Selective Phosphoranation of Unactivated Alkynes with Phosphonium Cation to Achieve Isoquinoline Synthesis

Article abstract of DOI:10.1021/acs.orglett.1c01237

We herein develop a selective phosphoranation of alkynes with phosphonium cation, which directs a concise approach to isoquinolines from unactivated alkyne and nitrile feedstocks in a single step. Mechanistic studies suggest that the annulation reaction is initiated by the unprecedented phosphoranation of alkynes, thus representing a unique reaction pattern of phosphonium salts and distinguishing it from existing protocols that largely rely on the utilization of highly functionalized imines/oximes and/or highly polarized alkynes.

Full text of DOI:10.1021/acs.orglett.1c01237

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Letter
Selective Phosphoranation of Unactivated Alkynes with
Phosphonium Cation To Achieve Isoquinoline Synthesis
Hong Cui,† Jinku Bai,† Tianyu Ai, Ye Zhan, Guanzhong Li, and Honghua Rao*
Cite This: Org. Lett. 2021, 23, 4023−4028
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ABSTRACT: We herein develop a selective phosphoranation of alkynes with phosphonium cation, which directs a concise
approach to isoquinolines from unactivated alkyne and nitrile feedstocks in a single step. Mechanistic studies suggest that the
annulation reaction is initiated by the unprecedented phosphoranation of alkynes, thus representing a unique reaction pattern of
phosphonium salts and distinguishing it from existing protocols that largely rely on the utilization of highly functionalized imines/
oximes and/or highly polarized alkynes.
Scheme 1. (a−f) Reported Reactivities of Phosphonium
Species and (g) Electrophilic Addition of Phosphonium
Cation to CC Bonds (This Work)
s phosphorus chemistry has always been extensively used
Ain biochemistry, materials science, and catalytic chem-
istry,1 considerable attention has long been paid to explore
novel reactivities of organophosphorus compounds or
intermediates (e.g., phosphonium salts). Typically, quaterniza-
tion of trivalent phosphorus (e.g., phosphine) with an
electrophile (e.g., alkyl halides) can produce the corresponding
phosphonium salts, which in the presence of a base readily
form P-ylides to engage the Wittig reaction, etc.2 Besides,
nucleophilic addition of phosphine to electron-deficient
alkenes or alkynes may generate the phosphonium-based
amphiphiles to finally accomplish the phosphine-catalyzed
Michael addition, Rauhut−Currier reaction, and Stetter
reaction, among others (Scheme 1a).3 In recent years, more
diverse reactivities for phosphonium salts have been developed.
For example, the Miura/Hirano group disclosed an electro-
philic ring-opening process of a transient phosphirenium
intermediate,4 while the Dalla/Taillier group achieved a similar
process for the phosphiranium cation (Scheme 1b).5 The
McNally group demonstrated that tetraarylphosphonium salts
can serve as pseudohalide handles to couple with aromatic
boronic acids (Scheme 1c).6 They also achieved a number of
phosphorus ligand-coupling reactions when treating phospho-
nium salts with various nucleophiles (Scheme 1d).7−10 In
addition, phosphonium salts were found to be viable radical
(Scheme 1e)11 or anion (Scheme 1f) precursors.12 Notwith-
standing these great advances, the reported reactivities of
phosphonium salts largely rely on the transformable potential
of the substituents attached to the phosphonium center.
Reactivities associated with the inherently strong electro-
philicity of phosphonium cation, such as electrophilic addition
to CC bonds, however, still remain unexploited. Here, we
Received: April 13, 2021
Published: May 7, 2021
https://doi.org/10.1021/acs.orglett.1c01237
© 2021 American Chemical Society
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a
report some novel findings on this reactivity (upper part of
Scheme 1g).
Table 1. Reaction Optimization and Control Studies
Isoquinolines are prevalent in many natural products,
bioactive molecules, and synthetic pharmaceuticals.13 Also,
they are in increasing demand as crucial ligands for the
preparation of organic light emitting diode (OLED)
materials14 and asymmetric catalysts.15 Therefore, numerous
named reactions based on condensation chemistry16−19 have
been developed, and annulation of (2-halo)aromatic imines20
or oximes21 with C−C multiple bonds or cyclization of 2-
alkynylbenzyl azides22 or 2-alkylnyl aromatic imines23 or
oximes24 are also promising under transition metal catalysis.
