Rapid ketone transfer hydrogenation by employing simple, in situ prepared iridium(I) precatalysts supported by "non-N-H" P,N ligands

Article abstract of DOI:10.1002/chem.200801530

The catalytic utility in ketone transfer hydrogenation (TH) of the preformed complexes [Ir(cod)(κ²-2-NMe₂-3-PiPr ₂-indene)]⁺X^- ([2a]⁺X^-; X: PF₆, BF₄, and OTf; cod: η⁴-1,5- cyclooctadiene; OTf: trifluoromethanesulfonate), [Ir(cod)(κ²-1- PiPr₂-2-NMe₂-indene)]⁺OTf^- ([2b]⁺OTf^-), [Ir-(cod)(κ²-2-NMe ₂-3-PiPr₂-indenide)] (3), and [Ir(cod) (κ²-o-tBu₂P-C₆H₄-NMe ₂)]⁺ PF₆^- ([4]⁺PF ₆^-), as well as of related mixtures prepared from [{IrCl(cod)}₂] and various P,N-substituted indene or phenylene ligands, was examined. Whereas [2a]⁺X^-, [2b] ⁺OTf^-, 3, and related in situ prepared Ir catalysts derived from P,N-indenes proved to be generally effective in mediating the reduction of acetophenone to 1-phenylethanol in basic iPrOH at reflux (0.1 mol% Ir; 81-99% conversion) in a preliminary catalytic survey, the structurally related Ir catalysts prepared from (o-R₂P-C₆H ₄)NMe₂ (R: Ph, iPr, or tBu) were observed to outperform the corresponding P,N-indene ligands under similar conditions. In the course of such studies, it was observed that alteration of the substituents at the donor fragments of the supporting P,N ligand had a pronounced influence on the catalytic performance of the derived catalysts, with ligands featuring bulky dialkylphosphino donors proving to be the most effective. Notably, the crystallographically characterized complex [4]⁺PF₆ ^-, either preformed or prepared in situ from a mixture of [{IrCl-(cod)}₂], NaPF₆, and (o-tBu₂P-C ₆H₄)NMe₂, proved to be highly effective in mediating the catalytic transfer hydrogenation (TH) of ketones in basic iPrOH, with near quantitative conversions for a range of alkyl and/or aryl ketones and with very high turnover-frequency values (up to 230000 h^-1 at > 50% conversion); this thereby enabled the use of Ir loadings ranging from 0.1 to 0.004 mol %. Catalyst mixtures prepared from [{IrCl-(cod)}₂], NaPF₆, and the chiral (αS,αS)-1,1'-bis[α- (dimethylamino)benzyl]-(R,R)-2,2'-bis(dicyclohexylphosphino)-ferrocene (Cy-Mandyphos) ligand proved capable of mediating the asymmetric TH of aryl alkyl ketones, including that of the hindered substrate 2,2- dimethylpropiophenone with an efficiency (0.5 mol % Ir; 95% conversion, 95% ee) not documented previously in TH chemistry.

Full text of DOI:10.1002/chem.200801530

DOI: 10.1002/chem.200801530
Rapid Ketone Transfer Hydrogenation by Employing Simple, In Situ
À
Prepared Iridium(I) Precatalysts Supported by “Non-N H” P,N Ligands
Rylan J. Lundgren and Mark Stradiotto[a]
Abstract: The catalytic utility in ketone
turally related Ir catalysts prepared
from (o-R2P-C6H4)NMe2 (R: Ph, iPr,
or tBu) were observed to outperform
the corresponding P,N-indene ligands
under similar conditions. In the course
of such studies, it was observed that al-
teration of the substituents at the
donor fragments of the supporting P,N
ligand had a pronounced influence on
the catalytic performance of the de-
rived catalysts, with ligands featuring
bulky dialkylphosphino donors proving
to be the most effective. Notably, the
crystallographically characterized com-
C6H4)NMe2, proved to be highly effec-
tive in mediating the catalytic transfer
hydrogenation (TH) of ketones in
basic iPrOH, with near quantitative
conversions for a range of alkyl and/or
aryl ketones and with very high turn-
transfer hydrogenation (TH) of the
preformed complexes [IrACHTNUTGRNEUNG
(cod)(k2-2-
NMe2-3-PiPr2-indene)]+XÀ ([2a]+XÀ;
X: PF6, BF4, and OTf; cod: h4-1,5-cy-
clooctadiene; OTf: trifluoromethane-
sulfonate), [Ir
indene)]+OTfÀ
(cod)(k2-2-NMe2-3-PiPr2-indenide)] (3),
G
over-frequency
values
(up
to
230000 hÀ1 at >50% conversion); this
thereby enabled the use of Ir loadings
ranging from 0.1 to 0.004 mol%. Cata-
lyst mixtures prepared from [{IrCl-
ACHTUNGTRENNUNG
and [Ir
(cod)(k2-o-tBu2P-C6H4-NMe2)]+
À
À
PF6 ([4]+PF6 ), as well as of related
mixtures prepared from [{IrCl
N
ACHTUNGTRNE(NUNG cod)}2], NaPF6, and the chiral (aS,aS)-
1,1’-bis[a-(dimethylamino)benzyl]-
(R,R)-2,2’-bis(dicyclohexylphosphino)-
and various P,N-substituted indene or
phenylene ligands, was examined.
Whereas [2a]+XÀ, [2b]+OTfÀ, 3, and
related in situ prepared Ir catalysts de-
rived from P,N-indenes proved to be
generally effective in mediating the re-
duction of acetophenone to 1-phenyle-
thanol in basic iPrOH at reflux
(0.1 mol% Ir; 81–99% conversion) in a
preliminary catalytic survey, the struc-
À
plex [4]+PF6 , either preformed or pre-
ferrocene
(Cy-Mandyphos)
ligand
pared in situ from a mixture of [{IrCl-
proved capable of mediating the asym-
metric TH of aryl alkyl ketones, includ-
ing that of the hindered substrate 2,2-
dimethylpropiophenone with an effi-
ciency (0.5 mol% Ir; 95% conversion,
95% ee) not documented previously in
TH chemistry.
