Synthesis of Z-alkenes from Rh(I)-catalyzed olefin isomerization of β,γ-unsaturated ketones

Article abstract of DOI:10.1021/ol401607c

Developing olefin isomerization reactions to reach kinetically controlled Z-alkenes is challenging because formation of trans-alkenes is thermodynamically favored under the traditional catalytic conditions using acids, bases, or transition metals as the catalysts. A new synthesis of Z-alkenes from Rh(I)-catalyzed olefin isomerization of β,γ-unsaturated ketones to α,β-unsaturated ketones was developed, providing an easy and efficient way to access various Z-enones.

Full text of DOI:10.1021/ol401607c

ORGANIC
LETTERS
2013
Vol. 15, No. 18
4634–4637
Synthesis of Z‑Alkenes from
Rh(I)-Catalyzed Olefin Isomerization
of β,γ-Unsaturated Ketones
Lian-Gang Zhuo, Zhong-Ke Yao, and Zhi-Xiang Yu*
Beijing National Laboratory of Molecular Sciences (BNLMS), Key Laboratory
of Bioorganic Chemistry and Molecular Engineering, College of Chemistry,
Peking University, Beijing 100871, China
yuzx@pku.edu.cn
Received June 7, 2013
ABSTRACT
Developing olefin isomerization reactions to reach kinetically controlled Z-alkenes is challenging because formation of trans-alkenes is
thermodynamically favored under the traditional catalytic conditions using acids, bases, or transition metals as the catalysts. A new synthesis of
Z-alkenes from Rh(I)-catalyzed olefin isomerization of β,γ-unsaturated ketones to r,β-unsaturated ketones was developed, providing an easy and
efficient way to access various Z-enones.
Because alkenes are ubiquitous in molecules and they
also serve as functional groups for a variety of further
transformations, developing new reactions for alkene
synthesis and expanding the scope of the existing alkene
synthesis methods are both very significant in today’s
science of synthesis.1 One powerful reaction to access
substituted alkenes is to use transition-metal-catalyzed
olefin isomerizations of the pre-existing CdC double
bonds (Scheme 1a). These isomerization processes have
been widely used in the syntheses of carbonyl compounds
(from allyl alcohols),2 enamines (from allyl amines),3 enol
ethers (from allyl ethers),4 and other internal alkenes (from
terminal alkenes).5À11 Usually, the olefin isomerizations
are catalyzed by acids or bases1 or transition metals (e.g.,
Fe,5 Ir,6 Ni,7 Pd,7d,8 Pt,9 Rh,5,10 and Ru5,11). A limitation
of these olefin isomerizations is that, in many cases, only
the E-alkenes are obtained. This is attributed to the facts
that the olefin isomerization reactions are usually reversi-
ble and E-alkenes in most cases are the thermodynamically
(8) Pd, see: Gautheir, D.; Lindhardt, A. T.; Olsen, E. P. K.; Overgaard,
J.; Skrydstrup, T. J. Am. Chem. Soc. 2010, 132, 7998.
(9) Pt, see: Scarso, A.; Colladon, M.; Sgarbossa, P.; Michelin, R. A.;
(1) Larock, R. C. Comprehensive organic transformations: a guide to
functional group preparations, 2nd ed.; Wiley-VCH: New York, 1999.
Strukul, G. Organometallics 2010, 29, 1487.
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(2) (a) Uma, R.; Crevisy, C.; Gree, R. Chem. Rev. 2003, 103, 27. (b)
Bouziane, A.; Carboni, B.; Bruneau, C.; Carreaux, F.; Renaud, J.
Tetrahedron 2008, 64, 11745.
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H.; Taketomi, T.; Takaya, H.; Miyashita, A.; Noyori, R.; Otsuka, S. J. Am.
Chem. Soc. 1984, 106, 5208. (b) Alphonse, F. A.; Yudin, A. K. J. Am. Chem.
Soc. 2006, 128, 11754. (c) Tsang, D. S.; Yang, S.; Alphonse, F. A.; Yudin,
A. K. Chem.;Eur. J. 2008, 14, 886.
(3) Krompiec, S.; Krompiec, M.; Penczek, R.; Ignasiak, H. Coord.
Chem. Rev. 2008, 252, 1819.
(4) Kuznik, N.; Krompiec, S. Coord. Chem. Rev. 2007, 251, 222.
(5) Fe, Rh, and Ru, see: Stille, J. K.; Becker, Y. J. Org. Chem. 1980,
45, 2139.
(6) Ir, see: (a) Ohmura, T.; Shirai, Y.; Yamamoto, Y.; Miyaura, N.
