynes in the presence of a catalytic amount
For full experiemntal details and characterization data of
all new compounds, see Supporting Information.
of [Pd
N
N
involves the intramolecular nucleophilic addition of a
vinylpalladium species to ketones and no redox re-
agent for the Pd(II)/Pd(0) system is involved. Further
studies on the asymmetric version of this reaction are
underway in our laboratory.
Acknowledgements
Major State Basic Research Program (2006CB806105). We
also thank the National Natural Science Foundation of China
(20423001) and Chinese Academy of Sciences for financial
support.
Experimental Section
Typical Procedure
References
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