A
NaPF6,
and
(o-tBu2P-
·
homogeneous catalysis · iridium ·
ketones · transfer hydrogenation
Introduction
effective.[2] The high turnover frequency values (TOFs; in
the very best cases, 106 hÀ1 at 50% conversion)[2c] and selec-
tivities offered by such precatalysts are commonly attributed
The catalytic transfer hydrogenation (TH) of ketones by
employing iPrOH [Eq. (1)] or other H2-donor solvents has
emerged as a mild, convenient, environmentally friendly
methodology for the synthesis of secondary alcohols that
avoids the use of high H2 pressures and stoichiometric re-
ductants.[1] Among the numerous classes of metal complexes
that have been shown to mediate the TH of ketones, preca-
À
to the formation of (H)Ru NH2R intermediates that can
transfer H2 to
a
ketone substrate in
a
bifunctional
manner.[2–5] The catalytic utility in TH chemistry of Rh[6]
and Ir[7] complexes that feature an M NH functionality has
À
also been demonstrated;[8] notably, Abdur-Rashid and co-
workers[7a] have described the use of IrH3[(iPr2P-C2H4)2NH],
which is among the most active of the previously reported Ir
precatalysts for the TH of ketones in iPrOH, with a TOF of
43000 hÀ1 (at 50% conversion) for the reduction of aceto-
phenone. Furthermore, the field of Rh- and Ir-mediated
asymmetric ketone TH is dominated by precatalysts featur-
À
talysts featuring an Ru NH linkage are generally the most
[a] R. J. Lundgren, Prof. Dr. M. Stradiotto
Department of Chemistry
À
À
ing an M NH linkage, with chiral [M(Cl)Cp*ACTHNURGTNEUNG(TsN NH2)]
Dalhousie University
(Cp*: h5-C5Me5; Ts: toluene-4-sulfonyl) and related spe-
Halifax, Nova Scotia B3H4J3 (Canada)
E-mail: mark.stradiotto@dal.ca
cies,[8a–j] as well as alternative non-Cp* catalyst systems pre-
10388
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Chem. Eur. J. 2008, 14, 10388 – 10395

FULL PAPER
[8k–o]
À
pared by using chiral tetradentate N H ligands,
among the most effective.
being
While progress in metal-mediated TH continues to be en-
abled through the study of precatalysts that exploit the now
À
well-established ancillary-ligand “N H effect”, the identifi-
cation of alternative ligation strategies that give rise to
highly active and/or selective TH precatalysts represents a
key step toward new and synthetically useful metal-mediat-
ed reactivity. In addition to advances that have been made
in Ru-mediated TH chemistry,[9] (NHC)Ir complexes (NHC:
N-heterocyclic carbene) have emerged as promising precata-
lysts for the TH of ketones.[10] For example, Crabtree, Faller,
and co-workers[10h] have reported an IrIII system of this type
that is capable of mediating the nearly quantitative reduc-
tion of benzophenone with a TOF of 50000 hÀ1 (at 50%
conversion). Notwithstanding such developments, (NHC)Ir
complexes that exhibit a combination of high TOFs and
high conversions for a broad range of ketone substrates at
low catalyst loadings have yet to be reported, and only
modest enantioselectivity has been achieved by the use of
chiral (NHC)Ir precatalysts.[10d,g] Indeed, the quest is ongo-
ing to identify alternative classes of simple and easily pre-
Scheme 2. Achiral ligands employed in the transfer-hydrogenation stud-
ies.
ed (for example, with a TOF of 180000 hÀ1 for acetophe-
none at 50% conversion).[9b] Encouraged by the catalytic
abilities of 1, and building on our previous studies of the re-
lated Ir complexes [Ir
([2a]+XÀ; cod: h4-1,5-cyclooctadiene), [Ir
NMe2-indene)]+OTfÀ ([2b]+OTfÀ; OTf: trifluoromethane-
sulfonate), and [Ir
(cod)(k2-2-NMe2-3-PiPr2-indenide)] (3) as
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
precatalysts in the direct hydrogenation of alkenes,[13] we
became interested in exploring the utility of [2a,b]+XÀ, 3,
and other (k2-P,N-ligand)IrI precatalysts (Scheme 1) in the
TH of ketones; we report herein the results of these catalyt-
ic studies. Notably, in the course of these investigations, we
À
pared “non-N H” ancillary ligands to support Ir and other
ketone-TH precatalysts that exhibit high efficiency and
broad substrate scope.[11,12]
discovered that the relatively simple complex [Ir
(cod)(k2-
À
In this context, we have described recently the application
of [RuCl(h6-p-cymene)(k2-2-NMe2-3-PiPr2-indenide)] (1, de-
rived from L1; Schemes 1 and 2) as a precatalyst for the TH
of ketones in iPrOH under basic conditions. Despite lacking
P,N-L8)]+PF6 ([4]+PF6À; L8: (o-tBu2P-C6H4)NMe2), either
preformed or prepared in situ from a mixture of [{IrCl-
AHCTUNGRTEGN(NNU cod)}2], NaPF6, and L8, affords an unusually active Ir cata-
lyst system for the TH of ketones in basic iPrOH, with
nearly quantitative conversions for a range of alkyl and/or
aryl ketones and with high TOFs (up to 230000 hÀ1 at
>50% conversion); this enabled the use of remarkably low
catalyst-to-substrate ratios (1:25000). Furthermore, catalyst
À
an ancillary-ligand N H functionality, complex 1 was shown
to be among the most active ketone-TH precatalysts report-
mixtures prepared in situ from [{IrClACTHNURGTNEUNG(cod)}2], NaPF6, and
the structurally related chiral ancillary ligand Cy-Mandy-
phos (L13; Scheme 4)[14] proved capable of mediating the
asymmetric TH of ketones, including that of the hindered
substrate 2,2-dimethylpropiophenone with an efficiency
(95% conversion, 95% ee) not documented previously in
the literature.
Results and Discussion
The reduction of acetophenone (K1) in basic iPrOH at
reflux was selected as a preliminary test reaction with which
to assess the catalytic utility of the Ir cations [2a,b]+XÀ and
zwitterion 3 (0.1 mol%) in the TH of ketones (Table 1).[15]
The preformed complexes [2a]+XÀ (X: PF6, BF4, and OTf),
[2b]+OTfÀ,[15b] and 3 each proved effective in mediating this
transformation and provided very good TOFs (0.1 mol% Ir;
Scheme 1. The structures of complexes 1, [2a]+XÀ, [2b]+XÀ, 3, and [4]+
À
PF6
.
Chem. Eur. J. 2008, 14, 10388 – 10395
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www.chemeurj.org
10389

R. J. Lundgren and M. Stradiotto
Table 1. Preliminary screening of Ir complexes for the transfer hydroge-
advantages of employing a bulky PtBu2 substituent in this
family of P,N-indene ligands, further elaboration of the N-
donor fragment proved deleterious (L4 and L5; Table 2, en-
tries 4 and 5, respectively).
nation of acetophenone (K1).[a]
Entry
Catalyst
t [h]
Conversion [%][b]
TOF [hÀ1] (%)[c]
À
1
2
3
4
5
6
N
2
2
2
3.25
2
96
98
93
99
95
29
47000 (39)
42000 (35)
36000 (30)
48000 (40)
37000 (31)
n.d.
[2a]+BF4
[2a]+OTfÀ
[2b]+OTfÀ
We have observed previously that the cationic k2-P,N-
indene complexes [2a,b]+XÀ can be transformed under
basic conditions into the corresponding zwitterionic k2-P,N-
indenide complex 3 upon loss of HX.[13] We became interest-
ed in determining whether the anionic nature of P,N-inden-
ide ligands formed in situ from L1 (as in 3) or L3 might play
a role in facilitating the observed ketone-TH chemistry
Crabtreeꢁs[d]
2
[a] Ir/ketone=1:1000; 0.8 mmol scale; 0.1m ketone; 828C; 1 mol%
NaOtBu in iPrOH. [b] On the basis of GC-FID data obtained at the
stated time. [c] Determined at 30 s, with the corresponding % conversion
given in parentheses. n.d.: not determined if the % conversion at 30 s was
mediated by mixtures of [{IrClACHTNUGRTENUNG(cod)Cl}2] and these P,N-in-
(pyridine)]+PF6À; Cy: cyclohexyl.
