Rhodium-catalyzed asymmetric transfer hydrogenation of aryl alkyl ketones employing ligands derived from amino acids

Article abstract of DOI:10.1002/adsc.200700345

The combination of (pentamethylcyclopentadienyl)rhodium dichloride dimer [{RhCl₂Cp*}₂] and pseudodipeptide ligands, formed from N-Boc protected amino acids and amino alcohols, resulted in efficient and selective catalysts for the asymmetric transfer hydrogenation of ketones in 2-propanol. A number of different secondary alcohols was obtained in high yields and in excellent enantioselectivity using these in situ formed catalysts. Deuterium-labeling experiments showed that the hydride transfer reaction occurs via the monohydridic route.

Full text of DOI:10.1002/adsc.200700345

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DOI: 10.1002/adsc.200700345
Rhodium-Catalyzed Asymmetric Transfer Hydrogenation of Aryl
Alkyl Ketones Employing Ligands Derived from Amino Acids
Jenny Wettergren,a Alexey B. Zaitsev,a and Hans Adolfssona,*
a
Department of Organic Chemistry, the Arrhenius Laboratory, Stockholm University, SE-10691 Stockholm, Sweden
Fax : (+46)-8-154-908; e-mail: hansa@organ.su.se
Received: July 13, 2007; Published online: November 21, 2007
Dedicated to Professor Jan-E. Bäckvall on the occasion of his 60th birthday.
Abstract: The combination of (pentamethylcyclopen- in high yields and in excellent enantioselectivity
tadienyl)rhodium dichloride dimer [{RhCl2Cp*}2] using these in situ formed catalysts. Deuterium-label-
and pseudodipeptide ligands, formed from N-Boc ing experiments showed that the hydride transfer re-
protected amino acids and amino alcohols, resulted action occurs via the monohydridic route.
in efficient and selective catalysts for the asymmetric
transfer hydrogenation of ketones in 2-propanol. A Keywords: amino acid ligands; asymmetric transfer
number of different secondary alcohols was obtained hydrogenation; ketones; reductions; rhodium
Introduction
the combination of a pseudodipeptide ligand with
[{RuCl2(p-cymene)}2] and alkali base form an efficient
AHCTREUNG
Asymmetric transfer hydrogenation (ATH) employ- catalyst for highly enantioselective ATH of aromatic
ing transition-metal[1–14] or purely organic[15–22] cata- ketones in 2-propanol. On the other hand, the corre-
lysts is a very useful process allowing for enantioselec- sponding rhodium complex [{RhCl2Cp*}2] in combina-
tive reduction of prochiral ketones, imines and acti- tion with pseudodipeptide 1 gave only 80% ee in the
vated alkenes. This process provides an easy access to
enantiomerically enriched chiral compounds and is es-
pecially attractive on a laboratory or small industrial
scale, since it avoids the use of molecular hydrogen
and hence often expensive specialized high pressure
equipment. However, further improvement in terms
of scope, selectivity and turnover frequency is re-
quired to make the process competitive with conven-
tional hydrogenations using molecular hydrogen. ATH of acetophenone versus 95% ee obtained with
Studies uncovering structural features which are es- the ruthenium complex.[25]
sential for high catalytic activity and selectivity are
important for facilitating further catalyst design. eral studies[31–36] on the ATH of aromatic ketones
Ru(II) and Rh(III) half-sandwich complexes are gen- using the [{RhCl2Cp*}2]-aminoindanol or monotosy-
This result appeared to be in discrepancy with sev-
ACHTREUNG
erally thought to form active catalysts for ATH when lated diamine system, where results matching those
combined with 1,2-amino alcohols or monotosylated obtained using the corresponding ruthenium precur-
1,2-diamines, containing a basic primary or secondary sor were achieved. Herein we describe how the highly
amino group in the b-position to a relatively acidic modular nature of pseudodipeptides can be used for
OH or NH group.[23] N-Boc-protected amino acid hy- fine-tuning of the ligand structure, which has eventu-
droxyamide (in our previous papers and later on in ally lead to rhodium catalysts giving high conversion
this study referred to as pseudodipeptide) ligands and excellent enantioselectivity in the ATH of aro-
(1)[24–29] previously developed by us represent a differ- matic ketones.
