Ruthenium-catalyzed oxidative cyanation of tertiary amines with molecular oxygen or hydrogen peroxide and sodium cyanide: Sp3 C-H bond activation and carbon-carbon bond formation

Article abstract of DOI:10.1021/ja8017362

Ruthenium-catalyzed oxidative cyanation of tertiary amines with molecular oxygen in the presence of sodium cyanide and acetic acid gives the corresponding α-aminonitriles, which are highly useful intermediates for organic synthesis. The reaction is the first demonstration of direct sp³ C-H bond activation α to nitrogen followed by carbon-carbon bond formation under aerobic oxidation conditions. The catalytic oxidation seems to proceed by (i) α-C-H activation of tertiary amines by the ruthenium catalyst to give an iminium ion/ruthenium hydride intermediate, (ii) reaction with molecular oxygen to give an iminium ion/ruthenium hydroperoxide, (iii) reaction with HCN to give the α-aminonitrile product, H₂O₂, and Ru species, (iv) generation of oxoruthenium species from the reaction of Ru species with H₂O₂, and (v) reaction of oxoruthenium species with tertiary amines to give α-aminonitriles. On the basis of the last two pathways, a new type of ruthenium-catalyzed oxidative cyanation of tertiary amines with H₂O₂ to give α-aminonitriles was established. The α-aminonitriles thus obtained can be readily converted to α-amino acids, diamines, and various nitrogen-containing heterocyclic compounds.

Full text of DOI:10.1021/ja8017362

Published on Web 07/23/2008
Ruthenium-Catalyzed Oxidative Cyanation of Tertiary Amines
with Molecular Oxygen or Hydrogen Peroxide and Sodium
3
Cyanide: sp C-H Bond Activation and Carbon-Carbon Bond
Formation
,†,‡
†
†
†
Shun-Ichi Murahashi,*
Takahiro Nakae, Hiroyuki Terai, and Naruyoshi Komiya
Department of Chemistry, Graduate School of Engineering Science, Osaka UniVersity,
1
-3 Machikaneyama, Toyonaka, Osaka 560-8531, Japan, and Department of Applied Chemistry,
Faculty of Engineering, Okayama UniVersity of Science, 1-1 Ridaicho, Okayama,
Okayama 700-0005, Japan
Received March 8, 2008; E-mail: murahashi@high.ous.ac.jp
Abstract: Ruthenium-catalyzed oxidative cyanation of tertiary amines with molecular oxygen in the presence
of sodium cyanide and acetic acid gives the corresponding R-aminonitriles, which are highly useful
3
intermediates for organic synthesis. The reaction is the first demonstration of direct sp C-H bond activation
R to nitrogen followed by carbon-carbon bond formation under aerobic oxidation conditions. The catalytic
oxidation seems to proceed by (i) R-C-H activation of tertiary amines by the ruthenium catalyst to give an
iminium ion/ruthenium hydride intermediate, (ii) reaction with molecular oxygen to give an iminium ion/
ruthenium hydroperoxide, (iii) reaction with HCN to give the R-aminonitrile product, H
iv) generation of oxoruthenium species from the reaction of Ru species with H
oxoruthenium species with tertiary amines to give R-aminonitriles. On the basis of the last two pathways,
a new type of ruthenium-catalyzed oxidative cyanation of tertiary amines with H to give R-aminonitriles
2
O
2
, and Ru species,
(
2 2
O , and (v) reaction of
2
O
2
was established. The R-aminonitriles thus obtained can be readily converted to R-amino acids, diamines,
and various nitrogen-containing heterocyclic compounds.
Introduction
Catalytic functionalization of amines by direct C-H activa-
Scheme 1. Substitution at the R Position of Tertiary Amines by (a)
C-H Activation with MdO Species and (b) C-H Activation with
Low-Valence Metal Complexes
tion has attracted much interest in organic chemistry and the
fine chemical industry in recent years, since functionalized
amines are versatile intermediates and have been widely used
in the construction of biologically active compounds and
functional materials. Direct introduction of a substituent at the
R position of tertiary amines would be performed by R-C-H
activation and subsequent carbon-carbon bond formation. In
3
order to activate sp C-H bonds of tertiary amines, one can
use two strategies: (i) C-H activation upon treatment with
oxometal (MdO) species such as cytochrome P-450 enzyme
1,2
The former strategy is oxidative activation of R-C-H bonds
of tertiary amines. In order to generate reactive species for
selective oxidation, much effort has been devoted to simulation
(
Scheme 1a) and (ii) C-H activation with low-valence metal
3
catalysts at the R position of amines (Scheme 1b). In either
case, generation of iminium ion intermediates followed by
reactions with carbon pronucleophiles would give R-substituted
products, as shown in Scheme 1.
1
,2
of the functions of cytochrome P-450. One of the typical
functions of cytochrome P-450 is chemoselective demethylation
of N-methyl tertiary amines. In 1988, we found that ruthenium-
catalyzed oxidation of tertiary amines with t-BuOOH gives
†
Osaka University.
Okayama University of Science.
4
‡
R-tert-butyldioxyamines (6a), as shown in Scheme 2.
(
1) (a) Cytochrome P-450, Structure, Mechanism, and Biochemistry, 2nd
ed.; Ortiz de Montellano, P. R., Ed.; Plenum Press: New York, 1995.
(
b) Gorrod, J. W. Biological Oxidation of Nitrogen; Elsevier/North
(3) (a) Murahashi, S.-I.; Takaya, H. Acc. Chem. Res. 2000, 33, 225–233.
(b) Murahashi, S.-I.; Naota, T. Bull. Chem. Soc. Jpn. 1996, 69, 1805–
1824. (c) Handbook of C-H Transformations: Applications in Organic
Synthesis; Dyker, G., Ed.; Wiley-VCH: Weinheim, Germany, 2005.
(d) Campos, K. R. Chem. Soc. ReV. 2007, 36, 1069–1084. (e) Godula,
K.; Sames, D. Science 2006, 312, 67–72. (f) Tobisu, M.; Chatani, N.
Angew. Chem., Int. Ed. 2006, 45, 1683–1684.
Holland Biomedical Press: New York, 1978.
(
2) (a) Murahashi, S.-I. Pure Appl. Chem. 1992, 64, 403–412. (b)
Murahashi, S.-I. Angew. Chem., Int. Ed. Engl. 1995, 34, 2443–2465.
(
c) Murahashi, S.-I.; Komiya, N. In Ruthenium in Organic Synthesis;
Murahashi, S.-I., Ed.; Wiley-VCH: Weinheim, Germany, 2004; pp
5
3-93. (d) Murahashi, S.-I.; Imada, Y. In Transition Metals for
Organic Synthesis; Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim,
Germany, 2004; Vol. 2, pp. 497-507.
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10.1021/ja8017362 CCC: $40.75

2008 American Chemical Society
J. AM. CHEM. SOC. 2008, 130, 11005–11012 9 11005

A R T I C L E S
Murahashi et al.
