Palladium-catalyzed cyclization of alkynoic acids to form vinyl dioxanones bearing a quaternary allylic carbon

Article abstract of DOI:10.1021/acs.orglett.7b02572

A palladium-catalyzed intramolecular reaction of carboxylic acids and alkynes in a novel cyclization manner was developed. This unique cyclization efficiently provided a wide range of complex ring systems-vinyl dioxanones bearing a quaternary allylic carbon. Mechanistic studies suggest an allenyl carboxylate as an intermediate.

Full text of DOI:10.1021/acs.orglett.7b02572

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Cyclization of Alkynoic Acids To Form Vinyl
Dioxanones Bearing a Quaternary Allylic Carbon
Yohei Ogiwara,* Kazuya Sato, and Norio Sakai*
Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science, Noda, Chiba
278-8510, Japan
S
* Supporting Information
ABSTRACT: A palladium-catalyzed intramolecular reaction of carboxylic acids and
alkynes in a novel cyclization manner was developed. This unique cyclization
efficiently provided a wide range of complex ring systemsvinyl dioxanones bearing
a quaternary allylic carbon. Mechanistic studies suggest an allenyl carboxylate as an
intermediate.
propargylic position to form a vinyl lactone instead of alkylidene
ransition-metal-catalyzed intramolecular cyclization via the
Taddition of heteroatom−hydrogen bonds to carbon− lactones (Scheme 1b).3b
In contrast to these traditional intramolecular additions and
carbon multiple bonds is a powerful synthetic strategy in organic
chemistry, because, in principle, the complicated and versatile
heterocycles are directly provided starting from readily accessible
substrates with 100% atom efficiency.1 Possibly the most
representative and extensively studied of starting molecules for
the intramolecular hydrocarboxylation of alkynes are alkynoic
acids. Generally, this type of reaction can occur in either an exo-
or endo-cyclization manner, both of which are favored depending
on the substrate, e.g. the Baldwin’s rules, and/or the choice of
catalyst. For example, the cyclization of benzoic acids bearing an
alkyne provides alkylidene lactones such as the 7-exo-dig and/or
8-endo-dig adducts in the presence of appropriate catalysts, such
as palladium,2a copper,2b silver,2c and gold2c complexes (Scheme
1a). Recently, Breit and co-workers reported a unique cyclization
of acids bearing a terminal alkyne by using a Rh(I)/DPEphos
catalyst system,3 in which the cyclization occurs at the
Breit’s cyclization, we describe herein an unprecedented type of
intramolecular cyclization for alkynoic acids employing a
Pd(0)/tBuXPhos system, to afford 4H-1,3-benzodioxin-4-one
derivatives bearing a vinyl substituent at the quaternary carbon
(Scheme 1c). The 6-membered 4H-1,3-benzodioxin-4-one
frameworks themselves are a core structural unit found in
many natural products.4 In addition, the vinyl substituent at the
quaternary carbon is available as a reaction site for further
transformations. The products provided by this method,
therefore, are considered valuable precursors to diverse,
complicated heterocyclic molecules.
To evaluate the cyclization of alkynoic acid 1a, which is derived
from salicylic acid, the reactions in the presence of a catalytic
amount of Pd(dba)2 and several phosphine ligands (1:2 Pd/P)
were conducted in toluene at 110 °C for 1 h (Table 1). When (2-
biphenyl)di-tert-butylphosphine (JohnPhos) was used as a
ligand, the formation of 6-membered cyclization product vinyl
dioxanone 2a was accomplished in an 80% GC yield, and then
the product was isolated in a 68% yield (entry 1).5 After the
screening of a series of dialkylbiarylphosphines (Buchwald-type
ligands), such as CyJohnPhos, XPhos, and tBuXPhos (entries 2−
4), tBuXPhos proved to be the most effective ligand, as shown in
entry 4 (95% GC yield, 86% isolated yield). However, triaryl- or
trialkylphosphines were less effective for this transformation
(entries 5−7). The bidentate ligands Xantphos and NiXantphos
were also found to be applicable and resulted in 51% and 70%
yields, respectively (entries 8 and 9).
Scheme 1. Transition-Metal-Catalyzed Cyclization of
Alkynoic Acids
Conversion of various alkynoic acids 1 into 2 was then
conducted in the presence of Pd(dba)2/tBuXPhos (Table 2).
The reactions of methyl-substituted versions at the 3-, 4-, and 5-
Received: August 21, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02572
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a
Table 1. Ligand Screening for the Pd(0)-Catalyzed
Cyclization of 1a to 2a
Table 2. Scope of Alkynoic Acids
a
a
Reaction conditions: 1a (0.5 mmol), Pd(dba)2 (0.025 mmol), ligand
b
c
(0.05 mmol), toluene (1 mL), 110 °C, 1 h. GC yield. Isolated yield
(1 mmol scale). Ligand (0.025 mmol).
d
position of the benzene ring, 1b−1d, afforded the expected
cyclization products 2b−2d in 79−82% yields (entries 1−3).
