Phosphine-Mediated MBH-Type/Umpolung Addition Domino Sequence: Divergent Construction of Coumarins

Article abstract of DOI:10.1021/acs.orglett.9b04248

We herein report a phosphine-mediated domino process of MBH-Type reaction/umpolung γ-Addition through the rational integration of the privileged reactivities of alkynoate. Simply by manipulating the nucleophilic reagent, the developed protocol offers a facile, diversity-oriented construction of a wide range of three-substituted coumarins.

Full text of DOI:10.1021/acs.orglett.9b04248

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Phosphine-Mediated MBH-Type/Umpolung Addition Domino
Sequence: Divergent Construction of Coumarins
Zhi-Xiong Deng,†,∥ Yu Zheng,†,∥ Zhen-Zhen Xie,† Yue-Heng Gao,† Jun-An Xiao,§ Si-Qi Xie,†
Hao-Yue Xiang,*,† Xiao-Qing Chen,*,†,‡ and Hua Yang*,†,‡
†College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, P. R. China
‡Key Laboratory of Hunan Province for Water Environment and Agriculture Product Safety, Central South University, Changsha
410083, P. R. China
§Guangxi Key Laboratory of Natural Polymer Chemistry and Physics, Nanning Normal University, Nanning 530001, P. R. China
S
* Supporting Information
ABSTRACT: We herein report a phosphine-mediated domino
process of MBH-type reaction/umpolung γ-addition through the
rational integration of the privileged reactivities of alkynoate. Simply
by manipulating the nucleophilic reagent, the developed protocol
offers a facile, diversity-oriented construction of a wide range of three-
substituted coumarins.
Scheme 1. Synthetic Profiles of Phosphine-Mediated
Reactions of Alkynoates and the Rationale of This Work
he past decades have witnessed the blossom of
Tphosphine-mediated transformations, many of which are
playing vital roles in carbon−carbon (C−C) bond-forming
events.1 Recently, because of their unique synthetic potentials
and reactivity, activated alkynes have been proven to be
suitable substrates for a range of phosphine-mediated
reactions.2 Mechanistically, these phosphine-mediated trans-
formations mainly depend on the formation of key zwitterionic
intermediates, which can be generated through the 1,4-
addition of phosphine to activated alkynes (Scheme 1A).3
Prominently, when a suitable nucleophile is available, a process
known as the umpolung γ-addition reaction may readily
occur.4 Alternatively, being one of the earliest disclosed
phosphine-catalyzed reactions, the Morita−Baylis−Hillman
(MBH) reaction could serve as an effective synthetic platform
for the construction of C−C bonds as well.5 Nevertheless, as
stated in Kataoka’s report,6 a longstanding challenge is still
waiting to be addressed for the mechanistically difficult MBH-
type reaction of the activated alkynes. In 2018, Ramasastry’s
group7 unveiled an unprecedented case for the MBH-type
reaction of α,β-ynones, providing access to a variety of
heteroarenes. Obviously, the success of this strategy will
expand the dimension of phosphine chemistry.
designed a sequential MBH reaction/umpolung addition
process by installing the alkynoate moiety into salicylaldehyde
substrates, leading to the rapid construction of structurally
diverse three-substituted coumarins by readily varying
nucleophiles (Scheme 1B).
Inspired by these advances, we rationalized that the
preinstallation of an electrophilic moiety at the suitable
position of alkynoate might facilitate the intramolecular
MBH-type reaction to generate the corresponding zwitterionic
intermediate, which could be trapped by external nucleophiles
to effect an umpolung γ-addition. Following this rationale, we
Received: November 26, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04248
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Coumarin and its derivatives, as privileged scaffolds, are
widely encountered in natural and synthetic compounds with a
wide range of pharmacological properties.8 Although impres-
sive advances in the construction of coumarins have been
encouragingly achieved,9 the diversity-oriented synthesis
(DOS) of this class of significant heterocycles is always an
everlasting goal being pursued by synthetic and medicinal
chemists. In this work, by manipulating the nucleophilic
reagents, the newly developed protocol offers a facile, diversity-
oriented construction of a wide range of three-substituted
coumarins, which would surely enrich the library of coumarins.
