Chiral phosphoric acid catalyzed enantioselective transfer hydrogenation of ortho-hydroxybenzophenone N-H ketimines and applications

Article abstract of DOI:10.1002/chem.201101694

Unprotected synthesis: The first enantioselective chiral phosphoric acid catalyzed transfer hydrogenation of unprotected ortho-hydroxybenzophenone N-H imines by using a Hantzsch ester as the hydrogen source afforded the corresponding chiral N,O-unprotected ortho-hydroxydiarylmethylamines in high yields with excellent enantioselectivities (see scheme).

Full text of DOI:10.1002/chem.201101694

DOI: 10.1002/chem.201101694
Chiral Phosphoric Acid Catalyzed Enantioselective Transfer Hydrogenation
À
of ortho-Hydroxybenzophenone N H Ketimines and Applications
Thanh Binh Nguyen,[a] Qian Wang,*[a, b] and FranÅoise Guꢀritte[a]
Enantiomerically pure diarylmethylamines are important
substructures found in a variety of biologically active com-
pounds.[1,2d] They are generally obtained by the chiral auxili-
ary or chiral ligand-based Rh-catalyzed addition of organo-
metallic reagents to imines.[2–4] Although many highly enan-
tioselective hydrogenations of various imines are known,[5,6]
the enantioselective reduction of substituted benzophenone
imines has been rarely studied. A notable exception is the
iridium-catalyzed asymmetric high-pressure hydrogenation
Table 1. Survey of reaction conditions for the enantioselective transfer
hydrogenation of imine 2a.[a]
À
(at 1500 psi) of ortho-substituted benzophenone N H imines
developed by Zhang and Gosselin et al.[6d]
Entry
Cat.
R
Solvent
T
[8C]
Yield
ee
[%][b]
Very recently, we have reported an enantioselective chiral
phosphoric acid catalyzed transfer hydrogenation of unpro-
tected ortho-hydroxyaryl alkyl N H ketimines and N-aryl
ortho-hydroxybenzophenone ketimines using a Hantzsch
ester as the hydrogen source.[7] Herein, we describe the first
organocatalytic enantioselective transfer hydrogenation of
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
Et
benzene
benzene
benzene
benzene
toluene
CHCl3
50
50
50
50
50
50
50
50
50
60
40
RT
60
60
50
50
94
92
96
96
92
88
60
16
8
99
83
56
80
88
80
30
20
38
56
96
90
80
90
94
87
91
92
91
91
91
90[c]
85[d]
À
THF
MeCN
À
unprotected ortho-hydroxybenzophenone N H ketimines
using chiral phosphoric acid catalysts and a Hantzsch ester
9
acetone
benzene
benzene
benzene
benzene
benzene
benzene
benzene
as the hydrogen source.[8–12]
10
11
12
13
14
15
16
A survey of reaction conditions was carried out using the
N H imine 2a as a model substrate. The screening of the
À
phosphoric acid catalysts was performed in benzene at 508C
(Table 1, entries 1–4). Several phosphoric acids with differ-
ent substituents at the 3- and 3’-positions of the binaphthyl
scaffold were tested. High reactivity was observed for all the
catalysts screened. The best enantiomeric excess (ee, 96%;
Table 1, entry 4) was obtained with catalyst 1d (X=SiPh3).
The other catalysts screened did not afford satisfactory re-
sults with respect to the enantioselectivity (Table 1, en-
tries 1–3). We next investigated the effects of the solvents.
Non-coordinating solvents (such as toluene and chloroform)
Me
tBu
tBu
[a] Reaction conditions: imine (2a, 0.5 mmol), Hantzsch ester
(0.65 mmol), catalyst 1 (0.05 mmol) in solvent (5 mL) for 16 h. [b] Deter-
mined by chiral HPLC analysis. [c] The reaction was carried out with 5%
of 1d. [d] The reaction was carried out with 1% of 1d.
afforded amine 3a with complete imine conversion and
good enantioselectivities (Table 1, entries 5 and 6), but ben-
zene stood out as the solvent of choice (entry 4). A signifi-
cant drop of reaction rate was observed with coordinating
solvents (such THF, MeCN, and acetone; Table 1, entries 7–
9). A decrease in catalyst loading (from 10 to 1%) resulted
in slight loss in enantioselectivity and a decrease of yield
(Table 1, entries 15 and 16). Increasing or lowering the tem-
perature diminished the enantioselectivity of the reaction.
With the above optimized conditions (1.3 equiv of
Hantzsch di-tert-butyl ester and 10% of 1d in benzene at
508C), we investigated the scope of this reduction using a
variety of different substituted ortho-hydroxybenzophenone
[a] Dr. T. B. Nguyen, Dr. Q. Wang, Dr. F. Guꢀritte
Centre de Recherche de Gif
Institut de Chimie des Substances Naturelles
CNRS, 91198 Gif-sur-Yvette cedex (France)
Fax : (+33)169077247
E-mail: qian.wang@icsn.cnrs-gif.fr
[b] Dr. Q. Wang
Institute of Chemical Sciences and Engineering
Ecole Polytechnique Fꢀdꢀrale de Lausanne (EPFL)
EPFL-SB-ISIC-LSPN-1015 Lausanne (Switzerland)
Fax : (+41)21-693-9740
E-mail: q.wang@epfl.ch
À
À
N H imines (Table 2). These N H imines are easily pre-
pared in quantitative yield in all cases by saturating a solu-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101694.
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Chem. Eur. J. 2011, 17, 9576 – 9580

