Cu-catalyzed synthesis of tetrasubstituted 2,3-allenols through decarboxylative silylation of alkyne-substituted cyclic carbonates

Article abstract of DOI:10.1021/acs.orglett.0c01222

An efficient and mild Cu-catalyzed protocol has been developed for the decarboxylative silylation of alkyne-functionalized cyclic carbonate substrates affording 2,3-allenols featuring four different substituents. This practical methodology gives access to a wide scope of tetrasubstituted functionalized allenes in excellent yields.

Full text of DOI:10.1021/acs.orglett.0c01222

pubs.acs.org/OrgLett
Letter
Cu-Catalyzed Synthesis of Tetrasubstituted 2,3-Allenols through
Decarboxylative Silylation of Alkyne-Substituted Cyclic Carbonates
Kun Guo and Arjan W. Kleij*
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ABSTRACT: An efficient and mild Cu-catalyzed protocol has been
developed for the decarboxylative silylation of alkyne-functionalized cyclic
carbonate substrates affording 2,3-allenols featuring four different
substituents. This practical methodology gives access to a wide scope of
tetrasubstituted functionalized allenes in excellent yields.
Scheme 1. Copper-Mediated Formation of Tetrasubstituted
2,3-Allenols Using Newly Designed Alkynyl-Derived Cyclic
Carbonates
llenes and their derivatives play an important role in
Aorganic synthesis constituting reactive intermediates en
route to more complex structures1 and medicinally useful
intermediates.2 The synthesis of allenes has rapidly advanced
over the past decade, and various efficient protocols for tri-3 and
tetrasubstituted4 scaffolds have been developed. Silylated
congeners have been frequently targeted as these scaffolds can
offer productive ways toward pharmaceutically relevant
molecules and natural products if properly equipped with
additional functionality. In this context, various groups have
reported on efficient catalytic silylation protocols using a wide
range of propargylic precursors,5 (Z)-2-alken-4-ynoates,6 and
enynes.7
The subcategory of 2,3-allenol compounds serve as building
blocks for organic synthesis8 and these compounds have
additionally successfully been probed in the construction of
natural products.9 These important 2,3-allenol precursors can be
conveniently prepared from alkynyl epoxides as demonstrated
previously by various groups,10 but despite progress in this area,
a general catalytic protocol that can further advance the access to
a wider diversity of functional tetrasubstituted 2,3-allenols
remains much desired.
Inspired by this synthetic challenge, we set out to explore a
new approach toward the preparation of tetrasubstituted
silylated allenes. In our approach, we used a newly developed
substrate based on a cyclic organic carbonate skeleton (Scheme
1) representing a propargylic surrogate.11 Functional cyclic
carbonates such as vinyl-12 and terminal alkyne-substituted
ones13 have recently emerged as highly versatile, modular, and
readily prepared compounds for the development of elusive CH
bond functionalization and allylic/propargylic substitution
reactions. Our new substrate design takes advantage of the
accessibility of both α-hydroxy ketones and terminal alkynes,
and their coupling mediated by n-butyl lithium affords key syn-
diols which are easily converted into the requisite alkynyl
carbonate substrates. Formation of a π-complex in the presence
of a Cu(I) species should lead to decarboxylative nucleophilic
functionalization of the alkyne carbonate by the activated silyl
reagent, affording the targeted tetrasubstituted 2,3-allenol
product.
This envisioned manifold proceeds through a syn-selective
1,2-addition across the CC bond followed by an anti-selective
β-elimination,5a triggering the extrusion of a noncharged leaving
group (CO2). The major advantage of using this type of alkynyl
carbonate is the highly diverse nature of its precursors, enabling
to forge a wide range of 2,3-allenols as demonstrated herein.
Received: April 6, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01222
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
First, the requisite alkynyl cyclic carbonates (Scheme 2, 1a−
1x) were prepared using a general protocol utilizing α-hydroxy
of 2,3-allenol 2a (Table 1).16 Productive conversion of 1a into
2a was accomplished using a combination of CuCN/ICy·HCl
Scheme 2. Two-Step Synthesis of Alkynyl Cyclic Carbonates
Table 1. Optimization of the Synthesis of 2,3-Allenol 2a from
Cyclic Carbonate 1a under Cu Catalysis
a
1a−1x Using α-Hydroxy Ketones and Terminal Alkynes as
a
Reagents
b
entry
variation from best conditions
yield of 2a (%)
c
1
2
3
4
5
6
none
without Cu salt
without ligand
without NaOtBu
without iPrOH and anhydrous
1.25 equiv of PhMe2SiBpin
95
11
41
<1
99
50
a
1a (0.20 mmol), PhMe2SiBPin (0.38 mmol), CuCN (5.0 mol %),
ICy·HCl (5.0 mol %), NaOtBu (25 mol %), iPrOH (2.5 equiv), THF
b
(0.20 M), Ar, rt, 3 h. NMR yield (CDCl3) of 2a with toluene as
c
internal standard. Isolated yield.
