Ligand-controlled iridium-catalyzed semihydrogenation of alkynes with ethanol: highly stereoselective synthesis of E- and Z-alkenes

Article abstract of DOI:10.1039/c8cc09714c

A ligand-controlled iridium-catalyzed semihydrogenation of alkynes to E- and Z-alkenes with ethanol was developed. Effective selectivity control was achieved by ligand regulation. The use of 1,2-bis(diphenylphosphino)ethane (DPPE) and 1,5-cyclooctadiene (COD) was critical for the stereoselective semihydrogenation of alkynes. The general applicability of this procedure was highlighted by the synthesis of more than 40 alkenes, with good stereoselectivities. The value of our approach in practical applications was investigated by studying the effects of pinosylvin and 4,4′-dihydroxystilbene (DHS) on zebrafish as a vertebrate model.

Full text of DOI:10.1039/c8cc09714c

ChemComm
View Article Online
View Journal
COMMUNICATION
Ligand-controlled iridium-catalyzed
semihydrogenation of alkynes with ethanol: highly
Cite this:DOI: 10.1039/c8cc09714c
stereoselective synthesis of E- and Z-alkenes†
Received 7th December 2018,
Accepted 18th January 2019
Jinfei Yang, *‡ Chengniu Wang,‡ Yufeng Sun, Xuyan Man, Jinxia Li and Fei Sun*
DOI: 10.1039/c8cc09714c
rsc.li/chemcomm
A ligand-controlled iridium-catalyzed semihydrogenation of alkynes
to E- and Z-alkenes with ethanol was developed. Effective selectivity
control was achieved by ligand regulation. The use of 1,2-bis(diphenyl-
phosphino)ethane (DPPE) and 1,5-cyclooctadiene (COD) was critical
for the stereoselective semihydrogenation of alkynes. The general
applicability of this procedure was highlighted by the synthesis of
more than 40 alkenes, with good stereoselectivities. The value of our
approach in practical applications was investigated by studying the
effects of pinosylvin and 4,40-dihydroxystilbene (DHS) on zebrafish as a
vertebrate model.
The selective semihydrogenation of unsaturated compounds is
one of the most important reactions in organic synthesis,1 and
has been widely used for the synthesis of synthetic intermediates,
natural products, fragrances, pharmaceuticals, and agrochemical
Scheme 1 Various strategies for semihydrogenation of alkynes.
products.2 Several catalytic systems for alkyne semihydro- selectivity for either the E- or Z-alkene isomer in a single
genation,3 e.g., Lindlar reduction,4 have been reported. The transformation.8 Recently, Du,9 Moran,10 and Liu7k have reported
homogeneous or heterogeneous catalytic hydrogenation of methods that give switchable selectivity for either the E- or
inner alkynes shows intrinsic stereoselectivity for Z-alkenes Z-alkene isomer. However, to obtain good product yields, these
because the reaction proceeds via syn addition. Many methods methods require flammable, explosive, corrosive, or expensive
for semihydrogenation of alkynes to Z-alkenes have been hydrogenation agents such as hydrogen, formic acid, and ammonia
reported,1,3,5 and these can provide good Z-selectivity. However, borane, and this has limited their use. The development of safer,
these methods require the use of flammable, explosive, corrosive, or convenient, and economical stereoselective semihydrogenation
expensive hydrogenating agents to achieve the semihydrogenation methods is therefore still necessary. Ethanol is the best choice of
reaction and to obtain good product yields. The stereocomple- transfer hydrogenation agent and the development of methods for
mentary formation of E-alkenes by hydrogenation is much synthesizing E- and Z-alkenes with ethanol as the hydrogen source
more difficult than Z-alkene formation.6 This is, in part, because is desirable. Very recently, Gru¨tzmacher,11 Swamy,12 and Huang13
addition of the hydrogenation agent favors one side of the reported transfer hydrogenation with ethanol. Unfortunately, the
substrate and therefore leads to cis addition. E-Selective alkyne semi-hydrogenation of simple disubstituted acetylene cannot
reductions are therefore being actively researched, and some be achieved by all three systems. Here, we report an example of
promising catalytic systems have been developed recently. ligand-controlled iridium-catalyzed semihydrogenation of alkynes
These involve use of transition-metal complexes in combination to E- and Z-alkenes with ethanol as the transfer hydrogenation
with hydrogen gas or various transfer hydrogenation agents agent (Scheme 1b).
(Scheme 1a).7 However, few catalytic systems allow switchable
Z-Alkene synthesis by transition metal catalytic hydrogenation
intrinsically involves cis hydrometalation of alkynes. The E-alkene
is usually obtained by isomerization of the Z-alkene (Scheme 2).
