Highly Enantioselective Hydrogen-Transfer Reductive Amination: Catalytic Asymmetric Synthesis of Primary Amines

Article abstract of DOI:10.1002/anie.200352503

Ammonium formate is the hydrogen source in the catalytic asymmetric reductive amination of ketones presented here (Leuckart-Wallach-type reaction). The reaction proceeds smoothly in methanol in the presence of Ir, Rh, and Ru catalysts. Primary amines were obtained as products in good yields with high enantioselectivities after hydrolytic workup when [((R)-tol-binap) RuCl ₂] was used as the catalyst (see scheme). R¹, R ²=alkyl, aryl.

Full text of DOI:10.1002/anie.200352503

Communications
anolic ammonia at 608C in the presence of a Rh catalyst
smoothly furnished N-(phenylacetyl)phenylalaninamide
[Eq. (1)]. The formation of this product from phenylpyruvic
acid and ammonium sulfate proceeds in the absence of a
catalyst at a higher temperature (1058C).[4]
This observation prompted us to investigate a reductive
amination mediated by chiral catalysts under hydrogen-
transfer conditions. The reduction of carbonyl compounds
to amines with formic acid or formamide is known as the
Leuckart–Wallach reaction.[5] Fewstudies on the use of
catalysts in this reaction have been reported in the litera-
ture.[6] As part of our ongoing research into the asymmetric
hydrogen-transfer reductive amination,[7] we report herein
our results from the screening of a variety of catalyst types
and describe an effective catalytic system for the production
of simple amines with high enantioselectivity.
Two conventional hydrogen sources, isopropyl alcohol
and formic acid,[8] were considered. In the reductive amina-
tion of acetophenone with ammonia in isopropyl alcohol only
[Rh(C5Me5)Cl2]2 demonstrated acceptable activity. In the
presence of this catalyst, 1-phenylethylamine (1) and 1-
phenylethanol (2) were produced in 12 h at 708C in yields of
30% and 1%, respectively. Figure 1 shows the yields deter-
mined by GC of 1 and 2 and the enantiomeric excess of 1 in
the reaction of acetophenone with ammonium formate for the
different Rh, Ir, and Ru complexes that were tested as
catalysts. The use of Rh and Ir complexes resulted in poor
enantioselectivities under all conditions investigated. There-
fore, we concentrated on Ru systems with ammonium
formate as the hydrogen donor (Leuckart–Wallach-type
reductive amination).
Asymmetric Reductive Amination
Highly Enantioselective Hydrogen-Transfer
Reductive Amination: Catalytic Asymmetric
Synthesis of Primary Amines**
Renat Kadyrov* and Thomas H. Riermeier
As can be seen in Figure 1, the best enantioselectivities
were observed with Ru catalysts with a binap or a tol-binap
ligand. The degree of asymmetric induction by both catalysts
was evaluated for a number of aryl ketones. The reactions
were quenched after 24 h, and the crude reaction mixtures
were analyzed directly by HPLC for the ee values of the
products. The results indicate that the Ru–tol-binap complex
gives higher enantioselectivities than the Ru–binap complex
(Table 1). As a result of the very broad peaks observed with
our fast method of HPLC analysis, we were unable to detect
another enantiomer in the reactions represented in entries 2,
3, and 5 of Table 1.
Optimization of the reaction conditions by screening
additives was performed with acetophenone in the presence
of [((R)-tol-binap)RuCl2] (Table 2). Acids were found to
accelerate the reaction but to lower the asymmetric induction.
The addition of ammonia led to enhancement of the
enantioselectivity but a decrease in the reactivity. However,
aqueous ammonia was found to increase the yield of the
alcohol. The best enantioselectivities were generally observed
when 5 to 10 equivalents of HCOONH4 in NH3/methanol
(15–25%) and temperatures between 60 and 858C were used.
Optically active amines are attracting increasing interest in
the food, agrochemical, and pharmaceutical industries as
building blocks for novel compounds and as templates for
asymmetric synthesis. One of the most common methods for
preparing amines is the reductive amination of carbonyl
compounds.[1] We have successfully explored the rhodium-
catalyzed asymmetric reductive amination with hydrogen as
the reducing agent.[2] Recently, we developed a highly active
and enantioselective catalytic system for the reductive
amination of a-keto acids.[3] In the course of our studies we
observed that the reaction of phenylpyruvic acid in meth-
[*] Dr. R. Kadyrov, Dr. T. H. Riermeier
Degussa AG, Projekthaus Katalyse
Industriepark Höchst, G 830, 65926 Frankfurt/Main (Germany)
Fax: (+49)69-305-27338
E-mail: renat.kadyrov@degussa.com
[**] We thank Prof. A. Börner, Prof. K.-H. Drauz, Dr. J. Almena, Dr. A.
Monsees, and Dr. V. I. Tararov for stimulating and helpful
discussions.