Chem. Commun. 1998, 1337. (b) Ohmura, T.; Yamamoto, Y.; Miyaura,
N. Organometallics 1999, 18, 413. (c) Yamamoto, Y.; Miyairi, T.;
Ohmura, T.; Miyaura, N. J. Org. Chem. 1999, 64, 296.
(7) Ni, see: (a) Wille, A.; Tomm, S.; Frauenrath, H. Synthesis 1998,
305. (b) Sharma, S. K.; Srivastava, V. K.; Jasra, R. V. J. Mol. Catal. A:
Chem. 2006, 245, 200. (c) Jinesh, C. M.; Antonyrai, C. A.; Kannan, S.
Catal. Today 2009, 141, 176. (d) Lim, H. J.; Smith, C. R.; RajanBabu,
T. V. J. Org. Chem. 2009, 74, 4565. (e) Wang, L.; Liu, Z.; Bai, R.; Pan, Y.;
Lei, A. Chem. Commun. 2013, 49, 7923.
(11) Ru, see: (a) Suzuki, H.; Koyama, Y.; Moro-Oka, Y.; Ikawa, T.
Tetrahedron Lett. 1979, 20, 1415. (b) Wipf, P.; Spencer, S. R. J. Am.
Chem. Soc. 2005, 127, 225. (c) Arisawa, M.; Terada, Y.; Takahashi, K.;
Nakagawa, M.; Nishida, A. J. Org. Chem. 2006, 71, 4255. (d) Hanessian,
S.; Giroux, S.; Larrson, A. Org. Lett. 2006, 8, 5481. (e) Grotjahn, D. B.;
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r
10.1021/ol401607c
Published on Web 09/04/2013
2013 American Chemical Society

favored products.8,9,11i Considering that Z-alkenes are
requiredand the synthesisofthese alkenes poses challenges
to synthetic chemists,12À16 it is highly desired to develop
new olefin isomerization approaches to obtain Z-alkenes.
Z-selectivity in these reported reactions was determined
by the favored coordination of heteroatoms of the sub-
strates to the metal atoms of the catalysts.
Here we report an unprecedented neutral Rh(I) complex
catalyzed olefin isomerization of β,γ-unsaturated ketones
to R,β-unsaturated ketones with high Z-selectivity, which
is complementary to the traditional olefin isomeriza-
tion catalyzed by acids or bases1,18 for the synthesis of
E-alkenes (Scheme 1b).
Scheme 1
Table 1. Screening of the Z-Selective Olefin Isomerization
Reaction Conditions of β,γ-Unsaturated Ketone 1a
temp
time
convc yieldc,d
entry
additivea
none
(°C) solventb (h) 2a-Z:2a-Ec (%)
(%)
1
2
75
75
75
75
75
75
75
80
80
80
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
18
18
23
23
23
23
23
23
23
23
23
4:1
<1:19
3:1
6:1
4:1
2:1
3:1
2:1
2:1
3:1
1:2
4:1
6:1
2:1
78
93
67
89
87
91
79
94
85
94
93
94
87
87
51
72
35
72
74
79
63
68
64
71
64
75
73
54
AgSbF6
However, only a few reports have touched this challenge
of reversing the selectivity of olefin isomerization to obtain
the thermodynamically less stable products, the Z-alkenes.
For example, Stille and Becker5 proposed previously that
the Z-product could be a kinetic product in their Fe-, Ru-,
or Rh-catalyzed isomerization of N-allylamide (only a
single example using CH2dCHCH2NHAc as the substrate
was reported there). Yudin and co-workers carried out a
Rh-catalyzed formation of Z-enamines via the alkene iso-
merization of very special substrates, allylaziridines.10b,c
Miyaura6a used Ir(I)-catalyzed isomerization of allyl silyl
ethers to silyl enol ethers. In the case of CH2dCHCH2OTBS,
the ratio of E/Z can be tuned from 99:1 (in acetone) to 1:3
(in CH2Cl2/acetone solvent). It was proposed that the
3e none
4
5
6
7
8
9
dppm
dppe
dppp
dppb
PCy3
PCyPh2
10 PiBu2biphenyl
11 P(2,6-diMeO-Ph)3 80
12 dppm
13 dppm
14 dppm
75
65
85
DME 23
DME 20
DCE
32
a dppp
(diphenylphosphino)methane, dppe
ethane, dppb = 1,4-bis(diphenylphosphino)butane, Cy = cyclohexyl.
b DCE = 1,2-dichloroethane, DME = 1,2-dimethoxyethane. c Deter-
mined by NMR. d Yield of mixture of Z- and E-enones. e Using 10 mol %
Rh(PPh3)3Cl as catalyst.
