Chiral phosphoric acid-catalyzed enantioselective transfer hydrogenation of ortho-hydroxyaryl alkyl N - H ketimines

Article abstract of DOI:10.1021/ol102043x

The first enantioselective chiral phosphoric acid-catalyzed transfer hydrogenation of unprotected ortho-hydroxyaryl alkyl N - H ketimines using Hantszch di-tert-butyl ester as a reductant is reported. A variety of ortho-hydroxybenzylamines were obtained in good to excellent yields and enantiomeric excesses.

Full text of DOI:10.1021/ol102043x

ORGANIC
LETTERS
2010
Vol. 12, No. 20
4705-4707
Chiral Phosphoric Acid-Catalyzed
Enantioselective Transfer Hydrogenation
of ortho-Hydroxyaryl Alkyl N-H
Ketimines
Thanh Binh Nguyen, Hadjira Bousserouel, Qian Wang,* and Franc¸oise Gue´ritte
Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles,
CNRS, 91198 Gif-sur-YVette Cedex, France
qian.wang@icsn.cnrs-gif.fr
Received September 2, 2010
ABSTRACT
The first enantioselective chiral phosphoric acid-catalyzed transfer hydrogenation of unprotected ortho-hydroxyaryl alkyl N-H ketimines using
Hantszch di-tert-butyl ester as a reductant is reported. A variety of ortho-hydroxybenzylamines were obtained in good to excellent yields and
enantiomeric excesses.
Enantiomerically pure ortho-hydroxybenzylamines are an
important class of chiral ligands for transition metal mediated
and catalyzed processes1 and have been used as chiral
auxiliaries in asymmetric synthesis.2 In addition, they are
useful chiral building blocks for syntheses of natural products
and many pharmacologically active compounds.3 This family
of aminophenols is generally obtained by enzymatic4 or
chemical resolution5 of racemics or by diastereoselective
alkylation/reduction of imines.1b,2c,5,6 Although enantiose-
lective reduction of N-protected enamides, enamines, and
imines is well developed,7-10 only very few reports have
dealt with the reduction of N-H imines.8 Very recently,
Zhang and Gosselin et al. reported an iridium-catalyzed
asymmetric hydrogenation of the hydrochloride salt of N-H
imines at high pressure leading directly to R-chiral primary
amines in good to excellent ee’s.8c,d
Since the pioneering work of Terada and Akiyama, the chiral
binol-derived phosphoric acids have found wide applications
in the development of catalytic enantioselective transforma-
tions,10,11 including the enantioselective reduction of N-
(3) (a) Kogen, H.; Toda, N.; Tago, K.; Marumoto, S.; Takami, K.; Ori,
M.; Yamada, N.; Koyama, K.; Naruto, S.; Abe, K.; Yamazaki, R.; Hara,
T.; Aoyagi, A.; Abe, Y.; Kaneko, T. Org. Lett. 2002, 4, 3359. (b)
Weisenburger, G. A.; Anderson, D. K.; Clark, J. D.; Edney, A. D.; Karbin,
P. S.; Gallagher, D. J.; Knable, C. M.; Pietz, M. A. Org. Process Res. DeV.
2009, 13, 60. (c) Ahond, A.; Fournet, A.; Moretti, C.; Philogene, E.; Poupat,
C.; Thoison, O.; Potier, P. Bull. Soc. Chim. Fr. 1984, 1-2 (2), 41. (d)
Houghton, P. J. In Alkaloids; Brossi, A., Ed.; Academic Press: San Diego,
1987; Vol. 31, pp 67-100. (e) Houghton, P. J. Chemistry and Biological
Activity of Natural and Semi-synthetic Chromone Alkaloids. Nat. Prod.
Chem. 2000, 21, 123.
(1) (a) Schwenkreis, T.; Berkessel, A. Tetrahedron Lett. 1993, 34, 4785.
(b) Palmieri, G. Tetrahredron: Asymmetry 2000, 11, 3361. (c) Yang, X.-
F.; Hirose, T.; Zhang, G.-Y. Tetrahedron: Asymmetry 2009, 20, 415.
(2) (a) Yamazaki, N.; Ito, T.; Kibayashi, C. Org. Lett. 2000, 2, 465. (b)
Yamazaki, N.; Dokoshi, W.; Kikayashi, C. Org. Lett. 2001, 3, 193. (c)
Atobe, M.; Yamazaki, N.; Kibayashi, C. J. Org. Chem. 2004, 69, 5595.
(4) Vaijayanthi, T.; Chadha, A. Tetrahedron: Asymmetry 2008, 19, 93.
