A Ba/Pd Catalytic System Enables Dehydrative Cross-Coupling and Excellent E-Selective Wittig Reactions

Article abstract of DOI:10.1021/acs.orglett.9b02623

A Ba/Pd cooperative catalysis system was developed to enable the dehydrative cross-coupling of allylic alcohols with P-ylides to occur directly and promote a subsequent Wittig reaction in one pot. A variety of multisubstituted 1,4-dienes were isolated in good to excellent yields with broad P-ylides (stabilized by both ester and ketone carbonyl groups) and aldehyde (aliphatic and aromatic) substrates with excellent E selectivity.

Full text of DOI:10.1021/acs.orglett.9b02623

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
A Ba/Pd Catalytic System Enables Dehydrative Cross-Coupling and
Excellent E‑Selective Wittig Reactions
Peizhong Xie,*,† Weishan Fu,† Xinying Cai,† Zuolian Sun,† Ying Wu,† Shuangshuang Li,†
Cuiqing Gao,‡ Xiaobo Yang,† and Teck-Peng Loh*,†,§
†School of Chemistry and Molecular Engineering, Institute of Advanced Synthesis, Nanjing Tech University, Nanjing 211816, P. R.
China
‡Co-Innovation Center for the Sustainable Forestry in Southern China, College of Forestry, Nanjing Forestry University, Nanjing
210037, China
§Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371
S
* Supporting Information
ABSTRACT: A Ba/Pd cooperative catalysis system was developed to enable the dehydrative cross-coupling of allylic alcohols
with P-ylides to occur directly and promote a subsequent Wittig reaction in one pot. A variety of multisubstituted 1,4-dienes
were isolated in good to excellent yields with broad P-ylides (stabilized by both ester and ketone carbonyl groups) and aldehyde
(aliphatic and aromatic) substrates with excellent E selectivity.
rivileged 1,4-diene motifs have received a growing amount
of attention in organic synthesis and life science owing to
allylic alkylation (ester-stabilized P-ylides with allylic carbo-
nates) and the Wittig process for the preparation of 1,4-dienes
were reported by You and co-workers.10 In this amazing
protocol, the Trost ligand (11 mol %) and Cs2CO3 (1.5 equiv)
were essential for suppressing the coordination of P-ylides to
Pd and ensuring the reactivity of the catalyst and the P-ylide
(Scheme 1a). Unfortunately, the reaction was sluggish toward
P
their versatile reactivity1 and wide distribution in pharmaceuti-
cally and biologically active molecules2 (such as ripostatin,2a−f
piericidin,2g−i jerangolid,2j,k and vicenistatin2l). The develop-
ment of powerful methodologies for preparing multisubstituted
1,4-dienes has been a major focus of the synthetic community.
With continuing efforts, many impressive advancements,
including ene reactions,3 transition metal-catalyzed cross-
coupling (activated allylic compounds with alkenylmetals4 or
simple alkenes5), formal Baylis−Hillman reactions,6 etc.,7 have
been reported. However, the drawbacks, including the harsh
reaction conditions, tedious operational processes, limited
substrate scope, and the poor selectivity, have impeded the
wide application of these methodologies. Thus, the develop-
ment of novel synthetic methods, especially with synthetically
reliable feedstocks, for the preparation of multisubstituted 1,4-
dienes in an environmentally benign manner is strongly
desired.
Scheme 1. Allylic Alkylation of P-Ylides and the Following
Wittig Reaction for the Preparation of Multisubstituted 1,4-
Dienes
Undoubtedly, the Wittig reaction of allylic P-ylides with
aldehydes is a straightforward method toward multisubstituted
1,4-dienes. However, the steps of the transformation and
tedious purification processes are inevitable for the preparation
of allylic P-ylides.8 Moreover, the inherent semistability of
allylic P-ylides and poor selectivity of Wittig reactions render
the preparation of 1,4-dienes via the Wittig protocol a
formidable task.9 In 2010, the one-pot palladium-catalyzed
Received: July 26, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02623
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Letter
aromatic or aliphatic aldehydes in addition to formaldehyde. In
the case of formaldehyde, allylic amines11 or alcohols12 were
then identified as suitable coupling partners of the much more
stable P-ylides (stabilized with a ketone carbonyl group) for
preparing allylic P-ylides, but the following Wittig reaction was
restricted to formaldehyde.11,12 This result can be attributed to
the steric effects and strong coordination to the transition
metal of the allylic P-ylide disfavored in the Wittig process.13
Therefore, the preparation of allylic P-ylides and the substrate
scope of the following Wittig reaction remain important
challenges. With our continued interest in green chemistry,14
we embarked on the development of a novel catalytic system to
address the obstacles concerning the poor synthetic efficiency
of allylic P-ylides and the sluggish reactivity of the Wittig
reaction toward carbonyl compounds besides formaldehyde.