Scheme 2. Two-Step Oxidative Functionalization of a C-H Bond
in Tertiary Amines
group exchange reactions and hydrolysis reactions of tertiary
3
amines, we concluded that activation of an sp C-H bond of a
tertiary amine by low-valence transition-metal catalysts generally
2
b,9
occurs, giving an iminium ion-metal complex (5).
This is
in contrast to activation of a primary or secondary amine, which
As shown in Scheme 1b,
coordination of the nitrogen to the metal and overlap of the
1
0,11
gives an imine-metal complex.
metal orbital with the R-C-H bond would induce C-H
2
activation to form the η -iminium hydride metal complex 5.
This has been proved by racemization experiments at the chiral
The products 6a can be converted into the corresponding
secondary amines upon hydrolysis similar to enzyme reactions.
R carbon of tertiary amines and deuterium-labeling experiments
1
9
at the R and ꢀ positions. Isolation of the Pd-iminium ion
This cytochrome P-450-type oxidation reaction can be applied
to various substrates. Thus, ruthenium-catalyzed oxidations of
complex and determination of its structure by X-ray diffraction
12
have been performed elegantly by Lu and Peters. Similar C-H
4
,5
6
tertiary amines and amides with peroxides give the corre-
activation in ruthenium cluster-catalyzed alkyl-exchange reac-
sponding R-oxygenated products highly efficiently, while oxida-
13
tions has been demonstrated by Wilson and Laine. This C-H
7
tive transformation of secondary amines gives imines. Strained
activation is the key step in the asymmetric isomerization of
allylamines to enamines in the industrially important chiral
and unstable of azetidinone molecules can be oxidized selec-
tively. Thus, ruthenium-catalyzed oxidation of ꢀ-lactams with
14
menthol synthesis.
6
peracetic acid in acetic acid gives 4-acetoxy-2-azetidinones.
Other attractive metal-catalyzed C-H activations of tertiary
By means of an industrial process, 100 tons per year of 7 is
now being produced as a versatile intermediate for synthesis of
fourth-generation antibiotics (eq 1).
15
amines have been reported. Murai, Chatani et al. demonstrated
that tertiary amines bearing an N-2-pyridyl group undergo
R-C-H activation adjacent to nitrogen and subsequent carbo-
nylation or coupling with an olefin by a pendant directing group
1
6
to chelate the metal catalyst. Sames and co-workers reported
the elegant iridium-catalyzed formation of pyrrolizidinones from
N-acylated pyrrolidines, which relied on direct R-C-H insertion
followed by intramolecular C-C bond formation with an olefin
tether. Insertion of carbenoids into C-H bonds adjacent to
nitrogens of tertiary amines has been found to proceed selec-
The R-oxygenated products 6 are useful synthetic intermedi-
ates because they can be easily transformed into the corre-
sponding R-functionalized compounds 3 by reaction with various
17
tively.
In a search for an environmentally benign and effective
method for direct oxidative transformation of amines, we aimed
8
carbon nucleophiles (Scheme 2). Typically, the reaction of
R-tert-butyldioxyamines 6a with allyltrimethylsilane gives R-al-
8a
lylated amines. Interestingly, an intramolecular version of the
carbon-carbon bond formation can be applied to the synthesis
of cyclic compounds via olefin-iminium ion cyclization.
Typically, N-methyl-N-2-(1-cyclohexenyl)ethylaniline (8) can
be converted into cis-R-hydroxy-2-phenyldecahydroisoquinoline
(
7) (a) Murahashi, S.-I.; Naota, T.; Taki, H. J. Chem. Soc., Chem. Commun.
1985, 613–614. (b) Murahashi, S.-I.; Okano, Y.; Sato, H.; Nakae, T.;
Komiya, N. Synlett 2007, 1675–1678. (c) Murahashi, S.-I.; Shiota, T.
Tetrahedron Lett. 1987, 28, 2383–2386. (d) Murahashi, S.-I.; Mitsui,
H.; Shiota, T.; Tsuda, T.; Watanabe, S. J. Org. Chem. 1990, 55, 1736–
1
744. (e) Mitsui, H.; Zenki, S.; Shiota, T.; Murahashi, S.-I. J. Chem.
(9) by ruthenium-catalyzed oxidation followed by treatment with
Soc., Chem. Commun. 1984, 874–875.
(
(
8) (a) Naota, T.; Nakato, T.; Murahashi, S.-I. Tetrahedron Lett. 1990,
an aqueous CF3CO2H solution (eq 2): Furthermore, stereose-
3
1, 7475–7478. (b) Murahashi, S.-I.; Naota, T.; Nakato, T. Synlett
1
992, 835–836. (c) Murahashi, S.-I.; Mitani, A.; Kitao, K. Tetrahedron
Lett. 2000, 41, 10245–10249.
9) (a) Murahashi, S.-I.; Hirano, T.; Yano, T. J. Am. Chem. Soc. 1978,
1
00, 348–350. (b) Murahashi, S.-I.; Watanabe, T. J. Am. Chem. Soc.
979, 101, 7429–7430.
1
(
10) (a) Yoshimura, N.; Moritani, I.; Shimamura, T.; Murahashi, S.-I. J. Am.
Chem. Soc. 1973, 95, 3038–3039. (b) Yoshimura, N.; Moritani, I.;
Shimamura, T.; Murahashi, S.-I. J. Chem. Soc., Chem. Commun. 1973,
lective biomimetic construction of the piperidine skeleton 11
4
3
07–308. (c) Murahashi, S.-I.; Yoshimura, N.; Tsumiyama, T.; Kojima,
from N-methylhomoallylamine (10) has been achieved (eq 3):
T. J. Am. Chem. Soc. 1983, 105, 5002–5011.
(
(
11) Yi, C. S.; Yun, S. Y.; Guzei, I. A. Organometallics 2004, 23, 5392–
5
395.
12) A Pd-iminium ion complex was isolated, and its structure was
determined by X-ray diffraction studies. See: Lu, C. C.; Peters, J. C.
J. Am. Chem. Soc. 2004, 126, 15818–15832.
(
(
13) Wilson, R. B., Jr.; Laine, R. M. J. Am. Chem. Soc. 1985, 107, 361–
3
69.
The second strategy for R-C-H activation adjacent to
nitrogen can be achieved upon treatment with low-valence
transition-metal complexes, as depicted in Scheme 1b. In 1978,
on the basis of our findings on transition-metal-catalyzed alkyl-
14) Tani, K.; Yamagata, T.; Akutagawa, S.; Kumobayashi, H.; Taketomi,
T.; Takaya, H.; Miyashita, A.; Noyori, R.; Otsuka, S. J. Am. Chem.
Soc. 1984, 106, 5208–5217.
(
15) Chatani, N.; Asaumi, T.; Yorimitsu, S.; Ikeda, T.; Kakiuchi, F.; Murai,
S. J. Am. Chem. Soc. 2001, 123, 10935–10941, and references cited
therein.
