Catalytic asymmetric reductive amination of aldehydes via dynamic kinetic resolution

Article abstract of DOI:10.1021/ja065404r

A novel organocatalytic asymmetric reductive amination of aldehydes has been developed. Treating racemic α-branched aldehydes with p-anisidine and a Hantzsch ester in the presence of our previously developed phosphoric acid catalyst, TRIP, gave β-branched secondary amines in excellent yields and enantioselectivities via an efficient dynamic kinetic resolution. The process is applicable to several different aromatic aldehydes and amines but gives slightly reduced enantiomeric ratios with aliphatic aldehydes. Copyright

Full text of DOI:10.1021/ja065404r

Published on Web 09/20/2006
Catalytic Asymmetric Reductive Amination of Aldehydes via Dynamic Kinetic
Resolution
Sebastian Hoffmann, Marcello Nicoletti, and Benjamin List*
Max-Planck-Institut fu¨r Kohlenforschung, D-45470 Mu¨lheim an der Ruhr, Germany
Received July 27, 2006; E-mail: list@mpi-muelheim.mpg.de
Catalytic asymmetric reductive aminations of carbonyl com-
pounds are useful for the synthesis of chiral amines and also
powerful C-N bond forming fragment coupling reactions.1 Al-
though selected asymmetric reductive aminations of ketones to give
chiral, R-branched amines in an enantioface-differentiating process
have been reported (eq 1),2,3 the corresponding reactions of
aldehydes are unknown. We reasoned that such a process might
be realized if enolizable, R-branched aldehydes are employed. Their
asymmetric reductive amination should give â-branched amines via
an enantiomer-differentiating kinetic resolution (eq 2).
included changing the dihydropyridine,9 lowering the catalyst
We have recently reported an organocatalytic ketimine reduction
loading, reducing the temperature, changing the solvent, and adding
as well as a reductive amination of ketones using Hantzsch esters
molecular sieves, the enantioselectivity could be improved signifi-
as hydride source and chiral Brønsted acids as catalysts.3,4 One of
cantly (98:2 er) and the optimized protocol was used for the direct
the most efficient and enantioselective catalysts identified to date
reductive amination of a variety of different aldehydes (Table 2).
is 3,3′-bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl-2,2′-diyl hy-
The efficient removal of water formed during the reaction seems
to be important as the enantiomeric ratio improved considerably
upon using 5 Å molecular sieves. This reagent has been used
drogen phosphate (TRIP, 5f),5 which at only 1 mol % catalyst
loading provides products of aromatic and aliphatic ketimine
intermediates in high enantioselectivities.3 We now report an
previously in the reductive amination of ketones, and other
extension of this methodology to aldehyde substrates. We found
dehydrating reagents proved less useful. Furthermore, oxygen-free
that TRIP also catalyzes the direct reductive amination of R-branched
conditions are required as substantial acetophenone and p-formyl-
anisidine formation was observed in the presence of oxygen,
aldehydes in an efficient dynamic kinetic resolution.
At the onset of this study, we hypothesized that under our
Table 1. Catalyst Screening
reductive amination conditions an R-branched aldehyde substrate
would undergo a fast racemization in the presence of the amine
and acid catalyst via an imine/enamine tautomerization. The
reductive amination of one of the two imine enantiomers would
then have to be faster than that of the other, resulting in an
enantiomerically enriched product via a dynamic kinetic resolution
(eq 3).6 Despite their general tendency toward facile racemization,
R-branched aldehydes have rarely been used in dynamic kinetic
resolutions before.7,8
Indeed, when we studied various phosphoric acid catalysts for
the reductive amination of hydratopicaldehyde (1a) with p-anisidine
(PMPNH2, 2) in the presence of Hantzsch ester 4 to give amine
3a, the observed enantioselectivities and conversions are consistent
with a facile in situ racemization of the substrate and a resulting
dynamic kinetic resolution (eq 4, Table 1). TRIP (5f) once again
turned out to be the most effective and enantioselective catalyst
for this transformation and provided the chiral amine product under
unoptimized conditions in 50% yield and an enantiomeric ratio of
84:16.
Other catalysts, such as 5e, which has previously been used in
the reductive amination of ketones, gave significantly inferior results
under identical conditions.3 After further optimization, which
a Determined by GC with internal standard. b Determined by HPLC.
9
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J. AM. CHEM. SOC. 2006, 128, 13074-13075
10.1021/ja065404r CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope of the Catalytic Asymmetric Reductive Amination
of Aldehydes
work. Generous support by the Max-Planck-Society and by Novartis
(Young Investigator Award to B.L.) is gratefully acknowledged.
We also thank Degussa, Lanxess, Merck, and BASF for general
support and donating chemicals.