Herein, we report that a Ba/Pd cocatalyst enables the allylic P-
ylides to be generated directly via a dehydrative cross-coupling
with allylic alcohols. Wide-spectrum aromatic and aliphatic
aldehydes were compatible in the following Wittig reaction,
which is attributed to the CO bond activation and six-
membered intermediate formed with the assistance of Ba
(Scheme 1b).
Scheme 2. Ba/Pd Cocatalyzed Dehydrative Cross-Coupling
and Wittig Reaction Involving Allylic Alcohols
a
We embarked on our investigation by selecting allylic
alcohols 1 and ester-stabilized P-ylides 2 as model substrates
with palladium as the catalyst. For the cocatalyst, we paid
special attention to alkaline-earth metals,15 which are abundant
and exhibit amazing catalytic activities for Friedel−Crafts and
related cationic cycloadditions involving alcohols.16 Initially,
Ca(NTf2)2 was introduced into this reaction mixture to
cooperate with palladium and promote the sequential reaction
transformation (Supporting Information, Table 1, entries 1−
3). In the presence of a Pd(PPh3)4 (3 mol %)/Ca(NTf2)2 (10
mol %) catalytic system in THF, the desired 1,4-diene 3a was
detected in 34% yield (NMR yield) after 48 h and quenching
with HCHO for an additional 12 h (Supporting Information,
Table 1, entry 2). Pd(dppf)Cl2·CH2Cl2 gave the best yield
(52%) among the palladium sources screened (Supporting
Information, Table 1, entries 2−6). Among all of the tested
alkaline-earth metal catalysts, Ba(NTf2)2 exhibited the best
performance (66% yield) (Supporting Information, Table 1,
entries 6 and 9−12). The traditional strong Lewis acids
Sc(OTf)3 and Al(OTf)3 delivered the desired product in a low
yield, or no reaction occurred (Supporting Information, Table
1, entries 10 and 11). Without a cocatalyst, Pd(dppf)Cl2·
CH2Cl2 itself can give only the 1,4-dienes in a much lower
yield (11%) (Supporting Information, Table 1, entry 7). The
effect of the solvent was subsequently investigated (Supporting
Information, Table 1, entries 12−16). The best result was
obtained in DMSO with 3a isolated in 90% yield. The reaction
also can performed well when the cocatalyst Ba(NTf2)2 loading
is decreased to 5 mol % (Supporting Information, Table 1,
entry 17). However, this cross-coupling step was sensitive to
the temperature and palladium loading (Supporting Informa-
tion, Table 1, entries 18−20).
a
Reaction conditions: Pd(dppf)Cl2·CH2Cl2 (3.0 mol %), Ba(NTf2)2
(5.0 mol %), 1 or 1′ (0.36 mmol), and 2 (0.3 mmol) in DMSO (2.0
mL) at 100 °C for the indicated time, then excess formaldehyde
(37%, 0.5 mL) added followed by stirring for an additional 12 h at
room temperature. Isolated yields are reported. Yields in parentheses
were generated from 1′.
incorporated into the desired 1,4-diene skeletons. Allylic
alcohols bearing heteroaryl groups, such as pyridien-3-yl
(3h) and furan-2-yl (3i), were well tolerated. Fused aromatic
allylic alcohols were also suitable substrates for this reaction
(3j and 3k). Moreover, 1,4,6-triene skeletons can be obtained
in good yield by selecting (E)-1-phenylpenta-1,4-dien-3-ol (3l)
or 5-methylhexa-1,4-dien-3-ol (3m) as the initial substrate.
Allylic compounds with alkyl substituents were more sluggish
compared with the aryl-substituted versions, and thus, harsh
reaction conditions was generally required to ensure the
desired transformations.12 Remarkably, either cyclic (3o) or
acyclic alkyl (3p−3r) substituted allylic alcohols were well
tolerated and generated the corresponding 1,4-dienes in
moderate to high yields.
Subsequently, the scope of the P-ylides and aldehydes was
investigated (Scheme 3). Increasing the steric hindrance of the
ester group on the P-ylides disfavored the process and resulted
in a lower yield (3s and 3t). As expected, P-ylides stabilized
with a benzoyl group can also participate in this transformation
and deliver the desired product in good to excellent yields
irrespective of the electron-withdrawing or electron-donating
group on the phenyl ring (3u−3ac). 3,3-Dimethyl-1-
(triphenyl-15-phosphaneylidene)butan-2-one (3ad) and 1-
cyclopropyl-2-(triphenyl-15-phosphaneylidene)ethan-1-one
(3ae) were found to be suitable precursors for this trans-
Under the optimized conditions, the generality of allylic
alcohols was first explored. As shown in Scheme 2, the reaction
performed well with a wide spectrum of allylic alcohols
containing a variety of substituents. For the aryl-substituted
allylic alcohols, the electronic properties and position of the
substituents on the phenyl ring had a limited effect on the yield
(3a−3g). The electron-deficient substrates can also participate
in this transformation, albeit with a lower yield (3d and 3e).