(
(
5) Murahashi, S.-I.; Naota, T.; Miyaguchi, N.; Nakato, T. Tetrahedron
Lett. 1992, 33, 6991–6994.
(16) (a) DeBoef, B.; Pastine, S. J.; Sames, D. J. Am. Chem. Soc. 2004,
126, 6556–6557. (b) Pastine, S. J.; Gribkov, D. V.; Sames, D. J. Am.
Chem. Soc. 2006, 128, 14220–14221.
6) (a) Murahashi, S.-I.; Naota, T.; Kuwabara, T.; Saito, T.; Kumobayashi,
H.; Akutagawa, S. J. Am. Chem. Soc. 1990, 112, 7820–7822. (b)
Murahashi, S.-I.; Saito, T.; Naota, T.; Kumobayashi, H.; Akutagawa,
S. Tetrahedron Lett. 1991, 32, 5991–5994.
(17) (a) Davies, H. M. L.; Venkataramani, C.; Hansen, T.; Hopper, D. W.
J. Am. Chem. Soc. 2003, 125, 6462–6468. (b) Axten, J. M.; Ivy, R.;
Krim, L.; Winkler, J. D. J. Am. Chem. Soc. 1999, 121, 6511–6512.
1
1006 J. AM. CHEM. SOC. 9 VOL. 130, NO. 33, 2008

Ruthenium-Catalyzed Oxidative Cyanation
A R T I C L E S
Table 1. Catalytic Activities for Oxidative Cyanation of 12 with
at direct oxidative cyanation of tertiary amines by simultaneously
accomplishing two challenging tasks: (1) oxidation with mo-
lecular oxygen, an environmentally benign oxidant, and (2)
trapping of the iminium ion intermediates with a carbon
nucleophile under oxidative conditions to give a carbon-carbon
bond-formation product. Here we report that ruthenium-
catalyzed oxidative cyanation of tertiary amines with molecular
oxygen in the presence of sodium cyanide gives the correspond-
a
Molecular Oxygen
b
b
entry
catalyst
conversion (%)
yield of 13 (%)
1
2
3
4
5
6
7
8
9
RuCl3
99
99
99
99
93
99
86
44
34
93
89
93
79
80
65
76
40
26
K2[RuCl5(H2O)]
Ru2(OAc)4Cl
RuCl2(PPh3)3
Ru(bpy)2Cl2
Pr4NRuO4
RuO2
1
8
ing R-aminonitriles highly efficiently (eq 4):
MnCl2
CuCl2
a
A mixture of 12 (1.0 mmol), catalyst (0.05 mmol), NaCN (1.2
mmol), and CH3CO2H (6 mmol) in methanol (1.2 mL) was stirred under
b
O2 (1 atm) at 60 °C for 2 h. Determined by GLC analysis using an
internal standard.
This is the first reported example of an aerobic catalytic
method for carbon-carbon bond formation under oxidative
conditions. The method is environmentally benign and highly
useful for organic synthesis. The R-aminonitriles thus obtained
exhibit valuable reactivities and are versatile intermediates for
Table 2. Effect of Solvents on Ruthenium-Catalyzed Oxidative
a
Cyanation of 12 with Molecular Oxygen
b
b
entry
solvent
time (h)
conversion (%)
yield of 13 (%)
1
9
organic synthesis. The nitrile functionality can be hydrolyzed
readily to produce R-amino acids. Nucleophilic addition to the
nitrile group provides valuable access to R-amino aldehydes,
1
2
3
4
5
6
7
8
9
CH3OH
1
2
1
1
1
2
1
1
1
1
52
99
<1
42
98
99
48
60
24
22
51
93
trace
34
88
88
40
40
16
3
CH OH
3
c
CH3OH
1
8b,19
CH CO H
3
2
R-amino ketones, R-amino alcohols, and 1,2-diamines.
C2H5OH
C2H5OH
i-PrOH
EtOAc
CH3CN
H2O
On the basis of a mechanistic investigation of the aerobic
oxidative cyanation reaction, we found that similar oxidative
cyanation occurs upon treatment with hydrogen peroxide. Thus,
ruthenium-catalyzed oxidative cyanation of tertiary amines with
hydrogen peroxide in the presence of sodium cyanide gives the
1
0
2
0
corresponding R-aminonitriles highly efficiently (eq 5):
a
A mixture of 12 (1.0 mmol), RuCl3 (0.05 mmol), NaCN (1.2
mmol), and CH3CO2H (6 mmol) in solvent (1.2 mL) was stirred under
b
O2 (1 atm) at 60 °C for 2 h. Determined by GLC analysis using an
c
internal standard. Reaction conducted in the absence of acetic acid.
and hydrolysis reactions of tertiary amines occur via R-C-H
2
1,22
Recently, Li and co-workers
reported interesting copper-
activation followed by formation of an iminium ion intermedi-
9
catalyzed oxidative R-functionalizations of tertiary amines using
tert-butyl hydroperoxide in the presence of carbon pronucleo-
philes. Thus, copper-catalyzed oxidation of tertiary amines with
ate, we attempted in vain to trap the iminium ion intermediate
with a carbon nucleophile. However, we succeeded in trapping
the intermediate under oxidative conditions. We examined
catalytic aerobic oxidation of N,N-dimethylaniline (12) in the
presence of sodium cyanide (eq 6): The activities of various
2
1a
21b
t-BuOOH in the presence of alkynes,
indoles,
2
1c
21d
nitromethane,
and malonates
gives the corresponding
2
3
R-substituted amines. Doyle and co-workers reported unique
dirhodium-catalyzed oxidative carbon-carbon bond formation
in tertiary amines upon treatment with t-BuOOH in the presence
of siloxyfuranes.
In this paper, full details regarding the scope and reaction
mechanism of aerobic ruthenium-catalyzed oxidative cyanation
of tertiary amines as well as of the similar oxidative cyanation
reaction with H2O2 are described.
catalysts are summarized in Table 1. RuCl3, K2[RuCl5(H2O)],
and Ru2(CH3CO2)4Cl (entries 1-3, respectively) proved to be
excellent catalysts for aerobic oxidative cyanation, while
RuCl2(PPh3)3, Ru(bpy)2Cl2, Pr4NRuO4, and RuO2 (entries 4-7,
respectively) showed moderate catalytic activities. Ruthenium
complex catalysts such as Ru3O(OAc)6(H2O)3, [Ru(CO)3Cl2]2,
Results and Discussion
Ruthenium-Catalyzed Oxidative Cyanation of Tertiary
Amines with Molecular Oxygen. On the basis of our previous
findings that transition-metal-catalyzed alkyl-group exchange
2
4
5
% Ru/C, K4Ru(CN)6, and Ru(TPFPP)(CO) and metal salt
catalysts such as MnCl2 (entry 8), CuCl2 (entry 9), and FeCl3
showed low catalytic activities.
The effect of the solvent was dramatic, as shown in Table 2.