Isomerization is usually achieved by Z-alkene coordination
with a metal center, followed by migration insertion, and then
Medical School, Institute of Reproductive Medicine, Nantong University,
Nantong 226019, China. E-mail: jfyang@ntu.edu.cn, sunfei@ntu.edu.cn
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c8cc09714c
‡ J.-F. Y. and C.-N. W. contributed equally to this work.
This journal is ©The Royal Society of Chemistry 2019
Chem. Commun.

View Article Online
Communication
ChemComm
Table 1 Effects of solvent, temperature, and ligand. 1,2-Diphenylethyne
(0.2 mmol), ethanol (4 mmol), [Ir(COD)Cl]2 (10 mmol), ligand (0.04 mmol),
THF (1.5 mL), at 120 1C under N2 for 22 h
Conv. Yield
Yield
Entry Ligand
Solvent
T (1C) 1a (%) 2aa (%) 3aa (%)
1
2
3
4
5
6
7
8
DPPE
DPPE
DPPE
DPPE
DPPE
DPPE
DPPE
DPPE
DPPE
DPPE
DPPE
DPPE
DPPBde
DIPAMP
BINAP
p-Xylene
Mesitylene 130
130
17
27
0
0
5
5
0
79
92
81
34
19
1
83
20
91
46
0
17
27
0
0
2
2
0
75
92
78
6
5
1
80
7
7
38
0
0
0
0
0
0
3
3
0
3
0
n-Hexane
Dioxane
DMF
Toluene
DMSO
THF
THF
THF
THF
THF
130
130
130
130
130
130
120
110
100
90
120
120
120
120
120
120
120
Scheme 2 Strategy for ligand control of stereo effects.
b-hydrogen elimination. In theory, coordination and insertion of
the Z-alkene intermediate require a less sterically hindered metal
center with an open coordination site, and this facilitates the
following b-hydride elimination step. We therefore envisaged that
isomerization to obtain E-alkenes requires a ligand that causes
less steric hindrance. Conversely, isomerization could be suppressed
by using an appropriate bulky ligand because coordination and
insertion of the Z-alkene would be sterically unfavorable. This
would result in selective generation of Z-alkene products. Ligand-
controlled stereodivergent transfer hydrogenation of alkynes is
therefore a promising approach.
9
10
11
12
13b
14c
15d
16e
17
18 f
19g
3
28
14
0
THF
THF
THF
3
13
84
8
0
0
DPPE + COD THF
None
DPPE
DPPE
THF
THF
THF
0
a
b
Yields were determined by GC analysis. DPPBde = 2-diphenyl-
phosphinobenzaldehyde. c DIPAMP = ethylenebis(2-methoxyphenylphenyl-
d
phosphine). BINAP = 2,20-bis(diphenylphosphino)-1,10-binaphthalene.
We began by treating 1,2-diphenylethyne and ethanol with
2.5 mol% [Ir(COD)Cl]2 as a catalyst, with DPPE as a ligand.
Initially, we screened various potential reaction solvents to
e
f
g
COD (0.4 mmol), 40 h. Without [Ir(COD)Cl]2. Without ethanol.
identify a suitable reaction solvent. THF was found to be the on the aryl rings all gave the corresponding (E)-1,2-diarylethenes
best solvent for the semihydrogenation of alkynes to E-alkenes with with high selectivities and in good yields. Aryls containing an
ethanol (Table 1, entries 1–8). To improve the reaction efficiency, we electron-withdrawing group such as fluoro, chloro, bromo, and
examined a wide range of reaction temperatures (Table 1, entries trifluoromethyl were also tolerated and afforded the corres-
9–12). The results show that 120 1C was the optimum temperature, ponding (E)-1,2-diarylethenes 2b–2v in moderate to good yields
and the corresponding (E)-1,2-diphenylethene was obtained in 92% with highly Z/E selectivities. Moreover, the reaction of 1,2-diaryl-
yield with 499 : 1 E/Z selectivity. It is worth noting that there is a ethynes containing two methoxy substituents or two trifluoromethyl
small amount of excessive hydrogenation product formation when substituents at the meta positions of the aromatic rings also gave the
the temperature is raised to 130 1C. To increase conversion to the corresponding (E)-1,2-diarylethene products 2w, 2x, and 2a in good
Z-alkene, we replaced DPPE with large sterically hindering ligands yields. To our delight, dialkylalkynes and methyl 3-phenylpropiolate
(Table 1, entries 13–16). GC analysis showed that a 3% yield of (Z)-3a are also suitable for this system, the corresponding products 2e, 2/
was obtained with DIPAMP, and a 13% yield was obtained when and 2g were obtained in good yields. In addition, terminal alkynes
BINAP was used. To further increase the conversion rate to the all give corresponding products 2A, 2B and 2C in good to excellent
Z-alkene, we added both COD and DPPE ligands to increase the yields. These results indicate that various groups, e.g., alkyl,
steric hindrance at the metal center. An 84% yield of 3a was phenyl, fluoro, chloro, bromo, methoxy, trifluoromethyl and
obtained, with 12 : 1 Z/E selectivity (Table 1, entry 16). This shows ester, were tolerated under the optimum reaction conditions.