ent class of ligands without an explicit basic nitrogen
center. Instead, we have demonstrated that alkali ions
play a crucial role in the hydrogen transfer step em-
ploying catalysts derived from such ligands.[30] Hence,
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Rhodium-Catalyzed Asymmetric Transfer Hydrogenation of Aryl Alkyl Ketones
Results and Discussion
Ligand Screening
Ligand Synthesis
We decided to exploit the highly modular nature of
pseudodipeptides in order to investigate if fine-tuning
The pseudodipeptide ligands were prepared in a of the ligand structure can significantly improve the
straightforward fashion from vicinal amino alcohols performance of the [{RhCl2Cp*}2]-pseudodipeptide
and N-protected amino acids (Scheme 1) according to catalytic system in the ATH of acetophenone. First,
we studied the catalytic system using the first-genera-
tion pseudodipeptides 1–8 (Table 1). A considerably
more pronounced matched-mismatched behavior of
the ligands in terms of enantioselectivity was ob-
served using the rhodium system as compared to the
ruthenium counterpart. For example, diastereomeric
ligand pairs 1, 2 and 3, 4 gave around 95% ee in com-
bination with [{RuCl2(p-cymene)}2], whereas signifi-
A
Scheme 1.
cantly different enantioselectivities were achieved
using the [{RhCl2Cp*}2] catalyst precursor (Table 1).
The bulkier substituents on the amino acid moiety,
the larger was the difference in ee obtained on going
the procedure described previously.[25] Ligands based from one diastereomer to another. Enantioselectivi-
on amino acid derivatives have previously been stud- ties up to 88% were achieved using the leucine- and
ied by several different research groups in transfer hy- phenylalanine-derived ligands 7 and 8. As observed in
drogenation processes.[37–49]
the Ru case, the absolute configuration of the product
phenylethanol, appeared to be strongly influenced by
Table 1. Effect of structural variations in the first generation pseudodipeptides on the performance of the [{RhCl2Cp*}2]-
pseudodipeptide-catalyzed ATH of acetophenone.[a]
Entry
Ligand
Time [h]
Conversion [%][b]
ee [%][b]
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
2
2
2
2
2
2
2
2
37
10
86
42
56
42
79
62
76 (S)
24 (S)
81 (S)
71 (S)
82 (S)
9 (S)
88 (S)
88 (S)
[a]
Reaction conditions: acetophenone (1 equiv., 0.2M in 2-propanol), [{RhCl2Cp*}2] (0.5 mol%), ligand (1.1 mol%) and
i-PrONa (5 mol%), room temperature.
Conversion and enantioselectivity were determined by GLC (CP Chirasil DEXCB).
[b]
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Table 2. Effect of structural variations in the second generation pseudodipeptides on the performance of the [{RhCl2Cp*}2]-
pseudodipeptide-catalyzed ATH of acetophenone.[a]
Entry
Ligand
Time [h]
Conversion [%][b]
ee [%][b]
1
2
3
4
5
6
7
8
9
0.5[c]
0.5
2
2
2
2
78
41
84
81
68
84
88
89
81
84
79
44
25
31
92 (S)
30 (S)
96 (S)
95 (S)
94 (S)
92 (S)
96 (S)
95 (S)
92 (S)
92 (S)
88 (S)
29 (S)
22 (S)
62 (R)
10
11
12
13
14
15
16
17
18
19
20
21
22
2
0.5[c]
9
2
10
11
12
13
14
0.5[c]
2
2
2
2
[a]
Reaction conditions: acetophenone (1 equiv., 0.2M in 2-propanol), [{RhCl2Cp*}2] (0.5 mol%), ligand (1.1 mol%) and
i-PrONa (5 mol%), room temperature.