Methanol and ethanol were excellent solvents, but 2-propanol
and ethyl acetate were not. Acetonitrile and water resulted in
very low conversion. It is important to note that acetic acid is
(
18) (a) Murahashi, S.-I.; Komiya, N.; Terai, H.; Nakae, T. J. Am. Chem.
Soc. 2003, 125, 15312–15313. Introduced as a highlight; see: (b) North,
M. Angew. Chem., Int. Ed. 2004, 43, 4126–4128.
(
(
19) Enders, D.; Shilvock, J. P. Chem. Soc. ReV. 2000, 29, 359–373.
20) Murahashi, S.-I.; Komiya, N.; Terai, H. Angew. Chem., Int. Ed. 2005,
4
4, 6931–6933.
(
21) (a) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2004, 126, 11810–11811. (b)
Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 6968–6969. (c) Li, Z.;
Li, C.-J. J. Am. Chem. Soc. 2005, 127, 3672–3673. (d) Li, Z.; Li,
C.-J. Eur. J. Org. Chem. 2005, 3173–3176.
essential: no cyanation took place in the absence of acetic acid
-
(
entry 3), indicating that the reagent is HCN rather than CN .
(
(
22) Basl e´ , O.; Li, C.-J. Green Chem. 2007, 9, 1047–1050.
23) Catino, A. J.; Nichols, J. M.; Nettles, B. J.; Doyle, M. P. J. Am. Chem.
Soc. 2006, 128, 5648–5649.
(24) (a) Murahashi, S.-I.; Naota, T.; Komiya, N. Tetrahedron Lett. 1995,
36, 8059–8062. (b) Groves, J. T.; Bonchio, M.; Carofiglio, T.;
Shalyaev, K. J. Am. Chem. Soc. 1996, 118, 8961–8962.
J. AM. CHEM. SOC. 9 VOL. 130, NO. 33, 2008 11007

A R T I C L E S
Murahashi et al.
Table 3. Aerobic Ruthenium-Catalyzed Oxidative Cyanation of
a
Tertiary Amines with Sodium Cyanide
Figure 1. Effect of temperature on RuCl3-catalyzed oxidative cyanation
with molecular oxygen. Conditions: 12 (1.0 mmol), RuCl3 (0.05 mmol),
NaCN (1.2 mmol), and CH3CO2H (6 mmol) in methanol (1.2 mL) stirred
under O2 (1 atm) for 2 h.
The reaction was found to be extremely sensitive to the
reaction temperature. The effect of temperature on oxidative
cyanation of 12 is shown in Figure 1. The product yield
increased from 1 to 93% when the reaction temperature was
raised from 20 to 60 °C. The maximum yield was obtained at
6
0 °C, above which the yield rapidly decreased with increasing
reaction temperature.
Typical results for ruthenium-catalyzed aerobic oxidative
cyanation of tertiary amines are summarized in Table 3. The
reaction of 12 with sodium cyanide (1.2 equiv) in the presence
of RuCl3 catalyst and acetic acid in methanol under molecular
oxygen (1 atm, balloon) at 60 °C for 2 h gave N-methyl-N-
phenylaminoacetonitrile in 88% isolated yield [93% yield by
gas-liquid chromatography (GLC)] (entry 1). The other prod-
ucts formed were N-methylaniline (<3% GLC yield) and
N-methylformanilide (trace). The reaction can be applied to
substituted N,N-dimethylanilines bearing either electron-donating
or electron-withdrawing groups (entries 2-7). It is noteworthy
that the present reaction tolerates other functional groups such
as bromine (entry 7), which is reactive toward low-valence
ruthenium species. The N-methyl group was oxidized chemose-
lectively in the presence of other alkyl groups. Thus, the reaction
of N-ethyl-N-methylaniline (entry 8) gave N-ethyl-N-pheny-
laminoacetonitrile in 57% yield along with 2-(N-methyl-N-
phenylamino)propionitrile (4%). This is due to a steric effect,
similar to that observed in chemoselective N-methyl oxidation
using cytochrome P-450. The oxidative cyanation of N-phenyl-
a
A mixture of tertiary amine (1.0 mmol), RuCl3 (0.05 mmol), NaCN
(
1.2 mmol), and CH3CO2H (6 mmol) in methanol (1.2 mL) was stirred
under O2 (1 atm) at 60 °C. Isolated yield, unless otherwise noted.
b
c
d
Determined by GLC analysis using an internal standard. Determined
1
e
by H NMR analysis. Ru(bpy)2Cl2 was used instead of RuCl3.
2
correlated (r ) 0.999) with the substituent constant (σ) values
of the Hammett linear free energy relationship (Figure 2). The
value of the Hammett reaction constant (F) for this catalyst was
3.35 (entry 1 in Table 4), which is larger than the value of
0.84 obtained for the RuCl2(PPh3)3-catalyzed oxidation of the
25
1
,2,3,4-tetrahydroisoquinoline (entry 9) took place selectively
at the C1 position, affording the corresponding R-cyanated
compound in 79% yield. The reaction is very simple and
convenient and can be applied in a preparative-scale synthesis.
Typically, the reaction of N,N-dimethyl-4-methylaniline (4.1 g,
-
-
same amines with t-BuOOH to give R-tert-butyldioxyamines
4
(
entry 3). The negative value of F indicates cationic interme-
3
0 mmol) with NaCN (36 mmol) in the presence of acetic acid
diacy in the rate-determining step.
in methanol at 60 °C gave N-methyl-N-(4-methylphenyl)aceto-
nitrile in 90% isolated yield (4.3 g). Tertiary alkylamines such
as tributylamine and N-methylpyrrolidine did not undergo
reaction under the present reaction conditions.
The intra- and intermolecular deuterium isotope effects (kH/
kD) for the RuCl3-catalyzed oxidative cyanation of N,N-
dimethylanilines and their deuterated analogues were determined
to be 2.40 and 2.62, respectively (entry 1 of Table 4). These
observed isotope effects are larger than the corresponding ones
observed for N-demethylation with cytochrome P-450
The present reaction is very simple; however, the reaction
mechanism is not so simple, and its elucidation is of great
interest. In order to clarify the mechanism, the relative rates of
oxidative cyanation of para-substituted N,N-dimethylanilines (p-
XC6H4NMe2, where X ) MeO, Me, H, Br) with molecular
oxygen in the presence of sodium cyanide were examined by
2
6
27
(
1.6-3.1 and 1.0-1.1 ) (entry 5), suggesting that cleavage
(
25) (a) Hammett, L. P. Chem. ReV. 1935, 17, 125–136. (b) McDaniel,
D. H.; Brown, H. C. J. Org. Chem. 1958, 23, 420–427. (c) Hine, J.
Structural Effects on Equilibria in Organic Chemistry; Wiley: New
York, 1975; Chapter 3.
