Iridium-catalyzed chemoselective and enantioselective hydrogenation of (1-Chloro-1-Alkenyl) boronic esters

Article abstract of DOI:10.1002/anie.201106262

Persistent chlorine: Hydrogenation of borolane-substituted vinylic chlorides catalyzed by Ir-P N complexes greatly preserved the chlorine substituent on the hydrogenated product, with only 3-19 % of dechlorinated byproducts present after hydrogenation. Th

Full text of DOI:10.1002/anie.201106262

.
Angewandte
Communications
DOI: 10.1002/anie.201106262
Chemoselective Hydrogenation
Iridium-Catalyzed Chemoselective and Enantioselective
Hydrogenation of (1-Chloro-1-Alkenyl) Boronic Esters**
´
´
Ivana Gazic Smilovic, Eva Casas-Arcꢀ, Stephen J. Roseblade, Ulrike Nettekoven,
ˇ
ˇ
ˇ
Antonio Zanotti-Gerosa, Miroslav Kovacevic, and Zdenko Casar*
Organoboron compounds[1] play important roles in chemistry,
especially in the field of organometallic catalysis[2] where
boronic acids, boronic esters,[3] and trifluoroborates[4] are
stereoselective fashion (for a detailed discussion, see the
Supporting Information).[3,10] The synthetic versatility of (a-
chloroalkyl) boronic esters, and particularly their utility for
the preparation of drugs such as bortezomib, prompted us to
consider new possibilities for their construction. We envi-
sioned that a very attractive route to (a-chloroalkyl) boronic
esters could be based on the asymmetric catalytic hydro-
genation of (1-chloro-1-alkenyl) boronic esters, which are
easily obtained by a two-step process from readily available
alkynes (Scheme 2).
À
À
À
invaluable for the construction of C O, C N, or C C bonds
through various coupling reactions.[3,5–8] a-Amino boronic
acids,[9] primarily obtained from (a-chloroalkyl) boronic
esters,[10] are a recent addition to this class of compounds,
expanding them into completely new areas of use.[11] They are
a crucial structural element in a new class of anti-cancer
peptide drugs.[12] One member of this class of drugs, which
contains a “borleucine” moiety, is marketed under the name
bortezomib (Scheme 1).[13,14]
Scheme 2. Retrosynthetic analysis for (a-chloroalkyl) boronic esters.
In the past decade, remarkable progress in the asymmetric
catalytic hydrogenation of olefins has been achieved, and this
technique has now become a part of the general repertoire of
synthetic organic chemistry.[16,17] Although some interesting
examples of rhodium[18] and iridium-catalyzed[19] asymmetric
hydrogenation of prochiral vinyl boronates have recently
been described, the reduction of (1-chloro-1-alkenyl) boronic
esters was expected to be a very challenging endeavor,
because these substrates tend to undergo dechlorination and
lack functional groups with an established mode of coordi-
nation to the transition metal catalysts. The asymmetric
hydrogenation of vinyl fluorides with both rhodium[20] and
iridium catalysts[21] bearing chiral P^N ligands has also been
recently investigated. High chemo- and enantioselectivities
were reported for selected experiments; however, substantial
defluorination was observed for some substrates. Further-
more, only a limited number of studies related to the
homogenous asymmetric hydrogenation of vinyl chlorides
have thus far been reported[22,23] and only examples of single
substrates bearing functional groups capable of coordination
to ruthenium catalysts were given. To the best of our
knowledge, catalytic asymmetric hydrogenation studies of
substrates bearing a vinyl chloride moiety and encompassing
a broader range of substrates have not yet been reported.
Our synthetic strategy for the synthesis of (a-chloroalkyl)
boronic esters starts with the preparation of (1-chloro-1-
alkenyl) boronic esters by expanding upon the method of
Srebnik et al.[24] Having prepared (1-chloro-1-alkenyl) bor-
onic esters 1a–j,[25] we decided to probe their hydrogenation
Scheme 1. Retrosynthetic analysis of bortezomib synthesis.