Conversion and enantioselectivity were determined by GLC (CP Chirasil DEXCB).
The reaction time had to be decreased due to higher reaction rates leading to a relatively fast achievement of the equilib-
rium product concentration (ca. 91%) and, hence, erosion of the ee.
[b]
[c]
the configuration of the amino acid moiety in the and isoleucine, valine, phenylalanine and phenylgly-
ligand. Thus, the S-isomer was obtained regardless of cine, respectively. The use of the second generation li-
the configuration on the stereogenic center present in gands resulted in more active catalysts as compared
the amino alcohol region.
to their first generation congeners, and in several
More promising results both in terms of conversion cases significantly shorter reaction times were re-
and enantioselectivity were obtained using the second quired for arriving at high conversions. The increase
generation pseudodipeptides 9–22 (Table 2). Enantio- of steric bulkiness of the substituents in the a-position
selectivities up to 96% were achieved using ligands of the amino acid moiety led to a drop in catalytic ac-
11, 12, 15, 16 prepared from (S)-1-amino-2-propanol tivity. The use of ligands derived from (S)-2-amino-1-
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Rhodium-Catalyzed Asymmetric Transfer Hydrogenation of Aryl Alkyl Ketones
Table 3. Effect of additives on the [{RhCl2Cp*}2]-pseudodipeptide-catalyzed ATH of acetophenone.[a]
Entry
Ligand
Additive
Time [h]
Conversion [%][b,c]
ee [%][b,c]
1
2
3
4
5
6
7
8
9
9
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
LiOAc
15-crown-5
t-BuOK[d]
0.5[c]
0.5
2
2
2
2
2
2
2
84 (78)
75 (41)
88 (79)
72 (44)
90 (86)
81 (42)
89 (84)
80
88 (92, S)
54 (30, S)
80 (88, S)
17 (29, S)
73 (81, S)
70 (71, S)
89 (96, S)
92 (S)
10
19
20
3
4
11
11
11
11
39
77
83 (S)
95 (S)
10
2
[a]
Reaction conditions: acetophenone (1 equiv., 0.2M in 2-propanol), [{RhCl2Cp*}2] (0.5 mol%), ligand (1.1 mol%) and i-
PrONa (5 mol%), room temperature.
Conversion and enantioselectivity were determined by GLC (CP Chirasil DEXCB).
The corresponding conversion and enantioselectivity obtained without additives are presented in parentheses.
t-BuOK (5 mol%) was used as base instead of i-PrONa.
[b]
[c]
[d]
phenylethanol (17–20) resulted in slightly lower enan- “standard” catalytic set-up (i.e.. no additional addi-
tioselectivity (Table 1). Surprisingly, ligand 21 for tives) showed no influence on the product enantiose-
which the phenyl substituents on the amino alcohol lectivity. We can therefore conclude that chloride ions
part were expected to act in a complimentary fashion are not directly involved in the enantiodiscriminating
(cf. ligands 5 and 18) gave a considerably lower con- step.
version and enantioselectivity as compared to the
The use of t-BuOK as a base only slightly decreases
seemingly doubly mismatched ligand 22.
enantioselectivity, whereas complexation of sodium
Modification of the [{RhCl2Cp*}2]-pseudodipeptide by 15-crown-5 led to a dramatic drop of conversion
catalytic system with LiCl was attempted in order to and enantioselectivity (Table 3, entries 9 and 10).
increase enantioselectivity of the process as was previ- Thus, “un-coordinated” sodium ions seem to be opti-
ously observed with the analogous [{RuCl2(p- mal for efficient enantiodiscrimination by the active
G
cymene)}2] catalyst. Unexpectedly, an opposite behav- complex.
