Rhodium-catalyzed enantioselective decarboxylative alkynylation of allenes with arylpropiolic acids

Article abstract of DOI:10.1021/acs.orglett.7b04035

A rhodium-catalyzed chemo-, regio-, and enantioselective intermolecular decarboxylative alkynylation of terminal allenes with arylpropiolic acids is reported. Employing a Rh(I)/(R)-Tol-BINAP catalytic system, branched allylic 1,4-enynes were obtained under mild conditions. The overall utility of this protocol is exemplified by a broad functional group compatibility.

Full text of DOI:10.1021/acs.orglett.7b04035

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Rhodium-Catalyzed Enantioselective Decarboxylative Alkynylation
of Allenes with Arylpropiolic Acids
Christian P. Grugel and Bernhard Breit*
Institut fur Organische Chemie, Albert-Ludwigs-Universitat Freiburg, Albertstrasse 21, 79104 Freiburg im Breisgau, Germany
̈
̈
S
* Supporting Information
ABSTRACT: A rhodium-catalyzed chemo-, regio-, and enantioselective intermolecular decarboxylative alkynylation of terminal
allenes with arylpropiolic acids is reported. Employing a Rh(I)/(R)-Tol-BINAP catalytic system, branched allylic 1,4-enynes were
obtained under mild conditions. The overall utility of this protocol is exemplified by a broad functional group compatibility.
Scheme 1. Strategies for Transition-Metal-Catalyzed
Asymmetric Syntheses of 1,4-Enynes
roperly addressing the prerequisites for the ideal organic
1
Psynthesis in which a selective extension of the carbon
skeleton is preferably accompanied by a direct installation of
desired functional groups within the molecule allowing for
further functionalization still remains of tremendous interest for
the development of useful synthetic methodologies.2 Aside from
significant advances during the past years, strategies allowing
enantioselective couplings of terminal alkynes to carbon
electrophiles still remains scarce, even though such methods
would grant access to new possibilities for synthetically
approaching more complex molecules like pharmaceuticals or
natural products.3 While methods for enantioselective additions
of alkyne-based nucleophiles to aldehydes,4 ketones,4 and
imines5 have been studied extensively, catalytic methods
involving additions to unactivated carbon−carbon multiple
bonds are far less represented.6
Chiral 1,4-enynes are valuable and versatile intermediates for
organic synthesis, mostly due to the fact that they bear two
different handles in direct vicinity to the stereogenic center that
allow for selective further functionalization.7 Transition-metal-
catalyzed synthesis thereof has predominantly been achieved by
strategies involving asymmetric allylic alkylation (Scheme 1).8 In
2012, Alexakis developed a protocol for selective displacement of
enyne-chlorides with Grignard reagents.8a Hoveyda8b,c and
Carreira8c independently reported the addition of alkynylalumi-
num and alkynylboron reagents to allylic electrophiles employing
copper- and iridum-based cataylsts. In 2014, Sawamura8d,e
reported the direct addition of terminal alkynes to (Z)-allylic
phosphates catalyzed by a Cu−NHC complex.
Throughout the last years, we reported on a series of
transition-metal-catalyzed regio- and enantioselective coupling
reactions involving allenes9,10 and alkynes11,12 as allylic electro-
phile precursors with various pronucleophiles, thus establishing a
more atom-economic alternative to the classic Tsuji−Trost
allylation.
However, all of these methods require rather basic reaction
conditions, premetalated alkyne nucleophiles, or multistep
substrate syntheses which diminishes their attractiveness and
utility regarding applications for the syntheses of more complex
scaffolds.
Received: December 27, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b04035
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Despite extensive investigations, a strategy involving the direct
addition of terminal alkynes to allenes could not be developed
yet, presumably due to their inherent high reactivity regarding
oxidative addition with transition metal catalysts. In this respect,
we envisioned that arylpropiolic acids13,14 could serve as terminal
alkyne surrogates in a similar manner to our previously
developed strategy on the decarboxylative allylation of β-
ketoacids as masked ketone pronucleophiles.10a We assumed
that introducing a carboxylic acid group may facilitate the
reaction through a faster formation of the desired allylrhodium
intermediate (vide infra) and eventually releases the desired C/
C-coupling product after decarboxylation (Scheme 1).
could obtain 3a in almost quantitative yield while maintaining an
excellent enantioselectivity (entry 9).
With this optimized protocol in hand, we investigated the
substrate scope of this decarboxylative alkynylation of allene 2d
with various arylpropiolic acids (Table 2). Efficient as well as
chemo- and enantioselective coupling reactions occur with a
variety of different substitution patterns.