<25%. [d] [IrACHTUNGTRENNUNG(cod)ACHTUNGTRENNUNG(PCy3)ACHTNUGTRENNUGN
denes in basic iPrOH (Table 2, entries 1 and 3). Toward this
end, the catalytic utility of the structurally related phenylene
P,N ligands (o-R2P-C6H4)NMe2 (R: Ph, L6; R: iPr, L7; R:
tBu, L8; Table 2, entries 6–8, respectively) was evaluated.[17]
Interestingly, L6–L8 were observed to outperform the corre-
sponding P,N-indene ligand in the Ir-mediated TH of aceto-
phenone under similar conditions, with mixtures of [{Ir-
36000–48000 hÀ1 measured at 30 s and 30–40% conver-
sion)[15c] and high final conversions to 1-phenylethanol (93–
99%; Table 1, entries 1–5). Poor results were obtained when
À
using 0.1 mol% [Ir
(cod)
E
G
hexyl; Table 1, entry 6) under similar conditions,[16] and neg-
ligible conversion was achieved by use of the Rh analogue
of 3.
AHCTUNGTERGN(NNU cod)Cl}2], NaPF6, and L8 affording a particularly active Ir
catalyst system (96%, 0.25 h, 0.05 mol% Ir; TOF=
150000 hÀ1 at 63% conversion; Table 2, entry 9).[15c] Con-
versely, tBu-DavePhos (L9; Scheme 2; Table 2, entry 10),
tBu3P (L10; Table 2, entry 11), 1:1 mixtures of tBu3P/
PhNMe2 (L10/L11; Table 2, entry 12), and PPh3 (2 equiv;
Table 2, entry 13)[12] proved ineffective in supporting similar-
ly active catalyst systems when used in place of L8, as did
Related catalyst mixtures prepared in situ from [{IrCl-
ACHTUNGTRENNUNG(cod)}2] and 1-PiPr2-2-NMe2-indene (L1; Scheme 2) were
also found to be reasonably effective under analogous con-
ditions (34000 hÀ1 at 28% conversion; Table 2, entry 1). On
Table 2. Transfer hydrogenation of acetophenone (K1) by employing
[{IrClACHTUNGTRENNUNG
(cod)}2] and various ligands.[a]
mixtures of L8 with either [{RhCl
[{RhCl2Cp*}2], [RuCl2A(PPh3)3], or [{RuCl
(0.1 mol% M, <10%, 0.25 h).
Intrigued by the remarkable activity of [{IrClACHTUNGTRENNUNG(cod)}2]/
ACHTUNGTRENNUNG
C
CHTUNGTRENNUNG
Entry
Ligand (L)
t [h]
Conversion [%][b]
TOF [hÀ1] (%)[c]
1
2
3
4
5
6
7
L1
L2
L3
L4
L5
L6
L7
L8
L8
L9
L10
L10/L11
2PPh3
2
2
0.25
2
2
2
2
0.25
0.25
2
2
2
81
54
98
57
39
84
96
94
96
4
34000 (28)
n.d.
59000 (49)
n.d.
n.d.
n.d.
42000 (35)
100000 (43)
150000 (63)
n.d.
n.d.
n.d.
NaPF6/L8 mixtures in mediating the catalytic TH of aceto-
phenone, we examined the reduction of other ketones in
basic iPrOH at reflux (Table 3, Scheme 3). This in situ pre-
pared catalyst mixture proved very effective for the TH of a
range of substituted acetophenones (K1–K5) and benzophe-
nones (K7–K9), as well as other aryl alkyl (K12 and K14)
and dialkyl (K15 and K16) ketones. In the case of cyclohex-
anone (K15), high conversions were achieved in relatively
short reaction times by the use of 0.01 mol% Ir (>99%,
0.33 h; Table 3, entry 19) and even 0.004 mol% Ir (95%,
1.5 h; Table 3, entry 20). In preliminary studies, imines and
aldehydes were resistant to reduction under our standard re-
action conditions.
8[d]
9[e]
10
11
12
13
21
14
43
2
n.d.
[a] Ir/L/ketone=1:1:1000; 0.8 mmol scale; 0.1m ketone; 828C; 1 mol%
NaOtBu in iPrOH. [b] On the basis of GC-FID data obtained at the
stated time. [c] Determined at 30 s, with the corresponding % conversion
given in parentheses. n.d.: not determined if the % conversion at 30 s is
<25%. [d] Ir/L/ketone=1:1:2000. [e] With NaPF6; Ir/L/NaPF6/ketone=
1:1:1.1:2000.
In an effort to support our view that [{IrClACTHNUGRTNEUNG(cod)}2]/NaPF6/
À
L8 mixtures give rise to [Ir
(cod)(k2-P,N-L8)]+PF6 ([4]+
À
PF6 ) as the precatalyst in these reactions, we sought to
the basis of these preliminary findings, we proceeded to in-
vestigate the influence of donor-fragment substitution on
the catalystꢁs performance by examining acetophenone TH
evaluate the catalytic utility of isolated [4]+PF6À; this com-
pound was prepared as an analytically pure solid in 64%
isolated yield. The solution NMR characterization of [4]+
À
mediated by mixtures of [{Ir
N
PF6 as a traditional square-planar [Ir
G
indene ligands (Scheme 2). While the PPh2 variant (L2;
Table 2, entry 2) proved inferior to L1, the closely related
PtBu2 derivative (L3) gave rise to a significantly more active
catalyst system and, thereby, allowed the near quantitative
reduction of acetophenone in only 0.25 h (59000 hÀ1 at 49%
conversion; Table 2, entry 3). Despite the apparent reactivity
XÀ complex is entirely consistent with the crystallographical-
ly determined structure; an ORTEP[18] diagram of [4]+PF6
is presented in Figure 1. Gratifyingly, the catalytic perfor-
À
mance of [4]+PF6 mirrored that of the [{IrCl
N
NaPF6/L8 mixture (Table 3); the TH of acetophenone (K1)
À
with [4]+PF6 (Table 3, entry 3) proceeded with a TOF of
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Chem. Eur. J. 2008, 14, 10388 – 10395

Ketone Transfer Hydrogenation with Iridium Catalysts
FULL PAPER
Table 3. Scope of ketone transfer hydrogenation with [{IrClACHTNUTRGNEUNG(cod)}2], L8,
À
[a]
and NaPF6, or with [4]+PF6
.
