Palladium-Catalyzed Cascade Arylation of Vinylogous Esters Enabled by Tris(1-adamantyl)phosphine

Article abstract of DOI:10.1021/acs.orglett.9b03071

Described is a method for the transformation of a cyclic vinylogous ester to the corresponding polyarylated product. We found a catalytic system comprising palladium diacetate and tris(1-adamantyl)phosphine is quite effective in promoting a set of control

Full text of DOI:10.1021/acs.orglett.9b03071

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium-Catalyzed Cascade Arylation of Vinylogous Esters
Enabled by Tris(1-adamantyl)phosphine
Yi-Chi Yang, Yi-Ching Lin, and Yen-Ku Wu*
Department of Applied Chemistry, National Chiao Tung University, 1001 University Road, Hsinchu 30010, Taiwan
S
* Supporting Information
ABSTRACT: Described is a method for the transformation
of a cyclic vinylogous ester to the corresponding polyarylated
product. We found a catalytic system comprising palladium
diacetate and tris(1-adamantyl)phosphine is quite effective in
promoting a set of controlled cascade arylations. As a result, a
range of novel (hetero)aryl-containing scaffolds was synthe-
sized with a high level of efficiency.
he prevalence of (hetero)aryl motifs in biologically active
installation of the second aryl group becomes more difficult
Tcompounds and organic electronic materials has spurred due to the lower reactivity (A vs B).14 As an initial foray to
considerable research efforts on the development of efficient
C−H arylation methods.1 In this context, direct arylation of
C(sp2)−H bonds in arenes has been widely applied for the
assembly of conjugated aromatic frameworks.2 Advancements
on transition-metal catalysis have notably expanded the
capacity of aliphatic C−H functionalization with aryl electro-
philes.3 A subgroup of these leading arylative transformations
involves deprotonative cross-coupling processes of C(sp3)−H
bonds adjacent to a carbanion-stabilizing group, collectively
referred to as α-arylation reactions.4 Building on the seminal
works of Buchwald,5 Miura,6 and Hartwig,7 the palladium-
catalyzed α-arylation of carbonyl derivatives has been refined
as an indispensible tool in the arsenal of synthetic chemists.8
Despite progress, only a handful of reaction systems have been
identified that could enable the successive incorporation of aryl
groups at the α-carbon.9 In particular, forging a polyarylated
quaternary center via α-arylation cascade remains a formidable
challenge.10−13 It is presumed that the nucleophilicity of
enolate B derived from the monoarylation product is
compromised by both stabilizing resonance effects and steric
hindrance posed by the α-aryl group (Scheme 1); hence, the
tackle such a challenge, we herein present novel deprotonative
arylations of cyclic vinylogous esters, facilitated by the
combination of palladium catalysis and tris(1-adamantyl)-
phosphine (PAd3).
Previous works by Zhang,15 Lautens,16 and Wu17 have
revealed that α-alkyl and α-unsubstituted vinylogous esters are
amenable to catalytic α-monoarylation reactions. From their
comprehensive survey, however, Lautens and co-workers found
that the established arylation conditions were not compatible
with a vinylogous ester substrate already bearing an α-aryl
substituent (i.e., 2b, vide infra); this observation echoes with
the presumption summarized in Scheme 1.16 As part of our
ongoing studies toward the synthesis of Amaryllidaceae
alkaloids, we have been optimizing the catalytic arylation of
3-ethoxy-2-cyclohexenone (1a) with 1-bromo-3,4-
(methylenedioxy)benzene. In this context, we sought to
leverage the unique electronic and steric properties of tris(1-
adamantyl)phosphine18 for improving the α-arylation reaction.
In the event, monoarylated product 2a could be synthesized in
relatively high yield in the presence of Pd(dba)2 (3 mol %) and
PAd3 (3.4 mol %) (Table 1, entries 1−4). With Pd(OAc)2 as
the palladium source, we observed that, compared with less
sterically bulky or less electron-releasing ligands, using PAd3 as
the ligand furnished more diarylated product 3a (cf. entries 5−
8). This finding enlightened us about the prospect of
developing synthetically useful cascade α-arylations; hence,
we undertook further variation of reaction parameters.