Table 2. Decarboxylative Alkynylation with Various
a
Arylpropiolic Acids
To test our hypothesis, we commenced our investigations
employing 3-(benzo[d][1,3]dioxol-5-yl)propiolic acid (1a) and
((penta-3,4-dien-1-yloxy)methyl)benzene (2c) as model sub-
strates (Table 1).
Table 1. Ligand Screening and Optimization of Reaction
a
Conditions
entry
ligand
DPEphos
yield (%)
er
1
2
3
4
5
6
29
44
19
88
43
54
51
70
99
rac-BINAP
(R)-MeO-Biphep
(S)-Segphos
64:36
89:11 (−)
60:40 (−)
94.5:5.5
97:3
(S)-BINAP
(R)-Tol-BINAP
(R)-Tol-BINAP
(R)-Tol-BINAP
(R)-Tol-BINAP
b
7
c
8
96:4
d
9
95:5
a
1a (0.2 mmol), 2c (0.6 mmol), [Rh(cod)Cl]2 (2.5 mol %), ligand
(7.5 mol %), acid cocatalyst (20 mol %), DCE (1.0 mL), 80 °C, 16 h.
b
All yields given as isolated yields. 20 mol % TFA used instead of
TsOH·H2O. Reaction performed in DCM at 60 °C. Reaction
performed in DCM/EtOH = 3:1 at 60 °C with 40 mol % TFA.
a
c
d
1 (0.2 mmol), 2d (0.6 mmol), [Rh(cod)Cl]2 (2.5 mol %), (R)-Tol-
BINAP (7.5 mol %), TFA (40 mol %), DCM/EtOH = 3:1 (1.0 mL),
60 °C, 16 h. All yields given as isolated yields. Enantioselectivities
determined by HPLC on chiral stationary phases. Absolute
configuration assigned by analogy.16
In this respect, phenylpropiolic acids bearing electron-
donating methoxy substituents at different positions reacted
smoothly to give rise to the corresponding 1,4-enynes in good to
excellent yields (3b−d) as well as enantioselectivities with a
substituent in the 4-position showing the highest er with 96.5:3.5.
Notably, even a sterically more congested substrate with a 2-
OMe substituent reacted well even though 3d was formed in a
slightly lower enantiomeric ratio of 90:10. Substrates with
electron-withdrawing substituents (e.g., F, Cl, Br) showed
slightly lower reactivity (73−95% isolated yields), although
3e−g were formed in excellent enantioselectivities. With more
electron-deficient arylpropiolic acids (e.g., 4-CF3) no reactivity is
observed at all. Moreover, commercially available phenyl-
propiolic acid without any further functionalizations (3h) as
well as related biphenyl (3i) and 1-naphthyl (3j) substrates
reacted smoothly and provided the desired products in good to
excellent yields and enantioselectivities. To our delight, even
heteroaryl residues (exemplified by thiophenylpropiolic acid)
could participate in the reaction (3k). However, when trying to
expand this protocol to alkyl (3l) or silyl (3m) residues only the
In the presence of 2.5 mol % of [Rh(cod)Cl]2 and 7.5 mol % of
DPEphos as phosphine ligand combined with 20 mol % of
TsOH·H2O as acid cocatalyst in 1,2-dichloroethane we were able
to isolate the desired 1,4-enyne coupling product in 29% yield
(entry 1). By changing the ligand to rac-BINAP the yield could
be further increased to 44% (entry 2), whichdue to the
possibility of easily introducing axial chiralitylay the basis for
the development of an asymmetric version thereof.
In this respect, we examined a variety of bidentate phosphine
ligands (entries 3−5) and were delighted to find that (R)-Tol-
BINAP provided the most promising result with an er of 94.5:5.5
aside from a moderate yield of 54% (entry 6). Striving for further
improvements, we examined different Brønsted acid cocatalysts
(entries 7 and 8) and solvents15 and were able to obtain the
desired product 3a in 70% yield when performing the reaction in
DCM at 60 °C with even a slight increase in enantioselectivity.
Ultimately, only by increasing the amount of TFA to 40 mol % as
well as performing the reaction in DCM/EtOH = 3:1 at 60 °C we
B
DOI: 10.1021/acs.orglett.7b04035
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
corresponding allylic esters could be isolated. This result
indicates that the presence of an aryl residue in direct vicinity
to the alkyne is mandatory to promote decarboxylation.
Additionally, various allenes were examined for their potential
to participate in this addition of 4-(methoxyphenyl)propiolic
acid (1b, Table 3).
In order to further unravel the underlying mechanism of this
decarboxylative reaction, deuterium-labeling studies were
conducted (Scheme 2).