Supporting Information Available: Experimental procedures,
compound characterization, NMR spectra, and HPLC traces (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
entry
R1
R2
R3
yield (%)
era
1
2b
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17c
Ph (3a)
Ph (3a)
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
PMP
87
80
86
81
85
96
92
89
84
49
81
77
40
39
92
78
54
98:2
99:1
97:3
97:3
99:1
98:2
97:3
97:3
97:3
94:6
89:11
90:10
90:10
70:30
99:1
97:3
95:5
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
Ph
4-MeC 6H4 (3b)
4-MeOC6H4 (3c)
1-naph (3d)
2-naph (3e)
4-BrC6H4 (3f)
2-F C6H4 (3g)
3-F C6H4 (3h)
thiophen-2-yl (3i)
cyclohexyl (3j)
tert-butyl (3k)
CF3 (3l)
References
(1) For a review on asymmetric reductive aminations, see: (a) Tararov, V.
I.; Bo¨rner, A. Synlett 2005, 203. For reviews on catalytic asymmetric imine
reductions, see: (b) Ohkuma, T.; Kitamura, M.; Noyori, R. In Catalytic
Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York,
2000; Chapter 1. (c) Ohkuma, T.; Noyori, R. In Comprehensive Asym-
metric Catalysis, Suppl. 1; Jacobsen, E. N., Pfaltz, A., Yamamoto, H.,
Eds.; Springer: New York, 2004; p 43. (d) Nishiyama, H.; Itoh, K. In
Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New
York, 2000; Chapter 2.
(2) For asymmetric reductive aminations catalyzed by metal complexes, see:
(a) Blaser, H.-U.; Buser, H.-P.; Jalett, H.-P.; Pugin, B.; Spindler, F. Synlett
1999, 867. (b) Kadyrov, R.; Riermeier, T. H. Angew. Chem., Int. Ed. 2003,
42, 5472. (c) Williams, G. D.; Pike, R. A.; Wade, C. E.; Wills, M. Org.
Lett. 2003, 5, 4227. (d) Kadyrov, R.; Riermeier, T. H.; Dingerdissen, U.;
Tararov, V.; Bo¨rner, A. J. Org. Chem. 2003, 68, 4067. (e) Chi, Y. X.;
Zhou, Y. G.; Zhang, X. M. J. Org. Chem. 2003, 68, 4120.
n-Pr (3m)
Ph (3n)
Ph (3o)
Ph (3p)
Me
Me
4-CF3C6H4
a Determined by HPLC. b Reaction was run for 96 h, using di-tert-butyl
2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate as the reductant. c After
168 h.
(3) For organocatalytic asymmetric reductive aminations, see: (a) Hoffmann,
S.; Seayad, A.; List, B. Angew. Chem., Int. Ed. 2005, 44, 7424. (b) Storer,
R. I.; Carrera, D. E.; Ni, Y.; MacMillan, D. W. C. J. Am. Chem. Soc.
2006, 128, 84. For organocatalytic asymmetric imine reduction using
Hantzsch dihydropyridine, see: (c) Singh, S.; Batra, U. K. Indian J. Chem.
1989, 27, 1. (d) Rueping, M.; Sugiono, E.; Azap, C.; Theissmann, T.;
Bolte, M. Org. Lett. 2005, 7, 3781. For organocatalytic asymmetric imine
reduction using silanes, see: (e) Iwasaki, F.; Onomura, O.; Mishima, K.;
Kanematsu, T.; Maki, T.; Matsumura, Y. Tetrahedron Lett. 2001, 42, 2525.
(f) Malkov, A. V.; Mariani, A.; MacDougall, K. N.; Kocovsky, P. Org.
Lett. 2004, 6, 2253. (g) Malkov, A. V.; Stoncius, S.; MacDougall, K. N.;
Mariani, A.; McGeoch, G. D.; Kocovsky, P. Tetrahedron 2006, 62, 264.
(h) Wang, Z.; Ye, X.; Wei, S.; Wu, P.; Zhang, A.; Sun, J. Org. Lett.
2006, 8, 999.
(4) For pioneering studies on the use of chiral phosphoric acid catalysts, see:
(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, 5356. For other chiral phosphoric acid catalyzed reactions, see: (c)
Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem. Soc. 2004, 126,
11804. (d) Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem. Soc.
2005, 127, 9360. (e) Akiyama, T.; Saitoh, Y.; Morita, H.; Fuchibe, K.
AdV. Synth. Catal. 2005, 347, 1523. (f) Akiyama, T.; Morita, H.; Itoh, J.;
Fuchibe, K. Org. Lett. 2005, 7, 2583. (g) Rowland, G. B.; Zhang, H.;
Rowland, E. B.; Chennamadhavuni, S.; Wang, Y.; Antilla, J. C. J. Am.