Substrates bearing a methoxy- and a chlorine-substituent, 1e and
1f, provided the products, 2e and 2f, in good yields, whereas with
the bromine-substituted 1g, the yield of 2g was 8% (entries 4−6).
Electron-withdrawing substituents, such as an acetyl, a
trifluoromethyl, and nitro groups, 1h−1k, were also suitable
for the reaction and provided the corresponding heterocycles
2h−2k (entries 7−10). Naphthoic acid derivatives 1l and 1m
afforded 2l and 2m in 72% and 75% yields (entries 11 and 12).
The molecular structure of 2m was confirmed by single crystal X-
ray diffraction analysis, and the ORTEP drawings of 2m are
illustrated in Figure 1.6 Intramolecular reactions of a carboxylic
a
t
Reaction conditions: 1 (1 mmol), Pd(dba)2 (0.05 mmol), BuXPhos
Figure 1. ORTEP drawings of the X-ray crystal structure of (a) (S)-2m
and (b) the packing structure. H-atoms are omitted for clarity.
b
c
(0.1 mmol), toluene (2 mL), 110 °C, 1 h. Isolated yield. JohnPhos
was used as a ligand instead of BuXPhos. 12 h. 20 mol % of
Pd(dba)2 (0.2 mmol) and 40 mol % of BuXPhos (0.4 mmol) were
d
e
t
t
acid with an internal alkyne substituted by a n-butyl, a tert-butyl,
or a phenyl group, 1n−1q, also proceeded in the same cyclization
manner, to form 2n−2q (entries 13−16). The anthranilic acid
derivative 1r was available for this cyclization, giving N-
containing heterocycle 2r in a 64% yield (entry 17). On the
other hand, the expected cyclization was not observed in the case
of an alkynoic acid bearing a methyl substituent at the propargylic
position as a starting substrate.
used.
conditions (Table 3). The reaction proceeded smoothly to
provide the cyclization product 2a-d2 in a 55% yield after 3 min
(entry 1). Then a significant incorporation of deuterium was
observed at the terminal vinylic carbon (C3) of 2a-d2 (1.73 D
with 0.27 H) by H and H NMR analyses, along with a small
amount of the deuterium incorporation at the methyl carbon
(C1) (0.21 D with 2.79 H). As the reaction time was extended to
1 h (86% isolated yield of 2a-d2), the deuterium content at C3
1
2
A deuterium-labeling experiment was next performed as a
preliminary mechanistic study. The reaction of 1a-d2, deuterated
at the propargylic carbon, was carried out under the standard
B
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a
products: the standard intramolecular cyclization products 2a
(0.18 mmol) and 2o (0.16 mmol), and also 2n (0.13 mmol) and
2b (0.12 mmol), produced by annulation via the exchange of the
propargyl fragments.
Table 3. Deuterium-Labeling Experiments
c
D (H) composition at Cn
yield
b
entry
1
time
(%)
C1
0.21 D
(2.79 H)
0.66 D
(2.34 H)
C2
C3
3 min
55
0.00 D
(1.00 H)
1.73 D
(0.27 H)
2
1 h
86
0.03 D
(0.97 H)
1.26 D
(0.74 H)
A migration of the propargyl fragment was also observed when
methyl ester 3a (1 mmol) was treated with benzoic acid (4, 0.5
mmol) under the standard conditions (eq 2). Along with the
production of methyl salicylate (5, 0.55 mmol) formed via
propargylic C−O bond cleavage of 3a, it was determined that the
cleaved propargyl unit was transferred into benzoic acid (4) to
form 1,3-butadien-2-yl benzoate (6, 0.42 mmol).
a
Reaction conditions: 1a-d2 (0.5 mmol), Pd(dba)2 (0.025 mmol),
b
tBuXPhos (0.05 mmol), toluene (1 mL), 110 °C. Isolated yield.
c
1
2
Determined by H and H NMR analyses of the isolated 2a-d2.
was decreased to 1.26 D (from 1.73 D), and instead small
increases were observed (entry 2) in deuterium incorporation at
the methyl- (C1) and at the internal vinylic- (C2) carbon (from
0.21 to 0.66 D at C1, from 0 to 0.03 D at C2). These results
indicated that deuterium is transferred from the propargylic
carbon of 1a-d2 into the terminal vinylic carbon (C3) of 2a-d2 in
the essential conversion process from 1a-d2 into 2a-d2. The
changes in the H/D components at the C1, C2, and C3 positions
of 2a-d2 are considered to be caused by the side reactions
described in Figure 3 (see below) and H/D scrambling process.7
On the basis of the results of the labeling studies, and literature
by several research groups,3,8 pathways involving an allene
intermediate were proposed (Figure 2). One of the possible
pathways is a reaction between Pd(0) and the carboxylic acid part
of 1a that leads to the formation of palladium carboxylate A1
(Figure 2, path A). The generation of allene intermediate B
occurs through either a sequential carboxy-palladation/β-aryloxy
elimination or a concerted SN2′-type substitution. A pathway
starting from the propargylic C−O bond cleavage to form A2
following cyclization is also plausible (Figure 2, path B).9
Regardless, both of the intermediates result in the production of
allenyl carboxylate B. The next step involves the insertion of the
allene into a Pd(II)−H bond to form the π-allylpalladium species
C, which finally undergoes reductive elimination of the allylic C−
O bond of the vinyl dioxanone 2a, with return of the Pd(0) to its
original state.
