Iridium-catalyzed asymmetric hydrogenation of vinyl ethers

Article abstract of DOI:10.1002/adsc.200700546

A carbene-oxazoline catalyst 1 proved to be an effective catalyst for reduction of an enol ether that the literature suggested could not be hydrogenated effectively by P,N-Ir catalysts. Thus, a series of ester and alcohol substrates were hydrogenated using catalyst 1. Good to excellent enantioselectivities and high conversions were obtained.

Full text of DOI:10.1002/adsc.200700546

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DOI: 10.1002/adsc.200700546
Iridium-Catalyzed Asymmetric Hydrogenation of Vinyl Ethers
Ye Zhua and Kevin Burgessa,*
a
Department of Chemistry, Texas A & M University, Box 30012, College Station, TX 77841-3012, USA
Fax : (+1)-979-845-8839; e-mail: burgess@tamu.edu
Received: November 16, 2007; Published online: March 7, 2008
Dedicated to Professor Andreas Pfaltzꢀs 60th birthday.
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A carbene-oxazoline catalyst 1 proved to
be an effective catalyst for reduction of an enol
ether that the literature suggested could not be hy-
drogenated effectively by P,N-Ir catalysts. Thus, a
series of ester and alcohol substrates were hydro-
genated using catalyst 1. Good to excellent enantio-
selectivities and high conversions were obtained.
have not reached levels that are practical for general
application in organic syntheses (alkylated enol
ethers,[14–16] silylated enol ethers,[17] furans[16,18]).
Keywords: alkenes; asymmetric catalysis; enol
ethers; N-heterocyclic carbenes; hydrogenation; iri-
dium
In our view, alkenes for asymmetric hydrogenations
can be divided into three categories.[1] At one ex-
treme, there are “coordinatively-functionalized al-
kenes”, that have proximal directing groups that are
likely to bind transition metals in a catalytic cycle. Al-
kenes with only alkyl substitutents are at the other ex-
treme; they are completely unfunctionalized. Inter-
mediate between these extremes are “non-coordina-
tively functionalized alkenes”. These have a proximal
functional group that does not coordinate to transition
metal catalysts and direct stereofacial modifications.
Pfaltzꢀs realization[19] that phosphine-oxazoline li-
There are more non-coordinative functional groups gands could be used to form chiral analogues of Crab-
than coordinative ones, so this intermediate category treeꢀs catalyst[20] has inspired many researchers. Fol-
is the largest. It also contains an abundance of precur- lowing his lead, Andersson and co-workers investigat-
sors to useful chirons for organic syntheses.
ed chiral N,P-ligated iridium complexes in asymmetric
Asymmetric hydrogenations of enol ethers illustrate hydrogenations of the silyl and methyl enol ethers D
the viewpoint outlined above. Enol acetates A have a and E, but complex mixtures were obtained using
coordinative functional group, the carbonyl of the four different catalysts. Subsequently, their study
acetate, that can transiently bind to a metal center. evolved into an investigation of the successful hydro-
Consequently, the literature contains many examples genations of the enol phosphinates F.[21] Our group
of asymmetric hydrogenations of enol acetates, and was also studying enol ethers as substrates at the time
most of them are quite successful.[2–13] Conversely, al- this research was published. Our data are now report-
kylated, and silylated enol ethers, B and C are, by our ed here.
definition, non-coordinatively functionalized. There
The reaction of Eq. (1) shows the first hydrogena-
are relatively few reports of asymmetric hydrogena- tion of an enol ether studied in our laboratories. 1-
tions of these, and the enantioselectivities observed Methoxy-1-phenylethene (E) was reduced efficiently
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Ye Zhu and Kevin Burgess
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to product using the carbene-oxazoline catalyst 1. The tions used in entry 4 were selected for application to
low enantioselectivity observed for this particular sub- different substrates.
strate was not a concern because there are many
Table 2 shows hydrogenations of similar substrates
routes to chiral aryl-(1-hydroxyethyl) compounds. On 2a–h at 48 h reaction time. High conversions could be
the other hand, the high conversion to one single
Table 2. Asymmetric hydrogenation of vinyl ether esters.
product obtained with the carbene-oxazoline catalyst
1 contrasted with the poor results reported for similar
N,P-ligands, and provided motivation to investigate
the substrate scope.