(5) Bernardinelli, G.; Fernandez, D.; Gosmini, R.; Meier, P.; Ripa, A.;
Schu¨pfer, P.; Treptow, B.; Ku¨ndig, E. P. Chirality 2000, 12, 529.
10.1021/ol102043x  2010 American Chemical Society
Published on Web 09/21/2010

protected imines.12 We report herein the first examples of
enantioselective transfer hydrogenation of unprotected ortho-
hydroxyaryl alkyl N-H ketimines using chiral phosphoric
acid as a catalyst and Hantzsch ester as the hydrogen source.
Table 1. Survey of Reaction Conditions for the Enantioselective
Transfer Hydrogenation of Imine 2aa
The ortho-hydroxyaryl alkyl N-H ketimines are synthesized
in quantitative yields by simply mixing ortho-hydroxyaryl alkyl
ketone with ammonia in methanol at room temperature.13 All
ortho-hydroxyaryl alkyl ketimines were quite stable at room
temperature and existed as one single E-isomer due to the
presence of an intramolecular H-bond (δOH ) 14.3-16.3 ppm).
Using 2a as a test substrate, the survey of reaction conditions
varying the solvents, the temperature, the structure of phosphoric
acids, and Hantzsch esters is shown in Table 1. The hindered
3,3′-bis(triphenylsilyl)-substituted phosphoric acid (S)-1d turned
out to be the most effective in terms of chirality transfer, and
benzene was a better reaction medium than other solvents
screened (Et2O, CHCl3, CH3CN, PhMe, entries 5-8). The
reaction temperature also played an important role. At room
temperature, the reaction went extremely slow (entry 9), while
at temperature higher than 60 °C, the reduction proceeded with
reduced enantioselectivity. A slight improvement of enantiose-
lectivity was observed when the Hantzsch di-tert-butyl ester
was used instead of diethyl ester (entry 11 vs 4). Overall, the
convn
entry
cat.
R
solvent
t (°C)
(%)b
ee (%)c
1
1a
1b
1c
1d
1d
1d
1d
1d
1d
1d
1d
1d
Et
PhH
60
60
60
60
60
60
60
60
rt
100
100
100
100
<5
20
54
60
89
-
71
74
83
-
87
90
92
2
Et
PhH
3
Et
PhH
4
Et
PhH
5
Et
Et2Od
CHCl3
CH3CN
PhMe
PhH
6
Et
100
100
100
<5
7
Et
8
Et
9
Et
10
11
12
Me
t-Bu
t-Bu
PhH
60
60
50
100
100
100
PhH
PhH
a Reaction conditions: imine (2a) (0.5 mmol), Hantzsch ester (0.65
mmol), catalyst (1) (0.05 mmol) in solvent (5 mL). b Determined by 1H
NMR analysis. c Determined by chiral HPLC analysis of the corresponding
acetamide. d The reaction was performed in a sealed tube.
(6) (a) Cimarelli, C.; Palmieri, G. Tetrahredron: Asymmetry 2000, 11,
2555. (b) Ku¨ndig, E. P.; Botuha, C.; Lemercier, G.; Romanens, P.; Saudan,
L.; Thibault, S. HelV. Chim. Acta 2004, 87, 561. (c) For reviews about
asymmetric addition to CdN bonds, see: (d) Enders, D.; Reinhold, U.
Tetrahedron: Asymmetry 1997, 8, 1895. (e) Bloch, R. Chem. ReV. 1998,
98, 1407. (f) Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069.
(7) For reviews of transition metal catalyzed enantioselective high-
pressure hydrogenations, hydrosilylations, and transfer hydrogenations of
imines, see: (a) Blaser, H.-U.; Spindler, F. In ComprehensiVe Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin,
Germany, 1999; Vol. 1, Chapter 6.2. (b) Nishiyama, H. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Berlin, Germany, 1999; Vol. 1, Chapter 6.3. (c) Ohkuma, T.;
Noyori, R. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz,
A., Yamamoto, H., Eds.; Springer: Berlin, Germany, 2003; Supp. 1, Chapter
6.2. (d) Ohkuma, T.; Noyori, R. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, Germany,
2003; Supp. 1, Chapter 6.3. (e) Carpentier, J. F.; Bette, V. Curr. Org. Chem.
2002, 6, 913. (f) Blaser, H. U.; Malan, C.; Pugin, B.; Spindler, F.; Steiner,
H.; Studer, M. AdV. Synth. Catal. 2003, 345, 103. (g) Tang, W.; Zhang, X.