Initially, alkynoate 1a and 2,5-pyrrolidinedione 2a were used
as the substrates to test our hypothesis (Table 1). It was found
solvent effect was also evaluated (entries 8−10), and
anhydrous CH3CN was finally proven to be the optimal
solvent for the formation of a1 (entry 8). Next, we would like
to manipulate the chemoselectivity, allowing the selective
formation of the reduced product b1. A literature survey
disclosed that the presence of water is beneficial for the
phosphine-involved reductive reactions.3a Thus 10 equiv of
water and a stoichiometric amount of phosphine were then
used. Similarly, the effects of phosphine, temperature, and
solvent were investigated (entries 11−20). P(p-FPh)3 and
PhCH3 gave the best results, whereas the formation of a1 was
almost completely sequestered (entry 16). It is worth
mentioning that, to a certain extent, the pH value of the
reaction media has an impact on the chemical yields of a1 and
b1 (entries 21 and 22). Gratifyingly, the practicality and
scalability of this protocol were successfully demonstrated by
performing the reaction for a1 on a 1 mmol scale under the
standard reaction conditions to give a similar result without
any loss of efficiency (entry 23).
a
Table 1. Optimization of Reaction Conditions
We were pleased to observe the diversified reactivities of this
designed domino sequence, which prompted us to extensively
evaluate the scope of alkynoates 1 as well as nucleophiles 2,
including C-, N-, and O-centered nucleophiles (Scheme 2).
First, by using 2a as the nucleophile, the substitution patterns
on alkynoate 1 were investigated, and moderate to good yields
were generally achieved in these transformations (a1−10 and
b1−10), whereas the yields for the series of products b were
slightly better than those for the corresponding products a.
Subsequently, further efforts were devoted to exploiting the
diversity of the nucleophile. Encouragingly, dimethyl fluo-
romalonate 2b, as a C-centered nucleophile, was also
compatible with this phosphine-mediated reaction system,
although with lower yields (c1−4). Furthermore, aiming to
expand the dimension of the structural complexity of
coumarins, other nucleophiles bearing a nucleophilic site and
electrophilic site simultaneously (2c−f) were also taken into
consideration. We envisaged that employing o-aminobenzalde-
hyde by introducing a carbonyl group at the ortho position of
aniline would allow us to design a new domino process, MBH
reaction/umpolung γ-addition/Witting reaction, delivering
difficultly accessible heterocycles. By slightly modifying the
reaction system, a wide range of novel coumarins possessing
significant dihydroquinoline (d1−11) were rapidly installed, in
which good yields were generally achieved and diverse
functional groups were well tolerated. Interestingly, phthalimi-
domalonate, bearing a C-centered nucleophilic site and
electrophilic site simultaneously, was also conducive to this
MBH reaction/umpolung γ-addition/Witting reaction se-
quence, successfully delivering novel pyrroloisoindolinone-
attached coumarins (e1−3). To investigate whether the
transformation could be directly trapped by water, the reaction
was conducted without adding any extra nucleophile.
Interestingly, the desired products 3-vinyl coumarins f1−9
were obtained in good yield. Ultimately, the structures of this
series of compounds were unequivocally confirmed by X-ray
crystallographic analysis (a1, c1, and d6).
b
entry
solvent
[P]
T (°C)
yield (%) (a1/b1)
c
1
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
CH3CN
THF
MePPh2
80
80
80
80
80
100
50
80
80
80
80
80
80
80
80
50
20
50
50
50
80
50
80
44/15
−/−
48/trace
20/30
30/10
47/6
42/10
60/trace
44/trace
12/11
15/50
8/50
9/−
trace/80
40/20
trace/84
10/38
c
2
P(n-Bu)3
P(p-Tol)3
P(p-FPh)3
PPh3
P(p-Tol)3
P(p-Tol)3
P(p-Tol)3
P(p-Tol)3
P(p-Tol)3
MePPh2
c
3
c
4
c
5
c
6
c
7
c
8
c
9
c
10
IPA
d
11
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
CH3CN
THF
d
12
PPh3
d
13
P(n-Bu)3
P(p-FPh)3
P(p-Tol)3
P(p-FPh)3
P(p-FPh)3
P(p-FPh)3
P(p-FPh)3
P(p-FPh)3
P(p-Tol)3
P(p-FPh)3
P(p-Tol)3
d
14
d
15
d
16
17
18
19
d
d
12/52
trace/78
13/35
51/trace
trace/70
61/trace
d
d
20
IPA
e
21
CH3CN
PhCH3
CH3CN
f
22
cg
,
23
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), phosphine (0.1
mmol), and solvent (2 mL), 12 h. Isolated yields. Anhydrous
solvent with 4 Å MS (100 mg), AcOH/AcONa (0.1 mmol/0.1
mmol), and 0.1 mmol of phosphine was used. 10 equiv of H2O,
AcOH/AcONa (0.1 mmol/0.1 mmol), and 0.24 mmol of phosphine
were used. Anhydrous solvent with 4 Å MS (100 mg) and 0.1 mmol
of phosphine was used. 10 equiv of H2O and 0.24 mmol of phosphine
b
c
d
e
f
g
were used. Performed on 1 mmol scale for 1a.
