Synthesis of α-amino acid amides: Ruthenium-catalyzed amination of α-hydroxy amides

Article abstract of DOI:10.1002/anie.201104309

Give me an N: The catalytic amination of α-hydroxy amides with a variety of amines, including anilines, primary and secondary aliphatic amines, and ammonia, yields a wide range of α-amino amides (see scheme). This atom-efficient amination protocol proceeds efficiently in the presence of a commercially available [Ru₃(CO)₁₂]/DCPE catalyst system. Copyright

Full text of DOI:10.1002/anie.201104309

DOI: 10.1002/anie.201104309
Catalytic Amination
Synthesis of a-Amino Acid Amides: Ruthenium-Catalyzed Amination
of a-Hydroxy Amides**
Min Zhang, Sebastian Imm, Sebastian Bꢀhn, Helfried Neumann, and Matthias Beller*
Dedicated to Professor Christian Bruneau on the occasion of his 60th birthday
a-Amino acid amides represent an interesting subclass of
amino acid derivatives. In general, such compounds are
biologically active and possess therapeutically useful proper-
ties. Selected examples of such compounds are: 1, which is
used for the treatment of metabolic syndrome,[1] potent
inhibitors for 11-b-hydroxysteroid dehydrogenase 1 (2),[2] and
top-selling drugs such as Lidoderm (3), Vyvanse (4), Altace
(5), and Cefprozil (6; Scheme 1). Additionally, a-amino acid
amides serve as synthetically useful intermediates for organic
synthesis[3] as well as organocatalysts[4] and bidentate ligands[5]
Scheme 2. Selected syntheses of a-amino acid amides.
for stereoselective transformations.
have been prepared by the classical Strecker reaction and
subsequent hydrolysis of the a-amino nitriles. Most often,
nucleophilic substitution reactions of naturally occuring a-
amino acids with amines are applied for the synthesis of
dipeptides, etc. For more sophisticated products, for example,
N-aryl-substituted amides, modern catalytic reactions such as
cross-coupling protocols are also known. Despite all these
achievements, the development of novel atom-efficient pro-
cedures for the preparation of N-substituted amino acid
amides still remains an interesting goal.
Owing to the importance of a-amino acid amides,
numerous protocols have been developed for their prepara-
tion (Scheme 2).[6] For example, simple a-amino acid amides
À
Among the various methods for C N bond formation, in
recent years the catalytic amination of alcohols has become a
useful tool for the synthesis of substituted amines. Notably,
water is the only sideproduct in this reaction, and less
environmentally benign alkylating agents such as alkyl
halides can be avoided.
Starting with the pioneering work of Grigg et al.[7] and
Watanabe et al.[8] in the early 80s, a series of ruthenium- and
iridium-catalyzed aminations of simple primary and secon-
dary alcohols have been described.[9] More recent examples
for such transformations came from the groups of Williams,[10]
Fujita,[11] Kempe,[12] and our group.[13] However, to the best of
our knowledge, the direct amination of a-hydroxy acid
derivatives to yield a-amino acid derivatives has not been
reported yet. Such a transformation differs significantly in
reactivity from known alcohol aminations. Notably, the amide
group may reduce the catalytic activity by blocking necessary
coordination sites on the metal centre.[14]
Scheme 1. Selected examples of biologically and therapeutically active
a-amino amides.
Based on our previous work on the amination of
alcohols[15] and amines,[16] we became interested in the
catalytic reaction of a-hydroxy amides with aryl and alkyl
amines as well as ammonia. In agreement with known
“borrowing-hydrogen”[17] or “hydrogen autotransfer” pro-
cesses[18] this transformation should proceed by the following
domino sequence (Scheme 3): 1) In situ dehydrogenation of
the a-hydroxy amide leads to the corresponding a-carbonyl
amide A. 2) A undergoes condensation with the amine to
generate an a-imino amide B. 3) Final hydrogenation of B
[*] Dr. M. Zhang, S. Imm, S. Bꢀhn, Dr. H. Neumann, Prof. Dr. M. Beller
Institut fꢁr Katalyse an der Universitꢀt Rostock e.V.
Albert-Einstein-Strasse 29a, 18059 Rostock (Germany)
E-mail: matthias.beller@catalysis.de
Homepage: http://www.catalysis.de
