Highly enantioselective asymmetric transfer hydrogenation (ATH) of α-phthalimide ketones

Article abstract of DOI:10.1039/c5ob00568j

A mild catalyst system for the synthesis of chiral amino alcohols via asymmetric transfer hydrogenation (ATH) of α-phthalimide ketones has been developed by using a chiral Ru-TsDPEN complex as the catalyst in DMF/MeOH at 40 °C. The reaction exhibits high reaction activity and excellent enantioselectivity where up to 96% yield and 99% ee of the product were obtained.

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Organic & Biomolecular Chemistry
Cite this: DOI: 10.1039/x0xx00000x
Highly Enantioselective Asymmetric Transfer
Hydrogenation （ATH）of α-Phthalimide Ketones†
Received 00th January 2012,
Accepted 00th January 2012
Zhou Xu,*ab Yong Li,b Jing Liu,b Nan Wu,c Ke Li,b Songlei Zhuab, Rongli Zhanga ,
Yi Liu*b
DOI: 10.1039/x0xx00000x
www.rsc.org/
hydrogen. These advantages have even allowed the development of
interesting industrial processes.9
A mild catalyst system for the synthesis of chiral amino alcohols
via asymmetric transfer hydrogenation (ATH) of α-phthalimide
ketones has been developed by using a chiral Ru-TsDPEN
complex as the catalyst in DMF/MeOH at 40oC.The reaction
exhibits high reaction activity and excellent enantioselectivity
where up to 96% yield and 99% ee of the product was obtained.
Previous resluts:
a.
Introduction
Varieties of optical amino alcohols has been reported as important
compounds due to their special biologically activites.1 They can also
been used as chiral building blocks and ligands in a variety of
asymmetric reactions.2 Lots of stuides have been focused on the
development of efficient methods for the synthesis of chiral amino
alcohols.3 One of the preferred method is the selective reduction of
protected amino ketone derivatives due to their good stability. α-
Phthalimide ketones are such kinds of presubstrates which can be
conveniently transferred to α-primary amino alcohols.
b.
For examples, Zhang et.al first reported the asymmetric
hydrogenation of α-phthalimide ketones using Ru TunePhos-derived
complex with high enantioselectivity under high pressure of hydrogen
o
at 80 C (Scheme 1, L1).4 Lin et.al used the modified bisphosphine
(Scheme 1, L2) combing with Ru(II) to catalyze the reaction.5 Zhou
and co-workers reported a homogeneous palladium (R, R)-Me-
DuPhos (Scheme 1, L3) to catalyze the reaction where up to 92.2%
ee was achieved under 100 atm H2.6 While with the modification of
the (S)-TunePhos, Zhang et.al found that the modified TuenPhos L4
combined with Pd(II) could catalyze the reaction giving the
corresponding product with good to excellent ee at 80oC under high
pressure of hydrogen (Scheme 1, L4).7
This work:
Although good results have been achieved, all of these reactions are
catalytic enantioselective hydrogenations. The high pressure of the
reactions made them difficult to operate. In addition, all of the above
methods focused on the usage of disphosphrious ligands. In other
words, challenges still exisit, such as high reaction temperature, high
reaction pressure and so on. Developing safety, easy to handle and
highly enantioselective methods to prepare amino alcohols with
efficiency still in great demand.
In recent years, transition-metal catalyzed asymmetric transfer
hydrogenation (ATH) has gained much attention due to its versatility,
operational simplicity and safety.8 Without using explosive hydrogen
gas or moisture-sensitive hydride reagents, ATH reactions use a
hydrogen donor, such as HCOOH which is much safer than molecular
Scheme 1 Ligands used for the asymmetric reduction of α-
phthalimide ketone.
Hererin, we reported an asymmetric transfer hydrogenation (ATH)
reaction via asymmetric transfer hydrogenation (ATH) of α-
phthalimide ketones using HCOOH as hydrogen resource under very
mild reaction conditions which may sulpply an alternative method to
synthesze chiral amino alcohols.