The importance of (a-chloroalkyl) boronic esters lies in
their versatility as chiral building blocks, which can be further
functionalized to asymmetric boronic esters incorporating
various functionalities and structural motifs.[3,10,15] To date,
access to (a-haloalkyl) boronic esters has been limited to
three different approaches, of which only one proceeds in a
ˇ
´
´
ˇ
ˇ
[*] Dr. I. Gazic Smilovic, Dr. M. Kovacevic, Dr. Z. Casar
Lek Pharmaceuticals d. d., Sandoz Development Center Slovenia,
API Development
ˇ
Kolodvorska 27, 1234 Menges (Slovenia)
E-mail: zdenko.casar@sandoz.com
Homepage: http://www.lek.si/en/
Dr. E. Casas-Arcꢀ, Dr. S. J. Roseblade, Dr. A. Zanotti-Gerosa
Johnson Matthey, Catalysis and Chiral Technologies, Cambridge
CB4 0FP (United Kingdom)
Dr. U. Nettekoven
Solvias A.G., Business Unit Synthesis and Catalysis, Basel (Swit-
zerland)
ˇ
´
ˇ
ˇ
[**] We thank A. Veskovic, S. Borisek, Dr. M. Crnugelj, S. Omovsek, D.
ˇ
Orkic, Dr. F. Nerozzi and Dr. D. Grainger for technical assistance in
ˇ
some experimental work, Dr. H. Nedden, Dr. D. Sterk, Dr. H.-U.
ˇ
Blaser, and Prof. A. Pfaltz for valuable discussions, P. Drnovsek for
support, and P. Skelton (Univ. of Cambridge) for HRMS analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201106262.
1014
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1014 –1018

Angewandte
Chemie
Table 1: Catalyst screening for the hydrogenation of 1a to 2a.
to the corresponding alkyl products 2a–j with various
catalysts (Scheme 3).
We started our hydrogenation experiments with the
biologically interesting “borleucine” precursor 1a. This sub-
Entry
Catalyst[a]
Conv.
2a
deCl-2a
[%][b]
ee
1
2
3
4
5
6
7
8
[Ru(cod)(CF3CO2)2]/L1
[Rh(nbd)2]BF4/L2
[Rh(nbd)2]BF4/L3
[Rh(cod)(L4)]BF4
[Rh(cod)(L5)]CF3SO3
[Rh(nbd)2]BF4/L6
[Ir(cod)2]BArF/L1
[Ir(cod)(PCy3)(Py)]PF6
[Ir(cod)(L7)]BArF
[Ir(cod)(L8)]BArF
[Ir(cod)(L8)]BArF
73
13
18
53
65
13
97
100
100
100
100
1
5
11
12
20
8
52
97
97
96
97
68
2
2
26
42
3
11
3
n.d.[c]
32(S)
21(S)
5(S)
rac.
85(R)
rac.
rac.
9
10
11
1
0
0
46(R)
62(R)
63(R)
Scheme 3. Hydrogenation of (1-chloro-1-alkenyl) boronic esters 1a–j.
pin=pinacolyl, Cy=cyclohexyl.
[a] Standard conditions: 4 mol% of catalyst precursor or 4 mol% of
metal precursor with 1.2 equiv of ligand per metal, 508C, 20 bar H2, 20 h,
and 0.08 m substrate concentration in given solvent (except entry 8,
where 10 bar H2 was applied over 10 days). Entries 1, 8, and 10 in THF;
entries 6, 7, 9, and 11 in ClCH2CH2Cl; entries 2, 3, and 5 in MeOH; and
entry 4 in CF3CH2OH.[25] [b] Conversions, yields, and enantiomeric
strate was subjected to a broad catalyst screening. A large
array of P^P and P^N ligands (Scheme 4) in combination
with ruthenium, rhodium, and iridium metal precursors were
investigated in a range of solvents.[25] Approximately two-
1
excesses calculated by GC analysis[25,26] and confirmed by H NMR. A
standard of the dechlorinated product (deCl-2a) was prepared by
reaction of alkyl boronic acids with pinacol.[25] [c] n.d.: not determined.
cod=cyclooctadiene, nbd=norbornadiene, BArF =tetrakis[3,5-bis(tri-
fluoromethyl)phenyl]borate, Cy=cyclohexyl, Py=pyridine.