that these two ligands have crucial roles. The stereostructure of More importantly, pinosylvin or DHS can be easily obtained by
the metal center is a key factor in the formation of cis-alkenes. demethylating 2x or 2y.
These results therefore support our initial hypothesis that the
As mentioned above, regulation of Z-selective semireduction
E/Z selectivity can be well controlled by the level of steric of alkynes can be achieved by increasing the steric hindrance at
hindrance at the metal center. No over-reduced alkane byproducts the metal center. The substrate scope was surveyed to investigate
were detected in this catalytic system.
the versatility of this iridium-catalyzed transfer hydrogenation of
With the optimum reaction conditions in hand, a series of alkynes for the synthesis of Z-alkenes, with use of a combination
1,2-disubstituted acetylene were investigated for extending the of DPPE/COD as ligands. The Z-alkene products were obtained
substrate scope (Scheme 3). This ligand-controlled iridium- in good yields with high Z/E selectivities for most tested
catalyzed semihydrogenation of alkynes with ethanol shows good substrates. A wide range of functional groups were also well
functional group tolerance. Diarylethynes with electron-neutral tolerated. The results, which are summarized in Scheme 4,
or electrondonating groups such as alkyl, phenyl, and methoxy show that aryls containing electron-neutral, electron-donating,
Chem. Commun.
This journal is ©The Royal Society of Chemistry 2019

View Article Online
ChemComm
Communication
Scheme 5 Effects of treatment with pinosylvin and DHS on vascular
system in trunk of Tg(kdrl:EGFP) zebrafish embryos at 48 hpf. (A–D) Control
group, pinosylvin and DHS group treated with 1, 0.1, and 0.01 mg mLꢀ1
.
Scale bar, 75 mm.
evaluating drug effects.14 To demonstrate the value of our approach
in practical applications, we study the effects of pinosylvin and DHS,
with zebrafish as a vertebrate model. On the basis of Ragunathan’s
work,15 we envisaged that the effects of pinosylvin and DHS on the
vascular system would differ from those of resveratrol. We therefore
examined the activities of pinosylvin and DHS in zebrafish. The test
results show that treatment of zebrafish embryos with 1 mg mLꢀ1
pinosylvin or DHS resulted in morphological malformations, and
treatment with 0.01–0.1 mg mLꢀ1 pinosylvin or DHS led to post-
antiangiogenic defects (Scheme 5). The results of this study will be
of great significance in research on drugs for treating cardiovascular
and cerebrovascular diseases.
Scheme 3 Isolated product yields and reaction conditions: substrate 1
(0.2 mmol), ethanol (4 mmol), [Ir(COD)Cl]2 (10 mmol), DPPE (0.04 mmol),
THF (1.5 mL), at 120 1C under N2 for 22 h. a Gram-scale synthesis. b 30 h.
c There is a partial over-reduction product generation. d 70 1C.
Additional experiments were performed to gain a better
understanding of the roles of the ligand, reductant, and iridium
in the stereoselective semihydrogenation of alkynes. Control
experiments showed that the absence of ethanol or [Ir(COD)Cl]2
shut down the reaction, and the absence of the ligand signifi-
cantly decreased the reaction selectivity and yield (Table 1,
entries 17–19). These results imply that each of the components
is essential to this reaction. We confirmed that one hydrogen
atoms in the reaction product were provided by ethanol by
conducting deuterium-labeling experiments (Scheme 6). When
C2D5OH was used, the reduction product was not deuterated in the
presence of [Ir(COD)Cl]2/DPPE/COD. Conversely, the di-deuterated
cis product was isolated when C2H5OD was used. Notably, the
di-deuterated cis product is difficult to be separated because of
the similar polarity to 1,2-diphenylethyne. These results show
that the hydroxyl group in ethanol acts as a hydrogen source in
the semihydrogenation reaction.