(ICy·HCl stands for the carbene ligand 1,3-dicyclohexylimida-
zolium chloride) in the presence of NaOtBu as base and THF/
iPrOH as medium (entry 1), providing the product in 95%
isolated yield. In the absence of the Cu precursor or supporting
ligand (ICy·HCl), much lower efficiency was noted (entries 2
and 3). The presence of the base was crucial as no conversion
was observed in its absence (entry 4). In the absence of any
proton source, nearly quantitative NMR yield of the precursor
2a was achieved but requiring extensive drying of all reagents
and solvents. Finally, the appropriate amount of silylating
reagent (PhMe2SiBPin) was also crucial. If PhMe2SiBPin was
used in larger excess than 1.9 equiv, it was highly difficult to
purify the final product. On the contrary, if it was lowered to 1.25
equiv (entry 1 vs 6), the yield of 2a was substantially reduced to a
moderate 50%. Combining all observations and for practical
reasons, we selected the conditions reported in entry 1 for the
product scope phase (Scheme 3: 2,3-allenol compounds 2a−
2x).
The devised protocol proved to be rather general, allowing the
introduction of various substituents (R1, R2, and R3) in the allene
targets. The presence of simple aryl, benzyl, and alkyl
substituents is well tolerated in this Cu-mediated synthesis,
providing a diverse range of 2,3-allenol compounds (2a−2q) in
typical high isolated yields of up to 95%. Selective C−O bond
cleavage in the carbonate 1g (rather than cleavage of the O−Me
group) takes place upon formation of 2g, whereas the
cyclopropyl fragment in 2l was also not affected. From the
observed high yields of most of the 2,3-allenols, it can be
assumed that electronic effects exerted by R1−R3 play a
negligible role, and further variation within the aromatic
substituents should allow to amplify the scope of these silylated
allenes. Notably, more bulky carbonate precursors with various
substituents α to the alcohol group were endorsed, including
alkyl (2f and 2i), double alkyl (2h), and benzyl (2p) groups.
In addition, the new silylation methodology also allows the
incorporation of several functional groups including alkyl halides
(2r−2t, 2w, and 2x) and a protected alcohol (2u), providing
further postsynthetic potential. The preparation of allene
product 2x having a CF3 group provides an alternative route
to the one recently reported by Xu and co-workers, who
developed Cu-catalyzed 1,4-protosilylation of CF3-substituted
a
Deviations from the first step of the standard protocol. For
compounds 1n−1p, Me−CC−MgBr was used. For 1q, the
reaction conditions are 2-methyl-1-hexen-3-yne (1 equiv), K3Fe-
(CN)6 (3 equiv), K2CO3 (3 equiv), quinuclidine (15 mol %),
K2OsO2(OH)4 (5 mol %), methane sulfonamide (1 equiv), and t-
BuOH/H2O (1:1 v/v), 48 h, rt; see ref 14. For compound 1x, see the
SI for details and ref 14.
ketones and terminal alkynes as easily accessible starting
reagents in most cases (with some exceptions noted). The
yields for most of the carbonate substrates in this two-step
sequence were appreciably high and typically in the range 70−
85% using a standard protocol, while for 1n−p, 1q, and 1x
adapted methods were used.14 The R-groups present in the
carbonate products show ample diversity in terms of positional
variation and functionality, with compounds 1r−1x being
exemplary. All carbonate compounds were fully characterized
by spectroscopic techniques (see the Supporting Information:
SI) and in the case of 1j also by single-crystal X-ray analysis.15
With this set of 24 alkynyl cyclic carbonates prepared, we then
first screened some reaction conditions to optimize the synthesis
B
https://dx.doi.org/10.1021/acs.orglett.0c01222
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Letter
Scheme 3. Preparation of 2,3-Allenols 2a−2x from Alkynyl
Cyclic Carbonates 1a−1x
Scheme 4. Scale Up of 2m and Additional Experiments
This clearly shows the delicate balance between the reactivity of
the silyl substrate and the influence of the ligand on the
efficiency of the catalytic transformation. Finally, 2m was used as
starting material to investigate its suitability to undergo a formal
5-endo-tet cyclization after initial iodination (Scheme 4c).9f This
afforded the dihydrofuran derivative 4 in 51% yield while
retaining the initial silyl functionality.