Trifluoromethyl (3d) and nitro (3e) groups can be
B
DOI: 10.1021/acs.orglett.9b02623
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Letter
corresponding 3-phenylpropionaldehyde or cinnamaldehyde as
the starting material, respectively. The diverse functional
groups connected with 1,4-dienes increase the likelihood of
their modulation and greatly enhance their synthetic utility.
Unfortunately, ketones such as acetophenone, propan-2-one,
and 2,2,2-trifluoro-1-phenylethan-1-one cannot participate in
this transformation under the standard conditions. In all test
cases, the trisubstituted 1,4-dienes were exclusively generated
with the E configuration, as confirmed by X-ray analysis (3al).
The synthetic utility of the current method was preliminarily
investigated (Scheme 4). Compound 3ao can be prepared in
Scheme 3. Ba/Pd Cocatalyzed Dehydrative Cross-Coupling
and Wittig Reaction Involving a Variety of P-Ylides and
Aldehydes
a
Scheme 4. Utility of This Protocol and Synthetic
Transformation of 1,4-Dienes
high yield on the gram scale (1.2 g). The TMS moiety of 3ao
can be conveniently removed by treatment with TBAF in
aqueous media to give 4. Compound 4 could be further
connected with the antiviral drug Zidovudine17 via a click
reaction, delivering the new compound 5 in 90% yield. Even
the steroid moiety with an active hydroxyl group was well
tolerated (compound 6), which further highlights the utility of
this method in pharmaceutical studies.
The detailed mechanism of this transformation is still
unclear. According to previous reports10−12 and our related
investigation,14g we proposed the mechanism shown in Figure
1. Initially, the C−OH bond is activated due to the formation
a
Reaction conditions: Pd(dppf)Cl2·CH2Cl2 (3.0 mol %), Ba(NTf2)2
(5.0 mol %), 1a (0.36 mmol), and 2 (0.3 mmol) in DMSO (2.0 mL)
at 100 °C for the indicated time, then excess formaldehyde (37%, 0.5
mL) or other aldehydes (0.36 mmol) added and stirred for an
additional 12 h at room temperature. Isolated yields are reported.
formation. We then switched our attention to the scope of
aromatic and aliphatic aldehydes. It should be noted that these
aldehydes were rarely explored and were considered sluggish
feedstocks when reacted with the stabilized allylic P-ylides,
even at high temperatures,10 although their incorporation can
greatly expand the range of applications of this reaction.
Pleasingly, the corresponding trisubstituted 1,4-dienes formed
in good to excellent yields with excellent E selectivity using our
developed Ba/Pd catalytic system (3af−3ap). Citronellal can
also be modified with this protocol, albeit with a slightly lower
yield (3ag). In addition to benzaldehyde and its related
derivatives, ferrocenyl aldehyde (3ak), 1H-indole-5-carbalde-
hyde (3al), and thiophene-2-carbaldehyde (3am) were also
compatible. 3,6-Diene-1-yne (3an and 3ao) or 1,3,6-triene
(3ap) skeletons can be obtained conveniently by selecting the
Figure 1. Proposed mechanism.
of the Ba−OH coordinating bond, which enables the direct
oxidative addition of palladium to the C−OH, giving π-
allylpalladium intermediates and hydroxide ions (stabilized
with barium ions). Subsequently, phosphonium salt inter-
mediate A goes through the cross-coupling process. The in
situ-generated hydroxide ion can serve as a base to deprotonate
the intermediate, generate the desired allylic P-ylide, and finish
catalytic cycle I with the regenerated Ba(NTf2)2 catalyst. This
process is also supported by our 31P NMR monitoring
experiments (Supporting Information, Figure 1). Then, the
following Wittig reaction is performed with the assistance of
Ba(NTf2)2 (catalytic cycle II). The CO bond might be
C
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Generated key intermediate B might account for the excellent
stereoselectivity in CC bond formation.
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In summary, we developed a novel Ba/Pd catalytic system
toward the direct dehydrative cross-coupling between P-ylides
and allylic alcohols delivering a variety of stabilized allylic P-
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02623.
Experimental procedures, screening reaction conditions,
analytical data for all new compounds, and NMR spectra
of products (PDF)
Accession Codes
CCDC 1936718 contains the supplementary crystallographic
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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
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*E-mail: peizhongxie@njtech.edu.cn.
*E-mail: teckpeng@ntu.edu.sg.
ORCID
Peizhong Xie: 0000-0002-6777-0443
Teck-Peng Loh: 0000-0002-2936-337X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge the financial support from
the National Natural Science Foundation of China
(21702108), the State Key Program of the National Natural
Science Foundation of China (21432009), the Natural Science
Foundation of Jiangsu Province, China (BK20160977), the Six
Talent Peaks Project in Jiangsu Province (YY-033), the
College Students’ Innovation and Open Experimentation
Fund Project (2019DC0416), the foundation from Singapore
[MOE2016-T1-002-043 (RG111/16)], and Nanjing Tech
University (39837101).
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