1
H NMR analysis of the corresponding cyanated products. The
measured rates for the RuCl3-catalyzed reaction were well-
1
1008 J. AM. CHEM. SOC. 9 VOL. 130, NO. 33, 2008

Ruthenium-Catalyzed Oxidative Cyanation
A R T I C L E S
32
of alcohols, and ruthenium-catalyzed oxidative transformation
3
3
of primary amines to nitriles. Subsequent reaction of the
n
iminium ion/Ru OOH complex 16 with HCN, which is gener-
3
4
ated from NaCN and acetic acid under the reaction conditions,
n
n
gives the R-aminonitrile 19, Ru , and H2O2. Reaction of Ru
n+2
5,35
with the newly-formed H2O2 yields the Ru dO species 17,
which reacts with another tertiary amine 1 to give the iminium
ion intermediate 18 by electron transfer and subsequent hydro-
4
gen transfer. The iminium ion intermediate 18 can be trapped
n
with cyanide to afford 19, Ru , and water, thereby completing
the catalytic cycle. At the stage of the mechanism involving
the transformation from 16 to 17, an alternative direct pathway
via protonolysis of 16 to give 17 cannot be excluded. It was
confirmed that oxidative cyanation of tertiary amines with H2O2
to give R-aminonitriles occurred. The corresponding N-oxide
of 12 could not be detected under the reaction conditions,
although the RuCl3-catalyzed aerobic oxidation of tertiary
Figure 2. Hammett plots for RuCl3-catalyzed oxidative cyanation of para-
substituted N,N-dimethylanilines (p-XC6H4NMe2 with X ) MeO, Me, H,
Br) with molecular oxygen (b) and hydrogen peroxide (×).
of the C-H bond proceeds via an intermediate bearing greater
ionic character. The intramolecular deuterium isotope effects
for the para-substituted N-methyl-N-trideuteromethylanilines
p-X-C6H4NMeCD3 (X ) MeO, Me, H, Br) were dependent on
the substituent σ values: the kH/kD values were 4.2, 3.1, 2.4,
and 1.1, respectively. Thus, the values decreased on going from
electron-donating to electron-withdrawing substituents, indicat-
ing that electron transfer from the amine to the ruthenium would
36
amines has been reported. The mechanism involving oxidation
with the N-oxide can thus be excluded. It is noteworthy that
22
Basl e´ and Li recently reported similar CuBr-catalyzed aerobic
oxidative alkylation of isoquinolines with nitromethane.
Ruthenium-Catalyzed Oxidative Cyanation of Tertiary
Amines with Hydrogen Peroxide. Given the reaction mechanism
described above, we expected that ruthenium-catalyzed oxidative
cyanation with H2O2 would occur, and indeed, RuCl3-catalyzed
oxidative cyanation of 12 with H2O2 in the presence of cyanide
gave the corresponding R-cyanated amines highly efficiently.
We examined the catalytic activities of various metal catalysts
for the oxidative cyanation of 12 with H2O2 via eq 7, and
2
8
take place in the initial step.
The results of measurements of molecular oxygen uptake
showed that 1 mol of molecular oxygen was consumed for every
2
mol of 12 oxidized under the standard reaction conditions,
indicating that one molecule of molecular oxygen is used for
the formation of two iminium ion intermediates, which are
trapped with cyanide to give the corresponding R-aminonitrile.
The reaction can be rationalized in terms of the mechanism
shown in Scheme 3. In this mechanism, the tertiary amine 1
n
coordinates to the low-valence ruthenium species Ru , yielding
1
4. Electron transfer and subsequent hydrogen transfer from
the amine to ruthenium results in the formation of an iminium
9
ion/ruthenium hydride complex (15), which undergoes reaction
n
with molecular oxygen to form an iminium ion/Ru OOH
representative results are given in Table 5.
complex (16). Such oxidation of a metal hydride (M-H) species
We found that the trend of catalytic activities for oxidation
with H O is similar to that described above for oxidation with
2
9,30
with molecular oxygen to give a MOOH species
was
2
2
demonstrated for the first time by asymmetric oxypalladation
molecular oxygen. As shown in Table 5, ruthenium complex
catalysts showed high catalytic activities. Among them, RuCl3
proved to be the best catalyst. Various solvents can be used for
the present reaction. We found that methanol is the best solvent,
although ethanol, ethyl acetate, acetonitrile, and dichloromethane
can also be used. The addition of acetic acid was necessary for
the reaction with sodium cyanide, and no reaction took place
in the absence of acetic acid.
Representative results for oxidative cyanation of tertiary
amines with H2O2 in the presence of sodium cyanide are
provided in Table 6. Various tertiary amines can be converted
into the corresponding R-aminonitriles highly efficiently. The
reaction of substituted N,N-dimethylanilines bearing either
2
9
of allylphenols and then by palladium-catalyzed aerobic
3
1
oxidation of alcohols, ruthenium-catalyzed aerobic oxidation
(
26) (a) Shono, T.; Toda, T.; Oshino, N. J. Am. Chem. Soc. 1982, 104,
639–2641. (b) Miwa, G. T.; Garland, W. A.; Hodshon, B. J.; Lu,
2
A. Y. H.; Northrop, D. B. J. Biol. Chem. 1980, 255, 6049–6054. (c)
Miwa, G. T.; Walsh, J. S.; Kedderis, G. L.; Hollenberg, P. F. J. Biol.
Chem. 1983, 258, 14445–14449.
(
(
(
(
27) (a) Thompson, J. A.; Holtzman, J. L. Drug Metab. Dispos. 1974, 2,
5
77–582. (b) Heimbrook, D. C.; Murray, R. I.; Egeberg, K. D.; Sligar,
S. G.; Nee, M. W.; Bruice, T. C. J. Am. Chem. Soc. 1984, 106, 1514–
1
515.
28) (a) Karki, S. B.; Dinnocenzo, J. P.; Jones, J. P.; Korzekwa, K. R.
J. Am. Chem. Soc. 1995, 117, 3657–3664. (b) Baciocchi, E.;
Lanzalunga, O.; Lapi, A.; Manduchi, L. J. Am. Chem. Soc. 1998, 120,
5
783–5787.
29) (a) Hosokawa, T.; Uno, T.; Inui, S.; Murahashi, S.-I. J. Am. Chem.
Soc. 1981, 103, 2318–2323. (b) Hosokawa, T.; Murahashi, S.-I. Acc.
Chem. Res. 1990, 23, 49–54. (c) Uozumi, Y.; Kato, K.; Hayashi, T.
J. Am. Chem. Soc. 1997, 119, 5063–5064.
(31) Nishimura, T.; Onoue, T.; Ohe, K.; Uemura, S. J. Org. Chem. 1999,
64, 6750–6755.
(32) Yamaguchi, K.; Mizuno, N. Angew. Chem., Int. Ed. 2003, 42, 1480–
1483.
30) For PdOOH from Pd-H and O2, see: (a) Denney, M. C.; Smythe,
N. A.; Cetto, K. L.; Kemp, R. A.; Goldberg, K. I. J. Am. Chem. Soc.
(33) Yamaguchi, K.; Mori, K.; Mizugaki, T.; Ebitani, K.; Kaneda, K. J. Am.