The enol ether 2a, available from the corresponding
keto ester and trimethyl orthoformate, was selected
as a substrate for further studies and optimization of
the reaction conditions (Table 1). Hydrogen pressures
Table 1. Optimization of hydrogenation conditions for sub-
strate 2a.
Entry Temp.
[oC]
Pressure
[bar]
Time Conversion[a] ee[b]
[h]
[%]
[%]
1
2
325
4
5
6
7
8
25
25
5
24
24
82
48
12
12
12
12
<5
81
5
78
50
24
50
50
50
50
50
100
79
25
50
>99
95
30
95
68
78
73
À20
83
25
77[c]
83[d]
25
[a]
1
Determined by H NMR.
Determined via chiral GC.
Catalyst loading, 5 mol%.
[b]
[c]
[d]
Catalyst loading, 0.2 mol%.
greater than 5 bar were shown to be necessary, but in-
creasing from 50 to 100 bar had no productive effect
(entries 1–3). Complete conversion was observed
when the reaction time was extended from 24 to 48 h
(entry 4). At 508C the reaction proceeded faster but
the enantioselectivity decreased (entry 5). Conversely,
a slightly higher enantioselectivity was observed at
À208C but the conversion was poor (entry 6). En-
tries 7 and 8 show that a slightly higher enantioselec-
tivity was observed at a lower catalyst loading, but
the conversion was less reflecting a slower reaction
rate. On the basis of these observations, the condi-
[a]
[b]
[c]
1
Determined by H NMR.
Determined via analysis on a chiral GC column.
Stereochemical assignments via reduction of the hydro-
genation products to primary alcohol then comparison
with authentic samples.
Assignment of the absolute configuration of the product
was not made.
[d]
[e]
E/Z isomerization occurs during the reaction and most of
the starting material remains.
980
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Iridium-Catalyzed Asymmetric Hydrogenation of Vinyl Ethers
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Table 4. Asymmetric hydrogenation of vinyl ether alcohols.
achieved for esters 2a–c where the substituents are
not large, but the isopropyl-substituted enol ether 2d
gave only 15% conversion in the first 48 h of the reac-
tion. The N-methoxy amide 2e was a good substrate
for this reaction; it gave a high conversion and the
best enantiomeric excess in the series. However, the
enantioselectivity for the corresponding acid 2f was
significantly diminished. When the size of the ester
group in this series was increased to tert-butyl as in
substrate 2g, the enantiomeric excess increased signif-
icantly. Finally, the phenyl ketone 2h did not hydro-
genate quickly under these conditions and E/Z-iso-
merization of the alkene was observed.
DIBAL reduction of the ester 2c gave the allylic al-
cohol 4b. However, when this was hydrogenated
under the conditions specified in Table 2 (and Table 3,
Table 3. Optimization of the hydrogenation conditions to
avoid ketone formation.
Entry
K2CO3 [mol%]
5b:6[a]
1
2
0
20
30:70
67:3
3
:17
33
4
83
50
>99:1.0
[a]
Determined by 1H NMR.
entry 1) then the ketone 6 was formed in preference
to the desired ether 5b. One explanation for this is
protonation of the hydroxy group, elimination to an
enone, then hydrogenation. Indeed, entries 2–4 in
Table 3show that progressively higher amounts of an-
hydrous potassium carbonate enhance the chemose-
lectivity of the reaction in favor of the hydrogenation
product 5b, and the ee values throughout were excel-
[a]
[b]
[c]
1
Determined by H NMR.[a] Determined via analysis on a
chiral GC column.
Stereochemical assignments were made via comparison
with authentic samples.