Entry
Ketone
Ir/ketone
t [min]
Conversion [%][b]
1[c]
K1
K1
K1
K2
K2
K3
K3
K4
K5
K6
K7
K8
1:2000
1:4000
1:2000
1:2000
1:2000
1:2000
1:2000
1:2000
1:1000
1:1000
1:2000
1:2000
1:2000
1:1000
1:2000
1:2000
1:2000
1:2000
1:10000
1:25000
1:10000
1:2000
15
60
15
15
15
15
15
15
5
96
96
97
98
99
95
97
93
2[c]
3[d]
4[c]
5[d]
6[c]
7[d]
8[c]
9[c]
>99[e]
99
90
94
91
87
79
83
96
>99
>99
95
99
98
10[d]
11[c]
12[c]
13[c]
14[d]
15[c]
16[d]
17[c]
18[c]
19[c]
20[c]
21[d]
22[c]
5
40
15
120
60
30
30
15
15
20
90
10
15
Figure 1. ORTEP diagram for [4]+PF6À. The hydrogen atoms and the
K9
À
À
PF6 anion have been omitted for clarity. Selected bond lengths: Ir P
K10
K12
K12
K14
K15
K15
K15
K15
K16
À
À
2.3212(6), Ir N 2.184(2), Ir alkene 2.118(3) and 2.166(2) (trans to N),
2.168(3) and 2.228(3) ꢂ (trans to P).
featured in L8, we identified commercially available Cy-Ta-
niaphos (L12; Scheme 4) and Cy-Mandyphos (L13) as at-
tractive ligand candidates for asymmetric-TH experiments
[a] Ir/L8/NaPF6 =1:1:1.1; 0.8 mmol scale; 0.1m ketone; 828C; 1 mol%
NaOtBu in iPrOH. [b] On the basis of GC-FID data obtained at the
À
stated time. [c] With [{IrCl
G
.
[e] When the reaction was conducted on a 2.0 mmol scale, the corre-
sponding secondary alcohol was isolated in 95% yield.
Scheme 4. Chiral ligands employed in the asymmetric transfer-hydroge-
nation studies.
in basic iPrOH. In a preliminary survey, good conversion
(94%, 4.5 h) and enantioselectivity (72% ee) were achieved
when Cy-Mandyphos was employed for the TH of acetophe-
none (K1) at 408C by using catalyst mixtures comprising
[{IrClACHTNUTGRENUNG(cod)}2]/NaPF6/L13 (1.0 mol% Ir; Table 4, entry 1). Al-
Scheme 3. Ketones employed in the transfer-hydrogenation studies.
Table 4. Asymmetric transfer hydrogenation of ketones by employing
[{IrCl
(cod)}2], Cy-Mandyphos (L13), and NaPF6.[a]
AHCTUNGTRENNUNG
230000 hÀ1 (measured at 20 seconds and 63% conver-
Entry
Ketone
t [h]
Conversion [%][b]
Enantiomer ratio (ee)[b]
sion).[15c] The demonstrated ability of [{IrCl
A
1
K1
K1
K2
K4
4.5
24
3
22
2.5
14
28
2
94
81
95
94
98
86
87
95
95
56
86:14 (72, S)[c]
85:15 (70)
79.5:20.5 (59)
84:16 (68)
61:39 (22)
89:11 (78)
90.5:9.5 (81)
96.5:3.5 (93)
97.5:2.5 (95)
97.5:2.5 (95)
L8 (or, alternatively, [4]+PF6 ) to mediate the rapid reduc-
tion of such a structurally diverse set of ketones with high
conversions and routinely low catalyst loadings (0.004–
0.1 mol% Ir) is noteworthy. These results serve to establish
L8 and other appropriately substituted simple P,N ligands as
a useful class of ancillary ligands in metal-mediated ketone-
TH chemistry.
À
2[d]
3
4
5
6
7
K5
K11
K12
K13
K13
K13
8
9[e]
10[d]
12
24
Having succeeded in establishing the utility of simple P,N
ligands such as L8 in the Ir-mediated TH of ketones, we
sought to develop asymmetric variants of this reaction by
employing structurally related chiral ancillary ligands. Given
the pairing of a bulky PR2 fragment with an NMe2 donor, as
[a] Ir/L13/NaPF6/ketone=1:1:1.1:100; 0.4 mmol; 0.1m ketone; 408C;
5 mol% NaOtBu in iPrOH. [b] On the basis of chiral GC-FID data at
the stated time. [c] Absolute configuration assignment made by compari-
son to literature data; see the Experimental Section. [d] Reaction con-
ducted at 308C. [e] Ir/L13/NaPF6/ketone=1:1:1.1:200.
Chem. Eur. J. 2008, 14, 10388 – 10395
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10391

R. J. Lundgren and M. Stradiotto
though the use of Cy-Taniaphos under similar conditions af-
forded good conversions, poor enantioselectivity (<50% ee)
was achieved. In keeping with the inferior performance of
catalysts prepared from the PPh2-substituted ligand L6 rela-
tive to those featuring the PtBu2 variant L8 (see above), Ph-
Mandyphos (L14, Scheme 4) displayed poor activity and se-
lectivity for the reduction of acetophenone under analogous
conditions (29% conversion, 37% ee, 4.5 h).
commercially available [{IrClACHTUGNTERNNU(G cod)}2], NaPF6, and the PCy2-
substituted chiral ligand Cy-Mandyphos (L13) proved capa-
ble of mediating the asymmetric TH of ketones, including
that of the hindered substrate 2,2-dimethylpropiophenone
with unprecedented efficiency (95% conversion, 95% ee).
Collectively, these results demonstrate that appropriately
constructed simple P,N ligands represent an effective class
À
of often-overlooked “non-N H” ancillary ligands in metal-
While [{IrCl
N
mediated ketone-TH chemistry. Encouraged by these pre-
liminary findings, we are currently exploring the utility of
L8 and related P,N ligands in a variety of metal-mediated
synthetic applications and will report on the results of these
investigations in due course.