[**] We are grateful to the Alexander von Humboldt Foundation for a
grant to M.Z. and to the support of the BMBF (Bundesministerium
fꢁr Bildung und Forschung).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201104309.
Angew. Chem. Int. Ed. 2011, 50, 11197 –11201
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Communications
Scheme 3. Proposed mechanism for the ruthenium-catalyzed amina-
tion of a-hydroxy amides.
releases the product and regenerates the catalyst. Advanta-
geously, the hydrogen required for the final hydrogenation
step is completely generated by the dehydrogenation of the
alcohol in the first step. Hence, there is no need for additional
hydrogen.
Previous studies from our group showed that [Ru3(CO)12]
in combination with bulky phosphine ligands led to high
conversion and selectivity for the amination of nonfunction-
alized aliphatic and benzylic alcohols.[19] We therefore tested
this catalyst precursor together with 17 different ligands in the
model reaction of lactic acid amide with aniline to give 2-
(phenylamino)propanamide 3a. Typically, 2-hydroxypropan-
amide 1a was reacted with 1.1 equiv of aniline 2a in the
presence of 2 mol% of [Ru3(CO)12] and 6 mol% of ligand in
tert-amyl alcohol as solvent.
Scheme 4. Screening of ligands for the model reaction. [a] Yield
determined by GC using hexadecane as an internal standard. Cy =
cyclohexyl.
As shown in Scheme 4 the tested monodentate ligands
(L1–L6) were not effective for the reaction (< 12% yield of
3a). However, the bidentate ligands Xantphos L16 and 1,2-
bis(dicyclohexylphosphino)ethane (DCPE; L17) gave
improved yields of 3a (33 and 61%, respectively). Notably,
in all reactions small amounts of the corresponding imine
were formed, which is in agreement with the proposed
mechanism (Scheme 3; intermediate B).
With the most promising ligand in hand, the influence of
temperature, solvent, and catalyst precursor on the model
reaction was further evaluated. Applying tert-amyl alcohol as
the solvent and heating to 1608C the product yield of 3a
increased to 90% (Table 1, entry 2). Changing the solvent to
n-heptane, toluene, 1,4-dioxane, and DMSO resulted in lower
yields of 3a (Table 1, entries 3–6). In addition, several other
catalyst precursors such as [RuHCl(CO)(PPh3)3],[20] [{Ru(p-
cymene)Cl2}2],[10c,d] and [{Cp*IrCl2}2][11] were also tested in
combination with L17 for the model reaction but gave low to
moderate yields (Table 1, entries 7–9). As expected the
reaction under ligand-free conditions only resulted in a
trace amount of product (Table 1, entry 11).
Table 1: Variation of reaction conditions for the synthesis of 3a.[a]
Entry
Catalyst
Solvent
Yield [%][b]
1
2
3
[Ru3(CO)12]
[Ru3(CO)12]
[Ru3(CO)12]
t-amyl alcohol
t-amyl alcohol
n-heptane
88[c]
90
9
4
5
6
7
8
9
10
11
[Ru3(CO)12]
[Ru3(CO)12]
[Ru3(CO)12]
toluene
1,4-dioxane
DMSO
t-amyl alcohol
t-amyl alcohol
t-amyl alcohol
t-amyl alcohol
t-amyl alcohol
34
41
8
26
2
42
66[f]
<1[g]
[RuHCl(CO)(PPh3)3][d]
[{Ru(p-cymene)Cl2}2][e]
[{Cp*IrCl2}2][e]
[Ru3(CO)12]
[Ru3(CO)12]
[a] Unless otherwise specified, all reactions were carried out with 1a
(1 mmol), 2a (1.1 mmol), [Ru3(CO)12] (0.02 mmol), and L17 (0.06 mol)
in t-amyl alcohol (1 mL) at 1608C for 24 h. [b] Yield of 3a determined by
GC using hexadecane as an internal standard. [c] Reaction time: 20 h.
[d] Catalyst (0.06 mmol), L17 (0.06 mmol). [e] Catalyst (0.03 mmol), L17
(0.06 mmol). [f] Catalyst (0.01 mmol), L17 (0.03 mol). [g] Catalyst
(0.02 mmol), ligand free. Cp*=h5-C5Me5, DMSO=dimethylsulfoxide.
Next, we examined the scope and limitations of this
ruthenium-catalyzed amination under the optimized reaction
conditions. As shown in Table 2, different a-hydroxy amides
and arylamines were effectively converted into the desired
amino acid amides. Both electron-withdrawing and electron-
donating substituents as well as ortho substitution on the aryl
ring of the anilines were tolerated (Table 2, entries 1–10).
More specifically, anilines containing electron-donating
methoxy or methyl substituents in the para position resulted
in higher product yields (Table 2, entries 2, 5, 7 and 8)
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Angew. Chem. Int. Ed. 2011, 50, 11197 –11201