Results and discussion
Initially, the reaction was carried out in DMF at 25oC using (1S, 2S)-
TsDPEN (Noyori ligand) as the ligand. However, no desired product
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f
g
was observed (Table 1, entry 1). To our delight, when the reaction DMF/MeOH (v/v, 4/1, 4 ml); DMF/MeOH (v/v, 3/1, 4 ml);
h
temperature was enhanced to 40oC, 67% isolated yield of the product DMF/MeOH (v/v, 5/1,
4
ml);
DMF/MeOH (v/v, 4/1),
with 95% ee was obtained (Table 1, entry 2). Futher increased the [Ru(cymene)Cl2]2 (15.2 mg, 0.025 mmol) and (1S, 2S)-Ts-DPEN
i
temperature to 60 oC has no significant effects on the reaction (Table (18.4 mg, 0.05 mmol) were used;
DMF/MeOH (v/v, 4/1),
1, entry 3).
[Ru(cymene)Cl2]2 (3.8 mg, 0.0063 mmol) and (1S, 2S)-Ts-DPEN (4.6
mg, 0.0125 mmol) were used.
Table 1 Optimization of the reaction condition. a
Ligands L6 and L7 which showed good activities on other
asymmetric transfer hydrogenation reactions were also studied.10
However, neither ligand L6 nor L7 can catalyze the reaction (Table 1,
entries 4-5). Thus, (1S, 2S)-TsDPEN (L5) was chosen as the best
ligand for further studies.
Firstly, solvent effects were considered. As can be seen from Table
1, this reaction was strongly solvent-dependent. When the reaction
was carried out in DMSO or THF, it needs longer reaction time than
in DMF (Table 1, entries 2, 6-7). Although the ee values were slightly
higher in DMSO, the yields were decreased dramatically. When
CH3CN and other moderate polarity solvents such as AcOEt, DCM
were chosen as the solvents, the reaction can hardly proceed (Table 1,
entries 8-10).
Entry
Solvent
L
T
(oC)
25
Time Yield
(h)
Ee
(%)c
-
(%)b
Interestingly, MeOH gave the highest ee, but it led to low activity
with only 46% yield (Table 1, entry 11). This may be due to the
solubility of the substrate in MeOH. The substrate can not
compeletely dissolve in 4 ml MeOH. Lowered the concentration of
the substrate to increase the solubiltiy of the substrate can improve the
yield to 82% (Table 1, entry 12). Unfortunately, the ee value was
DMF
DMF
L5
L5
L5
L6
L7
L5
L5
L5
L5
L5
L5
L5
L5
24
NR
1
2
40
60
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
30
30
30
30
72
72
24
24
24
72
72
48
48
72
72
72
54
120
67
69
95
95
-
DMF
3
i
decreased to 95%. Other alcohols, such as PrOH, CF3CH2OH were
DMF
NR
NR
35
4
also studied. None of them can improve the result (Table 1, entries
13-14). In this situation, mixture of MeOH and DMF was considered.
When the ratio of DMF/MeOH was 4/1 (v/v), it gave the best result.
The product can be obtained with 92% yield and 97% ee (Table 1,
entry 15-17).
Finally, catalyst loading was investigated. Increasing the catalyst
amount can shorten the reaction time with ee and yield kept, while
decreasing the catalyst amount required a significantly extended
reaction time for the complete consumption of 1a and thus resulted in
a lower yield (Table 1, entry 18-19).
Having established reaction conditions for highly enantioselective
transfer hydrogenation of substrate 1a, we next studied the substrate
scope. As can be seen from Table 2, both electron-deficient and
electron-rich aryl ketones could be converted to the corresponding
products with high yields and excellent enantioselectivities. To make
the reaction more practical, lower catalyst loading for the reaction was
also studied. When the loading of the catalyst decreased to only 1.25%,
the ATH reaction could still work well with yield and ee value kept
though it took longer reaction time (Table 2, entries 3-4).
Substrates bearing with different substituted group of R have
significant effects on the enantioselectivies of the products. Those
substrates with substituted group at the meta- position gave the
product with higher enantioselectivities than at the orth- or para-
position. For example, substrate 1b, which the R group bearing with
fluoro at the meta- position gave 94% ee of the corresponding product,
exhibiting higer ee than either orth- substituted substrate 1c or para-
substituted substrate 1d (Table 2, entries 3-6). The same phenomenon
was also observed between substrates 1e and 1f. When R was 3-
ClC6H5, 1e could convert into the product with 95% ee which was
much higher than 1f where R was 4-ClC6H5 showing 90% ee of
product (Table 2, entries 7-8). The same results were also happened
between substrates 1g and 1h (Table 2, entries 9-10).