uct in excellent chemoselectivity; only 3% of the dechlori-
nated byproduct deCl-2a (entry 8) was formed. This result
directed us to test asymmetric variants of the reaction that
involve iridium catalysts bearing chiral P^N oxazolino–
phosphinite ligands (L7 and L8). To our delight, these
catalysts, originally described by Pfaltz and co-workers for
the asymmetric hydrogenation of unfunctionalized alkenes,[29]
provided full conversions with excellent chemo- and good
enantioselectivities (entries 9 and 10). The best overall results
(100% conversion, 96–97% product yield and 62–63% ee,
without any deCl-2a observed) were obtained with the
catalyst [Ir(cod)(L8)]BArF (cod = cyclooctadiene, BArF =
tetrakis[3,5-bis(trifluoromethyl)phenyl]borate) in either
THF or dichloroethane solvent (entries 10 and 11, respec-
tively).
Scheme 4. Ligands used in the initial hydrogenation experiments.
Cy =cyclohexyl, Bn=benzyl.
The initial screening experiments shown in Table 1
revealed a clear direction for further research. We explored
a wider collection of P^N ligand-based catalysts, primarily
aiming towards improvement of the enantioselectivity while
preserving the activity and chemoselectivity. Several iridium
catalysts bearing PHOX,[30] PyrPHOX,[31] SimplePhox,[32] and
ferrocenyl oxazoline ligands[33] were investigated. In all of
these experiments, either lower yields or lower enantioselec-
tivities were observed relative to [Ir(cod)(L8)]BArF. Never-
theless, the chemoselectivities obtained were still high, with
less than 5% of deCl-2a present in the product.[25] Next,
iridium catalysts with ferrocenyl imidazoline ligands were
investigated (Scheme 5, Table 2). Remarkably, the catalyst
incorporating ligand L9 with an (R,R)-configuration for the
imidazoline ring (the planar stereogenic element being S)[34,35]
gave moderate conversion to 2a (66%), excellent chemo-
selectivity (4% of deCl-2a) and the highest enantioselectivity
observed to date (94% ee; Table 2, entry 1).[36] Having finally
identified a class of catalysts with the potential for a high
thirds of all the reactions gave conversions of less than 10%,
but a few encouraging results showed high conversion of 1a to
the alkyl product. Noteworthy results are summarized in
Table 1. Dechlorination was the most prominent side reac-
tion. In the presence of ruthenium-based catalysts, this
undesired reaction path was followed almost exclusively
(Table 1, entry 1). Rhodium-based catalysts provided variable
levels of conversion, chemoselectivity, and enantioselectivity.
A trend favoring a certain ligand class or solvent preference
could not be distinguished (Table 1, entries 2–6). The most
remarkable result was the 85% ee achieved with a rhodium
catalyst bearing Phanephos[27] (ligand L6, entry 6), but the
conversion was considered too low to be useful. An iridium
diphosphine system showed good activity, but gave only
moderate chemoselectivity and no enantioselectivity
(entry 7). However, a breakthrough result was obtained
with Crabtreeꢀs catalyst.[28] Indeed, this system gave rise to
complete conversion, delivering the expected racemic prod-
Angew. Chem. Int. Ed. 2012, 51, 1014 –1018
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
1015

.