COMMUNICATION
Table 2. Chiral phosphoric-acid-catalyzed transfer hydrogenation of
heating at higher temperature. On the contrary, ortho substi-
tution on ring B had no noticeable influence on the course
of the reduction (Table 2, entry 11).
ortho-hydroxybenzophenone ketimines 2.[a]
The absolute configuration of amine 3a was determined
to be S by comparing the sign of its optical rotation with
that of the known amine (see the Supporting Information
for details).
The imine function in 2 was stabilized by intramolecular
hydrogen bonding with the ortho-hydroxy group.[14,15] To ex-
plain the observed enantioselectivity, a model of the seven-
membered cyclic complex formed between phosphoric acid
1d and 2a was proposed (Figure 1).[13,16] The Si face of the
Entry
Amine
R’
R
Yield
[%][b]
ee
[%][c]
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
H
H
H
H
H
H
H
H
H
96
83
90
86
83
84
81
85
90
85
84
91
80
88
87
89
85
89
87
90
91
80
86
82
82
96
91
97
93
93
93
98
92
90
92
91
92
98
>99
99
88
93
96
90
99
93
98
96
93
99
4’-Me
4’-Ph
4’-Cl
4’-OPh
4’-NO2
4’-CO2Me
3’-Me
3’-OMe
3’-NO2
2’-F
H
H
H
H
H
H
H
H
9
H
H
H
10
11
12[d]
13
14
15
16
17
18
19
20
21
22
23
24
25
3-Me
4-Me
4-Ph
4-F
5-Me
5-Ph
5-Br
5-OMe
5-NO2
5-Bz
4-Me
5-Me
5-Br
H
3s
3t
H
H
3u
3v
3w
3x
3y
Figure 1. Proposed transition state for the enantioselective transfer hy-
drogenation of imine.
4’-Cl
4’-Ph
3’-Me
3’,4’-(CH)4
[a] Reaction conditions: imine (2, 0.5 mmol), Hantzsch di-tert-butyl ester
(0.65 mmol), catalyst (0.05 mmol) in benzene (5 mL) for 72 h. [b] Deter-
mined by 1H NMR spectroscopic analysis. [c] Determined by chiral
HPLC analysis. [d] The reaction was performed at 608C for 96 h.
imine was shielded by the lower SiPh3 group, thus prevent-
ing attack of the Hantzsch dihydropyridine. The Re face was
only shielded on the side of ring B but not on the side of
ring A. Moreover, due to a possible formation of an addi-
À
tional hydrogen bond between the H N of the dihydropyri-
tion of ortho-hydroxybenzophenone in methanol with am-
monia at room temperature.[13–15] All the ortho-hydroxyben-
dine and the phosphate oxygen (P=O) of 1d, approach of
the Hantzsch dihydropyridine on the side of ring A toward
the Re face could be highly favored leading to observed (S)-
3 enantiomer.[16b] The side A approach is also in agreement
with lower reactivity of the 3-substituted imine 2l (Table 2,
entry 12) compared with imines substituted on other posi-
tions.
À
zophenone N H imines we prepared were quite stable at
room temperature and existed exclusively as the E isomer
due to the presence of an intramolecular hydrogen bond
À
À
(O H···N; d=13.3–15.6 ppm in CDCl3). These N H imines
with different substituents in ring A (Table 2, entries 12–21)
and in ring B (Table 2, entries 1–11 and 25), or in both rings
(Table 2, entries 22–24) were reduced efficiently to provide
the corresponding diarylmethylamines in excellent yields (80
to 91%) and enantioselectivities (ee values from 88 up to
>99%, Table 2). Functional groups (such as OMe, OPh, F,
Cl, Br, NO2, CO2Me, and PhCO, Table 2) were all well toler-
ated, independent of their electronic nature and positions. It
is worth noting that the nitro group was perfectly stable
under these conditions. The presence of these functionalities
provided unique opportunity for the further structural elab-
orations. The reduction was slower when another ortho posi-
tion of the OH group was substituted by a methyl group
(Table 2, entry 12; under the same conditions at 508C, the
conversion is less than 10%). However, a satisfactory yield
and ee value could be obtained in this case by prolonged
The presence of the o-hydroxy group in 3 is very useful
for further synthetic elaborations as demonstrated in
Scheme 1. The palladium-catalyzed deoxygenation of 3d via
the intermediate triflate 4b gave rise to (R)-5 in 68% yield
(92% ee), which is a useful precursor for the synthesis of
enantiomerically pure levocetirizine, a non-sedating hista-
mine H1-receptor antagonist used for the treatment of aller-
gies.[17]
The palladium-catalyzed conversion of triflate 4a to isoin-
dolinone illustrated further the synthetic utility of chiral
amine 3. Using Mo(CO)6 as carbon monoxide source in the
presence of a Pd catalyst, 4a was transformed directly to the
isoindolinone (S)-6 (65% yield, 93% ee) through a sequence
of carbonylation/amidation.[18] It is worth noting that only
fewer catalytic enantioselective syntheses of isoindolinone
Chem. Eur. J. 2011, 17, 9576 – 9580
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9577