K2CO3 was not required in this case.
lent. It was also observed that when 4 Š molecular tively giving an inverted stereochemistry because the
sieves were used (and no potassium carbonate) then alkene geometry was reversed. Hydrogenation of sub-
5b could also be the major product (data not shown). strate 4e compared with the corresponding alcohol 4a
The observations outlined above led us to broaden indicates that the catalyst approaches the alkene from
the substrate scope to include those shown in Table 4. the same direction for the silylated substraste, and
Substrates 4a and b have methyl-to-ethyl relation- high enantiomeric selectivity is maintained. Similarly
ships, and this change did not significantly alter the the acetate 4f was hydrogenated with good enantiose-
enantioselectivities observed. The enantioselectivity lectivity and from the same face. Potassium carbonate
reduced only very slightly when the alkene methyl- was not required to obtain high conversions with the
substituent was replaced with an n-butyl as in sub- protected alcohols 4e and f. Conversions were very
strate 4c. Substrate 4d has a Z-stereochemistry and a high throughout this series and the reaction was faster
more bulky substituent (i-Pr). For this compound the than for the corresponding esters shown in Table 2.
enantioselectivity observed was also high, and the cat-
Finally, the reaction of Eq. (2) was performed on a
alyst approached the alkene from the same face effec- slightly larger scale than those shown in Table 4. The
Adv. Synth. Catal. 2008, 350, 979 – 983ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Ye Zhu and Kevin Burgess
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product of this reaction 5a was isolated in high yield molecules. That small motif is common in natural
via column chromatography.
products and their analogues; consequently, hydroge-
nation of these substrates, particularly 4, can be re-
garded as a route to this privileged chiron.
The data presented in this paper raise some inter- Experimental Section
esting questions. Firstly, why did these transforma-
tions succeed when similar ones featuring N,P-iridium Typical Hydrogenation Procedure
complexes did not, at least in the case of the reaction
The alkene was dissolved in CH2Cl2 (0.5M) and the iridium
of Eq. (1)?[21] We hypothesize that this difference
might be related to the Ir-electron densities in the cat-
alyst. Assuming that Ir(5+) complexes are in-
volved,[22–24] superior acceptor-backbonding to phos-
phine ligands relative to imidazolinidine ligands sta-
bilizes lower oxidation states. Lower oxidation states
result from deprotonation of the metal center. Thus
we predict that Ir(5+) intermediates are more acidic
for phosphine complexes compared to the corre-
sponding carbene ones (Figure 1). If so, this acidity
may be detrimental in hydrogenations of acid-sensi-
tive substrates like enol ethers.
catalyst 1 (1 mol%) was then added. The resulting solution
was degassed by three cycles of freeze-pump-thaw and then
transferred to a Parr bomb. The bomb was flushed with hy-
drogen for 1 min without stirring. The mixture was then
stirred at 700 rpm under 50 bars of H2. After 48 h (for esters
and its derivatives) or 12 h (for alcohols and its derivatives),
the bomb was vented and the solvent evaporated. The con-
1
version was measured by H NMR. The crude product was
passed through
a silica plug (EtOAc/hexanes=3:7) to
obtain the purified material. Enantiomeric ratios were mea-
sured through chiral capillary GC analysis using a b- or a g-
CD column (carrier gas: helium; column pressure: 18.21 psi;
gas flow rate: 1.6 mLminÀ1
;
gradient temperature:
58CminÀ1: 608C hold time: 10 min, 1208C, 15 min).[27]
Previous studies from our laboratory had highlight-
ed greater degrees of double bond migration in Ir-
mediated hydrogenations based on N,P-catalysts, rela-
tive to N,carbene-systems.[25] Enhanced acidities for
the phosphine catalysts may play a role in this situa-
tion.
Acknowledgements
Financial support for this work was provided by The Nation-
al Science Foundation (CHE-0456449) and The Robert A.
Welch Foundation.
Hydrogenation of substrates 2 and 4 both provide
access to the terminal fragment G in more complex
References
[1] X. Cui, K. Burgess, Chem. Rev. 2005, 105, 3272.
[2] M. J. Burk, J. Am. Chem. Soc. 1991, 113, 8518.
[3] Q. Jiang, D. Xiao, Z. Zhang, P. Cao, X. Zhang, Angew.