ior was observed with the Rh system. Addition of
LiCl to the system led to a significant decrease in
enantioselectivity when matched ligands were used, Substrate Scope
and the opposite was true for mismatched ligands
(Table 3 entries 1–7). Such a deviation in the behavior To assess the practical usefulness of the catalytic
of the Rh and Rucatalytic systems might be due to
such intrinsic differences between [{RhCl2Cp*}2] and in ATH in 2-propanol employing the [{RhCl2Cp*}2]-
[{RuCl2(p-cymene)}2] as a higher oxidation state of ligand 15 catalytic system (Table 4), which gave the
system, we evaluated a number of different substrates
ACHTREUNG
rhodium and (or) the presence of the negatively best results in ATH of acetophenone (see above).
charged aromatic Cp* ligand in the Rh complex. High isolated yields and enantioselectivities up to
These factors may be disadvantageous for the enan- 98% were obtained for most of the substrates studied.
tiodiscrimination in the transition state involving Li Particularly good results were achieved in the case of
ions. To rule out that the observed behavior of the electron-deficient ketones (entries 1–6). Substrates
catalytic system upon lithium chloride addition is not with electron-releasing substituents provided the
an effect of the halide anion, we performed reduc- same level of enantioselectivity, though the conver-
tions in the presence of lithium acetate (Table 3, sions in most cases were somewhat lower due to less
entry 8). The addition of LiOAc resulted in slightly favorable position of the equilibrium in reduction
lower conversion to, and enantiomeric excess of 1- with 2-propanol (entries 10–12).
phenylethanol, hence in line with the above observa-
4-Cyanoacetophenone reacted significantly slower,
tions for LiCl additions. This result is further strength- as compared to other electron-deficient ketones, and
ened by the fact that addition of silver triflate to the provided low enantioselectivity (entry 7). This behav-
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Table 4. Substrate scope of the [{RhCl2Cp*}2]-catalyzed transfer hydrogenation using pseudodipeptide 15 as ligand.[a]
Entry
Ar
Alk
Time [h]
Conversion [%][b]
Isolated yield [%]
ee [%][b]
1
2
3
4
5
6
7
8
3’-CF3-C6H4
4’-CF3-C6H4
3’-Br-C6H4
4’-Br-C6H4
2’-F-C6H4
3’-Pyridyl
4’-CN-C6H4
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Et
2
2
1
2
2
2
2
2
2
2
2
2
98
93
93
98
72
96
48
72
63
57
75
46
83
87
91
93
63
95
-
71
58
53
74
-
96 (S)
95 (S)
97 (S)
94 (S)
90 (S)
94 (S)
61 (S)
97 (S)
95 (S)
97 (S)
98 (S)
95 (S)
9
Ph
10
11
12
4’-Me-C6H4
3’-MeO-C6H4
3’,4’-dimethoxyphenyl
Me
Me
Me
[a]
Reaction conditions: acetophenone (1 equiv., 0.2M in 2-propanol), [{RhCl2Cp*}2] (0.5 mol%), ligand (1.1 mol%) and
i-PrONa (5 mol%), room temperature.
Conversion and enantioselectivity were determined by GLC (CP Chirasil DEXCB).
[b]
ior might be due to a relatively high affinity of the In the monohydridic route, the intermediate metal hy-
cyano substituent to the rhodium center, which can dride forms via abstraction of a hydrogen atom from
compete with the substrate carbonyl group and the the carbon on the donor, and the hydride is subse-
pseudodipeptide ligand in coordination to the active quently transferred exclusively to the carbonyl carbon
catalyst. The occurrence of such coordination obvi- of the acceptor. When the dihydridic route is operat-
ously leads to the formation of less selective catalytic ing, the hydrogen atoms which are transferred from
species. Attempts to reduce alkyl alkyl ketones result- the donor completely loose their identity since both
ed in poor conversion and in low stereoselectivity. the “hydride” and the “proton” end up coordinating
Thus, the quest to find an efficient and selective cata- to the metal. Consequently, the transfer of hydrides
lyst system for this considerably more challenging from the intermediate metal dihydride to the acceptor
substrate class remains.
occurs with complete scrambling and no prediction on
the origin of a specific hydrogen atom can be made.