pable of reducing other aryl alkyl ketones under relatively
mild conditions (Table 4), this catalyst mixture was found to
be particularly effective for the reduction of the sterically
encumbered substrate 2,2-dimethylpropiophenone (K13),
with excellent conversion (95%, 2 h) and enantioselectivity
(93% ee; Table 4, entry 8). Whereas lowering of the reaction
temperature from 40 to 308C decreased the extent of reduc-
tion without providing any gain in enantioselectivity
(Table 4, entries 2 and 10), enhanced enantioselectivity was
achieved by reducing the catalyst loading to 0.5 mol% Ir
(95% conversion, 12 h, 95% ee; Table 4, entry 9). To the
best of our knowledge, the metal-catalyzed asymmetric TH
of K13 with such efficiency has not documented in the liter-
ature. This result highlights the utility of employing Ir in
combination with this class of ligands in addressing challeng-
ing asymmetric-TH chemistry. Indeed, the efficient Ru-cata-
lyzed hydrogenation of K13 by use of dihydrogen gas has
been reported only recently.[19]
Experimental Section
General considerations: All manipulations were conducted in the ab-
sence of oxygen and water under an atmosphere of dinitrogen, either by
use of standard Schlenk methods or within an mBraun glovebox appara-
tus, by utilizing glassware that was oven dried (1308C) and evacuated
while hot prior to use. Celite (Aldrich) was oven dried (1308C) for 5 d
and then evacuated for 24 h prior to use. The nondeuterated solvents di-
ethyl ether, dichloromethane, tetrahydrofuran (THF), pentane, and
hexane were deoxygenated and dried by sparging with dinitrogen gas, fol-
lowed by passage through a double-column solvent-purification system
purchased from mBraun Inc. Diethyl ether, dichloromethane, and tetra-
hydrofuran were purified over two alumina-packed columns, while pen-
tane and hexane were purified over one alumina-packed column and one
column packed with copper-Q5 reactant. Purification of iPrOH (Aldrich,
anhydrous 99.5%) was achieved by sparging with dinitrogen over a
period of 0.25 h, followed by storage over 4 ꢂ sieves (approximately 10 g
per 100 mL of iPrOH) for a minimum of 24 h. All solvents used within
the glovebox were stored over activated 4 ꢂ molecular sieves. CDCl3
(Aldrich) was degassed by using 3 repeated freeze–pump–thaw cycles,
dried over CaH2 for 7 d, distilled in vacuo, and stored over 4 ꢂ molecular
sieves for 24 h prior to use. All ketone substrates were obtained from
commercial sources in high purity; solid ketones were dried in vacuo for
a minimum of 12 h prior to use, while liquid ketones were degassed by
use of 3 repeated freeze–pump–thaw cycles. In the cases of acetophe-
none, cyclohexanone, and cyclopentanone, the ketones were dried over
CaH2 for a minimum of 12 h and distilled before degassing. o-Bromo-
N,N-dimethylaniline (Alfa Aesar), N,N-dimethylaniline (L11, Alfa
Aesar), nBuLi (2.9m in hexanes, Alfa Aesar), ClPPh2 (Aldrich), ClPiPr2
(Aldrich), ClPtBu2 (Aldrich), and PtBu3 (L10, Strem) were used as re-
Conclusion
The catalytic utility in ketone TH of Ir complexes supported
by various P,N-substituted indene, indenide, or phenylene li-
gands was evaluated. In a preliminary catalytic survey the
cationic and formally zwitterionic complexes [2a,b]+XÀ and
3, as well as related in situ prepared Ir catalysts derived
from P,N-indenes, were found to be generally effective in
mediating the reduction of acetophenone to 1-phenylethanol
in basic iPrOH at reflux. Although the catalytic perfor-
mance of these Ir complexes proved inferior to that of the
highly active zwitterionic Ru species 1,[9b] the related Ir com-
ceived. [{IrCl
N
ACHTNUGTNERUN(GN cod)}2], [{IrCl2Cp*}2], [{RhCl2Cp*}2],
À
plex [4]+PF6 supported by the rather simple ancillary
[RuCl2A(PPh3)3], [{RuCl CHTUGNTRENNUNG
H
ligand (o-tBu2P-C6H4)NMe2 (L8) exhibited remarkable ac-
(L12), Cy-Mandyphos (L13), Ph-Mandyphos (L14), and Crabtreeꢁs cata-
lyst (all obtained from Strem), as well as NaPF6 (Aldrich) and NaOtBu
(Aldrich), were dried in vacuo for a minimum of 12 h prior to use. While
ligands 1-PiPr2-2-NMe2-indene (L1) and 1-PPh2-2-NMe2-indene (L2)
were prepared by employing published procedures,[20] these ligands are
now commercially available from Strem Chemicals Inc. The preparation
À
tivity that rivals that of 1. Notably, [4]+PF6 is a rare exam-
ple of a ketone-TH catalyst system that exhibits TOF values
of 105 hÀ1 and also provides high conversions for a diversity
of simple ketone substrates at low catalyst loadings (0.004–
0.1 mol% Ir). In addition, the outstanding catalytic perfor-
of (o-Ph2P-C6H4)NMe2 (L6),[21] [Ir
([2a]+XÀ),[13] [Ir(cod)(k2-1-PiPr2-2-NMe2-indene)]+OTfÀ ([2b]+OTfÀ),[13]
and [Ir
(cod)(k2-2-NMe2-3-PiPr2-indenide)] (3)[13] has been reported previ-
(cod)(k2-2-NMe2-3-PiPr2-indene)]+XÀ
ACHTUNGTRENNUNG
À
mance of [4]+PF6 was mirrored by in situ prepared catalyst
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
mixtures that were formed conveniently by the combination
of [{IrClACHTUNGTRENNUNG(cod)}2], NaPF6, and L8. In the course of these cata-
ously. The 2-NR2-indenes[22] used in the preparation of 1/3-PtBu2-2-
NMe2-indene (L3), 1/3-PtBu2-2-piperidyl-indene (L4), and 1/3-PtBu2-2-
morpholino-indene (L5) were prepared according to literature proce-
dures. 1H, 13C, and 31P NMR characterization data were collected at
300 K on a Bruker AV-500 spectrometer operating at 500.1, 125.8, and
202.5 MHz, respectively, with chemical shifts reported in parts per million
lytic studies, it was observed that alteration of the substitu-
ents at the donor fragments of the supporting P,N ligands
had a pronounced influence on the catalytic performance of
the derived catalysts, with ligands featuring bulky dialkyl-
phosphino donors proving to be the most effective. Based
on these observations, chiral catalysts prepared in situ from
1
downfield of SiMe4 for H and 13C data or of 85% H3PO4 in D2O for 31P
data. 1H and 13C NMR chemical shift assignments are based on data ob-
1
1
1
tained from 13C-DEPT, H–1H COSY, H–13C HSQC, and H–13C HMBC
10392
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 10388 – 10395

Ketone Transfer Hydrogenation with Iridium Catalysts
FULL PAPER
NMR experiments. In some cases, fewer than expected independent
13C NMR resonances were observed, despite prolonged data-acquisition
times. Elemental analyses were performed by Canadian Microanalytical
Service Ltd., Delta, BC, Canada.
0.20 mmol), and CH2Cl2 (8 mL) were added to a glass vial. The resulting
mixture was stirred magnetically at room temperature for 24 h, after
which the solvent was removed in vacuo. The residue was then taken up
in CH2Cl2 (5 mL) and filtered through a plug of silica. The solvent was
removed in vacuo and the residue was washed with pentane (2ꢃ2 mL).