Chem. ReV. 2003, 103, 3029. (h) Riant, O.; Mostefai, N.; Courmarcel, J.
Synthesis 2004, 2943. (i) Tararov, V. I.; Bo¨rner, A. Synlett 2005, 203. For
the first example of catalytic enantioselective reduction (hydrosilylation)
of imines, see: (j) Langlois, N.; Dang, T.-P.; Kagan, H. B. Tetrahedron
Lett. 1973, 4865.
optimal conditions consisted of performing the reduction of 2a
in benzene in the presence of chiral phosphoric acid 1d (0.1
equiv) and Hantzsch di-tert-butyl ester (1.3 equiv) at 50 °C.
Under these conditions, amine 3a was isolated in 94% yield
with 92% ee (cf. Table 2).14
Having established optimal conditions, we next examined the
scope of this reaction by varying the nature of R and R′
substituents in imines 2 (Table 2). A variety of ortho-
hydroxyaryl alkyl N-H ketimines having a substituent at the
(11) Selected recent examples: (a) Akiyama, T.; Itoh, J.; Yokota, K.;
Fuchibe, K. Angew. Chem., Int. Ed 2004, 43, 1566. (b) Uraguchi, D.; Terada,
M. J. Am. Chem. Soc. 2004, 126, 11804. (c) Rowland, G. B.; Zhang, H.;
Rowland, E. B.; Chennamadhavuni, S.; Wang, V.; Antilla, J. C. J. Am.
Chem. Soc. 2005, 127, 15696. (d) Rueping, M.; Sugiono, E.; Azap, C.
Angew. Chem., Int. Ed. 2006, 45, 2617. (e) Chen, X.-H.; Xu, X.-Y.; Liu,
H.; Cun, L.-F.; Gong, L.-Z. J. Am. Chem. Soc. 2006, 128, 14802. (f) Kang,
Q.; Zhao, Z.-A.; You, S.-L. J. Am. Chem. Soc. 2007, 129, 1484. (g) Jia,
Y.-X.; Zhong, J.; Zhu, S.-F.; Zhang, C.-M.; Zhou, Q. L. Angew. Chem.,
Int. Ed. 2007, 46, 5565. (h) Wanner, M. J.; van der Haas, R. N. S.; de
Cuba, K. R.; van Maarseveen, J. H.; Hiemstra, H. Angew. Chem., Int. Ed.
2007, 46, 7485. (i) Baudequin, C.; Zamfir, A.; Tsogoeva, S. B. Chem.
Commun. 2008, 4637. (j) Sickert, M.; Schneider, C. Angew. Chem., Int.
Ed. 2008, 47, 3631. (k) Enders, D.; Narine, A. A.; Toulgoat, F.; Bisschops,
T. Angew. Chem., Int. Ed. 2008, 47, 5661. (l) Cheon, C. H.; Yamamoto,
H. J. Am. Chem. Soc. 2008, 130, 9246. (m) Liu, H.; Dagousset, G.; Masson,
G.; Zhu, J. J. Am. Chem. Soc. 2009, 131, 4598. (n) Terada, M.; Tanaka,
H.; Sorimachi, K. J. Am. Chem. Soc. 2009, 131, 3430. (o) Lu, M.; Zhu, D.;
Lu, Y.; Zeng, X.; Tan, B.; Xu, Z.; Zhong, G. J. Am. Chem. Soc. 2009, 131,
4562. (p) Han, Z.-Y.; Xiao, H.; Chen, X.-H.; Gong, L.-Z. J. Am. Chem.
Soc. 2009, 131, 9182. (q) Akiyama, T.; Katoh, T.; Mori, K. Angew. Chem.,
Int. Ed. 2009, 48, 4226. (r) Mori, K.; Katoh, T.; Suzuki, T.; Noji, T.;
Yamanaka, M.; Akiyama, T. Angew. Chem., Int. Ed. 2009, 48, 9652. (s)
Yue, T.; Wang, M.-X.; Wang, D.-X.; Masson, G.; Zhu, J. Angew. Chem.,
Int. Ed. 2009, 48, 6717. (t) Gu, Q.; Rong, Z.-Q.; Zheng, C.; You, S.-L.
J. Am. Chem. Soc. 2010, 132, 4056. (u) Liao, S.; List, B. Angew. Chem.,
Int. Ed. 2010, 49, 628.
(8) For transition metal catalyzed hydrogen-transfer reductive amination
to primary amines: (a) Kadyrov, R.; Riermeier, T. H. Angew. Chem. Int.