Q. Wang et al.
prepared by mixing the amine with a few drops of a solution of HCl
(1m) in ether and then evaporating in vacuo. HPLC analyses were
carried out in the acetamide derivative, which was prepared by
mixing a solution of the amine in Et2O with a few drops of Ac2O and
then evaporating all the volatiles.
(S)-3-Phenylisoindolin-1-one ((S)-6): Under argon, Tf2O (168 mL,
282 mg, 1 mmol) was added dropwise to a solution of 3a (199 mg,
1 mmol, 96% ee) and NEt3 (138 mL, 101 mg, 1 mmol) in THF (10 mL)
at À788C. The resulting solution was stirred at this temperature for
5 min before being warmed up to RT then transferred to a tube
under argon containing Mo(CO)6 (532 mg, 2 mmol), PdACHTUNGTRENNUNG(OAc)2
(11 mg, 0.05 mmol), dppp (41 mg, 0.1 mmol), and NEt3 (207 mL,
152 mg, 1.5 mmol). The tube was sealed and heated at 608C for 6 h
then cooled to RT and opened carefully. The volatiles were removed
in vacuo. The residue was purified by silica gel flash column chroma-
tography (heptane/AcOEt 1:1) to afford the desired product as white
crystals (136 mg, 65%).
Scheme 1. Synthetic applications of diarylmethylamine 3a and 3d.
have been developed in spite of its widespread occurrence
in natural substances and pharmaceutically interesting mole-
cules.[19] We emphasize that the erosion of the ee value re-
mained minimal in both the palladium-catalyzed transforma-
tions shown in Scheme 1.
Acknowledgements
Financial support from CNRS and ICSN are gratefully acknowledged.
T.B.N. thanks ICSN for a postdoctoral fellowship. We thank the HPLC
service of ICSN for technical assistance.
In summary, we have developed the first metal-free highly
enantioselective chiral phosphoric acid-catalyzed reduction
À
of unprotected ortho-hydroxybenzophenone N H imines
using a Hantzsch ester as the hydrogen source.[20] The reduc-
tion tolerated a wide range of substituents with different
electronic properties leading to the ortho-hydroxydiarylme-
thylamines in high yields with excellent enantioselectivities.
We also demonstrated that the presence of the ortho-hy-
droxy group provided an invaluable handle for further trans-
formations offering a simple route to medicinally relevant
compounds. Further investigation of the reaction mechanism
and the extension of the reaction scope are currently ongo-
ing in our laboratory.
Keywords: amines · chirality · enantioselectivity · Hantzsch
ester · hydrogenation · phosphoric acid
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Experimental Section
General procedure for enantioselective reduction of imines 2a–y: A
20 mL tube equipped with a magnetic stir bar was charged with imine
(0.5 mmol, 1.0 equiv), Hantzsch di-tert-butyl ester (200 mg, 0.65 mmol,
1.3 equiv), catalyst 1d (43 mg, 10 mol%) and benzene (5 mL). The tube
was flushed with argon, closed, and heated with stirring at 508C for 72 h.
The crude product was directly purified by silica gel column chromatog-
raphy (hexane/AcOEt) to yield the title compound.
(R)-(4-Chlorophenyl)
ACHTUNGTRENNUNG
(168 mL, 282 mg, 1 mmol) was added dropwise to
a
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(234 mg, 1 mmol, 93% ee) and NEt3 (138 mL, 101 mg, 1 mmol) in THF
(10 mL) at À788C. The resulting solution was stirred at this temperature
for 5 min then warmed up to RT. The solvent was then removed in
vacuo. The residue was dissolved in DMF (10 mL) with PdACTHNUTRGNEUNG(OAc)2
(11 mg, 0.05 mmol), 1,3-bis(diphenylphosphino)propane (dppp, 41 mg,
0.1 mmol), NEt3 (1,38 mL, 1,10 g, 10 mmol) and HCOOH (380 mL,
460 mg, 10 mmol). The resulting mixture was heated at 508C for 2 h,
cooled to RT then partitioned between an aqueous solution of NaOH
(5%, 10 mL) and AcOEt (20 mL). The organic layer was separated, the
aqueous layer was extracted with AcOEt (2ꢂ20 mL). The combined or-
ganic layers were dried (Na2SO4) and concentrated in vacuo. The residue
was purified by silica gel flash column chromatography (heptane/AcOEt
1:1 to pure AcOEt) to afford the desired product as a colorless liquid
(145 mg, 67%). This product absorbed rapidly carbon dioxide from the
air, therefore the NMR spectra was recorded for the HCl salt, which was
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Enantioselective Transfer Hydrogenation
COMMUNICATION
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Received: June 2, 2011
Published online: July 29, 2011
9580
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Chem. Eur. J. 2011, 17, 9576 – 9580