=
1,3-bis(diphenylphosphino)propane, dppm
=
= bis-
1,2-bis(diphenylphosphino)-
(12) For a recent review focusing on the synthesis of Z-alkenes, see:
Oger, C.; Balas, L.; Durand, T.; Galano, J.-M. Chem. Rev. 2012, 113,
1313.
When we tested the olefin isomerization of 1a using
5 mol % catalyst of [Rh(CO)2Cl]2 in DCE at 75 °C,19 we
obtaineda mixture ofthe starting material and the targeted
enones (2a), which have a Z/E ratio of 4:1 (Table 1, entry 1).
Under these reaction conditions, the conversion of the
reaction (78%) was not satisfactory, and only a moderate
yield (51%) of 2a-Z was obtained.
To improve the reaction yield, conversion, and espe-
cially the Z/E ratio, we further screened the reaction
conditions. To our disappointment, cationic Rh(I) cata-
lyst, generated by the reaction of 5 mol % of [Rh(CO)2Cl]2
and 12 mol % of AgSbF6, gave overwhelmingly the
E-alkene product with a Z/E ratio <1:19 (Table 1, entry 2).
We hypothesized that cationic Rh(I) catalyst here acted
(13) For recent examples of Z-selected semihydogenations, see: (a)
La Pierre, H. S.; Arnold, J.; Toste, F. D. Angew. Chem., Int. Ed. 2011, 50,
3900. (b) Li, J.; Hua, R. Chem.;Eur. J. 2011, 17, 8462. (c) Reyes-
ꢀ
~
Sanchez, A. n.; Canavera-Buelvas, F.; Barrios-Francisco, R.; Cifuentes-
Vaca, O. L.; Flores-Alamo, M.; Garcıa, J. J. Organometallics 2011, 30,
´
3340. (d) Shen, R.; Chen, T.; Zhao, Y.; Qiu, R.; Zhou, Y.; Yin, S.; Wang,
X.; Goto, M.; Han, L.-B. J. Am. Chem. Soc. 2011, 133, 17037.
(14) For selected examples of Z-selected coupling reactions, see: (a)
Smitrovich, J. H.; Woerpel, K. A. J. Am. Chem. Soc. 1998, 120, 12998.
(b) Trost, B. M.; Heinemann, C.; Ariza, X.; Weigand, S. J. Am. Chem.
Soc. 1999, 121, 8667. (c) Smitrovich, J. H.; Woerpel, K. A. J. Org. Chem.
2000, 65, 1601. (d) Ely, R. J.; Morken, J. P. J. Am. Chem. Soc. 2010, 132,
2534. (e) Bohn, M. A.; Schmidt, A.; Hilt, G.; Dindaroglu, M.; Schmalz,
H. G. Angew. Chem., Int. Ed. 2011, 50, 9689. (f) Giannerini, M.;
Fananas-Mastral, M.; Feringa, B. L. J. Am. Chem. Soc. 2012, 134, 4108.
(15) For selected examples of Z-selected metathesis reactions: (a)
Ibrahem, I.; Yu, M.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc.
2009, 131, 3844. (b) Meek, S. J.; O’Brien, R. V.; Llaveria, J.; Schrock,
R. R.; Hoveyda, A. H. Nature 2011, 471, 461. (c) Wang, Y.; Jimenez, M.;
Hansen, A. S.; Raiber, E.; Schreiber, S. L.; Young, D. W. J. Am. Chem.
Soc. 2011, 133, 9196. (d) Rosebrugh, L. E.; Herbert, M. B.; Marx, V. M.;
Keitz, B. K.; Grubbs, R. H. J. Am. Chem. Soc. 2013, 135, 1276.
(16) For the Z-selected Wittig and HornerÀWadsworthÀEmmons
(17) For other selected examples of producing Z-olefins, see: (a)
Punner, F.; Schmidt, A.; Hilt, G. Angew. Chem., Int. Ed. 2012, 51,
1270. (b) Wang, Z.; Chen, Z. L.; Bai, S.; Li, W.; Liu, X. H.; Lin, L. L.;
Feng, X. M. Angew. Chem., Int. Ed. 2012, 51, 2776. (c) Egi, M.;
Umemura, M.; Kawai, T.; Akai, S. Angew. Chem., Int. Ed. 2011, 50,
12197. (d) Wang, D.; Ye, X.; Shi, X. Org. Lett. 2010, 12, 2088.
(18) Al-Masum, M.; Liu, K. Y. Tetrahedron Lett. 2011, 52, 5090.