Scheme 4 Isolated product yields and reaction conditions: substrate 1
(0.2 mmol), ethanol (4 mmol), [Ir(COD)Cl]2 (10 mmol), DPPE (0.04 mmol),
COD (0.4 mmol), THF (1.5 mL), at 120 1C under N2 for 44 h. a 40 h.
and electron-withdrawing groups all gave the corresponding
(Z)-alkenes with high selectivities and in good yields.
The synthetic utility of the current method was tested by
performing a gram-scale ligand-controlled iridium-catalyzed
semihydrogenation of an alkyne with ethanol under the optimum
conditions. The target (Z)-2a was obtained in 79% yield.
The zebrafish has become an important vertebrate model for
Scheme 6 Mechanism experiments.
This journal is ©The Royal Society of Chemistry 2019
Chem. Commun.

View Article Online
Communication
ChemComm
in Comprehensive Organic Synthesis, ed. B. M. Trost and I. Fleming,
Pergamon, Oxford, 1991, vol. 8, pp. 417–442; (d) H. Takaya and
R. Noyori, in Comprehensive Organic Synthesis, ed. B. M. Trost and
I. Fleming, Pergamon, Oxford, 1991, vol. 8, pp. 443–469;
(e) M. W. van Laren and C. J. Elsevier, Angew. Chem., Int. Ed., 1999,
Moreover, (Z)-1,2-diphenylethene can be completely converted
to (E)-1,2-diphenylethene in the presence of [Ir(COD)Cl]2/DPPE.
Based on these results, we propose the catalytic cycle (see the
Fig. S1 for details, ESI†).
´
´
´ ´
38, 3715; ( f ) A. Molnar, A. Sarkany and M. Varga, J. Mol. Catal. A:
Chem., 2001, 173, 185; (g) P. Hauwert, G. Maestri, J. W. Sprengers,
M. Catellani and C. J. Elsevier, Angew. Chem., Int. Ed., 2008, 47, 3223;
(h) M. Haberberger, E. Irran and S. Enthaler, Eur. J. Inorg. Chem.,
2011, 2797; (i) A. Brzozowska, L. M. Azofra, V. Zubar, I. Atodiresei,
L. Cavallo, M. Rueping and O. El-Sepelgy, ACS Catal., 2018, 8, 4103.
6 For a related discussion, see: (a) K. Radkowski, B. Sundararaju and
A. Fu¨rstner, Angew. Chem., Int. Ed., 2013, 52, 355; (b) M. Leutzsch,
In summary, we have developed a highly efficient ligand-
controlled iridium-catalyzed semihydrogenation of alkynes to
E- and Z-alkenes with ethanol as a transfer hydrogenation agent.
This method is safer, more convenient, and more economical
than traditional strategies. It is compatible with a range of
functional groups and is suitable for gram-scale reactions. The
value of our approach in practical applications was shown by
studying the effects of treatment with pinosylvin and DHS, with
zebrafish as a vertebrate model. The test results show that
pinosylvin and DHS significantly affect angiogenesis. The results
of this study will be of great significance in research on drugs for
treating cardiovascular and cerebrovascular diseases. Further
investigations of the use of cheaper metals, animal experiments,
and other reaction types are underway in our laboratory.
We thank the National Natural Science Foundation of China
(81430027 and 81671510), the National Basic Research Program
(973 Program) (2014CB943100) for financial support.
`
¨
L. M. Wolf, P. Gupta, M. Fuchs, W. Thiel, C. Fares and A. Furstner,
Angew. Chem., Int. Ed., 2015, 54, 12431; (c) M. Fuchs and A. Fu¨rstner,
Angew. Chem., Int. Ed., 2015, 54, 3978.
7 (a) C. E. Castro and R. D. Stephens, J. Am. Chem. Soc., 1964, 86, 4358;
(b) A. B. Smith, III, P. A. Levenberg and J. Z. Suits, Synthesis, 1986,
184; (c) K. Tani, A. Iseki and T. Yamagata, Chem. Commun., 1999,
¨
1821; (d) B. M. Trost, Z. T. Ball and T. Joge, J. Am. Chem. Soc., 2002,
124, 7922; (e) N. Hayashi, I. Shibata and A. Baba, Org. Lett., 2004,
6, 4981; ( f ) E. Shirakawa, H. Otsuka and T. Hayashi, Chem. Commun.,
2005, 5885; (g) R. Shen, T. Chen, Y. Zhao, R. Qiu, Y. Zhou, S. Yin,
X. Wang, M. Goto and L. Han, J. Am. Chem. Soc., 2011, 133, 17037;
(h) D. Srimani, Y. Diskin-Posner, Y. Ben David and D. Milstein, Angew.