Though it is not obvious which pathway proposed in Figure 2
is plausible, these results imply that the mechanism via the
intermediate A2 (path B) is more reasonable than that via A1
(path A) for the present cyclization. For the intermediate A2,
three coordination modes are possible; η1-propargyl, η3-allenyl/
propargyl, and η1-allenyl palladium species and a reaction at the
electrophilic central carbon of A2 can also occur (Figure 3).10 In
the pathway, after the initial nucleophilic addition of the
carboxylic acid to the central carbon, formation of the π-
allylpalladium species and β-hydride elimination leads to a
palladium complex bearing 1,3-butadien-2-yl benzoate fragment
D. Subsequently, hydropalladation affords the π-allylpalladium
C′, which gives the 6-membered product 2a′-d2 bearing
deuterium at the methyl carbon (C1), not at the terminal vinylic
carbon (C3). Although deuterium was predominantly located at
C3 of 2a-d2 in the labeling experiments (Table 3), a small amount
of the deuterium incorporation at C1 and formation of diene 6
A crossover experiment using different alkynoic acids, 1a and
1o, as starting substrates was then examined (eq 1). The reaction
of 1 equiv (0.5 mmol) each of 1a and 1o afforded four kinds of
Figure 2. Possible pathways for the palladium-catalyzed conversion of 1a-d2 into 2a-d2.
C
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(eq 2) indicate that the mechanism in Figure 3 also exists as a
minor pathway.
Yorimitsu (Kyoto University) for suggesting the crossover
experiment. We also thank Yui Suzuki (Tokyo University of
Science) for her assistance for this work.
REFERENCES
■
(1) Selected reviews of transition-metal-catalyzed cyclization of
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Figure 3. A possible minor pathway.
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In summary, we have developed an unprecedented entry for
intramolecular cyclization, which involves catalytic conversion of
alkynoic acids to 6-membered heterocyclic compounds contain-
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Pd(0)/tBuXPhos. No stoichiometric additive, such as a base, was
required, and therefore, various types of alkynoic acids were
available for this transformation. The preliminary mechanistic
studies implied that the allene species is a possible intermediate.
Further studies of this unique method must involve the
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application to other types of substrates such as carboxamides,
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experiments are now underway in this laboratory.
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(5) The structure of 2a was determined by 1H and 13C NMR, NOESY,
1
1H-1H COSY, HMQC, and HMBC analyses. The H and 13C NMR
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02572.
X-ray crystallographic data for 2m (CIF)
Experimental procedures and characterization data for 1,
2, and 3; X-ray crystallographic data for 2m (PDF)
(9) Selected examples of oxidative addition of propargylic C−OAr
bond to palladium(0): (a) Pal, M.; Parasuraman, K.; Yeleswarapu, K. R.
Org. Lett. 2003, 5, 349. (b) Rambabu, D.; Bhavani, S.; Swamy, N. K.;
Basaveswara Rao, M. V.; Pal, M. Tetrahedron Lett. 2013, 54, 1169.
(10) Selected examples and reviews: (a) Su, C.-C.; Chen, J.-T.; Lee, G.-
H.; Wang, Y. J. Am. Chem. Soc. 1994, 116, 4999. (b) Tsuji, J.; Mandai, T.
Angew. Chem., Int. Ed. Engl. 1995, 34, 2589. (c) Baize, M. W.; Blosser, P.
W.; Plantevin, V.; Schimpff, D. G.; Gallucci, J. C.; Wojcicki, A.
Organometallics 1996, 15, 164. (d) Tsutsumi, K.; Ogoshi, S.; Nishiguchi,
S.; Kurosawa, H. J. Am. Chem. Soc. 1998, 120, 1938. (e) Tsutsumi, K.;
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: yoheiogiwara@rs.tus.ac.jp.
*E-mail: sakachem@rs.noda.tus.ac.jp.
ORCID
Yohei Ogiwara: 0000-0003-1438-0916
Norio Sakai: 0000-0003-0722-4800
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partially supported by JSPS KAKENHI Grant
Number JP16K21400 and by a Research Grant from Shorai
Foundation for Science and Technology, a Grant from Central
Glass Co., Ltd. Award in Synthetic Organic Chemistry, Japan,
and a Research Grant from Takahashi Industrial and Economic
Research Foundation. We are grateful to Prof. Dr. Hideki
D
DOI: 10.1021/acs.orglett.7b02572
Org. Lett. XXXX, XXX, XXX−XXX