These approaches have shown great potential in synthesizing
isoquinolines but often require lengthy steps to obtain highly
functionalized substrates and usage of toxic and precious
catalysts. Therefore, developing a step- and cost-economical
approach is still of high interest. In 2016, the Maulide group
reported an elegant protocol toward isoquinoline synthesis,
wherein a metal-free annulation of ynamides with nitriles was
realized at 120 °C under microwave conditions. In this
reaction, the use of trifluoromethanesulfonic acid (TfOH) is
essential for the activation of ynamides to a reactive vinyl
cation.25 Despite its effectiveness, this method favors highly
polarized alkynes and did not tame less-polarized alkynes. On
the basis of this consideration, we hypothesized that a much
stronger alkyne activator might be crucial to open up an
avenue for the annulation of unactivated alkynes with nitriles.
Herein, by adopting the strong electrophilicity of the
phosphonium center, we present an unprecedented electro-
philic addition of phosphonium cation to unactivated alkynes,
which triggers a subsequent intermolecular annulation with
nitriles to afford diverse 3-arylated isoquinolines in a single
step (Scheme 1g).
To verify the feasibility of our assumption, we initiated our
investigations on this annulation reaction using bis(p-tolyl)-
acetylene (1b) and acetonitrile as model substrates. The
desired isoquinoline product 3ba was obtained in 96% yield
when using 1.4 equiv of PPh3 as the phosphorus source, 0.4
equiv of Tf2O, and 1.4 equiv of TfOH as the additives in a
mixed solvent of acetonitrile (MeCN)/1,2-dichloroethane
(DCE) (2:1, v/v) at 150 °C for 3 h under an argon
atmosphere (entry 1 in Table 1, at standard conditions).
Control experiments showed that only 15% yield or none of
compound 3ba was observed without PPh3 or Tf2O/TfOH
(entries 2 and 3), which imply that a phosphornium
species26,27 induced annulation rather than a common
phosphine-catalyzed transformation being involved in this
reaction.3 Triarylphosphines bearing either electron-donating
or electron-withdrawing groups exhibited suboptimal activities
(entries 4−9), while biarylalkylphosphine and trialkylphos-
phine gave inferior results (entries 10 and 11). Use of
(C4F9SO2)2O led to a significantly reduced yield of compound
3ba (entry 12). The choices of solvents were also important
for this reaction (entry 13). Changes in the loading of PPh3
(entry 14), Tf2O (entry 15), or TfOH (entry 16) caused
decreased yields of compound 3ba by 10−30%. Other
endeavors, such as shortening the reaction time or lowering
the reaction temperature, were also attempted, but none of
them afforded superior results (entries 17 and 18).
b
entry
variation from the standard conditions
yield (%)
1
2
3
4
5
6
7
8
none
96
15
0
no PPh3
no Tf2O and TfOH
(4-Me-Ph)3P instead of PPh3
(3-Me-Ph)3P instead of PPh3
(4-MeO-Ph)3P instead of PPh3
(4-F-Ph)3P instead of PPh3
(4-Cl-Ph)3P instead of PPh3
(2-Br-Ph)Ph2P instead of PPh3
PPh2Et instead of PPh3
76
73
58
77
72
63
57
11
77
9
10
11
12
13
tricyclohexylphosphine (PCy3) instead of PPh3
(C4F9SO2)2O instead of Tf2O
MeCN, MeCN/dichloromethane (DCM) (2:1), or 89, 83, or 89
MeCN/DCE (1:2) as the solvent
14
15
16
17
18
with 1.0, 1.2, or 2.0 equiv of PPh3
with 0.2 or 0.6 equiv of Tf2O
with 1.2 or 2.0 equiv of TfOH
reaction time of 2 h
72, 78, or 75
66 or 81
80 or 87
81
reaction temperature of 120 °C
75
a
Reaction conditions: compound 1b (0.10 mmol), Tf2O (0.4 equiv),
TfOH (1.4 equiv), and MeCN/DCE (1.2 mL, 2:1, v/v), under argon
at 150 °C for 3 h. Yields are determined by H nuclear magnetic
b
1
resonance (NMR) with mesitylene as the internal standard.