Chem. 1999, 111, 578; Angew. Chem. Int. Ed. 1999, 38,
516.
[4] M. J. Burk, Acc. Chem. Res. 2000, 33, 363.
[5] N. W. Boaz, Tetrahedron Lett. 1998, 39, 5505.
[6] E. A. Broger, W. Burkart, M. Hennig, M. Scalone, R.
Schmid, Tetrahedron: Asymmetry 1998, 9, 4043.
[7] K. Iseki, Y. Kuroki, T. Nagai, Y. Kobayashi, Chem.
Pharm. Bull. 1996, 44, 477.
[8] H. M. Jung, J. H. Koh, M.-J. Kim, J. Park, Org. Lett.
2000, 2, 2487.
[9] Y. Chi, X. Zhang, Tetrahedron Lett. 2002, 43, 4849.
[10] W. Tang, D. Liu, X. Zhang, Org. Lett. 2003, 5, 205.
[11] M. T. Reetz, L. J. Goossen, A. Meiswinkel, J. Paetzold,
J. F. Jensen, Org. Lett. 2003, 5, 3099.
Figure 1. Postulated increased acidity for phosphine Ir(5+)
[12] S. Wu, W. Wang, W. Tang, M. Lin, X. Zhang, Org. Lett.
complexes relative to the corresponding carbenes.
2002, 4, 4495.
982
asc.wiley-vch.de
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 979 – 983

Iridium-Catalyzed Asymmetric Hydrogenation of Vinyl Ethers
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[13] L. Qiu, J. Wu, S. Chan, T. T.-L. Au-Yeung, J.-X. Ji, R.
Guo, C.-C. Pai, Z. Zhou, X. Li, Q.-H. Fan, A. S. C.
Chan, Proc. Natl. Acad. Sci. USA 2004, 101, 5815.
[14] H. Leopold, S. Hardo, B. Helga, Angew. Chem. 1968,
80, 1034; Angew. Chem. Int. Ed. Engl.Angew. Chem.
Int. Ed. 1968, 712, 942.
[20] R. H. Crabtree, Acc. Chem. Res. 1979, 12, 331.
[21] P. Cheruku, S. Gohil, P. G. Andersson, Org. Lett. 2007,
9, 1659.
[22] P. Brandt, C. Hedberg, P. Andersson, Chem. Eur. J.
2003, 9, 339.
[23] Y. Fan, X. Cui, K. Burgess, M. B. Hall, J. Am. Chem.
Soc. 2004, 126, 16688.
[24] X. Cui, Y. Fan, M. B. Hall, K. Burgess, Chem. Eur. J.
[15] T. Hayashi, M. Tanaka, I. Ogata, Tetrahedron Lett.
1977, 295.
[16] T. Ohta, T. Miyake, N. Seido, H. Kumobayashi, H.
Takaya, J. Org. Chem. 1995, 60, 357.
[17] T. Tanaka, Y. Watanabe, T. A. Mitsudo, Y. Yasunori, Y.
2005, 11, 6859.
[25] M. C. Perry, X. Cui, M. T. Powell, D.-R. Hou, J. H. Rei-
benspies, K. Burgess, J. Am. Chem. Soc. 2003, 125, 113.
[26] J. Zhou, J. W. Ogle, Y. Fan, V. Banphavichit, Y. Zhu, K.
Burgess, Chem. Eur. J. 2007, 13, 7162.
Takegami, Chem. Lett. 1974, 137.
[18] S. Kaiser, P. Smidt Sebastian, A. Pfaltz, Angew. Chem.
2006, 118, 5318; Angew. Chem. Int. Ed. 2006, 45, 5194.
[19] A. Lightfoot, P. Schnider, A. Pfaltz, Angew. Chem.
1998, 110, 3047; Angew. Chem. Int. Ed. 1998, 37, 2897.
[27] D. U. Staerk, A. Shitangkoon, G. Vigh, J. Chromatogr.
A 1995, 702, 251.
Adv. Synth. Catal. 2008, 350, 979 – 983ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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