Synthesis of 1/3-PtBu2-2-NMe2-indene (L3), 1/3-PtBu2-2-piperidyl-indene
(L4), and 1/3-PtBu2-2-morpholino-indene (L5): These P,N-substituted in-
denes were prepared from the corresponding 2-aminoindenes by using
synthetic methods directly analogous to those employed in the prepara-
tion of the closely related indenes 1-PiPr2-2-NMe2-indene (L1) and 1-
PPh2-2-NMe2-indene (L2),[20] with the exception that extended reaction
times (up to 6 d) at ambient temperatures were required to obtain opti-
mal yields. The propensity of isomerically pure L1 and L2 to form a mix-
ture of allylic (1-PR2-2-NR2-indene) and vinylic (3-PR2–2-NR2-indene)
isomers upon standing in solution has been well-documented;[20b] similar-
ly, L3–L5 were obtained as varying mixtures of allylic and vinylic iso-
mers: L3: 48% yield; 31P{1H} NMR (CDCl3): d=51.6 (allylic), 14.6 ppm
(vinylic); L4: 47% yield; 31P{1H} NMR (CDCl3): d=55.3 (allylic),
15.7 ppm (vinylic); L5: 35% yield; 31P{1H} NMR (CDCl3): d=53.2 (al-
À
The product was then dried in vacuo to yield [4]+PF6 as an orange solid
(0.091 g, 0.13 mmol, 64% yield); 1H NMR (CDCl3): d=7.97 (m, 1H, Ar-
H), 7.91 (m, 1H, Ar-H), 7.73 (m, 1H, Ar-H), 7.47, (m, 1H, Ar-H), 4.70–
4.62 (m, 4H, cod), 3.31 (s, 6H, N
1.80 (m, 4H, cod), 1.41 ppm (d, 3JPH =14.5 Hz, 18H, P(C
13C{1H} NMR (CDCl3): d=163.1, 134.7, 128.7 (d, JPC =5.0 Hz), 123.4 (d,
PC =8.8 Hz), 89.4 (d, JPC =11.3 Hz, cod), 62.2 (cod), 53.6 (N(CH3)2), 32.9
(d, JPC =2.5 Hz, cod), 30.7 (d, JPC =3.8 Hz, P(C(CH3)3)2), 29.7 (P(C-
(CH3)3)2), 29.3 ppm (d, JPC=2.5 Hz, cod); 31P{1H} NMR (CDCl3): d=
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
J
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
52.8 ppm; elemental analysis calcd (%) for C24H40Ir1N1P2F6: C 40.56, H
À
5.67, N 1.97; found: C 40.21, H 5.54, N 1.89. A single crystal of [4]+PF6
suitable for single-crystal X-ray diffraction was obtained from vapor dif-
À
fusion of diethyl ether into a concentrated solution of [4]+PF6 in di-
lylic), 14.9 ppm (vinylic). Given that [IrACTHNUTRGNEUNG
(cod)(k2-1-PiPr2-2-NMe2-
chloromethane.
indene)]+OTfÀ ([2b]+OTfÀ) has been shown to isomerize rapidly to
[2a]+OTfÀ under basic conditions,[13] such as those employed in the cata-
lytic experiments detailed herein, and that a similar performance has
been observed for [2a]+OTfÀ and [2b]+OTfÀ in head-to-head acetophe-
none-transfer-hydrogenation experiments, it appears that the isomeric
form of the ancillary P,N-indene ligand backbone has minimal influence
over the performance of the derived catalyst complexes. As such, for sim-
plicity, only the allylic forms of L3–L5 are represented and discussed in
the text.
Typical procedure for the catalytic transfer hydrogenation of ketones: A
mixture of [{IrClACTHNUTRGNEUNG(cod)}2] (3.9 mg, 0.0058 mmol), L8 (3.2 mg,
0.0119 mmol), and NaPF6 (2.1 mg, 0.0125 mmol) was vigorously stirred in
THF (4.000 mL) for approximately 1 h before an aliquot (139 mL,
0.4 mmol) was delivered to a Schlenk flask by use of an Eppendorf pip-
ette. The solvent within the Schlenk flask was then removed in vacuo,
and ketone (0.8 mmol), followed by iPrOH (6 mL), was subsequently
added to the residue within the Schlenk flask. The solution was then
heated at 828C for 10 min, at which point a 0.004m solution of NaOtBu
in iPrOH (2 mL) was added to the Schlenk flask (Ir/L8/NaPF6/NaOtBu/
ketone 1:1:1.1:20:2000; [ketone]=0.1m), which resulted in rapid reduc-
tion of the ketone. Reactions were sampled by removing an aliquot
(0.25–1 mL) of the reaction mixture with a syringe and immediately fil-
tering it through a plug of silica. Conversions were determined by use of
GC-FID, and the identities of the hydrogenation products were con-
firmed by use of 1H NMR methods or by comparison to authentic sam-
ples. All reported data represent the average of a minimum of two cata-
lytic runs.
Synthesis of (o-R2P-C6H4)NMe2 (R: iPr, L7; R: tBu, L8): The analogous
compound in which R is Ph (L6) has been reported.[21] nBuLi (625 mL,
1.8 mmol) was added to a glass vial containing o-bromo-N,N-dimethylani-
line (218 mL, 1.5 mmol) in Et2O (3 mL, precooled to À358C). After the
reaction mixture had been maintained for 0.5 h at À358C and an addi-
tional 0.25 h at room temperature, the resulting yellow precipitate was
isolated by removing the solvent by pipette. This was followed by wash-
ing of the remaining solid with cold hexanes (2ꢃ2 mL), after which the
volatile materials were removed in vacuo. The resulting solid was dis-
solved in THF (3 mL), and ClPiPr2 (238 mL, 1.5 mmol) was added drop-
wise. The mixture was stirred magnetically at room temperature over-
night (ca. 18 h). The solvent and volatile materials were then removed in
vacuo. The resulting mixture was dissolved in CH2Cl2 and filtered
through a celite plug. Removal of the CH2Cl2 in vacuo yielded L7 as a
pale yellow oil (0.11 g, 0.47 mmol, 31% yield); 1H NMR (CDCl3): d=
7.37 (m, 1H, Ar-H), 7.31 (m, 1H, Ar-H), 7.17 (m, 1H, Ar-H), 7.09 (m,
Typical procedure for the catalytic asymmetric transfer hydrogenation of
ketones: [{IrClACHTNUTRGNEUNG(cod)}2] (7.1 mg, 0.011 mmol), Cy-Mandyphos (18.0 mg,
0.021 mmol), and NaPF6 (4.1 mg, 0.024 mmol) were vigorously stirred in
THF (4.000 mL) for approximately 1 h before an aliquot (379 mL,
0.002 mmol) was delivered to a Schlenk flask by use of an Eppendorf
pipette. The solvent within the Schlenk flask was then removed in vacuo,
and ketone (0.4 mmol), followed by iPrOH (2 mL), was subsequently
added to the residue within the Schlenk flask. The solution was then
heated at 408C for 10 min, at which point a 0.04m solution of NaOtBu in
iPrOH (2 mL) was added to the Schlenk flask (Ir/Cy-Mandyphos (L13)/
NaPF6/NaOtBu/ketone 1:1:1.1:10:200; [ketone]=0.1m). Conversions and
enantiomeric ratios were determined by use of chiral GC-FID (Astec
CHIRALDEX G-TA 30 mꢃ0.25 mm for all substrates with exception of
2’-chloroacetophenone for which a Supelco Beta-Dex 120 30 mꢃ0.25 mm
column was employed), and the identities of the hydrogenation products
1H, Ar-H), 2.77 (s, 6H, N
3JPH =14.2, 3JHH =7.0 Hz, 6H, P(CH
11.5, 3JHH =7.0 Hz, 6H, P(CH(CH3CH3)2); 13C{1H} NMR (CDCl3): d=
160.1 (d, JPC =18.6 Hz), 133.0 (d, JPC =3.3 Hz), 131.8 (d, JPC =17.4 Hz),
A
ACHTNUGTRNEN(UGN CH3)2)2), 1.15 (dd,
3
A
=
AHCTUNGTRENNUNG
129.5, 123.2, 119.7 (d, JPC =4.7 Hz), 45.8 (d, 4JPC =5.2 Hz, N
ACHTUNGTRENNUNG
(d, 1JPC =13.9 Hz, P(CH
(CH3CH3)2), 19.3 ppm (d, JPC =10.5 Hz, P(CH
G
2
N
(CDCl3): d=3.5 ppm.