Chem. Soc. 2000, 122, 7144–7145.
2
006, 128, 2508–2509. For PdOOH from PdO2, see: (b) Konnick,
(34) Allen, C. F. H.; Kimball, R. K. Organic Syntheses; Wiley: New York,
1943; Collect. Vol. II, 498-499.
M. M.; Gandhi, B. A.; Guzei, I. A.; Stahl, S. S. Angew. Chem., Int.
0
Ed. 2006, 45, 2904–2907. For PdO2 from Pd + O2, see: (c) Stahl,
S. S.; Thorman, J. L.; Nelson, R. C.; Kozee, M. A. J. Am. Chem. Soc.
(35) (a) Holm, R. H. Chem. ReV. 1987, 87, 1401–1449. (b) Griffith, W. P.
Chem. Soc. ReV. 1992, 21, 179–185. (c) Che, C.-M.; Yam, V. W. W.
AdVances in Transition Metal Chemistry; JAI Press: London, 1996;
Vol. 1, pp 209-237.
2
001, 123, 7188–7189; (d) Konnick, M. M.; Guzei, I. A.; Stahl, S. S.
J. Am. Chem. Soc. 2004, 126, 10212–10213; (e) Jensen, D. R.; Schultz,
M. J.; Mueller, J. A.; Sigman, M. S. Angew. Chem., Int. Ed. 2003,
(36) (a) Riley, D. P. J. Chem. Soc., Chem. Commun. 1983, 1530–1532.
(b) Jain, S. L.; Sain, B. Chem. Commun. 2002, 1040–1041.
4
2, 3810–3813.
J. AM. CHEM. SOC. 9 VOL. 130, NO. 33, 2008 11009

A R T I C L E S
Murahashi et al.
Table 4. Kinetics and Isotope Effects of Catalytic Oxidative Cyanation of XC6H4N(CH3)2 to XC6H4N(CH3)CH2Y
a
D
b
D
entry
catalyst
oxidizing agent
Y
F
H
k /k
H
k /k
source
1
2
3
4
5
RuCl3
RuCl3
RuCl2(PPh3)3
RuCl3
O2
CN
CN
OO-t-C4H9
OCH3
-3.35
-3.61
-0.84
-3.60
-0.74
2.40
4.06
3.53
3.47
1.6-3.1
2.62
3.74
1.64
3.72
1.0-1.1
this work
this work
ref 4
ref 5
refs 26, 27
H2O2
t-BuOOH
H2O2
O2
cytochrome P-450
(OH)
a
b
Intramolecular deuterium isotope effect. Intermolecular deuterium isotope effect.
Scheme 3. Proposed Mechanism for Ruthenium-Catalyzed Aerobic
Oxidative Cyanation
Table 6. Ruthenium-Catalyzed Oxidative Cyanation of Tertiary
a
Amines with Hydrogen Peroxide
Table 5. Catalytic Activities for Oxidative Cyanation of 12 with
3
0% Hydrogen Peroxide in the Presence of Sodium Cyanide and
Acetic Acid in Methanol
entry
catalyst
conversion (%)
yield of 13 (%)
1
2
3
4
5
RuCl3
99
99
99
48
34
90
79
65
41
25
RuCl2(PPh3)3
Pr4NRuO4
MnCl2
FeCl3
electron-donating or electron-withdrawing substituents gave the
corresponding cyanated products (entries 2-4). Furthermore,
the reaction can also be efficiently applied to cyclic amines.
Thus, piperidine, pyrrolidine, and tetrahydroisoquinoline deriva-
tives can be converted into the corresponding R-cyanoamines,
respectively (entries 6-9). It is noteworthy that for cyanation
of cyclic amines, the hydrogen peroxide system seems to be
more efficient than the aerobic oxidation system (e.g., compare
entry 8 with entry 10 of Table 3). This efficiency increase is
due to the greater reactivity of the oxoruthenium species derived
from hydrogen peroxide and low-valence ruthenium species in
comparison with C-H activation followed by reaction with
molecular oxygen in the aerobic oxidation system.
a
To a mixture of tertiary amine (1.0 mmol), RuCl3 (0.05 mmol),
NaCN (1.2 mmol), and CH3CO2H (6 mmol) in methanol (1.2 mL) was
added dropwise a 30% H2O2 aqueous solution (2.5 mmol) over a period
of 1 h. The mixture was stirred for the indicated time. Determined by
GLC analysis using an internal standard, unless otherwise indicated. In
this case, 1.5 mmol of H2O2 was used. In this case, 1.0 mmol of H2O2
b
c
d
e
1
f
was used. Determined by H NMR analysis. Isolated yield.
oxidative cyanation of N,N-dimethylanilines and their deuterated
analogues were determined to be 4.06 and 3.74, respectively
entry 2). The observed intra- and intermolecular isotope effects
are also similar to the corresponding ones (3.5 and 3.7) obtained
for RuCl3-catalyzed oxidation of para-substituted anilines with
H2O2 in methanol (entry 4). However, they are larger than those
observed for oxidative cyanation with O2 as described above
(2.40 and 2.62, respectively; entry 1), suggesting a more
important contribution from C-H bond cleavage than from
electron transfer in the rate-determining step.
(
In order to clarify the mechanism, the relative reaction rates
for oxidative cyanation of the four para-substituted N,N-
dimethylanilines p-XC6H4NMe2 (X ) MeO, Me, H, Br) with
H2O2 in the presence of sodium cyanide were determined by
1
H NMR analysis of the corresponding cyanated products. As
2
before, the rate data were well-correlated (r ) 0.998) with the
Hammett σ values, as shown in Figure 2. The F value was
determined to be -3.61 (entry 2 in Table 4), which is close to
the value of -3.60 obtained for the RuCl3-catalyzed oxidation
of p-substituted anilines with H2O2 in methanol to give
Given these data, the present reaction can be rationalized in
terms of the mechanism shown in Scheme 4. As we expected,
this mechanism is consistent with a portion of the one shown
in Scheme 3. The low-valence ruthenium species Ru reacts
with H2O2 to give the oxoruthenium species Ru dO, which
5
n
R-methoxy compounds (entry 4), suggesting the formation of
n+2
cationic intermediacy in the rate-determining step. The intra-
and intermolecular deuterium isotope effects kH/kD for the
produces the iminium ion intermediate 18 by electron transfer
1
1010 J. AM. CHEM. SOC. 9 VOL. 130, NO. 33, 2008

Ruthenium-Catalyzed Oxidative Cyanation
A R T I C L E S
Scheme 4. Proposed Mechanism for Oxidative Cyanation with
H2O2
Scheme 5. Usefulness of the R-Aminonitrile 13
3
7
and subsequent hydrogen transfer. Nucleophilic attack by
hydrogen cyanide on the iminium ion intermediate gives the
corresponding R-cyanated product, water, and the Ru species,
completing the catalytic cycle.