In summary, novel alkynyl cyclic carbonates have been
successfully prepared from simple and cheap starting materials,
possess a modular character and represent versatile propargylic
surrogates. The utilization of these carbonate substrates allowed
us to devise a diverse scope of tetrasubstituted 2,3-allenols
through a Cu-mediated silylation protocol that is characterized
by good yields and attractive reaction conditions.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01222.
■
conjugated enynes affording homoallenylsilanes instead of a silyl
2,3-allenol.7
sı
In order to examine the practicality of the catalytic formation
of these tetrasubstituted allenes, we carried out various
additional experiments (Scheme 4). Scale up of the preparation
of allene product 2m to gram quantities (Scheme 4a) is feasible,
which allows exploring further elaborations. The use of a
different silylating reagent (Et3SiBPin) was then considered to
potentially amplify the silyl group diversity in the 2,3-allenol
compounds (Scheme 4b). Notably, the high yield synthesis of 3
(81%) using CuCl/dppp as catalyst (dppp = 1,3-diphenylphos-
phino propane) could be realized under fairly similar reaction
conditions compared to the standard protocol.17 Interestingly,
switching the ligand from dppp to ICy·HCl under the same
conditions only provided 39% of the same 2,3-allenol product.
Experimental details and full characterizations of
substrates and products and copies of relevant NMR
spectra (PDF)
Accession Codes
CCDC 1994451 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 Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
C
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Huang, C.; Wu, P.; Qian, H.; Wang, L.; Guo, Y.-L.; Ma, S. Nat. Catal.
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AUTHOR INFORMATION
Corresponding Author
■
Arjan W. Kleij − Institute of Chemical Research of Catalonia
(ICIQ), The Barcelona Institute of Science and Technology,
43007 Tarragona, Spain; Catalan Institute of Research and
Advanced Studies (ICREA), 08010 Barcelona, Spain;
orcid.org/0000-0002-7402-4764; Email: akleij@iciq.es
́
Fernandez-Rodríguez, M. A. Tetrahedron 2019, 75, 4071. See also ref
3b.
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Z.-L.; Yang, C.; Xue, Q.-Y.; Zhao, M.; Shan, C.-C.; Xu, Y.-H.; Loh, T.-P.
Angew. Chem., Int. Ed. 2019, 58, 16538. (d) Ohmiya, H.; Ito, H.;
Sawamura, M. Org. Lett. 2009, 11, 5618. Also refer to: (e) Oestreich,
M.; Hartmann, E.; Mewald, M. Chem. Rev. 2013, 113, 402. (f) Delvos,
L. B.; Oestreich, M. In Science of Synthesis Knowledge Update 2017/1;
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(6) Wang, M.; Liu, Z.-L.; Zhang, X.; Tian, P.-P.; Xu, Y.-H.; Loh, T.-P.
J. Am. Chem. Soc. 2015, 137, 14830.
Author
Kun Guo − Institute of Chemical Research of Catalonia (ICIQ),
The Barcelona Institute of Science and Technology, 43007
Tarragona, Spain
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01222
(7) Yang, C.; Liu, Z.-L.; Dai, D.-T.; Li, Q.; Ma, W.-W.; Zhao, M.; Xu,
Y.-H. Org. Lett. 2020, 22, 1360.
Notes
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The authors declare no competing financial interest.
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(c) Mundal, D. A.; Lutz, K. E.; Thomson, R. J. J. Am. Chem. Soc. 2012,
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ACKNOWLEDGMENTS
■
A.W.K. thanks the CERCA/Generalitat de Catalunya, ICREA,
MINECO (CTQ2017-88920-P), and AGAUR (2017-SGR-
232) for support. K.G. acknowledges the CSC for a predoctoral
̈
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(d) Semple, J. E.; Wang, P. C.; Lysenko, Z.; Joullie, M. M. J. Am. Chem.
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Eduardo Escudero-Adan (ICIQ) are thanked for measuring the
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D
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