1
Compound L8 was prepared in a similar manner by using o-bromo-N,N-
dimethylaniline (288 mL, 2.0 mmol) and nBuLi (759 mL, 2.20 mmol), with
the exception that the resulting solid was dissolved in Et2O (6 mL; rather
than 3 mL of THF), ClPtBu2 (392 mL, 2.0 mmol) was used in place of
ClPiPr2, and the mixture was stirred at room temperature for 6 d at
which point no further conversion of the chlorophosphane was observed
(by 31P NMR spectroscopy). L8 was isolated as a beige powder (0.204 g,
0.78 mmol, 39% yield); 1H NMR (CDCl3): d=7.70 (m, 1H, Ar-H), 7.32
(m, 1H, Ar-H), 7.21 (m, 1H, Ar-H), 7.06 (m, 1H, Ar-H), 2.76 (s, 6H, N-
were confirmed by use of H NMR methods or by comparison to authen-
tic samples. The S-absolute configuration assigned to the major enantio-
mer of 1-phenylethanol formed in the reduction of K1 was determined
by comparison to literature data.[23] Retention times for substrates and
products were as follows. Acetophenone (K1; 1008C; 20 psi): 11.0 min; 1-
phenylethanol: t1 =11.6 min; t2 =12.4 min. 3-Chloroacetophenone (K2;
1458C; 12 psi): 8.3 min; 1-(m-chlorophenyl)ethanol: t1 =13.8 min; t2 =
14.8 min. 4-Fluoroacetophenone (K4; 1108C; 17 psi): 6.8 min; 1-(p-fluoro-
phenyl)ethanol: t1 =9.7 min; t2 =10.3 min. 2’-Chloroacetophenone (K5;
1458C; 12 psi): 8.0 min; 1-(o-chlorophenyl)ethanol: t1 =10.3 min; t2 =
10.8 min. Propiophenone (K11; 1108C; 17 psi): 10.6 min; 1-phenylpropan-
1-ol: t1 =12.7 min; t2 =13.1 min. n-Butyrophenone (K12; 1258C; 8 psi):
18.0 min; 1-phenylbutan-1-ol: t1 =21.7 min; t2 =22.5 min. 2,2-Dimethyl-
propiophenone (K13; 1258C; 8 psi): 14.5 min; 2,2-dimethyl-1-phenyl-
propanol: t1 =20.8 min; t2 =21.5. All reported data represent the average
of a minimum of two catalytic runs.
ACHTUNGTRENNUNG ACHTUNGTRENNUGN
(CH3)2), 1.21 ppm (d, 18H, 3JPC =11.5 Hz, P(C(CH3)3)2); 13C{1H} NMR
(CDCl3): d=161.0 (d, JPC =21.7 Hz), 136.2 (d, JPC =3.7 Hz), 133.6 (d,
J
N
PC =22.9 Hz), 129.8, 122.7, 120.4 (d, JPC =3.7 Hz), 46.0 (d, 4JPC =4.3 Hz,
2
G
G
=
15.4 Hz, P(CACHTUNGTRENNUNG
(CH3)3)2); 31P{1H} NMR (CDCl3): d=17.6 ppm.
À
Synthesis of [Ir
G
([4]+PF6À): [{IrCl
ACTHNGUTERNN(UG cod)}2]
(0.067 g, 0.20 mmol), L8 (0.053 g, 0.20 mmol), NaPF6 (0.034 g,
Chem. Eur. J. 2008, 14, 10388 – 10395
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10393

R. J. Lundgren and M. Stradiotto
Crystallographic solution and refinement details: Crystallographic data
Karvembu, R. Prabhakaran, K. Natarajan, Coord. Chem. Rev. 2005,
249, 911; f) reference [1b].
À
for [4]+PF6 were collected on
a Bruker PLATFORM/SMART
À
1000 CCD diffractometer by using graphite-monochromated Mo Ka (l=
0.71073 ꢂ) radiation and by employing a sample that was mounted in
inert oil and transferred to a cold gas stream on the diffractometer
(193(Æ2) K). Programs for diffractometer operation, data collection, data
reduction, and absorption correction (including SAINT and SADABS)
[4] Highly active Os NH TH precatalysts have emerged recently: a) W.
Baratta, M. Ballico, A. Del Zotto, K. Siega, S. Magnolia, P. Rigo,
Chem. Eur. J. 2008, 14, 2557; b) W. Baratta, M. Ballico, G. Chelucci,
K. Siega, P. Rigo, Angew. Chem. 2008, 120, 4434; Angew. Chem. Int.
Ed. 2008, 47, 4362.
À
were supplied by Bruker. The structure of [4]+PF6 was solved by use of
[5] For recent breakthroughs in Fe-mediated TH catalysis, see: a) C.
Sui-Seng, F. Freutel, A. J. Lough, R. H. Morris, Angew. Chem. 2008,
120, 954; Angew. Chem. Int. Ed. 2008, 47, 940; b) C. P. Casey, H.
Guan, J. Am. Chem. Soc. 2007, 129, 5816.
direct methods and refined by use of full-matrix least-squares procedures
2
2
2
2
(on F2) with R1 based on Fo ꢀ2s
G
ACHTUNGRTEN(NUNG Fo ).
Anisotropic displacement parameters were employed throughout for the
non-H atoms. All H atoms were added at calculated positions and re-
fined by use of a riding model employing isotropic displacement parame-
ters based on the isotropic displacement parameter of the attached atom.
Selected crystal data for [4]+PF6À: empirical formula C24H40F6Ir1N1P2;
crystal size 0.31ꢃ0.25ꢃ0.17 mm monoclinic; space group P2(1)/c; a=
9.7092(7), b=16.0329(12), c=17.0851(13) ꢂ; a=90, b=96.7480(10), g=
908; V=2641.2(3) ꢂ3; Z=4; m=5.232 mmÀ1; f range for data collection
1.75–27.518; limiting indices À12ꢁhꢁ12, À20ꢁkꢁ20, À22ꢁlꢁ22;
22776 reflections measured; 6062 unique reflections (Rint =0.0228); com-
pleteness 99.6%; max. and min. transmission 0.4699 and 0.2938; data/re-
straints/parameters 6062/0/307; goodness of fit on F2 1.035; final R indices
with I>2s(I): R1=0.0200, wR2=0.0496; final R indices (all data): R1=
0.0230, wR2=0.0509; largest diff. peak and hole 1.145 and À0.363 eꢂ3.