Angewandte
Communications
hydrogen bonding in combination with the proper steric bulk
led to a significant increase in catalytic activity. Protection of
the imidazoline ring with a trifluoroacetyl group in ligand L15
resulted in slightly better catalyst performance ([Ir(cod)-
(L15)]BArF, Table 2, entry 7) as compared to the unprotected
species ([Ir(cod)(L9)]BArF; entry 1). However, when the
imidazoline was protected with the bulkier benzoyl group
([Ir(cod)(L16)]BArF; entry 8), full conversion and a high
enantioselectivity (92% ee) were achieved. The catalyst
[Ir(cod)(L17)]BArF also achieved full conversion, albeit
with a reduced enantioselectivity (87% ee; entry 9). Remark-
ably, both catalysts demonstrated excellent chemoselectivities
with less than 3% of deCl-2a formed. The structurally fine-
tuned ligand L16 thus provided the best balance of steric and
electronic effects for the hydrogenation of substrate 1a. Apart
from stereoelectronic catalyst features, only substrate con-
centration was found to have a significant influence on
reaction outcome. Other parameters, such as solvent choice,
temperature, and hydrogen pressure had a relatively small
effect.[25]
Next, we evaluated the performance of the lead catalyst
system [Ir(cod)(L16)]BArF on a broader range of substrates
1b–j bearing aliphatic substituents with different steric
hindrances and aromatic substituents with different electronic
properties. Unsurprisingly, the more sterically hindered sub-
strates (aromatic derivatives 1 f–j and in particular 1c)
required the use of higher catalyst loadings. However, by
adjusting the reaction parameters, it was possible to success-
fully reduce all substrates 1b–j to products 2b–j. In all but one
case (1d), full conversions and high enantioselectivities were
achieved. The presence of bulky alkyl moieties or aryl
substituents within substrates was found to be beneficial for
enantiodifferentiation whereas dechlorination levels appear
to be affected by electronic and steric effects with no clear,
observable trend (Scheme 6).[25,38]
Scheme 5. Imidazoline-type P^N-ligands used for hydrogenation of 1a.
Cy =cyclohexyl, Xyl=xylyl.
Table 2: Investigation of iridium catalysts bearing ferrocenyl imidazoline
ligands for the hydrogenation of 1a to 2a.
Entry
Catalyst[a]
Conv.
2a
deCl-2a
[%][b]
ee
1
2
3
4
5
6
7
8
9
[Ir(cod)(L9)]BArF
[Ir(cod)(L10)]BArF
[Ir(cod)(L11)]BArF
[Ir(cod)(L12)]BArF
[Ir(cod)(L13)]BArF
[Ir(cod)(L14)]BArF
[Ir(cod)(L15)]BArF
[Ir(cod)(L16)]BArF
[Ir(cod)(L17)]BArF
72
20
72
55
79
66
79
>99
>99
66
13
66
48
72
59
72
95
95
4
4
4
4
4
5
4
3
3
94(S)
65(S)
93(S)
58(S)
92(S)
91(S)
94(S)
92(S)
87(S)
[a] Conditions: substrate, catalyst (4 mol%), CH2Cl2 (2.5 mL), 508C,
10 bar H2, 10 h and 0.087 m substrate concentration. [b] Conversions,
yields, and enantiomeric excesses calculated by GC analysis.[25,26]
cod=cyclooctadiene, BArF =tetrakis[3,5-bis(trifluoromethyl)phenyl]bo-
rate.
degree of stereoinduction, several new ligands based on the
ferrocenyl–imidazoline backbone were prepared to optimize
catalyst performance and identify potential structure–activity
relationships. Modifications of the ꢁparentꢀ L9 ligand involved
changes in the substituents on the imidazoline ring (entries 2
and 3), at the substituents on phosphorus (entries 4–6), and
substitution at the sp3 nitrogen of the imidazoline group
(entries 7–9).[25] Increasing electron density on the imidazo-
line by replacing the phenyl substituent R1 with a cyclohexyl
group in L10 was detrimental for catalyst productivity as well
as ee (entry 2). An additional electron-donating methoxy
group on the phenyl residue in L11 had little effect on catalyst
performance (entry 3). Analogously, the alkyl substituents on
phosphorus in ligand L12 caused a drop in catalyst reactivity
and product ee (entry 4). Steric effects are considered the
decisive factor in the observed increase of product yield upon
changing the R2 group from phenyl to 3,5-xylyl (L13, entry 5),
but with the o-tolyl substituent of L14 the useful degree of
steric hindrance was exceeded, resulting in a drop in
conversion compared to the catalyst bearing only a phenyl
phosphine moiety (entry 6).