(19) [Rh(CO)2Cl]2-catalyzed olefin isomerization was also found in diene
isomerization; see: Yao, Z.-K.; Li, J.; Yu, Z.-X. Org. Lett. 2011, 13, 134.
€
ꢀ
reactions, see: (a) Kurti, L.; Czako, B. Strategic Applications of Named
Reactions in Organic Sythesis: Background and Detailed Mechanisms;
Elsevier: Amsterdam, 2005. For selected recent examples, see: (b) Ando, K.;
Okumura, M.; Nagaya, S. Tetrahedron Lett. 2013, 54, 2026. (c) Hodgson,
D. M.; Arif, T. Chem. Commun. 2011, 47, 2685. (d) Dong, D.-J.; Li, H.-H.;
Tian, S.-K. J. Am. Chem. Soc. 2010, 132, 5018.
Org. Lett., Vol. 15, No. 18, 2013
4635

as a Lewis acid to facilitate the Z to E isomerization,
similar to those olefin isomerizations catalyzed by Lewis
acids. To avoid this Lewis acid catalysis conditions, we
decided to test other neutral Rh(I) species as the potential
catalysts for all further investigation. To our delight, we
found that bidentate phosphine ligands such as dppm,
dppe, dppp, and dppb (Table 1, entries 4À7) all can
improve the reaction conversions to about 90%. It was
observed that dppm ligand was the best one that can
promote the reaction to an acceptable Z/E ratio of
6:1 (Table 1, entry 4). Unfortunately, a variety of other
bidentate phosphine ligands (see the Supporting
Information) and monodentate phosphine ligands did
not exceed dppm in the target olefin isomerization reaction
(Table 1, entries 3, 8À11). Several solvents (Table 1, entry
12, and the Supporting Information) were examined under
the reaction conditions of using 5 mol % [Rh(CO)2Cl]2 and
12 mol % dppm as the catalyst at 75 °C, showing that DCE
is the best solvent at this temperature. Interestingly, at
a lower temperature (65 °C) in DME solution (Table 1,
entry 13), the olefin isomerization reaction gave the final
products with yields comparable to those in DCE at 75 °C.
It was found that longer reaction time or higher reaction
temperature can increase the conversion of the isomeriza-
tion reaction slightly, both the Z/E ratio and the yield
of the reaction, unfortunately, decreased dramatically
(Table 1, entry 14).
Table 2. Scope of the Z-Selective Olefin Isomerization Reaction
of β,γ-Unsaturated Ketones 1a
temp
time
convb yieldb,c
entry
1
Ar
(°C) solvent (h) 2-Z:2-Eb (%)
(%)
1a, Ph
75
65
75
65
75
65
65
65
75
65
DCE
DME 20
DCE 23
DME 20
DCE 23
DME 16
DME 19
DME 16
23
6:1
6:1
2:1
7:1
1:1
>19:1
12:1
11:1
4:1
5:1
5:1
89
87
93
>95
>95
>95
84
87
93
90
92
72
73
80
85
88
93
75
79
80
65
74
67
66
90
2
3
1b, 4-ClC6H4-
1c, 2-ClC6H4-
4
5
6
7
8
9
1d, 3-ClC6H4-
1e, 4-FC6H4-
1f, 4-MeC6H4-
1g, 3-MeC6H4-
1h, 4-MeOC6H4- 65
1i,3-MeOC6H4-
DCE
23
DME 24
DME 20
DME 19
65
75
75
10:1
3:1
7:1
89
80
>95
10 1j, 2-MeOC6H4-
11
DCE
23
1k, 3,4-di-
MeOC6H4-
DME 19
12
1l, 4-PhC6H4-
65
65
65
DME 16
DME 19
DME 20
3:1
11:1
13:1
85
82
13 1m, 2-naphthyl-
14e 1m, 2-naphthyl-
92 78 (53d)
94 81 (73d)
a 1.5 mL of solvent and 0.3 mmol of β,γ-unsaturated ketones were
used. b Determined by NMR. c Yield of mixture of Z- and E-enones.
d Isolated pure 2m-Z yield (by column chromatography). e 6 mLof DME
and 1.5 mmol of β,γ-unsaturated ketone were used.
