Ruthenium-catalyzed oxidative cyanation of tertiary amines with hydrogen peroxide and sodium cyanide

Article abstract of DOI:10.1002/anie.200501496

(Chemical Equation Presented) Versatile intermediates for the synthesis of N-aryl-α-amino acids and N,N-disubstituted 1,2-diamines can now be synthesized with high efficiency by the ruthenium-catalyzed oxidative cyanation of tertiary amines. The use of hy

Full text of DOI:10.1002/anie.200501496

Angewandte
Chemie
by two methods, that is, with low-valent transition metals by
oxidative addition[2,5] or with metal–oxo species.[2,3]
Although various compounds can be used for the
oxidation of amines, hydrogen peroxide is the oxidant that
satisfies recent environmental and sustainable demands,
because water is the sole by-product. Therefore, catalytic
oxidation of substrates such as alkenes, alcohols, amines,
sulfides, and alkanes with H2O2 has been explored exten-
sively.[6,7] However, there are few examples for the introduc-
tion of an external functional group to substrates upon H2O2
oxidation.[7r,8] We report here that a carbon–carbon bond
forms at the a position (with respect to the nitrogen atom) of
tertiary amines under the H2O2 oxidation conditions. Thus,
the ruthenium-catalyzed oxidative cyanation of tertiary
amines with H2O2 in the presence of sodium cyanide or
hydrogen cyanide gives the corresponding a-aminonitriles
with high efficiency [Eq. (1)]. The reaction is, to the best of
ꢀ
our knowledge, the first example of direct C H activation and
ꢀ
C Cbond formation under H O2 oxidation conditions.
2
Oxidative Cyanations
DOI: 10.1002/anie.200501496
Ruthenium-Catalyzed Oxidative Cyanation of
Tertiary Amines with Hydrogen Peroxide and
Sodium Cyanide**
The catalytic activity for the oxidative cyanation of N,N-
dimethylaniline with H2O2 in the presence of sodium cyanide
was examined. RuCl3 was found to be the most effective
catalyst. [RuCl2(PPh3)3] and Pr4N[RuO4] show moderate
catalytic activity, while K4[Ru(CN)6] retards the reaction.
Methanol is the most effective solvent, although ethanol,
ethyl acetate, and acetonitrile can also be used. The addition
of acetic acid is necessary for the reaction with sodium
cyanide, as otherwise no reaction takes place.
As shown in Table 1, various tertiary amines can be
efficiently converted into the corresponding a-aminonitriles[9]
with H2O2 in the presence of sodium cyanide. Reaction of
substituted N,N-dimethylanilines bearing both electron-
donating and electron-withdrawing substituents gave the
corresponding cyanated products (entries 1–3). In the pres-
ence of other alkyl groups, the N-methyl group reacts
predominantly. For example, the reaction of N-methyl-N-
ethylaniline gave N-cyanomethyl-N-ethylaniline (8) along
with a small amount of N-(1-cyanoethyl)-N-methylaniline (9;
entry 4). The reaction can also be applied efficiently to cyclic
amines: Piperidine, pyrrolidine, and tetrahydroisoquinoline
derivatives can be converted into the corresponding a-
cyanoamines (entries 5–8). In terms of the substrate, oxida-
tive cyanation with H2O2 is more versatile than with
molecular oxygen;[10] for example, molecular oxygen cannot
be used for reactions with piperidine and pyrrolidine deriv-
atives. The ruthenium-catalyzed oxidative cyanation of N-(4-
methoxyphenyl)pyrrolidine (14) with H2O2 gave the corre-
sponding a-cyanated amine 15 in 80% yield (entry 7), while
the same reaction with molecular oxygen provided the
product in only 23% yield.
Shun-Ichi Murahashi,* Naruyoshi Komiya, and
Hiroyuki Terai
There has been much interest in the development of clean and
environmentally benign methods for the transformation of
amines into the corresponding a-functionalized compounds.
These compounds have proven to be versatile intermediates
and have been widely used in the construction of biologically
active nitrogen compounds such as alkaloids.[1] Direct intro-
duction of a substituent at the a position of tertiary amines is
ꢀ
performed in two steps: a-C H activation to produce
iminium ion intermediates and subsequent reaction with
nucleophiles.[2–4] The initial C H activation has been achieved
ꢀ
[*] Prof. Dr. S.-I. Murahashi,[+] Dr. N. Komiya, H. Terai
Department of Chemistry
Graduate School of Engineering Science
Osaka University
1–3 Machikaneyama, Toyonaka, Osaka 560-8531 (Japan)
E-mail: murahashi@high.ous.ac.jp
[+] Present address: Department of Applied Chemistry
Faculty of Engineering
Okayama University of Science
1–1 Ridaicho, Okayama, Okayama 700-0005 (Japan)
Fax: (+81)86-256-9513
[**] This work was supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science, and
Technology, Japan.
To gain insight into the reaction mechanism, the relative
reaction rates for the oxidative cyanation of four para-
substituted N,N-dimethylanilines (p-XC6H4NMe2; X = MeO,