Increasing the loadings of both Pd(OAc)2 and PAd3 caused
a great improvement in yields of 3a (entries 9 and 10). When
more equivalents of the bromoarene and lithium bis-
Scheme 1. Synthesis of Bisbenzylic Quaternary Carbons by
Catalytic Cascade α-Arylation
Received: August 28, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03071
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Letter
a
Table 1. Evaluation of Conditions
Scheme 2. Comparison of Two Reaction Conditions
yield%
b
yield%
b
entry
1
m:n
[Pd] (mol %) ligand (mol %)
of 2a
of 3a
1.2:2 Pd(dba)2 (3) TTBP·HBF4
52
trace
(3.4)
2
3
4
5
1.2:2 Pd(dba)2 (3) BINAP (3.4)
1.2:2 Pd(dba)2 (3) xantphos (3.4)
1.2:2 Pd(dba)2 (3) PAd3 (3.4)
16
56
72
23
trace
<5
<5
a
Scheme 3. Scope of the Cascade Diarylation of 1a
1.2:2 Pd(OAc)2
(3)
PAd3 (3.4)
42
6
3:3
3:3
3:3
3:3
3:3
6:6
3:3
3:3
3:3
3:3
Pd(OAc)2
(3)
Pd(OAc)2
(3)
Pd(OAc)2
(3)
Pd(OAc)2
(5)
Pd(OAc)2
(10)
Pd(OAc)2
(10)
Pd(OAc)2
(10)
Pd(OAc)2
(10)
PAd3 (3.4)
trace
21
47
7
TTBP·HBF4
(3.4)
PPh3 (3.4)
PAd3 (6)
17
8
35
trace
45
9
trace
trace
trace
trace
trace
18
10
11
PAd3 (12)
PAd3 (12)
PAd3 (12)
PAd3 (12)
PAd3 (12)
PAd3 (12)
76
81
c
12
40
d
13
71
e
14
Pd(OAc)2
(10)
Pd(OAc)2
(10)
17
f
15
51
<5
a
Reactions were evaluated using 1.0 mmol of 1a. For detailed
b
c
procedures, see the Supporting Information. Isolated yield. With
NaHMDS as the base. With 1,4-dioxane as the solvent. Reaction
was conducted at 50 °C. Reaction was conducted at room
d
e
f
temperature. TTBP·HBF4: tri-tert-butylphosphonium tetrafluorobo-
rate. BINAP: ( )-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene.
Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.
(trimethylsilyl)amide (LiHMDS) were employed, 3a was
obtained in a slightly higher yield (cf. entries 10 and 11).
The reaction performed with a sodium base (sodium
bis(trimethylsilyl)amide (NaHMDS)) was less favorable than
that employing LiHMDS (entry 12). Changing the solvent to
1,4-dioxane caused no marked effects in the process (entry 13).
Additional experiments indicated that reaction temperature
(70 °C) is another crucial factor for attaining high efficiency
(entries 14 and 15). To validate that the arylation events
occurred in sequence, we prepared monoarylated product 2b
independently and then examined its conversion to 3b
(Scheme 2). Not unexpectedly, the Pd(OAc)2/PAd3 system
was proven highly competent in this previously elusive
arylation,16 thus delivering 3b in 84% yield.
We decided to apply conditions employing 3 equiv of
bromoarenes to examine the scope of the cascade diarylation
(Scheme 3). Synthesis of α,α-bis(phenyl), α,α-bis(2-naphthyl),
and α,α-bis(biphenyl) products (see 3c−f) could be readily
achieved with high efficiency. Aryl bromides that bear electron-
donating groups (−OMe, −OTBS, −OBn, −NMe2, etc.)
coupled uneventfully with 1a to afford the corresponding
diarylated products 3g−m. Fluoro and trifluoromethyl
a
b
Reactions were evaluated using 0.5 mmol of 1a. Isolated yield.
substituents are compatible with the reaction conditions (see
3n−p). At this stage, we found no apparent correlations
between the product yields and electronic properties of the aryl
bromides. The method also permitted successive installation of
bis(carbazolyl) and bis(indolyl) moieties at the α-carbon (see
3q−s). A five-membered-ring precursor 1b was amenable to
the diarylative protocol giving 3t in 52% yield.