5472
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DOI: 10.1002/anie.200352503
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Angewandte
Chemie
Figure 1. The yields of 1 (shadowed bars) and 2 (white bars), as determined by GC analysis, and the enantiomeric excess of 1 (black bars) after
24 h in the reductive amination of acetophenone (0.5 mmol) with ammonium formate in ammonia solution (15–25%, 1 mL) in methanol at 708C
in the presence of the catalyst indicated (0.5 mmol): Ru1=[Ru(DMSO)4Cl2]; Ru2=[Ru(cymene)4Cl2]2/2; Ru3=[Ru(PPh3)3Cl2]; Ru4=[Ru(C4H7)2-
(cod)]; Rh1=[Rh(cod)2]OTf; Rh2=[Rh(C5Me5)Cl2]2/2; Ir1=[Ir(cod)Cl]2/2; Ir2=[Ir(C5Me5)Cl2]2/2; Ir3=[Ir(C8H14)2Cl]2/2; L1=(1R,2R)-1,2-diaminocy-
clohexane-N,N’-bis(2’-diphenylphosphanylbenzoyl); L2=(R)-2,2’-bis(di-p-tolylphosphanyl)-1,1’-binaphthyl; L3=(2R,3R)-2,3-bis(diphenylphospha-
nyl)bicyclo[2.2.1]hept-5-ene; L4=(1R,2R)-1,2-diphenyl-1,2-ethylenediamine. DMSO=dimethyl sulfoxide; cod=cyclooctadiene; Tf=trifluorometha-
nesulfonate.
Table 1: Enantioselectivities in the Leuckart–Wallach-type reductive
Table 2: Effect of additives in the enantioselective Leuckart–Wallach-type
reductive amination of acetophenone with [((R)-tol-binap)RuCl2] as the
catalyst.[a]
amination of ketones.[a]
Entry
Ketone
ee [%][b]
Catalyst A[c]
Catalyst B[d]
Entry
Additive
Yield [%]
ee of 1 [%]
1
2
3
1
2
3
4
5
acetophenone
83 (S)
10 (R)
6 (R)
60 (S)
90 (S)
91 (R)
>95 (R)
>95 (R)
84 (R)
4’-methylacetophenone
4’-methoxyacetophenone
4’-bromoacetophenone
2-acetylnaphthalene
1
2
3
4
5
6
–
NH3
37.3
15.0
13.6
57.5
78.9
69.7
2.9
2.0
14.4
13.1
10.8
13.7
48.0
17.2
3.4
20.8
10.3
12.1
85
90
92
69
60
20
[b]
NH4OH/H20[c]
TsOH[d]
>95 (R)
HCl[d]
HBF4
[a] Ketone (0.5 mmol), ammonium formate (1 mmol), catalyst (5 mmol),
NH3/MeOH (15–20%, 1 mL), 24 h, 708C. [b] The ee values were
determined by HPLC analysis. [c] [((S)-binap)RuCl2]. [d] [((R)-tol-binap)-
RuCl2].
[d]
[a] Acetophenone (0.5 mmol), ammonium formate (2.5 mmol), [((R)-tol-
binap)RuCl2] (10 mmol), MeOH (1 mL), 10 h, 608C. The product ratio
was determined by GC analysis. [b] NH3/MeOH (20%); [c] Aqueous
ammonia (25%, 0.5 mL). [d] Additive: 0.5 mmol.
A series of ketones were exam-
Table 3: Enantioselective Leuckart–Wallach-type reductive amination of ketones with [((R)-tol-binap)-
ined under the optimized condi-
tions (Table 3). The desired prod-
ucts were formed as the free
amines and in their N-formylated
form. The N-formyl derivatives are
the main products in the Leuckart–
Wallach reductive amination of
aromatic ketones.[5b] The amines
were obtained in good yields with
moderate to high enantioselectiv-
ities (86–98% ee) after hydrolysis
when aromatic ketones were used
as substrates. The best asymmetric
induction was observed in the reac-
tion of 4’-nitroacetophenone at
608C (98% ee).
RuCl2] as the catalyst.[a]
Entry Substrate
t
Ketone Amine Formyl amine Alcohol Yield[d]
ee[e]
[%]
[h] [%]
[%]
[%]
[%]
[%]
1
2
3
4
5
6
7
8
acetophenone
propiophenone
3’-methylacetophenone
4’-methylacetophenone
4’-methoxyacetophenone 24
20
21
24 23
5
0
75
22
38
8
64
6
10
45
11
18
36
19
78
39
91
32
94
90
55
69
82
64
1
0
0
0
1
0
0
0
6
0
0
0
92
89
74
93
83
93
56
92
69
91
44
95
95
89
93
95
92
21
0
3
0
0
0
4’-chloroacetophenone
4’-bromoacetophenone
4’-nitroacetophenone
1-acetylnaphthalene
2-acetylnaphthalene
2-octanone[b]
24
48
48
30 14
30
17
91
95[f]
86
9
10
11
12
0
0
0
95
24 (S)
2-methylcyclohexanone[b,c] 20
(33:22) (32:13)
63 (64:36) 17:64[g]
[a] For the reaction conditions, see Experimental Section: substrate (5 mmol), ammonium formate
(50 mmol), [((R)-tol-binap)RuCl2] (1 mol%), 858C, NH3/MeOH (15–20%, 20 mL). The product ratio
was determined by GC analysis. [b] In MeOH (20 mL), without ammonia. [c] Cis/trans ratios are givenin
brackets. [d] Yield of the isolated amine after hydrolysis. [e] Products have the R configuration, with the
exceptionof the last two entries. [f] Whenthe reactionwas carried out at 60 8C, 98% ee was observed .