electron-donating substituents (e.g., Me, tBu; 88−92% yield)
displayed significantly higher efficiency than those with
electron-withdrawing groups (e.g., F; 40% yield) (1b or 1c
versus 1d). However, when the electron-donating groups were
positioned ortho to the alkynyl moiety (1e versus 1b) or the
annulated site (1f versus 1b), yields of the corresponding
products were reduced by 10−20%, which can be attributed to
the effects of steric hindrance. Next, the scope of unsymmetric
alkyne substrates was evaluated. In general, monosubstituted
alkynes bearing either electron-donating (1g−1k) or weak
electron-withdrawing (1l−1n) groups achieved good to
excellent yields of the desired products (59−85% yield), with
the annulation occurring mostly on less electron-rich aromatic
rings. Notably, electron-donating substituents showed marked
differences in regioselectivity. For instance, phenyl- or
phenoxyl-substituted alkyne yielded compound 3ga or 3ha as
the sole product, while alkyl substituents afforded mixtures of
isoquinolines in 10:1 regioselectivity (3ia/3ia′ and 3ja/3ja′).
Weak electron-withdrawing substituents, such as halides,
exhibited poor selectivity (1l−1n versus 1i−1j), among
which the fluoro substituent displayed the highest regiose-
lectivity (1l versus 1m versus 1n; ratio of isomers is 4.7:1,
1.7:1, and 1.1:1, respectively). Improving the electronic biases
between two aromatic rings by introducing strong electron-
withdrawing groups, such as trifluoromethyl (1o), ester (1p),
and cyano groups (1q), into alkyne substrates significantly
increased the regioselectivities, as the reaction selectively
cyclized on the electron-deficient aromatic ring in a syntheti-
cally useful yield (3oa/3oa′, 3pa, and 3qa; 23−43% yield). As
expected, installing substituents into both ortho positions to
the alkynyl moiety on either aromatic ring gave pure
isoquinoline products in good yields (3ra−3ta; 53−77%
With the optimal reaction conditions in hand, we sought to
demonstrate the generality of this annulation reaction. As
summarized in Scheme 2, the scope with respect to symmetric
diarylalkynes was first examined. Generally, the aryl ring with
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a,b,c
Scheme 2. Scope with Respect to Alkynes and Nitriles
Scheme 3. (a) Gram-Scale Synthesis of 3aa and Its Late-
Stage Diversification and (b) Utilization of the Optimal
Reaction Conditions
addition, the methyl group in compound 3aa can readily
convert into aldehyde 7 by SeO2 (90% yield) or
phthalimidated compound 8 via a copper-catalyzed dehydro-
genative C−H/N−H coupling (27% yield). Notably, exposure
of compound 3aa to the Pd(OAc)2/NHPI/tBuONO system30
gave nitrile compound 9 (40% yield), which, after successive
treatments with n-BuLi and N-methylpiperazine,31 was
formally transformed into the antitumor agent CWJ-a-5 in
70% yield. Moreover, as pyrimidines are fundamental structural
motifs in various function molecules,32 some elegant methods
with nitriles and ketone or N-vinylacetamides as the regents
and Lewis/Brønsted acids as the promoter have been
developed.33 Fortunately, when subjecting aromatic terminal
alkynes and 1-aryl aliphatic alkynes to our reaction conditions,
polysubstituted pyrimidines 10−13 can be obtained in 66−
92% yields as well.
a
Reaction conditions: compound 1 (0.10 mmol), PPh3 (1.4 equiv),
Tf2O (0.4 equiv), TfOH (1.4 equiv), and R3CN/DCE (1.2 mL, 2:1,
v/v), under argon at 150 °C for 3 h. Yields of isolated products. For
isomers, products are isolated as mixtures. Positions of the
substituents are labeled as indicated in the scheme. Numbers in
parentheses indicate the ratio of isomers. With CH3CN/DCE (1.2
mL, 1:2, v/v). With PPh3 (2.8 equiv), Tf2O (0.8 equiv), and TfOH
(2.8 equiv). With TfOH (1.0 equiv). With nPrCN/DCE (0.6 mL,
b
c
d
e
f
g
1:2, v/v).