Subsequently, we found that the arylation reaction of a α′-
methyl-substituted congener 1c took an interesting twist.
When 1c was subjected to the standard conditions with 4-
B
DOI: 10.1021/acs.orglett.9b03071
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Letter
bromotoluene, three polyarylated products were identified
(Scheme 4). The structure of the major component was fully
worked well in this reaction system (see 4e and 4f). In the case
with 1f, a vicinal triarylation proceeded smoothly to furnish a
densely functionalized cyclopentenone derivative 4g, whose
structural assignment was unambiguously determined by X-ray
diffraction analysis. It would be difficult to prepare these
triarylated products in one step by currently existing methods.
Mindful of the optimization study (cf. entries 10 and 15 in
Table 1), we noted that the kinetic barrier of the first arylation
reaction is lower than the second event. Taking advantage of
this phenomenon, we were able to achieve a one-pot sequential
introduction of two distinct aryl moieties at the α-carbon by
adding corresponding bromoarenes at different temperatures.
This modular sequence allows a facile construction of
bisbenzylic α-quaternary stereocenters, and its generality is
showcased in Scheme 6. The corresponding dihomo-arylated
Scheme 4. Cascade Triarylation of 1c
characterized and assigned as α,α,γ-triaryl vinylogous ester 4a.
An inseparable mixture of the expected product 3u and a
constitutional isomer 5 was also collected, which implied the
regioselectivity of the second arylative event with 1c is low.
While the distinct reactivity induced by the seemingly remote
methyl group (cf. 1a and 1c) could not be fully accounted, this
result constitutes a rare case in accessing γ-reactivity for the
direct arylation of conjugated carbonyls.19 To our delight, we
were able to increase yields of 4a by simply adding more
equivalents of LiHMDS and 4-bromotoluene. When the
reaction was conducted at room temperature (rt), mono-
arylated compound 2c was generated as the sole product in
76% yield (see Supporting Information).
Scheme 6. Scope of the One-Pot Sequential Diarylation of
1a
a
With viable conditions in hand for the cascade triarylation,
we investigated the scope of this one-step triarylative
transformation (Scheme 5). Representative bromoarenes with
different electronic properties all reacted with 1c to afford the
corresponding triarylated products 4b−d in moderate yields.
Cyclic vinylogous esters bearing n-butyl or benzyl group also
a
b
Scheme 5. Scope of the Cascade Triarylation of α′-
Reactions were evaluated using 0.5 mmol of 1a. Isolated yield.
a
Substituted Substrates
products were not observed in these transformations.
Analogously, we studied the one-pot sequential threefold
arylation of 1c by introducing 4-bromotoluene and 4-
bromoveratrole at different stages, through which a pair of
separable diastereomers 4h and 4h′ was generated in a
combined yield of 45% (see Supporting Information).
To showcase the utility of the method, compound 3a was
subjected to an oxidative aromatic coupling reaction, thereby
providing cyclized product 6 in 67% yield (Scheme 7).
Synthesis of enone 7 was accomplished via a standard Stork-
Danheiser transposition.20 Overall, by integrating the cascade
arylations and selected strategic transformations, we demon-
strated a rapid route to functionalized spiro-fluorene
derivatives of potential interests to organic material science.
Scheme 7. A Concise Synthesis of Spiro-Fluorenes
a
b
Reactions were evaluated using 0.5 mmol of 1. Isolated yield.
C
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(6) Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Palladium-
Catalyzed Regioselective Mono- and Diarylation Reactions of 2-
Phenylphenols and Naphthols with Aryl Halides. Angew. Chem., Int.