The participation of hydrogen cyanide, which is formed from
sodium cyanide and acetic acid under the reaction conditions,
was confirmed by the following reactions. The ruthenium-
catalyzed oxidation of 12 with H2O2 in the presence of hydrogen
cyanide in methanol at room temperature (eq 8) gave the
corresponding R-aminonitrile N-methyl-N-phenylaminoaceto-
nitrile (13) in 80% yield: The similar reaction with N-
4
4
45
n
hylene; and enzymatic reaction with rat liver microsomes.
46
Miura and co-workers reported iron-catalyzed aerobic oxida-
tive cyanation in the presence of benzoyl cyanide, giving the
corresponding R-aminonitrile and formanilide in 63% and 25%
yield, respectively.
The R-aminonitriles thus obtained are highly useful precursors
for R-amino acids. Thus, R-aminonitriles can be readily
47
converted to N-aryl-R-amino acids. Typically, the alkaline
hydrolyses of 13 and 2-cyano-N-(4′-methoxyphenyl)pyrrolidine
gave N-methyl-N-phenylglycine (22) and N-(4′-methoxyphe-
nyl)proline in 87% and 69% yield, respectively (Scheme 5).
Furthermore, the R-aminonitriles can be converted into unsym-
metrical 1,2-diamines, which are important ligands and precur-
4
8
sors of biologically active compounds. Typically, treatments
of 13 and 1-cyano-N-(4′-methoxyphenyl)pyrrolidine with lithium
aluminum hydride gave N-methyl-N-phenylethylenediamine (23)
and 2-aminomethyl-N-(4′-methoxyphenyl)pyrrolidine in 92%
and 99% yield, respectively. Furthermore, aminonitriles are
versatile synthetic intermediates for the construction of quinoline
skeletons. For example, the TiCl4-promoted reaction of 13 with
allyltrimethylsilane in CH2Cl2 gave 1-methyl-4-[(trimethylsi-
phenyltetrahydroisoquinoline (20) (eq 9) gave the corresponding
R-cyanated tetrahydroisoquinoline 21 in 97% yield: However,
in the absence of hydrogen cyanide, the oxidation of 12 in
5
MeOH gave R-methoxyamine in 82% isolated yield. From this
result, it could be inferred that the R-methoxyamine thus formed
undergoes reaction with hydrogen cyanide under the reaction
conditions to give the R-cyanated amine. However, this mech-
anism is unlikely because MeOH is not essential: other solvents,
such as ethyl acetate and acetonitrile, can be used instead of
MeOH for the oxidative cyanation.
(39) (a) Andreades, S.; Zahnow, E. W. J. Am. Chem. Soc. 1969, 91, 4181–
4
190. (b) Chiba, T.; Takata, Y. J. Org. Chem. 1977, 42, 2973–2977.
(
1
c) Konno, A.; Fuchigami, T.; Fujita, Y.; Nonaka, T. J. Org. Chem.
990, 55, 1952–1954. (d) Fuchigami, T.; Nakagawa, Y.; Nonaka, T.
J. Org. Chem. 1987, 52, 5489–5491. (e) Gall, E. L.; Hurvois, J.-P.;
Renaud, T.; Moinet, C.; Tallec, A.; Uriac, P.; Sinbandhit, S.; Toupet,
L. Liebigs Ann. 1997, 2089–2101. (f) Michel, S.; Gall, E. L.; Hurvois,
J.-P.; Moinet, C.; Tallec, A.; Uriac, P.; Toupet, L. Liebigs Ann. 1997,
One consequence of these catalytic cycles (Schemes 3 and
2
59–267.
4
) is that the steric center of the aminonitrile is created by the
addition of cyanide to a ruthenium-coordinated iminium ion
complex 16 or 18). Thus, by use of a chiral ligand attached to
(40) Chen, C.-K.; Hortmann, A. G.; Marzabadi, M. R. J. Am. Chem. Soc.
1
988, 110, 4829–4831.
(
(
41) (a) Zhdankin, V. V.; Kuehl, C. J.; Krasutsky, A. P.; Bolz, J. T.;
Mismash, B.; Woodward, J. K.; Simonsen, A. J. Tetrahedron Lett.
1995, 36, 7975–7978. (b) Lee, B. H.; Clothier, M. F.; Pickering, D. A.
Tetrahedron Lett. 1997, 38, 6119–6122.
(
the ruthenium, it may be possible to develop a catalytic
asymmetric synthesis of R-aminonitriles using this chemistry.
Transformation of r-Aminonitriles. The present ruthenium-
catalyzed oxidative cyanation is very simple and highly useful
42) (a) Ferroud, C.; Rool, P.; Santamaria, J. Tetrahedron Lett. 1998, 39,
9
423–9426. (b) Santamaria, J.; Kaddachi., M. T.; Rigaudy, J. Tetra-
hedron Lett. 1990, 31, 4735–4738. (c) Santamaria, J. Pure Appl. Chem.
1995, 67, 141–147.
18
for synthesis of R-aminonitriles. It is comparable with Strecker
38
(43) Leonard, N. J.; Hay, A. S. J. Am. Chem. Soc. 1956, 78, 1984–1987.
reactions but is superior to other methods, such as electrolysis
(
44) Ohashi, M.; Suwa, S.; Osawa, Y.; Tsujimoto, K. J. Chem. Soc., Perkin
3
9
40
of tertiary amines; oxidation with chlorine dioxide, 1-cyano-
Trans. 1 1979, 2219–2223.
4
1
42
3
-(1H)-1,2-benziodoxols, singlet oxygen, or mercuric ac-
etate; photoinduced reaction in the presence of tetracyanoet-
(45) Iley, J.; Tolando, R. J. Chem. Soc., Perkin Trans. 2 2000, 2328–2336.
(46) Murata, S.; Teramoto, K.; Miura, M.; Nomura, M. Bull. Chem. Soc.
Jpn. 1993, 66, 1297–1298.
4
3
(
47) For the hydrolysis reaction, see: (a) Barrett, G. C. In Chemistry and
Biochemistry of the Amino Acid; Barrett, G. C., Ed.; Chapman and
Hall: London, 1985; pp 246-296. For enzymatic hydrolysis, see: (b)
Wang, M.-X.; Lin, S.-J. J. Org. Chem. 2002, 67, 6542–6545.
(
(
37) Murahashi, S.-I.; Komiya, N.; Oda, Y.; Kuwabara, T.; Naota, T. J.
Org. Chem. 2000, 65, 9186–9193.
38) North, M. ComprehensiVe Organic Functional Group Transformations;
Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Pattenden, G., Eds.;
Pergamon Press: Oxford, U.K., 1995; Vol. 3, pp 611-617.
(48) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed. 1998,
37, 2580–2627.