Scheme 2. Deuterium Labeling and Crossover Experiments
Table 3. Decarboxylative Alkynylation with a Variety of
a
Functionalized Allenes
As expected for a reaction proceeding via a π-/σ-allylrhodium
intermediate, deuterium incorporation was observed at all three
positions of the allylic double bond indicating intermediary
reversibility.10a,12b,18 To gain deeper insight into the underlying
mechanism, a crossover experiment with allylic ester 5a was
conducted, indicating that 5a is not directly involved in the
catalytic cycle but more likely a reversibly formed off-cycle side
product. Moreover, it revealed that the relative rate of the
decarboxylation depends on the individual electronic properties
of the respective aryl substitution pattern with a higher rate for
electron-rich aryl residues. Together with the outcome of further
control experiments19 as well as previous mechanistic studies, we
propose the following reaction mechanism (Scheme 3).
Scheme 3. Proposed Catalytic Cycle
a
1 (0.2 mmol), 2d (0.6 mmol), [Rh(cod)Cl]2 (2.5 mol %), (R)-Tol-
BINAP (7.5 mol %), TFA (40 mol %), DCM:EtOH = 3:1 (1.0 mL),
60 °C, 16 h. All yields given as isolated yields. Enantioselectivities
b
determined by HPLC on chiral stationary phases. Reaction
c
performed at 80 °C. (S)-Tol-BINAP used instead.
The terminal allenic substrates utilized were easily prepared in
one step from commercially available starting materials.17 Linear
aliphatic chains (4a,b) as well as branched cycloaliphatic residues
(4c) reacted smoothly with excellent enantioselectivities. Higher
functionalized allenes bearing halogenated (4d) residues or
nitrile moieties (4e) also provided the coupled products in
excellent yields and enantioselectivities. When a methyl ester
moiety was introduced in the allene, an impressive enantiomeric
ratio of 99.5:0.5 was observed for the corresponding 1,4-enyne
4f. Moreover, different protected alcohols (4g,h) and amines
(4i) could be introduced, even though the presence of potentially
coordinating heteroatoms in the carbon chain slightly compro-
mised enantioselectivities. Interestingly, even an acid-sensitive
trialkyl phosphate (4j) could participate in the reaction in a
comparable yield and enantioselectivity without any occurring
hydrolysis. To highlight the general utility of this protocol, the
synthesis of the unsubstituted enyne 4k was performed with both
(commercially available) enantiomers of the Tol-BINAP ligand,
giving rise to (R)-4k and (S)-4k in comparable yields and
enantiomeric ratios.
After initial catalyst preformation from [Rh(cod)Cl]2 and (R)-
Tol-BINAP, a rhodium(III) hydride complex A is generated
upon reaction with TFA,20 followed by a hydrometalation of the
allene to give the allylrhodium(III) intermediate B. Subsequent
ligand exchange with the respective arylpropiolic acid 1 gives rise
to the allylrhodium complex C which can now undergo
decarboxylation to form the alkyne complex D. As stated
previously, this step is more likely to occur for more electron-rich
aryl residues. Ultimately, D undergoes a reductive elimination to
form the 1,4-enyne coupling product 3 while simultaneously
regenerating the Rh(I) catalyst.
C
DOI: 10.1021/acs.orglett.7b04035
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
see: (d) Trost, B. M.; Taft, B. R.; Masters, J. T.; Lumb, J.-P. J. Am. Chem.
Soc. 2011, 133, 8502.
In conclusion, we have accomplished a highly chemo-, regio-,
and enantioselective decarboxylative alkynylation of terminal
allenes with arylpropiolic acids to construct enantiomerically
enriched branched 1,4-enynes under mild conditions with
commercially available [Rh(cod)Cl]2 and (R)-Tol-BINAP.
This reaction releases CO2 as the only byproduct, and neither
requires strongly basic reaction conditions nor premetalated
alkyne nucleophiles. Further investigations regarding an
extension toward related arylpropiolic acid pronucleophiles as
well as alkynes as allene surrogates are ongoing in our laboratory.
(7) For selected examples on transformations of 1,4-enynes, see:
(a) Heffron, T. P.; Jamison, T. F. Org. Lett. 2003, 5, 2339. (b) Heffron,
T. P.; Trenkle, J. D.; Jamison, T. F. Tetrahedron 2003, 59, 8913. (c) Shi,
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2005, 127, 12468. (e) Buzas, A.; Gagosz, F. J. Am. Chem. Soc. 2006, 128,
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(g) Sato, T.; Onuma, T.; Nakamura, I.; Terada, M. Org. Lett. 2011, 13,
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(h) Jacobson, M.; Redfern, R. E.; Jones, W. A.; Aldridge, M. H. Science
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ASSOCIATED CONTENT
* Supporting Information
■
S
(k) Hickmann, V.; Alcarazo, M.; Furstner, A. J. Am. Chem. Soc. 2010,
̈
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b04035.