We envisaged that hydrogenation pathways for chloro-
vinyl boronates are similar to those followed by unfunction-
=
alized C C bonds in the presence of P^N-iridium catalysts. A
confirmed mechanistic model of these hydrogenations is not
yet available.[17] Indeed, catalytic cycles involving IrI/IrIII as
well as IrIII/IrV species as potential intermediates have
recently been discussed.[39] Nevertheless, both cycles might
be operational depending on the nature of the substrate and
the reaction conditions.[17,39i] Knowledge in the area of
catalytic dechlorination pathways of vinyl halide substrates
in the presence of homogeneous iridium catalysts is also
scarce.[40] The results of mechanistic investigations that have
been conducted on the dehalogenation of vinyl fluorides and
chlorides in the presence of rhodium systems are in favor of a
catalytic cycle involving insertion of the halo-olefin into a
metal hydride complex, followed by b-chloride elimination to
give the dehalogenated alkene substrate.[41] An alternative
À
As the iridium P^N-ligand catalysts are known to
deactivate in the presence of coordinating solvents or
additives, such as amines and anions, through the formation
of inactive, hydride-bridged, trinuclear iridium complex-
es,[17a,f,37] protection of the mildly acidic NH functionality in
the ferrocenyl imidazoline ligands was also explored. Indeed,
elimination of the potential for interaction/coordination or
mechanism involving C X oxidative addition of the vinyl
halide to a metal hydride appears less likely. In such a reaction
pathway, faster addition of the haloalkane versus haloalkene
would be expected, but this was not observed by Andersson
and co-workers for fluoro derivatives.[21b] In order to deter-
mine whether dechlorination occurs by oxidative addition of
the alkylchloride product, we submitted pure, racemic 2a to
1016
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1014 –1018

Angewandte
Chemie
[1] Reviews on organoboron compounds and their synthesis: a) A.
Pelter, K. Smith, H. C. Brown, Borane Reagents, Academic
Press, London, 1988; b) D. S. Matteson, Reactivity and Structure
Concept in Organic Synthesis: Stereodirected Synthesis with
Organoboranes, Vol. 32, Springer, New York, 1994; c) E. R.
Burkhardt, K. Matos, Chem. Rev. 2006, 106, 2617 – 2650; d) N. A.
Petasis, Aust. J. Chem. 2007, 60, 795 – 798.
[2] a) N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457 – 2483; b) A.
Suzuki, J. Organomet. Chem. 1999, 576, 147 – 168; c) N. Miyaura
in Cross-Coupling Reactions: A Practical Guide (Topics in
Current Chemistry), Vol. 219 (Ed.: N. Miyaura), Springer, Berlin,
2002, pp. 11 – 59; d) I. Nakamura, Y. Yamamoto, Chem. Rev.
2004, 104, 2127 – 2198; e) V. M. Dembitsky, H. A. Ali, M.
Srebnik, Appl. Organomet. Chem. 2003, 17, 327 – 345; f) A.
Suzuki, H. C. Brown, Organic Synthesis via Boranes, Vol. 3,
Aldrich Chemical Co., 2003.
[3] a) Boronic Acids-Preparation and Applications in Organic Syn-
thesis and Medicine (Ed.: D. G. Hall), Wiley-VCH, Weinheim,
2005; b) R. Zenk, S. Partzsch, Chim. Oggi 2003, 21, 70 – 73.
[4] a) S. Darses, J.-P. Genet, Eur. J. Org. Chem. 2003, 4313 – 4327;
b) G. A. Molander, R. Figueroa, Aldrichimica Acta 2005, 38, 49 –
56; c) G. A. Molander, N. Ellis, Acc. Chem. Res. 2007, 40, 275 –
286; d) S. Darses, J.-P. Genet, Chem. Rev. 2008, 108, 288 – 325.
[5] T. Ohmura, T. Awano, M. Suginome, Chem. Lett. 2009, 38, 664 –
665.
[6] Liebeskind-Srogl coupling: L. S. Liebeskind, J. Srogl, J. Am.
Chem. Soc. 2000, 122, 11260 – 11261.
[7] a) J. D. Sieber, S. Liu, J. P. Morken, J. Am. Chem. Soc. 2007, 129,
2214 – 2215; b) T. Hayashi, K. Yamasaki, Chem. Rev. 2003, 103,
2829 – 2844.
[8] Petasis reaction: a) H. Jourdan, G. Gouhier, L. Van Hijfte, P.
Angibaud, S. R. Piettre, Tetrahedron Lett. 2005, 46, 8027 – 8031,
and references therein; b) N. A. Petasis, I. A. Zavialov, J. Am.
Chem. Soc. 1997, 119, 445 – 446.
[9] a) D. S. Matteson, Med. Res. Rev. 2008, 28, 233 – 246; b) S.