To investigate which of the two proposed mecha-
nisms is operating in the [{RhCl2Cp*}2]-pseudodipep-
tide catalyst system, we performed a number of ex-
Mechanistic Considerations
Transition metal-catalyzed hydrogen transfer reac- periments using deuterium-labeled 2-propanol. In an
tions are typically progressing via either of two differ- initial experiment we carried out the reduction of ace-
ent hydridic mechanisms, the monohydridic route tophenone in fully deuterium labeled 2-propanol,
(Scheme 2a) or the dihydridic route (Scheme 2b).[50] which resulted in the incorporation of deuterium in
the former carbonyl carbon as well as in the a-methyl
group of the substrate. The incorporation of deuteri-
um atoms in the methyl group is probably the result
of a simple acid-base reaction involving the inter-
mediate enol or enolate of the ketone. The deuterium
exchange in the a-methyl group turned out to be
problematic, since that particular methyl group is the
natural “1H NMR marker” to which the level of deu-
terium or hydrogen addition to the carbonyl carbon is
compared. The analysis of the reaction outcome using
differently deuterium-labeled 2-propanols would
therefore be significantly more difficult when such a
“side-reaction” can occur. To overcome this problem
we instead performed transfer hydrogenations on 3’-
Scheme 2. Reaction outcome in transfer hydrogenations. a)
Monohydridic route. b) Dihydridic route.
methoxyacetophenone. This particular substrate con-
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Rhodium-Catalyzed Asymmetric Transfer Hydrogenation of Aryl Alkyl Ketones
tains an additional methyl group in which no deuteri- the corresponding [{RuCl2(p-cymene)}2] system. How-
N
um exchange can take place, and a simple analysis of ever, in each of the systems there are different struc-
the reaction outcome can therefore accurately be tural requirements on the ligand for obtaining high cat-
made even if deuterium atoms end up in the a-methyl alytic activity and selectivity. The addition of lithium
group of the substrate. Thus, when 3’-methoxyaceto- salts to the rhodium catalytic system causes a decrease
phenone was subjected to the reduction using the in enantioselectivity with matched ligands, which is in
[{RhCl2Cp*}2]-pseudodipeptide catalyst system in 2- contrast to the behavior of the ruthenium counterpart.
propanol-d8 we obtained, as expected, a product with In comparison to other catalytic transfer hydrogena-
the exclusive incorporation of deuterium in the tions systems based on [{RhCl2Cp*}2] (i.e., protocols
former carbonyl group (Scheme 3a).[51] Changing the using 1,2-aminoindanol or TsCYDN/TsDPEN ligands)
with 2-propanol as hydrogen source, the herein de-
scribed method gives better enantioselectivity than the
1,2-aminoindanol protocol for the reduction of aryl
alkyl ketones. Moreover, the use of pseudodipeptide li-
gands gives catalysts with significantly higher activity
in comparison to the TsCYDN/TsDPEN system. The
high modularity of the pseudodipeptide ligand system,
along with the low cost for ligand production repre-
sents additional advantages. In conclusion, the
[{RhCl2Cp*}2]-pseudodipeptide catalytic system, which
operates via the monohydridic route, has a wide sub-
strate scope that allows for high conversions and enan-
tioselectivities in ATH of various aromatic ketones in
Scheme 3. Deuterium incorporation into 3’-methoxyaceto-
2-propanol.
phenone. a) Reaction performed in 2-propanol-d8. b) Reac-
tion performed in 2-PrOD.