132, 11042.
(8) For transition-metal-catalyzed enantioselective syntheses of 1,4-
enynes, see: (a) Li, H.; Alexakis, A. Angew. Chem. 2012, 124, 1079;
Angew. Chem., Int. Ed. 2012, 51, 1055. (b) Dabrowski, J. A.; Gao, F.;
Hoveyda, A. H. J. Am. Chem. Soc. 2011, 133, 4778. (c) Hamilton, J. Y.;
Sarlah, D.; Carreira, E. M. Angew. Chem. 2013, 125, 7680; Angew. Chem.,
Int. Ed. 2013, 52, 7532. (d) Makida, Y.; Takayama, Y.; Ohmiya, H.;
Sawamura, M. Angew. Chem. 2013, 125, 5458; Angew. Chem., Int. Ed.
2013, 52, 5350. (e) Harada, A.; Makida, Y.; Sato, T.; Ohmiya, H.;
Sawamura, M. J. Am. Chem. Soc. 2014, 136, 13932.
Experimental procedures and analytical data for the
1
synthesized compounds, including H and 13C NMR
spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: bernhard.breit@chemie.uni-freiburg.de.
ORCID
(9) For a recent review, see: Koschker, P.; Breit, B. Acc. Chem. Res.
2016, 49, 1524.
(10) For examples of C−C bond formation, see: (a) Li, C.; Breit, B. J.
Am. Chem. Soc. 2014, 136, 862. (b) Beck, T. M.; Breit, B. Angew. Chem.
2017, 129, 1929; Angew. Chem., Int. Ed. 2017, 56, 1903.
(11) For a recent review, see: Haydl, A.; Breit, B.; Liang, T.; Krische, M.
J. Angew. Chem. 2017, 129, 11466; Angew. Chem., Int. Ed. 2017, 56,
11312.
(12) For examples of C−C bond formation, see: (a) Beck, T. M.; Breit,
B. Org. Lett. 2016, 18, 124. (b) Cruz, F. A.; Chen, Z.; Kurtoic, S. I.; Dong,
V. M. Chem. Commun. 2016, 52, 5836. (c) Li, C.; Grugel, C. P.; Breit, B.
Chem. Commun. 2016, 52, 5840. (d) Beck, T. M.; Breit, B. Eur. J. Org.
Chem. 2016, 2016, 5839. (e) Cruz, F. A.; Dong, V. M. J. Am. Chem. Soc.
2017, 139, 1029. (f) Cruz, F. A.; Zhu, Y.; Tercenio, Q. D.; Shen, Z.;
Dong, V. M. J. Am. Chem. Soc. 2017, 139, 10641.
Bernhard Breit: 0000-0002-2514-3898
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the DFG and the Fonds der
Chemischen Industrie. We thank Umicore, BASF, and Wacker
for generous gifts of chemicals. C.P.G. is grateful for a Ph.D.
fellowship from the Fonds der Chemischen Industrie. Thorsten
M. Beck, Zi Liu, and Dino Berthold (all University of Freiburg)
are acknowledged for sharing previously prepared allenes.
Technical support by Joshua Emmerich (University of Freiburg)
for HPLC separations is acknowledged.
(13) For a review on decarboxylative coupling reactions of propiolic
acids, see: Park, K.; Lee, S. RSC Adv. 2013, 3, 14165.
(14) For selected recent examples on decarboxylative reactions
involving propiolic acids, see: (a) Li, X.; Yang, F.; Wu, Y.; Wu, Y. Org.
Lett. 2014, 16, 992−995. (b) Sun, F.; Gu, Z. Org. Lett. 2015, 17, 2222.
(c) Sun, F.; Gu, Z. Org. Lett. 2015, 17, 2222. (d) Lim, J.; Choi, J.; Kim,
H.-S.; Kim, I. S.; Nam, K. C.; Kim, J.; Lee, S. J. Org. Chem. 2016, 81, 303.
(e) Yang, L.; Jiang, L.; Li, Y.; Fu, X.; Zhang, R.; Jin, K.; Duan, C.
Tetrahedron 2016, 72, 3858. (f) Lee, J.-H.; Raja, G. C. E.; Yu, S.; Lee, J.;
Song, K. H.; Lee, S. ACS Omega 2017, 2, 6259.
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D
DOI: 10.1021/acs.orglett.7b04035
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