that the reaction proceeded smoothly in the presence of
MePPh2 (50 mol %) and 4 Å MS in anhydrous PhCH3 at 80
°C, along with AcOH/AcONa as a buffer solution.4
Interestingly, both the corresponding product a1 and its
reduced analogue b1 were isolated in 44 and 15% yields,
respectively (entry 1). Next, various phosphines were then
investigated to modulate the product formation (entries 2−5).
It was found that P(p-Tol)3 favored the generation of product
a1. The effect of reaction temperature was then investigated
but with no improved yield (entries 6 and 7). Afterward, the
Whereas this attractive domino sequence offers a facile
pathway for rapidly enriching the library of coumarins, we
questioned whether the strategy could be extended to N-(2-
formylphenyl)-2-butynamide, thus generating quinolinones.
Significantly, N-(2-formylphenyl)-2-butynamide 3 was also
proven to be suitable for these transformations, giving the
corresponding quinolinones (g1−4) by simply modulating the
B
DOI: 10.1021/acs.orglett.9b04248
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Diversity-Oriented Studies on the Scope of Alkynoates 1 and Nucleophiles 2
a
Conditions A: 1 (0.3 mmol), 2a (0.6 mmol), P(p-Tol)3 (0.15 mmol), AcOH/AcONa (0.15 mmol/0.15 mmol) and 4 Å MS (150 mg) in
b
anhydrous CH3CN (2 mL), 80 °C, 12 h, isolated yields. Conditions B: 1 (0.3 mmol), 2a or 2b (0.6 mmol), P(p-FPh)3 (0.36 mmol), AcOH/
c
AcONa (0.15 mmol/0.15 mmol), and H2O (3 mmol) in PhCH3 (2 mL), 50 °C, 12 h, isolated yields. Conditions C: 1 (0.4 mmol), 2c-2g (0.2
d
mmol), MePPh2 (0.24 mmol) and 4 Å MS (100 mg) in anhydrous CH3CN (2 mL), 50 °C, 12 h, isolated yields. Conditions D: 1 (0.3 mmol),
P(p-Tol)3 (0.36 mmol) AcOH/AcONa (0.15 mmol/0.15 mmol) in PhCH3 (2 mL), 30 °C, 12 h, isolated yields.
nucleophiles under the corresponding conditions (Scheme 3).
These results further demonstrate the diversity-oriented
feature of this designed reaction sequence.
To gain mechanistic insights into the reaction pathways, a
series of monitoring experiments by 31P NMR spectroscopy
and labeling experiments were carried out (Figure 1; see the
Supporting Information for details). MePPh2 and MePPh2O
show characteristic peaks at −27 and 31 ppm, respectively.
Interestingly, while mixing 1a with MePPh2, three distinct
peaks around 31, 29, and 18 ppm were observed after 6 h.
Upon mixing 1a and 2a with MePPh2, only the characteristic
peak for MePPh2O at 31 ppm was observed after 6 h. These
results suggest that phosphine was actively involved with the
formation of the intermediates (29 and 18 ppm) (Figure 1A).
Meanwhile, the reaction mixture was also examined in situ by
HRMS. Encouragingly, the initial MBH-type adduct ylide I,
C
DOI: 10.1021/acs.orglett.9b04248
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
to be detected, indicating that water served as the major proton
source during the process (Figure 1C).