Table 2: Amination of a-hydroxy amides 1 using different anilines.[a]
amide 1d (Table 2, entry 10) provided moderate yields of the
a-amination products.
Furthermore, our protocol was tested by applying differ-
ent alkylamines as the coupling partner. As shown in
Scheme 5, primary amines such as n-octylamine and cyclo-
Entry
1
1
2
Product 3
Yield
[%][b]
78
83
2
3
72
42
Scheme 5. Amination of a-hydroxy amides 1 using alkylamines.
[a] Yield of the isolated product.
4
hexylamine exhibited high reactivity and provided the
corresponding products in good to excellent yields upon
isolation (5a–5d). Under the same reaction conditions, the
secondary amine morpholine also showed good reactivity and
gave product 5e in 80% yield, while the reaction between
piperidine and 2-hydroxy-N,2-diphenylacetamide resulted in
5 f in only 20% yield. This latter result indicates that steric
factors are a major influence on the employed catalyst system.
Finally, we focused on the synthesis of a-amino acid
amides using ammonia, which is the most challenging
coupling partner.[11a,19a,20] To our delight, in all cases examined
the catalytic amination proceeded smoothly and furnished the
products in good yields (Scheme 6). The less-reactive a-
phenyl substituted amides were well tolerated and gave
products 6c, 6d, and 6e in moderate to excellent yields upon
5
6
7
8
91
56
89
78
9
79
61
10
[a] All reactions were carried out with 1 (1 mmol), 2 (1 mmol) [Ru3(CO)12]
(0.02 mmol) and L17 (0.06 mol) in t-amyl alcohol (1 mL) at 1608C for
24 h. [b] Yield of the isolated product.
compared with the electron-poor 4-chloroaniline 2 f (Table 2,
entry 6). Sterically hindered ortho-methoxy-substituted ani-
line 2d (Table 2, entry 4) as well as a-phenyl-substituted
Scheme 6. Direct amination of a-hydroxy amides 1 with ammonia.
[a] Yield of the isolated product. [b] Products arising from a-hydroxy
esters.
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Communications
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hydroxypropanoate can also be effectively employed for the
amination protocol and provided product 6a in 78% yield.
In summary, we have developed the first catalytic
aminations of a-hydroxy acid derivatives. Using a variety of
amines including anilines, primary and secondary aliphatic
amines, and ammonia, a wide range of amino acid amides is
easily available from a-hydroxy amides or esters. This atom-
efficient amination protocol proceeds efficiently in the
presence of a commercially available [Ru3(CO)12]/DCPE
catalyst system without special equipment.
Experimental Section
Typical procedure for the preparation of 2-(phenylamino)propan-
amide (3a): In a glass pressure tube (50 mL) under argon [Ru3(CO)12]
(12.8 mg, 0.02 mmol), 1,2-bis(dicyclohexylphosphino)ethane (25.3 mg,
0.06 mmol), 2-hydroxypropanamide (1a; 89 mg, 1 mmol), and aniline
(2a; 102 mg, 1.1 mmol) were dissolved in tert-amyl alcohol (1 mL).
Next, the pressure tube was closed and the resulting mixture was
stirred at reflux at 1608C in an oil bath for 24 h. After cooling down to
room temperature, the solvent was removed under vacuum. The
residue was directly purified by flash chromatography on silica gel
eluting with heptane/ethanol (15:1) to give 2-(phenylamino)propa-
namide (3a) as a white solid (128 mg, 78%). For the amination of a-
hydroxy amides using alkylamines and ammonia, see in the Support-
ing Information for a detailed procedure.
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Received: June 22, 2011
Published online: October 10, 2011
Keywords: amines · a-amino acid amides · a-hydroxy amides ·
.
homogeneous catalysis · ruthenium
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