Chem., Int. Ed., 2013, 52, 14131; (i) K. Higashida and K. Mashima, Chem.
Lett., 2016, 45, 866; ( j) K. Tokmic and A. R. Fout, J. Am. Chem. Soc.,
2016, 138, 13700; (k) S. Fu, N. Chen, X. Liu, Z. Shao, S. Luo and Q. Liu,
J. Am. Chem. Soc., 2016, 138, 8588; (l) K. T. Neumann, S. Klimczyk,
M. N. Burhardt, B. Bang-Andersen, T. Skrydstrup and A. T. Lindhardt,
ACS Catal., 2016, 6, 4710.
8 (a) L. Yong, K. Kirleis and H. Butenschoen, Adv. Synth. Catal., 2006,
348, 833; (b) R. Barrios-Francisco and J. J. Garcia, Inorg. Chem., 2009,
48, 386; (c) F. Luo, C. Pan, W. Wang, Z. Ye and J. Cheng, Tetrahedron,
2010, 1399; (d) J. Li and R. Hua, Chem. – Eur. J., 2011, 17, 8462;
(e) C. Belger and B. Plietker, Chem. Commun., 2012, 48, 5419;
( f ) T. Schabel, C. Belger and B. Plietker, Org. Lett., 2013, 15, 2858;
(g) R. Kusy and K. Grela, Org. Lett., 2016, 18, 6196.
Conflicts of interest
There are no conflicts to declare.
Notes and references
1 J. G. de Vries and C. J. Elsevier, Handbook for Homogeneous Hydro-
genation, Wiley-VCH, Weinheim, 2007, vol. 1, pp. 375–411.
9 Y. Liu, L. Hu, H. Chen and H. Du, Chem. – Eur. J., 2015, 21, 3495.
2 (a) A. Cirla and J. Mann, Nat. Prod. Rep., 2003, 20, 558; (b) G. C. Tron, 10 E. Richmond and J. Moran, J. Org. Chem., 2015, 80, 6922.
T. Pirali, G. Sorba, F. Pagliai, S. Busacca and A. A. Genazzani, J. Med. 11 T. Zweifel, J.-V. Naubron, T. Bu¨ttner, T. Ott and H. Gru¨tzmacher,
Chem., 2006, 49, 3033; (c) J. A. Baur and D. A. Sinclair, Nat. Rev. Drug
Angew. Chem., Int. Ed., 2008, 47, 3245.
Discovery, 2006, 5, 493; (d) D. J. Ager, in Handbook for Homogeneous 12 A. Siva Reddy and K. C. Kumara Swamy, Angew. Chem., Int. Ed., 2017,
Hydrogenation, ed. J. G. de Vries and C. J. Elsevier, Wiley-VCH,
Weinheim, 1st edn, 2007, vol. 2, p. 745.
3 (a) H.-U. Blaser, A. Schnyder, H. Steiner, F. Rçssler and
56, 6984.
13 Y. Wang, Z. Huang, X. Leng, H. Zhu, G. Liu and Z. Huang, J. Am.
Chem. Soc., 2018, 140, 4417.
P. Baumeister, in Handbook of Heterogeneous Catalysis, ed. G. Ertl, 14 (a) Y.-W. Shi, W. Yuan, X. Wang, J. Gong, S.-X. Zhu, L.-L. Chai,
H. Knçzinger, F. Schth and J. Weitkamp, Wiley-VCH, Weinheim, 2nd
edn, 2008, vol. 7, pp. 3284–3308; (b) X. Qi, X. Liu, L.-B. Qu, Q. Liu
and Y. Lan, J. Catal., 2018, 362, 25.
J.-L. Qi, Y.-Y. Qin, Y. Gao, Y.-L. Zhou, X.-L. Fan, C.-Y. Ji, J.-Y. Wu,
Z.-W. Wang and D. Liu, Sci. Rep., 2016, 6, 30189; (b) J.-F. Yang,
X. Meng, K. Lu, Z.-H. Lu, M.-L. Huang, C.-N. Wang and F. Sun, RSC
Adv., 2018, 8, 31603.
4 H. Lindlar and R. Dubuis, Org. Synth., 1966, 46, 89.
5 (a) E. N. Marvell and T. Li, Synthesis, 1973, 457; (b) P. N. Rylander, 15 J. R. Nathan, B. Antony and M. Ragunathan, J. Chem. Pharm. Res.,
Hydrogenation Methods, Academic Press, London, 1985; (c) S. Siegel
2014, 6, 892.
Chem. Commun.
This journal is ©The Royal Society of Chemistry 2019