Jagannathan, T. P. Forsyth, C. A. Kettner, J. Org. Chem. 2001, 66,
6375 – 6380.
[10] a) D. S. Matteson, Chem. Rev. 1989, 89, 1535 – 1551; b) D. S.
Matteson, Tetrahedron 1989, 45, 1859 – 1885; c) D. S. Matteson,
Tetrahedron 1998, 54, 10555 – 10606.
[11] a) S. J. Baker, C. Z. Ding, T. Akama, Y.-K. Zhang, V. Hernandez,
Y. Xia, Future Med. Chem. 2009, 1, 1275 – 1288; b) V. M.
Dembitsky, A. A. Al Quntar, M. Srebnik, Chem. Rev. 2011,
111, 209 – 237.
[12] a) Y. Zhu, X. Zhao, X. Zhu, G. Wu, Y. Li, Y. Ma, Y. Yuan, J.
Yang, Y. Hu, L. Ai, Q. Gao, J. Med. Chem. 2009, 52, 4192 – 4199;
b) W. Yang, X. Gao, B. Wang, Med. Res. Rev. 2003, 23, 346 – 368;
c) J. Adams, Y.-T. Ma, R. Stein, M. Baevsky, L. Grenier, L.
Plamondon (ProScript Inc.), US-B 5780454, 1998; d) C. A.
Kettner, A. B. Shenvi, J. Biol. Chem. 1984, 259, 15106 – 15114.
[13] a) J. Albanell, J. Adams, Drugs Future 2002, 27, 1079 – 1092;
b) A. Paramore, S. Frantz, Nat. Rev. Drug Discovery 2003, 2,
611 – 612; c) A. M. Roccaro, A. Vacca, D. Ribatti, Recent Pat.
Anti-Cancer Drug Discovery 2006, 1, 397 – 403; d) M. P. Curran,
K. McKeage, Drugs 2009, 69, 859 – 888.
[14] For the synthesis of bortezomib, see: a) A. S. Ivanov, A. A.
Zhalnina, S. V. Shishkov, Tetrahedron 2009, 65, 7105 – 7108;
b) M. A. Beenen, C. An, J. A. Ellman, J. Am. Chem. Soc. 2008,
130, 6910 – 6911; c) J. Adams, M. Behnke, S. Chen, A. A.
Cruickshank, L. R. Dick, L. Grenier, J. M. Klunder, Y.-T. Ma,
L. Plamondon, R. L. Stein, Bioorg. Med. Chem. Lett. 1998, 8,
333 – 338.
Scheme 6. Scope of the asymmetric hydrogenation of 1a–j. pin=pina-
colyl.
the hydrogenation conditions with [Ir(cod)(L16)]BArF as
catalyst. The experiments revealed that 2a did not deha-
logenate;[25] results that disfavor dechlorination through
oxidative addition of the product to the catalyst and suggest
that dechlorination instead takes place in the catalytic cycle
from the starting olefin.[25]
In conclusion, our work is the first study in which a broad
range of (1-chlorovinyl) boronate substrates, with different
steric and electronic properties, have been successfully
hydrogenated in the presence of P^N-iridium catalysts with-
À
out significant cleavage of the C Cl bond. The rational
modification of the structural properties of the P^N ligands
has resulted in the preparation of new N-acyl-imidazoline
ferrocenyl-based iridium catalysts with broad substrate
acceptance. Excellent conversions, high chemoselectivities
(with dechlorinated byproducts in the range of 3–19%), and
enantioselectivities of up to 94% ee were achieved. The utility
of the hydrogenation method presented was demonstrated by
preparation of 2a, which serves as a key precursor for the
construction of the anticancer drug bortezomib.
Received: September 5, 2011
Published online: December 16, 2011
[15] a) D. S. Matteson, M. L. Peterson, J. Org. Chem. 1987, 52, 5121 –
5124; b) D. S. Matteson, R. Ray, R. R. Rocks, D. J. S. Tsai,
Organometallics 1983, 2, 1536 – 1543.
Keywords: asymmetric catalysis · hydrogenation · iridium ·
organoboron compounds · P,N ligands
.