[g] Cis isomer: 17% ee, trans isomer: 64% ee.
In the reaction of 2-octanone
under the standard conditions, full
consumption of the starting mate-
rial occurred within 24 h, but only a
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Communications
4851548, 1989 [Chem. Abstr. 1990, 112, 76922]; c) N. Kost,
Nauchn. Dokl. Vyssh. Shk. Khim. Khim. Tekhnol. 1958, 125 – 129
[Chem. Abstr. 1959, 53, 3112i]; d) N. Kost, I. I. Grandberg, Zh.
Obshch. Khim. 1955, 25, 1432 – 1437 [Chem. Abstr. 1956, 50,
4800i]; e) R. Stroh (Farbenfabriken Bayer), DE 861844, 1953
[Chem. Zentralbl. 1953, 5926]; f) J. F. Bunnett, J. L. Marks, J.
Am. Chem. Soc. 1949, 71, 1587 – 1589.
trace amount of 2-octylamine was detected. However, a 44%
yield of the desired product was isolated with 24% ee in the
absence of ammonia as additive (Table 3, entry 11). The
reductive amination of 2-methylcyclohexanone proceeded
well under both sets of conditions. Although the cis/trans
stereoselectivity was not affected by the inclusion of ammonia
as an additive, inferior enantioselectivities were observed.
Thus, the cis isomer was obtained in 9% ee and the trans
isomer in 43% ee under the standard reaction conditions,
whereas in the absence of ammonia 17% ee was observed for
the cis isomer and 64% ee for the trans isomer (Table 3,
entry 12). Interestingly, a nearly identical cis/trans ratio of 3:2
was reported for the corresponding Leuckart–Wallach reac-
tion.[9]
In summary, we have developed a new and efficient
method for the synthesis of primary amines from ketones in
an asymmetric catalytic manner. This method displays a high
level of asymmetric induction for aromatic ketones. Ammo-
nia is a crucial parameter in the catalytic system described, in
terms of the enantioselectivities observed.
[7] A. Börner, U. Dingerdissen, R. Kadyrov, T. H. Riermeier, V. I.
Tararov (Degussa AG), DE 10138140, 2001 [Chem. Abstr. 2003,
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1985, 85, 129 – 170; b) H. W. Gibson, Chem. Rev. 1969, 69, 673 –
692.
[9] D. S. Noyce, F. W. Bachelor, J. Am. Chem. Soc. 1952, 74, 4577 –
4579.
[10] M. Kitamura, M. Tokunaga, T. Ohkuma, R. Noyori, Org. Synth.
1993, 71, 1 – 13.
[11] a) E. Fernandez, K. Maeda, M. W. Hooper, J. M. Brown, Chem.
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Knight, J. M. Brown, Chem. Commun. 1997, 173 – 174.
Experimental Section
[((R)-tol-binap)RuCl2(DMF)x][10] (50 mg, ca. 50 mmol; DMF =
dimethylformamide), the ketone (5 mmol), and ammonium formate
(3.16 g, 50 mmol) were placed in a 35-mL Ace pressure tube (Aldrich)
under argon. Freshly condensed ammonia in dry methanol (20–25%,
20 mL) was added, then the tubes were sealed under argon and stirred
at 858C for the time indicated. Following evaporation of the volatile
components, the residue was dissolved in ethanol (10 mL), and
hydrochloric acid (6n, 5 mL) was added. The mixture was then
heated at reflux for 1 h to hydrolyze the formyl derivatives, then
cooled, diluted with water (10 mL), and extracted with ether to
remove any unreacted ketone. The aqueous layer was made alkaline
by the addition of ammonia solution (25%, 4 mL), then extracted
with dichloromethane (3 ” 5 mL). The combined organic extracts
were dried over Na2SO4 and concentrated to afford the crude amine,
1
which was shown to be pure by H NMR spectroscopy. The optical
purity was determined by GC analysis of the corresponding acet-
amide on a chiral phase (Chrompack, CP Chirasil-DEX CB), as
reported previously.[11]
Received: July 29, 2003 [Z52503]
Keywords: amination · amines · asymmetric catalysis · ketones ·
.
ruthenium
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Angew. Chem. Int. Ed. 2003, 42, 5472 –5474