Supporting information for this article is available on the WWW
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Table 1: Results of the ruthenium-catalyzed oxidative cyanation of
tertiary amines with hydrogen peroxide and NaCN [see Eq. (1)].[a]
lyzed oxidative cyanation of N-methyl-N-(trideuteriomethy-
l)aniline was found to be 4.1 by 1H NMR spectroscopy.
Similarly, the intermolecular deuterium isotope effect for the
oxidative cyanation of an equimolar mixture of N,N-dime-
thylaniline and N,N-bis(trideuteriomethyl)aniline was deter-
mined to be 3.7. These intra- and intermolecular isotope
effects are larger than those observed for N-demethylation
with cytochrome P450 (1.6–3.1,[11] and 1.0–1.1[12]), suggesting
Entry Substrate
t [h] Product
Yield [%][b]
1
2
90 (80)[c]
2
1.5
3
81
67
63
ꢀ
that cleavage of the C H bond proceeds via an intermediate
bearing more ionic character. Under consideration of these
data, the present reaction can be rationalized by assuming the
cytochrome P450 type mechanism, as shown in Scheme 1. The
3
4[d]
1.5
5
2
69[e]
73[e]
80[e]
83[e]
6[f]
7[g]
8
1.5
1.5
1.5
Scheme 1. The proposed reaction mechanism for the ruthenium-cata-
lyzed oxidative cyanation of tertiary amines with H2O2.
[a] The reaction was carried out as follows: A 30% aqueous solution of
H2O2 (2.5 mmol) was added dropwise over a period of 1 h to a mixture of
amine (1.0 mmol), RuCl3 (0.05 mmol), NaCN (1.2 mmol), and
CH3CO2H (6 mmol) in MeOH (1.2 mL). The reaction mixture was then
stirred for the given amount of time. [b] Determined by GLC using an
internal standard. [c] Yield of the isolated product. [d] A small amount of
low-valent ruthenium species [Run] undergoes reaction with
H2O2 to give the oxo–ruthenium species [Run+2 O], which
=
produces an iminium ion intermediate by electron transfer
and subsequent hydrogen transfer. Nucleophilic attack by
hydrogen cyanide on the iminium ion intermediate provides
the corresponding a-cyanated products, water, and the [Run]
species to complete the catalytic cycle.
9
was also formed. [e] Determined by 1H NMR spectroscopy.
[f] 1.5 mmol of H2O2 was used. [g] 1.0 mmol of H2O2 was used.
The participation of hydrogen cyanide, which is formed
from sodium cyanide and acetic acid under the reaction
conditions,[13] was confirmed by the following reactions: The
ruthenium-catalyzed oxidation of N,N-dimethylaniline with
H2O2 in the presence of hydrogen cyanide in methanol gave
the corresponding a-aminonitrile 2 in 80% yield (Scheme 2).
The analogous reaction with N-phenyltetrahydroisoquinoline
provided the a-cyanated tetrahydroisoquinoline 17 in 97%
yield.
Me, H, Br) with H2O2 in the presence of sodium cyanide were
1
determined by H NMR spectroscopy of the resulting cya-
nated products. The rate data correlate well (R2 = 0.998) with
the Hammett linear free energy relationship with use of s
values (Figure 1).
The 1 value was determined to be ꢀ3.61, indicating a
cationic intermediate at the rate-determining step. The intra-
molecular deuterium isotope effect for the ruthenium-cata-
The oxidative cyanation of tertiary amines provides a
convenient method for synthesizing various compounds,
Figure 1. Hammett plot for the RuCl3-catalyzed oxidative cyanation of
the para-substituted N,N-dimethylanilines p-XC6H4NMe2 (X=MeO,
Me, H, Br) with H2O2 in the presence of NaCN.
Scheme 2. The ruthenium-catalyzed oxidative cyanation of tertiary
amines with H2O2 in the presence of HCN. Reaction conditions: RuCl3
(5 mol%), H2O2 (1.5 equiv), MeOH, RT, 24 h (1!2) or 4 h (16!17).
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including N-aryl-a-amino acids[14,15] and N,N-disubstituted
1,2-diamines. Upon hydrolysis, 2-cyano-N-4’-methoxyphe-
nyl)pyrrolidine (15) can be converted into N-(4’-methoxy-
phenylproline (18) in 69% yield, while the reduction of 15
with LiAlH4 provides 2-aminoethyl-N-(4’-methoxyphenyl)-
pyrrolidine (19) in 99% yield. Quinoline skeletons can also be
constructed from tertiary arylamines by iminium ion cycliza-
tion. Typically, the TiCl4-promoted reaction of a-aminonitrile
2, derived from oxidative cyanation of 1 with allyltrimethyl-
silane in CH2Cl2 at ꢀ788C, gave 1-methyl-4-trimethylsilyl-
methyl-1,2,3,4-tetrahydroquinoline (20) in 75% yield.
In conclusion, we have demonstrated the novel ruthe-
nium-catalyzed oxidative cyanation of tertiary amines with
hydrogen peroxide. The reaction proceeds with high effi-
ciency to give the corresponding a-cyanated amines, and thus
provides a useful method for the synthesis of various nitrogen
compounds from tertiary amines. Research is currently
underway to elucidate the mechanism and to apply the
principle to other catalytic systems.
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Keywords: amines · cyanides · hydrogen peroxide · oxidation ·
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