Angew. Chem. Int. Ed. 2012, 51, 1014 –1018
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
1017

.
Angewandte
Communications
[16] For recent reviews on asymmetric hydrogenation, see: a) V.
Farina, J. T. Reeves, C. H. Senanayake, J. J. Song, Chem. Rev.
2006, 106, 2734 – 2793; b) C. Jꢂkel, R. Paciello, Chem. Rev. 2006,
106, 2912 – 2942.
Angew. Chem. 2001, 113, 4577 – 4579; Angew. Chem. Int. Ed.
2001, 40, 4445 – 4447; c) F. Menges, A. Pfaltz, Adv. Synth. Catal.
2002, 344, 40 – 44.
[30] a) A. Lightfoot, P. Schneider, A. Pfaltz, Angew. Chem. 1998, 110,
3047 – 3050; Angew. Chem. Int. Ed. 1998, 37, 2897 – 2899; b) G.
Helmchen, A. Pfaltz, Acc. Chem. Res. 2000, 33, 336 – 345.
[31] P. G. Cozzi, N. Zimmermann, R. Hilgraf, S. Schaffner, A. Pfaltz,
Adv. Synth. Catal. 2001, 343, 450 – 454.
[32] S. P. Smidt, F. Menges, A. Pfaltz, Org. Lett. 2004, 6, 2023 – 2026.
[33] a) Y. Nishibayashi, K. Segawa, K. Ohe, S. Uemura, Organo-
metallics 1995, 14, 5486 – 5487; b) X. Li, Q. Li, X. Wu, Y. Gao, D.
Xu, L. Kong, Tetrahedron: Asymmetry 2007, 18, 629 – 634; c) W.-
J. Lu, X.-L. Hou, Adv. Synth. Catal. 2009, 351, 1224 – 1228.
[34] N. W. Boaz, J. A. Ponasik Jr., (Eastman Chemical Company),
US-A1 0244319, 2007.
[17] For recent reviews on asymmetric hydrogenation using P^N-
iridium catalysts, including
a mechanistic discussion, see:
a) D. H. Woodmansee, A. Pfaltz, Top. Organomet. Chem. 2011,
34, 31 – 76; b) D. H. Woodmansee, A. Pfaltz, Chem. Commun.
2011, 47, 7912 – 7916; c) T. Yoshinari, J. Synth. Org. Chem. Jpn.
2011, 69, 426 – 427; d) T. L. Church, P. G. Andersson, Coord.
Chem. Rev. 2008, 252, 513 – 531; e) S. J. Roseblade, A. Pfaltz, C.
R. Chim. 2007, 10, 178 – 187; f) S. J. Roseblade, A. Pfaltz, Acc.
Chem. Res. 2007, 40, 1402 – 1411; g) K. Kꢂllstrçm, I. Munslow,
P. G. Andersson, Chem. Eur. J. 2006, 12, 3194 – 3200; h) X. Cui,
K. Burgess, Chem. Rev. 2005, 105, 3272 – 3296.
[18] a) W. J. Moran, J. P. Morken, Org. Lett. 2006, 8, 2413 – 2415;
b) J. B. Morgan, J. P. Morken, J. Am. Chem. Soc. 2004, 126,
15338 – 15339.
[19] A. Paptchikhine, P. Cheruku, M. Engman, P. G. Andersson,
Chem. Commun. 2009, 5996 – 5998.
[20] S. W. Krska, J. V. Mitten, P. G. Dormer, D. Mowrey, F. Mach-
rouhi, Y. Sun, T. D. Nelson, Tetrahedron 2009, 65, 8987 – 8894.
[21] a) P. Kaukoranta, M. Engman, C. Hedberg, J. Bergquist, P. G.
Andersson, Adv. Synth. Catal. 2008, 350, 1168 – 1176; b) M.
Engman, J. S. Diesen, A. Paptchikhine, P. G. Andersson, J. Am.
Chem. Soc. 2007, 129, 4536 – 4537.
[22] For an example of [RuL*Cl2 (DMF)n]-catalyzed hydrogenation,
see: X. Sun, L. Zhou, W. Li, X. Zhang, J. Org. Chem. 2008, 73,
1143 – 1146.