To shed light on the reaction mechanism, some 31P NMR
experiments were performed to elucidate the transformations
between phosphorus-containing species (please refer to
Section 15 in the Supporting Information). First, the 31P
NMR spectra indicate that mixing PPh3 with Tf2O in DCE
mainly produces (TfOPPh3)+Tf− with a chemical shift of δ
54.3 ppm,26 while PPh3 with TfOH in DCE merely produces
(HPPh3)+(OTf)− with a chemical shift of δ 5.1 ppm.27 Second,
after the addition of Tf2O to the pre-formed DCE solution of
PPh3 and TfOH, the 31P NMR spectra show that
(HPPh3)+(OTf)− can be partially converted into
(TfOPPh3)+Tf− upon heating the corresponding solution to
150 °C. Further, the pre-formed phosphonium salt
(TfOPPh3)+Tf− or (HPPh3)+(OTf)− was subjected to the
MeCN/DCE solution of diphenylacetylene at 150 °C for 3 h,
respectively, and (TfOPPh3)+Tf− delivered compound 3ba in
43% yield, while only a 6% yield was obtained with
(HPPh3)+(OTf)− (mechanistic studies a and b of Scheme
4). These results unequivocally confirmed that (TfOPPh3)+Tf−
yield). Moreover, alkynes possessing substituents on both
aromatic rings were smoothly converted to the desired
products in moderate to good yields (3ua and 3va/3va′, 65
and 45% yield). Pleasingly, not only the benzene ring but also
thiophene could be employed, affording a 3-thienyl-substituted
isoquinoline derivative in 35% yield (3wa). Finally, butyroni-
trile and isovaleronitrile were compatible with this protocol as
well, and the corresponding isoquinoline products were
obtained in 32−65% yields (3bb and 3bc).
To showcase the practicality of our strategy, gram-scale
synthesis and further transformations were thereby conducted
(Scheme 3). First, a 6 mmol scale reaction was performed, and
product 3aa was isolated in 70% yield (0.93 g). Because
fluorinated compounds are important in pharmaceuticals,
agrochemicals, and materials,28 a fluorine atom was readily
incorporated into compound 3aa to produce compound 4 in
40% yield with NFSI/Li2CO3. Direct C−H arylation of
compound 3aa with palladium catalysis afforded product 5
in 45% yield, which showed an unusual para-regioselectivity
compared to common 2-phenylpyridine substrates (preferring
ortho-C−H functionalization29). Oxidation on the nitrogen
atom can smoothly deliver compound 6 in 90% yield. In
1
is indispensable for our annulation process. Finally, H NMR
revealed 41% deuterium incorporation at the 4 position of
compound 3ba when performing the reaction under the
standard conditions (using TfOD instead of TfOH) (Scheme
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diately upon reaction with anion Tf−. The phosphorane-type
compound VI may function as an isoquinoline anion
equivalent, and a fragmentation-trapping event is driven by
forming Ph3PO (can be isolated) in the presence of TfOH to
finally deliver product 3.12b
Scheme 4. Mechanistic Studies
In summary, we have reported a selective phosphoranation
reaction of unactivated alkynes with phosphonium cation,
which leads to the successful synthesis of various isoquinoline
derivatives efficiently and regioselectively. This strategy marks
a significant differentiation from reported reaction patterns and
utilizations of phosphonium species. Besides, it provides a
complementary yet effective platform to previous protocols for
the elaboration of isoquinoline derivatives from simple readily
available alkyne and nitrile feedstocks in a single step. The
annulation reaction is believed to involve a series of cationic
intermediates, thereby ensuring high regioselectivity. In
addition, diverse modifications of the products indicate a
broad potential for this reaction in the development and
synthesis of new medicinal and pharmaceutical agents. Further
application of the phosphoranation reaction is under
investigation in our group.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01237.