Ed 2003, 42, 5472. For enantioselective reduction of trifluoromethylated
ketimines with borane-chiral oxazaborolidine (OAB): (b) Gosselin, F.;
O’Shea, P. D.; Roy, S.; Reamer, R. A.; Chen, C.; Volante, R. P. Org. Lett.
2005, 7, 355. For chiral Ir-complex catalyzed hydrogenation: (c) Hou, G.;
Gosselin, F.; Li, W.; McWilliams, J. C.; Sun, Y.; Weisel, M.; O’Shea, P. D.;
Chen, C.; Davies, I. W.; Zhang, X. J. Am. Chem. Soc. 2009, 131, 9882. (d)
Hou, G.; Tao, R.; Sun, Y.; Zhang, X.; Gosselin, F. J. Am. Chem. Soc. 2010,
132, 2124. For chiral Rh-complex catalyzed hydrogenation of unprotected
enamines: (e) Hsiao, Y.; Rivera, N. R.; Rosner, T.; Krska, S. W.; Njolito,
E.; Wang, F.; Sun, Y.; Armstrong, III, J. D.; Grabowski, E. J. J.; Tillyer,
R. D.; Spindler, F.; Malan, C. J. Am. Chem. Soc. 2004, 126, 9918.
(9) For the first asymmetric (63% ee) organocatalytic Hantzsch dihy-
dropyridine reduction of imines, see: (a) Singh, S.; Batra, U. K. Indian
J. Chem., Sect. B 1989, 28, 1. For reviews of enantioselective organocatalytic
transfer hydrogenation using Hantzsch dihydropyridines, see: (b) Connon,
S. J. Org. Biomol. Chem. 2007, 5, 3407. (c) You, S.-L. Chem. Asian J.
2007, 2, 820. (d) Ouellet, S. G.; Walji, A. M.; MacMillan, D. W. C. Acc.
Chem. Res. 2007, 40, 1327.
(10) For reviews on chiral phosphoric acid, see: (a) Akiyama, T. Chem. ReV.
2007, 107, 5744. (b) Yu, X.; Wang, W. Chem. Asian J. 2008, 3, 516. (c)
Terada, M. Chem. Commun. 2008, 4097. (d) Terada, M. Synthesis 2010, 1929.
4706
Org. Lett., Vol. 12, No. 20, 2010

efficiently to provide the corresponding amines (3m-3p,
entries 13-16, Table 2) in high yields and ee’s.
Table 2. Substrate Scope of Chiral Phosphoric Acid Catalyzed
Transfer Hydrogenation of ortho-Hydroxyaryl Alkyl N-H
Ketimines 2a
The absolute configuration of amine 3 was determined to be
“S” by comparison of the sign of its optical rotation with that
of the known amines (see the Supporting Information for
details). A control experiment indicated that reduction of imine
2a did not take place in the absence of phosphoric acid. In the
proton NMR spectrum of 2a (C6D6), the phenolic OH appeared
at δ ) 15.6 ppm indicating the presence of a strong intramo-
lecular H-bond between the phenolic O-H and the imine
nitrogen. Upon addition of 1.0 equiv of phosphoric acid (1d),
the resonance of this OH moved to higher field (aromatic
region). This experiment indicated that phosphoric acid (1d) is
capable of breaking this intramolecular H-bond and activating
the imine via, most probably, the formation of an intermolecular
H-bond with the imine nitrogen. Consequently, we assumed
that the reaction may proceed via a transition state A (Figure
1), wherein the phosphoric acid formed H-bonds with both the
entry
amine
R
R′
yield (%)b
ee (%)c
1
3a
3b
3c
3d
3e
3f
Me
H
94
56
91
93
68
88
86
70
97
85
77
56
86
98
81
98
92
97
89
96
94
96
91
90
90
87
92
99
89
89
89
81
2
Me
3-Me
4-F
3
Me
4
Me
4-Me
4-OMe
4-NO2
5-Me
5-t-Bu
5-Br
5-OMe
5-NO2
6-OEt
H
5
Me
6
Me
7
3g
3h
3i
Me
8
Me
9
Me
10
11
12
13
14
15
16
3j
3k
3l
3m
3n
3o
3p
Me
Me
Me
Et
n-Pr
n-hexyl
i-Pr
H
H
H
a Reaction conditions: imine (2) (0.5 mmol), Hantzsch di-tert-butyl ester
(0.65 mmol), and catalyst (0.05 mmol) in benzene (5 mL) for 72 h. b Yields
after chromatography. c Determined by chiral HPLC analysis of the
corresponding acetamide or propanamide.