solvent to 2-propanol-d1 where the only deuterium is Experimental Section
situated on the hydroxy group (2-PrOD), otherwise
keeping the reaction conditions unchanged, resulted General Procedure for the Synthesis of Ligands 1–22
in the almost exclusive formation (>98%) of a prod-
uct containing a hydrogen atom on the former car-
bonyl carbon (Scheme 3b). The absence of deuterium
N-Methylmorpholine (NMM, 1.1 mmol) and isobutyl chloro-
formate (1 mmol) were slowly added to a solution of N-
Boc-amino acid (1 mmol) in THF (5 mL) cooled to À158C
incorporation on the carbonyl carbon in the latter ex-
periment strongly suggests that the reaction follows
the monohydridic route. We can therefore conclude
that the ketone reduction occurs via a hydride trans-
fer from the rhodium metal and a proton or alkali
transfer from the ligand (cf. the mechanistic sugges-
tion presented in ref.[32]). Attempts to isolate rhodium
complexes containing pseudodipeptide ligands have
so far been unsuccessful and we cannot therefore pro-
vide further details on the catalyst structure.
(a white solid was formed upon the addition of i-BuO-
COCl). The reaction mixture was stirred for 1 h at À158C,
and then an amino alcohol (1 mmol) was added and the re-
sulting mixture was stirred at room temperature for an addi-
tional 3 h. The mixture was filtered through a plug of silica
(3”4 cm) and eluted with ethyl acetate (80 mL). The solvent
was evaporated under vacuum to give a pure product. For
spectroscopic characterization of the synthesized ligands see
refs.[25,26, 29]
General Procedure for the Transfer Hydrogenation of
Ketones Employing Ligands 1–22
Conclusions
Ligand (0.011 mmol) and [{RhCl2Cp*}2] (0.005 mmol) were
dried under vacuum in a dry Schlenk tube for 15 min. 2-
We have demonstrated that the modular nature of Propanol (4.5 mL), substrate (1 mmol) and a 0.1M solution
of i-PrONa (0.5 mL, 5 mol%) in i-PrOH were added under
nitrogen. The reaction mixture was stirred at ambient tem-
perature. Aliquots were taken after the reaction times indi-
cated in the Tables and were then passed through a pad of
silica using EtOAc as eluent. The resulting solutions were
analyzed by GLC (CP Chirasil DEXCB). The isolated
yields were obtained from reactions performed on a 5-mmol
scale of substrate. Column chromatography on silica was
used for isolation of the reaction products. For chromato-
graphic and spectroscopic characterization of the reaction
pseudodipeptides effectively could be used for fine-
tuning of the structure of novel rhodium catalysts, and
thereby obtain a highly selective ATH process for aro-
matic ketones in 2-propanol. High conversions (iso-
lated yields) and enantioselectivities up to 98% were
obtained using the [{RhCl2Cp*}2] catalyst precursor in
combination with pseudodipeptide ligands derived
from (S)-1-amino-propan-2-ol and isoleucine, valine,
phenylalanine or phenylglycine, respectively. The per-
formance of the rhodium system is comparable with products see refs.[25, 26,29]
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[26] A. Bøgevig, I. M. Pastor, H. Adolfsson, Chem. Eur. J.
2004, 10, 294.
Acknowledgements
[27] P. Västilä, J. Wettergren, H. Adolfsson, Chem.
The Swedish Research Council, the Carl Trygger Foundation
and the Wenner-Gren Foundations are thanked for financial
support and postdoctoral fellowship, respectively.
Commun. 2005, 4039.
[28] A. S. Y. Yim, M. Wills, Tetrahedron 2005, 61, 7994.
[29] J. Wettergren, A. Bøgevig, M. Portier, H. Adolfsson,
Adv. Synth. Catal. 2006, 348, 1277.
[30] P. Västilä, A. B. Zaitsev, J. Wettergren, T. Privalov, H.
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2562
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Adv. Synth. Catal. 2007, 349, 2556 – 2562