■
4c). However, no deuterium product was detected upon
reacting compound 3ba with TfOD in MeCN/DCE at 150 °C
for 3 h (Scheme 4d). Besides, a H/D exchange was also
observed on the methyl group (mechanistic studies c and e of
Scheme 4), which may be attributed to the deprotonation of
nitrilium species into keteneimines.34 Finally, upon treatment
of the pre-synthesized compound 14 with TfOH, a nearly
quantitative amount of isoquinoline was detected (Scheme 4f).
These findings suggest that the phosphorane-type (or
phosphonium) compounds most likely serve as a key
intermediate to release the final products through an
irreversible protonation reaction.
sı
FAIR data, including the primary NMR FID files, for
compounds 3aa−3ha, 3ia/3ia′−3oa/3oa′, 3pa−3ua,
3va/3va′, 3wa, 3bb, 3bc, 4−13, CWJ-a-5, 3ba with
TfOD, and 3ba with CD3CN (ZIP)
FAIR data for compounds 3aa−3ha, 3ia/3ia′−3oa/
3oa′, 3pa−3ua, 3va/3va′, 3wa, 3bb, 3bc, 4−13, CWJ-a-
5, 3ba with TfOD, and 3ba with CD3CN (ZIP)
Experimental details and characterization of new
compounds (PDF)
On the basis of the preliminary mechanistic studies, a
tentative mechanism is proposed for the phosphonium-
mediated annulation reaction in Scheme 5. The electrophile
Accession Codes
CCDC 2080984 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.
Scheme 5. Proposed Mechanism
AUTHOR INFORMATION
Corresponding Author
■
Honghua Rao − Department of Chemistry, Capital Normal
University, Beijing 100048, People’s Republic of China; Key
Laboratory of Bioorganic Phosphorus Chemistry and
Chemical Biology (Ministry of Education), Department of
Chemistry, Tsinghua University, Beijing 100084, People’s
Republic of China; orcid.org/0000-0003-1609-5692;
Email: raohonghua@tsinghua.org.cn; https://www.x-
mol.com/groups/raohonghua
(TfOPPh3)+Tf− [generated from the reaction of PPh3 and
Tf2O or from the conversion of (HPPh3)+(OTf)−] undergoes
an electrophilic addition reaction with alkynes to form the
phosphorane-containing vinyl cation II (disfavored) or I
(favored as the electron-rich nature of Ar2 may stabilize cation
I), which may readily react with acetonitrile to form the
corresponding N-vinylnitrilium intermediate III (may form
keteneimine IV after deprotonation32). Intermediate III then
undergoes an electrophilic cyclization to give compound V,
which subsequently forms compound VI [detected by
electrospray ionization mass spectrometry (ESI−MS)] imme-
Authors
Hong Cui − Department of Chemistry, Capital Normal
University, Beijing 100048, People’s Republic of China
Jinku Bai − Department of Chemistry, Capital Normal
University, Beijing 100048, People’s Republic of China
Tianyu Ai − Department of Chemistry, Capital Normal
University, Beijing 100048, People’s Republic of China
4026
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Letter
deuterium and tritium into pyridines, diazines, and pharmaceuticals. J.
Am. Chem. Soc. 2018, 140, 1990. (c) Che, Y.-Y.; Yue, Y.; Lin, L.-Z.;
Pei, B.; Deng, X.; Feng, C. Palladium-catalyzed electrophilic
functionalization of pyridine derivatives through phosphonium salts.
Angew. Chem., Int. Ed. 2020, 59, 16414.
(13) (a) Kartsev, V. G. Natural compounds in drug discovery.
Biological activity and new trends in the chemistry of isoquinoline
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Chou, P.-T.; Datta, S.; Liu, R.-S. Highly efficient red electro-
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Ye Zhan − Department of Chemistry, Capital Normal
University, Beijing 100048, People’s Republic of China
Guanzhong Li − Department of Chemistry, Capital Normal
University, Beijing 100048, People’s Republic of China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01237
Author Contributions
†Hong Cui and Jinku Bai contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation (NSFC; 21871185 and 21402128), Beijing
Natural Science Foundation (2172015), Key Laboratory of
Bioorganic Phosphorus Chemistry and Chemical Biology
(Ministry of Education, People’s Republic of China), and
Capital Normal University is gratefully acknowledged.
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