Ed. Engl. 1997, 36, 1740−1742.
In summary, we developed a series of new arylative
transformations pertaining to cyclic vinylogous esters. The
ability of these protocols to efficiently construct bisbenzylic α-
quaternary center from synthetically versatile precursors
provides a useful tactic for the synthesis of novel aromatic
architectures. We believe that the introduction of tris(1-
adamantyl)phosphine18 to the field of catalytic α-arylation
reactions presents a promising direction for the discovery of
new bond-forming reactions.21 Further studies aiming to
establish new types of α-arylation reactions by applying the
[Pd]/PAd3 system are currently under investigation.
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Towards New Diversification Tools for Halogenated Metabolites and
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ref 4.
ASSOCIATED CONTENT
■
S
* Supporting Information
(9) For the construction of α-tertiary carbon center via cascade
diarylations, see: (a) Nambo, M.; Crudden, C. M. Modular Synthesis
of Triarylmethanes through Palladium-Catalyzed Sequential Arylation
of Methyl Phenyl Sulfone. Angew. Chem., Int. Ed. 2014, 53, 742−746.
(b) Churruca, F.; SanMartin, R.; Tellitu, I.; Domínguez, E. Palladium-
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Tamoxifen-Related 1,2,2-Triarylethanones. Org. Lett. 2002, 4, 1591−
1594. (c) Astarloa, I.; SanMartin, R.; Herrero, M. T.; Domínguez, E.
Aqueous α-Arylation of Mono- and Diarylethanone Enolates at Low
Catalyst Loading. Adv. Synth. Catal. 2018, 360, 1711−1718. (d) Song,
B.; Himmler, T.; Gooßen, L. J. Palladium/Copper-Catalyzed Di-α-
arylation of Acetic Acid Esters. Adv. Synth. Catal. 2011, 353, 1688−
1694. (e) Satoh, T.; Kametani, Y.; Terao, Y.; Miura, M.; Nomura, M.
Palladium-catalyzed multiple arylation of phenyl ketones with aryl
bromides. Tetrahedron Lett. 1999, 40, 5345−5348. (f) Zheng, B.; Jia,
T.; Walsh, P. J. A General and Practical Palladium-Catalyzed Direct α-
Arylation of Amides with Aryl Halides. Adv. Synth. Catal. 2014, 356,
165−178.
(10) For related works on the synthesis of diarylfluorene via cascade
arylations, see: (a) Cao, X.; Yang, W.; Liu, C.; Wei, F.; Wu, K.; Sun,
W.; Song, J.; Xie, L.; Huang, W. Palladium-Catalyzed Direct Arylation
of C−H Bond To Construct Quaternary Carbon Centers: The
Synthesis of Diarylfluorene. Org. Lett. 2013, 15, 3102−3105.
(b) Chen, J.-J.; Onogi, S.; Hsieh, Y.-C.; Hsiao, C.-C.;
Higashibayashi, S.; Sakurai, H.; Wu, Y.-T. Palladium-Catalyzed
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of 9-Arylfluorene Derivatives. Adv. Synth. Catal. 2012, 354, 1551−
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03071.
Experimental procedures and characterization data
(PDF)
Accession Codes
CCDC 1943073−1943074 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yenkuwu@nctu.edu.tw
ORCID
Yen-Ku Wu: 0000-0002-9269-7444
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Young Scholar Fellowship Program by the
Ministry of Science and Technology in Taiwan (MOST108-
2636-M-009-003) for financial support of this work.
(11) Nambo, M.; Yar, M.; Smith, J. D.; Crudden, C. M. The Concise
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Sequential Arylation: A New Synthetic Approach to Tri- and
Tetraarylmethanes. Org. Lett. 2015, 17, 50−53.
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Triarylation of sp3 C−H Bonds in Heteroarylmethanes: Synthesis of
Triaryl(heteroaryl)methanes. Adv. Synth. Catal. 2018, 360, 1493−
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