Scheme 3. Extension of the Designed Domino Sequence to
the Synthesis of Quinolinones
On the basis of previous reports3a,10 and our control
experiments, we propose a plausible mechanism for this
phosphine-mediated domino process (Scheme 4). Initially, a
Scheme 4. Proposed Mechanism
a
Conditions: 3 (0.4 mmol), 2c or 2d or 2g (0.2 mmol), MePPh2 (0.1
mmol), and 4 Å MS (100 mg) in anhydrous CH3CN (2 mL), 50 °C,
b
12 h, isolated yield. Conditions: 3 (0.3 mmol), P(p-Tol)3 (0.36
mmol), AcOH/AcONa (0.15 mmol/0.15 mmol) in PhCH3 (2 mL),
c
30 °C, 12 h, isolated yield. Conditions: 3 (0.3 mmol), P(p-Tol)3
(0.36 mmol), AcOH/AcONa (0.15 mmol/0.15 mmol) in PhCH3 (2
mL), 30 °C, 12 h, isolated yield.
conjugate addition of PR3 to alkynoate 1a, followed by an
intramolecular nucleophilic attack to the aldehyde moiety
(MBH-type reaction) were underwent to generate the ylide
intermediate I. The subsequent protonation and dehydration
of ylide I delivered the phosphonium II. The phosphonium II
is susceptible to the attacks by various nucleophiles, leading to
ylide intermediates. Finally, dephosphorylation of intermedi-
ates gave diverse coumarins via divergent pathways: (1) Under
anhydrous conditions A, the direct elimination of phosphine of
III would be favored, giving the conjugate coumarin analogue
a. (2) In the presence of excess water, intermediate III was
prone to being attacked by water rather than undergoing an
elimination process. Further releasing the corresponding
phosphine oxide of the intermediates IV′ ultimately furnished
the corresponding products b. (3) The placement of a
carbonyl group juxtaposed with respect to a nucleophile
would promote an intramolecular cyclization to generate the
corresponding products d and e. (4) In the absence of any
extra nucleophile, the intermediate II would be directly
attacked by water to furnish the corresponding intermediate
III‴, which would further deliver the final products f. As we
can see, the structural features and the reaction conditions
would significantly affect the late-stage pathways, facilitating
the diversity-oriented synthesis of coumarin scaffolds.
In summary, we herein present a phosphine-mediated
domino process to assemble a wide range of coumarins with
high structural diversity, in which the MBH-type reaction,
umpolung γ-addition, and Witting reaction are rationally
integrated. This phosphine-mediated transformation demon-
strates high tolerance for the nucleophilic partners with
diversified structural features. As a result, a wide range of
coumarins with novel skeletons were rapidly assembled.
Moreover, intriguing mechanistic details governing these
processes were also elucidated. We believe that this work will
inspire the extensive exploitation of the phosphine-mediated
transformations in designing efficient pathways to access
synthetically challenging heterocycles.
Figure 1. 31P NMR, ESI-MS studies, and labeling experiments.
the dehydration intermediate II, and the γ-addition inter-
mediate III were able to be detected in the mixture of 1a with
MePPh2, respectively. To verify whether a1 is the precursor of
b1, a1 was subjected to the reaction conditions B. It was found
that compound b1 was unable to be obtained under these
conditions (Figure 1B). As a consequence, we speculated that
the reductant for this transformation was the phosphine.
Moreover, by adding D2O to the reaction system, the
corresponding deuterated products b1-D and f1-D were able
D
DOI: 10.1021/acs.orglett.9b04248
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04248.
■
S
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Experimental procedures and spectral data for all new
compounds (PDF)
Accession Codes
CCDC 1947132−1947133, 1947135, and 1947137 contain 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 Cambridge Crystallographic Data
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AUTHOR INFORMATION
Corresponding Authors
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M. Novel 3-Carboxamide-Coumarins as Potent and Selective FXIIa
Inhibitors. J. Med. Chem. 2008, 51, 3077−3080. (b) Maresca, A.;
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*E-mail: xianghaoyue@csu.edu.cn (H.-Y.X.).
*E-mail: xqchen@csu.edu.cn (X.-Q.C.).
*E-mail: hyangchem@csu.edu.cn (H.Y.)
ORCID
Hao-Yue Xiang: 0000-0002-7404-4247
Xiao-Qing Chen: 0000-0002-8768-8965
Hua Yang: 0000-0002-5518-5255
Author Contributions
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Fused Chromenes, and Versatility of Dihydrobenzo[h]Chromenes in
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D.; Yu, J.; Wu, J. Generation of Sulfonyl Radicals from Aryldiazonium
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at Atmospheric Pressure. Angew. Chem., Int. Ed. 2016, 55, 14151−
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Kwon, O. Bridged [2.2.1] Bicyclic Phosphine Oxide Facilitates
Catalytic γ-Umpolung Addition-Wittig Olefination. Chem. Sci. 2018,
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∥Z.X.D. and Y.Z. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support from the
National Natural Science Foundation of China (21576296,
21776318, 21676302, and 81703365), Central South Uni-
versity, and Guangxi Teachers Education University.
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