[23] For the preparation of 2-haloalkanoic acid from 2-halo-a,b-
alkenoic acid by hydrogenation in the presence of {(BINAP)-
RuII} as catalyst, see: E. G. Samsel, C. R. Bedell (Albemarle
Company), US-B1 6184415, 2001.
[24] L. Deloux, E. Skrzypczak-Jankun, B. V. Cheesman, M. Srebnik,
J. Am. Chem. Soc. 1994, 116, 10302 – 10303.
[25] For a discussion and experimental details, see the Supporting
Information.
[26] The sum of the conversions into 2a and deCl-2a is lower than the
total conversion owing to the presence of minor, unidentified
byproducts.
[35] For related ligands and catalysts see: a) C. A. Busacca, J. C.
Lorenz, N. Grinberg, N. Haddad, H. Lee, Z. Li, M. Liang, D.
Reeves, A. Saha, R. Varsolona, C. H. Senanayake, Org. Lett.
2008, 10, 341 – 344; b) E. Guiu, C. Claver, J. Benet-Buchholz, S.
Castillꢃn, Tetrahedron: Asymmetry 2004, 15, 3365 – 3373.
[36] The diastereomer of the catalyst, bearing a ligand with (S,S)-
configuration at the imidazolidine ring (the planar stereogenic
element being S), showed low activity (see Supporting Informa-
tion).
[37] S. P. Smidt, N. Zimmermann, M. Studer, A. Pfaltz, Chem. Eur. J.
2004, 10, 4685 – 4693 and references therein.
ˇ
´
´
[38] I. Gazic Smilovic, Z. Casar (Lek Pharmaceuticals d.d.), WO-A2
2010146176, 2010.
[39] a) M. M. Taquikhan, B. Taquikhan, S. Begum, J. Mol. Catal.
1986, 34, 9 – 18; b) P. Brandt, C. Hedberg, P. G. Andersson,
Chem. Eur. J. 2003, 9, 339 – 347; c) X. Cui, K. Burgess, J. Am.
Chem. Soc. 2003, 125, 14212 – 14213; d) C. Mazet, S. P. Smidt, M.
Meuwly, A. Pfaltz, J. Am. Chem. Soc. 2004, 126, 14176 – 14181;
e) Y. Fan, X. Cui, K. Burgess, M. B. Hall, J. Am. Chem. Soc. 2004,
126, 16688 – 16689; f) R. Dietiker, B. Chen, Angew. Chem. 2004,
116, 5629 – 5632; Angew. Chem. Int. Ed. 2004, 43, 5513 – 5516;
g) X. Cui, Y. Fan, M. B. Hall, K. Burgess, Chem. Eur. J. 2005, 11,
6859 – 6868; h) T. L. Church, T. Rasmussen, P. G. Andersson,
Organometallics 2010, 29, 6769 – 6781; i) K. H. Hopmann, A.
Bayer, Organometallics 2011, 30, 2483 – 2497.
[27] P. P. Pye, K. Rossen, R. A. Reamer, N. T. Tsou, R. P. Volante,
P. J. Reider, J. Am. Chem. Soc. 1997, 119, 6207 – 6208.
[28] a) R. Crabtree, Acc. Chem. Res. 1979, 12, 331 – 337; b) R. H.
Crabtree in Handbook of Homogeneous Catalysis (Eds.: J. G.
de Vries, C. J. Elsevier), Wiley-VCH, Weinheim, 2007, chap. 2,
pp. 31 – 44.
[40] A. Sisak, O. B. Simon in the Handbook of Homogeneous
Catalysis (Eds.: J. G. de Vries, C. J. Elsevier), Wiley-VCH,
Weinhiem, 2007, chap. 18, pp. 513 – 546. The order of reactivity
in dehalogenation reactions (I > Br> Cl > F) is related to the
strength of the carbon – halogen bond.
[41] See, for example, the mechanistic discussion in: A. A. Peterson,
K. A. Thoreson, K. McNeill, Organometallics 2009, 28, 5982 –
5991.
[29] a) A. Pfaltz, J. R. Blankenstein, F. Menges (Solvias AG, Switzer-
land), EP-A2 1191030, 2001; b) J. Blankenstein, A. Pfaltz,
1018
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1014 –1018