CCDC-683381 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
À
[6] A remarkably active class of Rh NH complexes that are capable of
mediating the TH of ketones with EtOH as the H2 donor has been
disclosed very recently: T. Zweifel, J.-V. Naubron, T. Bꢇttner, T.
Ott, H. Grꢇtzmacher, Angew. Chem. 2008, 120, 3289; Angew. Chem.
Int. Ed. 2008, 47, 3245.
[7] a) Z. E. Clarke, P. T. Maragh, T. P. Dasgupta, D. G. Gusev, A. J.
Lough, K. Abdur-Rashid, Organometallics 2006, 25, 4113; b) for
highly efficient Ir-mediated aldehyde TH, see: X. Wu, J. Liu, X. Li,
A. Zanotti-Gerosa, F. Hancock, D. Vinci, J. Ruan, J. Xiao, Angew.
Chem. 2006, 118, 6870; Angew. Chem. Int. Ed. 2006, 45, 6718.
[8] For select examples of efficient Rh- and Ir-mediated asymmetric
TH, see: a) X. Wu, X. Li, A. Zanotti-Gerosa, A. Pettman, J. Liu,
A. J. Mills, J. Xiao, Chem. Eur. J. 2008, 14, 2209; b) T. Ikariya, A. J.
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Deng, Green Chem. 2007, 9, 23; e) D. S. Matharu, D. J. Morris, G. J.
Clarkson, M. Wills, Chem. Commun. 2006, 3232; f) X. Wu, D. Vinci,
T. Ikariya, J. Xiao, Chem. Commun. 2005, 4447; g) D. S. Matharu,
D. J. Morris, A. M. Kawamoto, G. J. Clarkson, M. Wills, Org. Lett.
2005, 7, 5489; h) T. Hamada, T. Torii, K. Izawa, R. Noyori, T. Ikar-
iya, Org. Lett. 2002, 4, 4373; i) K. Murata, T. Ikariya, R. Noyori, J.
Org. Chem. 1999, 64, 2186; j) K. Mashima, T. Abe, K. Tani, Chem.
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Catal. A 2007, 273, 284; l) X.-Q. Zhang, Y.-Y. Li, H. Zhang, J.-X.
Gao, Tetrahedron: Asymmetry 2007, 18, 2049; m) B.-Z. Li, J.-S.
Chen, Z.-R. Dong, Y.-Y. Li, Q.-B. Li, J.-X. Gao, J. Mol. Catal. A
2006, 258, 113; n) Y. Xing, J.-S. Chen, Z.-R. Dong, Y.-Y. Li, J.-X.
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Acknowledgements
Acknowledgment is made to the Natural Sciences and Engineering Re-
search Council (NSERC) of Canada (for a Discovery Grant to M.S. and
a Postgraduate Scholarship to R.J.L.), the Canada Foundation for Inno-
vation, the Nova Scotia Research and Innovation Trust Fund, and Dal-
housie University for their generous support of this work. We also thank
Solvias for the gift of a chiral ligand kit, Dr. Michael Lumsden and Dr.
Katherine Robertson (Atlantic Region Magnetic Resonance Center, Dal-
housie) for their assistance in the acquisition of NMR data, and Dr. Mi-
chael Ferguson (Department of Chemistry X-Ray Crystallography Labo-
[9] For selected examples of effective Ru TH precatalysts that do not
ratory, University of Alberta) for collecting crystallographic data for [4]+
À
À
exploit N H or O H ancillary-ligand functionalities, see: a) E.
Mothes, S. Sentets, M. A. Luquin, R. Mathieu, N. Lugan, G. Lav-
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2291.
À
PF6
.
[1] For an overview of TH catalysis, see: a) S. Gladiali, E. Alberico,
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[2] For selected recent reports and reviews from the field of Ru-mediat-
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À
À
[3] Conceptually related net H2 transfer from Ru H/O H fragments is
observed in TH chemistry mediated by Shvoꢁs catalyst system and
related catalysts. For recent reports and reviews related to ketone
TH, see: a) C. P. Casey, S. E. Beetner, J. B. Johnson, J. Am. Chem.
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[11] While Ir-based ketone TH catalysts featuring high initial TOF
values (ca. 105 hÀ1) have been reported, the demonstrated substrate
scope is often small (ꢁ3 ketones) and, in some cases, the final con-
10394
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ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 10388 – 10395

Ketone Transfer Hydrogenation with Iridium Catalysts
FULL PAPER
versions achieved in the high-TOF experiments are low (<60%).
For selected examples, see: a) R. Spogliarich, G. Mestroni, M. Gra-
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times for the systems described herein (with the exception of cataly-
sis involving [4]+PF6À, for which reproducible TOF data were ob-
tained at 20 s). For the most active of the catalysts described herein,
this protocol can be viewed as underestimating catalyst activity,
since the conversion is beyond 50%. For relevant discussions per-
taining to the use of TOF data as an estimate of catalyst activity, see
reference [2d].
[16] The use of Crabtreeꢁs catalyst in the TH of cyclohexanone (92%,
9 h, 0.5 mol% Ir) in basic iPrOH has been described previously.[10i]
[17] The use of L6 in the Ir-mediated TH of selected a,b-unsaturated ke-
tones has been described: E. Farnetti, G. Nardin, M. Graziani, J.
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[12] Whereas a catalyst mixture prepared from [{IrClACHTNUTRGNEUNG(cod)}2] and PPh3
(Ir/P=1:2) followed by pretreatment with H2 has been claimed to
exhibit remarkable activity for the TH of 4-tBu-cyclohexanone in
basic iPrOH under reflux conditions (0.002 mol% Ir, 4.1ꢃ106 hÀ1 at
15 s and 34% conversion),[11a] we have thus far not been able to du-
plicate these results in our laboratory under similar conditions
(0.002 mol% Ir, no conversion after 0.25 or 1 h; 0.2 mol% Ir, 61
(0.25) and 95% (1 h) conversion).
[13] J. Cipot, R. McDonald, M. J. Ferguson, G. Schatte, M. Stradiotto,
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[15] a) The precatalysts described herein exhibited no ketone TH activity
in the absence of base (NaOtBu). b) Our investigations of [2b]+XÀ
are limited to the triflate salt (that is, [2b]+OTfÀ), due to the facile
isomerization of [2b]+XÀ into [2a]+XÀ in solution when X is PF6 or
BF4.[13] c) While meaningful TOF data are perhaps best reported
near 50% conversion, all TOF data reported herein were measured
at 30 s for convenience, with the corresponding percentage conver-
sion provided (rather than a determination of the time required for
50% conversion for each catalyst system). Although TOF values for
highly active TH catalysts are commonly quoted at shorter reaction
times,[2] we determined that reproducible TOF data (commonly
Æ5%) were most conveniently obtained at or beyond 30 s reaction
[21] H. P. Fritz, I. R. Gordon, K. E. Schwarzhans, L. M. Venanzi, J.
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Received: July 28, 2008
Published online: October 16, 2008
Chem. Eur. J. 2008, 14, 10388 – 10395
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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