Initially, we tried to study the scope (Tables 2 and 3) of
the olefin isomerization reactions by using the conditions
given in entry 4 (at 75 °C in DCE) or 13 (at 65 °C in DME)
in Table 1. However, we found that some substrates gave
dramatically different results in DCE and DME, in con-
trast to the reactions of 1a. For example, the isomerization
of 4-Cl-substituted substrate 1b (Table 2, entry 2) gave the
Z/E ratio of final products as 7:1 at 65 °C in DME in 20 h,
but this ratio dropped to 2:1 if the reaction was carried out
at 75 °C in DCE (the reaction conversions were almost the
same in both solvents). Similar phenomenon can be found
in other case (Table 2, entry 3). Therefore, we carried out
most of the olefin isomerizations in DME instead of DCE
solvent. For substrates that gave poor results in DME,
we then performed their reactions in DCE solvent to get
improved yields and Z-selectivities.
Table 3. Scope of the Z-Selective β,γ-Unsaturated Ketone
Isomerization Reaction of 3a
We were happy to find that almost all substrates 1 with
both electron-withdrawing and electron-donating groups
can undergo the olefin isomerizations in DME at 65 °C
with excellent conversions and decent to high Z-selectivities
(Table 2). Only substrate 1k (Table 2, entry 11) with two
electron-donating groups had to be subjected to DME
solution at 75 °C. For substrate 1f with a p-methyl group
and substrate 1j with an o-methoxy group, their isomeriza-
tions had to be carried out at 75 °C in DCE to get better
results (Table 2, entries 6 and 10). We scaled the reaction from
0.3 to 1.5 mmol, finding that similar conversions and selectivities
can be obtained (enties 13 and 14). Meanwhile, we were happy
to find that the isolated yields of pure 2m-Z can be improved
from 53% (0.3 mmol scale) to 73% (1.5 mmol scale).20
It is noteworthy that substrates with alkyl substituents
(3aÀi, Table 3) can also isomerize to the corresponding
a 1.5 mL of DME and 0.3 mmol of β,γ-unsaturated ketones were
used. b Determined by NMR. c Yield of mixture of Z- and E-enones.
4636
Org. Lett., Vol. 15, No. 18, 2013

Scheme 2
Scheme 3. Z-Enone to E-Enone Transformation
experimental observation that the Z/E ratio decreased
under higher temperature with prolonged reaction time.21
These results suggested the Z-isomers were the kinetically
favored products and the Z to E isomerization processes
are very slow. Because of this, the isomerization of ketones
under the catalysis of Rh can give Z-alkenes kinetically as
the major products. Further study using both experiments
and DFT calculations is ongoing to elucidate the detailed
reaction mechanism and the stereochemistry. At present,
we hypothesized that carbonyl group’s oxygen coordina-
tion to the Rh catalyst could be the major reason for the
observed Z-selectivity.
In summary, we have developed the first neutral Rh(I)-
complex catalyzed Z-selective olefin isomerization of
β,γ-unsaturated ketones to R,β-unsaturated ketones,
providing an efficient and versatile approach to the synthe-
tically challenging Z-alkenes.
R,β-unsaturated ketones, with the Z-alkenes as the major
products. In all cases, higher temperature (85 °C in DME)
was required. We speculated that this is because alkyl-
substituted ketones have stronger CÀH bonds at their Rpositions
than their counterparts in the aryl-substituted β,γ-unsaturated
ketones, and consequently the isomerization of these substrates
in Table 3 becomes more difficult than substrates in Table 2.
Further studies (Scheme 2) showed that neither the ter-
minally substituted substrates 5 and 6 nor the R-substituted
substrate 7 could undergo the Rh(I)-catalyzed Z-selective
olefin isomerization. The carbonyl group is very impor-
tant in the isomerization reaction: substrate 8 with a CN
instead of a carbonyl group failed in the isomerization
reaction, while substrate 9 without carbonyl group gave
E-alkene instead of Z-alkene dominantly.
Acknowledgment. We thank the Natural Science Foun-
dation of China (21232001) and the National Basic Re-
search Program of China-973 Program (2011CB808603)
for financial support.
Preliminary studies to elucidate the reaction mechanism
were performed (Scheme 3). Our chemical intuition sug-
gests that formations oftheE-alkene isomers werethe ther-
modynamically controlled products, while the Z-alkenes
in the present reaction were the kinetically controlled
products. To prove this, we carried out the Z to E
isomerization process of 4e-Z under the same reaction
conditions, finding that a mixture of Z and E isomers was
obtained with a conversion of 8%. This agrees with the
Supporting Information Available. Experimental de-
tails. This material is available free of charge via the
Internet at http://pubs.acs.org.
(21) Stille and Becker also found that the Z/E ratio decreased with
time (see ref 5).
(20) The substrates and Z-enones from the isomerizations have close
Rf (retention factor) values in chromatography, and their separation was
not satisfactory when the reactions were conducted on a small scale.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 18, 2013
4637