J. AM. CHEM. SOC. 9 VOL. 130, NO. 33, 2008 11011

A R T I C L E S
Murahashi et al.
lyl)methyl]-1,2,3,4-tetrahydroisoquinoline (24), an important
precursor of quinoline alkaloids, in 75% isolated yield.
flask was filled with molecular oxygen (1 atm) with a balloon,
methanol (36 mL), N,N-dimethyl-4-methylanline (4.05 g, 30.0
mmol), and acetic acid (10.8 g, 180 mmol) were added. The mixture
was stirred under molecular oxygen at 60 °C. After 8 h, the mixture
Conclusions
3
was poured into aqueous NaHCO solution and extracted with ethyl
We have demonstrated novel ruthenium-catalyzed oxidative
cyanation of tertiary amines upon treatment with molecular
oxygen or hydrogen peroxide. The reactions proceed highly
efficiently to give the corresponding R-cyanated amines, which
are highly useful compounds for synthesis of various nitrogen
acetate. The organic layer was washed with brine and dried over
sodium sulfate. Removal of the solvent followed by washing of
the residual solid with a small amount of hexane gave pure
N-methyl-N-(4-methylphenyl)acetonitrile (4.31 g, 90%) as a pale
brown solid.
3
compounds. The principle of direct sp C-H bond activation
General Procedure for Ruthenium-Catalyzed Oxidative
Cyanation of Tertiary Amines with 30% Aqueous Hydrogen
Peroxide in the Presence of Sodium Cyanide. Synthesis of
R to nitrogen followed by carbon-carbon bond formation under
oxidative conditions was first demonstrated. The biomimetic
principle of this reaction will provide a powerful means for
developing new types of catalytic aerobic oxidative transforma-
tion reactions.
1
-Cyano-2-phenyl-1,2,3,4-tetrahydrosioquinoline (21). A 25 mL
side-armed round-bottom flask equipped with a magnetic stirring
bar and a balloon filled with Ar was charged with RuCl (13 mg,
3
-2
5
1
.0 × 10 mmol), sodium cyanide (59 mg, 1.2 mmol), 2-phenyl-
Experimental Section
,2,3,4-tetrahydrosioquinoline (209 mg, 1.0 mmol), acetic acid (360
Caution! All reactions and treatments must be carried out in a
well-Ventilated hood because highly toxic HCN is formed from
NaCN in media that include acetic acid.
mg, 6 mmol), and MeOH (1.2 mL). To the mixture was added
dropwise a 30% H O aqueous solution (2.5 mmol) at room
temperature over a period of 1 h, and the mixture was stirred for
an additional 0.5 h. At the end of the reaction, the mixture was
2
2
General Procedure for Aerobic Ruthenium-Catalyzed
Oxidative Cyanation of Tertiary Amines with Sodium
Cyanide. Synthesis of N-Methyl-N-phenylacetonitrile (13). A 25
mL side-armed round-bottom flask equipped with a magnetic
3
poured into an aqueous NaHCO solution and extracted with ethyl
acetate. The organic layer was washed with brine and dried over
sodium sulfate. Chromatography on silica gel (hexane/ethyl acetate)
gave 1-cyano-2-phenyl-1,2,3,4-tetrahydrosioquinoline (21) (164 mg,
-
2
stirring bar was charged with RuCl
3
(13 mg, 5.0 × 10 mmol)
-
1
and sodium cyanide (59 mg, 1.2 mmol). After the flask was filled
with molecular oxygen (1 atm) with a balloon, methanol (1.2 mL),
70%) as a colorless solid. Mp: 101-102 °C. IR (KBr) ν (cm ):
3108, 2990, 2824, 2222 (Ct N), 1595, 1497, 1460, 1424, 1373,
1
2 (121 mg, 1.0 mmol), and acetic acid (360 mg, 6 mmol) were
added. The mixture was stirred under the oxygen atmosphere at
0 °C. After 2 h, the mixture was poured into an aqueous NaHCO
1356, 1339, 1309, 1273, 1221, 1206, 1142, 1026, 995, 938, 889,
1
779, 745, 693, 613. H NMR (CDCl
3
, 270 MHz): δ 2.96 (dt, J )
6
3
16.1 and 3.7 Hz, 1H), 3.15 (ddd, J ) 16.2, 10.5, and 5.9 Hz, 1H),
3.48 (ddd, J ) 12.3, 10.5, and 4.3 Hz, 1H), 3.77 (ddd, J ) 12.5,
6.1, 2.9, and 1.2 Hz, 1H), 5.50 (s, 1H), 7.01 (ddm, J ) 7.3 and 2.2
solution and extracted with ethyl acetate. The organic layer was
washed with brine and dried over sodium sulfate. The yields of
N-methyl-N-phenylacetonitrile, N-methylaniline, and N-methylfor-
mamide were determined to be 93%, <3%, and trace, respectively,
by GLC analyses using an internal standard of hexadecane.
Chromatography on silica gel (hexane/ethyl acetate) gave pure 13
1
3
Hz, 1H), 7.08 (ddm, J ) 7.1 and 2.2 Hz, 2H), 7.19 (m, 6H). C-
1
3
{ H} NMR (CDCl , 68 MHz): δ 148.4, 134.6, 129.7, 129.6, 129.3,
128.8, 127.1, 126.9, 121.9, 117.7, 117.6, 53.2, 44.2, 28.5. Anal.
Calcd for C H N : C, 82.02; H, 6.02; N, 11.96. Found: C, 82.04;
1
6
14
2
-
1
(
2
130 mg, 88%) as a brown oil. IR (neat) ν (cm ): 3096, 2896,
H, 6.05; N, 11.91.
325 (Ct N), 1601, 1580, 1505, 1478, 1456, 1424, 1356, 1338,
1
Acknowledgment. This work was supported in part by the
Research for the Future Program of the Japan Society for the
Promotion of Science and by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science, and
Technology of Japan.
1
248, 1202, 1161, 1119, 1034, 999, 926, 870, 756, 693. H NMR
(
CDCl
3
, 270 MHz): δ 3.01 (s, 3H), 4.16 (s, 2H), 6.87 (dd, J ) 8.7
and 1.1 Hz, 2H), 6.93 (dd, J ) 6.5 and 0.86 Hz, 1H), 7.31 (ddd, J
1
3
1
)
8.1, 8.1, and 1.1 Hz, 2H). C-{ H} NMR (CDCl
47.9, 129.5, 120.2, 115.4, 114.9, 42.3, 39.2. High-resolution
electron-impact mass spectrometry: calcd for C , m/z 146.0844;
found, m/z 146.0807.
3
, 68 MHz): δ
1
9 10 2
H N
Supporting Information Available: Detailed experimental
procedures, including analytical and spectroscopic data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Preparative Scale Reaction. Aerobic Ruthenium-Catalyzed
Oxidative Cyanation of N,N-Dimethyl-4-methylaniline with
Sodium Cyanide. A 200 mL side-armed round-bottom flask
equipped with a magnetic stirring bar was charged with RuCl
3
(390
mg, 1.5 mmol) and sodium cyanide (1.77 g, 36.0 mmol). After the
JA8017362
1
1012 J. AM. CHEM. SOC. 9 VOL. 130, NO. 33, 2008