DMF
-
5
DMSO
THF
96
96
-
6
51
7
CH3CN
EtOAc
DCM
MeOH
MeOH
iPrOH
NR
NR
NR
46
8
-
9
-
10
11
12d
13
14
15e
16f
17g
18h
19i
>99
95
-
82
trace
trace
92
CF3CH2OH L5
DMF/MeOH L5
DMF/MeOH L5
DMF/MeOH L5
DMF/MeOH L5
DMF/MeOH L5
-
97
97
95
97
97
90
92
91
87
a Reactions were performed with 1a (0.25 mmol), [Ru(cymene)Cl2]2
(7.6 mg, 0.0125 mmol) and (1S, 2S)-Ts-DPEN (9.2 mg, 0.0250 mmol)
in solvent (4 ml) under Ar;
Steric effects also have important effects on the reaction. With less
hinder group on the substrate, the corrosponding product can be
obained with much higher enantioselectivies. For example, substrate
1d with sustituted group fluoro atom on the orth position on the
benzen ring gave lower ee of the product which showed only 80% ee,
b
c
Yield after chromatography;
Enantiomeric excess was determined by HPLC using Chiracel IC
column. The absolute configuration was determinded to be R with
comparing to the literature;4-7
MeOH (10 ml) was used;
d
e
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while 1b or 1c which has less hinder group could give the product
with 94%, 93% respectively (Table 2, entries 4-6). Another example,
for substrate 1l where the R gruoup was 2-naphthyl which is
obviously less hinder comparing to substrate 1k, gave the product
with much higer ee (Table 2, entries 13-14).
For the aliphatic substituted α-phthalimide ketone 1m, the
reaction can proceed smoothly though the ee was not good (Table
2, entry 15).
Table 2 Scope of the reaction. a
Scheme 2 Synthesis of chiral amino alcohol 3a on gram scale.
Conclusions
In conclusion, we have developed highly efficient catalytic
enantioselective transfer hydrogenation reaction of α-phthalimide
ketones by a chiral Ru(II)/(1S, 2S)-Ts-DPEN complex, which provide
a facile access to the optically active amino alcohols in 65-96% yields
with 80-99% ee. The remarkable features of the method, such as
mild reaction conditions, simple procedure and broad substrate
scopes allow the practical asymmetric synthesis of chiral amino
molecules that are useful for further synthesis.
We are grateful for the financial support from the Natural Science
Foundation of Higher Education Institutions of Jiangsu Province,
China (No. 10KJB150018) and the Project of Science and Technology
of Xuzhou Government (No. XM12B012). The project was also
sponsored by Zhen Xing Project of Xuzhou Medical Collge.
Time
(h)
Yield
(%)b
92
Ee
(%)c
97
Entry
R
Substrate
1
2d
3
C6H5
C6H5
72
1a
1a
1b
1b
1c
1d
1e
1f
96
12
19
72
20
72
15
20
14
28
72
72
72
12
52
95
94
87
96
70
78
90
82
78
82
65
72
89
>99
94
94
93
80
95
90
97
91
92
98
91
95
25
m-FC6H5
m-FC6H5
p-FC6H5
o-FC6H5
m-ClC6H5
p-ClC6H5
m-BrC6H5
p-BrC6H5
p-IC6H5
4e
5
6
Notes and references
7
a
Department of Chemistry, Xuzhou Medical College, Jiangsu, Xuzhou,
8
221004, P.R. China.
b School of Pharmacy, Xuzhou Medical College, Jiangsu, Xuzhou, 221004,
9
1g
1h
1i
P.R. China.
c
Department of Chemistry, Xuzhou Airforce College, Jiangsu, Xuzhou,
10
11
12
13
14
15
221004, P.R. China.
E-mail: xuzhou@xzmc.edu.cn and zxu@chem.ucsb.edu
†
Electronic supplementary information (ESI) available: Experimental
1
procedures, HPLC spectra, H NMR and 13C NMR spectroscopic data of
all of the products and analytic data of the compound 3a are included. This
material is available free of charge via the Internet.
m-MeOC6H5
1-Naphthyl
2-Naphthyl
Methyl
1j
1k
1l
see DOI: 10.1039/c4cc07978g
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;
Yield after
b
c
chromatography; Enantiomeric excess was determined by HPLC
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Scheme 2 shows an example for a potential synthetic application
of the method to synthesis chiral amino alcohol in gram scale. The
starting materials 1a can be obtained easily and the reaction can run
on a gram scale with good yield. The hydrolysis of 2a in water at 60
oC gave the chiral amino alcohol 3a in 89% yield with 96% ee.
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