3, 4, 5, and 6 position of the aromatic ring were readily reduced
to afford the corresponding amines. The presence of either an
electron-withdrawing (F, Br, NO2) or an electron-donating group
(Me, OMe) at C-3, C-4, and C-5 of the aromatic ring did not
affect significantly the enantioselectivity. On the other hand,
an excellent enantioselectivity was observed in the reduction
of 2l having an ethoxy group at C-6 leading to the corresponding
amine (3l) with up to 99% ee (entry 12).
Previously, only N-Ar imines derived from acetophenone
were used as substrates in phosphoric acid-catalyzed transfer
hydrogenation,10a-c and a computational model was ad-
vanced to account for the observed selective reduction of
aryl methyl ketimines.10c It was thus remarkable to observe
that, in our case, other ortho-hydroxyaryl alkyl N-H
ketimines (R ) Et, n-Pr, n-hexyl, i-Pr) can also be reduced
Figure 1. Plausible transition state.
hydroxyl and the imine functions of 2.15 The hydride transfer
would then occur from the re face of the imines to deliver the
amines with the observed (S) configuration.
In summary, we have developed the first highly enanti-
oselective chiral phosphoric acid-catalyzed reduction of
bench-stable unprotected ortho-hydroxyaryl alkyl N-H
ketimines using Hantzsch ester as a hydrogen source. The
reaction is applicable to a wide range of substrates with
different electronic and steric properties. While ortho-
hydroxybenzylamines are interesting compounds in their own
right, the presence of a hydroxy group offered a valuable
opportunity for further modification on the ortho-position.16
Further investigation of the reaction mechanism and applica-
tion of the methodology to the synthesis of bioactive
compounds is currently ongoing in our laboratory.
(12) For chiral phosphoric acid catalyzed transfer hydrogenation of
imines with Hantzsch dihydropyridines: (a) Rueping, M.; Sugiono, E.; Azap,
C.; Theissmann, T.; Bolte, M. Org. Lett. 2005, 7, 3781. (b) Hoffmann, S.;
Seayad, A. M.; List, B. Angew. Chem., Int. Ed. 2005, 44, 7424. (c) Storer,
R. I.; Carrera, D. E.; Ni, Y.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006,
128, 84. (d) Hoffmann, S.; Nicoletti, M.; List, B. J. Am. Chem. Soc. 2006,
128, 13074. (e) Rueping, M.; Antonchick, A. P.; Theissmann, T. Angew.
Chem., Int. Ed. 2006, 45, 3683. (f) Rueping, M.; Antonchick, A. P.;
Theissmann, T. Angew. Chem., Int. Ed. 2006, 45, 6751. (g) Rueping, M.;
Antonchick, A. P. Angew. Chem., Int. Ed. 2007, 46, 4562. (h) Li, G.; Liang,
Y.; Antilla, J. C. J. Am. Chem. Soc. 2007, 129, 5830. (i) Zhou, J.; List, B.
J. Am. Chem. Soc. 2007, 129, 7498. (j) Kang, Q.; Zhao, Z.-A.; You, S.-L.
AdV. Synth. Catal. 2007, 349, 1657. (k) Guo, Q.-S.; Du, D.-M.; Xu, J.
Angew. Chem., Int. Ed. 2008, 47, 759. (l) Rueping, M.; Theissmann, T.;
Raja, S.; Bats, J. W. AdV. Synth. Catal. 2008, 350, 1001. (m) Kang, Q.;
Zhao, Z.-A.; You, S.-L. Org. Lett. 2008, 10, 2031. (n) Li, G.; Antilla, J. C.
Org. Lett. 2009, 11, 1075.
Acknowledgment. Financial support from CNRS and
ICSN is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures, product characterization, ee measurement, and
1
copies of the H and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL102043X
(13) Korotaev, V. Y.; Sosnovskikh, V. Y.; Kutyashev, I. B.; Barkov,
A. Y.; Matochkina, E. G.; Kodess, M. Tetrahedron 2008, 64, 5055.
(14) For reliable synthesis of free phosphoric acid and its catalytic
activity, see: Hatano, M.; Moriyama, K.; Maki, T.; Ishihara, K. Angew.
Chem., Int. Ed. 2010, 49, 3823.
(15) For related transition state, see: Akiyama, T.; Morita, H.; Fuchibe,
K. J. Am. Chem. Soc. 2006, 128, 13070.
(16) Mahdavian, E.; Sangsura, S.; Landry, G.; Eytina, J.; Salvatore, B. A.
Tetrahedron Lett. 2009, 50, 19.
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