Chem. Soc. 2005, 127, 15696. (h) Terada, M.; Sorimachi, K.; Uraguchi,
D. Synlett 2006, 133. (i) Terada, M.; Machida, K.; Sorimachi, K. Angew.
Chem., Int. Ed. 2006, 45, 2254. (j) Rueping, M.; Sugiono, E.; Azap, C.
Angew. Chem., Int. Ed. 2006, 45, 2617 and cited refs 3 and 5. Also see:
(k) Nakashima, D.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 9626.
(5) For other TRIP-catalyzed reactions, see: (a) Akiyama, T.; Tamura, Y.;
Itoh, J. Synlett 2006, 141. (b) Seayad, J.; Seayad, A. M.; List, B. J. Am.
Chem. Soc. 2006, 128, 1086. For TRIP in asymmetric counteranion-
directed reduction of R,â-unsaturated aldehydes, see: (c) Mayer, S.; List,
B. Angew. Chem., Int. Ed. 2006, 45, 4193.
presumably via an oxidative cleavage of the hydratopicaldehyde
enamine intermediate.10
The generality of the methodology is shown in Table 2, using a
broad range of aldehydes and amines under optimized conditions.
A variety of 2-arylpropionaldehydes can be successfully used with
p-anisidine as the amine component (entries 1-10). Noteworthy,
except in case of thiophene derivative 3e, all of the products derived
from both electron-deficient and electron-rich aromatic substrates
were obtained in very good yields (80-96%) and enantiomeric
ratios (97:3-99:1). Aliphatic aldehydes can also be employed in
the dynamic kinetic resolution (entries 11-14), although with lower
enantiomeric ratios. Interestingly, an ethylsrather than a methyls
substituent in the R-position of the aldehyde is also well tolerated
(entry 15). Electronically different anilines (entries 16 and 17) have
also been studied. While the enantiomeric ratios remain high, the
best yields were obtained using electron-rich p-anisidine.
The absolute configuration of amine 3a was established via
oxidative removal of the PMP group.9 An example for the synthetic
utility of amines 3 is shown in eq 6. Upon sequential protection
with benzyl chloroformate (CbzCl) and treatment with cerium(IV)
ammonium nitrate (CAN), carbamate 6a was obtained in good yield
and with no loss of enantiomeric purity (eq 6).11
(6) For reviews, see: (a) Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem.
Soc. Jpn. 1995, 68, 36. (b) Ward, R. S. Tetrahedron: Asymmetry 1995,
6, 1475. (c) Caddick, S.; Jenkins, K. Chem. Soc. ReV. 1996, 25, 447. (d)
Stecher, H.; Faber, K. Synthesis 1997, 1. (e) Huerta, F. F.; Minidis, A. B.
E.; Ba¨ckvall, J. E. Chem. Soc. ReV. 2001, 30, 321. (f) Perllissier, H.
Tetrahedron 2003, 59, 8291.
(7) A transfer hydrogenation of cyclic R-branched ketimines via dynamic
kinetic resolution has recently been described: Ros, A.; Magriz, A.;
Dietrich, H.; Ford, M.; Fernandez, R.; Lassaletta, J. M. AdV. Synth. Catal.
2005, 347, 1917.
(8) For selected examples, see: (a) Zuger, M. F.; Giovannini, F.; Seebach,
D. Angew. Chem., Int. Ed. Engl. 1983, 22, 1012. (b) Rein, T.; Zezschwitz,
P.; Wulff, C.; Reiser, O. Angew. Chem., Int. Ed. Engl. 1995, 34, 1023.
(c) Vogt, H.; Vanderheiden, S.; Bra¨se, S. Chem. Commun. 2003, 2448.
(d) Ward, D. E.; Jheengut, V.; Akinnusi, O. T. Org. Lett. 2005, 7, 1181.
(9) See Supporting Information.
In summary, we have developed an efficient enantioselective
reductive amination of R-branched aldehydes via dynamic kinetic
resolution. Our process is broad in scope, and both aromatic and
aliphatic aldehydes can be used, although enantiomeric ratios are
typically lower with simple aliphatic aldehydes. Currently, our
reaction is limited to the use of aromatic amines, but we expect to
overcome this limitation in ongoing studies in our laboratory.
(10) Witkop, B. J. Am. Chem. Soc. 1956, 78, 2873.
(11) Niwa, Y.; Takayama, K.; Shimizi, M. Bull. Chem. Soc. Jpn. 2002, 75,
1819.
Acknowledgment. We thank the DFG (Priority Program
Organocatalysis SPP1179) and Wacker for partially funding this
JA065404R
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